CN103804354A - Dabigatran preparation method - Google Patents
Dabigatran preparation method Download PDFInfo
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- CN103804354A CN103804354A CN201210445299.2A CN201210445299A CN103804354A CN 103804354 A CN103804354 A CN 103804354A CN 201210445299 A CN201210445299 A CN 201210445299A CN 103804354 A CN103804354 A CN 103804354A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention relates to a dabigatran preparation method, which is characterized in that in a saturated hydrochloric acid ethanol solution, a compound represented by a formula 1 is subjected to alcoholysis under catalysis of a Lewis acid to obtain a compound represented by a formula 2, the compound represented by a formula 2 reacts with ammonia to obtain a compound represented by a formula 3, and the compound represented by the formula 3 reacts with hexyl chloroformate in the presence of an alkali to obtain a compound represented by a formula 4, wherein the compound represented by the formula 4 is dabigatran.
Description
Technical field
The present invention relates to a kind of preparation method of dabigatran etcxilate.
technical field
The present invention relates to a kind of preparation method of dabigatran etcxilate.
Background technology
Dabigatran etcxilate (Dabigatran) is the novel anticoagulation medicine with various features of German Boehringer Ingelheim company exploitation.In April, 2008, first go on the market in Germany and Britain, commodity are called Pradaxa, for preventing and treating Acute Venous thrombus (VTE), are the oral new drugs of the anticoagulation of first listing over 50 years after warfarin.
Dabigatran etcxilate is well known in the prior art, and is disclosed in first in International Patent Application WO 98/37075.The method of preparing dabigatran etcxilate also can be known in the people's such as WO 2006/000353 or Hauel article (J.Med.Chem., 2002,45,1757 ff).Except International Patent Application WO 98/37075 and WO 2006/000353, WO 2007/071742Al and WO 2007/071713Al also disclose the possible preparation method of dabigatran etcxilate.
From above-mentioned patent, formula 3 compound 3-(2-(((4-amidino phenyl) amino) methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzoglyoxaline-5-formamido-) ethyl propionate is during dabigatran etcxilate synthesizes and important midbody product.
WO 98/37075 discloses by corresponding replacement (4-benzimidazolyl-2 radicals-ylmethyl amino)-benzyl cyanogen and ammonia react, (4-benzimidazolyl-2 radicals-ylmethyl amino) benzenyl amidine that preparation replaces.According to disclosed method in prior art, replace benzyl cyanogen and in saturated ethanol solution hydrochloride, react to complete, solvent distillation, then adds a small amount of dissolve with ethanol, then adds volatile salt reaction 4 hours, precipitation, column purification obtains product, yield 80%.This method long reaction time, generally all needs the time of several days, and reaction is not thorough, and yield is low.
The object of the invention is to provide a kind of with mode of ameliorating synthetic dabigatran etcxilate on a large scale, and can avoid the method for above-mentioned shortcoming, and about 10 hours reaction times, yield reaches more than 90%, and does not need column chromatography purification.
background technology
Dabigatran etcxilate (Dabigatran) is the novel anticoagulation medicine with various features of German Boehringer Ingelheim company exploitation.In April, 2008, first go on the market in Germany and Britain, commodity are called Pradaxa, for preventing and treating Acute Venous thrombus (VTE), are the oral new drugs of the anticoagulation of first listing over 50 years after warfarin.
Dabigatran etcxilate is well known in the prior art, and is disclosed in first in International Patent Application WO 98/37075.The method of preparing dabigatran etcxilate also can be known in the people's such as WO 2006/000353 or Hauel article (J.Med.Chem., 2002,45,1757 ff).Except International Patent Application WO 98/37075 and WO 2006/000353, WO 2007/071742Al and WO 2007/071713Al also disclose the possible preparation method of dabigatran etcxilate.
From above-mentioned patent, formula 3 compound 3-(2-(((4-amidino phenyl) amino) methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzoglyoxaline-5-formamido-) ethyl propionate is during dabigatran etcxilate synthesizes and important midbody product.
