CN108640903A - A kind of preparation method of dabigatran etexilate intermediate - Google Patents
A kind of preparation method of dabigatran etexilate intermediate Download PDFInfo
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- CN108640903A CN108640903A CN201810337379.3A CN201810337379A CN108640903A CN 108640903 A CN108640903 A CN 108640903A CN 201810337379 A CN201810337379 A CN 201810337379A CN 108640903 A CN108640903 A CN 108640903A
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- Prior art keywords
- preparation
- dabigatran etexilate
- etexilate intermediate
- intermediate according
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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 invention belongs to technical field of medicine preparation, more particularly to a kind of preparation method of dabigatran etexilate intermediate.Compound 6 of the present invention has the features such as property is stable, has no irritating odor, cheap.Overcome defect of the existing dabigatran etexilate intermediate synthetic route using acid anhydrides or acyl chloride compound, the shortcomings that this kind of compound is irritant smell, has hygroscopicity, high to the anhydrous requirement of reaction system.The reaction process of the present invention is easier to operate and controls, high selectivity, stable yield.
Description
Technical field
The invention belongs to technical field of medicine preparation, more particularly to a kind of preparation method of dabigatran etexilate intermediate.
Background technology
Dabigatran etcxilate is a kind of novel direct thrombin inhibitor developed by German Boehringer Ingelheim company,
It is the pro-drug of dabigatran, belongs to the thrombin inhibitor of non-peptides.Dabigatran etcxilate is in April, 2008 in Germany and English
State takes the lead in listing, and the same year August obtains the license of EU Committee, and in 27 member state's listings of European Union, in November, 2010, the medicine existed
The U.S. lists, trade name Pradaxa, it also becomes after Warfarin first direct mouth listed in the U.S. over 50 years
Clothes property anticoagulation kind new medicine.The structural formula of dabigatran etcxilate is as shown in Figure 1, it is a kind of direct fibrin ferment suppression of novel synthesis
Preparation, " novel " refer to its mechanism of action anti-freezing class drug different from the past, inhibit vitamin K unlike warfarin and coagulate
The combination of blood factor hinders the generation of fibrin ferment, also passes through unlike the drugs such as heparin, razaxaban and inhibits coagulation factor
The synthesis of fibrin ferment is hindered, but directly acts on fibrin ferment fibrin, plays anticoagulation.The listing of dabigatran etcxilate
It is a major progress in anticoagulant therapy field and potential lethal thrombus prevention field, there is milestone significance.Da Bijia
It is quickish that group's ester, which replaces the progress of warfarin, and market estimation dabigatran etcxilate has the potentiality as cookle, it is contemplated that most
High income from sales is up to 9,000,000,000 dollars or so.Therefore, it is of great immediate significance to the exploitation of dabigatran etcxilate project.
Boehringer Ingelheim in 2011 discloses the route (US2011/275824) of synthesis dabigatran etcxilate for the first time, such as Fig. 2
Shown, which has many advantages, such as high selectivity, easy to operate.It is obtained among key by using 2 cyclization of compound in the route
Body 3, compound 2 cover following reagent in that patent：Chloroacetic anhydride, monoxone, chloracetyl chloride.Chinese patent
In CN104447697, it was recently reported that with ethyl chloroacetate can also cyclization obtain key intermediate 3.
But the characteristics of said synthesis route all uses acid anhydrides or acyl chloride compound, this kind of compound is irritant
Smell has hygroscopicity, high to the anhydrous requirement of reaction system.
Invention content
It is an object of the invention to overcome the deficiencies of the prior art and provide a kind of high selectivity, stable yield, easy to operate,
Simultaneous reactions feedstock property is stable, has no irritating odor, the preparation method of cheap dabigatran etexilate intermediate.
In order to achieve the above object, the preparation method of a kind of dabigatran etexilate intermediate designed by the present invention, synthesis
Route is as follows：
Wherein：X in compound 6 refers to chlorine, bromine, iodine, TsO, MsO etc. easily by the leaving group of nucleopilic reagent attack；What R referred to
It is a carbon to the straight chain of six carbon, branch or contains cricoid alkyl, further R refers to methyl, ethyl, n-propyl, isopropyl
Base, normal-butyl or cyclohexyl, further R refer to methyl or ethyl.
Preferably, reaction dissolvent is DMF, DMSO, NMP, THF, dichloromethane, dioxane, methanol, ethyl alcohol, isopropyl
One or several kinds of mixed solvents in alcohol, acetone and water.
