CN102977077A - Method for preparing dabigatran etexilate intermediate - Google Patents
Method for preparing dabigatran etexilate intermediate Download PDFInfo
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- CN102977077A CN102977077A CN2012104940892A CN201210494089A CN102977077A CN 102977077 A CN102977077 A CN 102977077A CN 2012104940892 A CN2012104940892 A CN 2012104940892A CN 201210494089 A CN201210494089 A CN 201210494089A CN 102977077 A CN102977077 A CN 102977077A
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Abstract
The invention discloses a novel method for preparing p-toluenesulfonate (formula I) of 3-[[[2-[[(4-guanylphenyl)amino]methyl]-1-methyl-1H-benzimidazole-5-yl]carbonyl](pyridine-2-yl)amino]ethyl propionate. The method is characterized by comprising the following steps of: dissolving a compound of a formula II into an organic solvent, simultaneously adding inorganic acid and p-toluenesulfonic acid, carrying out an alcoholysis reaction in the promotion of inorganic acid catalysis and p-toluenesulfonic acid, obtaining a compound of a formula III, and directly adding an amide to carry out an ammonolysis reaction so as to convert into the compound of the formula I without separation. A synthesis method is changed, a process for separating or concentrating and directly salting is not required, the intermediate compound of the formula I is synthesized, the reaction yield is greatly improved, and crystallization and purification are convenient, so that the process for synthesizing the dabigatran etexilate mesylate is simplified, the production environment is improved, and large-scale production is promoted.
Description
Technical field
The invention belongs to field of medicine and chemical technology, specifically a kind of preparation method of dabigatran etcxilate intermediate.
Background technology
Methylsulfonic acid dabigatran etcxilate (dabigatran etexilate mesylate) is the prodrug of dabigatran, chemistry 3-［ 2-［ ［ 4-［ ［ ［ (hexyloxy) carbonyl ］ amino ］ formamino ］ phenyl ］ amino ］ methyl ］ by name-1-methyl isophthalic acid H-benzoglyoxaline-5-yl ］ carbonyl ］ (pyridine-2-yl) amino ］ the ethyl propionate mesylate, be that German Boehringer Ingelheim company develops, go on the market trade(brand)name Pradaxa in Germany and Britain first in April, 2008.The methylsulfonic acid dabigatran etcxilate is the brand-new oral direct anticoagulation medicine of first listing over 50 years after warfarin, gets permission prevention for full hip or total knee replacement surgery posterior vein thrombus in European Union in 2008.Discharge in vivo dabigatran after this medicine is oral, be combined with the scleroproein specific site of zymoplasm, stop Fibrinogen to be cracked into scleroproein, thus final step and the thrombosis of blocking-up blood coagulation waterfall network.In October, 2010, FDA ratifies again the generation that methylsulfonic acid dabigatran etcxilate capsule is used for the pre-preventing thrombosis of NVAF patient and cerebral apoplexy.Compare with vitamin K antagonists such as warfarins, the methylsulfonic acid dabigatran etcxilate not only has effective, measurable and consistent anticoagulation and good stroke prevention effect, and it is lower to have a bleeding risk, need not the advantages such as routine monitoring, the possibility of drug drug interaction is lower, and does not interact with food.The listing of methylsulfonic acid dabigatran etcxilate is an important breakthrough in anticoagulant treatment field and potential lethality thrombus prevention field, has milestone significance.
The synthesis technique of methylsulfonic acid dabigatran etcxilate, be disclosed in first among the international monopoly WO98/37075, existing many document and patent reports, its intermediate 3-[[[2-[[(4-carbamimido-phenyl) amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate salt synthetic be the committed step of preparation methylsulfonic acid dabigatran etcxilate, the salt of this intermediate mainly contains three kinds: 1) 3-[[[2-[[(4-carbamimido-phenyl) amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] the ethyl propionate hydrochloride; 2) 3-[[[2-[[(4-carbamimido-phenyl) amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate acetate; 3) 3-[[[2-[[(4-carbamimido-phenyl) amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] the ethyl propionate tosilate; but because its intermediate hydrochloride and acetate have very strong water absorbability; be difficult to crystallization and purification; be unfavorable for large-scale production; and the tosilate of intermediate; its water absorbability is not strong; have simultaneously good chemical stability and thermostability; be easy to crystallization and purification; thereby so that the technological process of synthesizing methanesulfonic acid dabigatran etcxilate is simplified; and improved production environment, more be conducive to large-scale production.
