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CAS No. : | 72830-09-2 | MDL No. : | MFCD02181083 |
Formula : | C8H11Cl2NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YYRIKJFWBIEEDH-UHFFFAOYSA-N |
M.W : | 224.08 | Pubchem ID : | 16216928 |
Synonyms : |
2-(Chloromethyl)-3,4-dimethoxypyridine hydrochloride
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.38 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 53.95 |
TPSA : | 31.35 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.23 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 2.02 |
Log Po/w (WLOGP) : | 2.49 |
Log Po/w (MLOGP) : | 0.83 |
Log Po/w (SILICOS-IT) : | 2.29 |
Consensus Log Po/w : | 1.52 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.65 |
Solubility : | 0.507 mg/ml ; 0.00226 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.31 |
Solubility : | 1.11 mg/ml ; 0.00495 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.3 |
Solubility : | 0.112 mg/ml ; 0.000498 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.18 |
Signal Word: | Danger | Class: | 9 |
Precautionary Statements: | P261-P264-P270-P271-P280-P302+P352-P304+P340-P305+P351+P338-P310-P330-P362+P364-P403+P233-P501 | UN#: | 3077 |
Hazard Statements: | H302-H315-H318-H335-H410 | Packing Group: | Ⅲ |
GHS Pictogram: |
* 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 - 5 h; | EXAMPLE 1 : PREPARATION OF 5-DIFLUOROMETHOXY-2(3,4-DIMETHOXY- PYRIDIN-2-YLMETHYL THIO)-1 H-BENZIMIDAZOLE (PANTOPRAZOLE SULFIDE) (FORMULA Ma)-USING 2.1 EQUIVALENTS OF SODIUM HYDROXIDE:Sodium hydroxide (37.4 g) and water (1000 ml) were taken into a clean and dry 4 neck round bottom flask and stirred for about 10 minutes. 5-difluoromethoxy-2- mercaptobenzimidazole (96.4 g) and 2-Chloromethyl-3, 4-dimethoxy-pyridine hydrochloride (100 g) dissolved in 500 ml of water was added slowly over about 2-3 hours at about 25-300C. The resultant reaction mixture was stirred for about 2 hours. The separated solid was filtered and washed with water (500 ml). <n="27"/>The obtained solid was again taken into a fresh round bottom flask containing water (500 ml) and stirred for about 20 minutes. The solid was filtered and suction dried for about 30 minutes. The obtained solid was dried under a vacuum of about 650 mm/Hg and a temperature of about 50 0C for 5 hours to afford 159 g (percent Yield: 97.5) of the title compound. Purity By HPLC: 99 percent. |
95.3% | With sodium hydroxide In methanol; water at 10 - 40℃; for 2.5 h; | 10percent NaOH solution (42.5 gm in 425 ml of water) is added drop wise to a solution of 5-(difluoromethoxy)-2-mercapto benzimidazole (100.0 gm; 0.462 moles) in methanol(350.0 ml) at 10-150C. To the above solution a clear solution of 2-chloro-3, 4-dimethoxy pyridine hydrochloride (105.5 gm.0.473 moles in 525 ml of methanol) was added at 10-150C. The reaction mass was maintained at 10-15°C for 30 minutes. The temperature of the reaction mass was slowly raised to 2O0C. The reaction mass was maintained at 20-25° C for 2 hours. Further the temperature was raised to 400C and maintained at 400C. Completion of the reaction is monitored by TLC. After completion of the reaction methanol is evaporated under reduced pressure to get a residue. Chilled water (600 ml) was added to the residue and the reaction mass was extracted with methylene chloride (600 ml, 300 ml x 2). The organic layers were separated and evaporated under reduced pressure to obtain a residue. Isopropyl alcohol (50 ml) and hexane (600 ml) were added to the reaction mass. The reaction mass was cooled to 0-50C and maintained at 0-5°C for 30 minutes. The reaction mass was filtered at 0-5°C and washed with chilled hexane (100 ml). The solids were dried under vacuum at 4O0C; Dry wt-162 gm (Yield=95.3percent); HPLC Purity=99.21percent w/w.; Melting range=l 15-1170C (Lit.7mp-H5-1 18°C); MS (ESI); 368.0(M+H) +. |
83% | With water; sodium hydroxide In methanol at 25 - 30℃; | Methanol (270 ml) was added to a solution of NaOH (41.5 gms) in water (180 ml), followed by addition of 5-difluoromethoxy-2-mercapto-1H-benzimidazole (105.2 gms). A solution of 2-chloromethyl-3,4-dimethoxy-pyridine.hydrochloride (100.3 gm in water (150 ml)) was gradually added to the reaction mixture and stirred at 25-30° C. till completion of the reaction. After completion, as monitored by TLC, the reaction mixture was filtered and the obtained solid was dried to give compound IV-A-11.Yield: 140.6 gm (83percent).1H NMR (400 MHz, CDCl3): δ 8.27 (d, J=5.6 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.32 (d, J=2 Hz, 1H), 6.99 (dd, J=2.4, 8.8 Hz, 1H), 6.87 (d, J=5.6 Hz, 1H), 6.50 (t, J=74.8 Hz, 1H), 4.39 (s, 2H), 3.95 (s, 3H), 3.93 (s, 3H).ESI-MS: 368.9 (M+1). |
