[ CAS No. 138786-67-1 ] {[proInfo.proName]}

Name: 138786-67-1|Sodium 5-(difluoromethoxy)-2-(((3,4-dimethoxypyridin-2-yl)methyl)sulfinyl)benzo[d]imidazol-1-ide|98%
Brand: Ambeed
SKU: A261610
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Quality Control of [ 138786-67-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 138786-67-1 ]

Product Details of [ 138786-67-1 ]

CAS No. :	138786-67-1	MDL No. :	MFCD01658543
Formula :	C₁₆H₁₄F₂N₃NaO₄S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YNWDKZIIWCEDEE-UHFFFAOYSA-N
M.W :	405.35	Pubchem ID :	15008962
Synonyms :	SKF96022 sodium;BY1023 sodium;SKF-96022;SK and F 96022;Protonix;Zurcal;Pantecta;Controloc;Pantoloc	Chemical Name :	Sodium 5-(difluoromethoxy)-2-(((3,4-dimethoxypyridin-2-yl)methyl)sulfinyl)benzo[d]imidazol-1-ide

Calculated chemistry of [ 138786-67-1 ]

Physicochemical Properties

Num. heavy atoms :	27
Num. arom. heavy atoms :	15
Fraction Csp3 :	0.25
Num. rotatable bonds :	7
Num. H-bond acceptors :	9.0
Num. H-bond donors :	0.0
Molar Refractivity :	89.33
TPSA :	102.64 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.09 cm/s

Lipophilicity

Log Po/w (iLOGP) :	-9.17
Log Po/w (XLOGP3) :	2.37
Log Po/w (WLOGP) :	4.07
Log Po/w (MLOGP) :	0.38
Log Po/w (SILICOS-IT) :	2.62
Consensus Log Po/w :	0.05

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.8
Solubility :	0.0649 mg/ml ; 0.00016 mol/l
Class :	Soluble
Log S (Ali) :	-4.17
Solubility :	0.0277 mg/ml ; 0.0000682 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-6.02
Solubility :	0.00039 mg/ml ; 0.000000962 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.68

Safety of [ 138786-67-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 138786-67-1 ]

* 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.

Upstream synthesis route of [ 138786-67-1 ]
Downstream synthetic route of [ 138786-67-1 ]

[ 138786-67-1 ] Synthesis Path-Upstream 1~10

1
[ 102625-70-7 ]
[ 138786-67-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium hydroxide In water; acetonitrile at 20℃;	Pantoprazole (5 g, 25.6 mmol) and 47percent NaOH (1 eq.) are added to acetonitrile (25ml) and stirred at room temperature. After 3 h, the mixture becomes clear, and crystals beginto form. The mixture is allowed to stand overnight. The crystals are filtered and dried at50°C under 10 mm Hg vacuum. The crystals are determined to be the sesquihydrate form ofpantoprazole sodium by PXRD and are found to have a water content of 7.0percent by Karl Fisheranalysis. Yield: 95percent.
95%	With sodium hydroxide In ethanol for 5 h; Reflux	In a 250 mL three-necked flask, pantoprazole (7.7 g, 20 mmol), sodium hydroxide (1 g, 25 mmol)Ethanol (50 mL), and the mixture was heated under reflux with stirring for 5 hours. Cooled to below 10 , precipitation of white solid precipitation, filtration crude. Recrystallization from ethanol-petroleum ether gave a white solid which was dried to give pantoprazole sodium, the product yield was 95percent.
92%	With sodium hydroxide In water; ethyl acetate at 20℃; for 5.5 h;	Pantoprazole (20 g), solid NaOH (2.089 g, 1 eq.), and water (3.3 ml) are added toethyl acetate (200 ml) and stirred at room temperature. The mixture becomes clear. Crystalsbegin to form after 30 min. The crystals are filtered after 5 h and dried at 50°C under 10 mmHg vacuum. The crystals (20.5 g) are determined to be the sesquihydrate form ofpantoprazole sodium by PXRD and are found to have a water content of 6.52percent by KarlFisher analysis. Yield: 92percent.

92.7%	With sodium hydroxide In water; acetone for 0.5 h;	[EXAMPLE 3]Preparation of pantoprazole sodium637mL of acetone and 102g of pantoprazole were introduced into a reactor and a sodium hydroxide solution (containing 11.7g of sodium hydroxide in 5OmL of purified water) was slowly added drop wise to the above mixture. After stirring the solution for 30 minutes, the reaction mixture was partially concentrated under vacuum. The remaining residue was cooled to 0 to 5 ^°C and the resultant solids were filtered. After adding 102OmL of acetone to the filtered solids, the mixture was dissolved at elevated temperature. The reaction mixture was again cooled to 0 to 5 ^°C and filtered. Finally, the filtered product was washed with acetone and subjected to vacuum drying, thus yielding a final product.Amount of final product: lOOg (yield: 92.7percent)
90%	With sodium hydroxide In methanol; toluene at 20℃;	Pantoprazole (5 g, 25.6 mmol), solid NaOH (0.574 g, 1.1 eq.), and methanol (MeOH)(0.5 ml) are added to toluene (25 ml) and stirred at room temperature. After 3 h, the mixturebecomes clear and crystals begin to form. The mixture is left overnight. The crystals arefiltered and dried at 50°C under 10 mm Hg vacuum. The crystals are determined to be thesesquihydrate form of pantoprazole sodium by powder X-ray diffraction (PXKD) and arefound to have a water content of 7.2percent by Karl Fischer analysis. Yield: 90percent.
85%	With sodium hydroxide; sodium hypochlorite In acetonitrile at 0℃; for 4 h;	A flask was charged with acetonitrile (60 ml). The flask was cooled to 0°C and thenNaOCl (72.6 g, 9.82percent active, 1.25 eq.), NaOH pellets (13.1 g, 4 eq.), and compound VI (30g) were added to the flask. The mixture was stirred at 0°C for 4 h. During that time,pantoprazole sodium precipitated. The recovered precipitate was recrystallized in ethylacetate involving hot filtration of inorganic salts. Pantoprazole sodium that was free ofcompound VI and the sulfone within the limit of detection was recovered in 85percent yield
65%	With sodium hydroxide In water; acetone at 2℃; for 2 h;	A 100 ML round bottomed flask equipped with a magnetic stir bar was charged with acetone (50 ml). Pantoprazole (10 g, 25.7 mmol) was then added to the flask. After the pantoprazole had completely dissolved, the solution was cooled to about 2 ° C. Forty seven percent sodium hydroxide (aq. ) equivalent to 2.4 grams of solid sodium hydroxide (60.0 mmol) was slowly added to the cooled solution. A precipitate began to form immediately. The mixture was stirred for another two hours while the flask was allowed to warm to room temperature. The precipitate was filtered and washed with acetone (20 ML) and dried at 40°C under vacuum to yield pantoprazole sodium Form II (6.9 g, 65percent).

Reference： [1] Patent: WO2004/111029, 2004, A2, . Location in patent: Page 24
[2] Patent: CN107011252, 2017, A, . Location in patent: Paragraph 0101; 0103
[3] Patent: WO2004/111029, 2004, A2, . Location in patent: Page 24
[4] Patent: WO2009/75516, 2009, A2, . Location in patent: Page/Page column 5
[5] Patent: WO2004/111029, 2004, A2, . Location in patent: Page 24
[6] Patent: WO2004/111029, 2004, A2, . Location in patent: Page 25
[7] Patent: WO2004/56804, 2004, A2, . Location in patent: Page 35
[8] Patent: WO2004/99183, 2004, A1, . Location in patent: Page 4
[9] Patent: WO2004/99183, 2004, A1, . Location in patent: Page 5
[10] Patent: WO2005/77936, 2005, A1, . Location in patent: Page/Page column 19-20
[11] Patent: WO2009/10937, 2009, A1, . Location in patent: Page/Page column 11
[12] Patent: WO2009/116072, 2009, A2, . Location in patent: Page/Page column 16
[13] Patent: CN108503622, 2018, A, . Location in patent: Paragraph 0033; 0036; 0037; 0038; 0041; 0042; 0043; 0046

2
[ 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

Reference： [1] Patent: WO2009/66317, 2009, A2, . Location in patent: Page/Page column 8
[2] Patent: CN104262326, 2016, B, . Location in patent: Paragraph 0034-0036
[3] Patent: US2010/210847, 2010, A1, . Location in patent: Page/Page column 4
[4] Patent: WO2013/108068, 2013, A1, . Location in patent: Page/Page column 18; 19
[5] Patent: CN108341800, 2018, A, . Location in patent: Paragraph 0007; 0008; 0009

3
[ 409098-86-8 ]
[ 138786-67-1 ]

Yield	Reaction Conditions	Operation in experiment
70.8%	With sodium methylate In methanol at 50℃; Heating / reflux	A 3000 ml round-bottom flask is loaded with 464 g (2.58 mol) of a 30percent solution of sodium methoxide in methanol and heated at 50° C. 200 g (0.516 mol) of 5-(difluoromethoxy)-2-[[(4-chloro-3-methoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole are then added in portions, while refluxing to complete the reaction. The reaction mixture is cooled to 35° C. and added with 700 ml of demineralised H₂O and 2000 ml of toluene, in portions. All the methanol is removed by azeotropical distillation under reduced pressure (about 50 mm Hg) without exceeding 35° C. Demineralised H₂O is then added at 50° C. until complete dissolution and the pantoprazole sodium salt is extracted by adding 850 ml of methyl ethyl ketone, then separating the exhausted aqueous phase. The organic phase is partially concentrated and cooled to 20° C.; the crystallized product is filtered and washed with 200 ml of methyl ethyl ketone and 200 ml of acetone. 185 g of wet product are obtained (equivalent to 148 g dry product-yield=70.8percent). The resulting pantoprazole sodium sesquihydrate can be further purified according to known methods

Reference： [1] Patent: US2005/96352, 2005, A1, . Location in patent: Page/Page column 4

4
[ 97963-62-7 ]
[ 72830-09-2 ]
[ 138786-67-1 ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: With sodium hydroxide In dichloromethane; water at 25 - 30℃; for 12 h; Stage #2: With sodium hydroxide; sodium hypochlorite In dichloromethane; water at 0 - 8℃; for 6 h;	2-Chloromethyl-3,4-dimethoxy pyridine hydrochloride (50 gms), 2-mercapto-5-difluoromethoxy15 benzimidazole (50 gms) and Tetra butyl ammonium bromide (2 gms) were added under stirring to dichloromethane (300 ml) followed by solution of sodium hydroxide ( 37.5 gms ) in 120 ml water.The contents were then stirred at 25 - 30° C for about 12 hours. After reaction completion, the dichloromethane layer was separated, then the aqueous layer was extracted with dichloromethane(60 ml) twice. The organic layers were combined together, water washed and distilled to about20 250ml and cooled to 0⁰C. 3.5percent aqueous sodium hypochlorite solution (464 g ) having a sodium hydroxide content of 2.2percent was added to the reaction mass, which was maintained at 5 - 8⁰C for about 6 hours. After completion of the reaction; the reaction mass was further cooled to 0 to 5°C.The resulting solid was then filtered and washed with cold acetone (about 100ml ) and dried under vacuum at 35-40⁰C to give pantoprazole sodium (75 gms, 83percent) of purity greater than 99.5percent.

