CN105601615A - Method for purifying kilogram-grade dabigatran etexilate free alkali - Google Patents
Method for purifying kilogram-grade dabigatran etexilate free alkali Download PDFInfo
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- CN105601615A CN105601615A CN201510785844.6A CN201510785844A CN105601615A CN 105601615 A CN105601615 A CN 105601615A CN 201510785844 A CN201510785844 A CN 201510785844A CN 105601615 A CN105601615 A CN 105601615A
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- free alkali
- dabigatran etcxilate
- silica gel
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for purifying a kilogram-grade dabigatran etexilate free alkali crude product, wherein a compound specifically refers to 3-(2-(4-amidino(hexyloxy carbonyl)-phenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-amido)ethyl propionate, and has the main use for preparing an anti-coagulant drug dabigatran etexilate mesylate. With adopting of a relatively simple purification method, the content of new impurities appearing in a process of kilogram-grade preparation of the dabigatran etexilate free alkali is effectively reduced, so that design and development of new pharmacological and toxicological tests are avoided. The purity of the product is also improved, and the preparation cost is reduced.
Description
Technical field
The present invention relates to a kind of method for purifying feather weight dabigatran etcxilate free alkali crude product, particular compound refers to 3-(2-(4-amidino groups(positive hexyloxy carbonyl)-phenylamino) methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzo [d] imidazoles-5-amide groups) propionic acid secondEster, the main application of described compound is to prepare anticoagulation medicine methanesulfonic acid dabigatran etcxilate.
Background technology
Methanesulfonic acid dabigatran etcxilate is a kind of novel synthetic direct thrombin inhibitor, is mainly used in the postoperative DVT of full hip/knee prosthesisPrevention, reduce the risk of NVAF patient's apoplexy and systemic embolism. At present, the aged of Chinese over-65s exceedes 1.5Hundred million, and according to statistics, in over-65s population, the illness rate of thrombotic disease is in 20% left and right. And the annual newly-increased ACS (acute coronary artery syndrome) of ChinaPatient exceedes 1,000,000, and the patient who dies from ACS exceedes 300,000. Therefore this product future market has good prospects.
We is according to patent US98802623.6, Hauel, and NorbertH. is at JournalofMedicinalChemistry, and YuChenIn the method for HETEROCYCLES magazine report in 2013, prepare dabigatran etcxilate free alkali (gram level) by amidineization intermediate acidylate, pass through secondAcetoacetic ester recrystallization method, can obtain qualified product. But along with the amplification (feather weight) of experimental size, there is new impurity,Original method can not reduce the content of new impurity (impurity B), and Given this impurity belongs to unknown impuritie, and its pharmacological toxicology character also belongs to notKnow, therefore must grope new purification process and reduce its content.
Expection impurity mechanism of production is as follows:
Summary of the invention
For the deficiencies in the prior art, the present invention has designed a kind of method of purifying feather weight dabigatran etcxilate free alkali crude product, tests by experimentCard, has determined suitable Reaction conditions range, comprises concrete reagent type and consumption etc. By above means, this reaction is being keptWhen yield, rationally control the content of impurity, obtain highly purified product, reduced the difficulty of removing impurity in subsequent experimental.
Use the present invention, can make dabigatran etcxilate free alkali product purity higher than known patent of invention, in final products, all impurity contents are all fewIn 0.1%.
Technical scheme of the present invention is as follows:
According to patent US98802623.6, YuChen is at HETEROCYCLES and Hauel, and NorbertH. is at JournalofMedicinalChemistry delivers in the preparation method of document, by 3-(2-(4-amidino groups-phenylamino) methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzo [d] imidazoles-5-amide groups) ethyl propionate synthesizes preparation 3-(2-(4-amidino groups (positive hexyloxy carbonyl)-phenylamino)Methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzo [d] imidazoles-5-amide groups) ethyl propionate, and use ethyl acetate to carry outOnce recrystallization, obtains dabigatran etcxilate free alkali crude product.
Then carry out following steps and carry out clarification:
(1) use carrene to dissolve dabigatran etcxilate free alkali crude product, quality used is 4-6 times of dabigatran etcxilate free alkali crude product quality.
(2) use silica gel or diatomite the dichloromethane solution of dabigatran etcxilate free alkali to be carried out to purifying, used silica gel or diatomaceousQuality is the 10-50% of dabigatran etcxilate free alkali quality.
Experiment shows:
Use a certain amount of silica gel or diatomite can meet requirement of experiment, ensureing, under the prerequisite of productive rate, can effectively to remove impurity; Consumption tooHigh meeting reduces product yield, the too low purification efficiency that can reduce.
Brief description of the drawings
Fig. 1: the dabigatran etcxilate free alkali crude product HPLC spectrogram that does not carry out purifying
Fig. 2: the dabigatran etcxilate free alkali highly finished product HPLC spectrogram that carries out purifying according to embodiment mono-
Fig. 3: the dabigatran etcxilate free alkali highly finished product HPLC spectrogram that carries out purifying according to embodiment bis-
Fig. 4: the dabigatran etcxilate free alkali highly finished product HPLC spectrogram that carries out purifying according to embodiment tri-
Fig. 5: the dabigatran etcxilate free alkali highly finished product HPLC spectrogram that carries out purifying according to embodiment tetra-
Fig. 6: the dabigatran etcxilate free alkali highly finished product HPLC spectrogram that carries out purifying according to embodiment five
Fig. 7: the dabigatran etcxilate free alkali highly finished product HPLC spectrogram that carries out purifying according to embodiment six
Fig. 8: the dabigatran etcxilate free alkali highly finished product HPLC spectrogram that carries out purifying according to comparative example one
Fig. 9: the dabigatran etcxilate free alkali highly finished product HPLC spectrogram that carries out purifying according to comparative example two
Figure 10: the dabigatran etcxilate free alkali highly finished product HPLC spectrogram that carries out purifying according to comparative example three
Detailed description of the invention
Embodiment mono-
Take amidineization product 2752g, according to patent US98802623.6, YuChen is at HETEROCYCLES and Hauel, and NorbertH. existsJournalofMedicinalChemistry delivers the preparation method of document, by washing, dry, distillation, re-crystallizing in ethyl acetate etc.Program, obtains dabigatran etcxilate free alkali crude product 2513g (HPLC is shown in Fig. 1).
