Name: 73590-58-6|6-Methoxy-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole|98%
Brand: Ambeed
SKU: A449839
Price: 5.0 USD
Availability: InStock
Rating: 98 (27 reviews)

1
[ 73590-58-6 ]
[ 109371-19-9 ]
[ 37052-78-1 ]

Reference： [1]Pharmazie,1997,vol. 52,p. 686 - 691

2
[ 73590-85-9 ]
[ 73590-58-6 ]
8-methoxy-2,4-dimethyl-5-thioxo-5-hydro-pyrido<1',2':3,4>imidazo<1,2-a>benzimidazol-3-one [ No CAS ]
omeprazole sulphone [ No CAS ]

Reference： [1]Pharmazie,1999,vol. 54,p. 734 - 737

3
[ 73590-58-6 ]
[ 119141-89-8 ]

Reference： [1]Tetrahedron Asymmetry,2000,vol. 11,p. 1729 - 1732

4
[ 73590-58-6 ]
[ 119141-88-7 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: omeprazole With titanium(IV) isopropylate; diethyl (2S,3S)-tartrate; water; triethylamine In acetone at 35 - 40℃; Large scale; Stage #2: With (S)-Mandelic acid In acetone at 35 - 40℃; for 2h; Large scale; Stage #3: With sodium hydrogencarbonate In dichloromethane; water for 0.5h; Large scale;
	inclusion complexation with (S)-(-)-2,2'-dihydroxy-1,1'-binaphthyl;
	With diethylamine In methanol Chiral high performance liquid chromatography; Resolution of racemate;	15 Preparation of S-Omeprazole from rac-Omeprazole by means of Chiral High Performance Liquid Chromatography (HPLC). Omeprazole (10.0373 g; 29.058 mmol) was placed in a volumetric flask (500 mL) with 0.1% diethylamine (DEA) in methanol, dissolved by means of sonication, and brought to volume. The solution was injected onto a Waters Delta Prep 4000 HPLC under the following conditions: Column: Chiralpak AD Column Dimensions: 20 mm×250 mm; 10 μm particle size Detection: 280 nm Flow rate: 10 mL/minute Mobile Phase: 100% Methanol Injection Volume: 10 mL The fractions of the S-omeprazole enantiomer were collected into a flask containing sodium carbonate (10 g). After collection, the sodium carbonate was removed by filtration and the solvent removed by rotary evaporation. The resulting oil was used directly in subsequent experiments (see Examples 1 and 2).

	In methanol Chiral high performance liquid chromatography; Resolution of racemate;	16 Preparation of S-Omeprazole from rac-Omeprazole by means of Chiral High Performance Liquid Chromatography (HPLC). Omeprazole (0.7307 g; 2.115 mmol) was dissolved in methanol (37 mL). The solution was injected onto a Waters Delta Prep 4000 HPLC under the following conditions: Column: Chiralpak AD Column Dimensions: 20 mm×250 mm; 10 μm particle size Detection: 280 nm Flow rate: 10 mL/minute Mobile Phase: 100% Methanol Injection Volume: 10 mL The fractions of the S-omeprazole enantiomer were collected into a flask and the methanol removed by nitrogen purge to produce an oil. The oil was used directly in a subsequent experiment (see Example 3).
	Stage #1: omeprazole With sodium hydroxide In methanol at 25 - 30℃; Stage #2: With titanium(IV) isopropylate; diethyl (2S,3S)-tartrate; (S)-Mandelic acid; triethylamine
98 % ee	With Escherichia coli DMSO reductase In methanol; aq. phosphate buffer at 37℃; for 3h; Resolution of racemate; Darkness; Enzymatic reaction;

Reference： [1]Reddy, Lekkala Amarnath; Malakondaiah, Golla China; Babu, Karrothu Srihari; Bhattacharya, Apurba; Bandichhor, Rakeshwar; Himabindu, Vimmidi; Reddy, Padi Pratap; Anand, Ramasamy Vijaya [Organic Process Research and Development, 2008, vol. 12, # 1, p. 66 - 68]
[2]Deng, Jingen; Chi, Yongxiang; Fu, Fangmin; Cui, Xin; Yu, Kaibai; Zhu, Jin; Jiang, Yaozhong [Tetrahedron Asymmetry, 2000, vol. 11, # 8, p. 1729 - 1732]
[3]Current Patent Assignee: AAI PHARMA - US2005/267157, 2005, A1 Location in patent: Page/Page column 12-13
[4]Current Patent Assignee: AAI PHARMA - US2005/267157, 2005, A1 Location in patent: Page/Page column 12
[5]Location in patent: scheme or table Reddy, Lekkala Amarnath; Malakondaiah, Golla China; Reddy, Alieti Sanjay; Bhaskar, Boluguddu Vijaya; Himabindu, Vurimidi; Bhattacharya, Apurba; Bandichhor, Rakeshwar [Organic Process Research and Development, 2009, vol. 13, # 6, p. 1122 - 1124]
[6]Nosek, Vladimír; Míšek, Jiří [Chemical Communications, 2019, vol. 55, # 70, p. 10480 - 10483]

5
[ 142885-92-5 ]
[ 73590-58-6 ]

Yield	Reaction Conditions	Operation in experiment
	With iodobenzene; silver(I) acetate In dichloromethane Heating / reflux;	6 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H-benzimidazole (omeprazole) EXAMPLE 6 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H-benzimidazole (omeprazole) A 50 ml three-necked round-bottom flask equipped with magnetic stirring, reflux condenser and under nitrogen atmosphere, is loaded with RuCl(PPh3)(SALEN) (SALEN=salycilaldehyde-ethylendiamine adduct) (0.77 mg, 0.0028 mmol), 5-methoxy-2-[(4-methoxy-3,5-dimethyl-1-oxy-2-pyridinyl)methyl]sulfanyl}-1H-benzimidazole (100 mg, 0.289 mmol) and dichloromethane (3.0 ml). To the solution thus obtained a drop of iodobenzene and 0.5 mg of AgOAc are added and the solution is stirred overnight at reflux. The solvent is then evaporated and the residue is purified by flash chromatography affording 10 mg of omeprazole. 1H NMR (300 MHz, CDCl3): δ 8.24 (1H, s), 7.58 (1H, mbroad), 7.08 (1H, mbroad), 6.96 (1H, dd), 4.78&4.60 (2*1H, system AB,), 3.87 (3H, s), 3.72 (3H, s), 2.25 (3H, s), 2.23 (3H, s).
	With iodobenzene; silver(I) acetate In dichloromethane Heating / reflux;	6 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H-benzimidazole (omeprazole) EXAMPLE 6 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H-benzimidazole (omeprazole) A 50 ml three-necked round-bottom flask equipped with magnetic stirring, reflux condenser and under nitrogen atmosphere, is loaded with RuCl(PPh3)(SALEN) (SALEN = salycilaldehyde-ethylendiamine adduct) (0.77 mg, 0.0028 mmol), 5-methoxy-2-[(4-methoxy-3,5-dimethyl-1-oxy-2-pyridinyl)methyl]sulfanyl}-1H-benzimidazole (100 mg, 0.289 mmol) and dichloromethane (3.0 ml). To the solution thus obtained a drop of iodobenzene and 0.5 mg of AgOAc are added and the solution is stirred overnight at reflux. The solvent is then evaporated and the residue is purified by flash chromatography affording 10 mg of omeprazole. 1H NMR (300 MHz, CDCl3): δ 8.24 (1H, s), 7.58 (1H, mbroad), 7.08 (1H, mbroad), 6.96 (1H, dd), 4.78 & 4.60 (2x1H, system AB,), 3.87 (3H, s), 3.72 (3H, s), 2.25 (3H, s), 2.23 (3H, s).

Reference： [1]Current Patent Assignee: DIPHARMA FRANCIS S.R.L. - US2007/249662, 2007, A1 Location in patent: Page/Page column 5
[2]Current Patent Assignee: DIPHARMA FRANCIS S.R.L. - EP1847538, 2007, A1 Location in patent: Page/Page column 7

6
[ 7218-04-4 ]
[ 73590-58-6 ]
omeprazole-N-acetyl cysteinn disulfide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water; at 20 - 40℃; for 1h;	Example 3Preparation of Omeprazole- N- Acetyl Cysteine Disulfide Complex in vitroThe mole ratio of Omeprazole to N-Acetyl Cysteine should typically be a minimum 1 :2 but more typically 1:2.5 or higher.140 g of N-acetyl cysteine and lOOg of Omeprazole was added to 260 g of water at 20 C and stirred over one hour until a clear solution was obtained. The reaction was slightly exothermic. Such reactions can typically rise in temperature to about 4OC. Larger batch sizes may require cooling to maintain the batch temperature below 4O C. The Omeprazole-N-acetyl cysteine disulfide solution was stored below 1O C.Samples of the disulfide solution of Example 3 when analysed by HPLC showed the disulfide compound as an earlier peak with a shorter retention time than Omeprazole. The parameters used in the HPLC analysis were as follows:Instrumental Parameters: 'Instrument: Waters HPLC Column: Zorbax Eclipse C 18, 4.6x 150mm Guard Column: Cl 8 UV Detector Wave Length: 300nmMobile Phase Composition: 30 Parts Acetonitrile to 70 Parts Phosphate Buffer pH 7.5 Flow Rate: ImI per minute Run Time: 20 minutes Injection Volume: lO microlitresThe HPLC data appears in Figure 1 and the relevant retention time data is shown below in Table 2:Table 2 HPLC Data for Omeprazole-N-acetyl cysteine disulfide solution prepared in accordance with Example 3Other proton pump inhibitors or PACs referred to herein can be made in a similar fashion.The disulfide compounds in these examples may be recrystallised, or recovered by HPLC, or other established techniques, and then formulated into tablets, powders, pastes, capsules, injectable or other dosage forms.

Reference： [1]Patent: WO2007/56817,2007,A1 .Location in patent: Page/Page column 26

7
[ 73590-58-6 ]
[ 501-53-1 ]
[ 960010-88-2 ]
[ 960010-87-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 0 - 10℃; for 2 - 3h;	3 The sulfoxide solution was treated with triethylamine (25.4 mL). The mixture was cooled to 0-10° C. and 95% benzyl chloroformate (13.5 g) in dichloromethane (30 mL) was added while keeping the temperature below 10° C. After stirring for 2-3 hours, water (90 mL) was added. The phases were separated and the aqueous phase was extracted with dichloromethane (60 mL). The combined organic phases were washed with brine (60 mL) and saturated sodium bicarbonate (30 mL) and vacuum distilled to 90 mL. Ethyl acetate (180 mL) was added to the solution and vacuumed distilled to 90 mL. The solution was stirred while 150 mL of heptanes was added at 20-25° C. The suspension was cooled to 0-5° C. and maintained at this temperature for 2-3 hours. The suspension was filtered and the damp cake was pulped in ethyl acetate (30 mL) and heptanes (120 mL) for 1-2 hours. The suspension was filtered, washed with heptanes/ethyl acetate (4/1) (2×30 mL) and dried under vacuum at room temperature to afford 5/6-methoxy-1-benzyloxycarbonyl-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole. Weight: 25.91 g. Yield: 59%. Ratio of 5- and 6-methoxy products: 3:2. The analytical data was consistent with the assigned structure.1H-NMR (300 MHz, CDCl3):5-Methoxy isomer: δ/ppm=2.19 (3H, s), 2.33 (3H, s), 3.74 (3H, s), 3.77 (3H, s), 4.68 (2H, dd, J=13, 29 Hz), 5.54 (2H, s), 6.96-7.03 (1H, m), 7.39 (1H, m). 7.40-7.42 (2H, m), 7.51-7.56 (2H, m), 7.70 (1H, d, J=9 Hz), 8.05 (1H, s);6-Methoxy isomer: δ/ppm=2.19 (3H, s), 2.33 (3H, s), 3.74 (3H, s), 3.84 (3H, s), 4.68 (2H, dd, J=13, 29 Hz), 5.53 (2H, s), 6.96-7.03 (1H, m), 7.30 (1H, d, J=2 Hz), 7.40-7.42 (2H, m), 7.51-7.56 (2H, m), 7.76 (1H, d, J=9 Hz), 8.05 (1H, s).

Reference： [1]Current Patent Assignee: SK CAPITAL PARTNERS LP - US2007/287839, 2007, A1 Location in patent: Page/Page column 6-7

8
[ 73590-58-6 ]
omeprazole sodium [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.8%	With sodium hydroxide; In methanol; isopropyl alcohol; at 20℃; for 2h;	Example 1: Preparation of sodium salt of <strong>[73590-58-6]omeprazole</strong> racemate128.0 g of sodium hydroxide was completely dissolved in 1.0 L of methanol by stirring at room temperature. After adding 9.0 L of isopropanol, stirring was performed at room temperature for 10 minutes. The resulting solution was filtered once through filter paper. After adding 1.0 kg of <strong>[73590-58-6]omeprazole</strong> racemate, stirring was performed at room temperature for 2 hours. The produced solid precipitate was collected by filtering, washed with 2.0 L of isopropanol and 1.0 L of ethyl ether, and dried in vacuum at room temperature for 2 days. 0.98 kg of sodium salt of <n="20"/><strong>[73590-58-6]omeprazole</strong> racemate was obtained (theoretical yield: 92.8%).
60%	With sodium hydroxide; In dichloromethane; water; at 20℃; for 0.0833333h;	EXAMPLE 1; Omeprazole Sodium Salt Sodium hydroxide (116 mg, 2.90 mmol) was dissolved in water (25 mL) and stirred at room temperature for 5 minutes. Omeprazole (1000 mg, 2.90 mmol) was then added to the colorless solution and stirring was continued at room temperature for an additional 5 minutes. Methylene chloride (5 mL) was added to the yellow solution and stirred for 1 minute. The aqueous and organic layers were then separated and the aqueous layer was washed twice with methylene chloride (2×5 mL). The aqueous layer was then concentrated under reduced pressure until a majority of the water was removed and methanol (10 mL) was added to the product. Further drying gave a slightly yellow solid to which ethyl acetate (20 mL) was added and heated at reflux for 20 minutes. After heating the slurry was cooled to room temperature and filtered. The filtered material was washed with diethyl ether and dried to give a white solid (741 mg, 60% TY). DSC, TGA and PXRD patterns are shown in FIGS. 2, 3 and 4, respectively. DSC of the <strong>[73590-58-6]omeprazole</strong> sodium salt characterized in FIG. 2 showed an exothermic transition at about 240 degrees C. TGA of the <strong>[73590-58-6]omeprazole</strong> sodium salt characterized in FIG. 3 showed about a 5.6 percent weight loss between about 30 and about 220 degrees C. Omeprazole sodium salt can be characterized by any one, any two, any three, any four, any five, or any six or more of the peaks in FIG. 4 including, but not limited to, 6.39, 8.75, 11.25, 12.25, 15.65, 21.03, 22.93 and 26.51 degrees 2-theta (background subtracted). The <strong>[73590-58-6]omeprazole</strong> sodium salt obtained according to the method above appears to be a hydrated salt based on the TGA data. A weight loss of about 4.7% would indicate that the salt is a monohydrate. Considering the TGA thermogram, a weight loss of about 5.6% is observed from about 30 degrees C. to about 220 degrees C. prior to decomposition of the salt. It is possible that the salt contained some residual water on the surface that gradually came off with heating. It is important to note that with further drying of <strong>[73590-58-6]omeprazole</strong> sodium salt, the peak at 2theta=8.75 degrees begins to decrease in intensity, as shown in FIG. 11.
	With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 1h;Purification / work up;	Preparation of Crystalline Form-A of Omeprazole Sodium Example-1 100 grams of <strong>[73590-58-6]omeprazole</strong> was added to the mixture of 400 ml of Tetrahydrofuran, 11.6 gms of sodium hydroxide and 22 ml of water and stirred for one hour at room temperature. The resultant reaction mixture was filtered through hyflow bed and then washed with 25 ml of tetrahydrofuron. The clear filtrate was added to 1.0 lit of ethylacetate at room temperature and the reaction mixture temperature was increased to 30 C. accompanied by gentle stirring for 2 hours to crystallize the solid mass. The solid mass was then filtered under reduced pressure, washed with 50 ml of ethylacetate and dried at the temperature of 50-70 C. to afford the crystalline polymorph Form-A of <strong>[73590-58-6]omeprazole</strong> sodium. (Weight: 108.8 grams, 97.3. %; M.C. by KF is 4.66%; Purity: 99.95%). _Preparation of Crystalline Form-C of Omeprazole Sodium:; Example-5 [0081] 100 grams of <strong>[73590-58-6]omeprazole</strong> was added to the mixture of 700 ml of tetrahydrofuran, 12.8 gms of sodium hydroxide and 20 ml of water and stirred for one hour at room temperature. The resultant reaction mixture was filtered through hyflow bed and then washed with 100 ml of tetrahydrofuran. 200 ml of ethylacetate was added to the clear filtrate at 25-35 C. accompanied by gentle stirring for 12 hours to crystallize the solid mass. The solid mass was filtered under reduced pressure, and dried at the temperature of 50-70 C. to afford the crystalline Form-C of Omeprazole sodium. [0082] (Weight: 90.0 grams, 80.44%; M.C. by KF is 4.76%; Purity: 99.89%)

	With sodium hydroxide; In tetrahydrofuran; water; ethyl acetate; at 25 - 30℃; for 8h;Purification / work up;	[0087] 20 grams of <strong>[73590-58-6]omeprazole</strong> sodium was added to the mixture of 160 ml of tetrahydrofuran, 40.0 ml of ethyl acetate and 4.0 ml of water and stirred for 8 hours at a temperature of 25-30 C. The resultant reaction mixture was filtered, washed with 20 ml of tetrahydrofuron under reduced pressure, and dried at the temperature of 50-70 C. to afford the crystalline Form-C of <strong>[73590-58-6]omeprazole</strong> sodium. [0088] (Weight: 18.0 grams, 90%; M.C. by KF is 4.7%; Purity: 99.88%)
	With sodium hydroxide; In water; acetonitrile; at 30℃; for 0.666667h;Purification / work up;	[0076] 25 grams of <strong>[73590-58-6]omeprazole</strong> was added to the mixture of 100 ml of dichloromethane, 3.2 grams of sodium hydroxide and 5.0 ml of water and stirred for 40 minutes at a 30 C. temperature. 200 ml+100 ml of methyl isobutyl ketone was added to the reaction mixture and stirred for 2.5 hours at 30 C. The resultant reaction mixture was filtered and then washed with 50 ml of methyl isobutyl ketone and dried at the temperature of 50-70 C. to afford the crystalline polymorph Form-A of <strong>[73590-58-6]omeprazole</strong> sodium. [0077] (Weight: 26.8 grams, 95.88; M.C. by KF is 4.7%; Purity: 99.887%)
	With sodium hydroxide; In water; acetonitrile; at 20 - 35℃; for 0.666667 - 1h;Purification / work up;	[0074] 50 grams of <strong>[73590-58-6]omeprazole</strong> was added to the mixture of 200 ml of acetonitrile, 5.8 gms of sodium hydroxide and 11.0 ml of water and stirred for 40 minutes at a temperature of 20-25 C. 500 ml of acetonitrile was added to the reaction mixture at room temperature and agitated for 1-1.5 hours. The resultant reaction mixture was filtered under reduced pressure and washed with 100.0 ml of acetonitrile and dried at the temperature of 50-70 C. to afford the crystalline polymorph Form-A of <strong>[73590-58-6]omeprazole</strong> sodium. [0075] (Weight: 53.90 grams, 96.35%; M.C. by KF is 6.2%; 99.88%). Example -9; Preparation of Crystalline Form-D of Omeprazole Sodium: Example-9 100 grams of <strong>[73590-58-6]omeprazole</strong> was added to the mixture of 400 ml of acetonitrile, 11.6 grams of sodium hydroxide and 10.0 ml of water and stirred for one hour at a temperature of 25-35 C. 1000 ml of dichloromethane was added to the above clear solution at a temperature of 25-35 C. accompanied by gentle stirring for 3 hours to crystallize the solid mass. The solid mass was filtered, washed with 200 ml of acetonitrile and dried at the temperature of 50-70 C. under reduced pressure to afford the crystalline Form-D of <strong>[73590-58-6]omeprazole</strong> sodium. (Weight: 90.0 grams, 80.44%; M.C. by KF is 5.39%)
	With sodium hydroxide; In water; acetone; at 25 - 30℃; for 0.5 - 10h;Purification / work up;	Example-4 [0078] 100 grams of <strong>[73590-58-6]omeprazole</strong> was added to the mixture of 100 ml of acetone, 12.8 grams of sodium hydroxide and 20.0 ml of water and stirred for 50 minutes at 30 C. The resultant reaction mixture was filtered through hyflow bed and then washed with 25 ml of acetone. Thus obtained clear filtrate was added to 800.0 lit tertiary butyl acetate at room temperature and the reaction mixture temperature was increased to 30 C. accompanied by gentle stirring for 2 hours to crystallize the solid mass. The solid mass was then filtered under reduced pressure and dried under reduced pressure to afford Form-A of <strong>[73590-58-6]omeprazole</strong> sodium and dried at a temperature of 50-70 C. [0079] (Weight: 105.0 grams, 93.85%; Purity: 99.88%) Example-6 [0083] 100 grams of <strong>[73590-58-6]omeprazole</strong> was added to the mixture of 800 ml of acetone, 12.8 gms of sodium hydroxide and 20.0 ml of water and stirred for 30 minutes at a temperature of 25-30 C. The resultant reaction mixture was filtered through hyflow bed and then washed with 100 ml of acetone. 200 ml of ethylacetate was added to the clear filtrate at 25-35 C. accompanied by gentle stirring for 13 hours to crystallize the solid mass. The solid mass was then filtered under reduced pressure, and dried at the temperature of 50-70 C. to afford the crystalline Form-C of Omeprazole sodium. [0084] (Weight: 92.0 grams, 82.23%; M.C. by KF is 5.09%; Purity: 99.80%) Example-7 [0085] 100 grams of <strong>[73590-58-6]omeprazole</strong> was added to the mixture of 800 ml of acetone, 11.6 gms of sodium hydroxide and 15.0 ml of water and stirred for 10 hours at a temperature of 25-30 C. to crystallize the solid mass. The resultant solid mass was filtered under reduced pressure, and dried at the temperature of 50-70 C. to afford the crystalline Form-C of <strong>[73590-58-6]omeprazole</strong> sodium. [0086] (Weight: 100.0 grams, 89.38%; M.C. by KF is 4.99%; Purity: 99.73%)
	In acetonitrile;	5-Methoxy-2-[(4-methoxy-3,5-dimethyl pyridin-2-yl) methylsulfinyl]benzimidazole (344 mg) was suspended in 20 ml of acetonitrile and sodium hydride (24 mg) was added. The suspension was stirred at room temperature for 2 hours to give sodium salt of 5-methoxy-2-[(4-methoxy-3,5-dimethyl pyridin-2-yl) methylsulfinyl]benzimidazole. To this suspension, benzene-1,2-disulfonic anhydride (221 mg) was added and stirred at room temperature for 3 hours.
	With sodium hydroxide; In water; at 20℃; for 0.166667h;	Example 13: Preparation of (S)-<strong>[73590-58-6]omeprazole</strong>»2[(S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol] from <strong>[73590-58-6]omeprazole</strong> sodium.To aqueous sodium hydroxide (2.03 ml, 1.5 M, 3.04 mmol) at ambient temperature was added <strong>[73590-58-6]omeprazole</strong> (1 g, 2.90 mmol) in 5 portions over 10 min. On complete dissolution, ethanol (35 ml) and (S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol (1.26 g, 4.34 mmol) were added. To the resulting colourless solution at ambient temperature was added a solution of aqueous acetic acid (3.04 ml, 1 M, 3.04 mmol) dropwise over 1 h and, on complete addition, <n="14"/>stirring was continued for 4 h. The solid was filtered, was washed with ethanol (3 x 15 ml) and was dried in vacuo to afford (S)-<strong>[73590-58-6]omeprazole</strong>»2[(S)-1 ,1 ,2- triphenyl-1 ,2-ethanediol] (925 mg, 69%, 96.4%ee) as a white powder.
	With sodium hydroxide; In methanol; isopropyl alcohol; at 20 - 30℃; for 1 - 2h;	Sodium hydroxide flakes (12.8 grams) were dissolved in methanol (100 ml) and stirred until complete dissolution. Isopropyl alcohol (900 ml) was added, and the reaction mixture cooled to [25-30 C.] The solution was filtered through a hi-flow bedded funnel, and washed with isopropyl alcohol (100 ml). Omeprazole (100 grams) was added to the clear filtered solution at ambient temperature, and stirred for 1-2 hours. The isolated product was filtered and washed with isopropyl alcohol (200 ml), followed by petroleum ether (200 ml), and dried at atmospheric temperature to afford the sodium salt of Omeprazole. Weight [:-100 GRAMS.]
	With sodium hydroxide; In methanol; water; at 35℃; for 2h;Large scale;	1) Omeprazole 1 kg was added to 1 L of methanol for dissolution.Separately, 250 g of sodium hydroxide was dissolved in 1.25 L of purified water.2) A solution of <strong>[73590-58-6]omeprazole</strong> in methanol was slowly added to an aqueous solution of sodium hydroxide at a temperature of 35 C and stirred for 2 hours to obtain a solution of <strong>[73590-58-6]omeprazole</strong> sodium salt as a solution 1.3) A solution of acetone and nitromethane in a volume ratio of 1: 4 was slowly added to the solution 1 at a temperature of 25C and a rotation speed of 50 rpm.3) The solution 2 was stirred at 13 C for 2.0 hours and then at 8 C for 2.5 hours, then left to stand for 5 hours, filtered, washed with diethyl ether, maintained at 35 C and vacuum dried for 6 hours to give <strong>[73590-58-6]omeprazole</strong> Sodium compound.