16.6 g | With sodium hydroxide In dichloromethane at 20 - 30℃; for 2 h; | To the reaction flask was added 10 g of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride(Compound 1), 10 g of 5-difluoromethoxy-2-mercapto-1H-benzimidazole(Compound 2), 100 ml of methylene chloride was added, and 130 g of a 10percent sodium hydroxide solution was added dropwise, and the mixture was stirred at 20 to 30 °C for 2 hours, Static separation, dichloromethane layer washed twice, each time with water 30ml,And then distilled under reduced pressure to give 16.6 g of a yellow oil (Intermediate 3); |
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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With bis(trichloromethyl) carbonate; Triphenylphosphine oxide; In toluene; at 20 - 60℃; for 4h; | Ph3PO (43.78 g, 157.5 mmol) was dissolved in toluene (100 mL) in a 500 mL three-necked flask and BTC(14.84 g, 50 mmol) was dissolved in toluene (60 mL) and placed in a 150 mL constant pressure dropping funnel. BTC was added dropwise at room temperature and the temperature was raised to 60 C after completion of the dropwise addition.After 2 hours of incubation, 2-hydroxymethyl-3,4-dimethoxypyridine (25.35 g, 150 mmol) was dissolved in 75 mL of toluene and added at 40 C to precipitate a white solid. After incubation for 2 hours, The reaction was stopped and the white solid was obtained by suction filtration and dried to give 32.78 g of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride, the product yield was 98% |
93% | With thionyl chloride; In dichloromethane; at 0 - 20℃; for 2h; | Thionyl chloride (4 mL, 15.0 mmol) in dry dichloromethane(20 mL) was added dropwise to acooled (0-5 oC)stirred solution of hydroxymethyl)-3,4-dimethoxypyridine (6.76 g, 40.0 mmol) in dichloromethane (60 mL). The mixture wasallowed to warm up to 20 oC. After 2 h, the reaction mixture as concentratedin vacuo to a small volume. Addition of toluene afforded title product as a colorless solid (8.4 g, 93%). 1H NMR (CDCl3) d 8.56 (d, 1H, J = 6.63 Hz), 7.56 (d, 1H, J = 6.63 Hz), 5.06 (s, 2H), 4.23(s, 3H), 4.09 (s, 3H). m/z (ESI) 187.93 (M+ +1). |
93.9% | With thionyl chloride; In dichloromethane; at 0 - 15℃; for 2h; | 41 g of 2-hydroxymethyl-3,4-dimethoxypyridine and 100 g of dichloromethane were added to the reaction flask, and the mixture was stirred and dissolved.30 g of thionyl chloride was slowly added dropwise at 0 to 5 C, and then slowly heated to 10 to 15 C for 2 h.Evaporate the dichloromethane under reduced pressure, add 90 g of absolute ethanol, and cool to 0 C.Drying to obtain 51 g of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (yield 93.9%) |
85% | With thionyl chloride; In dichloromethane; at 20℃; | A solution of (3,4-dimethoxypyridin-2-yl)methanol (1 g, 5.91 mmol) in CH2C12 (11.82 mL) was treated dropwise with thionyl chloride (1 mL, 13.70 mmol) with stirring at room temperature. The reaction mixture was stirred for 2 h, and then concentrated directly in vacuo. The resulting residue was washed with 3x 10 mL Et20, the resulting solids collected by filtration, and then dried under reduced pressure to afford the title compound as a white solid (1.12 g, 85%), which was used in the subsequent step without further purification. |
With thionyl chloride; In dichloromethane; | (a) 2-Chloromethyl-3,4-dimethoxy-pyridinium chloride 4.2 g (93% of theory) of the title compound are obtained as a colourless solid of m.p. 151-152 C. (decomp.) by the procedure described in Example A1a by reaction of 3.38 g of 2-hydroxymethyl-3,4-dimethoxypyridine with 2 ml of thionyl chloride in 30 ml of methylene chloride, after a reaction time of 2.5 hours and after the type of working up described in Example A2a. | |
With thionyl chloride; In dichloromethane; | (a) 2-Chloromethyl-3,4-dimethoxy-pyridinium chloride 4.2 g (93% of theory) of the title compound are obtained as a colorless solid of m.p. 151-152 C. (decomp.) by the procedure described in Example 32a by reacting 3.38 g of 2-hydroxymethyl-3,4-dimethoxypyridine with 2 ml of thionyl chloride in 30 ml of methylene chloride, after a reaction time of 2.5 hours and after the type of working up described in Example 33a. | |