Reference： [1] Patent: WO2006/64249, 2006, A2, . Location in patent: Page/Page column 8; 10

5
[ 97963-62-7 ]
[ 138786-67-1 ]

Yield	Reaction Conditions	Operation in experiment
79.6%	Stage #1: With thionyl chloride In dichloromethane at 0 - 15℃; for 1 h; Stage #2: With sodium hydroxide In dichloromethane; water at 10 - 30℃; for 12 h; Stage #3: With sodium hydroxide; sodium hypochlorite In dichloromethane; water at 0 - 8℃; for 6 h;	2-hydroxymethyl-3,4-dimethoxy pyridine hydrochloride (45.8g) was taken in dichloromethane (300 ml). Thionyl chloride (30.3 gms.) was added at about 0 to 5⁰C and reaction mass was further stirred EPO <DP n="12"/>at 10 - 15°C for 1 hour. After reaction completion, purified water (100 ml) was added maintaining the reaction temperature between 15 - 20° C. To this reaction mass, 2-mercapto 5-difluoromethoxy benzimidazole (50 gms) and tetra butyl ammonium bromide (2 gms) were added. The contents were cooled to 10° C and pH of the reaction mass was adjusted to 10 - 11 using aqueous sodium hydroxide solution (30percent solution) and the contents were stirred at 25 - 30° C for 12 hours. After completion of the reaction, dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane (60 ml) twice. The combined organic layer was washed with purified water (150 ml) twice. The dichloromethane layer was then cooled to 0° C, 3.5percent aqueous sodium hypochlorite solution (464 g ) having sodium hydroxide content of 2.1percent was added to the reaction mass, and maintained at 5 - 8° C for about 6 hours. After the completion of the reaction, the reaction mass was cooled to 0 to 5° C and the resulting solid was filtered and washed with cold acetone (about 100ml ) and dried under vacuum at 35-40⁰C to give pantoprazole sodium (72 gms, 79.6percent) of purity greater than 99.5percent.

Reference： [1] Patent: WO2006/64249, 2006, A2, . Location in patent: Page/Page column 8; 10-11

6
[ 368890-20-4 ]
[ 124-41-4 ]
[ 138786-67-1 ]

Yield	Reaction Conditions	Operation in experiment
70.8%	at 50℃; Heating / reflux	Example 5: Synthesis of 5-(difluoromethoxy)-2-[[(3,4-of-methoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole sodium salt, sesquihydrate (I) A 3000 ml round-bottom flask is loaded with 464 g (2,58 mol) of a 30percent solution of sodium methoxide in methanol and heated at 50°C. 200 g (0.516 mol) of 5-(difluoromethoxy)-2-[[(4-chloro-3-methoxy-2-pyridinyl)methyl]sulfinyl]-1H- benzimidazole are then added in portions, while refluxing to complete the reaction. The reaction mixture is cooled to 35°C and added with 700 ml of demineralised H2O and 2000 ml of toluene, in portions. All the methanol is removed by azeotropical distillation under reduced pressure (about 50 mm Hg) without exceeding 35°C. Demineralised H2O is then added at 50°C until complete dissolution and the pantoprazole sodium salt is extracted by adding 850 ml of methyl ethyl ketone, then separating the exhausted aqueous phase. The organic phase is partially concentrated and cooled to 20°C; the crystallized product is filtered and washed with 200 ml of methyl ethyl ketone and 200 ml of acetone. 185 g of wet product are obtained (equivalent to 148 g dry product- yield = 70.8percent). The resulting pantoprazole sodium sesquihydrate can be further purified according to known methods.

Reference： [1] Patent: EP1518857, 2005, A1, . Location in patent: Page/Page column 5-6

7
[ 97963-62-7 ]
[ 138786-67-1 ]

Yield	Reaction Conditions	Operation in experiment
19.61 g	Stage #1: With sodium hydroxide In ethanol; water at 35℃; for 2 h; Stage #2: With sodium borate In ethanol at 45℃; for 2 h; Stage #3: With dihydrogen peroxide In water at 20℃; for 2.5 h;	The 5-difruoro methoxy-2-mercapto-1-H-benzimidazole 40.12g is soluble in ethanol 400 ml, after stirring to dissolve, sequentially under the condition at room temperature slowly adding 2mol/L NaOH aqueous solution of 250 ml and 2-chloromethyl -3,4-dimethoxy-pyridine hydrochloride 41.23g, 35 °C stirring for 2 hours, reducing pressure and evaporating ethanol, dichloromethane is used for residue 100 ml extraction, the organic phase is dried with anhydrous sodium sulfate, filtered, pressure-reducing evaporate dichloromethane, dichloroethane for: methyl tert-butyl ether = 4: mixed solvent recrystallization 1(V/V), for 30 °C vacuum drying 4 hours, shall be intermediate 77.78 g. apply the above-mentioned intermediate 30.02g stirring dissolved in the ethanol 400 ml in, the temperature is increased to 45 °C adding sodium borate 35.05g and 500 ml, to continue to heat insulation stirring for 2 hours, reducing pressure and evaporating ethanol, dichloromethane is used for extraction residue, the organic phase is dried with anhydrous sodium sulfate, filtered, pressure-reducing evaporate dichloromethane. Using dichloroethane: methyl tert-butyl ether = 4: mixed solvent recrystallization 1(V/V), for 30 °C vacuum drying to obtain the intermediate 27.58 g. Apply the above-mentioned intermediate 25.23g slowly adding 0.5mol/L aqueous hydrogen peroxide solution of 100 ml in, 20 °C after stirring to dissolve reaction 2.5 hours, filtering, the filtrate 30 °C vacuum drying 5 hours, dichloromethane is used for dried 100 ml dissolved, 23 °C reaction 2.0 hours, filtration, the filtration cake at 30 °C dried under vacuum to get crude Pantoprazole sodium 22.15 g. crude [...] 20.00g soluble in water 150 ml in, with 5percent of sodium hydroxide solution to adjust the pH value to 5.5, agitating precipitated insolubles, filtering, adding ethanol to the solid in 100 ml dissolved, with D101 macroporous resin adsorption, dichloromethane is used for 50 ml elution, the eluent for 30 °C vacuum drying, to obtain pantoprazole sodium 19.61 g.

Reference： [1] Patent: CN104910136, 2016, B, . Location in patent: Paragraph 0035; 0036; 0037; 0038; 0039

8
[ 102625-64-9 ]
[ 138786-67-1 ]

Yield	Reaction Conditions	Operation in experiment
65%	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.

Reference： [1] Patent: WO2007/68925, 2007, A1, . Location in patent: Page/Page column 16; 17; 18

9
[ 1310-73-2 ]
[ 102625-70-7 ]
[ 138786-67-1 ]

Reference： [1] Patent: WO2008/45777, 2008, A2, . Location in patent: Page/Page column 27-28
[2] Patent: EP2030973, 2009, A1, . Location in patent: Page/Page column 10-11

10
[ 97963-62-7 ]
[ 138786-67-1 ]

Reference： [1] Patent: CN107011252, 2017, A,

[ 138786-67-1 ] Synthesis Path-Downstream 1~31

1
[ 138786-67-1 ]
magnesium bis[5-[difluoromethoxy]-2-[[3,4-dimethoxy-2-pyridinyl]-methylsulfinyl]-1H-benzimidazolide] [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With magnesium chloride; In water; at 20 - 30℃; for 21 - 22h;	Svnthesis of Magnesium bis [5-[difluoromethoxyl-2-[[3,4-dimethoxy-2-pyridinyl]- methyl] sulfinyl]-1H-benzimidazolidel dihydrate 3.85 kg (8.9 mol) of pantoprazole Na sesquihydrate [sodium [5-[difluoromethoxy]-2-[[3,4-dimethoxy- 2-pyridinyl] methyl]sulfinyl]-1H-benzimidazolide]sesquihydrate] are dissolved at 20-25C in 38.5 of purified water in a stirring vessel. A solution of 1.0 kg (4.90 mol) of magnesium dichloride hexahydrate in 8 I of purified water is added with stirring at 20-30C in the course of 3 to 4 h. After stirring for a further 18 h, the precipitated solid is centrifuged, washed with 23 I of purified water, stirred at 20-30C for 1 to 2 h in 35 1 of purified water, centrifuged again and washed again with 30-50 1 of purified water. The solid product is dried at 50C in vacuo (30-50 mbar) until a residual water content of < 4.8% is achieved. The product is then ground. The title compound is obtained as a white to beige powder, which is employed directly for further pharmaceutical processing. Yield: 3.40 kg (90% of theory) ; water content: 4.5-4.6%; melting point: 194-196C with decomposition.

Reference： [1]Patent: WO2005/107721,2005,A2 .Location in patent: Page/Page column 14

2
[ 138786-67-1 ]
pantoprazole sodium [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In ethanol; for 24h;Heating / reflux;	<strong>[138786-67-1]Pantoprazole sodium</strong> Form II (5.0 g) was dissolved at room temperature in absolute ethanol (120 ML) in a flask equipped with a Soxlet extractor containing 30 g of 4A molecular sieves and a condenser mounted atop the Soxlet extractor. The solution was refluxed for 24 h with the condensed solvent passing through the bed of molecular sieves and was returned to the flask. Ethanol was removed by evaporation under vacuum, giving a residue. The residue was triturated with MTBE (50.0 ML) for two hours. The solid was filtered and dried at 50 C under 10 mm Hg vacuum to afford amorphous <strong>[138786-67-1]pantoprazole sodium</strong>.
	In tert-butyl methyl ether; acetonitrile; at 20℃; for 48h;	<strong>[138786-67-1]Pantoprazole sodium</strong> Form II (5.0 g) was dissolved in acetonitrile (25 ML) at room temperature. MTBE (250 ML) was then slowly added. The solution was allowed to stand at room temperature for two days, giving the crystallized product. The precipitate was filtered and dried at 65 C for two hours under ambient pressure to afford a mixture of <strong>[138786-67-1]pantoprazole sodium</strong> monohydrate and amorphous <strong>[138786-67-1]pantoprazole sodium</strong>.
	at 100℃;	<strong>[138786-67-1]Pantoprazole sodium</strong> sesquihydrate was dried at 100C under 10 mm vacuum overnight, giving amorphous <strong>[138786-67-1]pantoprazole sodium</strong>

Reference： [1]Patent: WO2004/56804,2004,A2 .Location in patent: Page 36
[2]Patent: WO2004/56804,2004,A2 .Location in patent: Page 36
[3]Patent: WO2004/56804,2004,A2 .Location in patent: Page 36

3
[ 102625-70-7 ]
[ 138786-67-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium hydroxide; In water; acetonitrile; at 20℃;	Pantoprazole (5 g, 25.6 mmol) and 47% NaOH (1 eq.) are added to acetonitrile (25ml) and stirred at room temperature. After 3 h, the mixture becomes clear, and crystals beginto form. The mixture is allowed to stand overnight. The crystals are filtered and dried at50C under 10 mm Hg vacuum. The crystals are determined to be the sesquihydrate form ofpantoprazole sodium by PXRD and are found to have a water content of 7.0% by Karl Fisheranalysis. Yield: 95%.
95%	With sodium hydroxide; In ethanol; for 5h;Reflux;	In a 250 mL three-necked flask, pantoprazole (7.7 g, 20 mmol), sodium hydroxide (1 g, 25 mmol)Ethanol (50 mL), and the mixture was heated under reflux with stirring for 5 hours. Cooled to below 10 , precipitation of white solid precipitation, filtration crude. Recrystallization from ethanol-petroleum ether gave a white solid which was dried to give pantoprazole sodium, the product yield was 95%.
92%	With sodium hydroxide; In water; ethyl acetate; at 20℃; for 5.5h;	Pantoprazole (20 g), solid NaOH (2.089 g, 1 eq.), and water (3.3 ml) are added toethyl acetate (200 ml) and stirred at room temperature. The mixture becomes clear. Crystalsbegin to form after 30 min. The crystals are filtered after 5 h and dried at 50C under 10 mmHg vacuum. The crystals (20.5 g) are determined to be the sesquihydrate form ofpantoprazole sodium by PXRD and are found to have a water content of 6.52% by KarlFisher analysis. Yield: 92%.