Formula I compound: the 3-[[[2-[[(4-carbamimido-phenyl) amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] preparation of tosilate of ethyl propionate mainly contains following two kinds of methods:
First method; WO2008/095928 discloses at first and has synthesized corresponding amidine formula IV compound by corresponding formula III compound by the pinner method, filters, and removes insolubles, and filtrate decompression adds tosic acid ethanolic soln salify production I compound after being concentrated into and doing again.The formula IV compound that the method generates is difficult to concentrate drying, is difficult for separating-purifying, is unfavorable for the large-scale production of formula I compound.
Second method: WO2006/000353, among WO2007/071742 and the WO2012/004396, disclose at first and synthesized corresponding amidine by corresponding formula V compound by the Pd/C reduction, filter, remove insolubles, add again the ethanolic soln salify production I compound of p-methyl benzenesulfonic acid after filtrate decompression is concentrated into and does.The synthetic of the party's French V compound wants complicated with respect to the formula III compound, and needs the high-pressure hydrogenation reduction, and the same amidine that generates is difficult to concentrate drying, is difficult for separating-purifying, is unfavorable for the large-scale production of formula I compound.
Above-mentioned two kinds of operational paths all are to synthesize first amidine compound (formula IV), and then with the tosic acid salify, but amidine compound is unstable in building-up process, and industrial separation and purification difficulty is large, technique is loaded down with trivial details, need to expend a large amount of reagent and the energy, the problem that cost is higher; And if formula VI compound is not needed to be concentrated into dried, directly salify then can cause the problems such as product quality is not high, yield is low.
Summary of the invention
The object of the invention provides a kind of with the extensive synthetic compound of formula i of mode of ameliorating, and its Chinese style VI compound synthetic do not need to separate or be concentrated into driedly, can avoid the method for above-mentioned shortcoming.
A kind of 3-[[[2-[[(4-carbamimido-phenyl for preparing) amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] novel method of tosilate of ethyl propionate, it is characterized in that: with formula II compound dissolution in organic solvent, add simultaneously mineral acid and tosic acid, under mineral acid catalysis and tosic acid promotion, carry out alcoholysis reaction, obtain the formula III compound, without separation, directly add the amide ammonolysis reaction and transform accepted way of doing sth I compound, wherein, formula I compound is
, formula II compound is
, the formula III compound is
Reaction formula is as follows:
II III
I
Described synthetic method is characterized in that, described organic solvent is selected from methylene dichloride, 1,2-ethylene dichloride, chloroform, ethyl acetate, butylacetate, Virahol, acetone, methyl alcohol, ethanol, particular methanol, ethanol, most preferred ethanol.
Described synthetic method is characterized in that, described mineral acid is selected from hydrochloric acid, sulfuric acid or acetic acid, preferred hydrochloric acid, and the adding method of hydrochloric acid is to pass into excessive hydrogen chloride gas.
Described synthetic method is characterized in that, described amide reagent is volatile salt, ammonium chloride, ammoniacal liquor or liquefied ammonia, preferred volatile salt and liquefied ammonia.
Described synthetic method is characterized in that, the molar feed ratio of described formula II compound and tosic acid is 1:1 ~ 10, and preferred molar feed ratio is 1:1 ~ 5, especially preferred 1:1 ~ 2.
Described synthetic method is characterized in that, the amount ratio of the consumption of described organic solvent and formula II compound is 5.0-10.0ml/g, and preferable amount is than being 5.0-7.5ml/g.
Described synthetic method is characterized in that, described formula II compound and amic molar feed ratio are 1:1 ~ 10, and preferred molar feed ratio is 1:1 ~ 5.