With thionyl chloride; In toluene; at 3 - 40℃; | Add 9.22 kg of toluene,Add at room temperature2-hydroxymethyl-3,4-dimethoxypyridine 1.5kg,Cool down to 3 C ~ 10 C,Add 1.63 kg of thionyl chloride within 1 to 2 hours at 3 to 10 C.After the addition, the mixture was stirred at 5 to 10 C for 1 hour.Increase the temperature to 35 C ~ 40 C within 1 hour,Incubate at 35-40 C for 4 hours.After TLC detection, the temperature control is 35-40 C.Vacuum distilling thionyl chloride for 3 to 4 hours, adding 9 kg of toluene, and cooling to 20 to 25 C.Centrifugal filtration, 0.64 L of toluene washed filter cake, drained,Drying at 50-55 C for 6-8 hours,2-Chloromethyl-3,4-dimethoxypyridine hydrochloride (III) was obtained. |
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 |
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With sodium hydroxide; In ethanol; water; | 17. 2,2-Difluoro-6-[(3,4-dimethoxy-2-pyridyl)methylthio]-5H-[1,3]-dioxolo[4,5-f]benzimidazole 1.05 g (92% of theory) of the title compound are obtained as a finely crystalline, colorless powder of m.p. 185-187 C. by the procedure described in Example 13 by reaction of 0.69 g (3 mmol) of 2,2-difluoro-5H-[1,3]dioxolo[4,5-f]benzimidazole-6-thiol with 0.67 g (3 mmol) of 2-chloromethyl-3,4-dimethoxypyridinium chloride in a mixture of 10 ml of ethanol and 10 ml of water, with the addition of 3.3 ml of 2N sodium hydroxide solution, after a reaction time of 10 hours. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide; In ethanol; water; | 10. 2-[(3,4-Dimethoxy-2-pyridyl)methylthio]-5-(1,1,2,2-tetrafluoroethoxy)-1H-benzimidazole 0.38 g (1.7 mmol) of 2-chloromethyl-3,4-dimethoxypyridinium chloride is added to a solution of 0.46 g (1.7 mmol) of 2-mercapto-5-(1,1,2,2-tetra fluoroethoxy)-1H-benzimidazole in 10 ml of ethanol, 10 ml of water and 1.8 ml of 2N sodium hydroxide solution; after the mixture has been stirred at 20 C. for one hour, a further 10 ml of water are added dropwise. The mixture is then stirred at 20 C. for a further four hours. The solid which has precipitated out is filtered off, washed with 0.01N sodium hydroxide solution and then with water until neutral and dried to constant weight. 0.63 g (90% of theory) of the title compound is obtained as a colorless crystalline powder of m.p. 98-102 C. |
Yield | Reaction Conditions | Operation in experiment |
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42% | With sodium hydrogencarbonate; In ethanol; water; at 58℃; for 1.5h; | 1.05ml (14.9mmol) of cyclopropylamine was added to a solution of 695mg (2.66mmol) of 2- chloromethyl-3,4-dimethoxypyridinium hydrochloride in 4ml ethanol and 4ml of saturated aqueous sodium hydrogen carbonate. The reaction mixture was stirred for 1.5hrs at 580C and extracted with ethyl acetate (3 x 10ml). The combined organic layers were dried over magnesium sulphate and concentrated in vacuum. Column chromatography (gradient dichloromethane/methanol) yielded 263mg (42% yield) of N-[(3,4-dimethoxypyridin-2-yl)methyl] cyclopropylamine. |
Yield | Reaction Conditions | Operation in experiment |
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at 60℃; for 18h;Heating / reflux; | Examples; Starting compounds and intermediates; 2-(3,4-Dimethoxy-pyridine-2-ylmethylsulfanyl)-5-methoxy-3H-imidazo[4,5-b]pyridine A reaction mixture of 10.00 g (55.20 mmol) 5-methoxy-3H-imidazo[4,5-b]pyridine-2-thiol and 12.37 g (55.20 mmol) 2-chloromethyl-3,4-dimethoxy pyridinium chloride in isopropanol (200 ml) is stirred for 2 h under reflux. The mixture is concentrated, filtered and dried at 60C for 16 h. Afterwards the crude hydrochloride of the product is suspended in a mixture of water dichloromethane and is basified to pH 8 by adding sodium hydroxide solution (6 N). The mixture is extracted with dichloromethane three times. The combined organic layers are washed with water, dried over calcium chloride, concentrated in vacuo, reslurried in acetone and dried again in vacuo to give 14.76 g (44.4 mmol / 80 %) of the title product with a melting point of 157.0C (acetone). |
Yield | Reaction Conditions | Operation in experiment |
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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%. |
