* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With sodium hydroxide In water; isopropyl alcohol at 20℃; for 3 h;
[EXAMPLE 1]Preparation of 5-difluoromethoxy-2-(3,4-dimethoxy-benzylsulfanyl)-lH- benzimidazole 92OmL of isopropanol, 92.1g of 5-difluoromethoxy-2- mercaptobenzimidazole and 95.8g of 2-chloromethyl-3,4-dimethoxypyridine were introduced into a reactor. After adding a sodium hydroxide solution (containing 20.5g of sodium hydroxide in 92OmL of purified water) dropwise to the above mixture, this reaction mixture was stirred at room temperature for 2 hours. Introducing 92OmL of purified water to the mixture and stirring the same for 1 hour, the resultant solid material was subjected to filtration and vacuum drying, thus yielding a final product.Amount of final product: 137.4g (yield: 87.8percent)MP: 94 °C
Reference：
[1] Patent: WO2009/75516, 2009, A2, . Location in patent: Page/Page column 4
[2] Organic Process Research and Development, 2013, vol. 17, # 10, p. 1272 - 1276
2
[ 97963-62-7 ]
[ 102625-64-9 ]
Yield
Reaction Conditions
Operation in experiment
98.14%
With sodium carbonate In tetrahydrofuran; water at 30 - 50℃; for 2 h;
In the 500 ml flask, add 250 ml mixed solvent (mixed solvent by volume ratio of 3:1 tetrahydrofuran and water), then the 5 - difluoro -2 - mercapto - 1H - benzimidazole 21.62g (100mmol), iodo 1.27g (5mmol, alkali 31.8g (sodium carbonate, 300mmol) and 2 - chloromethyl - 3, 4 - dioxy pyridine hydrochloride 24.65g (110mmol) is added to the flask, 30 - 50 °C, stirring for 2 hours, cooled to the room temperature, dichloromethane extraction, water washing, petroleum ether/dichloromethane recrystallization, vacuum drying is shown in formula I of pantoprazole thioether 36.05g, yield is 98.14percent, purity 99.27percent.
Reference：
[1] Patent: CN106632250, 2017, A, . Location in patent: Paragraph 0032-0034
3
[ 97963-62-7 ]
[ 86604-75-3 ]
[ 102625-64-9 ]
Yield
Reaction Conditions
Operation in experiment
94%
With sodium hydroxide In ethanol at 80℃; for 8 h;
In a 500 mL three-necked flask,2-Chloromethyl-3,4-dimethoxypyridine hydrochloride (22.4 g,100 mmol), 5-difluoromethoxy-2-mercapto-1H-benzimidazole (21.6 g, 104 mmol), 80 g / L sodium hydroxide solution(110 mL),Ethanol (150 mL) and the mixture was heated to 80 ° C and stirred for 8 hours. The ethanol was recovered and the residue was extracted with dichloromethane (150 mL)extraction. Add anhydrous sodium sulfate drying overnight, vacuum recovery of dichloromethane was crude. Recrystallization from ethyl acetate-petroleum ether gave a white solid which was dried to give 5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methyl] Benzimidazole, product yield 94percent.
Reference：
[1] Patent: CN107011252, 2017, A, . Location in patent: Paragraph 0096; 0097
4
[ 97963-62-7 ]
[ 72830-09-2 ]
[ 102625-64-9 ]
Yield
Reaction Conditions
Operation in experiment
97.5%
With sodium hydroxide In water at 25 - 30℃; for 4 - 5 h;
EXAMPLE 1 : PREPARATION OF 5-DIFLUOROMETHOXY-2(3,4-DIMETHOXY- PYRIDIN-2-YLMETHYL THIO)-1 H-BENZIMIDAZOLE (PANTOPRAZOLE SULFIDE) (FORMULA Ma)-USING 2.1 EQUIVALENTS OF SODIUM HYDROXIDE:Sodium hydroxide (37.4 g) and water (1000 ml) were taken into a clean and dry 4 neck round bottom flask and stirred for about 10 minutes. 5-difluoromethoxy-2- mercaptobenzimidazole (96.4 g) and 2-Chloromethyl-3, 4-dimethoxy-pyridine hydrochloride (100 g) dissolved in 500 ml of water was added slowly over about 2-3 hours at about 25-300C. The resultant reaction mixture was stirred for about 2 hours. The separated solid was filtered and washed with water (500 ml). <n="27"/>The obtained solid was again taken into a fresh round bottom flask containing water (500 ml) and stirred for about 20 minutes. The solid was filtered and suction dried for about 30 minutes. The obtained solid was dried under a vacuum of about 650 mm/Hg and a temperature of about 50 0C for 5 hours to afford 159 g (percent Yield: 97.5) of the title compound. Purity By HPLC: 99 percent.
