CN106397400A - Preparation method for dabigatran etexilate - Google Patents
Preparation method for dabigatran etexilate Download PDFInfo
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- CN106397400A CN106397400A CN201610230951.7A CN201610230951A CN106397400A CN 106397400 A CN106397400 A CN 106397400A CN 201610230951 A CN201610230951 A CN 201610230951A CN 106397400 A CN106397400 A CN 106397400A
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- 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
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Abstract
The invention provides a method for preparing dabigatran etexilate. The method comprises the following steps: A) subjecting a compound as shown in a formula I and a compound as shown in a formula II to a reaction in an inert solvent so as to obtain a compound as shown in a formula III, wherein the compound as shown in the formula II comprises an R which is one selected from the group consisting of methyl, ethyl, propyl or isopropyl; B) subjecting the compound as shown in the formula III to activation through a hydrogen chloride solution in an inert solvent, and carrying out a reaction of the activated material and an ammonium salt so as to obtain a product IV; and C) subjecting a compound as shown in a formula IV and a compound as shown in a formula V to a reaction under the action of an acid-binding agent so as to obtain dabigatran etexilate VI. The method provided by the invention has the advantages of low cost, high yield, mild reaction conditions, avoidance of using unstable reagents, etc.
Description
Technical field
The present invention relates to technical field of medicine synthesis is and in particular to a kind of preparation method of dabigatran etcxilate.
Background technology
Dabigatran etcxilate (Dabigatran etexilate), chemical name：3- [[[2- [[[4- [[[(hexyloxy) carbonyl] amino] formamino] phenyl] amino] methyl] -1- methyl isophthalic acid H- benzimidazole -5- base] carbonyl] (pyridine -2- base) amino] ethyl propionate, chemical structural formula：
System, by the new oral anticoagulant of German Boehringer Ingelheim company research and development, belongs to non-peptide batroxobin inhibitor.Take the lead in listing in Germany and Britain in April, 2008, Europe in 2008 and Canada's approval dabigatran etcxilate are used for preventing and treating Acute Venous thrombus.Food and drug administration have approved in September, 2010 and for OA dabigatran etcxilate to be used for patients with atrial fibrillation stroke prevention.Japanese health ministry ratifies this medicine for the prevention of Non-valvular disease heart rate patients with abnormal ishemic stroke and the outbreak of general thrombus within 2011 2 months.
German Boehringer Ingelheim company reports a synthetic route of dabigatran etcxilate in 1998 (WO9837075), as follows：
Above-mentioned route compounds of formula I and Formula II ' compound is in N, N '-carbonyl dimidazoles (CDI) and the lower cyclization of acetic acid effect generate formula III compound, compound III reacts generation formula IV compound under acid effect with ammonium carbonate afterwards, and formula IV compound obtains dabigatran etcxilate end-product with Formula V compound addition again.But the Formula II used in first step reaction ' compound price is higher, and the CDI that uses hygroscopic rotten it is not easy to preserve.There is researcher that it is synthesized later to improve, for example use carboxylic acid halides in CN104003977A, CN102633713A, CN102850325A patent application instead and diamino compounds carry out synthesizing benzimidazole class formation, because chloride compounds are dazzling, toxicity is big, and relatively costly, it is unfavorable for industrialized production.Slightly improve in CN104987323A patent application again, synthesized with two ammoniac compounds with acid anhydrides, but acid anhydrides needs to be prepared with II ' compound with acyl chlorides, therefore still there is the high defect of production cost.
Content of the invention
The invention provides a kind of preparation method of dabigatran etcxilate, compared with known method before this, the method that the present invention provides has low production cost, high income and reaction condition is gentle, it is to avoid the advantages of using unstable reagent.
The present invention is that target is realized in direct cyclization with diamine compounds by providing preparation Formula II compound N-this compound that is easy to get of (4- cyano-phenyl) aminoacetate.
One aspect of the present invention, provides a kind of method preparing dabigatran etcxilate, comprises the steps：
A) in atent solvent, compound shown in Formulas I is reacted with compound shown in Formula II and obtains compound shown in formula III；
Wherein, R is selected from one of methyl, ethyl, propyl group or isopropyl；
B) in atent solvent, compound shown in formula III is reacted with ammonium salt after hydrogen chloride solution activation, obtains product IV；
C) in atent solvent, compound shown in formula IV is reacted under acid binding agent effect with compound shown in Formula V, obtains dabigatran etcxilate VI.
Above-described preparation method, wherein, described atent solvent includes one or more of toluene, dimethylbenzene, acetic acid, propionic acid, DMF, dimethyl sulfoxide (DMSO) or diphenyl ether；Preferably, described atent solvent is DMF.