Reference： [1]Patent: WO2009/145368,2009,A1 .Location in patent: Page/Page column 18-19
[2]Patent: EP1186602,2002,A2 .Location in patent: Page 5
[3]Patent: US2006/160783,2006,A1 .Location in patent: Page/Page column 8-9
[4]Patent: EP1186602,2002,A2 .Location in patent: Page 5
[5]Patent: US2004/224987,2004,A1 .Location in patent: Page 5
[6]Patent: US2004/224987,2004,A1 .Location in patent: Page 5
[7]Patent: US2004/224987,2004,A1 .Location in patent: Page 5
[8]Patent: US2004/224987,2004,A1 .Location in patent: Page 5-6
[9]Patent: US2004/224987,2004,A1 .Location in patent: Page 5
[10]Patent: US6559167,2003,B1
[11]Patent: WO2007/74099,2007,A1 .Location in patent: Page/Page column 12-13
[12]Patent: WO2004/2982,2004,A2 .Location in patent: Page 22
[13]Patent: CN104945380,2016,B .Location in patent: Paragraph 0036; 0037; 0038; 0039; 0040

9
[ 73590-58-6 ]
omeprazole magnesium [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
~ 90%	With magnesium hydroxide; In tetrahydrofuran; water; at 20 - 25℃;	Example:; 27 kg tetrahydrofurane, 0.5 kg (8.6 mole) magnesium hydroxide (20-30% aqueous solution) and then 3 kg (8.6 mole) <strong>[73590-58-6]omeprazole</strong> are charged into a clean reactor. The mixture is stirred at 20-25"C until it is dissolved completely. After completing the stirring, 10.5 kg of cyclohexan and 30 gr of seed are charged into the reactor and stirred for 15-20 hours at 20-25 C. At the end of the period the outer temperature is adjusted to 35-40 C and distilled under vacuum until all the solvent is evaporated. The product is dissolved by adding 47.5 kg of methanol and stirred for about 1 hour at 25-30 C at the end of the distillation. Undissolved portion is the excess of magnesium hydroxide. At the end of 1 hour, 150 gr of activated charcoal was added to the solution, stirred for 30 minutes at 25- 30 C and filtered. After charging the filtrate into a clean reactor 21 kg water is added and distilled with vacuum until 35-40 % of the total volume remains. After the distillation, the temperature is lowered to 20-25 C and stirred for about 2 hours, the crystallized product is filtrated and washed 3 times with water (3 x 3 kg). The product is dried at 60-65 C until moisture is about 10-12 %. Then, 13. 5 kg ethyl acetate and the product is charged into the clean reactor and filtered after stirring for 1 hour in 20-25 C, washed two times with ethyl acetate (2 x 2 kg) and finally dried at 40-50 C until moisture is 9-10 %. The yield at the end of the process is about 90%. According to the atomic absorption measurements content for magnesium is 3.33%, while theoretically calculated magnesium content is 3.37%.
	With magnesium methanolate; In methanol;	1.76 g of pure magnesium was added to 800 g of methanol in a 1000 mL glass flask. The flask was closed with a loose-fitting stopper (loose to allow hydrogen gas to escape), and the flask was allowed to sit overnight. The next morning it was observed that the magnesium had all been consumed and that the effervescence had ceased, resulting in a slightly hazy solution of magnesium methoxide in methanol. 50 grams of <strong>[73590-58-6]omeprazole</strong> (or the neutral form of S-<strong>[73590-58-6]omeprazole</strong> could be used) was then added to the contents of the flask and the contents were stirred for several minutes until dissolved to form a solution of magnesium <strong>[73590-58-6]omeprazole</strong> (or if the neutral form of S-<strong>[73590-58-6]omeprazole</strong> was used, magnesium S-<strong>[73590-58-6]omeprazole</strong>) in methanol. EXAMPLE 2 To produce a reference sample of magnesium <strong>[73590-58-6]omeprazole</strong> anhydrate according to the prior art (i.e. example 6 of EP 0124495), about 20% of the solution from step 2 was transferred to a 1000 mL beaker. The beaker was then placed in a vacuum oven for drying under vacuum at 50C for a period of 4 hours. At the end of this time, a solid material remained that had no evident odour of residual methanol. This solid material was tested to determine the level of residual methanol, which was found to be 7.2% by weight.EXAMPLE 3 To produce the present invention, the balance of the solution of Example 1 was spray-dried on a Yamato - Registered trademarkspray-dryer, using an inlet air temperature of about 140C and outlet air temperature of about 70C. The resulting dry material was a fine powder, which appeared non-crystalline (i.e. amorphous) and also had no evident odour of residual methanol. The powder was tested to determine the level of residual methanol, which was found to be 0.7%. This powder was examined for crystallinity by powder X-ray diffraction, and it was found that the powder was primarily amorphous (non-crystalline), having a degree of crystallinity of under 25%.
	With magnesium; In methanol; dichloromethane; at 5 - 30℃; for 1 - 1.25h;Product distribution / selectivity;	3.6 liters of methanol was taken into a round bottom flask and 72 g of magnesium turnings were added. 128 ml of dichloromethane was added to the above mixture. The temperature of the reaction mass was raised to 56 C. The mixture was maintained at 56 C for one hour, and then was cooled to 30 C. 50 liters of methanol was added to the reactor followed by 2 kg of <strong>[73590-58-6]omeprazole</strong> base. EPO <DP n="14"/>The mixture was then cooled to 15 C and maintained under a nitrogen atmosphere for 1 hour. The reaction mass was then filtered through a sparkler filter followed by a 0.45 micron candy filter. The filtrate was then subjected to drying in an ATFD-V apparatus at a temperature of 45 C, and pressure of 640 mm/Hg. The feed rate was adjusted to 7 liters per hour. The powder obtained from the ATFD was milled using an air jet mill to yield 1.55 kg of the material of the desired particle size.Residual methanol content: Before milling: 62,906; after milling: 49,502.The particle size data for the product before and after milling was as follows:18 liters of methanol was taken into a first reactor and 0.36 kg of magnesium turnings were added. The mixture was stirred for 10 minutes. 0.64 liters of dichloromethane was added to the above mixture. The mixture was agitated for 20 minutes and then the temperature was raised to 57 C. The mixture was maintained at 57 C for one hour, was cooled to 30 C, and then was added to 140 liters of methanol having a temperature of 5 C under a nitrogen atmosphere, in a second reactor. The first reactor was rinsed with 100 liters of methanol twice and the methanol was added to the second reactor and stirred for 10 minutes. The mixture was then cooled to 5 C and maintained under a nitrogen atmosphere. 10 kg of <strong>[73590-58-6]omeprazole</strong> was added to the above reaction mass at the same temperature. The reaction mass was maintained at 28 C for 1 hour, 15 minutes. The reaction mass was then filtered through a sparkler cartridge filter having a pore size of 15 microns at 5 C under a nitrogen atmosphere. The filter was washed with 20 liters of methanol. The combined filtrate was then transferred into the feeding tank of the ATFD-V equipment manufactured by Techno Force Solutions (India) Private Limited, Mumbai, India, Model No. ASME SEC. VIII DIV. I EPO <DP n="15"/>ED-2001+A03. The equipment was maintained at a temperature of 45 C and a pressure of 675 mm Hg. The feed rate of the reaction mass into the reactor was adjusted to 35 to 40 liters per hour. The temperature of the reaction mass being fed into the reactor was maintained at 5 C. The material was stored in clean polyethylene bags, and then sifted through a 40 mesh sieve. The sifted material was then subjected to drying in a fluidized bed drier (manufactured by Alliance Engineering Company of Mumbai, India, Model No. GM15 (S)) for 7 hours with a programmed temperature variation from 25 to 35 C for 3 hours and to 50 to 55 C for 4 hours. Atmospheric air was used to fluidize the particle bed, having an estimated relative humidity about 30-40 percent. The seal air pressure was 1.75 kg/cm2 and the blower discharge pressure was maintained at 110 mm Hg. Yield of the title compound was 8.0 kg. Finally the material was micronized in an air jet mill to yield 7.6 kg of the title compound.Methanol content: 1636 ppm; dichloromethane content: less than 40 ppm. Particle size distribution: Di0: 1 mum; D50: 3 mum; Dg0: 7 mum.Bulk Density before tapping: 0.3 g/ml ; After tapping: 0.5 g/mi using tapping Method I of the USP 24 bulk density test.Moisture content: 8.1 % w/w.Figs. 1 , 2 and 3 are the XRPD, DSC and IR results for the compound prepared in this example. Fig.»1 has a vertical axis in intensity units and a horizontal axis of the 20 angle, in degrees. Fig. 2 has a vertical axis of heat flow, in watts/gram, and a horizontal axis in degrees Celsius. Fig. 3 has a vertical axis of percent transmission and a horizontal axis of wavenumbers (cm"1).

Reference： [1]Patent: WO2005/82888,2005,A1 .Location in patent: Page/Page column 5
[2]Patent: EP1375497,2004,A1 .Location in patent: Page 5-6
[3]Patent: WO2006/96709,2006,A2 .Location in patent: Page/Page column 12-14

10
[ 73590-85-9 ]
[ 73590-58-6 ]

Yield	Reaction Conditions	Operation in experiment
91 - 92%	With dihydrogen peroxide;molybdenyl acetylacetonate; In methanol; water; at 0 - 5℃; for 3h;	EXAMPLE 3; 3 g of Omeprazole precursor: 2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylthio]-5-methoxy-1H-benzimidazole, 0.09 g of Mo(acac)2 oxidation catalyst were dissolved in 20 ml of methanol by stirring. The temperature of the resulting solution was reduced to 0-5° C., followed by adding 1.17 g of 35percent H2O2 aqueous solution. The reaction was carried out for about two hours, and then 60 ml of water was added, and the reaction was continued for another one hour while stirring. Finally, the precipitate formed was filtered, water washed, and dried to obtain Omeprazole with a yield of about 91-92percent (HPLC purity >98percent).
91%	With dihydrogen peroxide; sodium carbonate;sodium tungstate; In methanol; water; at 20℃; for 0.666667h;Product distribution / selectivity;	EXAMPLE 2; The procedures in Example 1 were repeated except that the 1.88 g of 45percent NaOH was replaced by 1.93 g of Na2CO3. Omeprazole yield: 91percent (LC purity>95percent).
~ 88%	With sodium hydroxide; dihydrogen peroxide;sodium tungstate; In methanol; water; at 20℃; for 0.666667h;Product distribution / selectivity;	EXAMPLE 1; 2 g of 2-[[(3,5-dimethyl-4-methoxy-2-pyridinyl)methyl]thio]-5-methoxy-1H-benzimidazole was suspended in 36 ml of methanol at room temperature, to which 1.88 g of 45percent NaOH in 14 ml water was added while stirring. 0.09 g of Na2WO4*2H2O oxidation catalyst was dissolved in 0.74 g H2O2 (50percent aqueous solution), and further diluted with 10 ml. of water. The oxidant/catalyst solution was added to the reactant/base solution dropwise so that the addition was completed in about 30 minutes while stirring at room temperature. The reaction was continued for additional 10 minutes while stirring. 10 ml of 10percent Na2S2O3 aqueous solution was then added, and the resulting mixture was subjected to a reduced pressure to remove methanol therefrom. Finally, a precipitate was formed after adding a diluted acetic acid aqueous solution to a pH value of about 8, which was filtered, water washed, and dried in vacuo to obtain Omeprazole with a yield of about 88percent (LC purity>95percent).

88%		10 g of <strong>[73590-85-9]omeprazole sulfide</strong>,8.6gTetraisopropyl titanate50 ml of toluene,Stirring at 30 ° C to dissolve and clarify.Cooling to 25 ,Insulated drop of 9.2gHydrogen peroxide cumene,60 minutes drop finished,After the drop,25 holding temperature 4h.The organic solvent was distilled off under reduced pressure,The residue was washed with acetone,filter,dry,To give 9.2 g of a white solid,The molar yield was 88percentChromatography purity 99.35percentThe content of peroxide impurity in formula III is 0.52percent.
88.4%		Omeprazole sulfide 6.58g (0.02mol)Soluble in 100ml of absolute ethanol,Adjust to pH=8-9 with triethylamine.240 mg of graphene oxide containing Ti4 + mass 4.0percent was added.Stir at 40 ° C for 10 min,3.4 g (0.03 mol) of 30percent hydrogen peroxide was slowly added dropwise.After the dropwise addition, the reaction was carried out for 3 h. The catalyst was filtered off.And washed three times,The collected filtrate was concentrated to give a crude omeprazole.Then beat with ethyl acetate and filter by suction.Drying to get omeprazole 6.1g,The yield was 88.4percent.
79.1%	With m-chloroperoxybenzoic acid; In ethyl acetate;	EXAMPLE 1 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole (10 g; 0.0304 mole) was suspended in ethyl acetate (100 ml) and cooled below 0° C. 3-chloroperoxybenzoic acid (5.25 g; 0.0304 mole) was added in such a manner that the temperature did not exceed 5° C. After completed addition it was left to crystallize for another half an hour at a temperature below 5° C. The product formed was filtered off, washed with ethyl acetate and dried in vacuo. Crude omeprazole (8.3 g; 79.1percent) was obtained.
76.2%	With m-chloroperoxybenzoic acid; sodium carbonate; In ethyl acetate;	EXAMPLE 2 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole (10 g; 0.0304 mole) was suspended in ethyl acetate (100 ml) and cooled below 0° C. 3-chloroperoxybenzoic acid (5.25 g; 0.0304 mole) was added in such a manner that the temperature did not exceed 5° C. After the completed addition it was stirred for half an hour, the cooling was removed, a 4percent sodium carbonate solution (40 ml) was added and it was stirred for another half an hour. The product was filtered off and washed with water. After drying in vacuo crude omeprazole (8.0 g; 76.2percent) was obtained and it was purified according to the process disclosed in Example 1.
75%	With titanium(IV) isopropylate; D-tartaric acid; Cumene hydroperoxide; N-ethyl-N,N-diisopropylamine; In toluene; at 20 - 65℃; for 1h;	In a 500 mL three-necked flask,A solution of 5-methoxy-2- (4-methoxy-3,5-dimethyl-2-pyridyl) methylthio-1H-benzimidazole(14.8 g, 45 mmol) was added to 75 mL of toluene, the temperature was raised to 65 ° C,Dissolved after addingD-tartrate(5.7 g, 27.5 mmol)And tetraisopropyl titanate(3.9 g, 13.8 mmol),While adding a small amount of purified water,After stirring for 1 hour,Down to 10 ° C. N, N-diisopropylethylamine (1.6 g, 12 mmol)And toluene-diluted cumene hydroperoxide (8 g, 45 mmol) were added and the reaction was continued at 20 ° C for 1 hour. After completion of the reaction, ammonia (60 mL) and purified water were added and stirred for 20 minliquid. The aqueous layer was added to dichloromethane (150 mL) and stirred for 20 min. The dichloromethane layer was added anhydrous sodium sulfate (15 g)Dried and dried for 1 hour, then filtered, and the dichloromethane was removed by steaming under reduced pressure at 50 ° C,The oil is an esomeprazole, Product yield 75percent.
~ 69%	With dihydrogen peroxide;sodium tungstate; In ethanol; water; at 20℃; for 6.5h;Product distribution / selectivity;	CONTROL EXAMPLE 2; 0.35 g of 2-[[(3,5-dimethyl-4-methoxy-2-pyridinyl)methyl]thio]-5-methoxy-1H-benzimidazole was suspended in 5 ml of ethanol at room temperature. 0.035 g of Na2WO4*2H2O oxidation catalyst was dissolved in 0.099 g H2O2 (35percent aqueous solution), and further diluted with 2 ml of water. The oxidant/catalyst solution was added to the reactant suspension dropwise so that the addition was completed in about 30 minutes while stirring at room temperature. The reaction was continued for additional 6 hours while stirring. 2 ml of 10percent Na2S2O3 aqueous solution was then, added, and the resulting mixture was subjected to a reduced pressure to remove ethanol therefrom. Finally, a precipitate was formed after adding a diluted acetic acid aqueous solution to a pH value of about 8, which was filtered, water washed, and dried in vacuo to obtain Omeprazole with a yield of about 69percent (LC purity>80percent).
63 - 79%	With tert.-butylhydroperoxide;bis(acetylacetonate)oxovanadium; In ethanol; water; at 16 - 17℃; for 3.08333h;	1.5 mg (0.6percent molar) VO(acac)2) was dissolved in 12 ml ethanol at room temperature. The solution was stirred and 3 grams of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole (MPB) were added. 1.5 ml aqueous tert-butyl hydroperoxide (TBHP) (70percent) was added over a 5-minute period at 16-17° C. and the solution was then stirred for 3 hours. After completion of the reaction, the product mixture was cooled to about 15° C. and treated with aqueous sodium metabisulphate. The resultant solid was filtered off, washed with cooled ethyl acetate to afford the end product as an almost white solid (2.5 grams, yield 79percent).
32%	With dihydrogen peroxide;bis(acetylacetonate)oxovanadium; In ethanol; water; at 20℃; for 12h;	4 mg (0.06percent molar) VO (acac)2 were added to suspension of 9 grams of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1H-benzimidazole (MPB) in 66 ml ethanol at room temperature. 35 ml of 35percent aqueous hydrogen peroxide (150percent mol) was added at room temperature with no visible exotherm, the mixture was then stirred. After 12 hours the reaction mixture still contained 65percent of untreated MPB and only 32percent omeprazole. Prolongation of the reaction time did not lead to further production of omeprazole.
	With sodium hydroxide; sodium hypochlorite; In dichloromethane; water; at -5 - 0℃; for 3h;	((5-METHOXY-2-[[(4-METHOXY-3, 5-DIMETHYL-2-PYIRDYL) METHYL]-THIO]-LH-BENZIMIDAZOLE, (20g) was suspended in 200ML of dichloromethane. 140g of sodium hypochlorite solution (chlorine content: 3.6-4. 2percent ; sodium hydroxide content: 2.8-3. 0 percent) was added over a period of 3 hours maintaining a temperature OF-5°C to 0°C. The organic layer was separated and extracted with 200ml of 5percent sodium hydroxide solution. The pH of the aqueous layer was adjusted to between 8-8.5 using dilute acetic acid. The solids were filtered, washed with chilled water and dried in an oven to give 17g of the title compound.
	With peracetic acid; In ethyl acetate;	Example 4 Preparation of Omeprazole To a solution of 100 g of the product from Example 3 in ethyl acetate (500 ml) was added peracetic acid (125 g) slowly at a temperature of -25°C. The contents were further stirred for 30 minutes and the pH of the mixture was adjusted to 8 with 10percent aqueous sodium hydroxide. The product thus precipitated was filtered and washed with water. The crude product was purified from methanol to afford 85g of pure omeprazole.
	With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 5℃; for 0.333333 - 0.416667h;	EXAMPLE 3; Preparation of 5/6-methoxy-1benzyloxycarbonyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazoleTo a solution of 5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylthio]-1H-benzimidazole (30 g) in dichloromethane (165 mL) at 0-5° C., under an inert atmosphere, was added meta-chloroperbenzoic acid (0.95 eq) over 10 minutes. The mixture was stirred for 10-15 minutes. To the reaction was added 12percent ammonium hydroxide (180 mL). The layers were separated. The organic layer was extracted with 12percent ammonium hydroxide (2.x.180 mL). The combined aqueous layers were washed with toluene (90 mL). To the aqueous layer was added dichloromethane (120 mL) and the mixture was cooled to 0-5° C. The pH was adjusted to pH=8.5-9.5 using 50percent aqueous acetic acid. The layers were separated. The aqueous layer was extracted with dichloromethane (2.x.90 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered through celite and vacuum distilled to 150 mL to give a solution of 5-methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulphinyl]1H-benzimidazole in dichloromethane.
	With trans-stilbene ozonide; In methanol; for 3.5h;Heating / reflux;Product distribution / selectivity;	Trans-stilbene ozonide was prepared following the recipe of example 1, in an amount of 0.031 mol.The thus-prepared ozonide was added drop-wise over 0.5h to a boiling solution of sulfide (0.031 mol) in 100 ml of methanol. The reaction solution is boiled for 3 hours under reflux conditions. The experiment was performed for a number of sulfides, generally represented by formula III. After 3 hours, the reaction mixtures were analyzed for conversion rate. The results are shown in table 1. In all cases, sulfoxide selectivity was 100percent.
	With 1-hexen-ozonide; In methanol; for 3.5h;Heating / reflux;Product distribution / selectivity;	21 g 1-Hexene (0.20 mol) in 500 ml of methanol at -15°C was converted with 1.2 molar equivalents of ozone, thus producing 1-hexen-ozonide. The ozonide was present as a clear solution in methanol.The solution was used directly for the oxidation of the sulfides represented by formula III. Thereto, the ozonide was added dropwise over 0.5h to the boiling solution of the sulfide (0.20 mol) in 200 ml methanol. The reaction solution was refluxed for 3 hours. After 3 hours, the reaction mixtures were analyzed for conversion rate. The results are shown in table 2. In all cases, sulfoxide selectivity was 100percent.
	With dihydrogen peroxide;sodium molybdate; In water; acetic acid; ethyl acetate; at 5 - 12℃; for 6.75h;pH 6 - 6.5;	2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride (IV) (100.0 g) and 2-mercapto-5-methoxy benzimidazole (III) (81.0 g) were taken in RBF. Ethyl Acetate (400 mL) was added to RBF at 25°C to 350C. Sodium hydroxide (50.0 g) solution in water (200 mL) was added to the reaction mass within 30 mins. The reaction0 mass was stirred for 1 hr and heated to 500C to 55°C for 1 hr. After completion of the reaction on TLC, reaction mass was cooled to 250C to 300C. Water (200 mL) was added and stirred to separate the organic and aqueous layers. Aqueous layer was extracted with ethyl acetate (150 mL) and separated. The combined ethyl acetate layer was charcaolised (5.0 g) and stirred for 30 mins. The reaction mass was filtered through hyflow bed and washed with ethyl acetate (50 mL). The pH of the organic layer was adjusted to about 6.0 to 6.5 with acetic acid (0.5 mL) and cooled to 5°C to 100C.Sodium molybdate (1.33 g) solution in water (13.2 mL) was added to the reaction mass and stirred for 15 mins. 50percent hydrogen peroxide (37.0 g) was added into the reaction mass within 1.5 hrs at 5°C to 12°C. The reaction mass was stirred for 5 hrs.After completion of the reaction on TLC, the reaction mass is treated with sodium thiosulphate (11.0 g) solution in water (11.0 mL). Sodium hydroxide (6.0 g) solution in water (6 mL) was added into the reaction mass to adjust the pH of about 7.0 to 7.5. The reaction mass was further cooled to 00C to 5°C and stirred for 60 mins. The product was filtered and washed with mixture of methanol (50 mL) and water (50 mL) followed by washing with chilled ethyl acetate (75 mL).Crude omeprazole (120.0 g) wet-cake as obtained above and methanol (160 mL) were taken in another RBF at 25°C to 35°C. Sodium hydroxide (15.8 g) solution in water (176 mL) was added into the reaction mass. Charcaol (2.6 g) was added and stirred for 30 mins. The reaction mass was filtered on hyflow bed and washed with mixture of methanol (10 mL) and water (10 mL). The filtrate was treated with sodium hydrosulphite (2.0 g). The reaction mass was slowly treated with acetic acid (22.5 mL) to adjust the pH of about 7.5 to 7.9. The product was filtered and washed with water(244 mL) and dried at 400C to 45°C to obtain 100.0 g crystalline omeprazole Form B. Yield 68percent based on input 2-(chloromethyl)-3,5-dimethyl-4-methoxy pyridine hydrochloride (IV).HPLC purity: 99.87percentIndividual Impurities are as under:Im purity- A at RRT 0.44 : 0.01percent Impurity-B at RRT 0.46 : Not detectedImpuriry-C at RRT 0.80 : 0.02percentImpurity-D at RRT 0.90 : Not detectedImpurity-E at RRT 3.26 : Not detectedUnk Impurity: 0.03percent Total Impurities : 0.13percentImpurity-A: 5-methoxy- 1 H-benzimidazole-2-thiolImpurity-B: 2-[(R,S)]-[(3,5-dimethylpyridine-2-yl)methyl]sulphinyl]-5-methoxy-lH- benzimidazole Impurity-C: 5-methoxy-2[[4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulphanyl]- lH-benzimidazole [Omeprazole Sulfide]Impurity-D: 5-methoxy-2[[4-methoxy-3,5-dimethylpyridin-2-yl)methyl]suIphonyl]- lH-benzimidazole [Omeprazole Sulfone] Impurity-E: 4-methoxy-2-[[(R,S)-(5-methoxy- 1 H-benzimidazole-2-yl)- sulphinyl]methyl)-3,5-dimethylpyridine- 1 -oxide [Omeprazole N-Oxide]
	With dihydrogen peroxide;bis(acetylacetonate)oxovanadium; In water; acetone; at 10 - 15℃; for 3.5h;	Preparation of omeprazoleVanadyl acetylacetonate (4.8 gm) was added to water (210 ml) and then cooled to 0 to 10°C. To the reaction mixture was added hydrogen peroxide (50 percent, 120 ml) at 0 to 10°C and stirred for 20 minutes. 5-Methyoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2- yl)methyl]thio]-l H-benzimidazole (480 gm) and acetone (1950 ml) were added to the reaction mixture. The reaction mixture was maintained for 3 hours 30 minutes at 10 to 15°C and then added sodium hydroxide (46 percent, 16 ml) and water (1600 ml). The reaction mass was then cooled to 0 to 5°C and pH of the reaction mass was adjusted to 7.5 to 8.5 with acetic acid (1 1 gm) at 0 to 10°C. The reaction mass was stirred for 2 hours and filtered to obtain a wet solid. To the wet solid was added water (700 ml) and then added liquor ammonia (38 gm) and methanol (700 ml) at room temperature. The reaction mass was then cooled to 0 to 10°C, stirred for 45 minutes and filtered. The solid obtained was dried to give 405 gm of omeprazole.