95.3%
With sodium hydroxide In methanol; water at 10 - 40℃; for 2.5 h;
10percent NaOH solution (42.5 gm in 425 ml of water) is added drop wise to a solution of 5-(difluoromethoxy)-2-mercapto benzimidazole (100.0 gm; 0.462 moles) in methanol(350.0 ml) at 10-150C. To the above solution a clear solution of 2-chloro-3, 4-dimethoxy pyridine hydrochloride (105.5 gm.0.473 moles in 525 ml of methanol) was added at 10-150C. The reaction mass was maintained at 10-15°C for 30 minutes. The temperature of the reaction mass was slowly raised to 2O0C. The reaction mass was maintained at 20-25° C for 2 hours. Further the temperature was raised to 400C and maintained at 400C. Completion of the reaction is monitored by TLC. After completion of the reaction methanol is evaporated under reduced pressure to get a residue. Chilled water (600 ml) was added to the residue and the reaction mass was extracted with methylene chloride (600 ml, 300 ml x 2). The organic layers were separated and evaporated under reduced pressure to obtain a residue. Isopropyl alcohol (50 ml) and hexane (600 ml) were added to the reaction mass. The reaction mass was cooled to 0-50C and maintained at 0-5°C for 30 minutes. The reaction mass was filtered at 0-5°C and washed with chilled hexane (100 ml). The solids were dried under vacuum at 4O0C; Dry wt-162 gm (Yield=95.3percent); HPLC Purity=99.21percent w/w.; Melting range=l 15-1170C (Lit.7mp-H5-1 18°C); MS (ESI); 368.0(M+H) +.
83%
With water; sodium hydroxide In methanol at 25 - 30℃;
Methanol (270 ml) was added to a solution of NaOH (41.5 gms) in water (180 ml), followed by addition of 5-difluoromethoxy-2-mercapto-1H-benzimidazole (105.2 gms). A solution of 2-chloromethyl-3,4-dimethoxy-pyridine.hydrochloride (100.3 gm in water (150 ml)) was gradually added to the reaction mixture and stirred at 25-30° C. till completion of the reaction. After completion, as monitored by TLC, the reaction mixture was filtered and the obtained solid was dried to give compound IV-A-11.Yield: 140.6 gm (83percent).1H NMR (400 MHz, CDCl3): δ 8.27 (d, J=5.6 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.32 (d, J=2 Hz, 1H), 6.99 (dd, J=2.4, 8.8 Hz, 1H), 6.87 (d, J=5.6 Hz, 1H), 6.50 (t, J=74.8 Hz, 1H), 4.39 (s, 2H), 3.95 (s, 3H), 3.93 (s, 3H).ESI-MS: 368.9 (M+1).
16.6 g
With sodium hydroxide In dichloromethane at 20 - 30℃; for 2 h;
To the reaction flask was added 10 g of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride(Compound 1), 10 g of 5-difluoromethoxy-2-mercapto-1H-benzimidazole(Compound 2), 100 ml of methylene chloride was added, and 130 g of a 10percent sodium hydroxide solution was added dropwise, and the mixture was stirred at 20 to 30 °C for 2 hours, Static separation, dichloromethane layer washed twice, each time with water 30ml,And then distilled under reduced pressure to give 16.6 g of a yellow oil (Intermediate 3);
Reference：
[1] Patent: WO2008/45777, 2008, A2, . Location in patent: Page/Page column 25-26
[2] Patent: WO2009/66317, 2009, A2, . Location in patent: Page/Page column 7
[3] Patent: US2015/232467, 2015, A1, . Location in patent: Paragraph 0070-0073
[4] Journal of Medicinal Chemistry, 1992, vol. 35, # 6, p. 1049 - 1057
[5] Patent: WO2005/77936, 2005, A1, . Location in patent: Page/Page column 16-17