Above-described preparation method, wherein, in the reaction of step (A), compound shown in Formulas I and the mol ratio of compound shown in Formula II are 1:1～2.
Above-described preparation method, wherein it is preferred to, in the reaction of step (A), compound shown in Formulas I and the mol ratio of compound shown in Formula II are 1:1.1.
Preparation method described in any of the above, wherein, the temperature of the reaction of step (A) is preferably 60 DEG C～200 DEG C, and the reaction time is preferably 2～20 hours.
Above-described preparation method, wherein it is preferred to, the temperature of described reaction is 100～150 DEG C.
Above-described preparation method, wherein, hydrogen chloride solution described in step (B) is dissolved in acquisition in reaction dissolvent for hydrogen chloride, and described reaction dissolvent is one or more of methyl alcohol, ethanol or isopropanol.
Above-described preparation method, wherein, ammonium salt described in step (B) is one of ammonium chloride, ammonium carbonate or ammonium sulfate.
Above-described preparation method, wherein, the acid binding agent that step (C) is used is one or more of sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus, triethylamine or pyridine.
Present invention firstly provides benzimidazole class compound III is prepared with N- (4- cyano-phenyl) amion acetic acid esters compound and diamine compounds condensation, decrease the use of CDI class reagent, make the preservation of reagent needed for reaction easier；Due to the present invention use compound shown in Formula II than Formula II used in prior art ' shown in compound easily prepared, so compound low price shown in Formula II, therefore can substantially reduce production cost, simplify production operation；Reaction condition is gentle, easy control of reaction；And the reagent that the present invention uses will not produce dazzling or sharp aroma, toxicity is low, safer to people；It is demonstrated experimentally that the yield of the dabigatran etcxilate of the present invention is higher, 78% can be reached it was demonstrated that being suitably applied industrialized production.
Figure of description
Fig. 1 is purity detecting HPLC collection of illustrative plates after dabigatran etcxilate crystallization once of the present invention, and as can be seen from the figure dabigatran etcxilate (11.60min) first product purity reaches 99.73%, single miscellaneous 0.26%.
Fig. 2 is the HPLC collection of illustrative plates after dabigatran etcxilate crystallization twice of the present invention, and as can be seen from the figure dabigatran etcxilate (11.60min) purity is 99.70%, single miscellaneous respectively less than 0.1%.
Specific embodiment
With reference to embodiments, the specific embodiment of the present invention is described in more details, so as to the advantage more fully understanding the solution of the present invention and its various aspects.However, specific embodiments described below and embodiment are only descriptive purposes, rather than limitation of the present invention.
Experimental technique used in following embodiments if no special instructions, is conventional method.
Material used, reagent etc. in following embodiments, if no special instructions, all commercially obtain.
Room temperature described in following embodiments refers both to 20～30 DEG C of temperature.
Embodiment 1 prepares N- (4- cyano-phenyl) ethyl aminoacetate (II)
Under room temperature, p-aminophenyl nitrile (11.8g, 0.1mol) and potassium carbonate (10.0g, 0.1mol) add in acetonitrile (100ml), stirring is lower to drip bromoacetate (16.7g, 0.1mol), it is warming up to backflow, after reaction 16h, be cooled to room temperature, filter, concentrate and remove solvent, residue adds water stirring, filter, twice of washing, then obtain II (17.9g, 88%) through re crystallization from toluene.
Embodiment 2 prepares the method () of 3- [[[2- [[(4- cyano-phenyl) amino] methyl] -1- methyl isophthalic acid H- benzimidazole -5- base] carbonyl] (pyridine -2- base) amino] ethyl propionate (III)
In 500mL reaction bulb; add 3- [N- (4- methylamino -3- amino benzoyl)-N- (pyridine -2- base) amino] ethyl propionate (I) (16.4g; 0.048mol), N- (4- cyano-phenyl) ethyl aminoacetate (II) (11.2g; 0.055mol) with 300mL DMF (N; dinethylformamide); stirring 1h, is warmed up to 120 DEG C of stirring reactions 10h.After being down to room temperature, reactant liquor pours precipitation solid, suction filtration in 1000ml frozen water into, and filter cake washes 3 times with water and obtains crude product III, is obtaining sterling (18.3g, 79%) with re-crystallizing in ethyl acetate.
