CN105175415A - Preparation method of two-crystal-water-containing H2-2 crystal form of Apixaban - Google Patents
Preparation method of two-crystal-water-containing H2-2 crystal form of Apixaban Download PDFInfo
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- CN105175415A CN105175415A CN201510678092.3A CN201510678092A CN105175415A CN 105175415 A CN105175415 A CN 105175415A CN 201510678092 A CN201510678092 A CN 201510678092A CN 105175415 A CN105175415 A CN 105175415A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of a two-crystal-water-containing H2-2 crystal form of Apixaban. The preparation method is characterized by comprising the steps of dissolving, cooling, stirring, filtering and drying, thus completing preparation of the H2-2 crystal form of Apixaban. The preparation method has the advantages that the purity of a crystal obtained by the preparation method is high, the operation is simple, and industrial production is facilitated.
Description
Technical field
The present invention relates to pharmacy field, be specifically related to Eliquis containing two crystal water
The preparation method of H2-2 crystal formation.
Background technology
Eliquis (Apixaban), chemical name: 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide, U.S. chemical abstract registration number CAS:503612-47-3, has the structural formula shown in following formula A; Eliquis is the direct inhibitor of the oral Ⅹ a factor of the 3rd approval listing, is developed jointly, for hip joint or the replacement knee in arthroplasty adult patients of selecting a time, to prevent venous thrombosis by Pfizer and Bristol Myers Squibb; Little and the multiple cancellation of possibility that is good due to its drug safety, drug interaction, is expected to the special population for suffering from hepatopathy or renal function damage.
In the document of current report, WO2003049681, US20060069258, WO2010030983, CN101967145, CN104045637 etc. disclose the preparation method of Eliquis and the preparation method of H2-2 crystal formation in succession, but the crystal form purity prepared is lower, the demand of people cannot be met.
Summary of the invention
The object of the invention is to for the deficiencies in the prior art, now provide one to prepare high
The preparation method of the H2-2 crystal formation containing two crystal water of the Eliquis of purity crystal formation.
For achieving the above object, technical scheme of the present invention is: the preparation method of the H2-2 crystal formation containing two crystal water of Eliquis, and its innovative point is: comprise the following steps:
(1) 100g Eliquis is placed in the DMF of 1L, is heated to 55 ~ 60 DEG C, fully stir until Eliquis dissolves completely;
(2) hot solution obtained in step (1) is instilled in 2L purified water, keep temperature to be no more than 30 DEG C;
(3) carry out naturally cooling after dripping off, then stir 1h, after stirring, then select Büchner funnel to filter;
(4) in clear water, clean twice by through filtering the filter cake obtained, gained solid adopts vacuum drying oven to carry out drying under reduced pressure and obtains H2-2 crystal 94-99g.
Further, the temperature in described step (2) is 20 ~ 30 DEG C.
Further, 15 ~ 25 DEG C are cooled in described step (3).
Beneficial effect of the present invention is as follows: the present invention is through dissolving, cooling, stir, filter and drying step, and complete the preparation of Eliquis H2-2 crystal formation, the crystal purity of gained is high, simple to operate, is conducive to factorial praluction.
Accompanying drawing explanation
Fig. 1 is the infrared spectra of H2-2 crystal formation of the present invention.
Fig. 2 is the X-grating spectrum of H2-2 crystal formation of the present invention.
Embodiment
By particular specific embodiment, embodiments of the present invention are described below, person skilled in the art scholar the content disclosed by this specification sheets can understand other advantages of the present invention and effect easily.
Embodiment 1
The preparation method of the H2-2 crystal formation containing two crystal water of Eliquis, comprises the following steps:
(1) 100g Eliquis is placed in the DMF of 1L, is heated to 55 DEG C, fully stir until Eliquis dissolves completely;
(2) instill in 2L purified water by the hot solution obtained in step (1), keep temperature to be no more than 30 DEG C, temperature is 20 DEG C;
(3) carry out naturally cooling after dripping off, be cooled to 15 DEG C, then stir 1h, after stirring, then select Büchner funnel to filter;
(4) in clear water, clean twice by through filtering the filter cake obtained, gained solid adopts vacuum drying oven to carry out drying under reduced pressure and obtains H2-2 crystal 94g.
The purity of the H2-2 crystal formation of the present embodiment gained is 94%.
Embodiment 2
The preparation method of the H2-2 crystal formation containing two crystal water of Eliquis, comprises the following steps:
(5) 100g Eliquis is placed in the DMF of 1L, is heated to 60 DEG C, fully stir until Eliquis dissolves completely;
(6) instill in 2L purified water by the hot solution obtained in step (5), keep temperature to be no more than 30 DEG C, temperature is 30 DEG C;
(7) carry out naturally cooling after dripping off, be cooled to 25 DEG C, then stir 1h, after stirring, then select Büchner funnel to filter;
(8) in clear water, clean twice by through filtering the filter cake obtained, gained solid adopts vacuum drying oven to carry out drying under reduced pressure and obtains H2-2 crystal 96g.
The purity of the H2-2 crystal formation of the present embodiment gained is 96%.