WO 98/37075 discloses by corresponding replacement (4-benzimidazolyl-2 radicals-ylmethyl amino)-benzyl cyanogen and ammonia react, (4-benzimidazolyl-2 radicals-ylmethyl amino) benzenyl amidine that preparation replaces.According to disclosed method in prior art, replace benzyl cyanogen and in saturated ethanol solution hydrochloride, react to complete, solvent distillation, then adds a small amount of dissolve with ethanol, then adds volatile salt reaction 4 hours, precipitation, column purification obtains product, yield 80%.This method long reaction time, generally all needs the time of several days, and reaction is not thorough, and yield is low.
The object of the invention is to provide a kind of with mode of ameliorating synthetic dabigatran etcxilate on a large scale, and can avoid the method for above-mentioned shortcoming, and about 10 hours reaction times, yield reaches more than 90%, and does not need column chromatography purification.
Summary of the invention
The present invention relates to a kind of method of preparing on a large scale following formula 4 dabigatran etcxilates, reaction equation is as follows:
It is characterized in that by the substituted benzene cyanogen of formula 1 compound (can be prepared by disclosed method in WO 98/37075) alcoholysis under lewis acid catalysis, obtains formula 2 compounds in saturated ethanol solution hydrochloride; Formula 2 compounds obtain formula 3 compounds with ammonia react again; Formula 3 compounds react the formula of obtaining 4 compounds, i.e. dabigatran etcxilate with the just own ester of chloroformic acid under alkali exists.
In the present invention, the substituted benzene cyanogen of formula 1 compound is reacted in saturated ethanol solution hydrochloride, quantity of solvent is that every gram of formula 1 compound is dissolved in 20mL solvent.Add lewis acid as catalyzer, the Lewis acid of use is preferably the one in aluminum chloride, iron(ic) chloride, zinc chloride, boron trifluoride, tin chloride, is more preferably zinc chloride.
The consumption of Lewis acid and the mol ratio 0.2 ~ 1.5: 1 of formula 1 compound that use, preferably 0.4: 1.
React completely, rotary evaporation heating concentrated solvent, preferred Heating temperature is 40-55 ℃, is more preferably 45-50 ℃; Concentrated volume to 1/5 ~ 1/8, preferably 1/8.Then add ethyl acetate dispersed with stirring solid, calculate with every gram of formula 1 compound used, preferably add the ethyl acetate of 10-25mL, be more preferably 15-20mL.Stir 3 hours, filter, obtain solid product; Solid is dispersed in normal hexane again, calculates with every gram of formula 1 compound used, preferably add the normal hexane of 5-15mL, be more preferably 5-10mL, stir 3 hours, filter, obtain the solid product of formula 2, in air, dry.
Then the solid product of formula 2 is dissolved in ethanol, quantity of solvent is that every gram of formula 2 compounds are dissolved in 13mL solvent.Add ammonia with gas form or with aqueous solution form.Preferably, according to the present invention, use the ammonia of aqueous solution form, especially preferably contain 25%(w/w) aqueous solution (NH of ammonia
4oH) form.At the interpolation initial stage, need in the ice-water bath of 0-10 ℃, carry out.This sentences every mole of formula 2 compounds used and calculates, and preferably adds 2-20mol, especially preferably 6-16mol, the more preferably ammonia of 6-13mol.
React completely, rotary evaporation heating concentrated solvent, preferred Heating temperature is 40-55 ℃, is more preferably 45-50 ℃; Concentrated volume to 1/5 ~ 1/8, preferably 1/8.Then add ethyl acetate and glycol dimethyl ether dispersed with stirring solid, calculate with every gram of formula 2 compounds used, preferably add the ethyl acetate of 5-20mL, be more preferably 10-15mL; Glycol dimethyl ether preferably adds 1-10mL, more preferably 2-5mL; Stir 3 hours, filter, obtain the solid product of formula 3, in air, dry.
Formula 3 compounds are dissolved in the mixed solvent of tetrahydrofuran (THF) and water 5:1, in every gram of formula 3 compounds used, add 30mL mixed solvent, stirring and dissolving, adds alkali, and the preferred alkali of the present invention is salt of wormwood; Then room temperature drips the just own ester of chloroformic acid, according to the present invention, preferably first drips the just own ester of chloroformic acid of an equivalent, reacts after 6 hours, then drips the just own ester of chloroformic acid of 0.2 equivalent.
