CN106083822A - A kind of preparation method of dabigatran etexilate methanesulfonate intermediate - Google Patents
A kind of preparation method of dabigatran etexilate methanesulfonate intermediate Download PDFInfo
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Abstract
The invention reside in the preparation method providing a kind of dabigatran etexilate methanesulfonate intermediate, this preparation method, its feature is to comprise the following steps: 3 [(3 amino 4 methylamino benzoyl) (pyridine 2 base) amino] ethyl propionates (2) and monochloroacetic acid anhydride generation ring-closure reaction generate N [[2 (chloromethyl) 1 methyl 1H benzimidazole 5 base] carbonyl] N 2 pyridine radicals beta Alanine ethyl ester (4), (4) 3 ({ 2 [(4 amidino groups benzene imido) methylene] 1 methylene 1H benzimidazole 5 carbonyl } pyridine 2 imines) ethyl propionate (3) is obtained with 4 aminobenzene carbonamidine dihydrochloride generation condensation reactions.The method yield is high, mild condition, and purification is convenient, meets the demand of industrialized production.
Description
Technical field
The present invention relates to the preparation method of a kind of dabigatran etexilate methanesulfonate intermediate.
Background technology
Dabigatran etexilate methanesulfonate (Dabigatran Etexilate Mesylate), by Germany's Boehringer Ingelheim
(Boehringer Ingelheim) company develops, and takes the lead in listing in Germany and Britain in April, 2008, trade name
Pradaxa Thailand Bi Quan.Dabigatran etexilate methanesulfonate is that the first new classification listed over 50 years after warfarin is administered orally anticoagulation
Medicine, can directly act on the fibrin specific binding site of thrombin, thus block the formation of thrombosis.New as one
The synthesis of type is administered orally class anticoagulation, has good clinical treatment and higher safety, it is easy to use, onset rapidly with
Food drug interaction is little, and bleeding risk is relatively low, is not required to detect coagulation indexes on time.Various advantages due to it so that it is face
Bed application prospect is optimistic.The listing of dabigatran etexilate methanesulfonate, is anticoagulation therapy field and potential lethal thrombus prevention neck
One major progress in territory, has milestone significance.
Dabigatran etexilate methanesulfonate, belongs to Beta-alanine batroxobin inhibitor, white crystalline powder shape, dissolves in water
Degree is 1.8mg/ml, is soluble in methanol, is slightly soluble in ethanol, stable under room temperature.Chemistry entitled 3-[[[2-[[[4-[[[(hexyloxy)
Carbonyl] amino] formamino] phenyl] amino] methyl]-1-methyl isophthalic acid H-benzimidazole-5-base] carbonyl] (pyridine-2-base) ammonia
Base] ethyl propionate mesylate, structure as the formula (1):
Dabigatran etexilate methanesulfonate has had more document to report, disclosed synthetic route mainly has two:
Synthetic route one: patent DE102005061624 discloses synthetic route in early days.The method is with 3-[(3-amino-4-first
Amido benzoyl) (pyridine-2-base) amino] ethyl propionate (2) is raw material, at propane phosphoric anhydride (PPA) or N, N '-carbonyl
Being condensed to yield benzimidazoles compound in the presence of diimidazole (CDI), benzimidazoles compound, after the catalysis reduction of palladium carbon, obtains
To 3-({2-[(4-amidino groups-benzene imido)-methylene]-1-methylene-1H-benzimidazole-5-carbonyl }-pyridine-2-imines)-
Ethyl propionate (3), intermediate (3) is again through becoming ester, becoming salt to obtain dabigatran etexilate methanesulfonate (1).Synthetic route is as follows:
Two: disclosed preparation method (patent WO2012152855) is with 3-[(3-amino-4-methylamino benzoyl) in recent years
(pyridine-2-base) amino] ethyl propionate (2) is raw material, with N-(4-cyano-phenyl) glycine is at N, N '-carbonyl dimidazoles
(CDI) or 1-(3-dimethylamino-propyl) the lower condensation of-3-ethyl-carbodiimide hydrochloride (EDCI) effect, closed loop obtain 3-
[[2-[(4-cyanophenyl amino) methyl]-1-methyl isophthalic acid H-benzimidazole-5-carbonyl] (pyridine-2-base) amino] propanoic acid second
