CN105153118A - Central control method of midbody in dabigatran etexilate mesylate preparation process - Google Patents
Central control method of midbody in dabigatran etexilate mesylate preparation process Download PDFInfo
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- CN105153118A CN105153118A CN201510617678.9A CN201510617678A CN105153118A CN 105153118 A CN105153118 A CN 105153118A CN 201510617678 A CN201510617678 A CN 201510617678A CN 105153118 A CN105153118 A CN 105153118A
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- dabigatran etcxilate
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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 relates to the technical field of medicine synthesis and purification, in particular to a central control method of a midbody V 3-{2-[(4-amidino-anilino)methyl]-1-methyl-benzimidazole-5-[N-(2-pyridyl)formamido]}-ethyl propionate in the dabigatran etexilate mesylate preparation process. Dry gas HCl is introduced into a midbody III-ethanol mixture in synthesized dabigatran etexilate mesylate, the temperature is controlled within the range of -10 DEG C to 0 DEG C, the gas introduction end point is monitored in the period through titration, and therefore the midbody is obtained. The end point control and purification method is easy to operate, safe, accurate, capable of removing impurities, high in yield and purity and suitable for large-scale industrial production.
Description
Technical field
The present invention relates to medicine synthesis and technical field of purification, be specifically related to intermediate V3-{2-in a kind of methylsulfonic acid dabigatran etcxilate preparation process [(4-amidino groups anilino) methyl]-1-methyl-benzoimidazole-5-[N-(2-pyridyl) formamido-] midpoint controlling method of-ethyl propionate.
Background technology
Dabigatran etcxilate is a kind of oral thrombin inhibitor developed by German Boehringer Ingelheim drugmaker, and in March, 2008 obtains listing license in Europe.This medicine is mainly used in postoperative venous thromboembolism and particular patient crowd.This is the five first new classification oral anticoagulant things gone on the market during the last ten years after warfarin.Dabigatran etcxilate is converted into activated dabigatran in vivo, and the latter plays anticoagulation effect by direct Trombin inhibiting.This medicine goes on the market, and is a major progress in anticoagulation therapy field and potential lethality thrombus prevention field, has milestone significance.
In dabigatran etcxilate building-up process, intermediate 3-{2-[(4-amidino groups anilino) methyl]-1-methyl-benzoimidazole-5-[N-(2-pyridyl) formamido-] } synthesis of-ethyl propionate is the key point of whole technique.What at present this step was taked more is pinner reaction, namely cyano group under HCl catalysis with the hydrochloride of alcohol production imines ester, then with NH
3reaction generates amidino groups.HCl amount cannot be reacted at least; Amount easily generates impurity greatly, and cause material waste, pollutes environment.Therefore the add-on of HCl is the key point of this step.
Its Patent CN103804354A, it is extremely saturated for ventilating at a certain temperature that WO2013024384A1 etc. report logical HCl gas end-point control method in intermediate V preparation process, so not only waste HCl gas and amplification production process in aeration time long, temperature is wayward; Separately have bibliographical information can accurately calculate HCl concentration by weighing reactor in the lab scale stage, but feasibility is not high in amplification is produced.
Summary of the invention
The object of the invention is to provide intermediate V3-{2-in a kind of methylsulfonic acid dabigatran etcxilate preparation process [(4-amidino groups anilino) methyl]-1-methyl-benzoimidazole-5-[N-(2-pyridyl) formamido-] } midpoint controlling method of-ethyl propionate.
For achieving the above object, the technical solution used in the present invention is:
The midpoint controlling method of intermediate in a kind of methylsulfonic acid dabigatran etcxilate preparation process, dry HCl gas is passed into the intermediate III-ethanol system in synthesizing methanesulfonic acid dabigatran etcxilate, control temperature-10-0 DEG C, period by titration monitoring ventilation terminal, thus realizes the acquisition of intermediate further.Described drop reaction adopts acid base titration, is reaction end during calculating concentration value > 30%.
Reaction scheme is as follows:
Titration monitoring extracts reaction solution and adds alcohol dilution, with the NaOH aqueous solution titration of normal concentration, be terminal as calculated value > 30% after being logical HCl gas for some time.Calculation formula is:
(C:NaOH concentration; V: the NaOH volume that titration consumes; M: reaction solution quality).
Specifically, pass into dry HCl gas to the intermediate III-ethanol system in synthesizing methanesulfonic acid dabigatran etcxilate, control temperature-10-0 DEG C, period is by titration monitoring ventilation terminal, be warming up to 0-10 DEG C of reaction 10-18h after reaching terminal, generate active intermediate IV; Then add ethanol to dilute system, logical NH at-5-5 DEG C
3to system alkalize, then temperature adjustment is to 10-20 DEG C, reaction 5-8h; Filter after reaction, add water making beating 2-5h at 10-30 DEG C, filters, dry intermediate V crude product.