React completely, separatory, water organic solvent extraction, merges organic phase, dry, precipitation.Crude product is dissolved in recrystallization in inert solvent.The acetone of the preferred solvent of the present invention, tetrahydrofuran (THF), 2-methyltetrahydrofuran, ethyl acetate, DMF/water, acetone/water, tetrahydrofuran (THF)/water, is more preferably acetone, 2-methyltetrahydrofuran.
summary of the invention
The present invention relates to a kind of method of preparing on a large scale following formula 4 dabigatran etcxilates, reaction equation is as follows:
It is characterized in that by the substituted benzene cyanogen of formula 1 compound (can be prepared by disclosed method in WO 98/37075) alcoholysis under lewis acid catalysis, obtains formula 2 compounds in saturated ethanol solution hydrochloride; Formula 2 compounds obtain formula 3 compounds with ammonia react again; Formula 3 compounds react the formula of obtaining 4 compounds, i.e. dabigatran etcxilate with the just own ester of chloroformic acid under alkali exists.
In the present invention, the substituted benzene cyanogen of formula 1 compound is reacted in saturated ethanol solution hydrochloride, quantity of solvent is that every gram of formula 1 compound is dissolved in 20mL solvent.Add lewis acid as catalyzer, the Lewis acid of use is preferably the one in aluminum chloride, iron(ic) chloride, zinc chloride, boron trifluoride, tin chloride, is more preferably zinc chloride.
The consumption of Lewis acid and the mol ratio 0.2 ~ 1.5: 1 of formula 1 compound that use, preferably 0.4: 1.
React completely, rotary evaporation heating concentrated solvent, preferred Heating temperature is 40-55 ℃, is more preferably 45-50 ℃; Concentrated volume to 1/5 ~ 1/8, preferably 1/8.Then add ethyl acetate dispersed with stirring solid, calculate with every gram of formula 1 compound used, preferably add the ethyl acetate of 10-25mL, be more preferably 15-20mL.Stir 3 hours, filter, obtain solid product; Solid is dispersed in normal hexane again, calculates with every gram of formula 1 compound used, preferably add the normal hexane of 5-15mL, be more preferably 5-10mL, stir 3 hours, filter, obtain the solid product of formula 2, in air, dry.
Then the solid product of formula 2 is dissolved in ethanol, quantity of solvent is that every gram of formula 2 compounds are dissolved in 13mL solvent.Add ammonia with gas form or with aqueous solution form.Preferably, according to the present invention, use the ammonia of aqueous solution form, especially preferably contain 25%(w/w) aqueous solution (NH of ammonia
4oH) form.At the interpolation initial stage, need in the ice-water bath of 0-10 ℃, carry out.This sentences every mole of formula 2 compounds used and calculates, and preferably adds 2-20mol, especially preferably 6-16mol, the more preferably ammonia of 6-13mol.
React completely, rotary evaporation heating concentrated solvent, preferred Heating temperature is 40-55 ℃, is more preferably 45-50 ℃; Concentrated volume to 1/5 ~ 1/8, preferably 1/8.Then add ethyl acetate and glycol dimethyl ether dispersed with stirring solid, calculate with every gram of formula 2 compounds used, preferably add the ethyl acetate of 5-20mL, be more preferably 10-15mL; Glycol dimethyl ether preferably adds 1-10mL, more preferably 2-5mL; Stir 3 hours, filter, obtain the solid product of formula 3, in air, dry.
Formula 3 compounds are dissolved in the mixed solvent of tetrahydrofuran (THF) and water 5:1, in every gram of formula 3 compounds used, add 30mL mixed solvent, stirring and dissolving, adds alkali, and the preferred alkali of the present invention is salt of wormwood; Then room temperature drips the just own ester of chloroformic acid, according to the present invention, preferably first drips the just own ester of chloroformic acid of an equivalent, reacts after 6 hours, then drips the just own ester of chloroformic acid of 0.2 equivalent.
React completely, separatory, water organic solvent extraction, merges organic phase, dry, precipitation.Crude product is dissolved in recrystallization in inert solvent.The acetone of the preferred solvent of the present invention, tetrahydrofuran (THF), 2-methyltetrahydrofuran, ethyl acetate, DMF/water, acetone/water, tetrahydrofuran (THF)/water, is more preferably acetone, 2-methyltetrahydrofuran.
Embodiment
The following example is with the exemplary explanation synthetic method of the mode of example.They are only as having the embodiment of possibility step, rather than content of the present invention is limited.