Ester, 3-[[2-[(4-cyanophenyl amino) methyl]-1-methyl isophthalic acid H-benzimidazole-5-carbonyl] (pyridine-2-base) amino] third
Acetoacetic ester becomes amidine reaction to prepare 3-({2-[(4-amidino groups-benzene imido)-methylene]-1-methylene-1H-benzo miaow through Pinnter
Azoles-5-carbonyl }-pyridine-2-imines)-ethyl propionate (3), intermediate (3) is again through becoming ester, becoming salt to obtain methanesulfonic acid dabigatran
Ester (1).Synthetic route is as follows:
Above two lines all refer to the preparation of intermediate (3).Route one palladium carbon when preparing intermediate (3) is easily poisoned, and works as
Raw material puts into be needed fresh palladium carbon is repeatedly added batch-wise when exceeding kilogram, increases production cost and inflammable and explosive, brings to production
Dangerous hidden danger.Route two is used Pinner and is become amidine reaction during preparing intermediate (3), mainly have three kinds of synthetic methods: first
Kind of method needs to be passed through dry hydrogen chloride gas, ammonia, has high toxicity, severe corrosive and zest, pollutes environment, and need
Will be through column chromatography purification, post processing bothers；Second method uses oxammonium hydrochloride. through ammonium formate, the reduction of palladium carbon, and Metal Palladium is urged
Agent is relatively costly；The third method is successively to react with hydrogen chloride gas and ammonium carbonate, and the response time is long, react insufficient and
Impurity is many, needs also exist for column chromatography purification.All there is certain shortcoming in comprehensive three kinds of synthesis conditions, is unfavorable for the work of intermediate (3)
The production of industry.
Described below is the preparation method of a kind of dabigatran etexilate methanesulfonate intermediate as the formula (3).Intermediate (3)
Chemistry entitled 3-({2-[(4-amidino groups-benzene imido)-methylene]-1-methylene-1H-benzimidazole-5-carbonyl }-pyridine-2-
Imines)-ethyl propionate.This preparation method successfully avoids the adverse effect condition of above-mentioned route, and product yield is high, condition temperature
With, purification is convenient, meets the demand of industrialized production.
Summary of the invention
Object of the present invention is to provide the preparation method of a kind of dabigatran etexilate methanesulfonate intermediate.This preparation side
Method, its feature is to comprise the following steps: 3-[(3-amino-4-methylamino benzoyl) (pyridine-2-base) amino] propanoic acid second
Ester (2) and monochloroacetic acid anhydride ring-closure reaction generate N-[[2-(chloromethyl)-1-methyl isophthalic acid H-benzimidazole-5-base] carbonyl]-N-2-
Pyridine radicals-Beta-alanine ethyl ester (4), (4) and 4-aminobenzene carbonamidine dihydrochloride generation condensation reaction obtain 3-({2-[(4-amidine
Base-benzene imido)-methylene]-1-methylene-1H-benzimidazole-5-carbonyl }-pyridine-2-imines)-ethyl propionate (3).Should
Method product yield is high, mild condition, and purification is convenient, meets the demand of industrialized production.Synthetic route is as follows:
The synthetic route of the present invention specifically includes following two step；
The first step: by formula (2) 3-[(3-amino-4-methylamino benzoyl) (pyridine-2-base) amino] ethyl propionate
With monochloroacetic acid anhydride generation ring-closure reaction, obtain formula (4) N-[[2-(chloromethyl)-1-methyl isophthalic acid H-benzimidazole-5-base] carbonyl
Base]-N-2-pyridine radicals-Beta-alanine ethyl ester (4).
The initiation material (2) of ring-closure reaction of the present invention is commercially available product, chemical entitled 3-[(3-amino-4-methylamino
Benzoyl) (pyridine-2-base) amino] ethyl propionate, No. CAS is 212322-56-0.
The preferred course of reaction of ring-closure reaction in the present invention is: raw material (2) and monochloroacetic acid anhydride, deposits at solvent and inorganic base
Under, agitating heating is reacted.Reacting liquid filtering, filtrate decompression is evaporated, residue recrystallization, obtains compound (4).