Reference： [1]Patent: US2006/128964,2006,A1 .Location in patent: Page/Page column 3
[2]Patent: US2009/5570,2009,A1 .Location in patent: Page/Page column 3
[3]Patent: US2009/5570,2009,A1 .Location in patent: Page/Page column 3
[4]Patent: CN106083819,2016,A .Location in patent: Paragraph 0038; 0039; 0040; 0041; 0042-0049; 0052; 0053
[5]Organic and Biomolecular Chemistry,2017,vol. 15,p. 2647 - 2654
[6]Patent: CN108395425,2018,A .Location in patent: Paragraph 0059; 0060; 0061; 0063; 0064; 0065; 0083; 0084
[7]Patent: JP2004/524303,2004,A .Location in patent: Page/Page column 10; 11-12
[8]Patent: US6268502,2001,B1
[9]Patent: US6268502,2001,B1
[10]Organic Process Research and Development,2016,vol. 20,p. 2092 - 2099
[11]Patent: CN107011252,2017,A .Location in patent: Paragraph 0089; 0090
[12]Patent: JP2004/524303,2004,A .Location in patent: Page/Page column 10; 11-12
[13]Patent: US2009/5570,2009,A1 .Location in patent: Page/Page column 4
[14]Patent: JP2004/524303,2004,A .Location in patent: Page/Page column 10
[15]Patent: US2004/138466,2004,A1 .Location in patent: Page 4-5
[16]Patent: JP2004/524303,2004,A .Location in patent: Page/Page column 10
[17]Patent: JP2004/524303,2004,A .Location in patent: Page/Page column 10; 11-12
[18]Patent: JP2004/524303,2004,A .Location in patent: Page/Page column 10; 11-12
[19]Patent: JP2004/524303,2004,A .Location in patent: Page/Page column 10; 11-12
[20]Patent: JP2004/524303,2004,A .Location in patent: Page/Page column 13
[21]Patent: US2004/138466,2004,A1 .Location in patent: Page 5
[22]Patent: JP2004/524303,2004,A .Location in patent: Page/Page column 12
[23]Patent: WO2004/63188,2004,A1 .Location in patent: Page 14
[24]Patent: EP1085019,2001,A1
[25]Patent: US2007/287839,2007,A1 .Location in patent: Page/Page column 6
[26]Patent: WO2009/14431,2009,A1 .Location in patent: Page/Page column 12
[27]Patent: WO2009/14431,2009,A1 .Location in patent: Page/Page column 13
[28]Patent: WO2004/35565,2004,A1 .Location in patent: Page 5
[29]Patent: WO2010/134099,2010,A1 .Location in patent: Page/Page column 16-18
[30]Patent: WO2012/104863,2012,A2 .Location in patent: Page/Page column 5
[31]Chemistry Letters,2016,vol. 45,p. 110 - 112

11
[ 73590-85-9 ]
[ 73590-58-6 ]
omeprazole sulphone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With oxone; sodium hydrogencarbonate;bis(acetylacetonate)oxovanadium; In methanol; water; at -2 - 0℃; for 5.5h;	A mixture of 3 grams 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl] thio]benzimidazole (MPB), 3 grams NaHCO3 and 20 ml aqueous methanol was cooled to -2° C. and 3.5 ml (5.69 mmol) Oxone.(R). was added. The mixture was stirred for 4 hours at 0° C. and a further 1 gram (mmol) Oxone.(R). was added and stirring continued for 1.5 hours. A solution of 0.8 gram sodium metabisulfite in 20 ml water was added dropwise over 5-10 minutes. After further stirring the resultant precipitate was filtered, washed successively with water and 50percent aqueous methanol and dried. [0064] Yield 2.7 grams, 84percent (purity 98.1percent), SOMP 0.15percent.
83.5%	With tert.-butylhydroperoxide;bis(acetylacetonate)oxovanadium; In water; isopropyl alcohol;	The above described processes of Example 1 and Example 2 were repeated while using the conditions given in Table I below, to give the following results:
74.6%	With tert.-butylhydroperoxide;bis(acetylacetonate)oxovanadium; In water; toluene;	The above described processes of Example 1 and Example 2 were repeated while using the conditions given in Table I below, to give the following results:

68.5 - 80.7%	With tert.-butylhydroperoxide;bis(acetylacetonate)oxovanadium; In toluene; at 5 - 22℃; for 3h;	15 mg (0.6percent molar) VO(acac)2) in 5 ml toluene were added to a suspension of 3 grams of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole (MPB) in 30 ml toluene at a temperature of about 5° C. 3.5 ml of tert-butyl hydroperoxide (TBHP) in toluene (3M, 115percent) were added dropwise, while the temperature was maintained between 5 and 7° C. Upon completing the addition of the TBHP, the temperature rose to 22° C. The reaction was allowed to proceed to completion (about 3 hours), after which the cooled product mixture was treated with aqueous sodium metabisulphite. The solid product was filtered off, washed with cooled ethyl acetate and dried in an oven (yield 80.7percent)
60%	With sodium hydrogencarbonate;bis(acetylacetonate)oxovanadium; In water; acetone; for 30.75h;	The above described reaction of Example 8 was repeated while using the conditions given in Table II below, to give the following results:
> 50%	With tert.-butylhydroperoxide;vanadium(V) oxide; SiO2; In methanol; water;	The above described processes of Example 1 and Example 2 were repeated while using the conditions given in Table I below, to give the following results:
> 50%	With tert.-butylhydroperoxide;sodium vanadate; In methanol; water;	The above described processes of Example 1 and Example 2 were repeated while using the conditions given in Table I below, to give the following results:
> 50%	With tert.-butylhydroperoxide;bis(acetylacetonate)oxovanadium; In methanol; water;	The above described processes of Example 1 and Example 2 were repeated while using the conditions given in Table I below, to give the following results:
50.7%	With tetrabutylammomium bromide; sodium hydrogencarbonate;bis(acetylacetonate)oxovanadium; In water; ethyl acetate; for 30.75h;	The above described reaction of Example 8 was repeated while using the conditions given in Table II below, to give the following results:

Reference： [1]Patent: US2004/138466,2004,A1 .Location in patent: Page 5
[2]Patent: JP2004/524303,2004,A .Location in patent: Page/Page column 12-13
[3]Patent: JP2004/524303,2004,A .Location in patent: Page/Page column 13
[4]Patent: US2004/138466,2004,A1 .Location in patent: Page 5
[5]Patent: US2004/138466,2004,A1 .Location in patent: Page 5
[6]Patent: US2004/138466,2004,A1 .Location in patent: Page 4-5
[7]Patent: US2004/138466,2004,A1 .Location in patent: Page 5
[8]Patent: JP2004/524303,2004,A .Location in patent: Page/Page column 13
[9]Patent: US2004/138466,2004,A1 .Location in patent: Page 5
[10]Patent: US2004/138466,2004,A1 .Location in patent: Page 5
[11]Patent: US2004/138466,2004,A1 .Location in patent: Page 5
[12]Patent: US2004/138466,2004,A1 .Location in patent: Page 5

12
[ 651728-72-2 ]
[ 73590-58-6 ]
[ 651728-73-3 ]
[ 651728-74-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; triethylamine In dichloromethane at 20℃; for 2h;	A mixture of 3-[5-methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-yl- [METHANESULFINYL)-BENZIMIDAZOLE-1-SULFONYL]-BENZOIC] acid [2- (TOLUENE-4-] sulfonyl ! ethyl ester (Intermediate 44) and [3- [6-METHOXY-2- (4-METHOXY-3, 5-] [ DIMETHYL-PYRIDIN-2-YL-METHANESULFMYL)-BENZIMIDAZOLE-1-SULFONYL] I-BENZOIC ACID] [2-(TOLUENE-4-SULFONYL ! ETHYL ESTER (INTERMEDIATE] 45) To a heterogeneous mixture of 5-methoxy-2- (4-methoxy-3, 5-dimethyl- pyridin-2-yl-methanesulfinyl)-lH-benzimidazole (OMEPRAZOLE, 1.0 g, 2.90 mmol), 5 mL [OF ET3N,] and about 1 g [OF NAHC03] in [CH2C12] (20 mL) was added the sulfonyl chloride (Intermediate 43,1. 4 g, 3.48 mmol, 1.2 eq) in [CH2C12] at room temperature, and then the mixture was stirred for 2 h. Thereafter water was added, the mixture was extracted with [CH2C12,] and the organic layers were dried, and concentrated. The oil was purified by column chromatography [(CH2C12] to 1% MeOH in CH2Cl2) to yield 1.67 g [(81 %)] of a mixture of 3- [5- [METHOXY-2- (4-METHOXY-3, 5-DIMETHYL-PYRIDIN-2-YLMETHANESULFINYL)-] [ BENZIMIDAZOLE-1-SULFONYL]-BENZOIC ACID 2- (TOLUENE-4-SULFONYL) ETHYL ESTER] (Intermediate 44) and 3- [6-methoxy-2- (4-methoxy-3, 5-dimethyl-pyridin-2- [YLMETHANESULFINYL)-BENZIMIDAZOLE-1-SULFONYL]-BENZOIC] acid [2- (TOLUENE-4-] sulfonyl) ethyl ester (Intermediate 45) as an off-white foam (1: 1 ratio between 5-and 6-isomer). ['H] NMR [(CDCL3,] 400 MHz) [152.] 25 (s, 3 H), 2.27 (s, 3 H), 2. [33 AND] 2.43 (s, 3 H, 5-and 6-isomers), 3.81 and 3.93 (s, 6 H, 5-and 6-isomers), 4.66 (m, 2 H), 5.07 (m, 2 H), 7.0-8. 6 (m, 12 H, 5-and 6-isomers).
	With sodium hydrogencarbonate; triethylamine In dichloromethane at 20℃; for 2h; Inert atmosphere;

Reference： [1]Current Patent Assignee: WINSTON PHARMACEUTICALS LLC - WO2004/9583, 2004, A2 Location in patent: Page 104-105
[2]Location in patent: experimental part Shin, Jai Moo; Sachs, George; Cho, Young-Moon; Garst, Michael [Molecules, 2009, vol. 14, # 12, p. 5247 - 5280]

13
[ 651728-83-5 ]
[ 73590-58-6 ]
[ 651728-84-6 ]
[ 651728-85-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; triethylamine In dichloromethane at 20℃; for 0.5h;	[ MIXTURE OF3- [5-METHOXY-2- (4-METHOXY-3. 5-DIMETHYL-PYRIDIN-2-YL-] methanesulfinyl)-benzimidazole-1-sulfonyl]-4-methylbenzoic acid [2- (TOLUENE-4-] [SULFONYL ! ETHYL] ester (Intermediate 50) and 3-[6-methoxy-2-(4-methoxy-3, 5- [DIMETHYL-PYRIDM-2-YL-METHANESULFMYL)-BENZIMIDAZOLE-1-SULFBNVLJ-4-] [METHYLBENZOIC] acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 51) To a heterogeneous mixture of 5-methoxy-2- (4-methoxy-3, 5-dimethyl- [PYRIDIN-2-YL-METHANESULFMYL)-LH-BENZIMIDAZOLE] (OMEPRAZOLE, 1.0 g, 2.90 mmol), 5 mL of Et3N, and about 1 g ofNaHCO3 in [CH2C12] (15 mL) was added the sulfonyl chloride (Intermediate 49,1. 45 g, 3.48 mmol, 1.2 eq) in [CH2C12] (5 mL) at room temperature, and then the mixture was stirred for 0.5 h. Thereafter water was added, the mixture was extracted with [CH2C12,] and the organic layers were dried, and concentrated. The oil was purified by column chromatography [(CH2CL2 TO 1 % MEOH IN CH2CL2)] to yield 1.5 g [(71%)] of mixture of 3- [5- [ METHOXY-2- (4-METHOXY-3, 5-DIMETHYL-PYRIDIN-2-YL-METHANESULFINYL)-] [BENZIMIDAZOLE-1-SULFONYL]-4-METHYLBENZOIC] acid 2- (toluene-4-sulfonyl) ethyl ester (Intermediate 50) and [3- [6-METHOXY-2- (4-METHOXY-3,] 5-dimethyl-pyridin- [2-YL-METHANESULFINYL)-BENZIMIDAZOLE-1-SULFONYL]-4-METHYLBENZOIC] acid 2- (toluene-4-sulfonyl) ethyl ester (Intermediate 51) (1: 1 ratio between [5-AND] 6- isomer) as a light brown foam. 'H NMR (CDCl3, 400 MHz) [J2.] 25 and 2.26 (s, 3 H, 5-and 6-isomers), 2.31 and 2.33 (s, 3 H, 5-and 6-isomers), 2.56 and 2.59 (s, 3 H, 5-and 6-isomers), 3.57 (m, [2 H),] 3.78 (s, 3 H), 3.83 (s, [3 H),] 4.66 (m, [2 H),] 4.99 (dd, [2 H),] 7.02 (m, [1] H), 7.26 (m, 5 H), 7.61 and 7.71 (d, [1] H, 5-and 6-isomers), 7.78 (d, 2 H), 7.92 (m, [1] H), 8.13 (s, [1] H), 8.62 (s, [1] H).

Reference： [1]Current Patent Assignee: WINSTON PHARMACEUTICALS LLC - WO2004/9583, 2004, A2 Location in patent: Page 114-115

14
[ 651729-01-0 ]
[ 73590-58-6 ]
[ 651729-02-1 ]
[ 651729-03-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; triethylamine In dichloromethane at 20℃; for 2h;	Mixture of 3-[2-methoxy-5-{5-methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2- yl-methanesulfinyl)-benzimidazole-1-sulfonyl}phenyl]propionic acid 2- [(TOLUENE-4-SULFONYL] ethyl ester (Intermediate 61) and [3] [ METHOXY-2- 4-METHOXY-3, 5-DIMETHYL-PYRIDIN-2L-METHANESULFINYL)-] benzimidazole-1-sulfonyl}phenyl]propionic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 62) To a heterogeneous solution [OF 5-METHOXY-2- (4-METHOXY-3,] 5-dimethyl- pyridin-2-yl-methanesulfinyl)-lH-benzimidazole (OMEPRAZOLE, 1.7 g, 4.93 mmol) and 6 mL [OF ET3N] in 20 mL [OF CH2C12] was added the [CHLOROSULFONYL] ester (Intermediate 60,2. 8 g, 6.0 mmol, 1.3 eq). About 1 g of solid [NAHC03] was added after the [CHLOROSULFONYL] ester has dissolved completely in the reaction mixture. The mixture was stirred at room temperature for 2 h. Thereafter the solvent was removed by evaporation and the residual oil was purified by column chromatography (silica gel, [CH2C12 TO] 2% [MEOH] in [CH2CL2)] to give a mixture of 3- [2-methoxy-5- {5-methoxy-2- (4-methoxy-3, 5-dimethyl-pyridin-2- [YL-METHANESULFINYL)-BENZIMIDAZOLE-L-SULFONYL} PHENYL]] propionic acid 2- (toluene-4-sulfonyl) ethyl ester (Intermediate 61) and [3-[2-METHOXY-5-{6-] methoxy-2- (4-methoxy-3, 5-dimethyl-pyridin-2-yl-methanesulfinyl) - [BENZIMIDAZOLE-1-SULFONYL}] phenyl] propionic acid 2- (toluene-4-sulfonyl) ethyl ester (Intermediate 62) (1.88 g, 50%) as an off-white foam [(1] : [1] ratio between 5-and 6-isomer). ['H] NMR [(CDCL3,] 400 MHz) [#2. ]25 (s, 3 H), 2.28 (m, 3 H), 2. 35 (m, 5 H), 2.77 (m, [2 H),] 2.39 (m, [2 H),] 3.77-3. 93 [(M,] 9 H), 4. 30 (m, [2 H),] 4.96 (m, 2 H), 6.90 (t, [1] HH), 7.00 (m, [1] H), 7.25-7. 50 (m, 3 H), 7.64-7. 86 (m, 3 H), 8.01 (m, [1] H), 8.20 (s, [1] H).