The ratio 0.4:1 of the consumption of embodiment 1:Lewis acid and compound 1
By the compound 80g(0.166mol of formula 1) be dissolved in the saturated ethanol solution hydrochloride of new system (1700ml), stirring at room temperature is dissolved to solution and is yellow-green colour clarification, then adds 9.03g (0.066mol) zinc chloride solid.React and within 3 hours, separate out white solid, thin-layer chromatography is followed the tracks of, and after 10 hours, reacts completely.Rotary evaporation heating is concentrated, and Heating temperature 45-50 ℃, is concentrated into 300ml, adds 1400ml ethyl acetate, stirs 3 hours, and the solid product of 115g formula 2 is dried to obtain in filtration in air.
By above-mentioned solid 1500ml anhydrous alcohol solution, the pinkiness that stirs muddiness, ice-water bath slowly drips 248ml ammoniacal liquor.In dropping process, reaction solution color is finally become colorless or faint yellow clear liquor by pink muddiness, ambient temperature overnight.After reacting completely, steam and remove most solvents, when remaining about 300ml solvent, under agitation add 1300ml ethyl acetate and 370ml glycol dimethyl ether, stirring at room temperature 3 hours.Filter, obtain the white solid 81g of formula 3, yield: 97.8%.
The ratio 0.2:1 of the consumption of embodiment 2:Lewis acid and formula 1 compound
By formula 1 compound 80g(0.166mol) be dissolved in the saturated ethanol solution hydrochloride of new system (1700ml), stirring at room temperature is dissolved to solution and is yellow-green colour clarification, then adds 4.52g (0.033mol) zinc chloride solid.React and within 3 hours, separate out white solid, thin-layer chromatography is followed the tracks of, and after 10 hours, reacts completely.Rotary evaporation heating is concentrated, and Heating temperature 45-50 ℃, is concentrated into 300ml, adds 1400ml ethyl acetate, stirs 3 hours, and the solid product of 120g formula 2 is dried to obtain in filtration in air.
By above-mentioned solid 1565ml anhydrous alcohol solution, the pinkiness that stirs muddiness, ice-water bath slowly drips 258ml ammoniacal liquor.In dropping process, reaction solution color is finally become colorless or faint yellow clear liquor by pink muddiness, ambient temperature overnight.After reacting completely, steam and remove most solvents, when remaining about 300ml solvent, under agitation add 1300ml ethyl acetate and 370ml glycol dimethyl ether, stirring at room temperature 3 hours.Filter, obtain the white solid 79g of formula 3.Yield: 95.38%.
The ratio 1.5:1 of the consumption of embodiment 3:Lewis acid and formula 1 compound
By formula 1 compound 80g(0.166mol) be dissolved in the saturated ethanol solution hydrochloride of new system (1700ml), stirring at room temperature is dissolved to solution and is yellow-green colour clarification, then adds 33.94g(0.249mol) zinc chloride solid.React and within 3 hours, separate out white solid, thin-layer chromatography is followed the tracks of, and after 10 hours, reacts completely.Rotary evaporation heating is concentrated, and Heating temperature 45-50 ℃, is concentrated into 300ml, adds 1400ml ethyl acetate, stirs 3 hours, and the compound of 118g formula 2 is dried to obtain in filtration in air.
By above-mentioned solid 1550ml anhydrous alcohol solution, the pinkiness that stirs muddiness, ice-water bath slowly drips 254ml ammoniacal liquor.In dropping process, reaction solution color is finally become colorless or faint yellow clear liquor by pink muddiness, ambient temperature overnight.After reacting completely, steam and remove most solvents, when remaining about 300ml solvent, under agitation add 1300ml ethyl acetate and 370ml glycol dimethyl ether, stirring at room temperature 3 hours.Filter, obtain the white solid 78g of formula 3.Yield: 94%.
Embodiment 4:
The compound 80g of modus ponens 3 is dissolved in 2330mL in the mixed solvent of tetrahydrofuran (THF) and water 5/1, and the turbid solution that is white in color, adds Anhydrous potassium carbonate 132.7g after stirring, stirring at room temperature 15min, and reaction solution gradually becomes yellow-green colour clarification.Slowly drip afterwards the just own ester 26.11g of chloroformic acid, in dropping process, reaction solution gradually becomes yellow-white clarification, and stirring reaction is after 6 hours, then drips the just own ester of 5.27g chloroformic acid, and reaction is spent the night.Leave standstill, separate organic layer, water extracts (300mLx 2) by ethyl acetate, merges organic phase, and anhydrous magnesium sulfate drying filters, and is concentrated into and separates out a large amount of white solids, filters and obtains thick product 71.23g, yield 70.86%.