Preferably, reaction temperature is -15 DEG C~100 DEG C, it is further 15 DEG C~40 DEG C.
Preferably, catalysts are the monohydrate or anhydride, acetic acid, trifluoroacetic acid, salt of p-methyl benzenesulfonic acid
Acid, sulfuric acid etc..
Preferably, the reaction time is 6~24 hours.
Compound 6 of the present invention has the features such as property is stable, has no irritating odor, cheap.It overcomes
Using the defect of acid anhydrides or acyl chloride compound, the shortcomings that this kind of compound is existing dabigatran etexilate intermediate synthetic route
Irritant smell has hygroscopicity, high to the anhydrous requirement of reaction system.The reaction process of the present invention is easier to operate and controls,
High selectivity, stable yield.
Can be to the bibliography that make explanations of reaction mechanism of the present invention：J.Med.Chem.,2015,58(22),
8877-8895, WO2006/20415, WO2006/96444.
Description of the drawings
Fig. 1 is the structural formula of dabigatran etcxilate.
Fig. 2 is the route for the synthesis dabigatran etcxilate that Boehringer Ingelheim is announced.
Fig. 3 is the route that 1-3 of the embodiment of the present invention synthesizes dabigatran etexilate intermediate.
Specific implementation mode
Embodiment 1
As shown in figure 3, a kind of preparation method of dabigatran etexilate intermediate, specific process step are as follows：
Compound 8 (5.0g, 14.60mmol) is dissolved in dichloromethane (50mL), (the 2- chlorine ortho-acetic acid three of compound 5 is added
Methyl esters, 6.77g, 43.81mmol), p-methyl benzenesulfonic acid (251mg, 1.46mmol)；After charging, reaction system is 20~25
It is reacted 11~12 hours at DEG C；Reaction finishes, and purified water (30mL), liquid separation extraction is added, and water phase is extracted with dichloromethane again
(20mL X 2)；Merge organic phase, is washed with saturated salt solution (40mL)；Organic phase is dried with anhydrous sodium sulfate, is filtered, is depressurized
It is concentrated to give crude product, through column chromatography (eluant, eluent：Dichloromethane:Methanol=15:1) compound 9 (4.7g, yield are obtained:80.3%).
Its nuclear magnetic resoance spectrum diagram data is as follows：1H NMR(400MHz,CDCl3)δ8.43-8.41(m,1H),7.70(s,
1H), 7.38-7.32 (m, 2H), 7.16 (d, J=8.48Hz, 1H), 7.00-6.96 (m, 1H), 6.70 (d, J=8.04Hz,
1H), 4.78 (s, 2H), 4.42 (t, J=7.24Hz, 2H), 4.06 (q, J=7.12Hz, 2H), 3.81 (s, 3H), 2.80 (t, J
=7.32Hz, 2H), 1.20 (t, J=7.12Hz, 2H).
Embodiment 2
As shown in figure 3, a kind of preparation method of dabigatran etexilate intermediate, specific process step are as follows：
Compound 8 (5.0g, 14.60mmol) is dissolved in dichloromethane (50mL), (the 2- chlorine ortho-acetic acid three of compound 5 is added
Ethyl ester, 8.62g, 43.81mmol), p-methyl benzenesulfonic acid (251mg, 1.46mmol)；After charging, reaction system is 20~25
It is reacted 11~12 hours at DEG C；Reaction finishes, and purified water (30mL), liquid separation extraction is added, and water phase is extracted with dichloromethane again
(20mL X 2)；Merge organic phase, is washed with saturated salt solution (40mL)；Organic phase is dried with anhydrous sodium sulfate, is filtered, is depressurized
It is concentrated to give crude product, through column chromatography (eluant, eluent：Dichloromethane:Methanol=15:1) compound 9 (4.3g, yield are obtained:73.5%).
Its nuclear magnetic resoance spectrum diagram data is as follows：1H NMR(400MHz,CDCl3)δ8.43-8.41(m,1H),7.70(s,
1H), 7.38-7.32 (m, 2H), 7.16 (d, J=8.48Hz, 1H), 7.00-6.96 (m, 1H), 6.70 (d, J=8.04Hz,
1H), 4.78 (s, 2H), 4.42 (t, J=7.24Hz, 2H), 4.06 (q, J=7.12Hz, 2H), 3.81 (s, 3H), 2.80 (t, J
=7.32Hz, 2H), 1.20 (t, J=7.12Hz, 2H).
