CN105732433A - Refining method of Dabigatran etexilate intermediate condensation compound - Google Patents
Refining method of Dabigatran etexilate intermediate condensation compound Download PDFInfo
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- CN105732433A CN105732433A CN201610227858.0A CN201610227858A CN105732433A CN 105732433 A CN105732433 A CN 105732433A CN 201610227858 A CN201610227858 A CN 201610227858A CN 105732433 A CN105732433 A CN 105732433A
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- Prior art keywords
- dabigatran etexilate
- condensation substance
- intermediate condensation
- etexilate intermediate
- acetone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/08—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a refining method of a Dabigatran etexilate intermediate condensation compound, and belongs to the technical field of medicine purification.The method includes the steps of adding acetone to the Dabigatran etexilate intermediate condensation compound, then adding oxalic acid dehydrate, and conducting crystallizing, filtering and washing to obtain oxalate of the Dabigatran etexilate intermediate condensation compound.The content of impurities is decreased, the refining rate is increased, cost is low, and industrialization is easy.
Description
Technical field
The present invention relates to the process for purification of a kind of dabigatran etexilate intermediate condensation substance, belong to drug purification technical field.
Background technology
Dabigatran etcxilate (commodity are called Pradaxa) is taken the lead in listing in Germany and Britain in April, 2008 by Boehringer Ingelheim company of Germany.Dabigatran etcxilate is direct thrombin inhibitor.
US8399678B2 provides a kind of preparation method, when preparing intermediate condensate (I), by just own ester (III) reaction of p-Aminobenzamidine dihydrochloride (II) and chloro-carbonic acid, obtains condensation substance (I) grease.Adding butyl acetate to dissolve, add hydrochloric acid and become salt, circulation distillation dewaters, and adds acetone crystallize, obtains condensation substance hydrochlorate (Ib).The synthetic reaction equation of condensation substance (I) and condensation substance hydrochlorate (Ib) is as follows:
In this patent, condensation substance grease uses hydrochloric acid to become salt, because hydrochloric acid is moisture, it is necessary to dewater, water removal operation is troublesome；Subtractive process needs to use acetone and butyl acetate, both mixed solvents, applies mechanically solvent to industrialization and make troubles.Meanwhile, product is easily damaged by hot environment when strong acid and circulation distillation dewater.
Summary of the invention
It is an object of the invention to provide the process for purification of a kind of dabigatran etexilate intermediate condensation substance, its technique is simple, reduces impurity content, improves refining rate, and cost is low, it is easy to accomplish industrialization.
The process for purification of dabigatran etexilate intermediate condensation substance of the present invention, it is addition acetone in dabigatran etexilate intermediate condensation substance, add oxalic acid dihydrate, then carry out crystallize, filtration and washing, obtain the oxalates of dabigatran etexilate intermediate condensation substance.
The mixture of dabigatran etexilate intermediate condensation substance and acetone is heated to 40～50 DEG C of dissolvings.
Oxalic acid dihydrate is added under 20～30 DEG C of conditions.
During washing, solvent for use is acetone.
The mol ratio of described dabigatran etexilate intermediate condensation substance and oxalic acid dihydrate is 1:1.0～1.1.
Compared with prior art, the method have the advantages that
The present invention does not use hydrochloric acid as salt forming agent, avoid that hydrochloric acid is moisture causes the later stage to dewater loaded down with trivial details problem, and use cheap and easy to get and water-free oxalic acid dihydrate as salt forming agent, simplify process for refining, crystallize speed is fast, it is to avoid high temperature and the strong acid environment destructiveness to product；Use acetone when dissolving dabigatran etexilate intermediate condensation substance, also only used acetone when crystallize and washing, namely in whole subtractive process, only need to use a kind of solvent, be beneficial to technology and apply mechanically solvent, energy-saving and emission-reduction.Present invention process is simple, reduces impurity content, improves refining rate, and cost is low, it is easy to accomplish industrialization.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated, but is not limiting as the enforcement of the present invention.
Embodiment 1
(1) preparation of dabigatran etexilate intermediate condensation substance grease:
21.2g (0.10mol) p-Aminobenzamidine dihydrochloride (II), 150ml dichloromethane is added in reaction bulb, control temperature 20 DEG C and add 80ml15% (0.12mol) sodium hydroxide solution, the dropping just own ester (III) of 16.5g (0.1mol) chloro-carbonic acid, reacts 4h.Branch vibration layer, steaming vibrating dichloromethane obtains the grease 26.4g of condensation substance (I).
(2) dabigatran etexilate intermediate condensation substance grease is refining:
In reaction bulb, add the grease (26.4g, 0.10mol) of condensation substance (I), then add acetone 100ml, heat to 45 ± 2 DEG C of dissolvings.25 ± 2 DEG C add 12.6g (0.10mol) oxalic acid dihydrate, crystallize.Filter, obtain oxalates (Ia) 32.0g of condensation substance with washing with acetone.Yield is 90%, and the purity of target product is 98.5%.
Embodiment 2
(1) preparation method of dabigatran etexilate intermediate condensation substance grease is with the step (1) in embodiment 1.