Described synthetic method is characterized in that, alcoholysis reaction is carried out in-10-30 ℃ temperature range, preferred-5-25 ℃, and especially preferred 0-10 ℃.
Described synthetic method is characterized in that, ammonolysis reaction carries out in 0-40 ℃ of temperature range, preferred 5-25 ℃, and especially preferred 20-25 ℃.
Described synthetic method is characterized in that, the alcoholysis reaction time is 12-72 hour, and preferred 24-48 hour, especially preferred 24 hours, the ammonolysis reaction time was 12-72 hour, preferred 24-48 hour, and especially preferred 24 hours.
Compared with prior art, the present invention has following technological merit:
(1) formula II compound is dissolved in the organic solvent, then adds simultaneously mineral acid and tosic acid and carry out alcoholysis reaction, its tosic acid has promoter action to alcoholysis reaction.
(2) the present invention just adds tosic acid in the initial stage of preparation; avoided synthetic amidine compound (formula IV) large in industrial separation and purification difficulty; technique is loaded down with trivial details; need to expend a large amount of reagent and the energy; the problem that cost is higher; can not need to separate or concentrate; directly the technique of salify makes formula I compound; not only greatly improved reaction yield; and be easy to crystallization and purification; thereby so that the technological process of synthesizing methanesulfonic acid dabigatran etcxilate simplifies, and improved production environment, more be conducive to large-scale production.
(3) the present invention just adds tosic acid in the initial stage of preparation, its elder generation and formula II compound formation tosilate, thus avoided formula II compound in organic solvent, to pass into the phenomenon of luming easily behind the hydrogen chloride gas.
Embodiment
Embodiment 1
Modus ponens II compound 130 grams (0.27mol) add 750 milliliters of dehydrated alcohols, add tosic acid 51.2 grams (0.30mol), lower in 0 degree, pass into dry hydrogen chloride gas, until after saturated, naturally be warming up to 20 ~ 25 degree and stirred 24 hours, lower in 20 ~ 25 degree, pass into liquefied ammonia, stirred 24 hours in 20 ~ 25 degree are lower, filtration obtains white solid, again to pull an oar under 1 liter of ethanol room temperature, filters to get product 172.2 grams, yield 94%, purity (HPLC): 99.8%.
Embodiment 2
Modus ponens II compound 130 grams (0.27mol) add 750 milliliters of dehydrated alcohols, add tosic acid 51.2 grams (0.30mol), lower in 0 degree, pass into dry hydrogen chloride gas, until after saturated, naturally be warming up to 20 ~ 25 degree and stirred 24 hours, lower in 20 ~ 25 degree, add volatile salt 28.8 grams (0.30mol), stirred 24 hours in 20 ~ 25 degree are lower, filtration obtains white solid, again to pull an oar under 1 liter of ethanol room temperature, filters to get product 175.8 grams, yield 96%, purity (HPLC): 99.8%.
Embodiment 3
Modus ponens II compound 130 grams (0.27mol) add 750 milliliters of dehydrated alcohols, add tosic acid 51.2 grams (0.30mol), lower in 0 degree, pass into dry hydrogen chloride gas, until after saturated, naturally be warming up to 20 ~ 25 degree and stirred 24 hours, lower in 20 ~ 25 degree, pass into liquefied ammonia, stirred 48 hours in 20 ~ 25 degree are lower, filtration obtains white solid, again to pull an oar under 1 liter of ethanol room temperature, filters to get product 166.6 grams, yield 91%, purity (HPLC): 99.6%.
Embodiment 4
Modus ponens II compound 130 grams (0.27mol) add 750 milliliters of dehydrated alcohols, add tosic acid 51.2 grams (0.30mol), lower in 0 degree, pass into dry hydrogen chloride gas, until after saturated, naturally be warming up to 20 ~ 25 degree and stirred 48 hours, lower in 20 ~ 25 degree, pass into liquefied ammonia, stirred 24 hours in 20 ~ 25 degree are lower, filtration obtains white solid, again to pull an oar under 1 liter of ethanol room temperature, filters to get product 164.8 grams, yield 90%, purity (HPLC): 99.5%.