Crude product is dissolved with 10L carrene, add 100-200 object silica gel (600g) column chromatography for, 25 DEG C of stirring 3h, suction filtration, 1LWashed with dichloromethane silica gel layer, by the organic phase decompression distillation (40 DEG C ,-0.09MPa) merging, to flowing out without carrene.
Add ethyl acetate 20L to be heated to 60 DEG C of dissolvings, stirring is spent the night, crystallization.
Suction filtration, 2.0L ethyl acetate washing leaching cake, by filter cake vacuum drying 12h.
Weigh, dabigatran etcxilate free alkali highly finished product 2093g, yield: 83.28%, sample presentation is examined entirely, qualified (HPLC is shown in Fig. 2) (99.36%).
Embodiment bis--six, and comparative example one-tri-all adopts as above processing step, only test parameters numerical value is different, therefore present in list mode.
Through above contrast test, illustrate:
1) diatomite, silica gel (60-100 order, 100-200 order, 200-300 order) all can effectively be removed in feather weight and prepare dabigatranThe impurity occurring in ester product process, shows selective absorption to impurity, and product yield is high;
2) calcium chloride can effectively be removed impurity, but in actual mechanical process, infers because of dry calcium chloride meeting intussusception moisture in air,Cause suspension to filter very difficult, filtration time reaches more than 10 hours; And cause product yield obviously to reduce, because ofThis puts aside that calcium chloride is as adsorbent;
3) active carbon, magnesium sulfate can not effectively be removed impurity, and the suction-operated of product and impurity is not shown selectively;
By the contrast test of above conventional adsorbent, the present invention is applied in dabigatran etcxilate product feather weight purge process, can be effectiveRemove impurity, product yield is higher, is a kind of effective purification process.
Claims (5)
1. for a method for purifying feather weight dabigatran etcxilate free alkali, particular compound refers to 3-(2-(4-amidino groups (positive hexyloxy carbonyl)-phenylaminoBase) methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzo [d] imidazoles-5-amide groups) ethyl propionate, it is characterized in that adopting solvent moltenSeparate dabigatran etcxilate free alkali crude product, add specific adsorbent (silica gel or diatomite) to reduce impurity content, thereby reach purifying object.
2. purification process according to claim 1, wherein dissolving dabigatran etcxilate free alkali crude product solvent used is carrene, quality used isThe 4-6 of dabigatran etcxilate free alkali quality doubly.
3. purification process according to claim 1, wherein adding dabigatran etcxilate free alkali dichloromethane solution adsorbent used is silica gel or siliconAlgae soil, sorbent used quality is the 10-50% of dabigatran etcxilate free alkali quality.
4. purification process according to claim 1, wherein the specification of adsorbent is diatomite, or 60-100 order, or 100-200 order, or 200-300Order column chromatography silica gel.
5. purification process according to claim 1, while wherein adding silica gel or diatomite in dabigatran etcxilate free alkali dichloromethane solution, stirsThe temperature of mixing is 20-40 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510785844.6A CN105601615A (en) | 2015-11-17 | 2015-11-17 | Method for purifying kilogram-grade dabigatran etexilate free alkali |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510785844.6A CN105601615A (en) | 2015-11-17 | 2015-11-17 | Method for purifying kilogram-grade dabigatran etexilate free alkali |
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| CN105601615A true CN105601615A (en) | 2016-05-25 |
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| CN201510785844.6A Pending CN105601615A (en) | 2015-11-17 | 2015-11-17 | Method for purifying kilogram-grade dabigatran etexilate free alkali |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106916141A (en) * | 2017-04-06 | 2017-07-04 | 南京生命能科技开发有限公司 | A kind of preparation method of dabigatran etexilate methanesulfonate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN104045628A (en) * | 2014-06-13 | 2014-09-17 | 深圳翰宇药业股份有限公司 | Purification method of benzimidazole derivative |
| CN104892501A (en) * | 2015-05-27 | 2015-09-09 | 上海应用技术学院 | Aftertreatment purification method for 3-[(3-amino-4-methylamino benzoyl)(pyridine-2-yl)amino]ethyl propionate |
| CN104910066A (en) * | 2015-05-27 | 2015-09-16 | 上海应用技术学院 | Ethyl 3-(pyridin-2-ylamino)propanoate post-treatment purification method |
-
2015
- 2015-11-17 CN CN201510785844.6A patent/CN105601615A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN104045628A (en) * | 2014-06-13 | 2014-09-17 | 深圳翰宇药业股份有限公司 | Purification method of benzimidazole derivative |
| CN104892501A (en) * | 2015-05-27 | 2015-09-09 | 上海应用技术学院 | Aftertreatment purification method for 3-[(3-amino-4-methylamino benzoyl)(pyridine-2-yl)amino]ethyl propionate |
| CN104910066A (en) * | 2015-05-27 | 2015-09-16 | 上海应用技术学院 | Ethyl 3-(pyridin-2-ylamino)propanoate post-treatment purification method |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106916141A (en) * | 2017-04-06 | 2017-07-04 | 南京生命能科技开发有限公司 | A kind of preparation method of dabigatran etexilate methanesulfonate |
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Application publication date: 20160525 |