Reference： [1]Current Patent Assignee: WINSTON PHARMACEUTICALS LLC - WO2004/9583, 2004, A2 Location in patent: Page 134-135

15
[ 651729-18-9 ]
[ 73590-58-6 ]
[ 1239887-11-6 ]
[ 1239887-13-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; triethylamine In dichloromethane at 20℃; for 2h;	Mixture of 2-(carboxymethoxy)-5-{5-methoxy-2-(4-methoxy-3,5-dimethyl- [ PYRIDIN-2-YL-METHANESULFMYL)-BENZIMIDAZOLE-L-SULFONYL-BENZOIC ACID] disodium salt (Compound 41) and 2-(carboxymethoxy)-5-{6-methoxy-2-(4- methoxy-3 [*5-DIMETHYL-PYRIDIN-2-YL-METHANESULFINYL !-BENZIMIDAZOLE-1-] [SULFONYLL-BENZOIC] acid disodium salt (Compound 42) To a heterogeneous solution of 5-methoxy-2-(4-methoxy-3, 5-dimethyl- [PYRIDIN-2-YL-METHANESULFINYL)-LH-BENZIMIDAZOLE] (OMEPRAZOLE, 1.0 g, 3.03 mmol) and 4 mL of Et3N in 20 mL of CH2Cl2 was added the [CHLOROSULFONYL] ester (Intermediate 69,2. 6 g, 3.95 mmol, 1.3 eq). About 1 g of solid [NAHC03] was added after the [CHLOROSULFONYL] ester has dissolved completely in the reaction mixture. The mixture was stirred at room temperature for 2 h. Thereafter water was added and the mixture was extracted with EtOAc (2x). The combined organic layers were washed with water, dried, and concentrated to give a mixture of Intermediates 71 and 72 (about 2.9 g) as off-white foam, which were used without further purification.
	With sodium hydrogencarbonate; triethylamine In dichloromethane at 20℃; Inert atmosphere;

Reference： [1]Current Patent Assignee: WINSTON PHARMACEUTICALS LLC - WO2004/9583, 2004, A2 Location in patent: Page 152
[2]Location in patent: experimental part Shin, Jai Moo; Sachs, George; Cho, Young-Moon; Garst, Michael [Molecules, 2009, vol. 14, # 12, p. 5247 - 5280]

16
[ 651728-13-1 ]
[ 73590-58-6 ]
[ 651728-39-1 ]
[ 651728-40-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; sodium hydrogencarbonate In dichloromethane at 20℃; for 8h;	Mixture of {4-[5-methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-yl- [METHANESULFMYD-BENZIMIDAZOLE-1-SULFBNYL] PHENOXY} ACETIC ACID 2- (TOLUENE-4-] sulfonyl)ethyl ester (Intermediate 22) and {4-[6-methoxy-2-(4-methoxy-3,5- [ DIMETHYL-PYRIDIN-2-VL-METHANESULFINYL)-BENZIMIDAZOLE-1-] [SULFONYLLPHENOXYLACETIC] acid [2-(TOLUENE-4-SULFONYL) ETHYL ESTER] (Intermediate 23) To a heterogeneous solution of 5-methoxy-2-(4-methoxy-3, 5-dimethyl- [PYRIDIN-2-YLMETHANESULFINYL)-LH-BENZIMIDAZOLE] (840 mg, 2.44 mmol) in 20 mL [OF CH2CL2] was added 90 mg of NaH (3.75 mmol, 1.5 eq) at room temperature resulting in a homogeneous mixture. To this clear reaction mixture was added powdered [(4-CHLOROSULFONYLPHENOXY)] acetic acid 2- (toluene-4-sulfonyl) ethyl ester (Intermediate 4,1. 26 g, 2.92 mmol, 1.2 eq. ) Solid [NAHC03] [(-1 G) WAS] also added to the reaction mixture. The reaction mixture was stirred for 8 hr at room temperature, and then the solid [NAHC03] was removed by filtration. The dichloromethane layer was evaporated under reduced pressure to give a residual oil, which was purified by column chromatography (silica gel, [CH2C12] to 4% [MEOH] in [CHZCLZ)] to give a mixture of Intermediate 22 and Intermediate 23 (1.6 g, 88%; 1: 1 ratio of 5-and 6-isomer) as an off-white foam. 'H NMR (CDC13, 400 MHz) [15 2.] 23 (s, 3 H), 2.29 (s, 3 H), 2. [39] (s, 3 H), 3.43 (t, 2 H), 3.76 (s, 3 H), 3.82 and 3.89 (2 s, 3 H, 5-OMe and 6-OMe), 4.52 [(M,] 4 H), 4.90 (m, 1 H), 4.99 (m, [1] H), 6.93 (dd, 2 H), 7.00 and 7.10 (2 [M,] [1] H), 7.24 and 7.43 (2 s, [1] H), 7.34 (d, 2 H), 7.67 and 7.84 (2 d, [1] H), 7.75 (d, 2 H), 8.06 (t, 2 H), 8.17 (s, [1 H).]
	Stage #1: omeprazole With sodium hydride In dichloromethane at 20℃; Inert atmosphere; Stage #2: (4-chlorosulfonylphenoxy)acetic acid 2-(toluene-4-sulfonyl)ethyl ester With sodium hydrogencarbonate In dichloromethane Inert atmosphere;

Reference： [1]Current Patent Assignee: WINSTON PHARMACEUTICALS LLC - WO2004/9583, 2004, A2 Location in patent: Page 75-76
[2]Location in patent: experimental part Shin, Jai Moo; Sachs, George; Cho, Young-Moon; Garst, Michael [Molecules, 2009, vol. 14, # 12, p. 5247 - 5280]

17
[ 651728-63-1 ]
[ 73590-58-6 ]
[ 651728-64-2 ]
[ 651728-65-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃; for 6h;	A mixture of [{4- [5-METHOXV-2- (4-METHOXY-3, 5-DIMETHYL-PVRIDIN-2-] ylmethanesulfinyl)-benzimidazole-1-sulfonyl]-2-[2-(toluene-4-sulfonyl)- [ETHOXYCARBONYLMETHOXYL-PHENOX-ACETIC] acid [2-(TOLUENE-4-SULFONYL ! ETHYL ESTER] (Intermediate 39) and [{4- [6-METHOXY-2- (4-METHOXY-3, 5-DIMETHYL-PVRIDM-2-] [ YLMETHANESULFMYD-BENZIMIDAZOLE-1-SULFBNYL]-2- [2- (TOLUENE-4-SULFBNYL)-] [ETHOXYCARBONYLMETHOXY]-PHENOXY}-ACETIC] acid [2-(TOLUENE-4-SULFONYL ! ETHYL ESTER] (Intermediate 40) [ {4-CHLOROSULFONYL-2- [2-(TOLUENE-4-SULFONYL)-ETHOXYCARBONYLMETHOXY]-] [PHENOXY}-ACETIC] acid 2- (toluene-4-sulfonyl) ethyl ester (Intermediate 38) (7.6 g, [11] mmole) and 5-methoxy-2- (4-methoxy-3, 5-dimethyl-pyridin-2- ylmethanesulfinyl)-benzimidazole (3.5 g, 10 mmole) were added to a solution composed of dichloromethane (50 mL) and triethylamine (6 mL). The reaction mixture was stirred at room temperature for 6 hr. Dichloromethane (200 mL) was added and the dichloromethane layer was washed with water (200 mL). The dichloromethane layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The concentrate was purified by chromatography on a silica gel column to give 6.7 g of a mixture of of {4-[5- methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethanesulfinyl)- [ BENZIMIDAZOLE-1-SULFONYL]-2- [(TOLUENE-4-SULFONYL)-ETHOXYCARBONYLMETHOXY]-] [PHENOXY}-ACETIC] acid [2- (TOLUENE-4-SULFONYL) ETHYL] ester (Intermediate 39) and {4-[6-methoxy-2-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethanesulfinyl)- [ BENZIMIDAZOLE-1-SULFONYLL-2- [2-(TOLUENE-4-SULFONYL)-ETHOXYCARBONYLMETHOXY]-] phenoxy}-acetic acid [2-(TOLUENE-4-SULFONYL ! ETHYL] ester (Intermediate 40). 'H NMR (CDCl3, 400 MHz) [152.] 27 (s, 3 H), 2.29 (s, 3 H), 2.39 (s, 6 H), 3.44 (m, [4 H),] 3.76-3. 91 [(3 S, 6 H),] 4.48 (m, [4 H),] 4.58 (m, 4 H), 5.03 (d, [1] H), 5.09 (d, 1 H), 6.85 (m, [1] H), 7.01-7. 09 (m, [1] H), 7.33 (m, 5 H), 7.63-7. 79 (m, 7 H), 8.20 (s, [1] H).
	With triethylamine In dichloromethane at 20℃; for 6h; Inert atmosphere;

Reference： [1]Current Patent Assignee: WINSTON PHARMACEUTICALS LLC - WO2004/9583, 2004, A2 Location in patent: Page 97-98
[2]Location in patent: experimental part Shin, Jai Moo; Sachs, George; Cho, Young-Moon; Garst, Michael [Molecules, 2009, vol. 14, # 12, p. 5247 - 5280]

18
[ 768-94-5 ]
[ 73590-58-6 ]
[ 847951-86-4 ]

Yield	Reaction Conditions	Operation in experiment
73%	In methanol; acetonitrile at 20 - 50℃; for 2h;	1 Omeprazole (1.0 g, 2.9 mmol) was dissolved in acetonitril (10 ml) and methanol (2 ml) at 40-50 °C. 1-adamantan amine (0.86 g, 5.7 mmol) was added and the mixture was then cooled to room temperature. At these conditions, a slurry was achieved. The slurry was stirred for additional two hours whereupon the precipitate was filtered off, washed with acetonitrile, and dried. 1 g (73 %) of the title compound was obtained. 1H-NMR (400 MHZ, CD2Cl2) : 1.5 (bs, 18H), 2.12 (s, 3H), 2.17 (s, 3H), 3.63 (s, 3H), 3.77 (s, 3H), 4.49 (d, 1H), 4.65 (d, 1H), 6. 84-6. 91 (dd, 1H), 6.99 (bs, 1H), 7.47 (m, 1H), 8.14 (s, 1H) The prepared compound was analysed by XRPD resulting in the diffractogram shown in Figure 1.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2005/23796, 2005, A1 Location in patent: Page/Page column 13

19
[ 73590-58-6 ]
[ 119141-89-8 ]
[ 119141-88-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In methanol;Chiral supercritical fluid chromatography; Resolution of racemate;Purification / work up;	Preparation of R-Omeprazole and S-Omeprazole from rac-Omeprazole by means of Chiral Supercritical Fluid Chromatography. Omeprazole (2517.6 mg; 7.289 mmol) was placed in a volumetric flask (100 mL) with 0.4% triethylamine (TEA) in methanol, dissolved by means of sonication, and brought to volume. The solution was injected onto a Berger Multigram Supercritical Fluid System under the following conditions: Column: Chiralpak AS-H SFC Column Dimensions: 20 mm×250 mm; 5 mum particle size Column Temperature: 35 C. Column Pressure: 100 bar Detection: 302 nm Flow rate: 50 mL/minute Mobile Phase: 75:25 Carbon Dioxide: Methanol with 0.4% TEA Injection Volume: 0.75 mL The fractions of each enantiomer were collected into separate ice chilled flasks. After collection, the solvent was removed by rotary evaporation and the resulting oils were used directly in a subsequent experiment (see Example 4).
	With N,N-dimethyl-ethanamine; In ethanol;Chiral supercritical fluid chromatography; Resolution of racemate;Purification / work up;	Preparation of R-Omeprazole and S-Omeprazole from rac-Omeprazole by means of Chiral Supercritical Fluid Chromatography. Omeprazole (2463.0 mg; 7.130 mmol) was placed in a volumetric flask (200 mL) with 0.3% dimethylethylamine (DMEA) in ethanol, dissolved by means of sonication, and brought to volume. The solution was injected onto a Berger Multigram Supercritical Fluid System under the following conditions: Column: Chiralpak AS-H SFC Column Dimensions: 20 mm×250 mm; 5 mum particle size Column Temperature: 35 C. Column Pressure: 150 bar Detection: 302 nm Flow rate: 50 mL/minute Mobile Phase: 75:25 Carbon Dioxide: Ethanol with 0.3% DMEA Injection Volume: 1.0 mL The fractions of each enantiomer were collected into separate ice chilled flasks. After collection, the solvent was reduced by rotary evaporation to approximately 10 ml, and the diluted products used in a subsequent experiment (see Examples 7 and 8)
	With N,N-dimethyl-ethanamine; In methanol;Chiral supercritical fluid chromatography; Resolution of racemate;Purification / work up;	Preparation of R-Omeprazole and S-Omeprazole from rac-Omeprazole by means of Chiral Supercritical Fluid Chromatography. Omeprazole (2552.4 mg; 7.389 mmol) was placed in a volumetric flask (100 mL) with 0.3% dimethylethylamine (DMEA) in methanol, dissolved by means of sonication, and brought to volume. The solution was injected onto a Berger Multigram Supercritical Fluid System under the following conditions: Column: Chiralpak AS-H SFC Column Dimensions: 20 mm×250 mm; 5 mum particle size Column Temperature: 35 C. Column Pressure: 100 bar Detection: 302 nm Flow rate: 50 mL/minute Mobile Phase: 75:25 Carbon Dioxide: Methanol with 0.3% DMEA Injection Volume: 0.75 mL The fractions of each enantiomer were collected into separate ice chilled flasks. After collection, the solvent was removed by rotary evaporation. The resulting oils were used in a subsequent experiment (see Example 6).

	at 20℃;Resolution of racemate;	Racemic mixtures of omeprazole were resolved and separated into (S)- and (R)-enantiomers using chiral column chromatography. The omeprazole mixture were dissolved in methanol and diluted to a concentration of about 22-25 g/L. About 0.01 v/v % of diethylamine was also added to the mixtures. The chromatographic separation was carried out under the following conditions: Stationary phase: CHIRALPAK AD, 20 mum particle size Column length: 250-350 mm Mobile phase: methanol Loading: mLOAD/SCOLUMN=175-220 mg/cm2, Flow rate=3.8-4.2 cm/min. Temperature: room temperature Flow rate during S-enantiomer elution: 5.7-6.2 cm/min. Flow rate during R-enantiomer elution: 9.0-11.8 cm/min. UV detector: 325 nm Run time: 22-26 min.
	With CHIRALPAK AD; diethylamine; In methanol;Resolution of racemate;	Example 1; Preparation of neutral esomeprazole Neutral racemic omeprazole of chemical purity of 99.91 % (commercially available) was dissolved in 0.005 % solution of diethylamine in methanol (24 g omeprazole per L) and the solution was loaded to column (ChiralPak AD, 20 mum particle size, column length 350 mm). Products were eluted by methanol and S-enantiomer was collected first. The prepared solution was injected several times to the top of chromatographic column until the wanted quantity was obtaining. The collected main fractions were evaporated at the temperature below 40C under reduced pressure until the concentration of 100 - 300 g/l of active substance was reached.
	With diethylamine; In methanol;Resolution of racemate;Product distribution / selectivity;	Racemic mixture of omeprazole is resolved and separated into S- and R-enantiomer using chiral column chromatography. Omeprazole is dissolved in methanol and diluted to a concentration of about 22 - 25 g / L. About 0.01 % (V/V) of diethylamine is also added to the solution. The chromatographic separation is carried out under the following conditions: Stationary phase: CHIRALPAK AD, 20 mum particle sizeColumn length: 250-350 mmColumn diameter : 5 cmMobile phase: methanolLoading: mLOAD/ SCOLUMN = 175-220 mg/cm2, Linear velocity = 3.8-4.2 cm/min.Temperature: room temperatureLinear velocity during S-enantiomer elution: 5.7-6.2 cm/min.Linear velocity during R-enantiomer elution: 9.0-11.8 cm/min.UV detector: 325 nmRun time: 22-26 min; Example 3 7.2 kg of omeprazole is resolved and separated into S- and R-enantiomers using chiral column chromatography. Omeprazole is dissolved in methanol and diluted to a concentration of about 22 - 25 g / L. About 0.01 % (V/V) of diethylamine is also added to the solution. The chromatographic separation is carried out under the analogous conditions as described in Example 2 using a column of length 300 mm and of diameter 15 cm.

Reference： [1]Patent: US2005/267157,2005,A1 .Location in patent: Page/Page column 10-11
[2]Patent: US2005/267157,2005,A1 .Location in patent: Page/Page column 11
[3]Patent: US2005/267157,2005,A1 .Location in patent: Page/Page column 11
[4]Patent: US2007/149573,2007,A1 .Location in patent: Page/Page column 5
[5]Patent: EP2143722,2010,A1 .Location in patent: Page/Page column 9
[6]Patent: EP1947099,2008,A1 .Location in patent: Page/Page column 11-12
[7]Organic Letters,2013,vol. 15,p. 5658 - 5661
[8]Chemical Communications,2017,vol. 53,p. 509 - 512
[9]Journal of Organic Chemistry,2018,vol. 83,p. 7453 - 7458
[10]Chemical Communications,2019,vol. 55,p. 10480 - 10483

20
[ 635751-00-7 ]
[ 73590-58-6 ]
ethyl 2-[[[6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate [ No CAS ]
ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine;dmap; In tetrahydrofuran; at 60℃; for 12h;	To a solution (10 mL) of bis(trichloromethyl)carbonate (0.291 g) in tetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.243 mL) in tetrahydrofuran under ice-cooling. After stirring under ice-cooling for 1 hr., ethyl 2-(methylamino)ethyl carbonate hydrochloride (0.551 g) obtained in Reference Example 14 was added. A solution (1 mL) of triethylamine (0.418 mL) in tetrahydrofuran was dropwise added, and the mixture was stirred at room temperature for 2 hrs. After concentration under reduced pressure, water (15 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL). 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (0.817 g), triethylamine (0.661 mL) and 4-dimethylaminopyridine (0.012 g) were added, and the mixture was stirred at 60C for 12 hrs. After concentration under reduced pressure, water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to give a 3:2 mixture (0.92 g) of the title compound and ethyl 2-[[[6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate as a pale-yellow amorphous solid.1H-NMR (CDCl3) : 1.27-1.34 (3H,m), 2.10-2.30 (3H,m), 2. 23 (3H, s), 2.99-3.23(3H,m), 3.40-3.85 (2H,m), 3.69 (6/5H,s), 3.71 (9/5H,s), 3.86(6/5H,s), 3.88(9/5H,s), 4.14-4.25(2H,m), 4.38-4.60(2H,m), 4.82-5.06(2H,m), 6.92-7.08(7/5H,m), 7.33(3/5H,d,J=9.0Hz), 7.66 (1H,m), 8.21 (1H,s).
	With dmap; triethylamine; In tetrahydrofuran; at 60℃; for 12h;	Synthetic Example 55 Ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate (0725) (0726) To a solution (10 mL) of bis(trichloromethyl)carbonate (0.291 g) in tetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.243 mL) in tetrahydrofuran under ice-cooling. After stirring under ice-cooling for 1 hr., ethyl 2-(methylamino)ethyl carbonate hydrochloride (0.551 g) obtained in Reference Example 14 was added. A solution (1 mL) of triethylamine (0.418 mL) in tetrahydrofuran was dropwise added, and the mixture was stirred at room temperature for 2 hrs. After concentration under reduced pressure, water (15 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL). 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (0.817 g), triethylamine (0.661 mL) and 4-dimethylaminopyridine (0.012 g) were added, and the mixture was stirred at 60 C. for 12 hrs. After concentration under reduced pressure, water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to give a 3:2 mixture (0.92 g) of the title compound and ethyl 2-[[[6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate as a pale-yellow amorphous solid. (0727) 1H-NMR (CDCl3): 1.27-1.34 (3H, m), 2.10-2.30 (3H, m), 2.23 (3H, s), 2.99-3.23 (3H, m), 3.40-3.85 (2H, m), 3.69 (6/5H, s), 3.71 (9/5H, s), 3.86 (6/5H, s), 3.88 (9/5H, s), 4.14-4.25 (2H, m), 4.38-4.60 (2H, m), 4.82-5.06 (2H, m), 6.92-7.08 (7/5H, m), 7.33 (3/5H, d, J=9.0 Hz), 7.66 (1H, m), 8.21 (1H, s).

Reference： [1]Patent: EP1607088,2005,A1 .Location in patent: Page/Page column 81-82
[2]Patent: US2016/128945,2016,A1 .Location in patent: Paragraph 0725; 0726; 0727

21
[ 635751-00-7 ]
[ 73590-58-6 ]
[ 635751-76-7 ]
[ 635751-75-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In tetrahydrofuran at 60℃; for 14h;	56 To a solution (10 mL) of bis(trichloromethyl)carbonate (0.291 g) in tetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.243 mL) in tetrahydrofuran under ice-cooling. After stirring under ice-cooling for 30 min., 2-anilinoethyl acetate hydrochloride (0.647 g) obtained in Reference Example 27 was added. A solution (1 mL) of triethylamine (0.419 mL) in tetrahydrofuran was dropwise added, and the mixture was stirred at room temperature for 3 hrs. After concentration under reduced pressure, water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL). 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (0.829 g), triethylamine (0.669 mL) and 4-dimethylaminopyridine (0.012 g) were added, and the mixture was stirred at 60°C for 14 hrs. After concentration under reduced pressure, water (40 mL) was added to the residue, and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2) to give a 1:1 mixture (1.10 g) of the title compound and 2-[[[6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl)carbonyl](phenyl)amino]ethyl acetate as a colorless amorphous solid.1H-NMR (CDCl3) : 1.99 (3H,s), 2.19 (1.5H.s), 2.21 (1.5H,s), 2.25(3H,s), 3.70 (1.5H,s), 3.71 (3H,s), 3.78 (1.5H,s), 3.84 (1.5H,s), 4.15-4.56(4H,m), 4.74-4.80 (1H,m), 4.91-4.98 (1H,m), 6.83-6.91 (1.5H,m), 7.04-7.19(3.5H,m), 7.25-7.53 (2.5H,m), 7.51 (0.5H,d,J=8.7Hz), 8.25 (1H,s).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1607088, 2005, A1 Location in patent: Page/Page column 82

22
C₁₁H₁₂ClNO₃ [ No CAS ]
[ 73590-58-6 ]
2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzoimidazol-1-yl]carbonyl](methyl)amino]ethyl benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine;dmap; In tetrahydrofuran; at 40℃; for 18h;	To a solution (10 mL) of bis(trichloromethyl)carbonate (0.344 g) in tetrahydrofuran was dropwise added a solution (5 mL) of pyridine (0.281 mL) in tetrahydrofuran under ice-cooling, and the mixture was stirred at 0C for 30 min. 2-(Methylamino)ethyl benzoate hydrochloride (0.750 g) obtained in Reference Example 5 was added to the reaction mixture. A solution (5 mL) of triethylamine (0.485 mL) in tetrahydrofuran was added, and the mixture was stirred at 0C for 1 hr. and at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure and water (30 mL) was added to the residue. The mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil was dissolved in tetrahydrofuran (5 mL), the mixture was added to a solution (10 mL) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (1.0 g), triethylamine (0.808 mL) and 4-dimethylaminopyridine (0.071 g) in tetrahydrofuran, and the mixture was stirred at 40C for 18 hrs. The reaction mixture was concentrated under reduced pressure and water (30 mL) was added to the residue. The mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane=1:1, then ethyl acetate) to give a 1:1 mixture (1.50 g) of the title compound and 2-[[[6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl benzoate as a pale-yellow amorphous solid.1H-NMR (CDCl3) : 2.05-2.35(6H,m), 3.00-3.30(3H,br), 3.60-4.40(8H,m), 4.60-5.10(4H,m), 6.80-7.00(2H,m), 7.20-7.70(4H,m), 7.95-8.25(3H,m).

Reference： [1]Patent: EP1607088,2005,A1 .Location in patent: Page/Page column 72-73

23
[ 73590-58-6 ]
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl]-1H-benzimidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With titanium(IV) isopropylate; diethyl (2S,3S)-tartrate; Cumene hydroperoxide; N-ethyl-N,N-diisopropylamine; In water; ethyl acetate; at 20 - 34℃; for 3.5h;	Reference Example prepared according to Example of WO 96/02535; Asymmetric synthesis of (-)-5-methoxy-2-(((4-methoxy-3,5-dimethyl-2-pyridinyl)-methyllsulphinyl]-lH-benzimidazole sodium salt, (-)-Na salt; 59 g (180 mmol) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-IH-benzimidazole was dissolved in 200 ml ethyl acetate. To the solution was added 0.3 ml(17 mmol) water. To the mixture was added 37 g (180 mmol) (+)-diethyl L-tartrate, 25 g(90 mmol) titanium(W) isopropoxide and 16 ml (90 mmol) diisopropylethylamine at roomtemperature. The addition of 30 ml (160 mmol) cumene hydroperoxide (80%) was thenperformed over a period of 90 minutes at 34C. After cooling to room temperature for 120minutes a small sample of the mixture was taken for chiral and achiral chromatographicanalyses.The mixture consisted of 82% sulphoxide with an enantiomeric excess (e.e.) of 87%. Themixture was diluted with 60 ml isooctane and 40 ml ethyl acetate whereupon the productwas extracted three times with an aqueous ammonia (12%) solution with a total volume of480 ml. The combined aqueous phases were neutralised by addition of 50 ml concentratedacetic acid. Thereafter, the workup procedure employed extraction, evaporation, sodiumhydroxide addition and crystallisation procedures yielding 32.7 g of the title compoundwith a purity of 95.2% (achiral analysis) and with an enantiomeric excess (e.e.) of 99.8%(chiral analysis).The overall yield was 47.2%.

