CN104744438A - Method for synthesising and preparing dabigatran benzimidazole intermediate - Google Patents
Method for synthesising and preparing dabigatran benzimidazole intermediate Download PDFInfo
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- CN104744438A CN104744438A CN201410778775.1A CN201410778775A CN104744438A CN 104744438 A CN104744438 A CN 104744438A CN 201410778775 A CN201410778775 A CN 201410778775A CN 104744438 A CN104744438 A CN 104744438A
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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 relates to a method for synthesising and preparing 3-(2-(4-cyanophenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d] imidazole-5-acetamido) ethyl propionate, wherein the main application of the compound is preparing an anticoagulant medicine dabigatran. According to the method disclosed by the invention, an acidic catalyst with a low price is used, and condensation is carried out during a relative low-temperature concentration process to prepare the product. The method disclosed by the invention is capable of effectively reducing a process operation time, reducing the energy consumption, improving the product purity, and reducing the product cost.
Description
Technical field
The present invention relates to a kind of for the synthesis of preparing 3-(2-(4-cyanophenylamino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzo [d] imidazoles-5-amide group) method of ethyl propionate, the main application of described compound prepares anticoagulation medicine dabigatran etcxilate.
Background technology
Cyclised products in following formula---3-(2-(4-cyanophenylamino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzo [d] imidazoles-5-amide group) ethyl propionate, structural formula is:
It is one of key intermediate preparing anticoagulation medicine dabigatran etcxilate.
Dabigatran etcxilate is a kind of direct thrombin inhibitor of novel synthesis, is mainly used in the prevention of the postoperative DVT of full hip/knee prosthesis, reduces the risk of NVAF patient's apoplexy and systemic embolism.At present, the aged of Chinese over-65s is more than 1.5 hundred million, and according to statistics, in over-65s population, the morbidity of thrombus disease is about 20%.And annual newly-increased ACS (acute coronary artery syndrome) patient of China is more than 1,000,000, die from the patient of ACS more than 300,000.Therefore this product future market has good prospects.
Prepare key intermediate cyclised products-3-(2-(4-cyanophenylamino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzo [d] imidazoles-5-amide group of dabigatran etcxilate at present) ethyl propionate, its preparation method is mainly from patent US98802623.6 and Hauel the earliest, Norbert H. delivers at Journal of Medicinal Chemistry in 2002, wherein synthetic route
as Fig. 1shown in, first fragment one and N, N '-carbonyl dimidazoles carries out reaction preparation active ester, then adds fragment two and carries out condensation and obtain condensation product, finally pyrocondensation in acetic acid solvent.
In addition, a lot of patent is also modified the method:
Patent WO2009111997 have employed different reaction solvents to improve product purity;
Patent EP2522662 and WO20124396 have employed different solvents to wash purified product, improves purity;
Patent WO200895928, US6087380 and WO2012152855 have employed different acid groups and carry out purified product, improve purity;
But it is long that above-mentioned all patents all exist distillation time, uses a large amount of acid solvent, long-time heat (more than 140 degree), the defects such as product purity is low, add product cost.
Summary of the invention
For the deficiencies in the prior art, the present invention designs a kind of for the synthesis of preparing 3-(2-(4-cyanophenylamino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzo [d] imidazoles-5-amide group) method of ethyl propionate, adopt cheap an acidic catalyst, in the concentration process of relative low temperature, carry out product condensation preparation.The present invention can reduce distillation time, reduces Heating temperature, improves product purity, greatly reduces energy consumption, reduces product cost.
Technical scheme of the present invention is as follows:
At patent US98802623.6 and Hauel, Norbert H. delivers on the basis of document at Journal of Medicinal Chemistry, and independent development is a kind of for the synthesis of preparing 3-(2-(4-cyanophenylamino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzo [d] imidazoles-5-amide group) method of ethyl propionate.And the stability of this method is demonstrated by lab scale and amplification.