[6] Patent: WO2008/1392, 2008, A2, . Location in patent: Page/Page column 17-20
[7] Patent: WO2009/10937, 2009, A1, . Location in patent: Page/Page column 11
[8] Patent: US2010/210847, 2010, A1, . Location in patent: Page/Page column 4
[9] Patent: WO2006/49486, 2006, A1, . Location in patent: Page/Page column 13; 14
[10] Organic Process Research and Development, 2004, vol. 8, # 2, p. 266 - 270
[11] Chemistry Letters, 2016, vol. 45, # 2, p. 110 - 112
[12] Patent: CN104262326, 2016, B, . Location in patent: Paragraph 0034; 0035
[13] Patent: CN105111187, 2017, B, . Location in patent: Paragraph 0012; 0027; 0028
[14] Patent: CN108341800, 2018, A, . Location in patent: Paragraph 0006; 0009
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 6, p. 1049 - 1057
7
[ 76015-11-7 ]
[ 102625-64-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 6, p. 1049 - 1057
8
[ 35392-65-5 ]
[ 102625-64-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 6, p. 1049 - 1057
9
[ 107512-34-5 ]
[ 102625-64-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 6, p. 1049 - 1057
10
[ 122307-41-9 ]
[ 102625-64-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 6, p. 1049 - 1057
11
[ 72830-08-1 ]
[ 102625-64-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 6, p. 1049 - 1057
12
[ 72830-07-0 ]
[ 102625-64-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 6, p. 1049 - 1057
13
[ 102625-99-0 ]
[ 102625-64-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 6, p. 1049 - 1057
14
[ 102625-64-9 ]
[ 138786-67-1 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With sodium hydroxide; tert-butylhypochlorite In dichloromethane; water at 0 - 5℃; for 1 h; Stage #2: With sodium hydroxide In water; acetone at 0 - 25℃; for 7 h;
Charge 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-ρyridinyl) methyl] Mo]-IH- benzimidazole (36.7 gm; 0.1 moles) and methylene chloride (367 ml) in a flask. Cool the reaction mass to 0-50C. Add a clear solution of sodium hydroxide (6.0 gm in 120.0 ml water) in the flask at 0-5°C. Add tert-butylhypochlorite solution in dichloromethane at 0-5°C. Maintain the reaction mass at 0-5°C for one hour. The completion of the reaction is monitored by TLC. After completion of the reaction, charge ammonium sulphate to the reaction mass at 5-1O0C. Stir the reaction mass for 15 minutes and separate the organic layer. Extract the aqueous layer with methylene chloride (100 ml x 2). Distill out the organic layer completely under vacuum below 3O0C to get a residue. To the residue acetone (100 ml x 2) was added and evaporated. Fresh acetone (150 ml) was added to the reaction mass and stirred the reaction mass to get a clear solution. Activated charcoal (1.0 gm) was added to the solution at 30- 350C and filtered through hyflow bed. The hyflow bed was washed with 50 ml acetone. The clear filtrate was cooled to 2O0C and sodium hydroxide solution (2.14 gm in 10.2 ml water) was added at 20-250C. The reaction mass was maintained at 20- 25°C for 4.00 hours and cooled to 00C and further maintained at 0-50C for 3 hours. Filtered the solids separated and washed the solids with chilled acetone (50 ml.) The solids were dried under vacuum at 40-450C for 6 hours, to get 18.0 gm of Pantoprazole sodium (Yield=95.0percent); HPLC purity= 99.65 percent w/w.; Melting range- 142-145°C.
