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Synonyms: Pantoprazole thioether
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CAS No. : | 102625-64-9 |
Formula : | C16H15F2N3O3S |
M.W : | 367.37 |
SMILES Code : | COC1=C(OC)C(CSC2=NC3=CC(OC(F)F)=CC=C3N2)=NC=C1 |
Synonyms : |
Pantoprazole thioether
|
MDL No. : | MFCD07368273 |
InChI Key : | UKILEIRWOYBGEJ-UHFFFAOYSA-N |
Pubchem ID : | 9799341 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 25 |
Num. arom. heavy atoms | 15 |
Fraction Csp3 | 0.25 |
Num. rotatable bonds | 7 |
Num. H-bond acceptors | 7.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 89.67 |
TPSA ? Topological Polar Surface Area: Calculated from | 94.56 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from | 2.66 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by | 3.66 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from | 4.56 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from | 1.25 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by | 3.93 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 3.21 |
Log S (ESOL):? ESOL: Topological method implemented from | -4.41 |
Solubility | 0.0144 mg/ml ; 0.0000393 mol/l |
Class? Solubility class: Log S scale | Moderately soluble |
Log S (Ali)? Ali: Topological method implemented from | -5.33 |
Solubility | 0.0017 mg/ml ; 0.00000462 mol/l |
Class? Solubility class: Log S scale | Moderately soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by | -6.12 |
Solubility | 0.000277 mg/ml ; 0.000000755 mol/l |
Class? Solubility class: Log S scale | Poorly soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg | High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg | No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) | No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) | Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) | Yes |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) | Yes |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) | Yes |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) | Yes |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from | -5.94 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from | 0.0 |
Ghose? Ghose filter: implemented from | None |
Veber? Veber (GSK) filter: implemented from | 0.0 |
Egan? Egan (Pharmacia) filter: implemented from | 0.0 |
Muegge? Muegge (Bayer) filter: implemented from | 0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat | 0.55 |
PAINS? Pan Assay Interference Structures: implemented from | 0.0 alert |
Brenk? Structural Alert: implemented from | 0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from | No; 1 violation:MW<2.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) | 3.04 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.5% | With sodium hydroxide; In water; at 25 - 30℃; for 4 - 5h; | EXAMPLE 1 : PREPARATION OF 5-DIFLUOROMETHOXY-2(3,4-DIMETHOXY- PYRIDIN-2-YLMETHYL THIO)-1 H-BENZIMIDAZOLE (PANTOPRAZOLE SULFIDE) (FORMULA Ma)-USING 2.1 EQUIVALENTS OF SODIUM HYDROXIDE:Sodium hydroxide (37.4 g) and water (1000 ml) were taken into a clean and dry 4 neck round bottom flask and stirred for about 10 minutes. 5-difluoromethoxy-2- mercaptobenzimidazole (96.4 g) and 2-Chloromethyl-3, 4-dimethoxy-pyridine hydrochloride (100 g) dissolved in 500 ml of water was added slowly over about 2-3 hours at about 25-300C. The resultant reaction mixture was stirred for about 2 hours. The separated solid was filtered and washed with water (500 ml). <n="27"/>The obtained solid was again taken into a fresh round bottom flask containing water (500 ml) and stirred for about 20 minutes. The solid was filtered and suction dried for about 30 minutes. The obtained solid was dried under a vacuum of about 650 mm/Hg and a temperature of about 50 0C for 5 hours to afford 159 g (% Yield: 97.5) of the title compound. Purity By HPLC: 99 %. |