Experiment shows:
(1) use the acid reagent of catalytic amount in the concentration process of relative low temperature, carry out product condensation preparation, can effective Reaction time shorten, reaction process is consistent with the method reported;
(2) use sodium hydroxide strong alkali aqueous solution to neutralize rear extraction to acid reagent, can effectively remove out this acidic catalyst;
(3) with extraction conditions, product purity is not had an impact in removal acid reagent;
(3) the method can reduce distillation time, reduces Heating temperature, improves product purity, reduces product cost, is more suitable for suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the HPLC spectrogram that the mode described by embodiment 1 prepares dabigatran etcxilate benzoglyoxaline intermediate;
Fig. 2 is the HPLC spectrogram that the mode described by embodiment 2 prepares dabigatran etcxilate benzoglyoxaline intermediate;
Fig. 3 is the HPLC spectrogram that the mode described by embodiment 3 prepares dabigatran etcxilate benzoglyoxaline intermediate;
Fig. 4 is the HPLC spectrogram that the mode described by embodiment 4 prepares dabigatran etcxilate benzoglyoxaline intermediate;
Embodiment
Condensation product-3-(3-(2-(4-cyano-aniline base) kharophen) 4-(methylamino)-N-(pyridine-2-base) benzoylamino)-ethyl propionate is prepared according to patent US98802623.6 report method:
In 50L reactor, under room temperature, by N, N '-carbonyl dimidazoles (CDI) 0.945kg adds in tetrahydrofuran (THF) (THF) the solution 20L of fragment one (1.03kg) in three batches, and is heated to 50 DEG C of reactions, after 10min, the fragment two 1.50kg tetrahydrofuran solution 5L prepared is added in 50L reactor, feed time 30min, and keep reactor temperature in reinforced process to be not less than 45 DEG C, be heated to 70 DEG C of reaction 4h after reinforced.Obtain the crude product solution of condensation product-3-(3-(2-(4-cyano-aniline base) kharophen) 4-(methylamino)-N-(pyridine-2-base) benzoylamino)-ethyl propionate at tetrahydrofuran (THF) 25L, stand-by.
Embodiment 1
1.5L acetic acid is added in tetrahydrofuran (THF) (25L) reaction soln of above-mentioned condensation product-3-(3-(2-(4-cyano-aniline base) kharophen) 4-(methylamino)-N-(pyridine-2-base) benzoylamino)-ethyl propionate, continue to react at 70 DEG C, and start distilled tetrahydrofuran, after 8h, obtain dope, reaction terminates (the non-cyclised products < 1% of HPLC);
Add ethyl acetate 21.5L fast, stirring and dissolving obtains uniform solution, and add in the 1M/L NaOH solution 25.0L prepared under stirring and acetic acid, stir 1h, leave standstill 0.5h, aqueous phase is released, and organic phase is for subsequent use;
In the organic phase of above-mentioned steps acquisition, add purified water 8.5L more subsequently, stir 1h, leave standstill 0.5h, aqueous phase is released; Repeatedly after twice washing, saturated aqueous common salt 2.5L is added again in organic phase, stir 1h, leave standstill 0.5h, aqueous phase is released, obtain crude product purity higher than 85% 3-(2-(4-cyanophenylamino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzo [d] imidazoles-5-amide group) ethyl acetate solution of ethyl propionate.
3-(2-(4-cyanophenylamino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzo [d] imidazoles-5-amide group by above-mentioned preparation) ethyl propionate crude product solution adds thermal distillation, and add Virahol 16L stirring and dissolving, saturated salt acid solution 510ml is dripped at 40 DEG C, stirring is cooled to 5 DEG C, spend the night crystallization, suction filtration is dry, obtains product 1.83kg, HPLC show purity > 98% (
fig. 1), three step overall yields 87%.
Embodiment 2
1.5L trichoroacetic acid(TCA) is added in tetrahydrofuran (THF) (25L) reaction soln of above-mentioned condensation product-3-(3-(2-(4-cyano-aniline base) kharophen) 4-(methylamino)-N-(pyridine-2-base) benzoylamino)-ethyl propionate, continue to react at 70 DEG C, and start distilled tetrahydrofuran, after 8h, obtain dope, reaction terminates (the non-cyclised products < 1% of HPLC);
Add ethyl acetate 21.5L fast, stirring and dissolving obtains uniform solution, and add in the 1M/L NaOH solution 14.3L prepared under stirring and acetic acid, stir 1h, leave standstill 0.5h, aqueous phase is released, and organic phase is for subsequent use;
In the organic phase of above-mentioned steps acquisition, add purified water 8.5L more subsequently, stir 1h, leave standstill 0.5h, aqueous phase is released; Repeatedly after twice washing, saturated aqueous common salt 2.5L is added again in organic phase, stir 1h, leave standstill 0.5h, aqueous phase is released, obtain crude product purity higher than 85% 3-(2-(4-cyanophenylamino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzo [d] imidazoles-5-amide group) ethyl acetate solution of ethyl propionate.
3-(2-(4-cyanophenylamino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzo [d] imidazoles-5-amide group by above-mentioned preparation) ethyl propionate crude product solution adds thermal distillation, and add Virahol 16L stirring and dissolving, saturated salt acid solution 510ml is dripped at 40 DEG C, stirring is cooled to 5 DEG C, spend the night crystallization, suction filtration is dry, obtains product 1.85kg, HPLC show purity > 98% (
fig. 2), three step overall yields 88%.