Solvent making beating 1-4h will be added, filtration, dry intermediate V3-{2-[(4-amidino groups anilino) the methyl]-1-methyl-benzoimidazole-5-[N-(2-pyridyl) formamido-] that must refine in above-mentioned acquisition intermediate V crude product }-ethyl propionate.
The mass volume ratio of described middle intermediate III and ethanol is 1:3-1:6, and preferred proportion is 1:4.
Preferably, pass into dry HCl gas to the intermediate III-ethanol system in synthesizing methanesulfonic acid dabigatran etcxilate, at-10--5 DEG C, carry out drop reaction; 0--5 DEG C is warming up to, reaction 15-18h after reaction.
Described generation active intermediate IV, through alcohol dilution, leads to NH at 0-5 DEG C
3to pH8-9, then temperature adjustment is to 15-20 DEG C, reaction 7-8h; Filter after reaction, add water making beating 2-4h at 10-20 DEG C, filters, dry intermediate V crude product; Wherein, ethanol and the volume mass of intermediate III are than being 10:1-15:1; Preferred 12:1.
The described making beating that adds water, water and intermediate III volume mass are than being 5:1-12:1, preferred 8:1.
Described solvent is the combination of one or more in ethyl acetate, ethanol, methyl tertiary butyl ether, propyl carbinol, methylene dichloride, Virahol, acetone, ethyl acetate; Solvent and intermediate III volume mass are than being 5:1-13:1, preferred 10:1.
The preferred time 2-3h of described solubilizing agent making beating.
Compared with prior art, advantage of the present invention and technique effect are: purification process of the present invention, simple to operate, safety, save cost; The making beating reagent source used is extensive, cheap, safety and environmental protection.The present invention proves that acid base titration judges ventilation end reaction stable yield by experiment, and the crystal purity after making beating purifying reaches more than 97% and the loose exquisiteness of crystal state, is beneficial to next step and feeds intake.The present invention is highly suitable for suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the intermediate V high performance liquid phase spectrogram in embodiment 1.
Fig. 2 is the intermediate V high performance liquid phase spectrogram in embodiment 2.
Fig. 3 is the intermediate V high performance liquid phase spectrogram in embodiment 2.
Fig. 4 is the intermediate V high performance liquid phase spectrogram in embodiment 4.
Embodiment
Below in conjunction with embodiment, technical scheme of the present invention is described in further detail.Following examples are intended to describe the present invention in detail, and unrestricted the present invention.
Embodiment 1
The midpoint controlling method of intermediate in a kind of methylsulfonic acid dabigatran etcxilate preparation process
Reaction scheme is as follows:
III: 3-[[[2-[[(4-cyano-phenyl) is amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-base] carbonyl] pyridine-2-base is amino] ethyl propionate
IV: N-[[2-[[[4-(oxyethyl group formimino) phenyl] is amino] methyl]-1-methyl isophthalic acid H-benzoglyoxaline-5-base] carbonyl]-N-2-pyridyl-BETA-ALA ethyl ester
V: 3-{2-[(4-amidino groups anilino) methyl]-1-methyl-benzoimidazole-5-[N-(2-pyridyl) formamido-] }-ethyl propionate.
Concrete reaction process is:
Get 3L four-hole boiling flask, add 100g intermediate III, 400ml ethanol, stir and be cooled to less than-8 DEG C, start to pass into HCl gas and maintain the temperature at-10 ~-8 DEG C by controlling gas speed.Take rapidly 1.23g reaction solution after 3h and add 50ml alcohol dilution.With the NaOH solution titration of normal concentration, calculating concentration is 31.8%, stops ventilation, is warming up to 5 DEG C of confined reaction 18h.
Then add 1.2L alcohol dilution, pass into NH
3, detection reaction liquid pH=9 after holding temperature 0-3 DEG C, 3.5h, stops logical NH
3, adjust the temperature to 20 DEG C of reaction 7.5h.
Filter ammonium chloride after reaction, concentration of reaction solution to condensation flows down and adds 800mL water normal temperature making beating 2h, to there being a large amount of white solid to separate out, filters, dry must intermediate V crude product.
Above-mentioned crude product is thrown to 2L flask, add 1.0L ethyl acetate and be warming up to backflow making beating 3h, be down to 10 DEG C and continue to stir 2h, filtration, the dry 87.8g intermediate V that must refine, be that to record purity be 98.00% (see Fig. 1) to 84.8%, HPLC with intermediate III calculated yield.