Embodiment 5:
Get the crude product 10g of embodiment 4,40 ℃ are dissolved in 50mL acetone to clarification, and room temperature is placed 3 hours, then places recrystallization for 4 ℃, filters, and in air, dries, and obtains the white crystal product of 7.5g formula 4, and it is 99.43% that HPLC detects purity;
Embodiment 6:
Get the crude product 10g of embodiment 4,65 ℃ are dissolved in 70mL ethyl acetate to clarification, and room temperature is placed 3 hours, then places recrystallization for 4 ℃, filters, and in air, dries, and obtains the white crystal product of 7.8g formula 4, and it is 98.25% that HPLC detects purity;
Embodiment 7:
Get the crude product 10g of embodiment 4, room temperature is dissolved in 35mL acetone and the extremely clarification of 32mL water, places recrystallizations for 4 ℃, filters, and in air, dries, and obtains the white crystal product of 10g formula 4, and it is 98.16% that HPLC detects purity;
Embodiment 8:
Get the crude product 10g of embodiment 4,50 ℃ are dissolved in 70mL2-methyltetrahydrofuran to clarification, and room temperature is placed 3 hours, then places recrystallization for 4 ℃, filters, and in air, dries, and obtains the white crystal product of 6.5g formula 4, and it is 99.38% that HPLC detects purity;
Embodiment 9:
Get the crude product 10g of embodiment 4, room temperature is dissolved in extremely clarification in 60mL tetrahydrofuran (THF) and 80mL water, places recrystallizations for 4 ℃, filters, and in air, dries, and obtains the white crystal product of 9.8g formula 4, and it is 99.01% that HPLC detects purity;
A kind of preparation method of dabigatran etcxilate
embodiment
The following example is with the exemplary explanation synthetic method of the mode of example.They are only as having the embodiment of possibility step, rather than content of the present invention is limited.
The ratio 0.4:1 of the consumption of embodiment 1:Lewis acid and compound 1
By the compound 80g(0.166mol of formula 1) be dissolved in the saturated ethanol solution hydrochloride of new system (1700ml), stirring at room temperature is dissolved to solution and is yellow-green colour clarification, then adds 9.03g (0.066mol) zinc chloride solid.React and within 3 hours, separate out white solid, thin-layer chromatography is followed the tracks of, and after 10 hours, reacts completely.Rotary evaporation heating is concentrated, and Heating temperature 45-50 ℃, is concentrated into 300ml, adds 1400ml ethyl acetate, stirs 3 hours, and the solid product of 115g formula 2 is dried to obtain in filtration in air.
By above-mentioned solid 1500ml anhydrous alcohol solution, the pinkiness that stirs muddiness, ice-water bath slowly drips 248ml ammoniacal liquor.In dropping process, reaction solution color is finally become colorless or faint yellow clear liquor by pink muddiness, ambient temperature overnight.After reacting completely, steam and remove most solvents, when remaining about 300ml solvent, under agitation add 1300ml ethyl acetate and 370ml glycol dimethyl ether, stirring at room temperature 3 hours.Filter, obtain the white solid 81g of formula 3, yield: 97.8%.
The ratio 0.2:1 of the consumption of embodiment 2:Lewis acid and formula 1 compound
By formula 1 compound 80g(0.166mol) be dissolved in the saturated ethanol solution hydrochloride of new system (1700ml), stirring at room temperature is dissolved to solution and is yellow-green colour clarification, then adds 4.52g (0.033mol) zinc chloride solid.React and within 3 hours, separate out white solid, thin-layer chromatography is followed the tracks of, and after 10 hours, reacts completely.Rotary evaporation heating is concentrated, and Heating temperature 45-50 ℃, is concentrated into 300ml, adds 1400ml ethyl acetate, stirs 3 hours, and the solid product of 120g formula 2 is dried to obtain in filtration in air.