95.3% | With sodium hydroxide; In methanol; water; at 10 - 40℃; for 2.5h; | 10% NaOH solution (42.5 gm in 425 ml of water) is added drop wise to a solution of 5-(difluoromethoxy)-2-mercapto benzimidazole (100.0 gm; 0.462 moles) in methanol(350.0 ml) at 10-150C. To the above solution a clear solution of 2-chloro-3, 4-dimethoxy pyridine hydrochloride (105.5 gm.0.473 moles in 525 ml of methanol) was added at 10-150C. The reaction mass was maintained at 10-15C for 30 minutes. The temperature of the reaction mass was slowly raised to 2O0C. The reaction mass was maintained at 20-25 C for 2 hours. Further the temperature was raised to 400C and maintained at 400C. Completion of the reaction is monitored by TLC. After completion of the reaction methanol is evaporated under reduced pressure to get a residue. Chilled water (600 ml) was added to the residue and the reaction mass was extracted with methylene chloride (600 ml, 300 ml x 2). The organic layers were separated and evaporated under reduced pressure to obtain a residue. Isopropyl alcohol (50 ml) and hexane (600 ml) were added to the reaction mass. The reaction mass was cooled to 0-50C and maintained at 0-5C for 30 minutes. The reaction mass was filtered at 0-5C and washed with chilled hexane (100 ml). The solids were dried under vacuum at 4O0C; Dry wt-162 gm (Yield=95.3%); HPLC Purity=99.21% w/w.; Melting range=l 15-1170C (Lit.7mp-H5-1 18C); MS (ESI); 368.0(M+H) +. |
93% | With sodium hydroxide; In methanol; water; at 40 - 55℃; for 3.5h; | This example provides another preparation of 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methyl]thio-1H-benzimidazole (IV). method.2500ml of water and 204g of NaOH were added to the glass reactor to stir and dissolve, and then 4000g of methanol and base were added.A mixture of (<strong>[97963-62-7]5-difluoromethoxy-2-mercapto-1H-benzimidazole</strong>, 500 g).After heating to 40 C, pyridine hydrochloride (2-chloromethyl-3,4-dimethoxypyridine hydrochloride, 500 g) was added, and the mixture was heated to 50-55 C for 3.5 hours.After the reaction is completed, the reaction solution is discharged, and the methanol is distilled off under reduced pressure by a rotary evaporator. The internal temperature is controlled to not exceed 50 C, and the mixture is distilled as much as possible. Then, the material is transferred to a stirred reaction tank, and 3000 ml of dichloromethane is added thereto, and the mixture is stirred and dissolved. The layers were allowed to stand, the aqueous layer was separated, and the aqueous layer was extracted twice with dichloromethane, and the amount of dichloromethane used was 1500 ml. After the extraction, the organic layer was combined, and the organic layer was transferred to a stirred reaction tank, and washed thoroughly with 0.8% dilute NaOH aqueous solution (2 times by weight based on the ruthenium base). After washing with alkali water, the organic layer was treated with 1000 ml of purified water. After washing again, the mixture is allowed to stand for stratification, and the organic layer is separated, and then concentrated under reduced pressure by a rotary evaporator, and dichloromethane is recovered (the internal temperature under reduced pressure does not exceed 55 C), and steamed until it becomes sticky. Add 2500ml of methyl ether, stir and crystallize at room temperature, then cool down to -10 C below the crystal for more than 3 hours, wash twice with 500 ml of methyl ether, each time. Filtration, drying, and natural drying, the yield was 93%. |
83% | With water; sodium hydroxide; In methanol; at 25 - 30℃; | Methanol (270 ml) was added to a solution of NaOH (41.5 gms) in water (180 ml), followed by addition of <strong>[97963-62-7]5-difluoromethoxy-2-mercapto-1H-benzimidazole</strong> (105.2 gms). A solution of 2-chloromethyl-3,4-dimethoxy-pyridine.hydrochloride (100.3 gm in water (150 ml)) was gradually added to the reaction mixture and stirred at 25-30 C. till completion of the reaction. After completion, as monitored by TLC, the reaction mixture was filtered and the obtained solid was dried to give compound IV-A-11.Yield: 140.6 gm (83%).1H NMR (400 MHz, CDCl3): delta 8.27 (d, J=5.6 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.32 (d, J=2 Hz, 1H), 6.99 (dd, J=2.4, 8.8 Hz, 1H), 6.87 (d, J=5.6 Hz, 1H), 6.50 (t, J=74.8 Hz, 1H), 4.39 (s, 2H), 3.95 (s, 3H), 3.93 (s, 3H).ESI-MS: 368.9 (M+1). |