The preferred potassium carbonate of ring-closure reaction inorganic base in the present invention, sodium carbonate, more preferably potassium carbonate.
Ring-closure reaction temperature in the present invention preferably 40 ~ 78 DEG C, more preferably 40 ~ 65 DEG C；Preferably 1 ~ 4 hour response time,
More preferably 1 ~ 2 hour.
Second step: formula (4) compound N-[[2-(chloromethyl)-1-methyl isophthalic acid H-benzimidazole-5-base] carbonyl]-N-2-pyrrole
Piperidinyl-Beta-alanine ethyl ester
With formula (5) compound, 4-aminobenzene carbonamidine dihydrochloride generation condensation reaction,
Obtain 3-({2-[(4-amidino groups-benzene imido)-methylene]-1-methylene-1H-benzimidazole-5-carbonyl }-pyridine-2-
Imines)-ethyl propionate (3).
The preferred course of reaction of condensation reaction in the present invention is: add formula (4) compound and formula (5) in two-phase solvent
Compound, heated and stirred reaction in the presence of iodide, inorganic base, phase transfer catalyst.Reactant liquor through cooling, crystallize, sucking filtration,
Obtain (3).
The preferred sodium iodide of iodide of the condensation reaction in the present invention, potassium iodide, more preferably sodium iodide.
The two-phase solvent of the condensation reaction in the present invention, a phase is water, and another phase is the organic solvent immiscible with water,
The preferred butyl acetate of organic solvent, ethyl acetate, more preferably butyl acetate.
The preferred potassium carbonate of condensation reaction inorganic base in the present invention, sodium bicarbonate, more preferably potassium carbonate.
The preferred tetrabutyl ammonium bromide of condensation reaction phase transfer catalyst in the present invention, tetrabutylammonium chloride, more preferably four
Butylammonium bromide.
Condensation reaction time in the present invention preferably 2 ~ 10 hours, more preferably 2 ~ 4 hours.
Research worker of the present invention is it has surprisingly been found that the reaction of formula (4) compound and formula (5) compound is by adding iodide
Activating, owing to formula (4) compound is soluble in organic solvent, formula (5) compound is soluble in water, adds phase transfer catalyst
After, formula (4) compound and formula (5) compound are able to, in two alternate abundant reactions, substantially increase target product formula (3) compound
Yield and content, simultaneous reactions condition milder, the response time is shorter, and the most economical.
The advantage of preparation method of the present invention is, with 3-[(3-amino-4-methylamino benzoyl) (pyridine-2-base) ammonia
Base] ethyl propionate (2) is initiation material, synthesizes N-[[2-(chloromethyl)-1-methyl isophthalic acid H-benzimidazole-5-with monochloroacetic acid anhydride
Base] carbonyl]-N-2-pyridine radicals-Beta-alanine ethyl ester (4), (4) contract with 4-aminobenzene carbonamidine dihydrochloride cheap and easy to get again
Close, because introducing phase transfer catalyst so that reaction is fully carried out between aqueous phase and organic solvent are biphase, hence it is evident that more
Effectively synthesize compound (3).Not only reaction temperature is relatively low, and obtains intermediate (3) purity and yield is the highest, successfully
Avoid original route Pinner reaction and have to use for hydrogen, ammonia, the unfavorable conditions of precious metal palladium etc..
Therefore the synthetic route of the present invention has the following characteristics that preparation is simple, and reaction raw materials is easy to get, hence it is evident that contribute to reducing
Cost, by-product is few, and reaction yield significantly improves, and total recovery reaches 75%, it is thus achieved that 3-({2-[(4-amidino groups-benzene imido)-sub-
Methyl]-1-methylene-1H-benzimidazole-5-carbonyl }-pyridine-2-imines) purity of-ethyl propionate (3) is high, easily carries out work
Industry metaplasia is produced.