By above-mentioned solid 1565ml anhydrous alcohol solution, the pinkiness that stirs muddiness, ice-water bath slowly drips 258ml ammoniacal liquor.In dropping process, reaction solution color is finally become colorless or faint yellow clear liquor by pink muddiness, ambient temperature overnight.After reacting completely, steam and remove most solvents, when remaining about 300ml solvent, under agitation add 1300ml ethyl acetate and 370ml glycol dimethyl ether, stirring at room temperature 3 hours.Filter, obtain the white solid 79g of formula 3.Yield: 95.38%.
The ratio 1.5:1 of the consumption of embodiment 3:Lewis acid and formula 1 compound
By formula 1 compound 80g(0.166mol) be dissolved in the saturated ethanol solution hydrochloride of new system (1700ml), stirring at room temperature is dissolved to solution and is yellow-green colour clarification, then adds 33.94g(0.249mol) zinc chloride solid.React and within 3 hours, separate out white solid, thin-layer chromatography is followed the tracks of, and after 10 hours, reacts completely.Rotary evaporation heating is concentrated, and Heating temperature 45-50 ℃, is concentrated into 300ml, adds 1400ml ethyl acetate, stirs 3 hours, and the compound of 118g formula 2 is dried to obtain in filtration in air.
By above-mentioned solid 1550ml anhydrous alcohol solution, the pinkiness that stirs muddiness, ice-water bath slowly drips 254ml ammoniacal liquor.In dropping process, reaction solution color is finally become colorless or faint yellow clear liquor by pink muddiness, ambient temperature overnight.After reacting completely, steam and remove most solvents, when remaining about 300ml solvent, under agitation add 1300ml ethyl acetate and 370ml glycol dimethyl ether, stirring at room temperature 3 hours.Filter, obtain the white solid 78g of formula 3.Yield: 94%.
Embodiment 4:
The compound 80g of modus ponens 3 is dissolved in 2330mL in the mixed solvent of tetrahydrofuran (THF) and water 5/1, and the turbid solution that is white in color, adds Anhydrous potassium carbonate 132.7g after stirring, stirring at room temperature 15min, and reaction solution gradually becomes yellow-green colour clarification.Slowly drip afterwards the just own ester 26.11g of chloroformic acid, in dropping process, reaction solution gradually becomes yellow-white clarification, and stirring reaction is after 6 hours, then drips the just own ester of 5.27g chloroformic acid, and reaction is spent the night.Leave standstill, separate organic layer, water extracts (300mL x 2) by ethyl acetate, merges organic phase, and anhydrous magnesium sulfate drying filters, and is concentrated into and separates out a large amount of white solids, filters and obtains thick product 71.23g, yield 70.86%.
Embodiment 5:
Get the crude product 10g of embodiment 4,40 ℃ are dissolved in 50mL acetone to clarification, and room temperature is placed 3 hours, then places recrystallization for 4 ℃, filters, and in air, dries, and obtains the white crystal product of 7.5g formula 4, and it is 99.43% that HPLC detects purity;
Embodiment 6:
Get the crude product 10g of embodiment 4,65 ℃ are dissolved in 70mL ethyl acetate to clarification, and room temperature is placed 3 hours, then places recrystallization for 4 ℃, filters, and in air, dries, and obtains the white crystal product of 7.8g formula 4, and it is 98.25% that HPLC detects purity;
Embodiment 7:
Get the crude product 10g of embodiment 4, room temperature is dissolved in 35mL acetone and the extremely clarification of 32mL water, places recrystallizations for 4 ℃, filters, and in air, dries, and obtains the white crystal product of 10g formula 4, and it is 98.16% that HPLC detects purity;
Embodiment 8:
Get the crude product 10g of embodiment 4,50 ℃ are dissolved in 70mL2-methyltetrahydrofuran to clarification, and room temperature is placed 3 hours, then places recrystallization for 4 ℃, filters, and in air, dries, and obtains the white crystal product of 6.5g formula 4, and it is 99.38% that HPLC detects purity;
Embodiment 9:
Get the crude product 10g of embodiment 4, room temperature is dissolved in extremely clarification in 60mL tetrahydrofuran (THF) and 80mL water, places recrystallizations for 4 ℃, filters, and in air, dries, and obtains the white crystal product of 9.8g formula 4, and it is 99.01% that HPLC detects purity.