With sodium hydroxide; In ethanol; water; at 20℃; for 5h; | Reaction vessel was charged with 1050 kg water, 1050 li- ters of ethyl alcohol and 15.2 kg of sodium hydroxide flakes. 19.5 kg of 2-mercapto-5-difluoromethoxybenzimidazole was added to the vessel followed by addition of 20 kg 2-chloromethyl-3,4- dimethoxypyridine. HCl. The mixture was stirred at room tempera- ture for 4 hours. HPLC analysis should confirm the total con- sumption of 2-chloromethyl-3,4-dimethoxypyridine. HCl. 500 li- ters of water were added to the vessel and the mixture was stirred for additional 1 hour at room temperature. Mixture was centrifuged. Centrifuge was first washed with 500 liters of 0,1 N sodium hydroxide and then with plenty of water till the wash water was neutral to litmus. Wet cake was charged another vessel containing 500 liters of methylene chloride and stirred till a clear solution was obtained. 200 liters of water were added to the vessel and stirred for 30 minutes. Organic phase was decanted, filtered over celite and transferred to a vessel equipped with brine cooling system. 26 kg of sulfide product on dry basis was ob- tained from this step. | |
With sodium hydroxide; In water; at 25 - 35℃; for 3h;Product distribution / selectivity; | Example 1: Preparation of Pantoprazole sodium compound of formula-la:Added a solution of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (50 grams in 250ml of water) to a solution of 49.8 grams of 5-difluoromethoxy 2-mercaptobenzimidazole, 500 ml water and sodium hydroxide (22.5 grams of flakes in 27.5 ml of water), slowly at 25-35C. Stirred the reaction mixture for 3 hours. Extracted the reaction mixture thrice with methylene chloride. Separated the organic and aqueous layer. Washed the organic layer with water. Cooled the organic layer to -5 to 0C. Added 550 grams of 3.1% sodium hypochlorite solution having pH 8.75 and assay 3.2 to the above reaction mixture at -5 to 0C. Stirred the reaction mixture for 3 hours at -5 to 0C. Quenched the reaction mixture with 56 grams of ammonium sulphate at below 10C. Stirred the reaction mixture for 30 minutes. Separated the organic and aqueous phases. Extracted the aqueous phase twice with methylene chloride. Washed the organic layer with water. Dried the organic phase over sodium sulphate. Distilled the solvent completely under reduced pressure at below 45C. Added 37.5 ml of acetone to the above crude and distilled the solvent completely under reduced pressure at below 45C. Dissolved the residue in 375 ml of acetone at 25-35C. Heated the reaction mixture to reflux temperature. Stirred the reaction mixture for 30 minutes at reflux temperature. Cooled the reaction mixture to 18-23C. Added aqueous sodium hydroxide solution (8.5 grams in 10 ml of water) at 18-23C. Stirred the reaction mixture for 1 hour at 18-23C. Cooled the reaction mixture to 0-5C. Stirred the reaction mixture for 3 hours. Filtered the solid and washed with acetone followed by washed with methylene chloride. The obtained solid is purified in acetone to get pure compound.The amount of sulfone compound of formula-6 and compound of formula- 1 present in the obtained solid was measured using HPLC and the results are as follows. <n="19"/>Yield: 65 grams Example-3: Preparation of pantoprazole sodium sesquihydrate compound of formula-la:Added a solution of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (50 grams in 250ml of water) to a solution of 49.8 grams of 5-difluoromethoxy-2- mercaptobenzimidazole, 500 ml of water and aqueous sodium hydroxide (22.5 grams of flakes in 27.5ml of water), slowly at 25-350C. Stirred the reaction mixture for 3 hours. Extracted the reaction mixture thrice with methylene chloride. Separated the organic and aqueous layer. Washed the organic layer with water. Added 550 grams of 3.1% sodium hypochlorite having pH 8.75 and assay 3.2 to the above reaction mixture at 25-300C for 2 hours. Stirred the reaction mixture for 10 hours at 25-3O0C. Quenched the reaction mixture with water at 25-300C. Stirred the reaction mixture for 30 minutes at 25-300C. Separated the organic and aqueous phases. Extracted the aqueous layer with methylene chloride. Washed the organic phase twice with aqueous sodium hydroxide solution. Separated the <n="20"/>phases. Cooled the aqueous layer to 10-150C. Adjusted the pH of the reaction mixture to 9.3 with aqueous acetic acid. Added 250 ml of methylene chloride. Stirred the reaction mixture for 15 minutes. Separated the organic phase. Extracted the reaction mixture with methylene chloride. Washed the organic layer with water. Distilled the solvent completely from organic