Detailed description of the invention
Embodiment 1
(1) ring-closure reaction
Room temperature downhill reaction device is sequentially added into 120ml ethyl acetate, 3-[(3-amino-4-methylamino benzoyl) (pyridine-
2-yl) amino] ethyl propionate 28g and 14.5g monochloroacetic acid anhydride, it is heated with stirring to 65 DEG C and is incubated 2 hours, be cooled to 40 DEG C, add
Potassium carbonate 15g, 40 DEG C are incubated 4 hours.Filtering, filtrate decompression is evaporated, and residue 150ml methyl tertiary butyl ether(MTBE) is cooled to 0 DEG C
Crystallize, obtains N-[[2-(chloromethyl)-1-methyl isophthalic acid H-benzimidazole-5-base] carbonyl]-N-2-pyridine radicals-Beta-alanine ethyl ester
(4) 29.5g, yield 90%, product HPLC purity 98.0%.1H-NMR (CDCl3) δ 1.1 (t, 3H ,-CH3), δ2.7
( t , 2H , -CH2- ), δ2.8( s , 3H ,-NCH3 ),δ4.1 ( m , 2H , -NCH2-) , δ4.2 ( s ,
2H , -CH2- ) , δ4.4 ( t , 2H , -CH2Cl ),δ6.5( m , 1H , Ar - H ) ,δ6.8( m , 1H
, Py - H ) ,δ7.2( m , 2H ,Ar - H ) ,δ7.4( m , 1H ,Py - H ) ,δ8.0( m , 1H ,Py
- H ) ,δ8.5( m , 1H ,Py - H )。
(2) condensation reaction
Room temperature downhill reaction device is sequentially added into 1.5g sodium iodide, 6.6g potassium carbonate, 0.75g tetrabutyl ammonium bromide, is subsequently adding
50ml water and 65ml butyl acetate, stirring.After solid is the most molten, add 10.0g N-[[2-(chloromethyl)-1-methyl isophthalic acid H-benzo
Imidazoles-5-base] carbonyl]-N-2-pyridine radicals-Beta-alanine ethyl ester and 4-aminobenzene carbonamidine dihydrochloride, Quan Rong, under nitrogen protection
It is to slowly warm up to 40 DEG C of quick stirrings react 2 hours.There is a large amount of yellow solid to separate out, be cooled to crystallize 2h is stirred at room temperature, drop afterwards
Temperature to 5 ~ 10 DEG C of stirring and crystallizing 2h, sucking filtration, filter cake with after the washing of cold butyl acetate in 40 DEG C of drying under reduced pressure to constant weight, obtain class white
Color solid 3-({2-[(4-amidino groups-benzene imido)-methylene]-1-methylene-1H-benzimidazole-5-carbonyl }-pyridine-2-Asia
Amine)-ethyl propionate (3) 10.9g, yield 88%, product HPLC purity 98.5%.1H-NMR (DMSO-d6) δ 1.1 (t,
3H , -CH3 ), δ2.7 ( t , 2H , -CH2- ),δ3.8 ( s , 3H, -NCH3 ),δ4.0 ( t , 2H , -
NCH2- ) , δ4.2 ( q , 2H ,-OCH2- ) , δ4.7 ( s , 2H , -NCH2- ),δ6.8( d , 2H ,Ar
- H ) ,δ6.9( m , 1H , Ar - H ) ,δ7.1 ( m , 1H ,Py - H ) , δ7.2( m , 1H ,Py -
H ) ,δ7.4 ( m , 1H , Ar - H ) , δ 7.5( m , 1H , Ar - H ) ,δ7.5( m , 1H ,Py -
H ), δ7.8( d , 2H , Ar - H ) , δ8.4( m , 1H ,Py - H ),δ8.7( brs , 2H ,-NH- ),
δ8.9( brs , 2H ,-NH2 )。
Embodiment 2
(1) ring-closure reaction
Room temperature downhill reaction device is sequentially added into 120ml ethyl acetate, 3-[(3-amino-4-methylamino benzoyl) (pyridine-
2-yl) amino] ethyl propionate 28g and 14.5g monochloroacetic acid anhydride, it is heated with stirring to 65 DEG C and is incubated 2 hours, reactant liquor is decreased slightly as Wen Houjia
Entering potassium carbonate 15g, 65 DEG C are incubated 2 hours.Filtering, filtrate decompression is evaporated, and residue 150ml methyl tertiary butyl ether(MTBE) is cooled to 0
DEG C crystallize, obtains N-[[2-(chloromethyl)-1-methyl isophthalic acid H-benzimidazole-5-base] carbonyl]-N-2-pyridine radicals-Beta-alanine second
Ester (4) 29.8g, yield 91%, product HPLC purity 98.0%.