Yield | Reaction Conditions | Operation in experiment |
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71% | With sodium hydroxide; In ethanol; water; | EXAMPLE I 5 Preparation of 5-Carbethoxy-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole 5-Carbethoxy-2-mercapto-1H-benzimidazole (2.0 g, 9 mmol) and NaOH (0.36 g, 9 mmol) in H2 O (1 ml) were dissolved in ethanol (30 ml). <strong>[72830-09-2]3,4-dimethoxy-2-chloromethylpyridine hydrochloride</strong> (~6.6 mmol) as a crude material were added and the mixture was heated to boiling. NaOH (0.26 g, 6.6 mmol) in H2 O (1 ml) was added and the reflux was continued for 6 hours. The solvent was evaporated off and the residue was diluted with methylene chloride and water. The organic phase was dried over Na2 SO4 and the solvent removed under reduced pressure. Crystallizing from CH3 CN gave the desired product (1.75 g, 71%). |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide; In ethanol; water; acetonitrile; | EXAMPLE I 4 Preparation of 5-acetyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole 5-Acetyl-6-methyl-2-mercapto-1H-benzimidazole (4.2 g, 20 mmol) and NaOH (0.8 g, 20 mmol) in H2 O (1 ml) were dissolved in 60 ml ethanol. <strong>[72830-09-2]3,4-dimethoxy-2-chloromethylpyridine hydrochloride</strong> (~17 mmol) as a crude material was added and the mixture was heated to boiling. NaOH (0.7 g, 17 mmol) in H2 O (1 ml) was added and the reflux was continued for 6 hours. The solvent was evaporated off and the residue was diluted with methylene chloride and water. The organic phase was dried over Na2 SO4 and the solvent was removed under reduced pressure. Crystallizing from acetonitrile gave the title compound, (3.75 g, 62%). |
Yield | Reaction Conditions | Operation in experiment |
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In a two-litre flask, a solution of 24 g of sodium hydroxide in 150 ml of distilled water was charged andi cooled to 20 to 25 C. A solution of 5-(difluoromethoxy) -2- mercapto-lH-benzimidazole (50 g) in acetone (250 ml) was added to it and stirred for <n="10"/>half an hour. A solution of 2-chloromethyl-3, 4-dimethoxypyridine hydrochloride (56 g) in distilled water (150 ml) was added over a period of one hr while maintaining the temperature in the range of 23 to 25 C. It was stirred for next half an hour and progress of the reaction was monitored by TLC. If unreacted 5-(difluoromethoxy) -2-S mercapto-lH-benzimidazole is still present, 0,50 g of 2-chloromethyl-3, 4- dimethoxypyridine hydrochloride was added, and stirring was continued for next half an hour. AqueouUSD Sodium hypochlorite solution (5.7%, 300 ml) diluted with equal volume of water was added to it over a period of three hrs. at 20 to 25 C and stirred for additional half an hour, The progress of the reaction was checked by TLC and if ^ still incomplete, the required quantity of additional sodium hypochlorite solution was added. The reaction was quenched with aqueous solution of sodium thiosulphate (8 g of sodium thiosulphate dissolved in 25 ml of distilled water). It was stirred at RT for next half an hr. Reaction mass was filtered off on the Celite bed, the insoluble material were dissolved in 200 ml of acetone and filtered. The solution was treated 5 with activated carbon, and filtered. Acetone was distilled off under vacuum and cooled to 25 C.The reaction mass was stirred with 500 ml of dichloromethane. Sodium chloride (17 to 20 % of the volume of aqueous layer) was added over a period of half an hour and the solid was precipitated. The stirring was continued for next half an hour and 0 material was filtered off and dried at 30 C for overnight. It was powdered and slurried with 400 ml of dichloromethane, followed by washing with 2X100 ml of dichloromethane and dried under vacuum at 40 C to obtain pantoprazole sodium sesquihydrate (65 g) having HPLC purity 99.90% and sulphone impurity 0.07%. The water content was 5.90% (measured by TGA). The characteristic X-ray powder 5 diffraction pattern, and the significant two-theta values confirm that the obtained product is pantoprazole sodium sesquihydrate. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide; In methanol; water; ethyl acetate; | EXAMPLE I 4 Preparation of 5-chloro-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole <strong>[72830-09-2]2-chloromethyl-3,4-dimethoxypyridine hydrochloride</strong> (896 mg, 0.004 mol) was dissolved in 25 ml MeOH and treated with NaOH (390 mg, 0.008 mol) dissolved in 1.5 ml H2 O. 5-chloro-2-mercapto-1H-benzimidazole (812 mg, was added and the resulting mixture allowed to react for 2h at room temperature. The solvent was evaporated and the residue partitioned between 50 ml 2.5 % NaOH and 75 ml CH2 Cl2. The aqueous layer was separated and extracted twice with 25 ml CH2 Cl2. The organic layers were combined, washed with 25 ml H2 O, dried over MgSO and the solvent was evaporated. The crude product was triturated with approximately 5 ml of EtOAc saturated with NH3. The solid was collected and the mother liquor reprocessed furnishing 650 mg (48%) of the title compound as an off white powder. NMR data is given below. | |
With sodium hydroxide; In methanol; water; ethyl acetate; | Example I 2 Preparation of 5-chloro-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole <strong>[72830-09-2]2-chloromethyl-3,4-dimethoxypyridine hydrochloride</strong> (896 mg, 0.004 mol) was dissolved in 25 ml MeOH and treated with NaOH (390 mg, 0.008 mol) dissolved in 1.5 ml H2 O. 5-chloro-2-mercapto-1H-benzimidazole (812 mg, 0.0044 mol) was added and the resulting mixture allowed to react for 2h at room temperature. The solvent was evaporated and the residue partitioned between 50 ml 2.5 % NaOH and 75 ml CH2 Cl2. The aqueous layer was separated and extracted twice with 25 ml CH2 Cl2. The organic layers were combined, washed with 25 ml H2 O, dried over MgSO4 and the solvent was evaporated. The crude product was triturated with approximately 5 ml of EtOAc saturated with NH3. The solid was collected and the mother liquor reprocessed furnishing 650 mg (48%) of the title compound as an off white powder. |
Yield | Reaction Conditions | Operation in experiment |
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In water; isopropyl alcohol; | 7. 5-Difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylthio]-4,6-dimethyl-1H-benzimidazole 0.45 g (1.8 mmol) of 5-difluoromethoxy-4,6-dimethyl-2-mercaptobenzimidazole and 0.41 g (1.8 mmol) of 2-chloromethyl-3,4-dimethoxypyridinium chloride are heated to the boil under reflux in 20 ml of dry isopropanol. Temporarily, a clear solution is formed, from which a colourless solid precipitates. After 3 h, the mixture is allowed to cool and is filtered, the filter residue is washed with isopropanol and then dissolved in water, and the pH of the solution is adjusted to 9 with 1N sodium hydroxide solution, with stirring. The precipitated product is filtered off, once suspended in 20 ml of water, filtered off again and washed until neutral. After drying to constant weight in vacuo, this gives 0.50 g (69% of theory) of the title compound as a colourless solid; m.p. 137-138 C. |
Yield | Reaction Conditions | Operation in experiment |
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Analogously, 5-[(2-chloro-1,1,2-trifluoro)ethoxy]-2-[(3,4-dimethoxy-2-pyridyl)methylthio]-1H-benzimidazole (m.p. 99-102 C.) is obtained by reacting 5-(2-chloro-1,1,2-trifluoroethoxy)-2-mercaptobenzimidazole with 2-chloromethyl-3,4-dimethoxypyridinium chloride. |
Yield | Reaction Conditions | Operation in experiment |
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6-[(3,4-Dimethoxy-2-pyridyl)methylthio]-5H-[1,3]-dioxolo[4,5-f]benzimidazole (m.p. 155-157 C.) is obtained analogously by reacting 5H-[1,3]-dioxolo[4,5-f]benzimidazole-6-thiol with 2-chloromethyl-3,4-dimethoxypyridinium chloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium carbonate; potassium iodide; In ethanol; acetone; at 45℃; for 4h; | 1.5 equiv of 2-chloromethyl pyridine hydrochloride, 1.5 equiv of K2CO3 and 0.15 equiv of KI were added to a magnetically stirred solution of 1.0 equiv of 5 or 12 (2.0mmol) in a mixture of acetone (15 mL) and EtOH (15 mL). The reaction mixture was stirred constantly at 45 C for about 4 h. When the reaction was finished, as monitored by HPLC-MS, enough water (50 mL) was added. Then the reaction mixture was extracted with DCM (20 mL × 3). The organic phase was combined and concentrated under reduced pressure to give crude compound 6 or 13. For a typical compound of 6, for example, 2-[(3,4-dimethoxypyridin-2-yl)methylthio]-6-nitro-5-(piperidin-1-yl)-1H-benzimidazole, the orange powder was