Claims (8)
1. a preparation method for dabigatran etcxilate, is characterized in that comprising the following steps:
(1), in saturated ethanol solution hydrochloride, the alcoholysis under Lewis acid catalysis of formula 1 compound, obtains formula 2 compounds;
(2) formula 2 compounds and ammonia react obtain formula 3 compounds;
(3) formula 3 compounds react the formula of obtaining 4 compounds with the just own ester of chloroformic acid under alkali exists, i.e. dabigatran etcxilate,
2. method according to claim 1, is characterized in that described Lewis acid is selected from the one in aluminum chloride, iron(ic) chloride, zinc chloride, boron trifluoride, tin chloride.
3. method according to claim 2, is characterized in that described Lewis acid is preferably zinc chloride.
4. according to the method described in claim 1-3 any one, it is characterized in that the consumption of described acid and the mol ratio 0.2 ~ 1.5:1 of formula 1 compound.
5. method according to claim 4, is characterized in that the consumption of described acid and the mol ratio of formula 1 compound are 0.4:1.
6. method according to claim 1, is characterized in that described formula 2 compounds and the mol ratio of ammonia are 1:2 ~ 20, is preferably 1:6 ~ 16, more preferably 1:6 ~ 13.
7. method according to claim 1, is characterized in that described alkali is the one in salt of wormwood, sodium carbonate, potassium hydroxide, sodium hydroxide.
8. method according to claim 8, is characterized in that described alkali is preferably salt of wormwood.
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| CN105218519A (en) * | 2014-06-04 | 2016-01-06 | 天津药物研究院 | A kind of preparation method of dabigatran etexilate intermediate |
| CN105566297A (en) * | 2015-12-31 | 2016-05-11 | 哈药集团技术中心 | Preparation method of dabigatran etexilate mesylate |
| WO2016132296A1 (en) * | 2015-02-18 | 2016-08-25 | Piramal Enterprises Limited | A process for the preparation of an intermediate of dabigatran etexilate |
| CN108640878A (en) * | 2018-04-20 | 2018-10-12 | 上海泰坦科技股份有限公司 | A kind of BenzoiminazoleflouriAnd class compound and its preparation method and application |
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| CN109232535A (en) * | 2018-09-25 | 2019-01-18 | 重庆奥舍生物化工有限公司 | A kind of preparation method of non-peptide batroxobin inhibitor dabigatran etcxilate |
| CN115322172A (en) * | 2022-09-22 | 2022-11-11 | 安徽美诺华药物化学有限公司 | High-yield synthesis process of dabigatran etexilate intermediate |
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| CN105218519A (en) * | 2014-06-04 | 2016-01-06 | 天津药物研究院 | A kind of preparation method of dabigatran etexilate intermediate |
| WO2016132296A1 (en) * | 2015-02-18 | 2016-08-25 | Piramal Enterprises Limited | A process for the preparation of an intermediate of dabigatran etexilate |
| CN105153118A (en) * | 2015-09-24 | 2015-12-16 | 青岛黄海制药有限责任公司 | Central control method of midbody in dabigatran etexilate mesylate preparation process |
| CN105566297A (en) * | 2015-12-31 | 2016-05-11 | 哈药集团技术中心 | Preparation method of dabigatran etexilate mesylate |
| CN108640878A (en) * | 2018-04-20 | 2018-10-12 | 上海泰坦科技股份有限公司 | A kind of BenzoiminazoleflouriAnd class compound and its preparation method and application |
| CN108640877A (en) * | 2018-04-20 | 2018-10-12 | 上海泰坦科技股份有限公司 | A kind of BenzoiminazoleflouriAnd class compound and its preparation method and application |
| CN108864047A (en) * | 2018-07-02 | 2018-11-23 | 河南师范大学 | A kind of preparation method of non-peptide batroxobin inhibitor dabigatran etcxilate |
| CN109232535A (en) * | 2018-09-25 | 2019-01-18 | 重庆奥舍生物化工有限公司 | A kind of preparation method of non-peptide batroxobin inhibitor dabigatran etcxilate |
| CN115322172A (en) * | 2022-09-22 | 2022-11-11 | 安徽美诺华药物化学有限公司 | High-yield synthesis process of dabigatran etexilate intermediate |
| CN115322172B (en) * | 2022-09-22 | 2024-01-26 | 安徽美诺华药物化学有限公司 | High-yield synthesis process of dabigatran etexilate intermediate |
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