(2) condensation reaction
Room temperature downhill reaction device is sequentially added into 1.5g sodium iodide, 8.0g sodium bicarbonate, 0.75g tetrabutylammonium chloride, then adds
Enter 50ml water and 65ml butyl acetate, stirring.After solid is the most molten, add 10.0g N-[[2-(chloromethyl)-1-methyl isophthalic acid H-benzene
And imidazoles-5-base] carbonyl]-N-2-pyridine radicals-Beta-alanine ethyl ester and 4-aminobenzene carbonamidine dihydrochloride, Quan Rong, nitrogen is protected
Under be to slowly warm up to 40 DEG C of quick stirrings and react 10 hours.There is a large amount of yellow solid to separate out, be cooled to crystallize 2h is stirred at room temperature, after
Be cooled to 5 ~ 10 DEG C of stirring and crystallizing 2h, sucking filtration, filter cake wash with cold butyl acetate after in 40 DEG C of drying under reduced pressure to constant weight, obtain class
White solid 3-({2-[(4-amidino groups-benzene imido)-methylene]-1-methylene-1H-benzimidazole-5-carbonyl }-pyridine-2-
Imines)-ethyl propionate (3) 10.5g, yield 85%, product HPLC purity 98.3%
Embodiment 3
(1) ring-closure reaction
Room temperature downhill reaction device is sequentially added into 120ml ethyl acetate, 3-[(3-amino-4-methylamino benzoyl) (pyridine-
2-yl) amino] ethyl propionate 28g and 14.5g monochloroacetic acid anhydride, it is heated with stirring to 65 DEG C and is incubated 2 hours, after being decreased slightly as temperature, add carbon
Acid sodium 12g, is warming up to 78 DEG C and reacts 1 hour.Filtering, filtrate decompression is evaporated, and residue 150ml methyl tertiary butyl ether(MTBE) is cooled to
0 DEG C of crystallize, obtains N-[[2-(chloromethyl)-1-methyl isophthalic acid H-benzimidazole-5-base] carbonyl]-N-2-pyridine radicals-Beta-alanine
Ethyl ester (4) 29.1g, yield 89%, product HPLC purity 98.1%.
(2) condensation reaction
Room temperature downhill reaction device is sequentially added into 1.5g potassium iodide, 6.6g potassium carbonate, 0.75g tetrabutyl ammonium bromide, is subsequently adding
50ml water and 65ml ethyl acetate, stirring.After solid is the most molten, add 10.0g N-[[2-(chloromethyl)-1-methyl isophthalic acid H-benzo
Imidazoles-5-base] carbonyl]-N-2-pyridine radicals-Beta-alanine ethyl ester and 4-aminobenzene carbonamidine dihydrochloride, Quan Rong, under nitrogen protection
It is to slowly warm up to 40 DEG C of quick stirrings react 4 hours.There is a large amount of yellow solid to separate out, be cooled to crystallize 2h is stirred at room temperature, drop afterwards
Temperature to 5 ~ 10 DEG C of stirring and crystallizing 2h, sucking filtration, filter cake wash with cold ethyl acetate after in 40 DEG C of drying under reduced pressure to constant weight, obtain class white
Color solid 3-({2-[(4-amidino groups-benzene imido)-methylene]-1-methylene-1H-benzimidazole-5-carbonyl }-pyridine-2-Asia
Amine)-ethyl propionate (3) 10.7g, yield 86%, product HPLC purity 98.5%.