78.7%
Stage #1: at -5 - 0℃; for 4.5 h; Stage #2: With sodium hydroxide In water at 20℃;
A solution of water, 1L, sodium hydroxide (43 g, 1.13 mol) and tetrabutylammonium bisulfate (5.08 g, 0.015 mol) were added to a 2.5 L three-necked flask, stirred to clarification, cooled to room temperature, And 5-difluoromethoxy-2-mercapto-1H-benzimidazole (100 g, 0.466 mol) were added and stirred to a solution of 2-chloromethyl 3,4-dimethoxypyridine hydrochloride (98.5 g , 0.44 mol) of water in 0.6 L solution, 1.6 h after the drop, 30 ~ 35 ° C reaction 4.5h, TLC [developing agent: ethyl acetate: methanol = 9: 1] detection reaction is completed after the separation, The chloroform layer was washed with O.lmol / L sodium hydroxide solution and then an aqueous solution of potassium tungstate(Na2W0.4H2O1818g, H200.76L), 30percent hydrogen peroxide (260ml), weak acid pH of 3? 5, - 5 ° C_0 ° C for 4.5 hours, TLC (developing solvent: ethyl acetate: methanol = 9: 1) detection, the reaction is completed by adding saturated sodium carbonate solution adjusted PH value to neutral, standing stratification, take the chloroform layer, add 15gNa0H and 50ml distilled water preparation of alkaline solution, stirring at room temperature 1.5-2 hours, the detection reaction is completed , The reaction solution was cooled to 0 ° C to crystallize, filtered, and the filter cake was washed with 200 ml of cold acetone solution and dried in vacuo at 35-40 ° C to give 170.9 g of crude pantoprazole sodium.170.9 g) and acetone (750 ml) were added to the reaction flask, heated to 50 ° C, and activated charcoal (7.3 g) was added to decolorize for 15 minutes and cooled to 40 to 45 ° C, filter the filter cake and wash with hot acetone (100ml). The filtrate and the washings were combined and concentrated under reduced pressure to about 300 ml. Ethyl acetate (1000 ml) was added and the mixture was stirred at 25 to 30 ° C. After stirring, the mixture was stirred for 2 hours, cooled to -2 to 4 ° C, (100 ml), dried at 40 to 45 ° C in vacuo to give 150.6 g of sodium pantoprazole white crystalline powder, the total yield of 78.7percent, mp> 150 ° C (decomposition), the content of 99 • 93percent. 7
With sodium hydroxide; sodium hypochlorite In water; ethyl acetate at -5℃; for 1 - 1.5 h;
A glass reactor equipped with a stirrer is charged with ethyl acetate (3286 mL) and 5- 5 (difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-lH-benzimidazole ("thioether") (260,0 g) is added. The flask is cooled to -5 0C, and mixture of 275,6 mL aqueous 16,9percent active sodium hypochlorite solution (or corresponding quantity depending on active chlorine assay) and 10percent sodium hydroxide solution (291,2 g) is dropped in approximately 1 hour. Oxidation reaction is monitored by IR spectroscopy 0 method as described above. After the aimed chemical conversion is achieved by the addition of extra oxidant defined through extrapolation, as described above, the reaction is stopped by interrupting the addition of further amounts of sodium hypochlorite. After stirring for a 5 minutes, aqueous 10percent Na2S2O3 (614 g) is added dropwise over 15 minutes, additionally stirred for 15 minutes, the phases are then separated. The organic 5 layer is washed twice with 15percent sodium carbonate solution (1390 mL). To the organic layer activated charcoal (13 g) is added and after stirring for 15 minutes mixture is filtrated. Organic layer is concentrated to give residue (600 mL) and after cooling to the room temperature acetone (858 mL) is added. By cooling the solution to 5°C and stirring it for 2 hours at this temperature crystallization occurs. A precipitate is filtered 0 off to give pantoprazole sodium salt monohydrate. <n="18"/>5-(Difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)metliyl]sulfinyl]-lH- benzimidazole sodium salt monohydrate (Pantoprazole Sodium Salt Monohydrate)The above results show that the reaction conditions can be varied to a large degree but using the process of the invention high quality pantoprazole is produced with low amounts of sulfone (III) present; Into a reactor with impeller agitator is charged ethyl acetate (13,9 L) and after that 5- (difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-lH-benzimidazole ("thioether") (1,1 kg) is added. The reactor is cooled to-5 °C, and mixture of 3,75 kg aqueous 15,2percent active sodium hypochlorite solution (or corresponding quantity depending on active chlorine assay) and 10percent sodium hydroxide solution (2,91 kg) is dropped for 90 minutes. The oxidation reaction is monitored by IR spectroscopy method. After the chemical conversion is achieved, reaction is stopped by stopping of the addition of further amounts of sodium hypochlorite. After stirring for a 15 minutes, aqueous 10percent Na2S2O3 (2,6 kg) is added drop wise with aim of the decomposition of any possible unreacted sodium hypochlorite. The content of reactor is stirred for an additional 15 minutes and the aqueous layer is separated from organic layer. The organic layer is washed twice with 15percent sodium carbonate solution (11,7 L). To the organic layer activated charcoal (60 g) in ethyl acetate (0,5 L) is added and after stirring for 15 minutes mixture is filtrated. Organic layer is concentrated to give residue (2,5 L) and after cooling to the room temperature acetone (3,6 L) is added. By cooling the solution to 5°C and stirring it for 2,5 hours at this temperature crystallization occurs. A precipitate is filtered off to give pantoprazole sodium salt monohydrate.
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