(2) dabigatran etexilate intermediate condensation substance grease is refining:
In reaction bulb, add the grease (52.8g, 0.20mol) of condensation substance (I), then add acetone 220ml, heat to 45 ± 5 DEG C of dissolvings.25 ± 3 DEG C add 25.2g (0.20mol) oxalic acid dihydrate, crystallize.Filter, obtain oxalates (Ia) 67.5g of condensation substance with washing with acetone.Yield is 95%, and the purity of target product is 99.2%.
Embodiment 3
(1) preparation method of dabigatran etexilate intermediate condensation substance grease is with the step (1) in embodiment 1.
(2) dabigatran etexilate intermediate condensation substance grease is refining:
In reaction bulb, add the grease (39.6g, 0.15mol) of condensation substance (I), then add acetone 110ml, heat to 45 ± 5 DEG C of dissolvings.28 ± 2 DEG C add 18.9g (0.15mol) oxalic acid dihydrate, crystallize.Filter, obtain oxalates (Ia) 48.5g of condensation substance with washing with acetone.Yield is 91%, and the purity of target product is 99.3%.
Embodiment 4
(1) preparation method of dabigatran etexilate intermediate condensation substance grease is with the step (1) in embodiment 1.
(2) dabigatran etexilate intermediate condensation substance grease is refining:
In reaction bulb, add the grease (26.4g, 0.10mol) of condensation substance (I), then add acetone 130ml, heat to 43 ± 5 DEG C of dissolvings.22 ± 2 DEG C add 12.6g (0.10mol) oxalic acid dihydrate, crystallize.Filter, obtain oxalates (Ia) 32.7g of condensation substance with washing with acetone.Yield is 92%, and the purity of target product is 98.9%.
Claims (5)
1. the process for purification of a dabigatran etexilate intermediate condensation substance, it is characterized in that: in dabigatran etexilate intermediate condensation substance, add acetone, add oxalic acid dihydrate, then carry out crystallize, filtration and washing, obtain the oxalates of dabigatran etexilate intermediate condensation substance.
2. the process for purification of dabigatran etexilate intermediate condensation substance according to claim 1, it is characterised in that: the mixture of dabigatran etexilate intermediate condensation substance and acetone is heated to 40～50 DEG C of dissolvings.
3. the process for purification of dabigatran etexilate intermediate condensation substance according to claim 1, it is characterised in that: under 20～30 DEG C of conditions, add oxalic acid dihydrate.
4. the process for purification of dabigatran etexilate intermediate condensation substance according to claim 1, it is characterised in that: during washing, solvent for use is acetone.
5. the process for purification of dabigatran etexilate intermediate condensation substance according to claim 1, it is characterised in that: the mol ratio of dabigatran etexilate intermediate condensation substance and oxalic acid dihydrate is 1:1.0～1.1.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610227858.0A CN105732433A (en) | 2016-04-13 | 2016-04-13 | Refining method of Dabigatran etexilate intermediate condensation compound |
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| CN201610227858.0A CN105732433A (en) | 2016-04-13 | 2016-04-13 | Refining method of Dabigatran etexilate intermediate condensation compound |
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| CN201610227858.0A Pending CN105732433A (en) | 2016-04-13 | 2016-04-13 | Refining method of Dabigatran etexilate intermediate condensation compound |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1310708A (en) * | 1998-07-23 | 2001-08-29 | 贝林格尔英格海姆法玛公司 | Substituted phenylamidines with antithrombotic action |
| 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 |
| WO2015128875A2 (en) * | 2014-02-26 | 2015-09-03 | Megafine Pharma (P) Ltd. | A process for preparation of dabigatran etexilate mesylate and intermediates thereof |
| CN104910047A (en) * | 2015-05-11 | 2015-09-16 | 常州市阳光药业有限公司 | Preparation method of dabigatran etexilate intermediate |
| CN105330568A (en) * | 2015-11-27 | 2016-02-17 | 山东省医学科学院药物研究所 | Preparation method for p-aminobenzamidine hydrochloride |
| CN105348148A (en) * | 2015-11-30 | 2016-02-24 | 山东新华制药股份有限公司 | Method for preparing impurity oxalate of intermediate condensation compound of pradaxa |
-
2016
- 2016-04-13 CN CN201610227858.0A patent/CN105732433A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1310708A (en) * | 1998-07-23 | 2001-08-29 | 贝林格尔英格海姆法玛公司 | Substituted phenylamidines with antithrombotic action |
| 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 |
| WO2015128875A2 (en) * | 2014-02-26 | 2015-09-03 | Megafine Pharma (P) Ltd. | A process for preparation of dabigatran etexilate mesylate and intermediates thereof |
| CN104910047A (en) * | 2015-05-11 | 2015-09-16 | 常州市阳光药业有限公司 | Preparation method of dabigatran etexilate intermediate |
| CN105330568A (en) * | 2015-11-27 | 2016-02-17 | 山东省医学科学院药物研究所 | Preparation method for p-aminobenzamidine hydrochloride |
| CN105348148A (en) * | 2015-11-30 | 2016-02-24 | 山东新华制药股份有限公司 | Method for preparing impurity oxalate of intermediate condensation compound of pradaxa |
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Application publication date: 20160706 |