Retention time 9.12min is the absorption peak of intermediate V as seen from Figure 1, and its relative peak area (i.e. purity) reaches 98.00%, visible logical HCl to 31.8%, then logical NH
3higher yield and purity can be obtained respectively through water and ethyl acetate making beating again to pH=9.
Embodiment 2
Concrete reaction process is:
Get 3L four-hole boiling flask, add 100g intermediate III, 400ml ethanol, stir and be cooled to less than-8 DEG C, start to pass into HCl gas and maintain the temperature at-10 ~-8 DEG C by controlling gas speed.Take rapidly 1.08g reaction solution after 3.5h and add 50ml alcohol dilution.With the NaOH solution titration of normal concentration, calculating concentration is 30.1%, stops ventilation, is warming up to 5 DEG C of confined reaction 18h.
Then add 1.2L alcohol dilution, pass into NH
3, holding temperature 0 ~ 3 DEG C, after 4h, detection reaction liquid pH is 8, stops logical NH
3, adjust the temperature to 25 DEG C of reaction 7.5h.
Filter ammonium chloride after reaction, concentration of reaction solution to condensation flows down and adds 800mL water normal temperature making beating 2h, to there being a large amount of white solid to separate out, filters, dry must intermediate V crude product.
Above-mentioned crude product is thrown to 2L flask, add 1.0L ethyl acetate and be warming up to backflow making beating 4h, be down to 10 DEG C and continue to stir 2h, filtration, the dry 84.8g intermediate V that must refine, be that to record purity be 97.27% (see Fig. 2) to 81.9%, HPLC with intermediate III calculated yield.
Retention time 8.78min is the absorption peak of intermediate V as seen from Figure 2, and its relative peak area (i.e. purity) reaches 97.27%, and visible logical HCl, to concentration 30.1%, then leads to NH
3higher yield and purity can be obtained respectively through water and ethyl acetate making beating again to pH=8.
Embodiment 3
Concrete reaction process is:
Get 3L four-hole boiling flask, add 100g intermediate III, 400ml ethanol, stir and be cooled to less than-8 DEG C, start to pass into HCl gas and maintain the temperature at-10 ~-8 DEG C by controlling gas speed.Take rapidly 1.51g reaction solution after 4h and add 50ml alcohol dilution.With the NaOH solution titration of normal concentration, calculating concentration is 32.3%, stops ventilation, is warming up to 5 DEG C of confined reaction 18h.
Then add 1.2L alcohol dilution, pass into NH
3, holding temperature 0 ~ 3 DEG C, after 4.2h, detection reaction liquid pH is 9, stops logical NH
3, adjust the temperature to 25 DEG C of reaction 7.5h.
Filter ammonium chloride after reaction, concentration of reaction solution to condensation flows down and adds 800L water normal temperature making beating 2h, to there being a large amount of white solid to separate out, filters, dry must intermediate V crude product.
By above-mentioned crude product throwing to 2L flask, add 1.0L ethyl acetate and be warming up to backflow making beating 4h, be down to 10 DEG C and continue to stir 2h, filtration, the dry 85.7g intermediate V that must refine are that 82.8%, HPLC records purity for 98.28% with intermediate III calculated yield.(see Fig. 3).
Retention time 9.09min is the absorption peak of intermediate V as seen from Figure 3, and its relative peak area (i.e. purity) reaches 98.28%, and visible logical HCl, to concentration 32.3%, then leads to NH
3higher yield and purity can be obtained respectively through water and ethyl acetate making beating again to pH=9.
Embodiment 4
Concrete reaction process is:
In 50L reactor, add 2kg intermediate III, 8L dehydrated alcohol, stir and be cooled to less than-8 DEG C, start to pass into HCl gas and maintain the temperature at-10 ~-8 DEG C by controlling gas speed.Take rapidly 1.51g reaction solution after 7.5h and add 50ml alcohol dilution.With the NaOH solution titration of normal concentration, calculating concentration is 30.9%, stops ventilation, is warming up to 5 DEG C of confined reaction 18h.
Then add 24L alcohol dilution, pass into NH
3, holding temperature 0 ~ 3 DEG C, after 6.2h, detection reaction liquid pH is 9, stops logical NH
3, adjust the temperature to 25 DEG C of reaction 7.5h.
Filter ammonium chloride after reaction, concentration of reaction solution to condensation flows down and adds 16L water normal temperature making beating 2h, to there being a large amount of white solid to separate out, filters, dry must intermediate V crude product.
By above-mentioned crude product throwing to 50L flask, add 20L ethyl acetate and be warming up to backflow making beating 4h, be down to 10 DEG C and continue to stir 2h, filtration, the dry 1.675kg intermediate V that must refine are that 80.9%, HPLC records purity for 99.58% with intermediate III calculated yield.(see Fig. 4).