92.7%	With sodium hydroxide; In water; acetone; for 0.5h;	[EXAMPLE 3]Preparation of pantoprazole sodium637mL of acetone and 102g of pantoprazole were introduced into a reactor and a sodium hydroxide solution (containing 11.7g of sodium hydroxide in 5OmL of purified water) was slowly added drop wise to the above mixture. After stirring the solution for 30 minutes, the reaction mixture was partially concentrated under vacuum. The remaining residue was cooled to 0 to 5 C and the resultant solids were filtered. After adding 102OmL of acetone to the filtered solids, the mixture was dissolved at elevated temperature. The reaction mixture was again cooled to 0 to 5 C and filtered. Finally, the filtered product was washed with acetone and subjected to vacuum drying, thus yielding a final product.Amount of final product: lOOg (yield: 92.7%)
90%	With sodium hydroxide; In methanol; toluene; at 20℃;	Pantoprazole (5 g, 25.6 mmol), solid NaOH (0.574 g, 1.1 eq.), and methanol (MeOH)(0.5 ml) are added to toluene (25 ml) and stirred at room temperature. After 3 h, the mixturebecomes clear and crystals begin to form. The mixture is left overnight. The crystals arefiltered and dried at 50C under 10 mm Hg vacuum. The crystals are determined to be thesesquihydrate form of pantoprazole sodium by powder X-ray diffraction (PXKD) and arefound to have a water content of 7.2% by Karl Fischer analysis. Yield: 90%.
85%	With sodium hydroxide; sodium hypochlorite; In acetonitrile; at 0℃; for 4h;	A flask was charged with acetonitrile (60 ml). The flask was cooled to 0C and thenNaOCl (72.6 g, 9.82% active, 1.25 eq.), NaOH pellets (13.1 g, 4 eq.), and compound VI (30g) were added to the flask. The mixture was stirred at 0C for 4 h. During that time,pantoprazole sodium precipitated. The recovered precipitate was recrystallized in ethylacetate involving hot filtration of inorganic salts. Pantoprazole sodium that was free ofcompound VI and the sulfone within the limit of detection was recovered in 85% yield
65%	With sodium hydroxide; In water; acetone; at 2℃; for 2h;	A 100 ML round bottomed flask equipped with a magnetic stir bar was charged with acetone (50 ml). Pantoprazole (10 g, 25.7 mmol) was then added to the flask. After the pantoprazole had completely dissolved, the solution was cooled to about 2 C. Forty seven percent sodium hydroxide (aq. ) equivalent to 2.4 grams of solid sodium hydroxide (60.0 mmol) was slowly added to the cooled solution. A precipitate began to form immediately. The mixture was stirred for another two hours while the flask was allowed to warm to room temperature. The precipitate was filtered and washed with acetone (20 ML) and dried at 40C under vacuum to yield pantoprazole sodium Form II (6.9 g, 65%).
	With sodium hydroxide; In methanol; at 25 - 30℃; for 2h;	Pantoprazole (10.0 gm) is dissolved in methanol (30 ML), sodium hydroxide (1.1 gm) is added at 25C and stirred for 2 hours at 25C to 30C. Then diisopropyl ether (250 ml) is added to the solution and stirred for 1 hour at 25C to 28C. The separated solid is filtered to give 9.0 gm of pantoprazole sodium FORM 1.
	With sodium hydroxide; In acetonitrile; at 25 - 30℃; for 3h;	Pantoprazole (10. 0 gm) is dissolved in acetonitrile (50 ML), sodium hydroxide (1.1 gm) is added slowly at 25C to the clear solution. The contents are stirred for 3 hours at 25C to 30C. Then diisopropyl ether (300 mi) is added to the solution and stirred for 2 hours at 25C to 30C. The separated solid is filtered to give 9.1 gm of pantoprazole sodium form LI.
	With sodium hydroxide; In water; acetonitrile; at 0 - 45℃; for 3.33333h;	20 kg of dry pantoprazole was charged to 100 liters of acetonitrile followed by warming to 40C to get a clear solu- tion. To this solution 2.1 kg of sodium hydroxide dissolved in 4 kg of water was added. Solution was stirred for 20 minutes at 40 to 45C, which then cooled the room temperature slowly and stirred for 1 hour. The mixture was then cooled to about 0 C and aged for 2 hours under ice-cooling. Precipitated product was centrifuged and washed with 20 liters of ice-cold acetonitrile. Centrifuge content was spun to dryness. 21 kg of wet cake was obtained. This product was optionally dried under vacuum or could directly be used in the purification process.
	With sodium hydroxide; In water; acetone; at 20 - 25℃;	Example 1 : Preparation of Pantoprazole Sodium2-Mercapto-5-difluoromethoxy benzimidazole (50 g) was added to an aqueous solution of sodium hydroxide (21.3 g in 350 mL de-ionized water) at room temperature to obtain a clear solution. An aqueous solution of 2-chloromethyl-3, 4-dimethoxypyridine hydrochloride (50 g in 150 mL water) was added to the above solution over a period of about 2.0-2.5 hours. The reaction mixture was stirred vigorously for about 2-2.5 hours. Progress of the reaction was monitored by thin-layer chromatography. The reaction mixture was extracted with dichloromethane and washed with water. Organic layer was concentrated. Methanol (50 mL) was added to the organic layer. The reaction mixture was cooled to -5 to -200C. Aqueous solution of sodium hydroxide (11.8 g in 50 mL water) was added followed by addition of sodium hypochlorite solution (431 mL) in an aqueous solution of sodium hydroxide (20 g/ 100 mL) over a period of about 30 to about 45 minutes. The progress of the reaction was monitored by thin-layer chromatography. After completion of the reaction, the reaction mixture was quenched with 5% sodium hydrogen sulphite solution (500 mL). Water (500 mL) was added. pH of the reaction mixture was adjusted to 9.0-10.5. Layers were separated and the aqueous layer was extracted with dichloromethane. The combined dichloromethane layers were concentrated completely to obtain a red-brown colored residue.The residue was dissolved in acetone (375 mL). The reaction mixture was cooled to 20-250C. Aqueous solution of sodium hydroxide (9.2 g in 25 mL water) was added followed by addition of a seed crystal of pantoprazole sodium. The reaction mixture was stirred, cooled, stirred, filtered and washed with cold acetone to obtain crude pantoprazole sodium as a wet cake.
	With sodium methylate; In methanol; at 20℃;	30g (0.078mol) of 5-(difluoro-methoxy)-2-[[3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]- lH-benzimidazole (Pantoprazole base) was dissolved in 16.24 g (0.078 mol) sodium methoxide solution at room temperature. The obtained mixture was treated with activated charcoal (3 g) & stirred for 30 minutes. Filter the reaction mixture through celite. The clear filtrate was concentrated under reduced pressure till dryness. To the resulting solid material, added methanol (20 ml) & water (6 ml) & stirred for 15 min to get clear solution. To this solution methylene chloride & diisopropyl ether were added and stirred. The precipitated solid was filtered, and washed with diisopropyl ether. Dried the product at 40-450C to obtain title compound 28.9 g (Yield: 85.5 % and HPLC: 99.88 %).
		Add pantoprazole 80g to the reaction flask.640mL of dichloromethane,Methanol 120mL,Stir until dissolved.Cool down to -5 C,In 30 minutes,Add 60 g of sodium hydroxide to a solution of 160 mL of water at 0 C;After the addition is completed,Temperature control 0 C,Reaction for 30 minutes;Filtered, dichloromethane 80mL / wash,Wash 3 times;The wet powder is dried under vacuum at 35 C to a constant weight.Get pantoprazole sodium 84.1g.Oxazole from pantoprazole sodium by weight of crude pantoprazole sodium to yield the finished product was 89.5%.
	With sodium hydroxide; In water; acetone; at 40 - 45℃;	120 ml of water and 80 g (2 mol) of sodium hydroxide were added to the stirred tank to stir and dissolve, and then 5000 ml of acetone was added. After heating to 40 C, 600 g of pantoprazole (1.57 mol, obtained in Example 41) was slowly added, and the temperature was raised to heating. After 45 C, stir the reaction for 25 to 30 minutes.Control the internal temperature at 45 C ~ 48 C, then add activated carbon,The decolorization reaction was stirred for 30 minutes while raising the temperature to 49 C to 50 C.After the reaction is finished, it is filtered while hot.60g of activated carbon was removed, the filtrate was stirred and crystallized at normal temperature, and the crystal was cooled to below -10 C for 3 hours or more, filtered, and the solid filtered out was washed twice with cold acetone. The amount of acetone used for each wash was 150 ml. Dry to give pantoprazole sodium in white powder.The impurity A content was 0.021%, the impurity B content was 0.008%, the impurity C content was 0.011%, and the HPLC purity was more than 99.5%. Further, when the sodium salt was prepared using the pantoprazole obtained in Examples 42 to 45 as a raw material, the content of the impurity A in the obtained sodium salt was between 0.010 and 0.035%, and the content of the impurity B was between 0.005 and 0.020%, and the impurity C The content is between 0.004 and 0.012%.
	With sodium hydroxide; In water; acetone; for 0.5h;Reflux;	Add 900kg of acetone to the reaction kettle, then add 56kg of sodium hydroxide solution (dissolve 27kg of sodium hydroxide in purified water and 29kg) and stir; weigh 125kg of pantoprazole free base, add to the reaction kettle and stir evenly; warm to reflux and stir 30 minutes.Turn off the stirring and heating, control the temperature 0-15 , let crystallize for 15-20 hours.After centrifugal spinning, the filtrate was dried in vacuum for 24 hours to obtain pantoprazole sodium monohydrate.

Reference： [1]Patent: WO2004/111029,2004,A2 .Location in patent: Page 24
[2]Patent: CN107011252,2017,A .Location in patent: Paragraph 0101; 0103
[3]Patent: WO2004/111029,2004,A2 .Location in patent: Page 24
[4]Patent: WO2009/75516,2009,A2 .Location in patent: Page/Page column 5
[5]Patent: WO2004/111029,2004,A2 .Location in patent: Page 24
[6]Patent: WO2004/111029,2004,A2 .Location in patent: Page 25
[7]Patent: WO2004/56804,2004,A2 .Location in patent: Page 35
[8]Patent: WO2004/99183,2004,A1 .Location in patent: Page 4
[9]Patent: WO2004/99183,2004,A1 .Location in patent: Page 5
[10]Patent: WO2005/77936,2005,A1 .Location in patent: Page/Page column 19-20
[11]Patent: WO2009/10937,2009,A1 .Location in patent: Page/Page column 11
[12]Patent: WO2009/116072,2009,A2 .Location in patent: Page/Page column 16
[13]Patent: CN108503622,2018,A .Location in patent: Paragraph 0033; 0036; 0037; 0038; 0041; 0042; 0043; 0046
[14]Patent: CN109354587,2019,A .Location in patent: Paragraph 0228-0236
[15]Patent: CN111057044,2020,A .Location in patent: Paragraph 0032-0034

Yield	Reaction Conditions	Operation in experiment
~ 100%	Purification / work up;	Pantoprazole sodium (5.0 gm) is dissolved in methanol (50 mi) at 25C. The solution is subjected to vacuum drying at about 50C for 7 hours to give amorphous pantoprazole sodium in near quantitative yield.
	Purification / work up;	Pantoprazole sodium (5.0 gm) is dissolved in methanol (15 ml) at 30C and then diisopropyl ether (250 mi) is added. The contents are stirred for 24 hours at 25C to 30C and filtered to give 4. 8 gm of pantoprazole sodium form 1.; Example 7; Example 1 is repeated using pantoprazole sodium form 11 instead of pantoprazole sodium. The yield of pantoprazole sodium form I is 4.6 gm.
	Purification / work up;	Pantoprazole sodium (10.0 gm) is dissolved in acetonitrile (50 ml) at 30C and then diisopropyl ether (300 ml) is added. The contents are stirred for 6 hours at 25C to 30C and filtered to give 4.5 gm of pantoprazole sodium form 11.; Example 6; Example 3 is repeated using PANTOPRAZOLE sodium FORM I instead of pantoprazole sodium. The yield of pantoprazole sodium form 11 is 4.1 gm.