Embodiment 5
Modus ponens II compound 130 grams (0.27mol) add 750 milliliters of anhydrous methanols, add tosic acid 51.2 grams (0.30mol), lower in 0 degree, pass into dry hydrogen chloride gas, until after saturated, naturally be warming up to 20 ~ 25 degree and stirred 24 hours, lower in 20 ~ 25 degree, pass into liquefied ammonia, stirred 48 hours in 20 ~ 25 degree are lower, filtration obtains white solid, again to pull an oar under 1 liter of ethanol room temperature, filters to get product 168.5 grams, yield 92%, purity (HPLC): 99.3%.
Embodiment 6
Modus ponens II compound 130 grams (0.27mol) add 750 milliliters of dehydrated alcohols, add tosic acid 102.4 grams (0.60mol), lower in 0 degree, pass into dry hydrogen chloride gas, until after saturated, naturally be warming up to 20 ~ 25 degree and stirred 24 hours, lower in 20 ~ 25 degree, pass into liquefied ammonia, stirred 24 hours in 20 ~ 25 degree are lower, filtration obtains white solid, again to pull an oar under 1 liter of ethanol room temperature, filters to get product 168.5 grams, yield 92%, purity (HPLC): 99.3%.
Embodiment 7
Modus ponens II compound 130 grams (0.27mol) add the 975ml dehydrated alcohol, add tosic acid 51.2 grams (0.30mol), lower in 0 degree, pass into dry hydrogen chloride gas, until after saturated, naturally be warming up to 20 ~ 25 degree and stirred 24 hours, lower in 20 ~ 25 degree, the liquefied ammonia that passes into, stirred 24 hours in 20 ~ 25 degree are lower, filtration obtains white solid, again to pull an oar under 1 liter of ethanol room temperature, filters to get product 170.7 grams, yield 93%, purity (HPLC): 99.8%.
Embodiment 8
Modus ponens II compound 130 grams (0.27mol) add the 750ml dehydrated alcohol, add tosic acid 51.2 grams (0.30mol), lower in 10 degree, pass into dry hydrogen chloride gas, until after saturated, naturally be warming up to 20 ~ 25 degree and stirred 24 hours, lower in 20 ~ 25 degree, pass into liquefied ammonia, stirred 24 hours in 20 ~ 25 degree are lower, filtration obtains white solid, again to pull an oar under 1 liter of ethanol room temperature, filters to get product 168.5 grams, yield 92%, purity (HPLC): 99.8%.
Embodiment 9
Modus ponens II compound 130 grams (0.27mol) add the 750ml dehydrated alcohol, add tosic acid 51.2 grams (0.30mol), lower in 10 degree, pass into dry hydrogen chloride gas, until after saturated, naturally be warming up to 20 ~ 25 degree and stirred 24 hours, lower in 20 ~ 25 degree, pass into liquefied ammonia, stirred 48 hours in 20 ~ 25 degree are lower, filtration obtains white solid, again to pull an oar under 1 liter of ethanol room temperature, filters to get product 164.8 grams, yield 90%, purity (HPLC): 99.6%.
Embodiment 10
Modus ponens II compound 130 grams (0.27mol) add the 750ml dehydrated alcohol, add tosic acid 51.2 grams (0.30mol), lower in 10 degree, pass into dry hydrogen chloride gas, until after saturated, naturally be warming up to 20 ~ 25 degree and stirred 24 hours, lower in 10 ~ 15 degree, the liquefied ammonia that passes into, stirred 48 hours in 10 ~ 15 degree are lower, filtration obtains white solid, again to pull an oar under 1 liter of ethanol room temperature, filters to get product 159.3 grams, yield 87%, purity (HPLC): 99.2%.
The above only is preferred embodiment of the present invention, not in order to limiting the present invention, all any modifications of doing within the spirit and principles in the present invention, is equal to and replaces and improvement etc., all is included within protection scope of the present invention.