Reference： [1]Patent: WO2006/1755,2006,A1 .Location in patent: Page/Page column 9

24
[ 73590-58-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
1.3 g (50%)	With magnesium In methanol; water	R.A S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole Magnesium Salt Reference Example A S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole Magnesium Salt (The Method Used is in Accordance with the Method Described in Example A in WO 96/01623) Magnesium (0.1 μg, 4.5 mmol) was dissolved and reacted with methanol (50 ml) at 40° C. with a catalytic amount of methylene chloride. The reaction was run under nitrogen and was finished after five hours. At room temperature a mixture of the two enantiomers [90% (-)-isomer and 10% (+)-isomer] of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (2.84 g, 8.2 mmol) was added to the magnesium methoxide solution. The mixture was stirred for 12 hours whereupon a small amount of water (0.1 ml) was added in order to precipitate inorganic magnesium salts. After 30 minutes stirring, these inorganic salts were filtered off and the solution was concentrated on a rotavapor. The residue was now a concentrated methanolic solution of the enantiomeric mixture (i.e. the title compound contaminated with the (+)-isomer), with an optical purity (enantiomeric excess, e.e.) of 80%. This mixture was diluted with acetone (100 ml) and after stirring at room temperature for 15 minutes, a white precipitate was obtained. Additional stirring for 15 minutes and thereafter filtration afforded 1.3 g (50%) of the title compound as white crystals. Chiral analyses of the crystals and mother liquor were performed by chromatography on an analytical chiral column. The optical purity of the crystals and mother liquor was found to be 98.4 e.e. and 64.4% e.e., respectively. Thus, the optical purity (e.e.) has been enhanced from 80% to 98.4% simply by crystallizing the Mg-salt from a mixture of acetone and methanol. The product was crystalline as shown by powder X-ray diffraction and the magnesium content was 3.44% as shown by atomic absorption spectroscopy. [a]D20=-131.5° (c=0.5%, methanol). The product was analyzed using X-ray powder diffraction as described in Example 1 and gave the diffractogram depicted in and given below in Table 5. Some additional very weak peaks found in the diffractograms have been omitted from Table 5.
1.3 g (50%)	With magnesium In methanol; water	R.A S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole magnesium salt Reference Example A S-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole magnesium salt (The method used is in accordance with the method described in Example A in WO 96/01623) Magnesium (0.11 g, 4.5 mmol) was dissolved and reacted with methanol (50 ml) at 40° C. with a catalytic amount of methylene chloride. The reaction was run under nitrogen and was finished after five hours. At room temperature a mixture of the two enantiomers [90%(-)-isomer and 10%(+)-isomer] of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (2.84 g, 8.2 mmol) was added to the magnesium methoxide solution. The mixture was stirred for 12 hours whereupon a small amount of water (0.1 ml) was added in order to precipitate inorganic magnesium salts. After 30 minutes stirring, these inorganic salts were filtered off and the solution was concentrated on a rotavapor. The residue was now a concentrated methanolic solution of the enantiomeric mixture (i.e. the title compound contaminated with the (+)-isomer), with an optical purity (enantiomeric excess, e.e.) of 80%. This mixture was diluted with acetone (100 ml) and after stirring at room temperature for 15 minutes, a white precipitate was obtained. Additional stirring for 15 minutes and thereafter filtration afforded 1.3 g (50%) of the title compound as white crystals. Chiral analyses of the crystals and mother liquor were performed by chromatography on an analytical chiral column. The optical purity of the crystals and mother liquor was found to be 98.4 e.e. and 64.4% e.e., respectively. Thus, the optical purity (ee.) has been enhanced from 80% to 98.4% simply by crystallizing the Mg-salt from a mixture of acetone and methanol. The product was crystalline as shown by powder X-ray diffraction and the magnesium content was 3.44% as shown by atomic absorption spectroscopy. [α]D20=-131.5° (c=0.5%, methanol).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - US2003/4190, 2003, A1
[2]Current Patent Assignee: ASTRAZENECA PLC - US6369085, 2002, B1

25
aqueous sodium metabisulphate [ No CAS ]
(acac)2 [ No CAS ]
aqueous tert-butyl hydroperoxide (TBHP) [ No CAS ]
[ 73590-85-9 ]
[ 73590-58-6 ]

Yield	Reaction Conditions	Operation in experiment
79%	In ethanol;	Example 1 Selective Oxidation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl]thio]-1H-benzimidazole to form 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl]sulfinyl]-1H- benzimidazole (Omeprazole) 1.5 mg (0.6percent molar) VO (acac)2) was dissolved in 12 ml ethanol at room temperature. The solution was stirred and 3 grams of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole (MPB) were added. 1.5 ml aqueous tert-butyl hydroperoxide (TBHP) (70percent) was added over a 5-minute period at 16-17° C. and the solution was then stirred for 3 hours. After completion of the reaction, the product mixture was cooled to about 15° C. and treated with aqueous sodium metabisulphate. The resultant solid was filtered off, washed with cooled ethyl acetate to afford the end product as an almost white solid (2.5 grams, yield 79percent).

Reference： [1]Patent: US2003/36554,2003,A1

26
aqueous sodium metabisulphite [ No CAS ]
[ 73590-85-9 ]
[ 73590-58-6 ]

Yield	Reaction Conditions	Operation in experiment
	With tert.-butylhydroperoxide;VO(acac)2; In toluene;	Example 2 Selective Oxidation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1H-benzimidazole to form 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl]sulfinyl]-1H-benzimidazole (Omeprazole) 15 mg (0.6percent molar) VO(acac)2) in 5 ml toluene were added to a suspension of 3 grams of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]benzimidazole (MPB) in 30 ml toluene at a temperature of about 5° C. 3.5 ml of tert-butyl hydroperoxide (TBHP) in toluene (3M, 115percent) were added dropwise, while the temperature was maintained between 5 and 7° C. Upon completing the addition of the TBHP, the temperature rose to 22° C. The reaction was allowed to proceed to completion (about 3 hours), after which the cooled product mixture was treated with aqueous sodium metabisulphite. The solid product was filtered off, washed with cooled ethyl acetate and dried in an oven (yield 80.7percent)

Reference： [1]Patent: US2003/36554,2003,A1

27
[ 69812-29-9 ]
[ 73590-58-6 ]
[ 259183-12-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane;	EXAMPLE 39 Preparation of 1-[2-acetamido-4-methyl-5-thiazolylsulfonyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole 172 mg of 5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole was dissolved in 10 ml of dichloromethane and 0.4 ml of triethylamine, and 128 mg of 2-acetamido-4-methyl-5-thiazolyl sulfonyl chloride was added. The reaction mixture was stirred at room temperature for 15 hr. Product spot was shown at slightly higher position than 5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole in thin layer chromatography (developing solvent: dichloromethane-acetonitrile-methanol=100: 10: 5). Product was separated by silica gel column chromatography. 145 mg of the titled product was isolated.

Reference： [1]Patent: US6559167,2003,B1

28
concentrated acetic acid [ No CAS ]
[ 408332-88-7 ]
[ 73590-85-9 ]
racemic omeprazole [ No CAS ]
[ 73590-58-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; isopropylbenzene hydroperoxide;titanium(IV) isopropylate; In 2,2,4-trimethylpentane; water; ethyl acetate; acetone;	Example 9 Asymmetric synthesis followed by optical purification of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole, (+)-(Ia) 1.6 kg (5.0 mol) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole was dissolved in 7.51 of ethyl acetate. To the solution was added 31 ml (1.7 mol) water. To the mixture was added 856 ml (5.0 mol) of (+)-diethyl L-tartrate, 744 ml (2.5 mol) of titanium(IV) isopropoxide and 436 ml (2.5 mol) diisopropylethylamine at room temperature. The addition of 830 ml (4.5 mol) cumene hydroperoxide was then performed at 30° C. After stirring for one hour at 30° C. the reaction was complete. Chiral and achiral chromatographic analyses showed that the mixture consited of 75percent sulphoxide with an enantiomeric excess (e.e.) of 80percent. The mixture was cooled to 10° C. and after addition of 1.5 l of isooctane and ethyl acetate (0.5 l), the product was extracted three times with an aqueous ammonia (12percent) solution with a total volume of 14 l. The combined aqueous phases were neutralised by addition of 1.5 l of concentrated acetic acid in the presence of ethyl acetate (4 l). The phases were separated and the aqueous phase was extracted with ethyl acetate (4 l). The solvent of the combined organic solutions was removed. Acetone (3.0 l) was added to precipitate the racemate of omeprazole which was filtered off. HPLC--analyses (achiral and chiral columns) of the filtrate showed that this solution consisted of 90percent sulphoxide with an optical purity of 95percent e.e. and thus the optical purity has been improved from 80percent e.e. to 95percent e.e. simply by one precipitation of racemic omeprazole. Further, a content analysis (HPLC) of the filtrate showed that the yield was 1.0 kg (58percent).

Reference： [1]Patent: US5929244,1999,A

29
concentrated acetic acid [ No CAS ]
[ 13811-71-7 ]
[ 73590-85-9 ]
racemic omeprazole [ No CAS ]
[ 73590-58-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; isopropylbenzene hydroperoxide;titanium(IV) isopropylate; In 2,2,4-trimethylpentane; water; ethyl acetate; acetone; acetonitrile;	Example 8 Asymmetric synthesis followed by optical purification of (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinl]-1H-benzimidazole, (-)-(Ia) 1.6 kg (5.0 mol) of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole was dissolved in 5.01 of ethyl acetate. To the solution was added 31 ml (1.7 mol) of water. To the mixture was added 856 ml (5.0 mol) of (-)-diethyl D-tartrate, 744 ml (2.5 mol) of titanium(IV) isopropoxide and 435 ml (2.5 mol) of diisopropylethylamine at room temperature. The addition of 830 ml (4.5 mol) cumene hydroperoxide was then performed at 30° C. After stirring for one hour at 30° C. the reaction was complete. Chiral and achiral chromatographic analyses showed that the mixture consisted of 71.4percent sulphoxide with an enantiomeric excess (e.e.) of 72.9percent. The mixture was cooled to 10° C. and after addition of 1.7 l of isooctane, the product was extracted three times with an aqueous ammonia (12percent) solution with a total volume of 10 l. The combined aqueous phases were neutralised by addition of 1.5 l of concentrated acetic acid in the presence of ethyl acetate (3 l). The phases were separated and the aqueous phase was extracted with ethyl acetate (3 l). The solvent of the combined organic solutions was removed and at the end of the evaporation acetonitrile (1.5 l) was added to facilitate the removal of solvent. Acetone (2.5 l) was added to precipitate the racemate of omeprazole which was filtered off (254 g). HPLC-analyses (achiral and chiral columns) of the filtrate showed that this solution consited of 88percent sulphoxide with an optical purity of 96.3percent e.e. and thus the optical purity has been improved from 72.9percent e.e. to 96.3percent e.e. simply by one precipitation of racemic omeprazole. Further, a content analysis (HPLC) of the filtrate showed that the yield was 0.8 kg (46percent).

Reference： [1]Patent: US5929244,1999,A

30
[ 861359-74-2 ]
[ 408332-88-7 ]
[ 73590-85-9 ]
[ 73590-58-6 ]

Yield	Reaction Conditions	Operation in experiment
	With isopropylbenzene hydroperoxide;titanium(IV) isopropylate; In water; toluene;	Example 2 Asymmetric synthesis of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazole, (+)-(Ia) Titanium(IV) isopropoxide (1.3 ml, 4.5 mmol) and water (41 mul, 2.3 mmol) were added with stirring to a solution of (+)-diethyl L-tartrate (1.5 ml, 9.0 mmol) dissolved in toluene (10 ml). The mixture was stirred for 20 minutes at room temperature and then 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole (3.0 g, 9 mmol) and diisopropylethyl amine (0.45 ml, 2.6 mmol) were introduced. At 30 C. cumene hydroperoxide (tech, 80%, 1.8 ml, 9.9 mmol) was added. After 3 h at 30 C. the mixture consisted of 2.1% sulphide, 8.8% sulphone and 86.8% sulphoxide with an enantiomeric excess of 74%.

Reference： [1]Patent: US5948789,1999,A

31
[ 408332-88-7 ]
[ 73590-85-9 ]
[ 73590-58-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydrogencarbonate; isopropylbenzene hydroperoxide;titanium(IV) isopropylate; In water; ethyl acetate;	Example 3 Asymmetric synthesis of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazole, (+)-(Ia). To a mixture of (+)-diethyl L-tartrate (4.2 g, 20 mmol), titanium(IV) isopropoxide (2.9 g, 10 mmol) and ethyl acetate was added water (0.18 ml, 10 mmol). The solution was stirred for 20 minutes whereupon 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]thio]-1H-benzimidazole (3,4 g, 10 mmol) was added together with KHCO3 (0.31 g, 3.1 mmol) and cumene hydroperoxide (1.8 ml, 10 mmol). The addition was performed at room temperature. HPLC analysis was performed after 1.5 hours which showed 63.3percent sulphoxide with an enantiomeric excess of 38.9percent.
	With isopropylbenzene hydroperoxide;titanium(IV) isopropylate; In dichloromethane; water;	Example 6 Asymmetric synthesis of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazole, (+)-(Ia). (+)-Diethyl L-tartrate (1.71 ml, 10 mmol) and titanium(IV) isopropoxide (1.5 ml, 5 mmol) were dissolved in methylene chloride (50 ml). Water (90 mul, 5 mmol) was added with stirring and the resultant mixture was heated to reflux for one hour. The mixture was cooled to room temperature. Thereafter, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole (1.65 g, 5 mmol) and cumene hydroperoxide (80percent, 1.05 g, 5.5 mmol) were added at room temperature. The solution was stirred at room temperature for 90 minutes. The crude mixture was shown to consist of 42.8percent sulphide, 4.1percent sulphone and 48.3percent sulphoxide with an optical purity of 43percent e.e. The product was not isolated.
	With isopropylbenzene hydroperoxide;titanium(IV) isopropylate; In dichloromethane; water;	Example 7 Asymmetric synthesis of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazole, (+)-(Ia). 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole (1.65 g, 5 mmol) was dissolved in methylene chloride (50 ml). (+)-Diethyl L-tartrate (1.71 ml, 10 mmol), titanium(IV) isopropoxide (1.5 ml, 5 mmol) and water (90 mul, 5 mmol) were added with stirring. The resultant mixture was stirred at room temperature for 20 minutes. Thereafter, cumene hydroperoxide (80percent, 1.05 g, 5.5 mmol) were added at room temperature and the solution was stirred at room temperature for 90 minutes. The crude mixture was shown to consist of 38.9percent sulphide, 8.4percent sulphone and 47.6percent sulphoxide with an optical purity of 32percent e.e. The product was not isolated.

With isopropylbenzene hydroperoxide;titanium(IV) isopropylate; In water; toluene;

Example 8 Asymmetric synthesis of (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazole, (+)-(Ia). 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole (0.5 g, 1.5 mmol) was suspended in toluene (2.5 ml). Water 9.2 mul (0.5 mmol), (+)-Diethyl L-tartrate (0.39 ml, 2.3 mmol) and titanium(IV) isopropoxide (0.27 ml, 0.91 mmol) were added at 50° C. The mixture was warmed at 50° C. for 90 minutes whereupon 0.25 ml of the solution was transferred to a test-tube. To this tube was then added 25 mul of cumene hydroperoxide (80percent) and almost immediately thereafter this mixture consisted of 41percent desired sulphoxide with an optical purity of 69.5percent ee. The product was not isolated.

Reference： [1]Patent: US5948789,1999,A
[2]Patent: US5948789,1999,A
[3]Patent: US5948789,1999,A
[4]Patent: US5948789,1999,A

32
[ 13811-71-7 ]
[ 73590-85-9 ]
[ 73590-58-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; isopropylbenzene hydroperoxide;titanium(IV) isopropylate; In toluene;	Example 5 Asymmetric synthesis of (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulphinyl]-1H-benzimidazole, (-)-(Ia). 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-thio]-1H-benzimidazole (4.0 g, 12.1 mmol) was suspended in toluene (12 ml) (-)-Diethyl D-tartrate (0.17 ml, 1.0 mmol) and titanium(IV) isopropoxide (0.15 ml, 0.50 mmol) were added with stirring at 50° C. The mixture was stirred at 50° C. for 50 minutes and then N,N-diisopropylethylamine (0.085 ml, 0.50 mmol) was added at ca. 30° C. Then, cumene hydroperoxide (83percent, 2.1 ml, 11.9 mmol) was added and the mixture was stirred for 15 minutes at 30° C. The crude mixture was shown to consist of 3.6percent sulphide, 2.7percent sulphone and 93percent sulphoxide with an optical purity of 91percent e.e. The product was not isolated.

Reference： [1]Patent: US5948789,1999,A

33
Sodium perborate 4H₂O [ No CAS ]
[ 73590-85-9 ]
[ 73590-58-6 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic anhydride; In methanol; water; toluene;	Example 10 Synthesis of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylsulfinyl]-1H-benzimidazole (Omeprazole) Sodium perborate 4H2O (11.2 g, 73.0 mmol) was suspended in water (50 ml), followed by the dropwise addition of a solution of acetic anhydride (6.87 ml, 73.0 mmol)/methanol (5.75 ml) at 15.4° C. over 6 minutes and then, the mixture was stirred for about 13 min to prepare a homogenous solution (bulk temperature; 15.4° C. to 19.4° C.). The resulting solution was added dropwise to a solution (220 ml) of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-1H-benzimidazole (20.0 g, 60.8 mmol) in toluene/methanol (10:1) at -20° C. over 2 hr. The resulting mixture was further stirred at the same temperature for 1hr. The resulting crystals were collected by filtration, washed for three times with water (20 ml) and washed twice with tert-butyl methyl ether (20 ml). The resulting crystals were dried, to give the title compound (17.8 g, yield; 85.0percent) as a white solid. 1H-NMR (400 MHz, CDCl3); delta ppm) 2.20(s, 3H), 2.25(s, 3H), 3.68(s, 3H), 3.86(s, 3H), 4.70(Abq, 2H, J=13.7 Hz), 6.98-7.00(m, 2H), 7.65(br-d, 1H, J=8.29 Hz), 8.24(s, 1H), 1.19(br-s, 1H).

Reference： [1]Patent: US6313303,2001,B1

34
[ CAS Unavailable ]
[ 39307-32-9 ]
[ 73590-58-6 ]
[ CAS Unavailable ]
[ 259182-45-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine; benzenesulfonyl chloride; sodium chloride In n-heptane; dichloromethane	1 1-Benzenesulfonyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole EXAMPLE 1 1-Benzenesulfonyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole Method A: 5-Methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole(172 mg, 0.5 mmole) was dissolved in 20 ml of dichloromethane and 0.140 ml of triethylamine. The solution was cooled to 0-4° C. in an ice bucket. Benzenesulfonyl chloride (96 mg, 0.55 mmole) was slowly added and stirred at 0-4° C. with thin layer chromatography monitoring (developing solvent system: chloroform-methanol (10:1) and acetonitrile-chloroform (1:1)). After the reaction was complete, the organic layer was washed with an aqueous solution composed of 0.1M NaCl, and 0.1M sodium phosphate, pH 8.5. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residual material was crystallized from dichloromethane-ethyl ether-heptane to provide 127 mg of product. M. p. 87-89° C. (decomposition). Heptane was introduced to the remaining organic layer to provide a second crop of product (104 mg). After combining the solids, 231 mg of the product (yield 95%) was obtained. 1H NMR (CDCl3, δ: 8.10-8.15 (m, 2H), 7.45-7.80(m, 5H), 7.26(s, 1H), 7.0-7.1(m, 1H), 4.8-5.0(q, 2H), 3.92(s, 3H), 3.75(s, 3H), 2.31(s, 3H), 2.23(s, 3H)

Reference： [1]Current Patent Assignee: ALEVIUM PHARMACEUTICALS - US6093734, 2000, A

35
[ 73590-58-6 ]
[ 109-89-7 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
76%	With MgCl₂ In methanol; water	5 Preparation of 5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, magnesium salt. Example 5 Preparation of 5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, magnesium salt. 5-Methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (1.0 g, 2.9 mmol) together with diethylamine (0.35 ml, 3.4 mmol) were added to methanol (9 ml). To the obtained mixture MgCl2 (142 mg, 1.5 mmol) in methanol (2 ml) was added at ambient temperature. Water (6.5 ml) was added dropwise. The obtained product was filtered off and was washed with a mixture of MeOH/water (20 ml, 1:1). Yield: 76%. (Mg content: 3.38; calculated theoretically: 3.41)

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - US6124464, 2000, A

36
[ 73590-58-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
71%	With aqueous NH₃; magnesium sulfate In methanol; water	1 Preparation of 5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, magnesium salt. Example 1 Preparation of 5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, magnesium salt. 5-Methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (31.6 kg, 91.6 mol) together with aqueous NH3 (7.4 kg, 107 mol) was added to methanol (212 l). To the obtained mixture MgSO4 *7 H2 O (17.6 kg, 69.9 mol) was added at ambient temperature. After the reaction was completed inorganic salts were removed by means of filtration. Water was added to the filtrate, the mixture was clarified and water (91 l) was added. The mixture was kept for stirring in order to crystallize the product. The obtained product was centrifuged and was washed with a mixture of MeOH/water. The product was dried at reduced pressure at 40° C. Yield: 71%. (Mg content: found 3.47%, Theoretically calculated 3.41%)

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - US6124464, 2000, A

37
[ 73590-58-6 ]
[ 75-31-0 ]
5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, magnesium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With magnesium sulfate; In methanol; water;	Example 2 Preparation of 5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, magnesium salt. 5-Methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (25 g, 72.4 mmol) together with isopropylamine (7.4 ml, 86.9 mmol) was added to methanol (100 ml). To the obtained mixture MgSO4 *7 H2 O (8.85 g, 35.9 mmol) was added at ambient temperature. After the reaction was completed inorganic salts were removed by means of filtration. Water was added to the filtrate, the mixture was clarified and water (100 ml) was added dropwise. The product was filtered off and was washed with a mixture of MeOH/water (50 ml, 1:1). The product was dried at reduced pressure overnight. Yield: 95%. (Mg-content: 3.41; calculated theoretically 3.41).
92%	In methanol; water;	Example 3 Preparation of 5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, magnesium salt. 5-Methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (25 g, 72.4 mmol) together with isopropylamine (7.4 ml, 86.9 mmol) was added to methanol (100 ml). To the obtained mixture Mg(OAc)2 *4 H2 O (9.34 g, 43.6 mmol) was added at ambient temperature. After the radiation was completed inorganic salts were removed by means of filtration. Water was added to the filtrate, the mixture was clarified and water (100 ml) was added dropwise. The obtained product was filtered off and was washed with a mixture of MeOH/water (50 ml, 1:1). The product was dried at reduced pressure overnight. Yield: 92%. (Mg content: 3.42; calculated theoretically: 3.41)

Reference： [1]Patent: US6124464,2000,A
[2]Patent: US6124464,2000,A

38
[ CAS Unavailable ]
[ 73590-58-6 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
89%	In methanol; water	4 Preparation of 5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, magnesium salt. Example 4 Preparation of 5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, magnesium salt. 5-Methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (25 g, 72.4 mmol) together with isopropylamine (7.4 ml, 86.9 mmol) was added to methanol (100 ml). To the mixture Mg(NO3)2 *6 H2 O (11.2 g, 43.7 mmol) was added at ambient temperature. After the reaction was completed inorganic salts were removed by means of filtration. Water was added to the filtrate, the mixture was filtered and the filter cake was washed with methanol (10 ml). Water (100 ml) was added dropwise to the combined organic layers. The product was filtered off and was washed with a mixture of MeOH/water (50 ml, 1:1). The product was dried overnight. Yield: 89%. (Mg content: 3.39; calculated theoretically: 3.41))

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - US6124464, 2000, A

39
[ 18531-99-2 ]
[ 73590-58-6 ]
S-omeprazole*(S)-[1.1'-binaphthalen]-2.2'-diol inclusion complex [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine; In n-heptane; toluene; at 70℃; for 0.5h;Product distribution / selectivity;	10.0 g of <strong>[73590-58-6]omeprazole</strong> (29.0 mmol) and 12.4 g of (S)-(-)-[1 ,1'-binaphthalen]- 2,2'-diol (43.4 mmol) were suspended in 96 ml of toluene, 24 ml of heptane and 2 ml of triethylamine. It was heated at 70 0C for 30 min. It was cooled at 0-5 0C, the suspending solid was filtered and dried in vacuo at 40 0C. S-<strong>[73590-58-6]omeprazole</strong>*(S)-[1 ,1'-binaphthalen]-2,2'-diol inclusion complex with 1 :1 stoichiometric ratio was obtained with a 94% yield (corrected by HPLC) and a 97% e.e. (according to HPLC). 1 H-RMN (400 MHz, CDCI3): delta 11.9 (1 H, wide signal), 7.96 (1 H, s), 7.86 (2H, d, J=8.9 Hz), 7.82 (2H, d, J=8.0 Hz), 7.51 (1 H, wide signal), 7.32 (4H, m), 7.25 (2H, t, J=8.0 Hz), 7.14 (2H, d, J=8.3 Hz), 6.89 (1 H, d, J=8.5 Hz), 6.79 (1 H, wide signal), 4.70 (1 H, d, J=13.6 Hz), 4.63 (1 H, d, J=13.6 Hz), 3.80 (3H, s), 3.67 (3H, s), 2.17 (6H, s).
89%	With triethylamine; In toluene; at 70℃; for 0.5h;Product distribution / selectivity;	10.0 g of <strong>[73590-58-6]omeprazole</strong> (29.0 mmol) and 12.4 g of (S)-(-)-[1 ,1'-Binaphthalen]- 2,2'-diol (43.4 mmol) were suspended in 80 ml of toluene and 2 ml of triethylamine. It was heated at 70 0C for 30 min. It was cooled at 0-5 0C, the suspending solid was filtered and dried in vacuo at 40 0C. S-<strong>[73590-58-6]omeprazole</strong>*(S)- [1 ,1'-Binaphthalen]-2,2'-diol inclusion complex with 1 :1 stoichiometric ratio was obtained with a 89% yield corrected by HPLC and a 97% e.e. according to HPLC. 1H-RMN (400 MHz, CDCI3): delta 11.9 (1 H, wide signal), 7.96 (1 H, s), 7.86 (2H, d, J=8.9 Hz), 7.82 (2H, d, J=8.0 Hz), 7.51 (1 H, wide signal), 7.32 (4H, m), 7.25 (2H, t, J=8.0 Hz), 7.14 (2H, d, J=8.3 Hz), 6.89 (1 H, d, J=8.5 Hz), 6.79 (1 H, wide signal), 4.70 (1 H, d, J=13.6 Hz), 4.63 (1 H, d, J=13.6 Hz), 3.80 (3H, s), 3.67 (3H, s), 2.17 (6H, s).
89%	With ammonia; In water; isopropyl alcohol; at 50 - 60℃;Product distribution / selectivity;	99.6 g of (S)-(-)-binol (0.35 mol) was dissolved in a mixture of 1200 ml of isopropanol and 200 ml of water at 60 C , and 10 ml of 28% ammonia (0.15 mol) and 200.0 g of the racemic form of <strong>[73590-58-6]omeprazole</strong> (0.58 mol) were added thereto while maintaining the temperature at 50-55 C . 600 ml of water was slowly added to the resulting solution and after the complete dissolution of the contents was achieved, 0.2 g of the inclusion complex of es<strong>[73590-58-6]omeprazole</strong> and (S)-(- )-binol was added as a seed thereto. The resulting solution was slowly cooled to room temperature and stirred for 6 hrs, and further cooled to 5-10 C and stirred for 4 hrs. The precipitated solids were filtered, washed sequentially with a mixture of 160 ml of isopropanol and 40 ml of water and with 200 ml of n-hexane, and dried at 40 C to obtain 163.1 g of the white-yellow title compound (yield: 89%). The proton nuclear magnetic resonance (1H-NMR) and infrared ray (IR) spectra of the product were identical to those obtained in Example 1. Mp.: 157-159 C .Specific linear luminosity: [alpha]D 20 = -145.9 (c=1, THF).Optical purity: 96.8% ee (chiral HPLC).