	Purification / work up;	Pantoprazole sodium (5.0 gm) is mixed with toluene (100 ML), heated to 70C and then acetonitirile (50 ml) is added to form a clear solution. The solution is cooled to 30C, stirred for 20 hours at 25C to 30C and the separated solid is filtered to give 4.3 gm of pantoprazole sodium form 11.
	Purification / work up;	Example 8 is repeated by subjecting the solution to spray drying instead of vacuum drying to give amorphous PANTOPRAZOLE sodium.
	In di-isopropyl ether; acetone; at 25 - 55℃; for 0.25h;Purification / work up;	Pantoprazole sodium (75 gms) as prepared according to Example- 1 or Example-2 was dissolved in 375 ml of acetone at about 50 - 55 C, and reaction mass was stirred for 15 minutes and filtered hot. The resulting clear filtrate was cooled to about 25-300C and 375ml of diisopropyl ether was added under stirring the resulting product was filtered and dried at 35-400C to give pantoprazole sodium (72 gms ). The dried product was stirred in mixture of 216ml ethylacetate and 3.6ml purified water forl hr.; the slurry was then chilled and stirred at 0-50C for about 1 hr. The product was filtered and dried at 40 - 45 C under vacuum to give pantoprazole sodium sesquihydrate (68 gms.) having a moisture content of 6.5 %.Example- 6Preparation of pantoprazole sodium monohydratePantoprazole sodium (75 gms) as prepared according to Example- 1 or Example-2 was dissolved in 375 ml of acetone at about 50 - 55 C, and reaction mass was stirred for 15 minutes and filtered hot. The resulting clear filtrate was cooled to about 25-300C and 375ml of diisopropyl ether was added the resulting solid was filtered and dried under vacuum at 35-400C to give pantoprazole sodium (72 gms ). The dried product was stirred in 216ml ethylacetate forl hr. and was then chilled and stirred at 0-50C for 1 hr. The product was isolated by filtration and dried at 40 - 45 C under vacuum to give pantoprazole sodium monohydrate (68 gms.) having a moisture content of 4.5 %.

5
[ 651728-72-2 ]
[ 138786-67-1 ]
3-[5-difluoromethoxy-2-{(3,4-dimethoxy-pyridin-2-yl)-methanesulfinyl}-benzimidazole-1-sulfonyl]benzoic acid 2-(toluene-4-sulfonyl)ethyl ester [ No CAS ]
[ 651728-78-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; triethylamine; In dichloromethane; at 20℃; for 1.5h;	To a heterogeneous mixture [OF 5-DIFLUOROMETHOXY-2-{(3, 4-DIMETHOXY-] [PYRIDIN-2-YL)-METHANESULFINYL}-LH-BENZIMIDAZOLE SODIUM] salt (PANTAPRAZOL sodium salt, 1.0 g, 2.3 mmol), 5 [ML] of Et3N, and about 1 g [OF NAHCO3] in [CHZCLZ] (15 mL) was added the sulfonyl chloride (Intermediate 43,1. 12 g, 2.77 mmol, 1.2 eq) in [CH2CL2AT] room temperature, and then the mixture was stirred for 1.5 h. Thereafter water was added, the mixture was extracted with [CH2CL2,] and the organic layers were dried, and concentrated. The resulting residual oil was purified by column chromatography [(CH2CL2TO 1%] [MEOH] in [CH2C12)] to yield 1.0 g (58%) of a mixture of 3- [5-difluoromethoxy-2- { (3, [4-DIMETHOXY-PYRIDIN-2-YL)-METHANESULFINYL}-BENZIMIDAZOLE-1-] sulfonyl] benzoic acid 2- (toluene-4-sulfonyl) ethyl ester (Intermediate [46)] and 3-[6-difluoromethoxy-2-{(3,4-dimethoxy-pyridin-2-yl)-methanesulfinyl}- benzimidazole-1-sulfonyl] benzoic acid 2- (toluene-4-sulfonyl) ethyl ester (Intermediate 47) as an off-white foam (1: 1 ratio between 5-and 6-isomer). 'H NMR (CDC13, 400 MHz) [52.] 27 and 2.29 (2 s, 3 H), 3.57 (m, 2 H), 3.93 (s, 6 H), 4.66 (m, 2 H), 5.03 (dd, 2 H), 6.53 (t, [J= 73.] 4, [5-OCHF2] or 6-OCHF2,1/2 H), 6.63 (t, [J=] 73.4, [5-OCHF2 OR 6-OCHF2,] 1/2 H), 6.86 (m, [1] H), 7.25 (m, 3 H), 7.59 (m, 1.5 H), 7.77 (m, 3 H), 8.05 (m, 1.5 H), 8.12 (d, [1] H), 8.32 (m, [1] H), 8.58 (2 s, 1 H).

Reference： [1]Patent: WO2004/9583,2004,A2 .Location in patent: Page 108

6
[ 651728-13-1 ]
[ 138786-67-1 ]
4-[5-difluoromethoxy-2-{(3,4-dimethoxypyridin-2-yl)methanesulfinyl}benzimidazole-1-sulfonyl]phenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester [ No CAS ]
[ 651728-69-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; triethylamine; In dichloromethane;	To a heterogeneous solution [OF 5-DIFLUOROMETHOXY-2- [ (3, 4-DIMETHOXY-] pyridin-2-yl)-methanesulfinyl]-1H-benzimidazole sodium salt (4.3 g, 10.0 mmol) and 6 mL of Et3N in 50 mL [OF CH2CL2 WAS] added the [CHLOROSULFONYL] ester (Intermediate 4,5. [0] g, 11. [5] mmol, 1.15 [EQ).] About 2 g of solid [NAHC03] was added after the [CHLOROSULFONYL] ester has dissolved completely in the reaction mixture. (Without addition of NaHC03 the mixture became black when the reaction was complete. ) 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 7.8 g (99%) of a mixture of 4- [5- difluoromethoxy-2- [{ (3, 4-DIMETHOXY-PYRIDIN-2-YL)-METHANESULFINYL}-] benzimidazole-1-sulfonyl] phenoxyacetic acid 2- (toluene-4-sulfonyl) ethyl ester and [4-[6-DIFLUOROMETHOXY-2-{(3, 4-DIMETHOXY-PYRIDIN-2-YL)-METHANESULFINYL}-] [BENZIMIDAZOLE-1-SULFONYL] PHENOXYACETIC] acid 2- (toluene-4-sulfonyl) ethyl ester (Intermediates 41 and 42; 1: 1 ratio) as an off-white foam. 'H NMR (CDC13, 400 MHz) [J2.] 40 (s, 3 H), 3.43 (m, 2 H), 3.90 (s, 3 H), 3.93 (s, 3 H), 4.52 (m, 4 H), 4.95 (dd, 2 H), 6.55 [(T,] J= 73.4, [5-OCHF2 OR] 6-OCHF2, 1/2 H), 6.59 (t, [J=] 73.4, 5-OCHF2 or 6-OCHF2, 1/2 H), 6.78 (m, 1 H), 6.95 (dd, 2 H), 7.20-7. 70 (m, 4 H), 7.77 (m, 3 H), 7.92-8. 20 (m, 3 H).

Reference： [1]Patent: WO2004/9583,2004,A2 .Location in patent: Page 100-101
[2]Molecules,2009,vol. 14,p. 5247 - 5280

7
[ 368890-20-4 ]
[ 124-41-4 ]
[ 138786-67-1 ]

Yield	Reaction Conditions	Operation in experiment
70.8%	In methanol; at 50℃;Heating / reflux;	Example 5: Synthesis of 5-(difluoromethoxy)-2-[[(3,4-of-methoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole sodium salt, sesquihydrate (I) A 3000 ml round-bottom flask is loaded with 464 g (2,58 mol) of a 30% solution of sodium methoxide in methanol and heated at 50C. 200 g (0.516 mol) of 5-(difluoromethoxy)-2-[[(4-chloro-3-methoxy-2-pyridinyl)methyl]sulfinyl]-1H- benzimidazole are then added in portions, while refluxing to complete the reaction. The reaction mixture is cooled to 35C and added with 700 ml of demineralised H2O and 2000 ml of toluene, in portions. All the methanol is removed by azeotropical distillation under reduced pressure (about 50 mm Hg) without exceeding 35C. Demineralised H2O is then added at 50C until complete dissolution and the pantoprazole sodium salt is extracted by adding 850 ml of methyl ethyl ketone, then separating the exhausted aqueous phase. The organic phase is partially concentrated and cooled to 20C; the crystallized product is filtered and washed with 200 ml of methyl ethyl ketone and 200 ml of acetone. 185 g of wet product are obtained (equivalent to 148 g dry product- yield = 70.8%). The resulting pantoprazole sodium sesquihydrate can be further purified according to known methods.

Reference： [1]Patent: EP1518857,2005,A1 .Location in patent: Page/Page column 5-6

Yield	Reaction Conditions	Operation in experiment
		Under nitrogen atmosphere, 0.276 G Ethylenediamine tetraacetic acid disodium salt and 6.7 G sodium hydroxide (1 N aqueous solution) are added to 480 G water for injection of 4C to 8C. 12.47 G panto- PRAZOLE sodium sesquihydrate is added while stirring to give a clear solution. The weight of the solution is adjusted to 500 G by addition of water for injection. The pH of the solution is 11.76. The solution is filtered through a 0.2 um membrane filter and filled in glass vials (1.81 G by vial ; glass vial of type I glass according to European Pharmacopoeia having a nominal content of 12 ML-FIOLAX(at)). FILLED VIALS are semi-stoppered (type 1 butyl rubber stopper according to European Pharmacopoeia 2002; nominal size 20) and put into a freeze-dryer (e. g. GT4 Edwards/Kniese or GT8 Amsco) for lyophilisation. The vials are cooled TO-45C, then the temperature is raised to-20 TO-5C under vacuum (0.1 to 0.5 mbar) for drying. After finishing main drying the temperature is raised to 30C, the vacuum is adjusted to 0.01 mbar and drying is continued for an additional 3 hours. The pressure is raised to 500 mbar by flushing with nitrogen and the vials are stoppered and crimped. An off-white lyophilized product is ob- tained which is easily reconstituted with physiological saline to give a clear solution.
		Under nitrogen atmosphere, 2.45 G sodium hydroxide (1 N aqueous solution) is added to 480 G water for injection OF 4C to 8C. 12.47 G PANTOPRAZOLE sodium sesquihydrate is added while stirring to give a clear solution. The weight of the solution is adjusted to 500 G by addition of water for injection. The pH of the solution is 11.5. The solution is filtered through a 0. 2 um membrane filter and filled in glass vials (1.81 G by vial ; glass vial of TYPE I glass according to European Pharmacopoeia having a nominal con- tent of 12 ML-FIOLAX0). FILLED VIALS are semi-stoppered (type 1 butyl rubber stopper according to European Pharmacopoeia 2002; nominal size 20) and put into a freeze-dryer (e. g. GT4 Ed- wards/Kniese or GT8 Amsco) for lyophilisation. The vials are COOLED TO-45C, then the temperature is raised to-20 to-5C under vacuum (0.1 to 0.5 mbar) for drying. After finishing main drying the tem- perature is raised to 30C, the vacuum is adjusted to 0.01 mbar and drying is continued for an addi- tional 3 hours. The pressure is raised to 500 mbar by flushing with nitrogen and the vials are stoppered and crimped. An OFF-WHITE LYOPHILIZED product is obtained.
		Under nitrogen atmosphere, 0.05 G Ethylenediamine tetraacetic acid disodium salt is added to 480 G water for injection OF 4C to 8C. 12.47 G <strong>[138786-67-1]pantoprazole sodium</strong> sesquihydrate is added while stirring to give a clear solution. The weight of the solution is adjusted to 500 G by addition of water for injection. The pH of the solution is 10.2. The solution is filtered through a 0.2 um membrane filter and filled in glass vials (1.81 G by vial ; glass vial of type I glass according to European Pharmacopoeia having a nominal content of 12 ML-FIOLAX0). FILLED VIALS are semi-stoppered (type 1 butyl rubber stopper ac- cording to European Pharmacopoeia 2002; nominal size 20) and put into a freeze-dryer (e. g. GT4 Ed- wards/Kniese or GT8 Amsco) for lyophilisation. The vials are cooled TO-45C, then the temperature is raised to-20 to-5C under vacuum (0.1 to 0.5 mbar) for drying. After finishing main drying the tem- perature is raised to 30C, the vacuum is adjusted to 0.01 mbar and drying is continued for an addi- tional 3 hours. The pressure is raised to 500 mbar by flushing with nitrogen and the vials are stoppered and crimped. An OFF-WHITE LYOPHILIZED product is obtained.