obtained in 91% yield, with an HPLC purity >98%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; potassium iodide; In ethanol; acetone; at 45℃; for 4h; | 1.5 equiv of 2-chloromethyl pyridine hydrochloride, 1.5 equiv of K2CO3 and 0.15 equiv of KI were added to a magnetically stirred solution of 1.0 equiv of 5 or 12 (2.0mmol) in a mixture of acetone (15 mL) and EtOH (15 mL). The reaction mixture was stirred constantly at 45 C for about 4 h. When the reaction was finished, as monitored by HPLC-MS, enough water (50 mL) was added. Then the reaction mixture was extracted with DCM (20 mL × 3). The organic phase was combined and concentrated under reduced pressure to give crude compound 6 or 13. For a typical compound of 6, for example, 2-[(3,4-dimethoxypyridin-2-yl)methylthio]-6-nitro-5-(piperidin-1-yl)-1H-benzimidazole, the orange powder was obtained in 91% yield, with an HPLC purity >98%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; potassium iodide; In ethanol; acetone; at 45℃; for 4h; | 1.5 equiv of 2-chloromethyl pyridine hydrochloride, 1.5 equiv of K2CO3 and 0.15 equiv of KI were added to a magnetically stirred solution of 1.0 equiv of 5 or 12 (2.0mmol) in a mixture of acetone (15 mL) and EtOH (15 mL). The reaction mixture was stirred constantly at 45 C for about 4 h. When the reaction was finished, as monitored by HPLC-MS, enough water (50 mL) was added. Then the reaction mixture was extracted with DCM (20 mL × 3). The organic phase was combined and concentrated under reduced pressure to give crude compound 6 or 13. For a typical compound of 6, for example, 2-[(3,4-dimethoxypyridin-2-yl)methylthio]-6-nitro-5-(piperidin-1-yl)-1H-benzimidazole, the orange powder was obtained in 91% yield, with an HPLC purity >98%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; potassium iodide; In ethanol; acetone; at 45℃; for 4h; | 1.5 equiv of 2-chloromethyl pyridine hydrochloride, 1.5 equiv of K2CO3 and 0.15 equiv of KI were added to a magnetically stirred solution of 1.0 equiv of 5 or 12 (2.0mmol) in a mixture of acetone (15 mL) and EtOH (15 mL). The reaction mixture was stirred constantly at 45 C for about 4 h. When the reaction was finished, as monitored by HPLC-MS, enough water (50 mL) was added. Then the reaction mixture was extracted with DCM (20 mL × 3). The organic phase was combined and concentrated under reduced pressure to give crude compound 6 or 13. For a typical compound of 6, for example, 2-[(3,4-dimethoxypyridin-2-yl)methylthio]-6-nitro-5-(piperidin-1-yl)-1H-benzimidazole, the orange powder was obtained in 91% yield, with an HPLC purity >98%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; potassium iodide; In ethanol; acetone; at 45℃; for 4h; | 1.5 equiv of 2-chloromethyl pyridine hydrochloride, 1.5 equiv of K2CO3 and 0.15 equiv of KI were added to a magnetically stirred solution of 1.0 equiv of 5 or 12 (2.0mmol) in a mixture of acetone (15 mL) and EtOH (15 mL). The reaction mixture was stirred constantly at 45 C for about 4 h. When the reaction was finished, as monitored by HPLC-MS, enough water (50 mL) was added. Then the reaction mixture was extracted with DCM (20 mL × 3). The organic phase was combined and concentrated under reduced pressure to give crude compound 6 or 13. For a typical compound of 6, for example, 2-[(3,4-dimethoxypyridin-2-yl)methylthio]-6-nitro-5-(piperidin-1-yl)-1H-benzimidazole, the orange powder was obtained in 91% yield, with an HPLC purity >98%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; potassium iodide; In ethanol; acetone; at 45℃; for 4h; | 1.5 equiv of 2-chloromethyl pyridine hydrochloride, 1.5 equiv of K2CO3 and 0.15 equiv of KI were added to a magnetically stirred solution of 1.0 equiv of 5 or 12 (2.0mmol) in a mixture of acetone (15 mL) and EtOH (15 mL). The reaction mixture was stirred constantly at 45 C for about 4 h. When the reaction was finished, as monitored by HPLC-MS, enough water (50 mL) was added. Then the reaction mixture was extracted with DCM (20 mL × 3). The organic phase was combined and concentrated under reduced pressure to give crude compound 6 or 13. For a typical compound of 6, for example, 2-[(3,4-dimethoxypyridin-2-yl)methylthio]-6-nitro-5-(piperidin-1-yl)-1H-benzimidazole, the orange powder was obtained in 91% yield, with an HPLC purity >98%. |
Yield | Reaction Conditions | Operation in experiment |