Prepare the method (two) of 3- [[[2- [[(4- cyano-phenyl) amino] methyl] -1- methyl isophthalic acid H- benzimidazole -5- base] carbonyl] (pyridine -2- base) amino] ethyl propionate (III)
In 500mL reaction bulb; add 3- [N- (4- methylamino -3- amino benzoyl)-N- (pyridine -2- base) amino] ethyl propionate (I) (16.4g; 0.048mol), N- (4- cyano-phenyl) ethyl aminoacetate (II) (14.7g; 0.072mol) with 300mL dimethylbenzene; stirring 1h, is warmed up to 100 DEG C of stirring reactions 20h.After being down to room temperature, reactant liquor separates out solid, suction filtration, and filter cake washes 3 times with water and obtains crude product III, is obtaining sterling (13.5g, 58%) with re-crystallizing in ethyl acetate.
Prepare the method (three) of 3- [[[2- [[(4- cyano-phenyl) amino] methyl] -1- methyl isophthalic acid H- benzimidazole -5- base] carbonyl] (pyridine -2- base) amino] ethyl propionate (III)
In 500mL reaction bulb; add 3- [N- (4- methylamino -3- amino benzoyl)-N- (pyridine -2- base) amino] ethyl propionate (I) (16.4g; 0.048mol), N- (4- cyano-phenyl) ethyl aminoacetate (II) (14.7g; 0.072mol) with 300mL DMSO (dimethyl sulfoxide); stirring 1h, is warmed up to 140 DEG C of stirring reactions 20h.After being down to room temperature, reactant liquor pours precipitation solid, suction filtration in 1000ml frozen water into, and filter cake washes 3 times with water and obtains crude product III, is obtaining sterling (17.8g, 77%) with re-crystallizing in ethyl acetate.
Prepare the method (four) of 3- [[[2- [[(4- cyano-phenyl) amino] methyl] -1- methyl isophthalic acid H- benzimidazole -5- base] carbonyl] (pyridine -2- base) amino] ethyl propionate (III)
In 500mL reaction bulb; add 3- [N- (4- methylamino -3- amino benzoyl)-N- (pyridine -2- base) amino] ethyl propionate (I) (16.4g; 0.048mol), N- (4- cyano-phenyl) ethyl aminoacetate (II) (11.8g; 0.058mol) with 300mL propionic acid; stirring 1h, is warmed up to 130 DEG C of stirring reactions 12h.After being down to room temperature, reactant liquor is poured in (10%) in 1000ml sodium carbonate liquor and is separated out solid, suction filtration, and filter cake washes 3 times with water and obtains crude product III, is obtaining sterling (18.8g, 81%) with re-crystallizing in ethyl acetate.
Embodiment 3 prepares 3- [[[2- [[(4- carbamimido-phenyl) amino] methyl] -1- methyl isophthalic acid H- benzimidazole -5- base] carbonyl] (pyridine -2- base) amino] ethyl propionate (IV)
3- [[[2- [[(4- cyano-phenyl) amino] methyl] -1- methyl isophthalic acid H- benzimidazole -5- base] carbonyl] (pyridine -2- base) amino] ethyl propionate (III) (10.0g, 0.021mol) add the ethanol solution (50ml) of the hydrogen chloride of 6M, an evening is stirred at room temperature.Boil off excessive solvent, residue is dissolved in 40ml ethanol solution, add ammonium carbonate (19.2g, 0.2mol), be stirred overnight under room temperature.Filter, remove insoluble matter, filtrate reduced in volume is extremely dry.Residue is dissolved in 60ml ethyl acetate and the mixed solution (5: 1) of ethanol, reaction 2h is stirred at room temperature.Suction filtration, is dried, obtains the hydrochloride (10.2g, 92%) of compound IV.
Embodiment 4 prepares dabigatran etcxilate (VI)
By IV (10.0g, 18.6mmol) dissolve in THF (oxolane) (75ml) and water (15ml), add potassium carbonate (9.4g, 65.0mmol), 0.5h is stirred at room temperature, is cooled to less than 10 DEG C, add the just own ester (4.30g of chloro-carbonic acid, 26.1mmol), stir 2h.Concentrated solvent, adds ethanol 100ml, stirs 1h, suction filtration, reduced pressure concentration.Residue with ethyl acetate recrystallizes twice, obtains 8.62g solid dabigatran etcxilate, yield 78%, mp:127～128 DEG C.HPLC detection, testing equipment are carried out respectively to the dabigatran etcxilate crystallizing acquisition twice：Agilent 1200 high performance liquid chromatograph, VWD detector；Chromatographic column：Octadecylsilane chemically bonded silica is the chromatographic column (150 × 4.6mm, 5 μm) of filler；Column temperature：30 DEG C, (mobile phase)：0.2%H3PO4Phosphoric acid-acetonitrile (3:2), flow velocity：1.0ml/min, Detection wavelength：254nm, sample size 10 μ L, from testing result as can be seen that dabigatran etcxilate crystallization purity twice is all higher than 99%, specifically the peak area situation of each testing result is shown in Tables 1 and 2, can also intuitively impurity removal peak area very little (being specifically shown in Fig. 1 and Fig. 2) from collection of illustrative plates.