		Under nitrogen atmosphere, 12.47 G <strong>[138786-67-1]pantoprazole sodium</strong> sesquihydrate is added to 480 G water for injection of 4C to 8C while stirring to give a clear solution. The volume of the solution is adjusted to 500 G by addition of water for injection. The pH of the solution is 10.85. The solution is filtered through a 0.2 um membrane filter and filled in glass vials (1.81 G by vial ; glass vial of TYPE I glass according to European Pharmacopoeia having a nominal content of 12 ML-FIOLAX (E)). FILLED VIALS are semi- stoppered (type 1 butyl rubber stopper according to European Pharmacopoeia 2002; nominal size 20) and put into a freeze-dryer (e. g. GT4 Edwards/Kniese or GT8 Amsco) for lyophilisation. The vials are cooled TO-45C, then the temperature is raised to-20 to-5C under vacuum (0.1 to 0.5 mbar) for drying. After finishing main drying the temperature is raised to 30C, the vacuum is adjusted to 0.01 mbar and drying is continued for an additional 3 hours. The pressure is raised to 500 mbar by flushing with nitrogen and the vials are stoppered and crimped. An OFF-WHITE LYOPHILIZED product is obtained.
	In acetone;Reflux;Purification / work up;	The wet cake of <strong>[138786-67-1]pantoprazole sodium</strong> (115 g) obtained in example-1 was dissolved in acetone (250 mL) at reflux, charcoalized, filtered and washed with acetone to obtain a clear filtrate. The filtrate was partially concentrated under reduced pressure. The precipitated solid was stirred at room temperature for about 1 hour. The reaction mixture was cooled to about 10 C. to about 20 C., stirred for about 1 hour, filtered and washed with acetone to obtain pure <strong>[138786-67-1]pantoprazole sodium</strong> monohydrate. Yield: 84 g HPLC Purity: 99.9%
	In ethanol; dichloromethane; at 0 - 5℃;Purification / work up;	<strong>[138786-67-1]Pantoprazole sodium</strong> monohydrate (50 g) was dissolved in a mixture of dichloromethane (500 mL) and ethanol (30 mL). A seed crystal (0.2 g) was added followed by addition of dichloromethane (750 mL). The reaction mixture was cooled to about 0-5 C., stirred for about 5-6 hours, filtered and washed with dichloromethane to obtain <strong>[138786-67-1]pantoprazole sodium</strong> sesquihydrate. Yield: 45 g HPLC Purity: 99.9% Water Content: 6.1-6.5

9
[ 138786-67-1 ]
[ 812664-93-0 ]
[ 812664-94-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; sodium hypochlorite; In water; acetonitrile; at 20℃; for 12h;	<strong>[138786-67-1]Pantoprazole sodium</strong> (5.0g, 12 mmol) was dissolved in 100 ml of acetonitrile. Then 4nil of 20% aq. sodium hydroxide (4 ml, 1.8 eq.) was added followed by addition of sodiumhypochlorite (17 ml, 9%, 24 mmol, 1.8 eq.) dropwise at room temperature. The mixture wasstirred for additional 12 hours and then 10% aq. sodium metabisulfite solution was added topH 8-9, and the mixture was stirred at room temperature for 1 hour. After phase separation,acetonitrile was evaporated under vacuum at room temperature. The products were separatedby flash column chromatography (SiOi, ethyl acetate) giving compound IV (200 mg) andcompound V (200 mg).Compound IV: .H-NMR (600 MHz, CD3CN) 8 (ppm): 3.86 (s,3H), 3.88 (s,3H), 6.63(s,lH), 6.83 (t,lH, JH-F=74.5Hz, JC-F=257.5Hz), 7.04 (d,lH, J=5.6Hz), 7.20 (dd, 1H, .7=1.8and 8.4Hz), 7.43 (br,lH), 7.66 (br,lH), 8.32 (d,lH, /=5.6Hz); 13C-NMR (300 MHz, CD3CN),8 (ppm): 56.88, 62.33,69.72,107.80,110.52,117.73,118.03,145.60,146.86,146.94,147.67,148.96,149.07,154.33,160.11; MS (FAB+), m/z 418.031 (MH+ ion, calculated forCieHisNsC^CuSS: 418.0435; the m/z 420 isotope ion supports presence of one Cl atom).Compound V: .H-NMR (600 MHz, CD3CN) 5 (ppm): 3.888 (s,3H), 3.894 (s,3H),6.76 (t,lH, JH-F =75Hz, JC-F=256.5Hz), 7.06 (d,lH, /=5.4Hz), 7.07 (dd,lH, .7=2.4 and 9.0Hz),7.43 (dd,lH, .7=0.6 and 2.4Hz), 7.67 (dd,lH, .7=0.6 and 2.9Hz), 8.03 (d,lH, J=5.4Hz); 13C-NMR (300 MHz, CD3CN), 5 (ppm): 57.11,61.60, 98.07,108.65,111.83,117.25,118.11,120.27,141.54,143.50,143.81,146.34,146.51,148.61,150.66,161.37; MS (Cl+),m/z 434.0380 (MH+ ion, calculated for Ci6Hi5N3O5ClF2S: 434.0425; the m/z 436 isotope ionsupports presence of one Cl atom).

Reference： [1]Patent: WO2004/111029,2004,A2 .Location in patent: Page 26-27

10
[ 409098-86-8 ]
[ 138786-67-1 ]

Yield	Reaction Conditions	Operation in experiment
70.8%	With sodium methylate; In methanol; at 50℃;Heating / reflux;	A 3000 ml round-bottom flask is loaded with 464 g (2.58 mol) of a 30% solution of sodium methoxide in methanol and heated at 50 C. 200 g (0.516 mol) of 5-(difluoromethoxy)-2-[[(4-chloro-3-methoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole are then added in portions, while refluxing to complete the reaction. The reaction mixture is cooled to 35 C. and added with 700 ml of demineralised H2O and 2000 ml of toluene, in portions. All the methanol is removed by azeotropical distillation under reduced pressure (about 50 mm Hg) without exceeding 35 C. Demineralised H2O is then added at 50 C. until complete dissolution and the pantoprazole sodium salt is extracted by adding 850 ml of methyl ethyl ketone, then separating the exhausted aqueous phase. The organic phase is partially concentrated and cooled to 20 C.; the crystallized product is filtered and washed with 200 ml of methyl ethyl ketone and 200 ml of acetone. 185 g of wet product are obtained (equivalent to 148 g dry product-yield=70.8%). The resulting pantoprazole sodium sesquihydrate can be further purified according to known methods

Reference： [1]Patent: US2005/96352,2005,A1 .Location in patent: Page/Page column 4

11
[ 138786-67-1 ]
magnesium [5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazolide} hydroxy [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52.7%		25.0 G of <strong>[138786-67-1]pantoprazole sodium</strong> sesquihydrate are dissolved in 250 mi of water. 1.33 ML of NAOH 40 % are added at 25 C and the solution is stirred for 15 min. 3.92 g of magnesium chloride hexahydrate are dissolved in 31 ml of water. The magnesium chloride solution is added drop wise under stirring at 25 C to the PANTOPRAZOLE sodium salt solution. Stirring is continued for 2.5 h. The resulting suspension is filtered with suction, the precipitate washed in 3 portions with 150 mi of water. The precipitate is dried in a vacuum dryer (< 50 mbar) at 40-45 C to give 12.47 g (52.7 %) of the title compound of M. p. 182-185 C (decomposition) as off-white solid. Analysis : EXPECTED* FOUND C 44,87 45,50 H 4,00 4,03 N 9,81 10,01 Mg 3, 78 3, 9 *as tetrahydrate

Reference： [1]Patent: WO2005/11692,2005,A1 .Location in patent: Page/Page column 8

12
[ 138786-67-1 ]
clcium [5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazolide} hydroxy [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91.8%		21.6 g of <strong>[138786-67-1]pantoprazole sodium</strong> sesquihydrate are dissolved in 250 ml of water. 2.00 g of NAOH are added at 25 C and the solution is stirred for 1 hour. 5.55g of calcium chloride (dry) are dissolved in 50 ml of water. The calcium chloride solution is added drop by drop under stirring at 25 C to the <strong>[138786-67-1]pantoprazole sodium</strong> solution. Stirring is continued for 20 hours. The resulting suspension is filtered with suction, the precipitate is washed with 200 ml of water and dried in a vacuum dryer (< 50 mbar) at 40-45 C to afford 21.86 g (91.8 %) of the title compound as off-white solid. Water (Karl-Fischer titration): 7.6 % Melting point: 157-160 C (decomposition) Analysis: expected found C 42.01 42,63 H 3.75 3.95 N 9. 19 9. 13

Reference： [1]Patent: WO2005/11692,2005,A1 .Location in patent: Page/Page column 10

13
[ 138786-67-1 ]
magnesium [5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazolide} hydroxy [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.6%		10. 7 G of PANTOPRAZOLE sodium sesquihydrate are dissolved in 110 ML of water. 2.48 g of NAOH 40 % are added at 25 OC and the solution is stirred for 1 h. 5. 01 g of magnesium chloride hexahydrate are dissolved in 20 ML of water, the solution is added drop wise under stirring at 25 C to the <strong>[138786-67-1]pantoprazole sodium</strong> salt solution. Stirring is continued for 1 h. The resulting suspension is filtered with suction, the precipitate washed with 50 mi of water. The precipitate is re-suspended in 100 mi of water and again filtered and dried in a vacuum dryer (< 50 mbar) at 40-45 C to give 10.76 g (94.6 %) of the title compound of m. p. 184-187 C (decomposition) as off-white solid. Analysis: EXPECTED FOUND C 43, 51 43, 87 H 3,88 4,10 N 9,51 9,68 Mg 5, 50 5, 2

Reference： [1]Patent: WO2005/11692,2005,A1 .Location in patent: Page/Page column 7

14
[ 138786-67-1 ]
[ 102625-70-7 ]

Yield	Reaction Conditions	Operation in experiment
		Crude sodium salt of pantoprazole was dissolved in 400 li- ters of ethylalcohol. The cloudy solution was filtered over celite to remove the insolubles. To thus obtained clear solu- tion 400 liters of water was added. Alcohol-water mixture was distilled to dryness under vacuum. The residue inside the ves- sel was cooled to 20 to 25C. 100 liters of 90 % v/v aqueous acetonitrile was added over the residue in order to precipitate the product. The mixture was stirred at room temperature until precipitation started and then cooled to-5/-10C and aged for 3 hours. Slurry was centrifuged and washed with 20 liters of ice- cooled acetonitrile and spun to dryness. Pure product was dried at 50C under vacuum to constant weight. Loss on drying test of the product: 0.12 %-by weight Total water content, determined by K. F.: 6.13 %-by weight Sulfone content 0,15 %-by weight Sulfide content 0,05 %-by weight Melting point 137C to 145C Crystallinity Needles

Reference： [1]Patent: WO2005/77936,2005,A1 .Location in patent: Page/Page column 20

15
[ 138786-67-1 ]
calcium bis[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl)-methylsulphinyl]-1H-benzimidazolide} [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With calcium chloride; In water; at 20℃; for 1.91667h;	Pantoprazole-Ca-Salt 43,2 g (100 mmol) of Pantoprazole-Na sesquihydrate are added to 600 mi of water and dissolved. 8,1 g (55 mmol) of calcium chloride are dissolved in 50 mi of water. The solution of calcium chloride is added to the solution of Pantoprazole-Na sesquihydrate at room temperature within 5 minutes. The suspension is stirred for additional 1,5 hours and the precipitation is filtered. The salt is washed with 300 mi of water, dried at 40-45 C in vacuum and yields 73% of theory. Mp: 158, 5 C (degradation), water content (Karl-Fischer) 7,5 %. CHN-Analysis : expected found (dihydrate) C 44,75 44,25 H 3,99 4,09 N 9, 79 9, 67 3.