89%	With ethylamine; In ethanol; water; at 20 - 55℃;Product distribution / selectivity;	Examples 3 to 14The procedure of Example 1 or 2 was repeated employing 50.0 g of the racemic form of <strong>[73590-58-6]omeprazole</strong> (144.8 mmol), 500 ml of a reaction solvent and the other specifics shown in Table I5 to obtain various compounds, whose yields and optical purities are listed in Table 1.Table 1
87.3%	With phenol; In toluene; at 20 - 30℃;seeded with esomeprazole-BINOL;Product distribution / selectivity;	EXAMPLE 2Preparation of Es<strong>[73590-58-6]omeprazole</strong>-BINOL Inclusion ComplexBINOL (6.22 g; 21.72 mmol) and phenol (4.09 g; 43.46 mmol) were added to toluene (70 ml) at 20-30 C. Omeprazole (10 g; 28.95 mmol) was added to the reaction mixture and seeded with es<strong>[73590-58-6]omeprazole</strong>-BINOL inclusion complex. Thereafter, the reaction mass was stirred for 2 h to crystallize the product. Then, hexane (35 ml) was added to the reaction mass and stirred for 15 h at 20-30 C. for complete crystallization of title compound, which was filtered, washed with toluene-hexane mixture and dried to obtain white solid of es<strong>[73590-58-6]omeprazole</strong>-BINOL inclusion complex.
86%	With ammonia; In water; acetone; at 50 - 60℃;Product distribution / selectivity;	Examples 3 to 14The procedure of Example 1 or 2 was repeated employing 50.0 g of the racemic form of <strong>[73590-58-6]omeprazole</strong> (144.8 mmol), 500 ml of a reaction solvent and the other specifics shown in Table I5 to obtain various compounds, whose yields and optical purities are listed in Table 1.Table 1
85%	With triethylamine; In ethanol; water; at 20 - 60℃; for 12h;Product distribution / selectivity;	25.0 g of (S)-(-)-binol (87.3 mmol) was dissolved in a mixture of 400 ml of ethanol and 100 ml of water at 60 C, and 5.0 ml of triethylamine (35.9 mmol) and 50.0 g of the racemic form of <strong>[73590-58-6]omeprazole</strong> (144.8 mmol) were dissolved thereto while maintaining the temperature at 50-55 C . Then, the resulting solution was slowly cooled to room temperature and stirred at that temperature for 12 hrs. The precipitated solids were filtered, washed sequentially with a mixture of 85 ml of ethanol and 15 ml of water and with 100 ml of n-hexane, and dried at 40 C to obtain 38.9 g of the white-yellow title compound (yield: 85%). M.p.: 158-160 C .Specific linear luminosity: [alpha]D20 = -146.2 (c=1, THF).Optical purity: 98.7% ee (chiral HPLC).1H-NMR (CDCl3, ppm): delta 2.24 (s, 6H), 3.73 (s, 3H), 3.87 (s, 3H), 4.65 (d, 1H), 4.78 (d, 2H), 5.50 (br. s, 2H), 6.96 (br. s, 2H), 7.18 (d, 2H), 7.40-7.28 (m, 8H), 7.70 (br. s, 1H), 7.90 (d, 2H), 7.98 (d, 2H), 8.16 (s, 1H), 11.60 (bs, 1H).IR (KBr, cm-1): 3057, 1619, 1595, 1576, 1471, 1462, 1401, 1380, 1271, 1205, 1146, 1073, 1028, 815, 570, 506, 422.
85%	With ammonia; In water; butan-1-ol; at 50 - 60℃;Product distribution / selectivity;	Examples 3 to 14The procedure of Example 1 or 2 was repeated employing 50.0 g of the racemic form of <strong>[73590-58-6]omeprazole</strong> (144.8 mmol), 500 ml of a reaction solvent and the other specifics shown in Table I5 to obtain various compounds, whose yields and optical purities are listed in Table 1.Table 1
85%	In cyclohexane; toluene; at 0 - 55℃; for 1.5 - 1.75h;	EXAMPLE 1; Preparation of (S)-<strong>[73590-58-6]omeprazole</strong>-(S)-(-)-BINOL complex; Omeprazole (100 g, 0.2898 mole) was added to a mixture of toluene (1600 ml) and cyclohexane (400 ml) in a round bottom flask kept at 25-30 0C. (S)-(-)-BINOL (124.3 g, 0.4346 mole) was added and the content warmed to about 50-55 0C with stirring for 30-45 minutes. The content of the flask was allowed to attain the ambient temperature and then cooled to 0-5 0C with Stirling for about an hour. The (S)-<strong>[73590-58-6]omeprazole</strong>-(S)-(-)-BINOL complex crystallizes out, filtered and washed with a mixture of cyclohexane/toluene (1 :4, v/v) pre-cooled to 0-5 0C. The (S)-<strong>[73590-58-6]omeprazole</strong>-(S)-(-)-BINOL complex was dried at 35- 40 0C under reduced pressure. The e.e. of (S)-<strong>[73590-58-6]omeprazole</strong> in the complex was found to be99.5%. Yield: 85 %.The IR spectrum of the complex is given in Fig. 3. The powder X-ray diffraction pattern is given in Fig. 4
83%	With ammonia; In methanol; water; at 50 - 60℃;Product distribution / selectivity;	Examples 3 to 14The procedure of Example 1 or 2 was repeated employing 50.0 g of the racemic form of <strong>[73590-58-6]omeprazole</strong> (144.8 mmol), 500 ml of a reaction solvent and the other specifics shown in Table I5 to obtain various compounds, whose yields and optical purities are listed in Table 1.Table 1
81%	With ammonia; In water; acetonitrile; at 50 - 60℃;Product distribution / selectivity;	Examples 3 to 14The procedure of Example 1 or 2 was repeated employing 50.0 g of the racemic form of <strong>[73590-58-6]omeprazole</strong> (144.8 mmol), 500 ml of a reaction solvent and the other specifics shown in Table I5 to obtain various compounds, whose yields and optical purities are listed in Table 1.Table 1
80 - 92%	With ammonia; In ethanol; water; at 50 - 60℃;Product distribution / selectivity;	Examples 3 to 14The procedure of Example 1 or 2 was repeated employing 50.0 g of the racemic form of <strong>[73590-58-6]omeprazole</strong> (144.8 mmol), 500 ml of a reaction solvent and the other specifics shown in Table I5 to obtain various compounds, whose yields and optical purities are listed in Table 1.Table 1
40%	With ammonia; In 1,4-dioxane; water; at 50 - 60℃;Product distribution / selectivity;	Examples 3 to 14The procedure of Example 1 or 2 was repeated employing 50.0 g of the racemic form of <strong>[73590-58-6]omeprazole</strong> (144.8 mmol), 500 ml of a reaction solvent and the other specifics shown in Table I5 to obtain various compounds, whose yields and optical purities are listed in Table 1.Table 1
25%	In n-heptane; toluene; at 85℃; for 0.5h;Product distribution / selectivity;	20.0 g of <strong>[73590-58-6]omeprazole</strong> (57.9 mmol) and 25.0 g of (S)-(-)-[1 ,1'-binaphthalen]- 2,2'-diol (86.8 mmol) were suspended in 600 ml of toluene and 150 ml of heptane. It was heated at 85 0C for 30 min. It was cooled at 0-5 0C, the suspending solid was filtered and dried in vacuo at 40 0C. S-<strong>[73590-58-6]omeprazole</strong>*(S)- [1 ,1'-Binaphthalen]-2,2'-diol inclusion complex with 1 :1 stoichiometric ratio was obtained with a 25% yield corrected by HPLC and a 94% e.e. according to HPLC.
	In hexane; benzene; at 0 - 110℃; for 12h;Product distribution / selectivity;	Preparation of inclusion complex of es<strong>[73590-58-6]omeprazole</strong> and (S)-(-)-binol (formula (I)) in accordance with the method disclosed in [J. Deng et al., Tetrahedron: Asymmetry, 11, 1729-1732, 2000] and [H. Cotton et al., Tetrahedron: Asymmetry, 11, 3819-3825, 2000](S)-(-)-binol and 10.0 g of the racemic form of <strong>[73590-58-6]omeprazole</strong> were dissolved in a mixture of 288 ml of benzene and 72 ml of n-hexane at 110 C . The (S)-(-)-binol was used in the amount of 0.6 mole equivalents based on <strong>[73590-58-6]omeprazole</strong>. Then, the resulting solution was slowly cooled to 0 C and stirred for 12 hrs. The precipitated solids were filtered, and washed with a mixture of benzene and hexane to obtain the title compound.Color of the product: yellow.Optical purity: 20.0 %ee (chiral HPLC).
94%Chromat.	With triethylamine; In n-heptane; toluene; at 70℃; for 0.5h;Product distribution / selectivity;	Example 1 Preparation of the S-<strong>[73590-58-6]omeprazole</strong>.(S)-[1,1'-binaphthalen]-2,2'-diol inclusion complex in toluene/heptane with triethylamine 10.0 g of <strong>[73590-58-6]omeprazole</strong> (29.0 mmol) and 12.4 g of (S)-(-)-[1,1'-binaphthalen]-2,2'-diol (43.4 mmol) were suspended in 96 ml of toluene, 24 ml of heptane and 2 ml of triethylamine. It was heated at 70 C. for 30 min. It was cooled at 0-5 C., the suspending solid was filtered and dried in vacuo at 40 C. S-<strong>[73590-58-6]omeprazole</strong>.(S)-[1,1'-binaphthalen]-2,2'-diol inclusion complex with 1:1 stoichiometric ratio was obtained with a 94% yield (corrected by HPLC) and a 97% e.e. (according to HPLC). 1H-RMN (400 MHz, CDCl3): delta 11.9 (1H, wide signal), 7.96 (1H, s), 7.86 (2H, d, J=8.9 Hz), 7.82 (2H, d, J=8.0 Hz), 7.51 (1H, wide signal), 7.32 (4H, m), 7.25 (2H, t, J=8.0 Hz), 7.14 (2H, d, J=8.3 Hz), 6.89 (1H, d, J=8.5 Hz), 6.79 (1H, wide signal), 4.70 (1H, d, J=13.6 Hz), 4.63 (1H, d, J=13.6 Hz), 3.80 (3H, s), 3.67 (3H, s), 2.17 (6H, s).
89%Chromat.	With triethylamine; In toluene; at 70℃; for 0.5h;Product distribution / selectivity;	Example 2Preparation of the Inclusion Complex S-<strong>[73590-58-6]omeprazole</strong>.(S)-[1,1-Binaphthalen]-2,2'-diol in toluene with triethylamine10.0 g of <strong>[73590-58-6]omeprazole</strong> (29.0 mmol) and 12.4 g of (S)-(-)-[1,1'-Binaphthalen]-2,2'-diol (43.4 mmol) were suspended in 80 ml of toluene and 2 ml of triethylamine. It was heated at 70 C. for 30 min. It was cooled at 0-5 C., the suspending solid was filtered and dried in vacuo at 40 C. S-<strong>[73590-58-6]omeprazole</strong>.(S)-[1,1'-Binaphthalen]-2,2'-diol inclusion complex with 1:1 stoichiometric ratio was obtained with a 89% yield corrected by HPLC and a 97% e.e. according to HPLC. 1H-RMN (400 MHz, CDCl3): delta 11.9 (1H, wide signal), 7.96 (1H, s), 7.86 (2H, d, J=8.9 Hz), 7.82 (2H, d, J=8.0 Hz), 7.51 (1H, wide signal), 7.32 (4H, m), 7.25 (2H, t, J=8.0 Hz), 7.14 (2H, d, J=8.3 Hz), 6.89 (1H, d, J=8.5 Hz), 6.79 (1H, wide signal), 4.70 (1H, d, J=13.6 Hz), 4.63 (1H, d, J=13.6 Hz), 3.80 (3H, s), 3.67 (3H, s), 2.17 (6H, s).
25%Chromat.	In n-heptane; toluene; at 85℃; for 0.5h;Product distribution / selectivity;	Comparative Example 2Preparation of the inclusion complex S-<strong>[73590-58-6]omeprazole</strong>.(S)-[1,1'-binaphthalen]-2,2'-diol in toluene/heptane without amine20.0 g of <strong>[73590-58-6]omeprazole</strong> (57.9 mmol) and 25.0 g of (S)-(-)-[1,1'-binaphthalen]-2,2'-diol (86.8 mmol) were suspended in 600 ml of toluene and 150 ml of heptane. It was heated at 85 C. for 30 min. It was cooled at 0-5 C., the suspending solid was filtered and dried in vacuo at 40 C. S-<strong>[73590-58-6]omeprazole</strong>.(S)-[1,1'-Binaphthalen]-2,2'-diol inclusion complex with 1:1 stoichiometric ratio was obtained with a 25% yield corrected by HPLC and a 94% e.e. according to HPLC.
	In dichloromethane; toluene; at 20℃; for 4.25h;	Preparation of es<strong>[73590-58-6]omeprazole</strong>-S-BINOLS-l ,l '-bi-2-naphthol (364.5 gm) was added to a solution of <strong>[73590-58-6]omeprazole</strong> (405 gm) as obtained in example 1 in methylene chloride (1000 ml) at room temperature and stirred for 15 minutes. To the reaction mixture was added toluene (6000 ml) and maintained for 4 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 310 gm of es<strong>[73590-58-6]omeprazole</strong>-S-BINOL.

Reference： [1]Patent: WO2006/94904,2006,A1 .Location in patent: Page/Page column 9
[2]Patent: WO2006/94904,2006,A1 .Location in patent: Page/Page column 10
[3]Patent: WO2007/13743,2007,A1 .Location in patent: Page 8
[4]Patent: WO2007/13743,2007,A1 .Location in patent: Page 8
[5]Patent: US2010/125142,2010,A1 .Location in patent: Page/Page column 3
[6]Patent: WO2007/13743,2007,A1 .Location in patent: Page 8
[7]Patent: WO2007/13743,2007,A1 .Location in patent: Page 7
[8]Patent: WO2007/13743,2007,A1 .Location in patent: Page 8
[9]Patent: WO2008/4245,2008,A1 .Location in patent: Page/Page column 15-16
[10]Patent: WO2007/13743,2007,A1 .Location in patent: Page 8
[11]Patent: WO2007/13743,2007,A1 .Location in patent: Page 8
[12]Patent: WO2007/13743,2007,A1 .Location in patent: Page 8
[13]Patent: WO2007/13743,2007,A1 .Location in patent: Page 8
[14]Patent: WO2006/94904,2006,A1 .Location in patent: Page/Page column 9-10
[15]Patent: WO2007/13743,2007,A1 .Location in patent: Page 13
[16]Patent: US2008/167473,2008,A1 .Location in patent: Page/Page column 3
[17]Patent: US2008/167473,2008,A1 .Location in patent: Page/Page column 4
[18]Patent: US2008/167473,2008,A1 .Location in patent: Page/Page column 3-4
[19]Patent: WO2012/104863,2012,A2 .Location in patent: Page/Page column 5-6

40
[ 85-44-9 ]
5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridinyl)methylthio]-1H-benzimidazole hydrochloride [ No CAS ]
[ 73590-58-6 ]

Yield	Reaction Conditions	Operation in experiment
85.90%	With sodium hydroxide; dihydrogen peroxide; sodium carbonate; In water; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran;	Example 10 Omeprazole from 5-Methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridinyl)methylthio]-1H-benzimidazole Hydrochloride Sodium hydroxide solution (5%, 100 ml) was added to a suspension of 36.50 gm of 5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridinyl)methylthio]-1H-benzimidazole hydrochloride (X) in DCM (200 ml) and stirred for 10 mins. The DCM (dichloromethane) layer was separated and to it was added phthalic anhydride (20 gm, 0.135 mole). The reaction mixture was cooled and to it was added sodium carbonate (18 gm) and water 20 ml. Hydrogen peroxide (45%, 12 ml) was added dropwise at -5 to 0 C. when the reaction was complete it was worked-up as in Example-9 to yield 29.4 gm of Omeprazole. Yield 85.90%.

Reference： [1]Patent: US6245913,2001,B1

41
[ 108998-83-0 ]
[ 73590-58-6 ]
(S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole [(S)-1,1,2-triphenyl-1,2-ethanediol]2 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	In n-heptane; toluene; at 20 - 100℃; for 1h;Product distribution / selectivity;	Example 1; : Preparation of (S)-omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol] in toluene/heptaneA mixture of omeprazole (5 g, 14.5 mmol) and (S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol (6.30 g, 21.7 mmol) was dissolved in a minimum of a toluene/heptane mixture (0.84:0.16, 190 ml) at 100 0C. On dissolution, the solution was cooled to ambient temperature slowly with vigorous stirring, and on reaching this temperature was stirred for a further 1 h. The precipitate was filtered, was washed with a toluene/heptane mixture (3:1 , 2 x 50 ml) and was dried in vacuo to afford (S)-omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2-ethanediol] inclusion complex (6.108 g, 91 %, 96.3% e.e.) as an off-white powder.
90%	In ethanol; at 20℃; for 30h;Product distribution / selectivity;	Example 9; : Preparation of (S)-omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol] in ethanolA suspension of omeprazole (20 g, 57.9 mmol) and (S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol (25.2 g, 86.9 mmol) in ethanol (700 ml) at ambient temperature was stirred for 30 h. The solid was filtered, was washed with ethanol (2 x 150 ml) and was dried in vacuo to afford (S)-omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol] (24.1 g, 90%, 95.5% e.e.) as a white powder.
87 - 96%	In toluene; at 20 - 90℃; for 1 - 18h;Product distribution / selectivity;	Example 2:; Preparation of (S)-omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol] in tolueneA mixture of omeprazole (250 mg, 0.72 mmol) and (S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol (315 mg, 1.08 mmol) was dissolved in a minimum volume of toluene (11 ml) at 90 0C. On dissolution, the solution was cooled to ambient temperature slowly with vigorous stirring, and on reaching this temperature was stirred for a further 1 h. The precipitate was filtered, was washed with toluene (2 x 3 ml) and was dried in vacuo to afford (S)-omeprazole»2[(S)- 1 ,1 ,2-triphenyl-1 ,2-ethanediol] inclusion complex (291 mg, 87%, 95% e.e.) as an off-white powder.; Example 8: Preparation of (S)-omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol]: recycling of (S)-1 ,1 ,2-triphenyl-1 ,2-ethanediolA mixture of omeprazole (500 mg, 1.45 mmol) and (S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol (630 mg, 2.17 mmol, 99.3% e.e. recovered according to Example 24) was dissolved in a minimum volume of toluene (18 ml) at 90 0C. On dissolution, the solution was cooled to ambient temperature slowly with vigorous stirring, and on reaching this temperature was stirred for a further 1 h. The precipitate was filtered, was washed with toluene (2 x 5 ml) and was dried in vacuo to afford (S)-omeprazole»2[(S)-1 , 1 ,2-triphenyl-1 ,2-ethanediol] inclusion complex (627 mg, 94%, 93.7% e.e.) as an off-white powder.Example 12: Preparation of (S)-omeprazole»2[(S)-1 , 1 ,2-triphenyl-1 ,2- ethanediol] in tolueneA suspension of omeprazole (250 mg, 0.72 mmol) and (S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol (315 mg, 1.09 mmol) in toluene (8.8 ml) at ambient temperature was stirred for 18 h. The solid was filtered, was washed with toluene (2 x 2 ml) and was dried in vacuo to afford (S)-omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol] (320 mg, 96%, 94.6% e.e.) as a white powder.