Table 1 is the peak area situation of the detection collection of illustrative plates of the dabigatran etcxilate first time crystallized product of Fig. 1 of the present invention
Table 2 is the peak area situation of the detection collection of illustrative plates after second crystallization of dabigatran etcxilate of Fig. 2 of the present invention
Finally it should be noted that：Obviously, above-described embodiment is only intended to clearly illustrate example of the present invention, and the not restriction to embodiment.For those of ordinary skill in the field, can also make other changes in different forms on the basis of the above description.There is no need to be exhaustive to all of embodiment.And the obvious change thus amplified out or change still in protection scope of the present invention among.
Claims (9)
1. a kind of method preparing dabigatran etcxilate is it is characterised in that comprise the steps：
A) in atent solvent, compound shown in Formulas I is reacted with compound shown in Formula II and obtains formula III
Shown compound；
Wherein, R is selected from one of methyl, ethyl, propyl group or isopropyl；
B) in atent solvent, compound shown in formula III is reacted with ammonium salt after hydrogen chloride solution activation,
Obtain product IV；
C) in atent solvent, compound shown in formula IV is acted in acid binding agent with compound shown in Formula V
Lower reaction, obtains dabigatran etcxilate VI.
2. preparation method as claimed in claim it is characterised in that described atent solvent include toluene,
One of dimethylbenzene, acetic acid, propionic acid, N,N-dimethylformamide, dimethyl sulfoxide (DMSO) or diphenyl ether
Or it is multiple.
3. preparation method as claimed in claim 1 is it is characterised in that in the reaction of step (A)
Compound shown in Formulas I is 1 with the mol ratio of compound shown in Formula II:1～2.
4. preparation method as claimed in claim 3 is it is characterised in that in the reaction of step (A)
Compound shown in Formulas I is 1 with the mol ratio of compound shown in Formula II:1.1.
5. as described preparation method arbitrary in Claims 1-4 it is characterised in that step (A)
Reaction temperature be 60 DEG C～200 DEG C.
6. preparation method as claimed in claim 5 it is characterised in that described reaction temperature be 100～
150℃.
7. preparation method as claimed in claim 1 is it is characterised in that chlorine described in step (B)
Change hydrogen solution be hydrogen chloride be dissolved in reaction dissolvent obtain, described reaction dissolvent be methyl alcohol, ethanol or
One or more of isopropanol.
8. preparation method as claimed in claim 1 is it is characterised in that ammonium described in step (B)
Salt is one of ammonium chloride, ammonium carbonate or ammonium sulfate.
9. preparation method as claimed in claim 1 is it is characterised in that what step (C) was used
Acid binding agent is one of sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus, triethylamine or pyridine
Or it is multiple.
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| CN201610230951.7A CN106397400A (en) | 2016-04-14 | 2016-04-14 | Preparation method for dabigatran etexilate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110981858A (en) * | 2019-12-16 | 2020-04-10 | 南通常佑药业科技有限公司 | Preparation method of anticoagulant drug dabigatran etexilate and analogue thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998037075A1 (en) * | 1997-02-18 | 1998-08-27 | Boehringer Ingelheim Pharma Kg | Disubstituted bicyclic heterocycles, their production and use as medicaments |
| CN104987323A (en) * | 2015-07-10 | 2015-10-21 | 浙江美诺华药物化学有限公司 | Preparation method of Dabigatran etexilate |
-
2016
- 2016-04-14 CN CN201610230951.7A patent/CN106397400A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998037075A1 (en) * | 1997-02-18 | 1998-08-27 | Boehringer Ingelheim Pharma Kg | Disubstituted bicyclic heterocycles, their production and use as medicaments |
| CN104987323A (en) * | 2015-07-10 | 2015-10-21 | 浙江美诺华药物化学有限公司 | Preparation method of Dabigatran etexilate |
Non-Patent Citations (3)
| Title |
|---|
| 《化工百科全书》编辑委员会等: "《化工百科全书》", 31 August 1996, 北京：化学工业出版社 * |
| 杨江涛: "新型口服抗凝血药物达比加群酯的合成工艺研究", 《中国优秀硕士学位论文全文数据库 工程科技I辑（月刊）》 * |
| 邢松松等: "达比加群酯的合成", 《中国医药工业杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110981858A (en) * | 2019-12-16 | 2020-04-10 | 南通常佑药业科技有限公司 | Preparation method of anticoagulant drug dabigatran etexilate and analogue thereof |
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