Embodiment 3
The preparation method of the H2-2 crystal formation containing two crystal water of Eliquis, comprises the following steps:
(9) 100g Eliquis is placed in the DMF of 1L, is heated to 57 DEG C, fully stir until Eliquis dissolves completely;
(10) instill in 2L purified water by the hot solution obtained in step (9), keep temperature to be no more than 30 DEG C, temperature is 25 DEG C;
(11) carry out naturally cooling after dripping off, be cooled to 20 DEG C, then stir 1h, after stirring, then select Büchner funnel to filter;
(12) in clear water, clean twice by through filtering the filter cake obtained, gained solid adopts vacuum drying oven to carry out drying under reduced pressure and obtains H2-2 crystal 99g.
The purity of the H2-2 crystal formation of the present embodiment gained is 99%; Fig. 1 is the infrared spectra of the present embodiment H2-2 crystal formation; Fig. 2 is the X-grating spectrum of the present embodiment H2-2 crystal formation.
The present invention is through dissolving, cooling, stir, filter and drying step, and complete the preparation of Eliquis H2-2 crystal formation, the crystal purity of gained is high, simple to operate, is conducive to factorial praluction.
Above-described embodiment is preferred embodiment of the present invention; it is not the restriction to technical solution of the present invention; as long as without the technical scheme that creative work can realize on the basis of above-described embodiment, all should be considered as falling within the scope of the rights protection of patent of the present invention.
Claims (3)
1. the preparation method of the H2-2 crystal formation containing two crystal water of Eliquis, is characterized in that: comprise the following steps:
(1) 100g Eliquis is placed in the DMF of 1L, is heated to 55 ~ 60 DEG C, fully stir until Eliquis dissolves completely;
(2) hot solution obtained in step (1) is instilled in 2L purified water, keep temperature to be no more than 30 DEG C;
(3) carry out naturally cooling after dripping off, then stir 1h, after stirring, then select Büchner funnel to filter;
(4) in clear water, clean twice by through filtering the filter cake obtained, gained solid adopts vacuum drying oven to carry out drying under reduced pressure and obtains H2-2 crystal 94-99g.
2. the preparation method of the H2-2 crystal formation containing two crystal water of Eliquis according to claim 1, is characterized in that: the temperature in described step (2) is 20 ~ 30 DEG C.
3. the preparation method of H2-2 crystal formation containing two crystal water of Eliquis according to claim 1, is characterized in that: be cooled to 15 ~ 25 DEG C in described step (3).
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510678092.3A CN105175415A (en) | 2015-10-20 | 2015-10-20 | Preparation method of two-crystal-water-containing H2-2 crystal form of Apixaban |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510678092.3A CN105175415A (en) | 2015-10-20 | 2015-10-20 | Preparation method of two-crystal-water-containing H2-2 crystal form of Apixaban |
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| CN105175415A true CN105175415A (en) | 2015-12-23 |
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| CN201510678092.3A Pending CN105175415A (en) | 2015-10-20 | 2015-10-20 | Preparation method of two-crystal-water-containing H2-2 crystal form of Apixaban |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021056850A1 (en) * | 2019-09-26 | 2021-04-01 | 浙江天宇药业股份有限公司 | Eutectic crystal formed by apixaban and carboxylic acid, and preparation method therefor |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101065379B (en) * | 2004-09-28 | 2011-05-11 | 布里斯托尔-迈尔斯斯奎布公司 | Process for preparing 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones |
| WO2012168364A1 (en) * | 2011-06-10 | 2012-12-13 | Dipharma Francis S.R.L. | Apixaban preparation process |
| WO2013174498A1 (en) * | 2012-05-24 | 2013-11-28 | Ratiopharm Gmbh | Dosage forms comprising apixaban and matrix former |
| CN104910147A (en) * | 2014-03-11 | 2015-09-16 | 北京万生药业有限责任公司 | Apixaban crystals and preparation methods thereof |
-
2015
- 2015-10-20 CN CN201510678092.3A patent/CN105175415A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101065379B (en) * | 2004-09-28 | 2011-05-11 | 布里斯托尔-迈尔斯斯奎布公司 | Process for preparing 4,5-dihydro-pyrazolo [3,4-c] pyrid-2-ones |
| WO2012168364A1 (en) * | 2011-06-10 | 2012-12-13 | Dipharma Francis S.R.L. | Apixaban preparation process |
| WO2013174498A1 (en) * | 2012-05-24 | 2013-11-28 | Ratiopharm Gmbh | Dosage forms comprising apixaban and matrix former |
| CN104910147A (en) * | 2014-03-11 | 2015-09-16 | 北京万生药业有限责任公司 | Apixaban crystals and preparation methods thereof |
Non-Patent Citations (3)
| Title |
|---|
| 何超等: "阿哌沙班的合成", 《中国医药工业杂志》 * |
| 王辉等: "阿哌沙班的合成新工艺", 《中国新药杂志》 * |
| 陶海燕等: "啊哌沙班的合成工艺研究", 《中国药物化学杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021056850A1 (en) * | 2019-09-26 | 2021-04-01 | 浙江天宇药业股份有限公司 | Eutectic crystal formed by apixaban and carboxylic acid, and preparation method therefor |
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Application publication date: 20151223 |