Embodiment 3
As shown in figure 3, a kind of preparation method of dabigatran etexilate intermediate, specific process step are as follows：
Compound 8 (5.0g, 14.60mmol) is dissolved in dichloromethane (50mL), (the 2- bromines ortho-acetic acid three of compound 5 is added
Methyl esters, 8.72g, 43.81mmol), p-methyl benzenesulfonic acid (251mg, 1.46mmol)；After charging, reaction system is 20~25
It is reacted 11~12 hours at DEG C；Reaction finishes, and purified water (30mL), liquid separation extraction is added, and water phase is extracted with dichloromethane again
(20mL X 2)；Merge organic phase, is washed with saturated salt solution (40mL)；Organic phase is dried with anhydrous sodium sulfate, is filtered, is depressurized
It is concentrated to give crude product, through column chromatography (eluant, eluent：Dichloromethane:Methanol=15:1) compound 9 (5.1g, yield are obtained:78.4%).
Its nuclear magnetic resoance spectrum diagram data is as follows：1H NMR(400MHz,CDCl3)δ8.43-8.41(m,1H),7.70(s,
1H), 7.38-7.32 (m, 2H), 7.16 (d, J=8.48Hz, 1H), 7.00-6.96 (m, 1H), 6.70 (d, J=8.04Hz,
1H), 4.65 (s, 2H), 4.42 (t, J=7.24Hz, 2H), 4.06 (q, J=7.12Hz, 2H), 3.81 (s, 3H), 2.80 (t, J
=7.32Hz, 2H), 1.20 (t, J=7.12Hz, 2H).
Claims (8)
1. a kind of preparation method of dabigatran etexilate intermediate, it is characterised in that：Its synthetic route is as follows：
Wherein：X in compound 6 refers to chlorine, bromine, iodine, TsO, MsO etc. easily by the leaving group of nucleopilic reagent attack；R refers to one
A carbon is to the straight chain of six carbon, branch or contains cricoid alkyl.
2. a kind of preparation method of dabigatran etexilate intermediate according to claim 1, it is characterised in that：R refers to first
Base, ethyl, n-propyl, isopropyl, normal-butyl or cyclohexyl.
3. a kind of preparation method of dabigatran etexilate intermediate according to claim 2, it is characterised in that：R refers to first
Base or ethyl.
4. a kind of preparation method of dabigatran etexilate intermediate according to claim 1, it is characterised in that：Reaction dissolvent is
One or several kinds in DMF, DMSO, NMP, THF, dichloromethane, dioxane, methanol, ethyl alcohol, isopropanol, acetone and water
Mixed solvent.
5. a kind of preparation method of dabigatran etexilate intermediate according to claim 1, it is characterised in that：Reaction temperature
It is -15 DEG C~100 DEG C.
6. a kind of preparation method of dabigatran etexilate intermediate according to claim 5, it is characterised in that：Reaction temperature is
15 DEG C~40 DEG C.
7. a kind of preparation method of dabigatran etexilate intermediate according to claim 1, it is characterised in that：Catalysts
For one kind in the monohydrate or anhydride of p-methyl benzenesulfonic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid.
8. a kind of preparation method of dabigatran etexilate intermediate according to claim 1, it is characterised in that：Reaction time is
6~24 hours.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101454292A (en) * | 2006-03-31 | 2009-06-10 | 阿斯利康(瑞典)有限公司 | Bicyclic benzimidazole compounds and their use as metabotropic glutamate receptor potentiators |
| US20110275824A1 (en) * | 2009-11-18 | 2011-11-10 | Boehringer Ingelheim International Gmbh | Process for the manufacture of dabigatran etexilate |
| CN102850325A (en) * | 2012-06-19 | 2013-01-02 | 上海现代制药海门有限公司 | Preparation method of Dabigatran etexilate key intermediate |
-
2018
- 2018-04-16 CN CN201810337379.3A patent/CN108640903A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101454292A (en) * | 2006-03-31 | 2009-06-10 | 阿斯利康(瑞典)有限公司 | Bicyclic benzimidazole compounds and their use as metabotropic glutamate receptor potentiators |
| US20110275824A1 (en) * | 2009-11-18 | 2011-11-10 | Boehringer Ingelheim International Gmbh | Process for the manufacture of dabigatran etexilate |
| CN102850325A (en) * | 2012-06-19 | 2013-01-02 | 上海现代制药海门有限公司 | Preparation method of Dabigatran etexilate key intermediate |
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Application publication date: 20181012 |