CN106083822B - 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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- 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 reside in a kind of preparation method of dabigatran etexilate methanesulfonate intermediate, the preparation method is provided, feature is to include the following steps：3‑[（3 amino, 4 methylamino benzoyl）（2 base of pyridine）Amino] ethyl propionate（2）Ring-closure reaction occurs with chloroacetic anhydride and generates 2 pyridyl group beta Alanine ethyl esters of N [[2 (chloromethyl) 1 methyl 1H benzimidazoles, 5 base] carbonyl] N（4）,（4）Condensation reaction occurs with 4 aminobenzene carbonamidine dihydrochlorides and obtains 3 [[[2 [[(4 carbamimido-phenyl) amino] methyl] 1 methyl 1H benzimidazoles, 5 base] carbonyl] (2 base of pyridine) amino] ethyl propionates（3）.This method high income, mild condition, purifying is convenient, meets the demand of industrialized production.
Description
Technical field
The present invention relates to a kind of preparation methods of dabigatran etexilate methanesulfonate intermediate.
Background technology
Dabigatran etexilate methanesulfonate（Dabigatran Etexilate Mesylate）, by German Boehringer Ingelheim
（Boehringer Ingelheim）Company develops, and takes the lead in listing in Germany and Britain in April, 2008, trade name
Pradaxa Thailands Bi Quan.Dabigatran etexilate methanesulfonate is that the first new category listed over 50 years after warfarin takes orally anticoagulation
Drug can directly act on the fibrin specific binding site of fibrin ferment, to block the formation of thrombus.As a kind of new
The synthesis of type takes orally class anticoagulation, has good clinical treatment and a higher safety, it is easy to use, work rapidly with
Food drug interaction is small, and bleeding risk is relatively low, is not required to detect coagulation indexes on time.Due to its various advantages, it is made to face
Bed application prospect is optimistic.The listing of dabigatran etexilate methanesulfonate is anticoagulant therapy field and potential lethal thrombus prevention neck
One major progress in domain has milestone significance.
Dabigatran etexilate methanesulfonate, belongs to Beta-alanine batroxobin inhibitor, and white crystalline powder shape dissolves in water
Degree is 1.8mg/ml, is soluble in methanol, is slightly soluble in ethyl alcohol, stablizes under room temperature.The entitled 3- of chemistry [[[2- [[[4- [[[（Hexyloxy）
Carbonyl] amino] formamino] phenyl] amino] methyl] -1- methyl-1 H- benzimidazole -5- bases] carbonyl]（Pyridine -2- bases）Ammonia
Base] ethyl propionate mesylate, structure such as formula（1）It is shown：
Dabigatran etexilate methanesulfonate has had more document report, disclosed synthetic route mainly to have two:
Synthetic route one：Patent DE102005061624 discloses the synthetic route of early stage.This method with 3- [（3- amino-
4- methylamino benzoyls）（Pyridine -2- bases）Amino] ethyl propionate（2）For raw material, in propane phosphoric anhydride（PPA）Or N, N '-
Carbonyl dimidazoles（CDI）In the presence of be condensed to yield benzimidazoles compound, benzimidazoles compound is catalyzed through palladium carbon and restores
Afterwards, 3- [[[2- [[(4- carbamimido-phenyls) amino] methyl] -1- methyl-1 H- benzimidazole -5- bases are obtained
] carbonyl] (pyridine -2- bases) amino]-ethyl propionate（3）, intermediate（3）It is reached again through obtaining methanesulfonic acid at ester, at salt
Than adding group ester（1）.Synthetic route is as follows：
Two：Disclosed preparation method in recent years（Patent WO2012152855）With 3- [（3- amino -4- methylamino benzoyls
Base）（Pyridine -2- bases）Amino] ethyl propionate（2）For raw material, with N-（4- cyano-phenyls）Glycine is in N, N '-carbonyl dimidazoles
（CDI）Or 1-（3- dimethylamino-propyls）- 3- ethyl-carbodiimide hydrochlorides（EDCI）The lower condensation of effect, closed loop obtain 3-
[[2- [(4- cyanophenyl aminos) methyl] -1- methyl-1 H- benzimidazole -5- carbonyls]（Pyridine -2- bases）Amino] propionic acid second
Ester, 3- [[2- [(4- cyanophenyl aminos) methyl] -1- methyl-1 H- benzimidazole -5- carbonyls]（Pyridine -2- bases）Amino] third
Acetoacetic ester, which is reacted through Pinnter at amidine, is made 3- [[[2- [[(4- carbamimido-phenyls) amino] methyl] -1- methyl
- 1H- benzimidazole -5- bases] carbonyl] (pyridine -2- bases) amino]-ethyl propionate（3）, intermediate（3）It passes through again
Dabigatran etexilate methanesulfonate is obtained at ester, at salt（1）.Synthetic route is as follows：
The above two lines all refer to intermediate（3）Preparation.Route one is preparing intermediate（3）When palladium carbon be easily poisoned,
And when raw material input is more than kilogram need that fresh palladium carbon is repeatedly added batch-wise, increase production cost and inflammable and explosive, to production
Bring dangerous hidden danger.Route two prepares intermediate（3）It uses Pinner in the process to react at amidine, there are mainly three types of synthetic methods：
First method needs to be passed through dry hydrogen chloride gas, ammonia, has high toxicity, strong corrosive and irritation, pollutes environment,
And it needs to purify by column chromatography, post-processing trouble；Second method is restored using hydroxylamine hydrochloride through ammonium formate, palladium carbon, metal
Palladium catalyst cost is higher；The third method is successively to be reacted with hydrogen chloride gas and ammonium carbonate, and the reaction time is long, and reaction is not filled
Divide and impurity is more, also needs column chromatography purifying.There is certain disadvantage in comprehensive three kinds of synthesis conditions, be unfavorable for intermediate（3）
Industrialized production.
One kind is described below such as formula（3）Shown in dabigatran etexilate methanesulfonate intermediate preparation method.Intermediate（3）
Entitled 3- [[[2- [[(4- carbamimido-phenyls) amino] the methyl] -1- methyl-1 H- benzimidazoles -5- of chemistry
Base] carbonyl] (pyridine -2- bases) amino]-ethyl propionate.The preparation method successfully avoids above-mentioned route not
Sharp reaction condition, product yield is high, mild condition, and purifying is convenient, meets the demand of industrialized production.
Invention content
The object of the present invention is to provide a kind of preparation methods of dabigatran etexilate methanesulfonate intermediate.The preparation side
Method, feature are to include the following steps：3-[（3- amino -4- methylamino benzoyls）（Pyridine -2- bases）Amino] propionic acid second
Ester（2）N- [[2- (chloromethyl) -1- methyl-1 H- benzimidazole -5- bases] carbonyl]-N-2- is generated with chloroacetic anhydride ring-closure reaction
Pyridyl group-Beta-alanine ethyl ester（4）,（4）With 4- aminobenzene carbonamidine dihydrochlorides occur condensation reaction obtain 3- [[[2- [[(
4- carbamimido-phenyls) amino] methyl] -1- methyl-1 H- benzimidazole -5- bases] carbonyl] (pyridine -2-
Base) amino]-ethyl propionate（3）.This method product yield is high, mild condition, and purifying is convenient, meets the need of industrialized production
It asks.Synthetic route is as follows：
The synthetic route of the present invention specifically includes following two steps；
The first step：By formula（2）3-[（3- amino -4- methylamino benzoyls）（Pyridine -2- bases）Amino] ethyl propionate
Ring-closure reaction occurs with chloroacetic anhydride, obtains formula（4）N- [[2- (chloromethyl) -1- methyl-1 H- benzimidazoles -5-
Base] carbonyl]-N-2- pyridyl groups-Beta-alanine ethyl ester（4）.
The starting material of ring-closure reaction of the present invention（2）For commercially available product, the entitled 3- of chemistry [（3- amino -4- methylaminos
Benzoyl）（Pyridine -2- bases）Amino] ethyl propionate, No. CAS is 212322-56-0.
The preferred reaction process of ring-closure reaction in the present invention is：Raw material（2）And chloroacetic anhydride, it is deposited in solvent and inorganic base
Under, agitating and heating reaction.Reaction solution filters, and filtrate decompression is evaporated, and residue recrystallization obtains compound（4）.
The preferred potassium carbonate of ring-closure reaction inorganic base, sodium carbonate in the present invention, more preferable potassium carbonate.
Preferably 40 ~ 78 DEG C, more preferable 40 ~ 65 DEG C of ring-closure reaction temperature in the present invention；Preferably 1 ~ 4 hour reaction time,
More preferable 1 ~ 2 hour.
Second step：Formula（4）Compound N-[[2- (chloromethyl) -1- methyl-1 H- benzimidazole -5- bases] carbonyl]-N-2- pyrroles
Piperidinyl-Beta-alanine ethyl ester
With formula（5）Condensation reaction occurs for compound, 4- aminobenzene carbonamidine dihydrochlorides,
Obtain 3- [[[2- [[(4- carbamimido-phenyls) amino] methyl] -1- methyl-1 H- benzimidazoles -
5- yls] carbonyl] (pyridine -2- bases) amino]-ethyl propionate（3）.
The preferred reaction process of condensation reaction in the present invention is：Formula is added in two-phase solvent（4）Compound and formula（5）
Compound, heating stirring is reacted in the presence of iodide, inorganic base, phase transfer catalyst.Reaction solution through cooling, crystallization, suction filtration,
It obtains（3）.
The preferred sodium iodide of iodide of condensation reaction in the present invention, potassium iodide, more preferable sodium iodide.
The two-phase solvent of condensation reaction in the present invention, a phase are water, and another phase is the organic solvent immiscible with water,
The preferred butyl acetate of organic solvent, ethyl acetate, more preferable butyl acetate.
The preferred potassium carbonate of condensation reaction inorganic base, sodium bicarbonate in the present invention, more preferable potassium carbonate.
The preferred tetrabutylammonium bromide of condensation reaction phase transfer catalyst in the present invention, tetrabutylammonium chloride, more preferable four
Butylammonium bromide.
Condensation reaction time in the present invention preferably 2 ~ 10 hours, more preferable 2 ~ 4 hours.
Researcher of the present invention is it has surprisingly been found that formula（4）Compound and formula（5）The reaction of compound is by being added iodide
It is activated, due to formula（4）Compound is soluble in organic solvent, formula（5）Compound is soluble easily in water, and phase transfer catalyst is added
Afterwards, formula（4）Compound and formula（5）Compound is able to, in two alternate abundant reactions, substantially increase target product formula（3）Compound
Yield and content, simultaneous reactions condition milder, the reaction time is shorter, and more economical.
The advantage of preparation method of the present invention is, with 3- [（3- amino -4- methylamino benzoyls）（Pyridine -2- bases）Ammonia
Base] ethyl propionate（2）For starting material, N- [[2- (chloromethyl) -1- methyl-1 H- benzimidazoles -5- are synthesized with chloroacetic anhydride
Base] carbonyl]-N-2- pyridyl groups-Beta-alanine ethyl ester（4）,（4）It contracts again with 4- aminobenzene carbonamidine dihydrochlorides cheap and easy to get
It closes, because introducing phase transfer catalyst so that reaction is fully carried out between water phase and organic solvent two-phase, hence it is evident that more
Effectively synthesize compound（3）.Not only reaction temperature is relatively low, but also obtains intermediate（3）Purity and yield are higher, successfully
It avoids original route Pinner and reacts the hydrogen that must be used, ammonia, the unfavorable conditions of precious metal palladium etc..
Therefore the synthetic route of the present invention has the characteristics that：It prepares simply, reaction raw materials are easy to get, hence it is evident that help to reduce
Cost, by-product is few, and reaction yield significantly improves, and total recovery reaches 75%, the 3- [[[2- [[(4- carbamimido-phenyls) of acquisition
Amino] methyl] -1- methyl-1 H- benzimidazole -5- bases] carbonyl] (pyridine -2- bases) amino] -
Ethyl propionate（3）Purity it is high, easily carry out industrialized production.
Specific implementation mode
Embodiment 1
（1）Ring-closure reaction
Sequentially added at room temperature into reactor 120ml ethyl acetate, 3- [（3- amino -4- methylamino benzoyls）（Pyrrole
Pyridine -2- bases）Amino] ethyl propionate 28g and 14.5g chloroacetic anhydride, it is heated with stirring to 65 DEG C and keeps the temperature 2 hours, be cooled to 40 DEG C, add
Enter potassium carbonate 15g, 40 DEG C keep the temperature 4 hours.Filtering, filtrate decompression are evaporated, and residue is cooled to 0 with 150ml methyl tertiary butyl ether(MTBE)s
DEG C crystallization, obtains N- [[2- (chloromethyl) -1- methyl-1 H- benzimidazole -5- bases] carbonyl]-N-2- pyridyl groups-Beta-alanine second
Ester（4）29.5g yield 90%, product HPLC purity 98.0%.1H - NMR （CDCl3）δ 1.1 (t, 3H ,-CH3), δ
2.7 ( 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
Sequentially add 1.5g sodium iodides into reactor at room temperature, 6.6g potassium carbonate, 0.75g tetrabutylammonium bromide, then
50ml water and 65ml butyl acetates, stirring is added.Solid it is complete it is molten after, 10.0g N- [[2- (chloromethyl) -1- methyl-1s H- are added
Benzimidazole -5- bases] carbonyl]-N-2- pyridyl groups-Beta-alanine ethyl ester and 4- aminobenzene carbonamidine dihydrochlorides, Quan Rong, nitrogen protects
40 DEG C are to slowly warm up under shield to be quickly stirred to react 2 hours.There are a large amount of yellow solids to be precipitated, be cooled to and crystallization 2h is stirred at room temperature,
After be cooled to 5 ~ 10 DEG C of stirring and crystallizing 2h, filter, filter cake is dried under reduced pressure to constant weight in 40 DEG C after being washed with cold butyl acetate, obtains
Off-white powder 3- [[[2- [[(4- carbamimido-phenyls) amino] methyl] -1- methyl-1 H- benzimidazoles -5-
Base] carbonyl] (pyridine -2- bases) amino]-ethyl propionate（3）10.9g, yield 88%, product HPLC purity
98.5%.1H - NMR （DMSO-d6）δ1.1 ( 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
Sequentially added at room temperature into reactor 120ml ethyl acetate, 3- [（3- amino -4- methylamino benzoyls）（Pyrrole
Pyridine -2- bases）Amino] ethyl propionate 28g and 14.5g chloroacetic anhydride, it is heated with stirring to 65 DEG C and keeps the temperature 2 hours, reaction solution is decreased slightly as temperature
Potassium carbonate 15g is added afterwards, 65 DEG C keep the temperature 2 hours.Filtering, filtrate decompression are evaporated, and residue is cooled down with 150ml methyl tertiary butyl ether(MTBE)s
To 0 DEG C of crystallization, N- [[2- (chloromethyl) -1- methyl-1 H- benzimidazole -5- bases] carbonyl]-N-2- pyridyl groups-the third ammonia of-β is obtained
Acetoacetic ester（4）29.8g, yield 91%, product HPLC purity 98.0%.
（2）Condensation reaction
Sequentially add 1.5g sodium iodides into reactor at room temperature, 8.0g sodium bicarbonates, 0.75g tetrabutylammonium chlorides, so
50ml water and 65ml butyl acetates, stirring are added afterwards.Solid it is complete it is molten after, 10.0g N- [[2- (chloromethyl) -1- methyl-is added
1H- benzimidazole -5- bases] carbonyl]-N-2- pyridyl groups-Beta-alanine ethyl ester and 4- aminobenzene carbonamidine dihydrochlorides, Quan Rong, nitrogen
40 DEG C are to slowly warm up under gas shielded to be quickly stirred to react 10 hours.There are a large amount of yellow solids to be precipitated, is cooled to and analysis is stirred at room temperature
Brilliant 2h, after be cooled to 5 ~ 10 DEG C of stirring and crystallizing 2h, filter, filter cake is dried under reduced pressure in 40 DEG C to perseverance after being washed with cold butyl acetate
Weight, obtains off-white powder 3- [[[2- [[(4- carbamimido-phenyls) amino] methyl] -1- methyl-1 H- benzos
Imidazoles -5- bases] carbonyl] (pyridine -2- bases) amino]-ethyl propionate（3）10.5g, yield 85%, product HPLC
Purity 98.3%
Embodiment 3
（1）Ring-closure reaction
Sequentially added at room temperature into reactor 120ml ethyl acetate, 3- [（3- amino -4- methylamino benzoyls）（Pyrrole
Pyridine -2- bases）Amino] ethyl propionate 28g and 14.5g chloroacetic anhydride, it is heated with stirring to 65 DEG C and keeps the temperature 2 hours, after being decreased slightly as temperature, be added
Sodium carbonate 12g is warming up to 78 DEG C and reacts 1 hour.Filtering, filtrate decompression are evaporated, and residue is cooled down with 150ml methyl tertiary butyl ether(MTBE)s
To 0 DEG C of crystallization, N- [[2- (chloromethyl) -1- methyl-1 H- benzimidazole -5- bases] carbonyl]-N-2- pyridyl groups-the third ammonia of-β is obtained
Acetoacetic ester（4）29.1g, yield 89%, product HPLC purity 98.1%.
（2）Condensation reaction
Sequentially add 1.5g potassium iodide into reactor at room temperature, 6.6g potassium carbonate, 0.75g tetrabutylammonium bromide, then
50ml water and 65ml ethyl acetate, stirring is added.Solid it is complete it is molten after, 10.0g N- [[2- (chloromethyl) -1- methyl-1s H- are added
Benzimidazole -5- bases] carbonyl]-N-2- pyridyl groups-Beta-alanine ethyl ester and 4- aminobenzene carbonamidine dihydrochlorides, Quan Rong, nitrogen protects
40 DEG C are to slowly warm up under shield to be quickly stirred to react 4 hours.There are a large amount of yellow solids to be precipitated, be cooled to and crystallization 2h is stirred at room temperature,
After be cooled to 5 ~ 10 DEG C of stirring and crystallizing 2h, filter, filter cake is dried under reduced pressure to constant weight in 40 DEG C after being washed with cold ethyl acetate, obtains
Off-white powder 3- [[[2- [[(4- carbamimido-phenyls) amino] methyl] -1- methyl-1 H- benzimidazoles -5-
Base] carbonyl] (pyridine -2- bases) amino]-ethyl propionate（3）10.7g, yield 86%, product HPLC purity
98.5%.
Claims (6)
1. a kind of preparation method of dabigatran etexilate methanesulfonate intermediate, feature are to include the following steps：
(a) 3-[（3- amino -4- methylamino benzoyls）（Pyridine -2- bases）Amino] ethyl propionate (2) and chloroacetic anhydride closed loop
Reaction generates N- [[2- (chloromethyl) -1- methyl-1 H- benzimidazole -5- bases] carbonyl]-N-2- pyridyl groups-Beta-alanine ethyl ester
（4）;
(b) N- [[2- (chloromethyl) -1- methyl-1 H- benzimidazole -5- bases] carbonyl]-N-2- pyridyl groups-Beta-alanine ethyl ester
（4）3- [[[2- [[(4- carbamimido-phenyls) amino] methyl] are obtained with 4- aminobenzene carbonamidine dihydrochloride condensation reactions
- 1- methyl-1 H- benzimidazole -5- bases] carbonyl] (pyridine -2- bases) amino]-ethyl propionate（3）.
2. method described in claim 1, step（b）Condensation reaction, it is characterised in that：Compound is added in two-phase solvent
（4）With 4- aminobenzene carbonamidine dihydrochlorides, heating stirring is reacted in the presence of iodide, inorganic base, phase transfer catalyst, reaction
Liquid obtains compound through cooling, crystallization, suction filtration（3）.
3. the method described in claim 2, which is characterized in that the iodide are selected from sodium iodide, potassium iodide.
4. the method described in claim 2, which is characterized in that a two-phase solvent wherein phase is water, and another phase is and the mutual not phase of water
Molten organic solvent, organic solvent are selected from butyl acetate, ethyl acetate.
5. the method described in claim 2, which is characterized in that inorganic base is selected from potassium carbonate, sodium bicarbonate.
6. the method described in claim 2, which is characterized in that phase transfer catalyst is selected from tetrabutylammonium bromide, tetrabutyl chlorination
Ammonium.
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