Claims (10)
1. one kind prepares the 3-[[[2-[[(4-carbamimido-phenyl) amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-yl] carbonyl] (pyridine-2-yl) amino] novel method of tosilate of ethyl propionate, it is characterized in that: with formula II compound dissolution in organic solvent, add simultaneously mineral acid and tosic acid, under mineral acid catalysis and tosic acid promotion, carry out alcoholysis reaction, obtain the formula III compound, without separation, directly add the amide ammonolysis reaction and transform accepted way of doing sth I compound, wherein, formula I compound is
, formula II compound is
, the formula III compound is
2. synthetic method according to claim 1 is characterized in that, described organic solvent is selected from methylene dichloride, 1,2-ethylene dichloride, chloroform, ethyl acetate, butylacetate, Virahol, acetone, methyl alcohol, ethanol.
3. synthetic method according to claim 1 is characterized in that, described mineral acid is selected from hydrochloric acid, sulfuric acid or acetic acid.
4. synthetic method according to claim 1 is characterized in that, described amide reagent is volatile salt, ammonium chloride, ammoniacal liquor or liquefied ammonia.
5. described synthetic method is characterized in that according to claim 1-4, and the molar feed ratio of described formula II compound and tosic acid is 1:1 ~ 10.
6. described synthetic method is characterized in that according to claim 1-4, and the amount ratio of the consumption of described organic solvent and formula II compound is 5.0-10.0ml/g.
7. described synthetic method is characterized in that according to claim 1-4, and described formula II compound and amic molar feed ratio are 1:1 ~ 10.
8. described synthetic method is characterized in that according to claim 1-4, and alcoholysis reaction is carried out in-10-30 ℃ temperature range.
9. described synthetic method is characterized in that according to claim 1-4, and ammonolysis reaction carries out in 0-40 ℃ of temperature range.
10. described synthetic method is characterized in that according to claim 1-4, and the alcoholysis reaction time is 12-72 hour, and the ammonolysis reaction time is 12-72 hour.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106397403A (en) * | 2016-08-30 | 2017-02-15 | 苏州天马精细化学品股份有限公司 | Method for purifying dabigatran etexilate mesylate intermediate |
| CN106946846A (en) * | 2013-06-19 | 2017-07-14 | 上海医药工业研究院 | Dabigatran etcxilate new intermediate and preparation method thereof |
| CN111793058A (en) * | 2019-04-09 | 2020-10-20 | 鲁南制药集团股份有限公司 | Improved method for preparing dabigatran etexilate intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1248251A (en) * | 1997-02-18 | 2000-03-22 | 贝林格尔英格海姆法玛公司 | Disubstituted bicyclic heterocycles, their production and use as medicaments |
| CN101600709A (en) * | 2007-02-06 | 2009-12-09 | 贝林格尔·英格海姆国际有限公司 | The method for preparing benzimidizole derivatives |
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2012
- 2012-11-28 CN CN2012104940892A patent/CN102977077A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1248251A (en) * | 1997-02-18 | 2000-03-22 | 贝林格尔英格海姆法玛公司 | Disubstituted bicyclic heterocycles, their production and use as medicaments |
| CN101600709A (en) * | 2007-02-06 | 2009-12-09 | 贝林格尔·英格海姆国际有限公司 | The method for preparing benzimidizole derivatives |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106946846A (en) * | 2013-06-19 | 2017-07-14 | 上海医药工业研究院 | Dabigatran etcxilate new intermediate and preparation method thereof |
| CN106946846B (en) * | 2013-06-19 | 2019-11-29 | 上海医药工业研究院 | Dabigatran etcxilate new intermediate and preparation method thereof |
| CN106397403A (en) * | 2016-08-30 | 2017-02-15 | 苏州天马精细化学品股份有限公司 | Method for purifying dabigatran etexilate mesylate intermediate |
| CN111793058A (en) * | 2019-04-09 | 2020-10-20 | 鲁南制药集团股份有限公司 | Improved method for preparing dabigatran etexilate intermediate |
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Application publication date: 20130320 |