Claims (6)
1. a preparation method for dabigatran etexilate methanesulfonate intermediate, its feature is to comprise the following steps:
(a) 3-[(3-amino-4-methylamino benzoyl) (pyridine-2-base) amino] ethyl propionate (2) and monochloroacetic acid anhydride closed loop
Reaction generates N-[[2-(chloromethyl)-1-methyl isophthalic acid H-benzimidazole-5-base] carbonyl]-N-2-pyridine radicals-Beta-alanine ethyl ester
(4);
(b) N-[[2-(chloromethyl)-1-methyl isophthalic acid H-benzimidazole-5-base] carbonyl]-N-2-pyridine radicals-Beta-alanine ethyl ester
(4) 3-({2-[(4-amidino groups-benzene imido)-methylene]-1-methylene is obtained with 4-aminobenzene carbonamidine dihydrochloride condensation reaction
Base-1H-benzimidazole-5-carbonyl }-pyridine-2-imines)-ethyl propionate (3).
2. the method described in claim 1, the condensation reaction of step (b), it is characterised in that: in two-phase solvent, add compound
And 4-aminobenzene carbonamidine dihydrochloride (4), heated and stirred reaction in the presence of iodide, inorganic base, phase transfer catalyst, reaction
Liquid, through cooling, crystallize, sucking filtration, obtains compound (3).
3. the method described in claim 2, it is characterised in that described iodide are selected from sodium iodide, potassium iodide.
4. the method described in claim 2, it is characterised in that a two-phase solvent wherein phase is water, another phase is and water the most not phase
Molten organic solvent, organic solvent is selected from butyl acetate, ethyl acetate.
5. the method described in claim 2, it is characterised in that inorganic base is selected from potassium carbonate, sodium bicarbonate.
6. the method described in claim 2, it is characterised in that phase transfer catalyst is selected from tetrabutyl ammonium bromide, tetrabutyl chlorination
Ammonium.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116003384A (en) * | 2023-01-31 | 2023-04-25 | 宿迁盛基医药科技有限公司 | Synthesis method of dabigatran etexilate important intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102612517A (en) * | 2009-11-18 | 2012-07-25 | 贝林格尔.英格海姆国际有限公司 | Method for producing dabigatran etexilate |
| WO2012152855A1 (en) * | 2011-05-11 | 2012-11-15 | Medichem S.A. | Dabigatran etexilate and related substances, processes and compositions, and use of the substances as reference standards and markers |
| CN105523999A (en) * | 2014-10-21 | 2016-04-27 | 重庆医药工业研究院有限责任公司 | Dabigatran etexilate intermediate synthesis method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102612517A (en) * | 2009-11-18 | 2012-07-25 | 贝林格尔.英格海姆国际有限公司 | Method for producing dabigatran etexilate |
| WO2012152855A1 (en) * | 2011-05-11 | 2012-11-15 | Medichem S.A. | Dabigatran etexilate and related substances, processes and compositions, and use of the substances as reference standards and markers |
| CN105523999A (en) * | 2014-10-21 | 2016-04-27 | 重庆医药工业研究院有限责任公司 | Dabigatran etexilate intermediate synthesis method |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116003384A (en) * | 2023-01-31 | 2023-04-25 | 宿迁盛基医药科技有限公司 | Synthesis method of dabigatran etexilate important intermediate |
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Effective date of registration: 20191230 Address after: 124000 f0001, Zhonghua Road West, Doudou Street North, Shuangtaizi District, Panjin City, Liaoning Province Patentee after: Panjin Zhonghong Chemical Co.,Ltd. Address before: 117004 B2-1 District, China Medicine Innovation Park, Mulan Road, hi tech Zone, Liaoning, Benxi Patentee before: BENXI ECONOMIC DEVELOPMENT ZONE BOMEI PHARMACEUTICAL NEW TECHNOLOGY DEVELOPMENT Co.,Ltd. |
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| TR01 | Transfer of patent right |
Effective date of registration: 20220831 Address after: No. B30-1, Antuo International Intelligent Manufacturing Industrial Park, No. 33, Quanyun 5th Road, Shenyang Area, China (Liaoning) Pilot Free Trade Zone, Shenyang City, Liaoning Province 110167 Patentee after: Liaoning Huifeng Biomedical Technology Co.,Ltd. Address before: 124000 f0001, North duplex street, West Zhonghua Road, Shuangtaizi District, Panjin City, Liaoning Province Patentee before: Panjin Zhonghong Chemical Co.,Ltd. |