76%	In 4-methyl-2-pentanone; at 20 - 90℃; for 1h;Product distribution / selectivity;	Example 4:; Preparation of (S)-omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol] in methyl isobutyl ketoneA mixture of omeprazole (250 mg, 0.72 mmol) and (S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol (315 mg, 1.08 mmol) was dissolved in a minimum volume of methyl isobutyl ketone (8 ml) at 90 0C. On dissolution, the solution was cooled to ambient temperature slowly with vigorous stirring, and on reaching this temperature was stirred for a further 1 h. The precipitate was filtered, was washed with methyl isobutyl ketone (2 x 2 ml) and was dried in vacuo to afford (S)-omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2-ethanediol] inclusion complex (253 mg, 76%, 94% e.e.) as an off-white powder.
72%	In isopropyl alcohol; at 20℃; for 1h;Heating / reflux;Product distribution / selectivity;	Example 3: Preparation of (S)-omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol] in isopropyl alcoholA mixture of omeprazole (250 mg, 0.72 mmol) and (S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol (315 mg, 1.08 mmol) was dissolved in a minimum volume of isopropyl alcohol (10 ml) at reflux temperature. On dissolution, the solution was cooled to ambient temperature slowly with vigorous stirring, and on reaching this temperature was stirred for a further 1 h. The precipitate was filtered, was washed with isopropyl alcohol (2 x 2 ml) and was dried in vacuo <n="11"/>to afford (S)-omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2-ethanediol] inclusion complex (240 mg, 72%, 97% e.e.) as an off-white powder.
71%	In acetonitrile; at 20℃; for 1h;Heating / reflux;Product distribution / selectivity;	Example 6: Preparation of (S)-omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol] in acetonitrileA mixture of omeprazole (250 mg, 0.72 mmol) and (S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol (315 mg, 1.08 mmol) was dissolved in a minimum volume of acetonitrile (4 ml) at reflux temperature. On dissolution, the solution was cooled to ambient temperature slowly with vigorous stirring, and on reaching this temperature was stirred for a further 1 h. The precipitate was filtered, was washed with acetonitrile (2 x 2 ml) and was dried in vacuo to afford (S)- <n="12"/>omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2-ethanediol] inclusion complex (239 mg, 71 %, 95% e.e.) as an off-white powder.
64 - 79%	In methoxybenzene; at 20 - 90℃; for 1 - 72h;Product distribution / selectivity;	Example 5: Preparation of (S)-omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol] in anisole.A mixture of omeprazole (250 mg, 0.72 mmol) and (S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol (315 mg, 1.08 mmol) was dissolved in a minimum volume of anisole (4 ml) at 90 0C. On dissolution, the solution was cooled to ambient temperature slowly with vigorous stirring, and on reaching this temperature was stirred for a further 1 h. The precipitate was filtered, was washed with anisole (2 x 2 ml) and was dried in vacuo to afford (S)-omeprazole»2[(S)- 1 ,1 ,2-triphenyl-1 ,2-ethanediol] inclusion complex (215 mg, 64%, 96% e.e.) as an off-white powder.Example 10: Preparation of (S)-omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol] in anisoleA suspension of omeprazole (250 mg, 0.72 mmol) and (S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol (315 mg, 1.09 mmol) in anisole (8.8 ml) at ambient temperature was stirred for 72 h. The solid was filtered, was washed with anisole (2 x 2 ml) and was dried in vacuo to afford (S)-omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol] (265 mg, 79%, 96.6% e.e.) as a white powder.
42%	In chloroform; at 20℃; for 1h;Heating / reflux;Product distribution / selectivity;	Example 7: Preparation of (S)-omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol] in chloroform.A mixture of omeprazole (250 mg, 0.72 mmol) and (S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol (315 mg, 1.08 mmol) was dissolved in a minimum volume of chloroform (4 ml) at reflux temperature. On dissolution, the solution was cooled to ambient temperature slowly with vigorous stirring, and on reaching this temperature was stirred for a further 1 h. The precipitate was filtered, was washed with chloroform (2 x 2 ml) and was dried in vacuo to afford (S)- omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2-ethanediol] inclusion complex (141 mg, 42%, 94% e.e.) as an off-white powder.

Reference： [1]Patent: WO2007/74099,2007,A1 .Location in patent: Page/Page column 9
[2]Patent: WO2007/74099,2007,A1 .Location in patent: Page/Page column 11
[3]Patent: WO2007/74099,2007,A1 .Location in patent: Page/Page column 9; 11; 12
[4]Organic Process Research and Development,2013,vol. 17,p. 946 - 950
[5]Patent: WO2007/74099,2007,A1 .Location in patent: Page/Page column 10
[6]Patent: WO2007/74099,2007,A1 .Location in patent: Page/Page column 9-10
[7]Patent: WO2007/74099,2007,A1 .Location in patent: Page/Page column 10-11
[8]Patent: WO2007/74099,2007,A1 .Location in patent: Page/Page column 10; 12
[9]Patent: WO2007/74099,2007,A1 .Location in patent: Page/Page column 11

42
[ 108998-83-0 ]
[ 73590-58-6 ]
(R)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole [(S)-1,1,2-triphenyl-1,2-ethanediol]2 [ No CAS ]
(S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole [(S)-1,1,2-triphenyl-1,2-ethanediol]2 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In 4-methyl-2-pentanone; at 20℃; for 72h;Product distribution / selectivity;	Example 11 : Preparation of (S)-omeprazole»2[(S)-1 , 1 ,2-triphenyl-1 ,2- ethanediol] in methyl isobutyl ketoneA suspension of omeprazole (250 mg, 0.72 mmol) and (S)-1 ,1 ,2-triphenyl-1 ,2- ethanediol (315 mg, 1.09 mmol) in methyl isobutyl ketone (8.8 ml) at ambient temperature was stirred for 72 h. The solid was filtered, was washed with methyl isobutyl ketone (2 x 2 ml) and was dried in vacuo to afford (S)- omeprazole»2[(S)-1 ,1 ,2-triphenyl-1 ,2-ethanediol] (286 mg, 69.1% e.e.) as a white powder.

Reference： [1]Patent: WO2007/74099,2007,A1 .Location in patent: Page/Page column 12

43
[ 1080503-61-2 ]
[ 109371-19-9 ]
[ 73590-58-6 ]

Yield	Reaction Conditions	Operation in experiment
86%		Example 9.- Preparation of omeprazole, compound of general formula (II) wherein R 2 is 5-methoxy, R4 and R 6 are methyl, and R5 is methoxy; [Show Image] 1.0 g (6.61 mmol) of 4-methoxy-2,3,5-trimethylpiridine were dissolved in 10 ml of anhydrous tetrahydrofuran at room temperature under inert atmosphere, and the solution obtained was cooled to below -90 C. 4-methoxy-2,3,5-trimethylpiridine may be prepared in accordance with the process described in EP-A-0005129. Thereafter, 2.6 ml (6.5 mmol) of a 2.5 M solution of n-butyl lithium was added dropwise and the temperature was maintained below - 80C. After 30 minutes at this temperature, the mixture was slowly added to a solution of 0.65 g (1.86 mmol) of (-)-menthyl 5-methoxy-2-benzimidazolylsulphinate, as prepared in Example 4, in 3.7 ml of tetrahydrofuran cooled below -80C as well. Once the addition was completed, the resulting mixture was allowed to stand up to -20 C, then 20 ml of water were slowly added and it was allowed to reach room temperature. The reaction mixture was analyzed by HPLC, and conversion and yield were found to be 99% and 86% respectively.

Reference： [1]Patent: EP1992619,2008,A1 .Location in patent: Page/Page column 15-16

44
[ 557-20-0 ]
[ 73590-58-6 ]
[ 912968-18-4 ]

Yield	Reaction Conditions	Operation in experiment
91%	In tetrahydrofuran; hexane; at 20℃;	Es<strong>[73590-58-6]omeprazole</strong> (1 g, 2.9 mmol) was dissolved in 10 ml tetrahydrofuran while stirring for 5 hours, and 2.9 ml diethyl zinc (1 M solution in hexane) were slowly added. The resulting mixture was stirred at ambient temperature overnight. 10 ml distilled water were added, and the precipitate formed was filtered off and washed with distilled water. 1 g (91%) of the title compound was obtained.

Reference： [1]Patent: US2008/319195,2008,A1 .Location in patent: Page/Page column 5

45
[ 32315-10-9 ]
[ 73590-58-6 ]
2-(methylamino)ethyl benzoate hydrochloride [ No CAS ]
2-[[[6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl] sulfinyl]-1H-benzoimidazol-1-yl]carbonyl](methyl)amino]ethyl benzoate [ No CAS ]
2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzoimidazol-1-yl]carbonyl](methyl)amino]ethyl benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution (10 mL) of bis (trichloromethyl) carbonate (0.344 g) in tetrahydrofuran was dropwise added a solution (5 mL) of pyridine (0.281 mL) in tetrahydrofuran under ice- cooling, and the mixture was stirred at [0C] for 30 min. 2- (Methylamino) ethyl benzoate hydrochloride (0.750 g), obtained in Reference Example 5 was added. A solution (5 mL) of triethylamine (0.485 mL) in tetrahydrofuran was added, and the mixture was stirred at 0C for 1 hr. and at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure and water (30 mL) was added to the residue. The mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil was dissolved in tetrahydrofuran (5 mL), added to a solution (10 mL) of 5- [METHOXY-2- [ [ (4-METHOXY-3,] 5-dimethyl-2- pyridyl) [METHYL] SULFINYL]-LH-BENZOIMIDAZOLE] (1.0 g), triethylamine (0.808 mL) and 4-dimethylaminopyridine (0.071 g) in tetrahydrofuran, and the mixture was stirred at [40C] for 18 hrs. The reaction mixture was concentrated under reduced pressure and water (30 mL) was added to the residue. The mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate: hexane=1 : 1, then ethyl acetate) to give a 1: 1 mixture (1.50 g) of the title compound and 2- [[ [ [6-METHOXY-2- [ [ (4-METHOXY-3,] 5-dimethyl-2- pyridyl) [METHYL] SULFINYL]-LH-BENZOIMIDAZOL-1-] yl] carbonyl] (methyl) amino] ethyl benzoate as a pale-yellow amorphous solid. [H-NMR] [(CDCL3)] : 2.05-2. 35 (6H, m), 3.00-3. 30 (3H, br), 3.60- 4.40 (8H, m), 4.60-5. 10 (4H, m), 6.80-7. 00 (2H, m), 7.20-7. 70 (4H, m), 7.95-8. 25 (3H, m).
		To a solution of bis(trichloromethyl) carbonate (0.344 g) in tetrahydrofuran (10 mL) was added dropwise a solution of pyridine (0.281 mL) in tetrahydrofuran (5 mL) under ice-cooling, and stirred for 30 minutes at 0C. To the reaction solution was added 2-(methylamino)ethyl benzoate hydrochloride (0.750 g) obtained in Reference Synthetic Example 5. A solution of triethylamine (0.485 mL) in tetrahydrofuran (5 mL) was added, and stirred at 0C for 1 hr, and further at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and to the residue was added water (30 mL), and then extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate, followed by concentrating under reduced pressure. The resulting oil was dissolved in tetrahydrofuran (5 mL), and the solution was added to a solution of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (1.0 g), triethylamine (0.808 mL) and 4-dimethylaminopyridine (0.071 g) in tetrahydrofuran (10 mL), and stirred at 40C for 18 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (30 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate, followed by concentrating under reduced pressure. The residue was purified with silica gel column chromatography (eluted with ethyl acetate : hexane = 1 : 1, then ethyl acetate) to give a mixture of 1 : 1 of title compound and 2-[[[6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl benzoate as pale yellow amorphous solid (1.50 g).1H-NMR (CDCl3): 2.05-2.35(6H,m), 3.00-3.30(3H,br), 3.60-4.40(8H,m), 4.60-5.10(4H,m), 6.80-7.00(2H,m), 7.20-7.70(4H,m), 7.95-8.25(3H,m).

Reference： [1]Patent: WO2003/105845,2003,A1 .Location in patent: Page 151-153
[2]Patent: EP1602362,2005,A1 .Location in patent: Page/Page column 92

46
[ 635750-86-6 ]
[ 32315-10-9 ]
[ 73590-58-6 ]
ethyl 2-[[[6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate [ No CAS ]
ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution (10 mL) of bis (trichloromethyl) carbonate (0.291 g) in tetrahydrofuran was dropwise added a solution (1 mL) of pyridine (0.243 mL) in tetrahydrofuran under ice- cooling. After stirring under ice-cooling for 1 hr. , ethyl 2- (methylamino) ethyl carbonate hydrochloride (0.551 g) obtained in Reference Example 14 was added. A solution (1 mL) of triethylamine (0.418 mL) in tetrahydrofuran was dropwise added, and the mixture was stirred at room temperature for 2 hrs. After concentration under reduced pressure, water (15 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL). 5-Methoxy-2- [[ [ (4-METHOXY-3,] 5-dimethyl-2-pyridyl) methyl] [SULFINYL]-LH-] benzimidazole (0.817 g), triethylamine (0.661 [ML)] and 4- dimethylaminopyridine (0.012 g) were added, and the mixture was stirred at 60C for 12 hrs. After concentration under reduced pressure, water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane=1 : 2, then 1: 1) to give a 3: 2 mixture (0.92 g) of the title compound and ethyl [2- [ [ [6-METHOXY-2- [ [ (4-METHOXY-] 3,5-dimethyl-2-pyridyl) [METHYL] SULFINYL]-LH-BENZIMIDAZOL-1-] [YL3CARBONYL]] (methyl) amino] ethyl carbonate as a pale-yellow amorphous solid. [H-NMR] [(CDCL3)] : 1.27-1. 34 (3H, m), 2.10-2. 30 (3H, m), 2.23 [(3H,] [S),] 2.99-3. 23 (3H, m), 3.40-3. 85 (2H, m), 3.69 (6/5H, s), 3.71 (9/5H, s), 3.86 (6/5H, s), 3.88 (9/5H, s), 4.14-4. 25 (2H, m), 4.38-4. 60 (2H, m), 4.82-5. 06 (2H, m), 6.92-7. 08 (7/5H, m), 7.33 (3/5H, d, J=9. [OHZ),] 7.66 (lH, m), 8.21 [(1H,] s).
		To a solution of bis(trichloromethyl) carbonate (0.291 g) in tetrahydrofuran (10 mL) was added dropwise a solution of pyridine (0.243 mL) in tetrahydrofuran (1 mL) under ice-cooling. The reaction solution was stirred for 1 hr under ice-cooling, and ethyl 2-(methylamino)ethyl carbonate hydrochloride (0.551 g) obtained in Reference Synthetic Example 14 was added thereto. A solution of triethylamine (0.418 mL) in tetrahydrofuran (1 mL) was added dropwise, and stirred at room temperature for 2 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (15 mL), and then extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL), and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). To the solution were added 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (0.817 g), triethylamine (0.661 mL) and 4-dimethylaminopyridine (0.012 g), and stirred at 60C for 12 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (20 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL), and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified with basic silica gel column chromatography (eluted with ethyl acetate : hexane = 1 : 2, then 1 : 1) to give a mixture of 3 : 2 of title compound and ethyl 2-[[[6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate as pale yellow amorphous solid (0.92 g).1H-NMR(CDCl3): 1.27-1.34(3H,m), 2.10-2.30(3H,m), 2.23(3H,s), 2.99-3.23(3H,m), 3.40-3.85(2H,m), 3.69 (6/5H, s), 3.71(9/5H, s), 3.86 (6/5H, s), 3.88 (9/5H,s), 4.14-4.25(2H,m), 4.38-4.60(2H,m), 4.82-5.06(2H,m), 6.92-7.08(7/5H,m), 7.33(3/5H,d,J=9.0Hz), 7.66(1H,m), 8.21 (1H,s).

Reference： [1]Patent: WO2003/105845,2003,A1 .Location in patent: Page 182-184
[2]Patent: EP1602362,2005,A1 .Location in patent: Page/Page column 115

47
[ 30761-89-8 ]
[ 32315-10-9 ]
[ 73590-58-6 ]
2-[[[6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](phenyl)amino]ethyl acetate [ No CAS ]
2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](phenyl)amino]ethyl acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution (10 mL) of bis (trichloromethyl) carbonate (0.291 g) in tetrahydrofuran was dropwise added a solution [(1] mL) of pyridine (0.243 mL) in tetrahydrofuran under ice- cooling. After stirring under ice-cooling for 30 min. , 2- anilinoethyl acetate hydrochloride (0.647 g) obtained in Reference Example 27 was added. A solution [(1] mL) of triethylamine (0.419 mL) in tetrahydrofuran was dropwise added, and the mixture was stirred at room temperature for 3 hrs. After concentration under reduced pressure, water (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL). 5-Methoxy-2- [[ [ (4-METHOXY-3,] 5-dimethyl-2-pyridyl) methyl] sulfinyl]-lH- benzimidazole (0.829 g), triethylamine (0.669 mL) and 4- dimethylaminopyridine (0.012 g) were added, and the mixture was stirred at [60C] for 14 hrs. After concentration under reduced pressure, water (40 mL) was added to the residue, and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate: hexane=1 : 2) to give a 1: 1 mixture (1.10 g) of the title compound and [2- [ [ [6-METHOXY-2- [ [ (4-METHOXY-3,] 5-dimethyl- 2-pyridyl) [METHYL] SULFINYL]-LH-BENZIMIDAZOL-1-] yl] carbonyl] (phenyl) amino] ethyl acetate as a colorless amorphous solid. H-NMR [(CDCL3)] : 1.99 (3H, s), 2.19 [(1.] 5H. s), 2.21 [(1.] 5H, s), 2.25 (3H, s), 3.70 [(1.] 5H, s), 3.71 (3H, s), 3.78 [(1.] 5H, s), 3.84 [(1.] 5H, s), 4.15-4. 56 (4H, m), 4.74-4. 80 [(LH,] m), 4.91- 4.98 (lH, m), 6.83-6. 91 [(1.] 5H, m), 7.04-7. 19 (3.5H, m), 7.25- 7.53 (2.5H, m), 7.51 (0.5H, d, J=8.7Hz), 8.25 [(LH,] s).
		To a solution of bis(trichloromethyl) carbonate (0.291 g) in tetrahydrofuran (10 mL) was added dropwise a solution of pyridine (0.243 mL) in tetrahydrofuran (1 mL) under ice-cooling. The reaction solution was stirred for 30 minutes under ice-cooling, and 2-anilinoethyl acetate hydrochloride (0.647 g) obtained in Reference Synthetic Example 27 was added thereto. A solution of triethylamine (0.419 mL) in tetrahydrofuran (1 mL) was added dropwise, and stirred at room temperature for 3 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (20 mL), and then extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL), and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). To the solution were added 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (0.829 g), triethylamine (0.669 mL) and 4-dimethylaminopyridine (0.012 g), and stirred at 60C for 14 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (40 mL), and extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with saturated brine (15 mL), and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified with basic silica gel column chromatography (eluted with ethyl acetate : hexane = 1 : 2) to give a mixture of 1 : 1 of title compound and 2-[[[6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](phenyl)amino]ethyl acetate as colorless amorphous solid (1.10 g).1H-NMR (CDCl3) : 1.99(3H,s), 2.19(1.5H.s), 2.21(1.5H,s), 2.25(3H,s), 3.70(1.5H,s), 3.71(3H,s), 3.78(1.5H,s), 3.84(1.5H,s), 4.15-4.56(4H,m), 4.74-4.80 (1H,m), 4.91-4.98 (1H,m), 6.83-6.91 (1.5H,m), 7.04-7.19(3.5H,m), 7.25-7.53(2.5H,m), 7.51(0.5H,d,J=8.7Hz), 8.25 (1H,s).

Reference： [1]Patent: WO2003/105845,2003,A1 .Location in patent: Page 185-186
[2]Patent: EP1602362,2005,A1 .Location in patent: Page/Page column 116

48
[ 73590-58-6 ]
5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole potassium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In methanol; ethylene glycol; at 20℃; for 3h;	Racemic <strong>[73590-58-6]omeprazole</strong> (1.01 g) is dissolved in a mixture of methanol and ethylene glycol (respectively 4 ml and 1 ml) in the presence of potassium hydroxide (180 mg, 1.1 molar equivalents). After stirring at ambient temperature for 3 hours, the solid is recovered by filtration on a Buechner funnel. The solid obtained corresponds to a mixture of phases between the methanol solvate and the ethylene glycol solvate of the potassium salt of racemic <strong>[73590-58-6]omeprazole</strong>. After drying, the methanol solvate becomes amorphous; the only phase observed by X-ray powder diffraction is the ethylene glycol solvate. The diffractogram (XRPD) is presented in FIG. 5.

Reference： [1]Patent: US2009/124811,2009,A1 .Location in patent: Page/Page column 12
[2]Organic Process Research and Development,2013,vol. 17,p. 946 - 950
[3]Organic Process Research and Development,2018,vol. 22,p. 321 - 327

49
[ 73590-58-6 ]
esomeprazole sodium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium hydroxide; In ethanol; for 2h;Reflux;	In an 100 mL three-necked flask, es<strong>[73590-58-6]omeprazole</strong> (8.3 g, 24 mmol) was added to 50 mL of absolute ethanol and dissolvedSodium hydroxide (1 g, 25 mmol) was added and stirred at reflux for 2 hours. Activated charcoal (0.3 g) was added and stirred for 30 minutesThe filtrate was evaporated under reduced pressure at 60 C to remove the solvent. The resulting oil was added with acetone (50 mL) and dissolved in the chamberTemperature, slow stirring crystallization 4 hours, pumping filter was es<strong>[73590-58-6]omeprazole</strong> sodium, product yield 70%.

Reference： [1]Patent: CN107011252,2017,A .Location in patent: Paragraph 0089; 0091
[2]Patent: US2011/213155,2011,A1

50
[ 73590-58-6 ]
[ 1227380-90-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: omeprazole With water In acetonitrile at 20 - 75℃; for 21h; Aqueous phosphate buffer; Stage #2: With sodium hydroxide In water	1 Examples; 1. Preparation of OMP-A; A reaction mixture, constituted of 20 g omeprazole, 2 I of 50 mM phosphate buffer, pH 3.6 and 2 I of acetonitrile, was prepared. The above mentioned reaction mixture was heated to 75 °C, stirred at that temperature for one hour and left at room temperature for the next 20 hours. The reaction mixture was then concentrated by evaporation under reduced pressure to approximately 1.5 I. The obtained solution was neutralized by addition of aqueous solution of sodium hydroxide to a pH between 7 and 8. The clear solution was decanted and further concentrated by evaporation under reduced pressure to approximately 1 I. OMP-A was isolated from the obtained solution by preparative HPLC. Chromatographic conditions of the preparative separation: Column: Luna 10µm prep C18(2) (200 x 50) mm Mobile phase A: 10 mM ammonium hydrogen carbonate Mobile phase B: Acetonitrile Flow rate: 140 ml/min Gradient: Sample load: 80 ml Detector: UV, 280 nm A fraction was collected from 3rd to 4th minute. The collected fraction was concentrated by evaporation at reduced pressure. The final product was dried in vacuum. 4.9g of the pure final product was obtained.

Reference： [1]Current Patent Assignee: Sandoz (in: Novartis); NOVARTIS AG - EP2189456, 2010, A1 Location in patent: Page/Page column 5

51
[ 73590-58-6 ]
[ 2413170-36-0 ]
[ 2413170-35-9 ]

Yield	Reaction Conditions	Operation in experiment
99 % ee	With sodium hydroxide In methanol at 0 - 25℃; for 15.5h; Resolution of racemate;	3 Example 3; The 5-Methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]1-H- benzimidazole (40 gm, esomeprazole: R-omeprazole = 1 1 :1) obtained as in example 1 was dissolved in methanol (80 ml) at 25°C and the solution was cooled to 10°C. Sodium hydroxide solution in methanol (10 gm in 120 ml methanol) was added slowly for 30 min. The contents were stirred for 3 hours at 5-10°C. The temperature was raised to 20-25°C for 10 hours and then cooled to O°C and stirred for 2 hours at 0-5°C. The solid obtained was collected by filtration and the solid was washed with chilled methanol (20 ml) and diisopropylether (100 ml) to obtain 26 gm of sodium salt of (S)-5-Methoxy-2- [(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]1-H-benzimidazole (Esomeprazole sodium) (Enantiomeric excess : 99%).