Reference： [1]Patent: WO2005/74929,2005,A2 .Location in patent: Page/Page column 5

16
[ 138786-67-1 ]
zinc (S)-bis[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl)-methylsulphinyl]-1H-benzimidazolide} [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With zinc(II) chloride; In water; at 20℃; for 1.5h;	Examples 1. Pantoprazole-Zn-Salt 60 g (139 mmol) of Pantoprazole-Na sesquihydrate are added to 1 1 of water and dissolved. 11,37 g (83 mmol) of zinc chloride are dissolved in 200 mlof water. The moody solution of zinc chloride is filtered before use and added to the solution of Pantoprazole-Na sesquihydrate at room temperature within 30 minutes. The suspension is stirred for one additional hour and the precipitation is filtered. The salt is washed with 500 ml of water free of chloride, dried at 60 C in vacuum and yields 95% of theory. Mp: 166 C (degradation), water content (Karl-Fischer) 2,1 %. CHN-Analysis : expected found (monohydrate) C 45, 32 45,08 H 3,57 3,66 N 9, 91 9, 88 2.

Reference： [1]Patent: WO2005/74929,2005,A2 .Location in patent: Page/Page column 5

17
[ 97963-62-7 ]
[ 72830-09-2 ]
[ 138786-67-1 ]

Yield	Reaction Conditions	Operation in experiment
83%		2-Chloromethyl-3,4-dimethoxy pyridine hydrochloride (50 gms), 2-mercapto-5-difluoromethoxy15 benzimidazole (50 gms) and Tetra butyl ammonium bromide (2 gms) were added under stirring to dichloromethane (300 ml) followed by solution of sodium hydroxide ( 37.5 gms ) in 120 ml water.The contents were then stirred at 25 - 30 C for about 12 hours. After reaction completion, the dichloromethane layer was separated, then the aqueous layer was extracted with dichloromethane(60 ml) twice. The organic layers were combined together, water washed and distilled to about20 250ml and cooled to 00C. 3.5% aqueous sodium hypochlorite solution (464 g ) having a sodium hydroxide content of 2.2% was added to the reaction mass, which was maintained at 5 - 80C for about 6 hours. After completion of the reaction; the reaction mass was further cooled to 0 to 5C.The resulting solid was then filtered and washed with cold acetone (about 100ml ) and dried under vacuum at 35-400C to give pantoprazole sodium (75 gms, 83%) of purity greater than 99.5%.

Reference： [1]Patent: WO2006/64249,2006,A2 .Location in patent: Page/Page column 8; 10

18
[ 138786-67-1 ]
[ 797789-88-9 ]

Yield	Reaction Conditions	Operation in experiment
	In acetone;Heating / reflux;Purification / work up;	Example 2: Purification of Pantoprazole SodiumThe wet cake of <strong>[138786-67-1]pantoprazole sodium</strong> (115 g) obtained in example-1 was dissolved in acetone (250 mL) at reflux, charcoalized, filtered and washed with acetone to obtain a clear filtrate. The filtrate was partially concentrated under reduced pressure. The <n="13"/>precipitated solid was stirred at room temperature for about 1 hour. The reaction mixture was cooled to about 100C to about 200C, stirred for about 1 hour, filtered and washed with acetone to obtain pure <strong>[138786-67-1]pantoprazole sodium</strong> monohydrate.Yield: 84 g HPLC Purity: 99.9%
	With water; In ethyl acetate; acetone; at 0 - 55℃; for 2.25h;Product distribution / selectivity;	<strong>[138786-67-1]Pantoprazole sodium</strong> (75 gms) as prepared according to Example-1 or Example-2 was dissolved in 375 ml of acetone at about 50 - 55C, charcoal (5 gms) was added and the reaction mass was stirred EPO <DP n="13"/>for 15 minutes and filtered hot. The resulting clear filtrate was concentrated to approx. volume of 150 ml and ethyl acetate (400 ml) was added, distillation was continued until precipitation was observed in the reaction mass. The reaction mass was cooled to room temperature and the suspension was stirred for 1 hr. and later chilled and stirred at 0-50C for 1 hr. The product was isolated by filtration and dried at 40 - 45 C under vacuum to give <strong>[138786-67-1]pantoprazole sodium</strong> monohydrate (64 gms.) having a moisture content of 4.5%.
	With water; In ethyl acetate; at 0 - 5℃; for 2h;Product distribution / selectivity;	<strong>[138786-67-1]Pantoprazole sodium</strong> (75 gms) as prepared according to Example- 1 or Example-2 was dissolved in 375 ml of acetone at about 50 - 55 C, and reaction mass was stirred for 15 minutes and filtered hot. The resulting clear filtrate was cooled to about 25-300C and 375ml of diisopropyl ether was added the resulting solid was filtered and dried under vacuum at 35-400C to give <strong>[138786-67-1]pantoprazole sodium</strong> (72 gms ). The dried product was stirred in 216ml ethylacetate forl hr. and was then chilled and stirred at 0-50C for 1 hr. The product was isolated by filtration and dried at 40 - 45 C under vacuum to give <strong>[138786-67-1]pantoprazole sodium</strong> monohydrate (68 gms.) having a moisture content of 4.5 %.

Reference： [1]Patent: WO2009/10937,2009,A1 .Location in patent: Page/Page column 11-12
[2]Patent: WO2006/64249,2006,A2 .Location in patent: Page/Page column 11-12
[3]Patent: WO2006/64249,2006,A2 .Location in patent: Page/Page column 12

19
[ 138786-67-1 ]
pantoprazole sodium sesquihydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With water; In ethyl acetate; acetone; at 0 - 55℃; for 2.25h;Product distribution / selectivity;	<strong>[138786-67-1]Pantoprazole sodium</strong> (75 gms) as prepared according to Example- 1 or Example-2 was dissolved in 375 ml of acetone at about 50 - 55 C, charcoal (5 gms) was added and the reaction mass was stirred for 15 minutes and clarified hot. The resulting clear filtrate was concentrated to approx. volume of 150 ml, ethyl acetate (400 ml) was added and distillation was continued until precipitation was observed in the reaction mass. The reaction mass was cooled to room temperature and water (4.2 ml) was added, the suspension was stirred for 1 hr. and later chilled and stirred at 0-50C for 1 hr. The product was the isolated by filtration and was dried at 40 - 45 C under vacuum to give <strong>[138786-67-1]pantoprazole sodium</strong> sesquihydrate (68 gms.) having a moisture content of 6.5 %.
	With water; In ethyl acetate; at 0 - 5℃; for 2h;Product distribution / selectivity;	<strong>[138786-67-1]Pantoprazole sodium</strong> (75 gms) as prepared according to Example- 1 or Example-2 was dissolved in 375 ml of acetone at about 50 - 55 C, and reaction mass was stirred for 15 minutes and filtered hot. The resulting clear filtrate was cooled to about 25-300C and 375ml of diisopropyl ether was added under stirring the resulting product was filtered and dried at 35-400C to give <strong>[138786-67-1]pantoprazole sodium</strong> (72 gms ). The dried product was stirred in mixture of 216ml ethylacetate and 3.6ml purified water forl hr.; the slurry was then chilled and stirred at 0-50C for about 1 hr. The product was filtered and dried at 40 - 45 C under vacuum to give <strong>[138786-67-1]pantoprazole sodium</strong> sesquihydrate (68 gms.) having a moisture content of 6.5 %.

Reference： [1]Patent: WO2006/64249,2006,A2 .Location in patent: Page/Page column 11
[2]Patent: WO2006/64249,2006,A2 .Location in patent: Page/Page column 12

20
[ 97963-62-7 ]
[ 138786-67-1 ]

Reference： [1]Patent: CN107011252,2017,A
[2]Patent: CN109354587,2019,A

21
[ 138786-67-1 ]
pantoprazole sodium sesquihydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.4%	With water; In tert-butyl methyl ether; at 20 - 30℃; for 12h;Product distribution / selectivity;	EXAMPLES : Preparation of 5-(Difluoromethoxy)-2-[[(3,4-di-methoxy-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole sodium sesquihydrate Form-I (<strong>[138786-67-1]Pantoprazole sodium</strong> sesquihydrate Form-I)To a suspension of methyl tert-butyl ether (0.1L) and distilled water (0.0006L) was added <strong>[138786-67-1]pantoprazole sodium</strong> (0.01k) in one lot at room temperature. The suspension was stirred at room temperature (25-300C) for 12hrs to directly result in preparation of <strong>[138786-67-1]pantoprazole sodium</strong> sesquihydrateForm-I. The white solid was filtered and dried at 40-450C for 3 to 3.5hrs under 700mm vacuum to directly furnish <strong>[138786-67-1]pantoprazole sodium</strong> sesquihydrate Form-I which has also been observed to have PXRD, DSC scan and IR spectra similar to the one as shown in Figures IV, V and VI respectively, and expected C, H and N. Yield of end product has been found to be 92.4% and MC 6.69%.
91.93 - 93.7%	With water; In di-isopropyl ether; at 20 - 30℃; for 1 - 12h;Product distribution / selectivity;	EXAMPLE-I : Preparation of 5-(Difluoromethoxy)-2-[[(3,4-di-methoxy-2 -pyridinyl) methyl] sulfinyl]- lH-benzimidazole sodium sesquihydrate Form-I (<strong>[138786-67-1]Pantoprazole sodium</strong> sesquihydrate Form-I)To a suspension of diisopropyl ether (0.2L) and distilled water(0.0024L) was added <strong>[138786-67-1]Pantoprazole sodium</strong> (0.02K) in one lot at room temperature. The suspension was stirred at room temperature (25-300C) for lhr to directly result in preparation of <strong>[138786-67-1]pantoprazole sodium</strong> sesquihydrate Form-I. The white solid was Filtered and dried at 40-45C for 3 to 3.5hrs. under 700mm vacuum to directly furnish <strong>[138786-67-1]pantoprazole sodium</strong> sesquihydrate Form-I which has been observed to have PXRD, DSC scan and IR spectra shown in Figures IV, V and VI respectively, and expected C,H and N. Yield of end product has been found to be 93.7% and MC 7.01%. EXAMPLE-2 : Preparation of 5-(Difluoromethoxy)-2-[[(3,4-di-methoxy-2-pyridinyl)methyl] sulfinyl] - 1 H-benzimidazole sodium sesquihydrate Form-I (<strong>[138786-67-1]Pantoprazole sodium</strong> sesquihydrate Form-I)To a suspension of diisopropylether (5.0L) and <strong>[138786-67-1]pantoprazole sodium</strong> (0.5k) was added distilled water (0.03L) in one lot at room temperature. The suspension was stirred at room temperature (25-300C) for 12hrs to directly result in preparation of <strong>[138786-67-1]pantoprazole sodium</strong> sesquihydrate EPO <DP n="24"/>Form-I. The white solid was filtered and dried at 40-450C under 700mm vacuum for 3 to 3.5hrs to directly furnish <strong>[138786-67-1]pantoprazole sodium</strong> sesquihydrate Form-I which has also been observed to have PXRD, DSC scan and IR spectra similar to the one as shown in Figures IV, V and VI respectively, and expected C, H and N. Yield of end product has been found to be 93% and MC 6.59%.EXAMPLES : Preparation of 5-(Difluoromethoxy)-2-[[(3,4-di-methoxy-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole sodium sesquihydrate Form-I (<strong>[138786-67-1]Pantoprazole sodium</strong> sesquihydrate Form-I)To a suspension of diisopropylether (0.1L) and distilled water(0.0003L) was added <strong>[138786-67-1]pantoprazole sodium</strong> (0.01k) in one lot at room temperature. The suspension was stirred at room temperature (25-300C) for12hrs to directly result in preparation of <strong>[138786-67-1]pantoprazole sodium</strong> sesquihydrate Form-I. The white solid was filtered and dried at 40-450C for 3 to 3.5hrs under 700mm vacuum to directly furnish <strong>[138786-67-1]pantoprazole sodium</strong> sesquihydrate Form-I which has also been observed to have PXRD, DSC scan and IR spectra similar to the one as shown in Figures IV, V and VI respectively, and expected C, H and N. Yield of end product has been found to be 91.93% and MC 6.65%.
91.93%	With water; In diethyl ether; at 20 - 30℃; for 12h;Product distribution / selectivity;	EXAMPLE-4 : Preparation of 5-(Difluoromethoxy)-2-[[(3,4-di-methoxy-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole sodium sesquihydrate Form-I (<strong>[138786-67-1]Pantoprazole sodium</strong> sesquihydrate Form-I) To a suspension of diethyl ether (0.1L) and distilled water(0.0006L) was added <strong>[138786-67-1]pantoprazole sodium</strong> (0.01k) in one lot at room temperature. The suspension was stirred at room temperature (25-300C) for 12hrs to directly result in preparation of <strong>[138786-67-1]pantoprazole sodium</strong> sesquihydrate Form-I. The white solid was filtered and dried at 40-450C for 3 to 3.5hrs under 700mm vacuum to directly furnish <strong>[138786-67-1]pantoprazole sodium</strong> sesquihydrate Form-I which has also been observed to have PXRD, DSC scan and IR spectra similar to the one as shown in Figures IV, V and VI EPO <DP n="25"/>respectively, and expected C, H and N. Yield of end product has been found to be 91.93% and MC 6.75%.