layer at below 45C under reduced pressure. Added 37.5 ml of acetone to the crude and distilled the solvent completely under reduced pressure at below 45C. Dissolved the residue in 375 ml of acetone at 25-35C. Heated the reaction mixture to reflux temperature. Stirred the reaction mixture for 30 minutes at reflux temperature. Cooled the reaction mixture to 18-23C. Added aqueous sodium hydroxide solution (8.5 grams in 10 ml of water) at 18-23C. Stirred the reaction mixture for 1 hour at 18-23C. Cooled the reaction mixture to 0-50C and 35 ml of methylene chloride was added. Stirred the reaction mixture for 3 hours. Filtered the solid and washed with methylene chloride. The above obtained compound can optionally purified as follows.Acetone (400 ml) was added to the above obtained wet compound and heated to reflux. The obtained solution was treated with carbon and cooled the filtrate to 0-5C. Stirred for 2 hours. Filtered the precipitated solid and washed with 30 ml of chilled acetone followed by washing with 50 ml of methylene chloride. Methylene chloride (250 ml) was added to the obtained wet compound at 25-35C. Stirred the reaction mixture for 90 minutes at 25-350C. Filtered the precipitated solid and washed with 25 ml of methylene chloride. Dried the compound at 40-500C for 10 hours.Yield: 70 grams W.C : 5.9 %HPLC : 99.93 %; 0.02 % (Sulfone Impurity) PSD : before micronization : D (v, 0.1) is 0.4 mum ; D (v, 0.5) is 8.73 mum; D (v, 0.9) is 27.7 mum andD(4,3) is 12.02 mum.PSD : after micronization :D (v,0.1) is 1.75 mum; D (v,Q.5) is 4.92 mum; D (v,0.9) is 13.10 mum andD(4,3) is 6.35 mum.Exam... | |
With sodium hydroxide; In water; at 20℃; for 4 - 5h; | 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. | |
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. | ||
Example 3 - Synthesis of 24(3,4-Dimethoxy)pyridme-2-vI)methylsulphinyl]-5- difluoromethoxy-lH-benzimidazole without isolation of sulphide To a solution of NaOH (46.59 g in 500 ml demineralised water) 5-difiuoromethoxy-2- mercaptobenzimidazole was added and the mixture obtained was stirred for 15 minutes for complete dissolution. Then 200 ml methanol was added and the mixture cooled to 15 0C. 2-chloromethyl-3,4-dimethoxypyridine hydrochloride was added slowly at 10 to 15 0C. The reaction mass was warmed up to 20 -300C and stirred for 6-8 hours. Then 600 ml methylene dichloride was added and the reaction mixture was cooled to 0 - 5 0C, followed by charging 2 g TBAB and 5 % sodium hypochlorite solution in water (602 ml) thereto, the latter slowly for 45 min. The temperature was raised to 10 - 15 0C and the reaction mass was stirred for 2-3 hours.5 % sodium thiosulphate solution (100 ml) was added and the mixture was stirred for 30 min. The methylene dichloride layer was separated and the aqueous layer was extracted with 2 X 200 ml methylene dichloride. The aqueous layer was charcoalised with 5% carbon, filtered and cooled. Then the pH was adjusted with 50 % acetic acid to 8.5, the gummy compound extracted with methylene dichloride 3 X 300 ml. The EPO <DP n="15"/>solvent was evaporated under vacuum at 35C and 300 ml ethyl acetate was added at RT. Then it was heated to 50-550C to dissolve the residue completely, cooled to 0-5 0C and maintained for 1.0 hour. The compound was filtered and washed with 2x 25 ml of acetonitrile. Drying was performed at 40 - 450C under vacuum for 2-3 hrs. The dry product thus obtained weighed 85 - 9O g (65% yield based on 2- chloromethyl-3,4-dimethoxypyridine hydrochloride, purity as determined by HPLC was 98.5 - 99 %. | ||
With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide; In dichloromethane; water; at 30 - 35℃; for 6.1h; | 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 <strong>[97963-62-7]5-difluoromethoxy-2-mercapto-1H-benzimidazole</strong> (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. | |
16.6 g | With sodium hydroxide; In dichloromethane; at 20 - 30℃; for 2h; | To the reaction flask was added 10 g of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride(Compound 1), 10 g of <strong>[97963-62-7]5-difluoromethoxy-2-mercapto-1H-benzimidazole</strong>(Compound 2), 100 ml of methylene chloride was added, and 130 g of a 10% sodium hydroxide solution was added dropwise, and the mixture was stirred at 20 to 30 C for 2 hours, Static separation, dichloromethane layer washed twice, each time with water 30ml,And then distilled under reduced pressure to give 16.6 g of a yellow oil (Intermediate 3); |