Retention time 9.44min is the absorption peak of intermediate V as seen from Figure 4, and its relative peak area (i.e. purity) reaches 99.58%, leads to HCl to concentration 30.9% as seen when being amplified to feather weight and producing, then logical NH
3also higher yield and purity can be obtained respectively through water and ethyl acetate making beating again to pH=9.
Claims (10)
1. the midpoint controlling method of intermediate in a methylsulfonic acid dabigatran etcxilate preparation process, it is characterized in that: pass into dry HCl gas to the intermediate III-ethanol system in synthesizing methanesulfonic acid dabigatran etcxilate, control temperature-10-0 DEG C, period by titration monitoring ventilation terminal, thus realizes the acquisition of intermediate further.
2. by the midpoint controlling method of intermediate in methylsulfonic acid dabigatran etcxilate preparation process according to claim 1, it is characterized in that: described drop reaction adopts acid base titration, is reaction end during calculating concentration value > 30%.
3. by the midpoint controlling method of intermediate in the methylsulfonic acid dabigatran etcxilate preparation process described in claim 1 or 2, it is characterized in that: pass into dry HCl gas to the intermediate III-ethanol system in synthesizing methanesulfonic acid dabigatran etcxilate, control temperature-10-0 DEG C, period is by titration monitoring ventilation terminal, be warming up to 0-10 DEG C of reaction 10-18h after reaching terminal, generate active intermediate IV; Then add ethanol to dilute system, logical NH at-5-5 DEG C
3to system alkalize, then temperature adjustment is to 10-20 DEG C, reaction 5-8h; Filter after reaction, add water making beating 2-5h at 10-30 DEG C, filters, dry intermediate V crude product.
4. by the midpoint controlling method of intermediate in methylsulfonic acid dabigatran etcxilate preparation process according to claim 3, it is characterized in that: solvent making beating 1-4h will be added in above-mentioned acquisition intermediate V crude product, filtration, dry intermediate V3-{2-[(4-amidino groups anilino) the methyl]-1-methyl-benzoimidazole-5-[N-(2-pyridyl) formamido-] that must refine-ethyl propionate.
5., by the midpoint controlling method of intermediate in methylsulfonic acid dabigatran etcxilate preparation process according to claim 1, it is characterized in that: the mass volume ratio of described middle intermediate III and ethanol is 1:3-1:6.
6. by the midpoint controlling method of intermediate in methylsulfonic acid dabigatran etcxilate preparation process according to claim 1, it is characterized in that: pass into dry HCl gas to the intermediate III-ethanol system in synthesizing methanesulfonic acid dabigatran etcxilate, at-10 DEG C--5 DEG C, carry out drop reaction; 0-5 DEG C is warming up to, reaction 15-18h after reaction.
7. by the midpoint controlling method of intermediate in methylsulfonic acid dabigatran etcxilate preparation process according to claim 1, it is characterized in that: described generation active intermediate IV, through alcohol dilution, leads to NH at 0-5 DEG C
3to pH8-9, then temperature adjustment is to 15-20 DEG C, reaction 7-8h; Filter after reaction, add water making beating 2-4h at 10-20 DEG C, filters, dry intermediate V crude product; Wherein, ethanol and the volume mass of intermediate III are than being 10:1-15:1.
8., by the midpoint controlling method of intermediate in methylsulfonic acid dabigatran etcxilate preparation process according to claim 3, it is characterized in that: described in add water making beating, water and intermediate III volume mass are than being 5:1-12:1.
9., by the midpoint controlling method of intermediate in methylsulfonic acid dabigatran etcxilate preparation process according to claim 4, it is characterized in that: described solvent is the combination of one or more in ethyl acetate, ethanol, methyl tertiary butyl ether, propyl carbinol, methylene dichloride, Virahol, acetone; Solvent and intermediate III volume mass are than being 5:1-13:1.
10., by the midpoint controlling method of intermediate in methylsulfonic acid dabigatran etcxilate preparation process according to claim 1, it is characterized in that: described solubilizing agent beating time 2-3h.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2022198361A1 (en) * | 2021-03-22 | 2022-09-29 | 天津睿创康泰生物技术有限公司 | Novel crystal form of dabigatran etexilate ethyl ester hydrochloride, preparation method therefor and use thereof |
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2022198361A1 (en) * | 2021-03-22 | 2022-09-29 | 天津睿创康泰生物技术有限公司 | Novel crystal form of dabigatran etexilate ethyl ester hydrochloride, preparation method therefor and use thereof |
| 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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Application publication date: 20151216 |