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D-29 D-30Step 3. In a 250 mL round bottom flask a mixture of D-29 (5 g, 18.6 mmol) and cesium carbonate (18.2 g, 55.9 mmol) in DMF (80 mL) was stirred at ambient temperature for 30 minutes. The mixture was heated to 60C and a solution of <strong>[72830-09-2]2-chloromethyl-3,4-dimethoxy pyridine hydrochloride</strong> (3.97 g, 17.7 mmol) in DMF (60 mL) was added dropwise. The reaction mixture was stirred for 2 hours at 60C. The reaction was allowed to cool and the salts were removed by filtration. The reaction mixture was concentrated under reduced pressure and D-30 was used as such in the next step. LC-MS: Anal. Calcd. For C20H29N5O5: 419.22; found 420 [M+H]+ 1H NMR (400 MHz, DMSO-d6) delta ppm 0.83 (t, J=7.4 Hz, 3 H), 1 .18 - 1 .32 (m, 2 H), 1 .41 - 1 .71 (m, 4 H), 2.14 (s, 3 H), 3.34 - 3.40 (m, 2 H), 3.78 (s, 3 H), 3.91 (s, 3 H), 4.17 - 4.29 (m, 1 H), 4.41 (t, J=5.3 Hz, 1 H), 5.09 (s, 2 H), 6.79 (d, J=8.8 Hz, 1 H), 7.15 (d, J=5.7 Hz, 1 H), 7.75 (s, 1 H), 8.24 (d, J=5.5 Hz, 1 H), 9.75 (s, 1 H) | ||
10231] Step 3. In a 250 mE round bottom flask a mixture of D-29 (5 g, 18.6 mmol) and cesium carbonate (18.2 g, 55.9 mmol) in DMF (80 mE) was stirred at ambient temperature for 30 minutes. The mixture was heated to 60 C. and a solution of <strong>[72830-09-2]2-chloromethyl-3,4-dimethoxy pyridine hydrochloride</strong> (3.97 g, 17.7 mmol) in DMF (60 mE) was added dropwise. The reaction mixture was stirred for 2 hours at 60 C. The reaction was allowed to cool and the salts were removed by filtration. The reaction mixture was concentrated under reduced pressure and D-30 was used as such in the next step.10232] EC-MS: Anal. Calcd. For C20H29N505: 419.22; found 420 [M+H]10233] ?H NMR (400 MHz, DMSO-d5) oe ppm 0.83 (t,J=7.4 Hz, 3H), 1.18-1.32 (m, 2H), 1.41-1.71 (m, 4H), 2.14 (s,3H), 3.34-3.40 (m, 2H), 3.78 (s, 3H), 3.91 (s, 3H), 4.17-4.29(m, 1H), 4.41 (t, J=5.3 Hz, 1H), 5.09 (s, 2H), 6.79 (d, J=8.8Hz, 1H), 7.15 (d, J=5.7 Hz, 1H), 7.75 (s, 1H), 8.24 (d, J=5.5Hz, 1H), 9.75 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 4h; | 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (100 mg, 0.454 mmol), 1-1 (85 mg, 0.454 mmol), and 2C03 (157 mg, 1.136 mmol) were combined in a 50-mL round bottom flask with a stirbar. DMF (3.03 mL) was added, and the reaction mixture was heated to 90 C for 4 h. The reaction mixture was diluted with EtOAc (30 mL), and washed sequentially with sat. aq. NaHC03 (30 mL) and brine (30 mL). The combined organics were dried over MgS0 , filtered, and concentrated in vacuo to afford the title compound as a tan solid (155 mg, 78%, >85% pure), which was used in the subsequent step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With potassium carbonate; potassium iodide; In ethanol; acetone; at 60℃; for 8h;Inert atmosphere; | General procedure: 2-Chloromethyl pyridine hydrochloride (0.8 g, 5.0 mmol), 2-chloromethyl-4-methoxy-3-methylpyridine hydrochloride (1.0 g, 5.0 mmol), 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride (1.1 g, 5.0 mmol), <strong>[72830-09-2]2-chloromethyl-3,4-dimethoxypyridine hydrochloride</strong> (1.12 g, 5.0 mmol), K2CO3 (1.1 g, 8.0 mmol) and KI (1.32 g, 8 mmol) were added to a magnetically stirred solution of 9 (1.24 g, 5.0 mmol) in a mixture of acetone (30 ml) and ethanol (30 ml). The reaction mixture was stirred constantly at 60 C for about 8 h. When the reaction was finished, as monitored by TLC, water (100 ml) was added. Then the reaction mixture was extracted with DCM (30 ml × 4). The organic phase was combined and concentrated under reduced pressure gave crude compounds 11a-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With triethylamine; In acetonitrile; at 20℃; for 12h;Inert atmosphere; | tert-Butyl 5-(2-mercapto-1H-benzo[d]imidazol-5-yloxy)pentylcarbamate(0.9 g, 2.56 mmol) (7), 2-(chloromethyl)-3,4-dimethoxypyridine.HCl(8) (0.689g, 3.07 mmol) and triethylamine (1.8 mL, 12.80 mmol) were dissolved in dry acetonitrile (20 mL) and thereaction mixture was stirred under nitrogen at room temperature overnight (TLCmonitored completion of reaction). The solvent was removed under reducedpressure and the resulting crude was purified by silica-gel columnchromatography using 2% MeOH/DCM as eluent to afford title product as brownishsolid (1.25 g, 97%). 