Embodiment 3
1.5L trifluoroacetic acid is added in tetrahydrofuran (THF) (25L) reaction soln of above-mentioned condensation product-3-(3-(2-(4-cyano-aniline base) kharophen) 4-(methylamino)-N-(pyridine-2-base) benzoylamino)-ethyl propionate, continue to react at 70 DEG C, and start distilled tetrahydrofuran, after 8h, obtain dope, reaction terminates (the non-cyclised products < 1% of HPLC);
Add ethyl acetate 21.5L fast, stirring and dissolving obtains uniform solution, and add in the 1M/L NaOH solution 19.3L prepared under stirring and acetic acid, stir 1h, leave standstill 0.5h, aqueous phase is released, and organic phase is for subsequent use;
In the organic phase of above-mentioned steps acquisition, add purified water 8.5L more subsequently, stir 1h, leave standstill 0.5h, aqueous phase is released; Repeatedly after twice washing, saturated aqueous common salt 2.5L is added again in organic phase, stir 1h, leave standstill 0.5h, aqueous phase is released, obtain crude product purity higher than 85% 3-(2-(4-cyanophenylamino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzo [d] imidazoles-5-amide group) ethyl acetate solution of ethyl propionate.
3-(2-(4-cyanophenylamino) methyl)-1-methyl-N-(pyridine-2-base)-14-benzo [d] imidazoles-5-amide group by above-mentioned preparation) ethyl propionate crude product solution adds thermal distillation, and add Virahol 16L stirring and dissolving, saturated salt acid solution 510ml is dripped at 40 DEG C, stirring is cooled to 5 DEG C, spend the night crystallization, suction filtration is dry, obtains product 1.81kg, HPLC show purity > 98% (
fig. 3), three step overall yields 87%.
Embodiment 4
Condensation product-3-(3-(2-(4-cyano-aniline base) kharophen) 4-(methylamino)-N-(pyridine-2-base) benzoylamino)-ethyl propionate is prepared according to patent US98802623.6 report method:
In 150L reactor, under room temperature, by N, N '-carbonyl dimidazoles (CDI) 2.85kg adds in tetrahydrofuran (THF) (THF) the solution 60L of fragment one (3.09kg) in three batches, and is heated to 50 DEG C of reactions, after 10min, the fragment two 4.50kg tetrahydrofuran solution 15L prepared is added in 150L reactor, feed time 30min, and keep reactor temperature in reinforced process to be not less than 45 DEG C, be heated to 70 DEG C of reaction 4h after reinforced.Obtain the crude product solution of condensation product-3-(3-(2-(4-cyano-aniline base) kharophen) 4-(methylamino)-N-(pyridine-2-base) benzoylamino)-ethyl propionate at tetrahydrofuran (THF) 75L, stand-by.
4.5L acetic acid is added in tetrahydrofuran (THF) (25L) reaction soln of above-mentioned condensation product-3-(3-(2-(4-cyano-aniline base) kharophen) 4-(methylamino)-N-(pyridine-2-base) benzoylamino)-ethyl propionate, continue to react at 70 DEG C, and start distilled tetrahydrofuran, after 8h, obtain dope, reaction terminates (the non-cyclised products < 1% of HPLC);
Add ethyl acetate 21.5L fast, stirring and dissolving obtains uniform solution, and add in the 1M/L NaOH solution 25.0L prepared under stirring and acetic acid, stir 1h, leave standstill 0.5h, aqueous phase is released, and organic phase is for subsequent use;
In the organic phase of above-mentioned steps acquisition, add purified water 8.5L more subsequently, stir 1h, leave standstill 0.5h, aqueous phase is released; Repeatedly after twice washing, saturated aqueous common salt 2.5L is added again in organic phase, stir 1h, leave standstill 0.5h, aqueous phase is released, obtain crude product purity higher than 85% 3-(2-(4-cyanophenylamino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzo [d] imidazoles-5-amide group) ethyl acetate solution of ethyl propionate.
3-(2-(4-cyanophenylamino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzo [d] imidazoles-5-amide group by above-mentioned preparation) ethyl propionate crude product solution adds thermal distillation, and add Virahol 16L stirring and dissolving, saturated salt acid solution 510ml is dripped at 40 DEG C, stirring is cooled to 5 DEG C, spend the night crystallization, suction filtration is dry, obtains product 5.67kg, HPLC show purity > 98% (
fig. 4), three step overall yields 89.5%.