91.4%	With water; at 0 - 35℃;Product distribution / selectivity;	[EXAMPLE 4] Preparation of <strong>[138786-67-1]pantoprazole sodium</strong> sesquihydrateWhile slowly introducing 70Og of <strong>[138786-67-1]pantoprazole sodium</strong> to 70OmL of purified water in a reactor, a temperature of the mixture was elevated to 25 to 35 C in order to dissolve the same. After dissolution was completed, the solution was again stirred at room temperature for 2 hours. Then, the solution was cooled to 0 to 5C and stirred overnight. The resultant crystals were subjected to filtration and vacuum drying at 30 to 35 C for 3 to 4 hours, thus yielding a final product.Amount of final product: 684g (yield: 91.4%)Moisture content (KF): 6.5% Residual solvent: acetone 9ppmH1 NMR (D2O, ppm): 3.60(s, 3H), 3.69(s, 3H), 4.47(d, IH), 4.68(d, IH), 6.68(s, IH), 6.72-6.87(m, 2H), 7.35(d, IH), 7.51(d, IH), 7.94(d, IH)
	With water; In dichloromethane; at 25 - 35℃; for 1.5h;Product distribution / selectivity;	Example-5: Preparation of <strong>[138786-67-1]pantoprazole sodium</strong> sesquihydrate form-I:A mixture of <strong>[138786-67-1]pantoprazole sodium</strong> anhydrous crystalline form (100 gr), methylene chloride (300 ml) and water (5 ml) was stirred for 90 minutes at 25-350C. Filtered the solid and washed with 25 ml of methylene chloride. Dried the compound at 40-5 O0C for 10 hours.Yield: 90 grams W.C : 6.1 %

Reference： [1]Patent: WO2007/17890,2007,A2 .Location in patent: Page/Page column 23
[2]Patent: WO2007/17890,2007,A2 .Location in patent: Page/Page column 21-22
[3]Patent: WO2007/17890,2007,A2 .Location in patent: Page/Page column 22-23
[4]Patent: WO2009/75516,2009,A2 .Location in patent: Page/Page column 5
[5]Patent: WO2008/1392,2008,A2 .Location in patent: Page/Page column 21

22
[ 102625-64-9 ]
5-(difluoromethoxy)-2-[(3,4-dimethoxypyridin-2-yl-1-oxide)methylsulfonyl]-1H-benzoimidazole [ No CAS ]
[ 138786-67-1 ]
Pantoprazole sulfone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65 - 74%	With sodium hydroxide; sodium hypochlorite; In water; ethyl acetate; at -5℃; for 1 - 1.5h;Product distribution / selectivity;	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 16,9% active sodium hypochlorite solution (or corresponding quantity depending on active chlorine assay) and 10% 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 10% 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 15% 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 5C 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 15,2% active sodium hypochlorite solution (or corresponding quantity depending on active chlorine assay) and 10% 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 10% 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 15% 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 5C and stirring it for 2,5 hours at this temperature crystallization occurs. A precipitate is filtered off to give pantoprazole sodium salt monohydrate.

Reference： [1]Patent: WO2007/68925,2007,A1 .Location in patent: Page/Page column 16; 17; 18

23
[ 1310-73-2 ]
[ 102625-70-7 ]
[ 138786-67-1 ]

Yield	Reaction Conditions	Operation in experiment
	In water; acetonitrile; at 25 - 35℃; for 1h;	EXAMPLE 4: PREPARATION OF PANTOPRAZOLE SODIUM SESQUIHYDRATE:A solution of sodium hydroxide (2.41 kg) in water (4.8 liters) was prepared and added to acetonitrile (10 liters) at 25 to 35 0C. The mixture was stirred for about 10 minutes and pantoprazole (22 kg) obtained above was added to it. The reaction mass was stirred for about 1 hour at 25 to 35 0C and checked for clear dissolution. Carbon (1.0 kg) was added to it and stirred for about 60 minutes. The reaction mass was filtered and the filtered bed was washed with acetonitrile (22 liters). The filtrate was distilled off completely at about 18 0C under a vacuum of 650 mm/Hg. The obtained residue was cooled to 25 to 35 0C and ethyl acetate (1 10 liters) was added to it. The reaction mass was stirred for about 20 minutes. The reaction mass was then stirred for about 5 hours at 25 to 35 0C and pure pantoprazole sodium sesquihydrate (0.1 1 kg) <n="29"/>was added as seeding material. The reaction mass was further maintained at 25 to 35 0C for about 5 hours, and then further cooled to about 0 to 5 0C. The reaction mass was stirred at 0 to 5 0C for about 3 hours and then filtered. The filtered solid was washed with ethyl acetate (22 liters), and dried at about 50 0C under a vacuum of about 650 mm/Hg for 12 hours to yield 19.5 kg of the title compound. Purity By HPLC: 99.93%. Impurity 1 (pantoprazole sulfide): 0.01 %. Impurity 1 (pantoprazole sulfone): 0.04%.
	In ethanol; dichloromethane; water; at 20℃;pH 12.5;Product distribution / selectivity;	iv. Preparation of pantoprazole sodium sesquihydrate; 50.0 g of pantoprazole were dissolved in 250 ml of methylene chloride and 15 ml of ethanol at room temperature. The resulting mixture was filtered to remove any undissolved particles. The solution of pantoprazole in methylene chloride and ethanol was treated with 25 ml of 6M aqueous solution of sodium hydroxide until the pH was 12.5 +/- 0.5 at 20 +/- 3 C. 500 ml of diisopropyl ether were slowly added to the solution of pantoprazole sodium. Crystallization was carried out at 20 +/- 3 C. The product was collected by filtration and washed with 50 ml of diisopropyl ether. The product was dried in a dryer at a temperature below 45C. During drying the product was sieved to deagglomerate lumps. 51.5 g of crystalline pantoprazole sodium sesquihydrate were obtained (purity: 99.70%, 0.15% PN2, 0.02% PN3, 0.03% PN4, 0.02% PN1). The X-ray powder diffraction pattern of the obtained pantoprazole sodium sesquihydrate (obtained on a Phillips PW3040/60 X'Pert PRO diffractometer using CuKalpha radiation, Filter: Ni; Voltage: 45kV; Current: 40mA) is shown in Figure 1. The water content measured according to Ph. Eur. 2.5.12. Method A was about 6.0 to 8.0 wt.-%.; vi. Preparation of pantoprazole sodium sesquihydrate 43.0 g (100 mmoles) pantoprazole magnesium dihydrate were suspended in 400 ml of ethanol at 20-25C, then 200 ml of water were added and the pH was adjusted to 7.5 - 8.0 using 6 % acetic acid. Pantoprazole was extracted with methylene chloride and clarified with activated charcoal. Collected organic layers were concentrated to 200 ml. The resulting mixture was optionally filtered to remove any undissolved particles. The solution of pantoprazole in methylene chloride and ethanol was treated with 23 ml of a 6M aqueous solution of sodium hydroxide until the pH was 12.5 +/- 0.5 at 20 +/- 3 C. 450 ml of diisopropyl ether were slowly added to the solution of pantoprazole sodium. Crystallization was carried out at 20 +/- 3 C. The product was collected by filtration and washed with 50 ml of diisopropyl ether. The product was dried in a dryer at a temperature below 45C. During drying the product was sieved to deagglomerate lumps. 38.5 g of crystalline pantoprazole sodium sesquihydrate were obtained.

Reference： [1]Patent: WO2008/45777,2008,A2 .Location in patent: Page/Page column 27-28
[2]Patent: EP2030973,2009,A1 .Location in patent: Page/Page column 10-11

24
[ 102625-64-9 ]
[ 138786-67-1 ]

Yield	Reaction Conditions	Operation in experiment
95.0%		Charge 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-rhoyridinyl) 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 0-5C. Add tert-butylhypochlorite solution in dichloromethane at 0-5C. Maintain the reaction mass at 0-5C 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- 25C 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=95.0%); HPLC purity= 99.65 % w/w.; Melting range- 142-145C.
78.7%		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), 30% 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 78.7%, mp> 150 C (decomposition), the content of 99 ? 93%. 7
	With sodium hypochlorite; sodium hydroxide; In methanol; water; at -20 - -5℃;	2-Mercapto-5-difluoromethoxy benzimidazole (50 g) was added to an aqueous solution of sodium hydroxide (21.3 g in 350 mL de-ionized water) at room temperature to obtain a clear solution. An aqueous solution of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (50 g in 150 mL water) was added to the above solution over a period of about 2.0-2.5 hours. The reaction mixture was stirred vigorously for about 2-2.5 hours. Progress of the reaction was monitored by thin-layer chromatography. The reaction mixture was extracted with dichloromethane and washed with water. Organic layer was concentrated. Methanol (50 mL) was added to the organic layer. The reaction mixture was cooled to -5 to -20 C. Aqueous solution of sodium hydroxide (11.8 g in 50 mL water) was added followed by addition of sodium hypochlorite solution (431 mL) in an aqueous solution of sodium hydroxide (20 g/100 mL) over a period of about 30 to about 45 minutes. The progress of the reaction was monitored by thin-layer chromatography. After completion of the reaction, the reaction mixture was quenched with 5% sodium hydrogen sulphite solution (500 mL). Water (500 mL) was added. pH of the reaction mixture was adjusted to 9.0-10.5. Layers were separated and the aqueous layer was extracted with dichloromethane. The combined dichloromethane layers were concentrated completely to obtain a red-brown colored residue. The residue was dissolved in acetone (375 mL). The reaction mixture was cooled to 20-25 C. Aqueous solution of sodium hydroxide (9.2 g in 25 mL water) was added followed by addition of a seed crystal of pantoprazole sodium. The reaction mixture was stirred, cooled, stirred, filtered and washed with cold acetone to obtain crude pantoprazole sodium as a wet cake.