Reference： [1]Current Patent Assignee: HETERO DRUGS LIMITED - WO2010/58409, 2010, A2 Location in patent: Page/Page column 6-7

52
C₁₀H₁₂N₂O₃S [ No CAS ]
[ 84006-10-0 ]
C₁₈H₂₄N₂O₂ [ No CAS ]
[ 73590-58-6 ]

Yield	Reaction Conditions	Operation in experiment
30%	Stage #1: (chloromethyl)-4-methoxy-3,5-dimethylpyridine With [Mg(anthracene)(THF)3] In tetrahydrofuran at -5 - 0℃; Inert atmosphere; Stage #2: C₁₀H₁₂N₂O₃S In tetrahydrofuran at -5 - 30℃; for 4h; Inert atmosphere;

Reference： [1]Location in patent: experimental part Bhalerao, Dinesh S.; Kondaiah, Golla China Mala; Dwivedi, Namrata; Mylavarappu, Ravi Kumar; Reddy, Lekkala Amarnath; Roy, Arnab; Nagaraju, Gudimalla; Reddy, Padi Pratap; Bhattacharya, Apurba; Bandichhor, Rakeshwar [Synthetic Communications, 2010, vol. 40, # 20, p. 2983 - 2987]

53
[ CAS Unavailable ]
[ 73590-58-6 ]
[ 119141-88-7 ]

Yield	Reaction Conditions	Operation in experiment
91.67 % ee	Stage #1: Camphorsulfonyl chloride; omeprazole With N-ethyl-N,N-diisopropylamine In dichloromethane at 5 - 10℃; for 0.5h; Stage #2: With acetic acid In dichloromethane at 5 - 10℃; Stage #3: With ammonia In dichloromethane	1 Preparative Example 1 Racemate of 5-Methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]-1H-benzimidazole (100 gm) was dissolved in dichloromethane (1000 ml) and dimethyl amino pyridine (4 gm) at 25° C. and the solution was cooled to 0-5° C. N,N-diisopropylethylamine (85 ml) was added to the solution and cooled to 0-5° C. (S)-Camphor sulfonyl chloride (100 gm) dissolved in methylenechloride (150 ml) was added slowly for 30 minutes at 5-10° C. To the reaction mass, was added acetic acid (5 ml) at 5-10° C. The pH was adjusted to 6.5-7.0 with ammonia, and then ice-cooled water (500 ml) was added and stirred for 15 minutes at 25° C. The layers were separated. The organic layer was washed with 10% aqueous sodium chloride. The organic layer was distilled under reduced pressure to obtain a residue. The residue was stirred with ethanol (744 ml) for 20 hours at 25° C. The solid obtained was collected by filtration and the solid was washed with chilled ethanol (50 ml) and diisopropylether (200 ml) to obtain a diastereomeric mixture of 1-(S)-camphor sulfonyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(R/S)-sulfinyl]-1H-benzimidazole and 1-(S)-camphor sulfonyl-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(R/S)-sulfinyl]-1H-benzimidazole (120 gm, 13:7).The above solid (120 gm) was dissolved in tetrahydrofuran (1800 ml) at 25° C. for 30 minutes. Distilled off the solvent completely under vacuum and tetrahydrofuran (160 ml) was added. t-Butyl alcohol (160 ml) was slowly added to reaction mass for 15 minutes. Then the contents were stirred for 20 hours at 25° C. and cooled to 0-5° C. and stirred for 2 hours at 0-5° C. The solid obtained was collected by filtration and the solid was washed with chilled tetrahydrofuran and t-butyl alcohol mixture (20 ml, 1:1). Finally washed with diisopropylether (100 ml) to obtain a diastereomeric mixture of 1-(S)-camphor sulfonyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(R/S)-sulfinyl]-1H-benzimidazole and 1-(S)-camphor sulfonyl-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(R/S)-sulfinyl]-1H-benzimidazole (60 gm, 4:1).The above solid (60 gm) was dissolved in tetrahydrofuran (900 ml) and distilled off the solvent completely under vacuum. The contents were stirred with tetrahydrofuran (90 ml) and t-butyl alcohol mixture (90 ml) for 20 hours at 25° C. Cooled to 0-5° C. and stirred for 2 hours at 0-5° C. The solid obtained was collected by filtration and the solid was washed with chilled tetrahydrofuran and t-butyl alcohol mixture (20 ml, 1:1). Finally washed with diisopropylether (100 ml) to obtain a diastereomeric mixture of 1-(S)-camphor sulfonyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(R/S)-sulfinyl]-1H-benzimidazole and 1-(S)-camphor sulfonyl-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(R/S)-sulfinyl]-1H-benzimidazole (35 gm, 9:1).Example 1 Water (580 ml) and 5% aqueous sodium chloride (70 ml) solution were added to the diastereomeric mixture of 1-(S)-camphor sulfonyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(R/S)-sulfinyl]-1H-benzimidazole and 1-(S)-camphor sulfonyl-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl-(R/S)-sulfinyl]-1H-benzimidazole (35 gm, 9:1) obtained as in preparative example 1 at 25° C., then sodium hydroxide solution (11 gm in 58 ml water) was added slowly for 30 minutes. The contents were stirred for 6 hours at 25° C. To the reaction mass, was added dichloromethane (350 ml), the pH was adjusted to 7.0 with hydrochloric acid and the reaction mass was extracted with dichloromethane. The layers were separated. The organic layer was washed with 5% aqueous sodium chloride (70 ml), dried with sodium sulfate and the solvent was distilled to obtain 21 gm residue containing 5-Methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]1-H-benzimidazole (esomeprazole:R-omeprazole=11:1).

Reference： [1]Current Patent Assignee: HETERO DRUGS LIMITED - US2011/213155, 2011, A1 Location in patent: Page/Page column 2

54
[ 1345092-48-9 ]
[ 73590-58-6 ]
[ 1345092-10-5 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap In dichloromethane at 0℃; for 1h; Inert atmosphere;	34 Example 34 (Z)-4-((1-(nitrooxy)ethoxy)carbonyloxy)but-2-enyl 6-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl)-1H-benzo[d]imidazole-1-carboxyla [NO-Omeprazole (I-AD7-L2-R1)] This compound was synthesized as shown in Scheme 7 and the experimental procedure is described below: Diphosgene (0.2 g, 1.3 mmol) was added drop-wise to a stirred solution of (Z)-4-hydroxybut-2-enyl 1-(nitrooxy)ethyl carbonate (HO-L2-R1, 0.5 g, 2.3 mmol, freshly prepared as described in Example 4) and triethylamine (0.1 mL, 1.4 mmol) in 5 mL of dry DCM at 0° C. under nitrogen and the mixture was stirred for 30 minutes. The reaction mixture was concentrated to get the corresponding formyl chloride, CI-L2-R1, as yellow residue. This residue was re-dissolved in DCM (5 mL) and the resulting solution was added to a stirred mixture of omeprazole (AD7, 0.4 g, 1.1 mmol)) and DMAP (0.3 g, 2.3 mmol) in DCM (5 mL) at 0° C. and the mixture was stirred for 1 h when TLC analysis of the mixture indicated formation of a major new product. The reaction mixture was diluted with DCM (15 mL), washed with water, dried over anhydrous Na2SO4, concentrated and purified by column chromatography on silica gel by eluting with methanol/dichloromethane gradient to afford the title compound I-AD7-L2-R1 as a brown gum. Yield: 0.3 g (45.0%); 1H NMR (CDCl3, 300 MHz, mixture of diastereomers, ~0.55:0.45): δ 1.61 (d, J=5.7, 3H), 2.21 (s, 3H), 2.37 (s, 3H), 3.76 (unsymmetrical d, J=1.2 Hz, 3H), 3.88, 3.92 (two singlets, 3H), 4.65-4.94 (m, 4H), 5.02-5.21 (m, 2H), 5.90-6.10 (m, 2H), 6.93 (q, J=5.7 Hz, 1H), 7.03 (dd, J=2.4, 9.0 Hz, 0.5H), 7.09 (dd, J=2.4, 9.0 Hz, 0.5H), 7.33 (d, J=2.4 Hz, 0.45H), 7.49 (d, J=1.8 Hz, 0.55H), 7.75 (d, J=9.0 Hz, 0.55H), 7.83 (dd, J=9.0, 1.8 Hz, 0.45H), 8.06 (br s, 1H); MS (ES+) m/z: 593.2 [M+H]+, 615.1 [M+Na]+.

Reference： [1]Current Patent Assignee: PIRAMAL ENTERPRISES LIMITED - US2011/263526, 2011, A1 Location in patent: Page/Page column 90

55
[ 73590-58-6 ]
[ 161973-10-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: dichloromethane; toluene / 4.25 h / 20 °C 2: toluene; water / 1 h / 35 - 40 °C 3: acetone; methanol / 2.5 h / 20 °C

Reference： [1]Current Patent Assignee: HETERO DRUGS LIMITED - WO2012/104863, 2012, A2

56
[ 1288986-37-7 ]
[ 73590-58-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In ethyl acetate at 5 - 10℃; for 0.5h;	13 To a stirred solution of S-omeprazole-(R)-BNPPA complex (10 gm) in ethyl acetate (200 ml) was slowly added sodium bicarbonate (30 ml, 10%) at 5 to 10° C. The solution was stirred for 30 minutes at 5 to 10° C. and layers were separated. The organic layer was washed with water and concentrated on a rotavapor. The residue obtained was dissolved in methanol (10 ml) and was added to ice cold water (50 ml) dropwise, stirred for 30 minutes. The solid obtained was collected by filtration and the solid was dried at 45 to 50° C. deg C under vacuum for 12 hours to obtain 3 gm of esomeprazole (chiral purity: 84%).

Reference： [1]Current Patent Assignee: HETERO DRUGS LIMITED - US2012/197021, 2012, A1 Location in patent: Page/Page column 8

57
[ CAS Unavailable ]
[ 73590-58-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
60%	In N,N-dimethyl-formamide; acetone at 20℃; for 3h;	2.2 [Co(H₂O)₂(OMZ)₂]Cl_2*H₂O An acetone solution (70 mL) of OMZ (0.02 mmol, 69.08 mg) was added to a N,N-dimethylformamide (N,N-DMF) solution (5 mL) of CoCl2⋅6H2O (0.01 mmol, 23.79 mg) and the reaction mixture was stirred for 3 h at room temperature. The solution was filtered and left for slow evaporation. After a few days a blue microcrystalline product was collected and washed with a water-acetone solution (1:1). Yield: 60% (55 mg). Anal. Found: C, 45.35; H, 4.88; N, 9.61; S, 7.13%. Calc. for C34H46N6O10S2Cl2Co (MW: 892.71 g/mol): C, 45.74; H, 5.19; N, 9.41; S, 7.18%. IR (KBr, ν, cm-1): ν (C-N)BZ: 1636-1573, ν (C-N)PYR: 1572, ν (S=O): 1066, ν (O-M): 558, ν (O-M): 440.

Reference： [1]Russo, Marcos G.; Vega Hissi, Esteban G.; Rizzi, Alberto C.; Brondino, Carlos D.; Salinas Ibañez, Ángel G.; Vega, Alba E.; Silva, Humberto J.; Mercader, Roberto; Narda, Griselda E. [Journal of Molecular Structure, 2014, vol. 1061, # 1, p. 5 - 13]

58
[ CAS Unavailable ]
[ 73590-58-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
65%	In methanol at 20℃; for 3h;	2.1 Synthesis of the metal complexes 2.2.1 [Fe(OMZ)2(H2O)2]Cl3⋅2H2O A methanolic solution (70 mL) of OMZ (0.02 mmol, 69.08 mg) was added to a methanolic solution (20 mL) of FeCl3.6H2O (0.01 mmol, 27.03 mg) and the reaction mixture was stirred for 3 h at room temperature. The solution was filtered and left for slow evaporation. After a few days a red microcrystalline product was collected and washed with a water-methanol solution (1:1). Yield: 65% (67 mg). Anal. Found: C, 43.88; H, 4.02; N, 9.17; S, 6.78%. Calc. for C34H46N6O10S2Cl3Fe (MW: 925.22 g/mol): C, 44.09; H, 4.97; N, 9.07; S, 6.91%. (KBr, ν, cm-1): ν(C-N)BZ: 1637-1569, ν (C-N)PYR: 1569, ν (S=O): 1065, ν (O-M): 557, ν (O-N): 464.

Reference： [1]Russo, Marcos G.; Vega Hissi, Esteban G.; Rizzi, Alberto C.; Brondino, Carlos D.; Salinas Ibañez, Ángel G.; Vega, Alba E.; Silva, Humberto J.; Mercader, Roberto; Narda, Griselda E. [Journal of Molecular Structure, 2014, vol. 1061, # 1, p. 5 - 13]

59
[ 73590-58-6 ]
[ 37052-78-1 ]
[ 86604-78-6 ]

Reference： [1]Pharmazie,2013,vol. 68,p. 749 - 754

60
[ 73590-58-6 ]
[ 4887-80-3 ]
[ 109371-19-9 ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2015,vol. 58,p. 433 - 441

61
[ 73590-58-6 ]
[ 88546-55-8 ]

Yield	Reaction Conditions	Operation in experiment
	With glucose-6-phosphate dehydrogenase; glucose-6-phosphate; ferredoxin 8; ferredoxin-NADP<SUP>+</SUP> reductase B; recombinant CYP₂₆₇B₁ from Sorangium cellulosum So ce56; NADPH In dimethyl sulfoxide at 30℃; for 3h; Enzymatic reaction;	In Vitro Conversions. General procedure: A reconstituted in vitro system containing the corresponding P450 (0.5 mM), FdR_B (1.5 mM), and Fdx8 (10 mM), and acofactor regenerating system with glucose-6-phosphate (5 mM) and glucose-6-phosphate dehydrogenase (2 U/ml) in potassium phosphate buffer (20 mM, pH 7.4,1% glycerin) was used. The potential substrates, except olanzapine and omeprazole(both dissolved in dimethylsulfoxide),were dissolved in ethanol (10mM) and addedto an end concentration of 200 mM. The total volume of the reaction was 250 ml.The reaction was started by the addition of NADPH (800 mM) and carried out for3 hours at 30C. For substrates 1, 9, 11-15, and 18-21, 1M glycine buffer (pH 11)or acetate buffer (pH 4) was added after reaction to enable improved recovery of theanalytes. Therefore, the reaction was stopped by adding buffer (300 ml) ororganic solvent (500 ml). The extraction was performed twice with 500 ml of theappropriate solvent (see (Supplemental Table 0). A negative control withoutP450 was implemented for each substrate to verify the P450-dependent reaction.

Reference： [1]Kern, Fredy; Khatri, Yogan; Litzenburger, Martin; Bernhardt, Rita [Drug Metabolism and Disposition, 2016, vol. 44, # 4, p. 495 - 504]

62
[ 37052-78-1 ]
[ 73590-58-6 ]

Reference： [1]Chemistry Letters,2016,vol. 45,p. 110 - 112

63
[ 18531-99-2 ]
[ 73590-58-6 ]
esomeprazole (S)-(-)-binol complex [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.9%	In dichloromethane; di-isopropyl ether at 20 - 25℃; for 4.58333h;	3 Esomeprazole (S)-(-)-BINOL complex To an enantiomerically enriched mixture of S and R enantiomers (56.46:43.54) of Omeprazole (15.0 g, 43.4 mmol) in dichloromethane (75.0 ml) was added (S)-BINOL (18.65 g, 65.1 mmol) and the resulting mixture was stirred at 20-25° C. for 10 min until complete dissolution was observed. Diisopropyl ether (75.0 ml) (abbreviated IPE) was then added at 20-25° C. in 55 min (precipitation occurred at the end of the addition) and the resulting mixture was stirred at 20-25° C. for 3.5 h. The slurry was filtered and the filter-cake was washed with diisopropyl ether (2×15.0 ml). The collected solid was dried at 35° C. to afford 14.7 g of Esomeprazole (S)-BINOL complex (molar yield 94.9%).

Reference： [1]Current Patent Assignee: HOLDING F.I.S. S.P.A. - US2016/244428, 2016, A1 Location in patent: Paragraph 0089-0090

64
[ 695-98-7 ]
[ 37052-78-1 ]
[ 407-25-0 ]
[ 73590-58-6 ]

Yield	Reaction Conditions	Operation in experiment
55.6%		In 23 °C the 96.8g the 2, 3, 5-trimethyl pyridine, 40g particle size is 50 loaded with phosphotungstic acid is added to the molecular sieve containing 200g benzene and 100g in mixed solution of acetonitrile, then the temperature is 95 °C into the 90 ml concentration is 30 wt percent of the hydrogen peroxide reaction, dropping time 1.5h, through nitration, after methoxy, adding 96.8g trifluoroacetic anhydride and 560 ml chloroform, heating to reflux reaction 4.5h, through rearrangement reaction to obtain the trifluoroacetate ester, the three perfluoroethylene-ester and 13g naoh, 25g2-mercapto-5-methoxy-benzimidazole added to 200g reaction is carried out in ethanol, the recovery after ethanol 25 °C drop under 24g concentration is 50 wt percent hydrogen peroxide oxidation, in 29 °C lower heat insulating reaction 3h after cooling, filtering, drying, obtain 153.2g omperazole white crystalline powder, to yield 55.6percent, purity of 99.5percent.

Reference： [1]Patent: CN105399729,2016,A .Location in patent: Paragraph 0025; 0026

65
[ 73590-58-6 ]
[ 73590-85-9 ]

Reference： [1]European Journal of Organic Chemistry,2017,vol. 2017,p. 3427 - 3430
Khim. Prir. Soedin.,2017,vol. 53,p. 318 - 319,2

66
[ 86604-75-3 ]
[ 37052-78-1 ]
[ 73590-58-6 ]

Yield	Reaction Conditions	Operation in experiment
96%		In a 1000 mL three-necked flask,Sodium hydroxide (5 g, 0.13 mol) was added to ethanol (50 mL) and heated to 70-90After dissolving, 2-mercapto-5-methoxybenzimidazole (17.8 g, 0.10 mol) was added,Reflux dissolved,Cooling to below 10 .2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride (20 g, 0.09 mol) was dissolved in a 200 mL constant pressure dropping funnelIn water (100 mL), the aqueous solution of hydrochloric acid was slowly added dropwise, and the temperature was raised to 30 C. After the incubation reaction was carried out for 4 hours,Cooling to 10 ,500 mL of water was added and stirred for 12 hours. A white solid was obtained by suction filtration and dried to give 5-methoxy-2- (4-methoxy-3,5-dimethylYl-2-pyridyl) methylthio-1H-benzimidazole in a yield of 96%.

Reference： [1]Patent: CN107011252,2017,A .Location in patent: Paragraph 0084; 0085

67
[ 73590-58-6 ]
[ 92340-57-3 ]

Yield	Reaction Conditions	Operation in experiment
	With omeprazole 5‐hydroxylase for 0.25h; Enzymatic reaction;
	With 8-methylene-tert-butylamine-3',5,7-trihydroxy-4'-methoxyflavanone; water In aq. phosphate buffer at 37℃; Enzymatic reaction;

Reference： [1]Shon, Jong Cheol; Phuc, Nguyen Minh; Kim, Won Cheol; Heo, Jae Kyung; Wu, Zhexue; Lee, Hyunyoung; Liu, Kwang-Hyeon [Biopharmaceutics and Drug Disposition, 2017, vol. 38, # 9, p. 553 - 556]
[2]Qin, Yan; Dong, Haijun; Sun, Jiayin; Zhang, Yilong; Li, Jun; Zhang, Tianci; Chen, Guanjun; Wang, Sheng; Song, Shuai; Wang, Wei; Fan, Yuru; Wang, Jie; Huang, Xiaohui; Shen, Chenlin [Xenobiotica, 2021, vol. 51, # 12, p. 1389 - 1399]

68
[ CAS Unavailable ]
[ 73590-58-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
80%	In dichloromethane at 0 - 20℃; Inert atmosphere;	1 Example 1 Synthesis, Purification and MTT Cancer Toxicity of a Novel Drug Complex Coupled with Vitamin D 3 and Omeprazole test. Synthesis of Novel Drug Complexes with Vitamin D 3 Coupling with Omeprazole The synthetic route is as follows:Weigh 100mg (0.26mmol) vitamin D3 was dissolved in 3ml anhydrous dichloromethane solution,115 mg (0.39 mmol) of triphosgene and 54 μL (0.39 mmol) of triethylamine were added under N2 atmosphere,0 ° C the reaction was stirred for 3 ~ 4h until the end of the reaction,The mixed solution was vacuum dried 0.5h dissolved in 3ml dichloromethane solution,134 mg (0.39 mmol) of omeprazole dichloromethoxide solution was added dropwise under N2 atmosphere,0 ° C under stirring 3 ~ 5h after reaction at room temperature overnight. Add 20mlNaHC03 aqueous solution, extracted three times with dichloromethane, washed with saturated brine,Then dried over anhydrous Na2SO4 filtered and concentrated.(2) Purification of Novel Drug Complex Coupled with Omeprazole by Vitamin D3] First separated and purified by silica gel chromatography, the eluent was methanol and methylene chloride, the volume ratio of 1: 100, the crude compound obtainedproduct. Then purified by high performance reversed-phase liquid chromatography, the mobile phase A was 0.01% TFA aqueous solution, Mobile phase B is 100% acetonitrileLadderDegree of elution, Elution program: 0 ~ 5min, 5% B; 5 ~ 10min; 5% ~ 90Β; 10 ~ 60min,90% B, to obtain a complexRefined products, The yield is about 80%

Reference： [1]Current Patent Assignee: CHANGZHOU UNIVERSITY - CN105175395, 2017, B Location in patent: Paragraph 0028-0033

69
[ 73590-58-6 ]
[ 591-22-0 ]
[ 51-17-2 ]
[ 2080-75-3 ]
C₁₅H₁₃N₃O₆ [ No CAS ]
C₈H₁₃NO₃ [ No CAS ]
C₁₅H₁₉N₃O₂S [ No CAS ]
C₁₆H₁₅N₃O₂ [ No CAS ]
C₁₂H₁₃N₃O₄S [ No CAS ]
[ 106135-28-8 ]
[ 10045-42-8 ]

Reference： [1]Journal of Physical Organic Chemistry,2020,vol. 33

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

CAS No. :	73590-58-6	MDL No. :	MFCD00083192
Formula :	C₁₇H₁₉N₃O₃S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SUBDBMMJDZJVOS-UHFFFAOYSA-N
M.W :	345.42	Pubchem ID :	4594
Synonyms :	H 16868;OMEP;OMZ;OMP	Chemical Name :	6-Methoxy-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P264-P280-P302+P352-P312-P337+P313-P305+P351+P338-P362+P364-P332+P313	UN#:	N/A
Hazard Statements:	H302-H315-H319	Packing Group:	N/A
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 73590-58-6 ] {[proInfo.proName]}

Quality Control of [ 73590-58-6 ]

Related Doc. of [ 73590-58-6 ]

Product Details of [ 73590-58-6 ]

Safety of [ 73590-58-6 ]

Application In Synthesis of [ 73590-58-6 ]

[ 73590-58-6 ] Synthesis Path-Upstream 1~5

[ 73590-58-6 ] Synthesis Path-Downstream 1~69

Similar Product of
[ 73590-58-6 ]

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

[ CAS No. 73590-58-6 ] {[proInfo.proName]}

Quality Control of [ 73590-58-6 ]

Related Doc. of [ 73590-58-6 ]

Product Details of [ 73590-58-6 ]

Safety of [ 73590-58-6 ]

Application In Synthesis of [ 73590-58-6 ]

[ 73590-58-6 ] Synthesis Path-Upstream 1~5

[ 73590-58-6 ] Synthesis Path-Downstream 1~69

Similar Product of [ 73590-58-6 ]

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Similar Product of
[ 73590-58-6 ]