1H NMR(CDCl3) d 8.25 (d, 1H, J = 5.62 Hz ), 7.40 (d, 1H, J = 8.70 Hz ), 7.02 (d, 1H, J = 1.67 Hz ), 6.84 (d, 1H, J= 5.62 Hz ), 6.80 (dd, 1H, J = 8.70 Hz, J = 1.67 Hz ), 4.56 (br s,1H), 4.37 (s, 2H), 3.99 (t, 2H, J = 6.36Hz), 3.95 (s, 3H), 3.93 (s, 3H), 3.15 (t, 2H, J = 5.98 Hz), 1.83 (m, 2H), 1.55-1.44 (m, 13H). 13C NMR(75 MHz, CDCl3) d 160.2, 157.1, 153.1, 152.1, 145.9, 143.5, 111.1, 108.9, 69.3, 61.8,56.6, 40.1, 31.2, 29.8, 29.1, 28.2, 22.5. MS m/z (ESI) 503.25 (M+ +1).IR: 3867, 3679, 2943, 1690, 1585, 1489, 1300, 1162 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20 mg | With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 100℃; for 1h; | 4-(2,6-Difluorobenzyl)-2-[(3,4-dimethoxypyridin-2-yl)methyl]-2H-1 ,2,4- benzothiadiazin-3(4H)-one 1 ,1 -dioxide (121 ) A mixture of (lntE3) (100 mg, 0.31 mmol), <strong>[72830-09-2]2-(chloromethyl)-3,4-dimethoxypyridine hydrochloride</strong> (173 mg, 0.77 mmol), Kl (10.2 mg, 0.06 mmol) and K2C03 (170 mg, 1.23 mmol) in DMF (6 mL) was heated at 100C for 1 d. After cooling to rt, EtOAc (40 mL) and H20 (10 mL) were added, the phases were separated and the organic phase was washed with H20 (4 x 10 mL), dried over MgS04 and concentrated in vacuo. Purification by preparative HPLC (method A) yielded the title compound (20 mg, 0.04 mmol). LCMS (Method B): m/z 476.1 (M+H)+ (ES+), at 4.19 min, 95% 1H NMR: (400 MHz, DMSO) delta: 3.79 (s, 3H), 3.87 (s, 3H), 5.12 (s, 2H), 5.45 (s, 2H), 6.95 (d, J=5.5, 1 H), 7.04 (t, J=8.3, 2H), 7.34-7.41 (m, 2H), 7.69 (d, J=8.3, 1 H), 7.79 (t, J=8.3, 2H), 7.88 (d, J=5.5, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | The above mentioned protocol was adapted for preparation ofligand L2. In a solution of 2-(chloromethyl)-3,4-dimethoxypyridinehydrochloride (2.09 g, 9.34 mmol) in 10 mL of water, a solution ofpotassium bicarbonate(2.73 g, 19.74 mmol) in water (10 mL) wasadded dropwise. The reaction mixture was stirred at room temperaturefor next 30 min. After stirring is done, solution was extractedwith dichloromethane (3 20 mL). The combined dichloromethanelayer was treated with anhydrous sodium sulfate. Thesolution was filtered and solvent was removed by rotatory evaporation.The collected light yellow oil was dissolved in dichloromethane(10 mL). The 2-(chloromethyl)-3,4-dimethoxypyridinesolution in dichloromethane was added dropwise to a solution of N,N0-dimethylethylenediamine (0.503 mL, 4.67 mmol) in dichloromethane(15 mL). In the next step aqueous 1 M sodium hydroxide(10 mL) was slowly added and solution was stirred for additional60 h at room temperature. After 60 h of stirring followed by therapid addition of a second fraction of aqueous 1 M sodium hydroxide(10 mL, 10 mmol), the product was extracted with dichloromethane(3 25 mL). The combined organic layers were driedover anhydrous sodium sulfate and filtered. Subsequently, theexcess solvent was evaporated by vacuum to afford yellow colorviscous oil (1.86 g, Yield 89%). 1H NMR (500 MHz, Methanol-d4) d8.14 (d, 2H, pyridine ring), 7.05 (d, 2H, pyridine ring), 3.95 (s,6H,-O-CH3-Py), 3.85 (s, 6H,-O-CH3-Py), 3.66 (s, 4H,-N-CH2-Py),2.67 (s, 4H, -CH2-CH2-), 2.26 (s, 6H, -N-CH3). 13C NMR (126 MHz,Methanol-d4) d 160.77, 152.19, 147.28, 146.07 (d, J = 10.3 Hz),108.87, 61.40, 58.17, 56.43, 56.07, 43.10. ESI-MS (in CH3OH).observed m/z 391.3 [(L2 + H)+] (z = 1); theoretical-391.23[(L2 + H)+] (z = 1). IR (cm1): 3375, 2945, 1626, 1584, 1447, 1425,1261, 1228, 1173, 1073, 994, 828, 651, 603. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.5% | With sodium hydroxide; In ethanol; water; at 20℃; for 8h; | General procedure: 4-Nitrobenzenethiol 1 (1.55 g, 0.01 mol), and 2-(chloromethyl)pyridine hydrochloride derivatives 2(0.01 mol) were dissolved in EtOH (100 mL), then aqueous NaOH (2M) was added dropwise. After theaddition completed, the solution was stirred for 8 h at room temperature. Upon completion, the excessethanol was evaporated to give the residue. A large number of white solids have been precipitatedwhen 200 mL of water was added. The Precipitate was filtered o and washed with water to obtain theintermediates (3a-3d), which was used for next step without further purification. |
Tags: 72830-09-2 synthesis path| 72830-09-2 SDS| 72830-09-2 COA| 72830-09-2 purity| 72830-09-2 application| 72830-09-2 NMR| 72830-09-2 COA| 72830-09-2 structure
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