This patent method and report method contrast:
| This patent method | US98802623.6 | WO2009111997 | |
| Reaction Heating temperature | 70℃ | 130℃ | 130℃ |
| Distillation top temperature | 75℃ | 150 DEG C (decompression operation) | 150 DEG C (decompression operation) |
| Distillation time | 8-12h | 30-36h | 30-36h |
| Product yield | 90％ | 78％ | 82％ |
| Product purity | 98％ | 94％ | 95％ |
Claims (7)
1. one kind for the synthesis of preparing 3-(2-(4-cyanophenylamino) methyl)-1-methyl-N-(pyridine-2-base)-1H-benzo [d] imidazoles-5-amide group) method of ethyl propionate, it is characterized in that synthetic method used is by 3-(3-(2-(4-cyano-aniline base) kharophen) 4-(methylamino)-N-(pyridine-2-base) benzoylamino)-ethyl propionate catalyzing and condensing under specific acidic chemical reagent conditions, and carry out aftertreatment purifying and form.
2. synthetic method according to claim 1, wherein specific acidic chemical reagent is formic acid, acetic acid, propionic acid, trifluoroacetic acid, trichoroacetic acid(TCA), HCl (gas) and any mixture thereof.
3. synthetic method according to claim 1, its specific an acidic catalyst volume, is specially the 1-10% of 3-(3-(2-(4-cyano-aniline base) kharophen) 4-(methylamino)-N-(pyridine-2-base) benzoylamino)-ethyl propionate tetrahydrofuran solution volume.
4. synthetic method according to claim 1, the method for condensing that its catalyzing and condensing uses carries out in concentration process.
5. synthetic method according to claim 1, its post-treating method uses alkali liquid washing reaction solution.
6. post-treating method according to claim 1 or 5, the alkali wherein used is sodium hydroxide, potassium hydroxide.
7. post-treating method according to claim 1 or 5, wherein use the amount of alkali be the 0.9-1.1 of sour molar equivalent used doubly.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866626A (en) * | 2015-12-14 | 2017-06-20 | 天津药物研究院有限公司 | A kind of preparation method of dabigatran etexilate intermediate |
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| 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 |
| CN102985416A (en) * | 2010-07-09 | 2013-03-20 | 埃斯特维化学股份有限公司 | Process of preparing a thrombin specific inhibitor |
| CN103387566A (en) * | 2012-05-09 | 2013-11-13 | 上海医药工业研究院 | Preparation method of 3-[[[2-[[4-cyanophenyl) amino] methyl]-1-methyl-1H-benzimidazole-5-yl] carbonyl] (pyridine-2-yl) amino] ethyl propionate |
| WO2014012880A1 (en) * | 2012-07-16 | 2014-01-23 | Interquim, S.A. | Process for the preparation of intermediates for the synthesis of dabigatran etexilate, and crystalline forms of said intermediates |
| WO2014049585A2 (en) * | 2012-09-28 | 2014-04-03 | Ranbaxy Laboratories Limited | Process for the preparation of dabigatran etexilate or pharmaceutically acceptable salt thereof |
| WO2014068587A2 (en) * | 2012-10-29 | 2014-05-08 | Biophore India Pharmaceuticals Pvt. Ltd. | An improved process for the synthesis of dabigatran and its intermediates |
| WO2014192030A2 (en) * | 2013-05-29 | 2014-12-04 | Laurus Labs Private Limited | An improved process for preparation of dabigatran etexilate and pharmaceutically acceptable acid addition salts thereof |
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- 2014-12-17 CN CN201410778775.1A patent/CN104744438A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| CN102985416A (en) * | 2010-07-09 | 2013-03-20 | 埃斯特维化学股份有限公司 | Process of preparing a thrombin specific inhibitor |
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| WO2014012880A1 (en) * | 2012-07-16 | 2014-01-23 | Interquim, S.A. | Process for the preparation of intermediates for the synthesis of dabigatran etexilate, and crystalline forms of said intermediates |
| WO2014049585A2 (en) * | 2012-09-28 | 2014-04-03 | Ranbaxy Laboratories Limited | Process for the preparation of dabigatran etexilate or pharmaceutically acceptable salt thereof |
| WO2014068587A2 (en) * | 2012-10-29 | 2014-05-08 | Biophore India Pharmaceuticals Pvt. Ltd. | An improved process for the synthesis of dabigatran and its intermediates |
| WO2014192030A2 (en) * | 2013-05-29 | 2014-12-04 | Laurus Labs Private Limited | An improved process for preparation of dabigatran etexilate and pharmaceutically acceptable acid addition salts thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106866626A (en) * | 2015-12-14 | 2017-06-20 | 天津药物研究院有限公司 | A kind of preparation method of dabigatran etexilate intermediate |
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Application publication date: 20150701 |