With sodium hydroxide; In water; at 25 - 30℃; | Add water (solvent) to the reaction kettle, add sodium hydroxide (neutralizer) in portions, stir to dissolve at 27-30 C, add the starting reactant III (starting material), stir at 27-30 C Dissolve, control the drop rate to add an aqueous solution of II (starting material) within 2.0 to 2.9 hours. The reaction of II with III is that the hydrogen on the sulfhydryl group on the starting material III is replaced by the starting material II while losing one molecule of hydrogen chloride. After the completion of the dropwise addition, the reaction was stirred at 25-30 C for 3 hours, and the basic reaction of the raw material III was monitored. After centrifugation, the filter cake was washed with purified water and dried to obtain pantoprazole sulfide wet product IV (solid). The wet product does not have to be dried and is directly fed to the next reaction. | |
16.6 g | With sodium hydroxide; In dichloromethane; at 20 - 30℃; for 2h; | (1) 10 g of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (Compound 1), 10 g of <strong>[97963-62-7]5-difluoromethoxy-2-mercapto-1H-benzimidazole</strong> (Compound 2), 100 ml of dichloromethane were added to the reaction flask. Stir. Add 130 g of sodium hydroxide solution with a concentration of 10%. Stir at 20-30 C for 2 h. standing layering, washing twice with dichloromethane, 30 ml each time, Then distilled under reduced pressure to give 16.6 g of yellow oil (Intermediate 3); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.8% | With sodium hydroxide; In water; isopropyl alcohol; at 20℃; for 3h; | [EXAMPLE 1]Preparation of 5-difluoromethoxy-2-(3,4-dimethoxy-benzylsulfanyl)-lH- benzimidazole 92OmL of isopropanol, 92.1g of 5-difluoromethoxy-2- mercaptobenzimidazole and 95.8g of 2-chloromethyl-3,4-dimethoxypyridine were introduced into a reactor. After adding a sodium hydroxide solution (containing 20.5g of sodium hydroxide in 92OmL of purified water) dropwise to the above mixture, this reaction mixture was stirred at room temperature for 2 hours. Introducing 92OmL of purified water to the mixture and stirring the same for 1 hour, the resultant solid material was subjected to filtration and vacuum drying, thus yielding a final product.Amount of final product: 137.4g (yield: 87.8%)MP: 94 C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.14% | With sodium carbonate; In tetrahydrofuran; water; at 30 - 50℃; for 2h; | In the 500 ml flask, add 250 ml mixed solvent (mixed solvent by volume ratio of 3:1 tetrahydrofuran and water), then the 5 - difluoro -2 - mercapto - 1H - benzimidazole 21.62g (100mmol), iodo 1.27g (5mmol, alkali 31.8g (sodium carbonate, 300mmol) and 2 - chloromethyl - 3, 4 - dioxy pyridine hydrochloride 24.65g (110mmol) is added to the flask, 30 - 50 C, stirring for 2 hours, cooled to the room temperature, dichloromethane extraction, water washing, petroleum ether/dichloromethane recrystallization, vacuum drying is shown in formula I of pantoprazole thioether 36.05g, yield is 98.14%, purity 99.27%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium hydroxide; In ethanol; at 80℃; for 8h; | In a 500 mL three-necked flask,2-Chloromethyl-3,4-dimethoxypyridine hydrochloride (22.4 g,100 mmol), <strong>[97963-62-7]5-difluoromethoxy-2-mercapto-1H-benzimidazole</strong> (21.6 g, 104 mmol), 80 g / L sodium hydroxide solution(110 mL),Ethanol (150 mL) and the mixture was heated to 80 C and stirred for 8 hours. The ethanol was recovered and the residue was extracted with dichloromethane (150 mL)extraction. Add anhydrous sodium sulfate drying overnight, vacuum recovery of dichloromethane was crude. Recrystallization from ethyl acetate-petroleum ether gave a white solid which was dried to give 5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methyl] Benzimidazole, product yield 94%. |
Tags: 102625-64-9 synthesis path| 102625-64-9 SDS| 102625-64-9 COA| 102625-64-9 purity| 102625-64-9 application| 102625-64-9 NMR| 102625-64-9 COA| 102625-64-9 structure
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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