		Preparation of Solution A: Dissolved 16.4g of sodium hydroxide in 200ml water at 25-30C and added it to a solution of l OOg of 5-(Difluoromethoxy)-2-[[(3,4- dimethoxy-2-pyridinyl)methyl]thio]- l H-benzimidazole in 200ml of acetonitrile at 25-30C to obtain solution A. Preparation of solution B: Dissolved 7.17g of sodium hydroxide in 65ml of water at 25-30C and added to 708.8g of sodium hypochlorite solution (4%) to obtain solution B. The solution of A and B prepared above were cooled to -5 to 0C. The temperature of plug flow reactor was set to -5 to -10C. The plug flows were fed simultaneously with solution A at flow rate 22ml/minutes and solution B at flow rate 32ml/minutes at -5 to -10C. After the completion of reaction, the resulting reaction mass was treated with an aqueous solution of sodium thiosulphate (8.0g sodium thiosulphate in 20ml water), then the reaction mass was washed with 100ml dichloromethane. The pH of reaction mass was adjusted to 8.0-8.5 by addition of acetic acid at 25-30C. The reaction mass was extracted with dichloromethane The organic layer was then treated with a solution of 9.0g sodium hydroxide in 9.0ml water at 25-30C. The organic solvent was distilled out under vacuum at 40-45C. To the resulting reaction mass 200ml of acetonitrile and 5.0ml of water was added at 25-30C. The reaction mass was then stirred at 25-30C for 30 minutes. The reaction mass was maintained at 25-30C for 8-10hours. The reaction mass was then cooled to at 10-15C to obtain the solid which was filtered and dried under vacuum to obtain the title compound. HPLC purity: 99.9% Sulphone impurity: 0.03%
		Ethyl acetate (organic solvent, extractant) was added to the reaction vessel, and the reaction product IV of the above step was added, and the mixture was cooled at 0 to 10 C, and stirred and dissolved completely. The mixed solution of sodium hypochlorite (oxidant) (sodium hydroxide, dissolved in water, and then added with 9 to 10% sodium hypochlorite solution) was added dropwise to the above solution within 2 hours of controlling the dropping rate, and the reaction was further stirred for 5 hours after the completion of the dropwise addition. After the reaction, a sodium thiosulfate (reducing agent) solution (sodium thiosulfate) was added, and the mixture was stirred for about 20 minutes. The liquid phase was separated, and the aqueous phase was extracted with ethyl acetate (extractant, crude product of product pantoprazole sodium V), and the organic phase was combined. Ethyl acetate (kg) was recovered to the end. Add acetone to the residue, stir and crystallize at room temperature, then cool to 0~10 C, stir and crystallize for 2 hours, centrifuge, filter cake acetone and wash, centrifuge, get pantoprazole sodium crude V, the crude product does not have to be dried Directly invested in the next step.

Reference： [1]Patent: WO2009/66317,2009,A2 .Location in patent: Page/Page column 8
[2]Patent: CN104262326,2016,B .Location in patent: Paragraph 0034-0036
[3]Patent: US2010/210847,2010,A1 .Location in patent: Page/Page column 4
[4]Patent: WO2013/108068,2013,A1 .Location in patent: Page/Page column 18; 19
[5]Patent: CN108341800,2018,A .Location in patent: Paragraph 0007; 0008; 0009

25
[ 138786-67-1 ]
[ 7646-85-7 ]
zinc [5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazolide} hydroxy [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.2%		21.6 g of <strong>[138786-67-1]pantoprazole sodium</strong> sesquihydrate are dissolved in 250 ml of water. 2.00 g of NAOH are added at 25 C and the solution is stirred for 1 hour. 6.80 g of zinc chloride (dry) are dissolved in 50 ML of water. The zinc chloride solution is added drop by drop under stirring at 25 C to the PANTOPRAZOLE sodium solution. Stirring is continued for 20 hours. The resulting suspension is filtered with suction, the precipitate is washed with 200 ml of water and dried in a vacuum dryer (< 50 mbar) at 40-45 C to afford 23.08 g (94.2 %) of the title compound as off-white solid. Water (Karl-Fischer titration): 5.1 % Melting point: 167-179 C (decomposition) Analysis : expected found C 39.81 40.55 H 3.55 3.25 N 8. 70 8. 74

Reference： [1]Patent: WO2005/11692,2005,A1 .Location in patent: Page/Page column 11

26
[ 651728-13-1 ]
[ 138786-67-1 ]
4-[6-difluoromethoxy-2-{(3,4-dimethoxypyridin-2-yl)methanesulfinyl}benzimidazole-1-sulfonyl]phenoxyacetic acid sodium salt [ No CAS ]
4-[5-difluoromethoxy-2-{(3,4-dimethoxypyridin-2-yl)methanesulfinyl}benzimidazole-1-sulfonyl]phenoxyacetic acid sodium salt [ No CAS ]

Reference： [1]Molecules,2009,vol. 14,p. 5247 - 5280

27
2-hydroxymethyl-3,4-dimethoxypyridine hydrochloride [ No CAS ]
[ 97963-62-7 ]
[ 138786-67-1 ]

Yield	Reaction Conditions	Operation in experiment
79.6%		2-hydroxymethyl-3,4-dimethoxy pyridine hydrochloride (45.8g) was taken in dichloromethane (300 ml). Thionyl chloride (30.3 gms.) was added at about 0 to 50C and reaction mass was further stirred EPO <DP n="12"/>at 10 - 15C for 1 hour. After reaction completion, purified water (100 ml) was added maintaining the reaction temperature between 15 - 20 C. To this reaction mass, 2-mercapto 5-difluoromethoxy benzimidazole (50 gms) and tetra butyl ammonium bromide (2 gms) were added. The contents were cooled to 10 C and pH of the reaction mass was adjusted to 10 - 11 using aqueous sodium hydroxide solution (30% solution) and the contents were stirred at 25 - 30 C for 12 hours. After completion of the reaction, dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane (60 ml) twice. The combined organic layer was washed with purified water (150 ml) twice. The dichloromethane layer was then cooled to 0 C, 3.5% aqueous sodium hypochlorite solution (464 g ) having sodium hydroxide content of 2.1% was added to the reaction mass, and maintained at 5 - 8 C for about 6 hours. After the completion of the reaction, the reaction mass was cooled to 0 to 5 C and the resulting solid was filtered and washed with cold acetone (about 100ml ) and dried under vacuum at 35-400C to give pantoprazole sodium (72 gms, 79.6%) of purity greater than 99.5%.

Reference： [1]Patent: WO2006/64249,2006,A2 .Location in patent: Page/Page column 8; 10-11

28
2-chloromethyl-3,4-dimethoxypyridine hydrochloride [ No CAS ]
[ 97963-62-7 ]
[ 138786-67-1 ]

Yield	Reaction Conditions	Operation in experiment
19.61 g		The 5-difruoro methoxy-2-mercapto-1-H-benzimidazole 40.12g is soluble in ethanol 400 ml, after stirring to dissolve, sequentially under the condition at room temperature slowly adding 2mol/L NaOH aqueous solution of 250 ml and 2-chloromethyl -3,4-dimethoxy-pyridine hydrochloride 41.23g, 35 C stirring for 2 hours, reducing pressure and evaporating ethanol, dichloromethane is used for residue 100 ml extraction, the organic phase is dried with anhydrous sodium sulfate, filtered, pressure-reducing evaporate dichloromethane, dichloroethane for: methyl tert-butyl ether = 4: mixed solvent recrystallization 1(V/V), for 30 C vacuum drying 4 hours, shall be intermediate 77.78 g. apply the above-mentioned intermediate 30.02g stirring dissolved in the ethanol 400 ml in, the temperature is increased to 45 C adding sodium borate 35.05g and 500 ml, to continue to heat insulation stirring for 2 hours, reducing pressure and evaporating ethanol, dichloromethane is used for extraction residue, the organic phase is dried with anhydrous sodium sulfate, filtered, pressure-reducing evaporate dichloromethane. Using dichloroethane: methyl tert-butyl ether = 4: mixed solvent recrystallization 1(V/V), for 30 C vacuum drying to obtain the intermediate 27.58 g. Apply the above-mentioned intermediate 25.23g slowly adding 0.5mol/L aqueous hydrogen peroxide solution of 100 ml in, 20 C after stirring to dissolve reaction 2.5 hours, filtering, the filtrate 30 C vacuum drying 5 hours, dichloromethane is used for dried 100 ml dissolved, 23 C reaction 2.0 hours, filtration, the filtration cake at 30 C dried under vacuum to get crude Pantoprazole sodium 22.15 g. crude [...] 20.00g soluble in water 150 ml in, with 5% of sodium hydroxide solution to adjust the pH value to 5.5, agitating precipitated insolubles, filtering, adding ethanol to the solid in 100 ml dissolved, with D101 macroporous resin adsorption, dichloromethane is used for 50 ml elution, the eluent for 30 C vacuum drying, to obtain pantoprazole sodium 19.61 g.

Reference： [1]Patent: CN104910136,2016,B .Location in patent: Paragraph 0035; 0036; 0037; 0038; 0039

29
[ 138786-67-1 ]
[ 7585-39-9 ]
C₁₆H₁₄F₂N₃O₄S^(1-)*C₄₂H₇₀O₃₅*Na⁽¹⁺⁾ [ No CAS ]

Reference： [1]Journal of Inclusion Phenomena and Macrocyclic Chemistry,2018,vol. 91,p. 179 - 188

30
[ 138786-67-1 ]
[ 259886-50-5 ]
C₁₆H₁₄F₂N₃O₄S^(1-)*Na⁽¹⁺⁾*C₄₂H₄₂N₂₈O₁₄ [ No CAS ]

Reference： [1]Journal of Inclusion Phenomena and Macrocyclic Chemistry,2018,vol. 91,p. 179 - 188

31
[ 108998-83-0 ]
[ 138786-67-1 ]
C₂₀H₁₈O₂*C₁₆H₁₅F₂N₃O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With acetic acid; In ethanol; for 0.5h;pH 7 - 8;Reflux; Industrial scale;	5 kg of absolute ethanol was added to the reaction kettle, 1 kg of racemic <strong>[138786-67-1]pantoprazole sodium</strong> was added to the reaction kettle, Ph value of the solution was slowly adjusted with glacial acetic acid to 7-8, then 1 kg of S-1, 1, 2-triphenyl-1, 2-ethylene glycol was added, heated at reflux for 30 minutes, after the completion of the reflux, the reaction solution was slowly cooled and crystallized at -5 to 0 C for 12 hours, the filter cake was rinsed with a small amount of cold absolute ethanol, the filter cake was dried under vacuum at 35 C for 8 hours, weighed 1.05 kg, the yield was 88.3%, and the isomer value was 97.8%.

Reference： [1]Patent: CN104513228,2018,B .Location in patent: Paragraph 0026-0031

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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. 138786-67-1 ] {[proInfo.proName]}

Quality Control of [ 138786-67-1 ]

Related Doc. of [ 138786-67-1 ]

Product Details of [ 138786-67-1 ]

Calculated chemistry of [ 138786-67-1 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 138786-67-1 ]

Application In Synthesis of [ 138786-67-1 ]

[ 138786-67-1 ] Synthesis Path-Upstream 1~10

[ 138786-67-1 ] Synthesis Path-Downstream 1~31

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry