CN106866626A - 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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- CN106866626A CN106866626A CN201510937880.XA CN201510937880A CN106866626A CN 106866626 A CN106866626 A CN 106866626A CN 201510937880 A CN201510937880 A CN 201510937880A CN 106866626 A CN106866626 A CN 106866626A
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- 0 C*1(N(CCC*)*(c2cc(CN)c(CNC)cc2)=[O+])N=CCCC1 Chemical compound C*1(N(CCC*)*(c2cc(CN)c(CNC)cc2)=[O+])N=CCCC1 0.000 description 2
- VCRFJOCBGOMGCG-UHFFFAOYSA-N CCCCCCOC(NC(c(cc1)ccc1NCc([n](C)c1c2)nc1ccc2C(N(CCC(OCCCC)=O)c1ccccn1)=O)=N)=O Chemical compound CCCCCCOC(NC(c(cc1)ccc1NCc([n](C)c1c2)nc1ccc2C(N(CCC(OCCCC)=O)c1ccccn1)=O)=N)=O VCRFJOCBGOMGCG-UHFFFAOYSA-N 0.000 description 1
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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
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Abstract
The present invention is a kind of preparation method of dabigatran etexilate intermediate, belong to pharmaceutical technology field, specifically related to a kind of method of synthesis 3- { 2- [(4- cyano-anilines base) methyl] -1- methyl-benzoimidazoles -6- [N- (2- pyridine radicals) formamido] }-ethyl propionate, the method is comprised the following steps：A () 2- (4- cyano-anilines base) acetic acid (2) reacts to form mixture with condensing agent；B () adds the reaction of 3- [3- amino -4- methylaminos-N- (2- pyridine radicals)-benzamido]-ethyl propionate (3)；C () adds acidifying silica gel reaction；D () has been reacted, filter silica gel, is spin-dried for, and 3- { 2- [(4- cyano-anilines base) methyl] -1- methyl-benzoimidazoles -6- [N- (2- pyridine radicals) formamido] }-ethyl propionate is recrystallized to give in organic solvent.The method of the present invention is simple, and post processing generation spent acid is few, and energy consumption is low, and side reaction is few, is suitable to industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology field, in particular it relates in the middle of direct thrombin inhibitor dabigatran etcxilate
The system of body 3- { 2- [(4- cyano-anilines base) methyl] -1- methyl-benzoimidazoles -6- [N- (2- pyridine radicals) formamido] }-ethyl propionate
Preparation Method.
Background technology
Dabigatran etcxilate (4) is researched and developed by German Boehringer Ingelheim companies, on March 18th, 2008 European Union
Listing, suitable for hip joint and the thrombus prevention of knee prosthesis；The FDA on the 20th of September in 2010 ratifies it is used for hip pass
The thrombus prevention of section and knee prosthesis simultaneously increases indication：Non-valve artrial fibrillation patient (AF).Dabigatran etcxilate
Medicine permits do not have domestic registration in the approval of import of in March, 2013, and specification is 75mg and 150mg capsules.
The preparation of dabigatran etcxilate has had lot of documents to report, in these synthetic routes, major part is with 3- { 2- [(4-
Cyano-aniline base) methyl] -1- methyl-benzoimidazoles -6- [N- (2- pyridine radicals) formamido] }-ethyl propionate (1) is used as pole
Its important intermediate.
Original grinds compound patent CN1248251A, the technique patent of Boehringer Ingelheim companies application
In the article (J.Med.Chem.2002,45,1757-1766) of CN101600709A and Hauel et al., with change
Compound 1 prepares dabigatran etcxilate 4 as important intermediate, and the route of the method is as follows：
Research display, prior art has many defects, and such as compound 2 and 3 is added substantial amounts of pure after condensation
Acetic acid is simultaneously heated, and reaction obtains the intermediate 1 of dabigatran etcxilate, and violent mild acidic conditions high make side reaction degree
Higher, removal of impurities is difficult；In addition, the post processing of reaction needs that substantial amounts of acetic acid is evaporated in vacuo, residue is water-soluble through alkalescence
After liquid washing, then carry out the intermediate 1 for post-processing and just obtaining more than 99% purity such as purifying；Meanwhile, locate after reaction
Reason produces substantial amounts of spent acid, increased the cost and difficulty of liquid waste processing.
These defects, largely have impact on the industrialized developing of dabigatran etexilate intermediate 1.
The content of the invention
It is simple it is an object of the invention to provide one kind operation for above-mentioned technological deficiency, green cleaning, convenient post-treatment
And it is suitable to synthesis 3- { 2- [(4- cyano-anilines base) methyl] -1- methyl-benzoimidazoles -6- [N- (2- pyridine radicals) of industrialized production
Formamido] } method of-ethyl propionate (1).
Above-mentioned purpose of the invention realizes that the method comprises the following steps by following methods：
A () 2- (4- cyano-anilines base) acetic acid (2) reacts to form mixture with condensing agent；
B () adds the reaction of 3- [3- amino -4- methylaminos-N- (2- pyridine radicals)-benzamido]-ethyl propionate (3)；
C () adds acidifying silica gel reaction；
D () has been reacted, filter silica gel, is spin-dried for, and 3- { 2- [(4- cyano-anilines base) methyl] -1- are recrystallized to give in organic solvent
Methyl-benzoimidazole -6- [N- (2- pyridine radicals) formamido] }-ethyl propionate (1).
Reaction equation is as follows：
2- (4- cyano-anilines base) acetic acid (2) of the present invention and 3- [3- amino -4- methylaminos-N- (2- pyridine radicals)-benzene
Formamido]-ethyl propionate (3) reaction, step a by compound 2 and condensing agent reaction generation mixture, it is used
Condensing agent be selected from N, N '-carbonyl dimidazoles, carbonyl-two-(1,2,4- triazole), N, N '-dicyclohexyl carbon two is sub-
Amine, N, N '-DIC, 1- ethyls -3- (3- dimethylamino-propyls) carbodiimide hydrochlorides and 1- hydroxyls
Any one or its mixture in BTA.
2- (4- cyano-anilines base) acetic acid (2) of the present invention and 3- [3- amino -4- methylaminos-N- (2- pyridine radicals)-benzene
Formamido]-ethyl propionate (3) reaction, acidifying silica gel used by step c and 2- (4- cyano-anilines base) acetic acid
Mass ratio is 2：1~0.2：1.
2- (4- cyano-anilines base) acetic acid (2) of the present invention and 3- [3- amino -4- methylaminos-N- (2- pyridine radicals)-benzene
Formamido]-ethyl propionate (3) reaction, the acidifying silica gel preparation method used by step c is：Column chromatography silica gel exists
Soaked more than 1 hour in specific acid or its solution, filter acid, tetrahydrofuran or ethyl acetate are washed, drying；It is specific
Acid is selected from inorganic acid such as hydrochloric acid, sulfuric acid and organic acid such as formic acid, acetic acid, trifluoroacetic acid；The acid that this method is used can be with
Recycling, does not influence reaction effect.
2- (4- cyano-anilines base) acetic acid (2) of the present invention and 3- [3- amino -4- methylaminos-N- (2- pyridine radicals)-benzene
Formamido]-ethyl propionate (3) reaction, step d recrystallization organic solvent be selected from ethyl acetate, the tertiary fourth of acetic acid
Ester, ethanol, n-hexane or methyl tertiary butyl ether(MTBE).
Technology is compared, and preparation method of the invention has but is not limited to advantages below：
1st, the reaction reagent used by the present invention is acidifying silica gel, and the pure acetic acid consumption than document report is small, and side reaction is few,
Obtain intermediate 1 i.e. 3- { 2- [(4- cyano-anilines base) methyl] -1- methyl-benzoimidazoles -6- [N- (2- pyridine radicals) formamido] } -
The purity of ethyl propionate is high.
2nd, the present invention is reacted with acidifying silica gel catalyst, and the pure acetic acid method post processing compared to document report is easy, has reacted
Silica gel is filtered, revolving removes solvent, then it is that can obtain intermediate 1 i.e. 3- { 2- [(4- cyano-anilines to be recrystallized with organic solvent
Base) methyl] -1- methyl-benzoimidazoles -6- [N- (2- pyridine radicals) formamido] }-ethyl propionate, it is to avoid the vacuum of pure acetic acid is steamed
Evaporate the complex operations such as acetic acid and aqueous alkali washing, energy consumption reduction.
3rd, the present invention is reacted with acidifying silica gel catalyst, compared to the pure acetic acid method of document report, is produced in last handling process
Acid waste liquid greatly reduce, method is more green, pollutes small, the reduction of the cost of liquid waste processing, and treatment silica gel
Acid can be recycled.
4th, the inventive method compares literature procedure, more suitable for industrialized production.
Specific embodiment
The present invention is described in further detail with reference to specific embodiment, the embodiment for being given is only for illustrating
The present invention, rather than in order to limit the scope of the present invention.
In the following embodiments, 2- (4- cyano-anilines base) acetic acid (2) and the 3- [3- amino -4- methylamino-N- (2- of use
Pyridine radicals)-benzamido]-ethyl propionate (3) is purchased from Shanghai Hong Bang Pharmaceutical Technology Co., Ltd, technical grade；Other examinations
Agent and solvent be it is commercially available, analyze it is pure.
Embodiment 1
By 2.66gN, N '-carbonyl dimidazoles and 30mL tetrahydrofurans add reaction bulb, and stirring is lower to add 2.75g2- (4-
Cyano-aniline base) acetic acid (2), it is stirred at room temperature 1 hour, by 5.00g3- [3- amino -4- methylaminos-N- (2- pyridine radicals)
- benzamido]-ethyl propionate (3) added in reaction solution, back flow reaction 2 hours.Add sulfuric acid-treated silicon
Glue 1g, is refluxed 6 hours, and reaction is complete, and suction filtration, filtrate is spin-dried for, and adds 20mL ethyl acetate stirring and crystallizings,
Obtain white powder 3- { 2- [(4- cyano-anilines base) methyl] -1- methyl-benzoimidazoles -6- [N- (2- pyridine radicals) formamides
Base] }-ethyl propionate (1).
Yield：91.6%
HPLC purity：99.2%
Embodiment 2
By 2.66gN, N '-carbonyl dimidazoles and 30mL tetrahydrofurans add reaction bulb, and stirring is lower to add 2.75g2- (4-
Cyano-aniline base) acetic acid (2), it is stirred at room temperature 1 hour, by 5.00g3- [3- amino -4- methylaminos-N- (2- pyridine radicals)
- benzamido]-ethyl propionate (3) added in reaction solution, back flow reaction 2 hours.Add through the silicon of HCl treatment
Glue 5g, is refluxed 4 hours, and reaction is complete, and suction filtration, filtrate is spin-dried for, and adds the stirring analysis of 20mL n-butyl acetates
Crystalline substance, obtains white powder 3- { 2- [(4- cyano-anilines base) methyl] -1- methyl-benzoimidazoles -6- [N- (2- pyridine radicals) formyls
Amido] }-ethyl propionate (1).
Yield：91.2%
HPLC purity：99.1%
Embodiment 3
By 26.6gN, N '-carbonyl dimidazoles and 300mL tetrahydrofurans add reaction bulb, and stirring is lower to add 27.5g2- (4-
Cyano-aniline base) acetic acid (2), it is stirred at room temperature 1 hour, by 50.0g3- [3- amino -4- methylaminos-N- (2- pyridine radicals)
- benzamido]-ethyl propionate (3) added in reaction solution, back flow reaction 2 hours.Add through the silicon of HCl treatment
Glue 50g, is refluxed 3 hours, and reaction is complete, and suction filtration, filtrate is spin-dried for, and adds 100mL ethanol stirring and crystallizings,
Obtain white powder 3- { 2- [(4- cyano-anilines base) methyl] -1- methyl-benzoimidazoles -6- [N- (2- pyridine radicals) formamides
Base] }-ethyl propionate (1).
Yield：90.1%
HPLC purity：99.4%
Embodiment 4
By 26.6gN, N '-carbonyl dimidazoles and 400mL tetrahydrofurans add reaction bulb, and stirring is lower to add 27.5g2- (4-
Cyano-aniline base) acetic acid (2), it is stirred at room temperature 1 hour, by 50.0g3- [3- amino -4- methylaminos-N- (2- pyridine radicals)
- benzamido]-ethyl propionate (3) added in reaction solution, back flow reaction 2 hours.Add through the silicon of acetic acid treatment
Glue 100g, is refluxed 3 hours, and reaction is complete, and suction filtration, filtrate is spin-dried for, and adds the stirring analysis of 300mL n-hexanes
Crystalline substance, obtains white powder 3- { 2- [(4- cyano-anilines base) methyl] -1- methyl-benzoimidazoles -6- [N- (2- pyridine radicals) formyls
Amido] }-ethyl propionate (1).
Yield：92.3%
HPLC purity：99.0%
Embodiment 5
By 26.6gN, N '-carbonyl dimidazoles and 400mL tetrahydrofurans add reaction bulb, and stirring is lower to add 27.5g2- (4-
Cyano-aniline base) acetic acid (2), it is stirred at room temperature 1 hour, by 50.0g3- [3- amino -4- methylaminos-N- (2- pyridine radicals)
- benzamido]-ethyl propionate (3) added in reaction solution, back flow reaction 2 hours.Add and processed through trifluoroacetic acid
Silica gel 25g, be refluxed 3 hours, reaction is complete, and suction filtration, filtrate is spin-dried for, and adds 300mL methyl tertbutyls
Ether stirring and crystallizing, obtains white powder 3- { 2- [(4- cyano-anilines base) methyl] -1- methyl-benzoimidazoles -6- [N- (2- pyrroles
Piperidinyl) formamido]-ethyl propionate (1).
Yield：92.6%
HPLC purity：99.1%
Embodiment 6
By in 10mL formic acid and 10g column chromatography silica gels addition sesame seed cake, soak 1 hour, filter silica gel, ethyl acetate
Washing, drying obtains being acidified silica gel.
Embodiment 7
Sulfuric acid/the tetrahydrofuran solution of 10mL mass fractions 20% and 10g column chromatography silica gels are added into sesame seed cake
In, soak 1 hour, silica gel is filtered, tetrahydrofuran washing, drying obtains being acidified silica gel.
Comparative example 1
By 2.66gN, N '-carbonyl dimidazoles and 30mL tetrahydrofurans add reaction bulb, and stirring is lower to add 2.75g2- (4-
Cyano-aniline base) acetic acid (2), it is stirred at room temperature 1 hour, by 5.00g3- [3- amino -4- methylaminos-N- (2- pyridine radicals)
- benzamido]-ethyl propionate (3) added in reaction solution, back flow reaction 2 hours.Revolving removes tetrahydrofuran, plus
Enter 20mL acetic acid, except most of acetic acid, raffinate adds 100mL acetic acid second to 100 DEG C of stirrings, 1 hour vacuum revolving
Ester, sodium bicarbonate aqueous solution is washed to alkalescence, and organic phase is dried, is spin-dried for, and adds 20mL ethyl acetate stirring and crystallizings,
Obtain the powdered 3- of dark white { 2- [(4- cyano-anilines base) methyl] -1- methyl-benzoimidazoles -6- [N- (2- pyridine radicals) formyls
Amido] }-ethyl propionate (1).
Yield：74.3%
HPLC purity：97.8%
Comparative example 2
By 8.8gN, N '-carbonyl dimidazoles and 120mL tetrahydrofurans add reaction bulb, and stirring is lower to be added
9.0g2- (4- cyano-anilines base) acetic acid (2), is stirred at room temperature 1 hour.By 16.0g 3- [3- amino -4- methylamino-N- (2-
Pyridine radicals)-benzamido]-ethyl propionate (3) and 30mL tetrahydrofurans added into reaction bulb, 50 DEG C of reactions 4
Hour.Revolving removes about 50mL tetrahydrofurans, adds 6.5g acetic acid, and 80 DEG C of stirrings, 3 hours vacuum revolvings remove tetrahydrochysene furan
Mutter and most of acetic acid, raffinate adds 300mL ethyl acetate, sodium bicarbonate aqueous solution to wash to alkalescence, organic phase
Dry, be spin-dried for, add 60mL ethyl acetate stirring and crystallizings, obtain the powdered 3- of dark white { 2- [(4- cyano-anilines base)
Methyl] -1- methyl-benzoimidazoles -6- [N- (2- pyridine radicals) formamido] }-ethyl propionate (1).
Yield：81.5%
HPLC purity：98.2%
Although present invention has been detailed description, it is to be understood that, foregoing description is not limited to the present invention,
In the case of not departing from the spirit and scope of the present invention, any modification, equivalent substitution and improvements made etc. all should be included
Within protection scope of the present invention.
Claims (7)
1. one kind prepares 3- { 2- [(4- cyano-anilines base) methyl] -1- methyl-benzoimidazoles -6- [N- (2- pyridine radicals) formyls
Amido] } method of-ethyl propionate, comprise the following steps：
A () 2- (4- cyano-anilines base) acetic acid reacts to form mixture with condensing agent；
B () adds the reaction of 3- [3- amino -4- methylaminos-N- (2- pyridine radicals)-benzamido]-ethyl propionate；
C () adds acidifying silica gel reaction；
D () has been reacted, filter silica gel, is spin-dried for, and is recrystallized to give 3- { 2- [(4- cyano-anilines base) methyl] -1- methyl
- benzimidazole -6- [N- (2- pyridine radicals) formamido] }-ethyl propionate.
2. preparation method according to claim 1, the wherein condensing agent used by step a are selected from N, N '-carbonyl
Diimidazole, carbonyl-two-(1,2,4- triazole), N, N '-dicyclohexylcarbodiimide, N, N '-diisopropyl
Base carbodiimide, 1- ethyls -3- (3- dimethylamino-propyls) carbodiimide hydrochlorides or I-hydroxybenzotriazole
In any one or its mixture.
3. preparation method according to claim 1, acidifying silica gel and 2- (4- cyano group wherein used by step c
Anilino-) acetic acid mass ratio be 2：1~0.2：1.
4. preparation method according to claim 1, the acidifying silica gel preparation method wherein used by step c is such as
Under：Column chromatography silica gel soaks more than 1 hour in specific acid or its solution, filters acid, tetrahydrofuran or
Ethyl acetate is washed, drying.
5. preparation method according to claim 1, wherein step d recrystallizations organic solvent used is selected from
Ethyl acetate, tert-butyl acetate, ethanol, n-hexane or methyl tertiary butyl ether(MTBE).
6. preparation method according to claim 4, the specific acid is selected from inorganic acid or organic acid.
7. preparation method according to claim 6, described inorganic acid is selected from hydrochloric acid, sulfuric acid；Described
Organic acid is selected from formic acid, acetic acid or trifluoroacetic acid.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110878083A (en) * | 2018-09-05 | 2020-03-13 | 连云港恒运药业有限公司 | Purification method of dabigatran etexilate intermediate |
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| CN101600709A (en) * | 2007-02-06 | 2009-12-09 | 贝林格尔·英格海姆国际有限公司 | The method for preparing benzimidizole derivatives |
| CN102911160A (en) * | 2012-06-29 | 2013-02-06 | 上海奥博生物医药技术有限公司 | Method for preparing and purifying dabigatran etexilate intermediate |
| CN104744438A (en) * | 2014-12-17 | 2015-07-01 | 烟台东诚药业集团股份有限公司 | Method for synthesising and preparing dabigatran benzimidazole intermediate |
-
2015
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| CN101600709A (en) * | 2007-02-06 | 2009-12-09 | 贝林格尔·英格海姆国际有限公司 | The method for preparing benzimidizole derivatives |
| CN102911160A (en) * | 2012-06-29 | 2013-02-06 | 上海奥博生物医药技术有限公司 | Method for preparing and purifying dabigatran etexilate intermediate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110878083A (en) * | 2018-09-05 | 2020-03-13 | 连云港恒运药业有限公司 | Purification method of dabigatran etexilate intermediate |
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