CN110256341A - A kind of pleasure is cut down for the preparation method of Buddhist nun's Mesylate Form C - Google Patents
A kind of pleasure is cut down for the preparation method of Buddhist nun's Mesylate Form C Download PDFInfo
- Publication number
- CN110256341A CN110256341A CN201910564696.3A CN201910564696A CN110256341A CN 110256341 A CN110256341 A CN 110256341A CN 201910564696 A CN201910564696 A CN 201910564696A CN 110256341 A CN110256341 A CN 110256341A
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- CN
- China
- Prior art keywords
- buddhist nun
- pleasure
- mesylate form
- cut down
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- 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
Abstract
The present invention relates to pleasures to cut down for the preparation method of Buddhist nun's Mesylate Form C, 4- (3- chloro- 4- (cyclopropylaminocarbonyl) amino-benzene oxygen) -7- methoxyl group -6- quinolinecarboxamideas and methanesulfonic acid are reacted in specific organic solvent into salt, cooling stirs to get crystal form C.The method disclosed by the invention for preparing crystal form C, easy to operate, technique favorable reproducibility, to commercially producing with important value for the drug.
Description
Technical field:
The present invention relates to field of pharmaceutical chemistry technology, and in particular to a kind of pleasure is cut down for the preparation side of Buddhist nun's Mesylate Form C
Method.
Background technique:
Happy cut down for Buddhist nun's (Lenvatinib, trade name: Lenvima) is a kind of oral polyceptor tyrosine kinase (RTK) suppression
Preparation has novel binding pattern, except other Angiogensis that inhibition participates in tumor proliferation are related to oncogenic signals access
Outside RTK, additionally it is possible to the kinase activity of selective depression vascular endothelial growth factor (VEGF) receptor.Pleasure is cut down for Buddhist nun in 2015 2
The acquisition U.S. FDA approval of the moon 13 has advanced, the patient of differentiated thyroid carcinoma for treating.Chemical name are as follows: 4- [3-
Chloro- 4- (cyclopropylaminocarbonyl) amino-benzene oxygen] -7- methoxyl group -6- quinolinecarboxamideas, structural formula such as Formulas I:
Listing used in granted drug is that pleasure is cut down for Buddhist nun's mesylate, and patent WO2005063713 (A1) is disclosed
Happy crystal form A, B, C, F, I and happy crystal form α, β cut down for Buddhist nun's esilate cut down for Buddhist nun's mesylate.
This patent reports 4 kinds of preparation methods of crystal form C:
Method (1), by 4- (3- chloro- 4- (cyclopropylaminocarbonyl) amino-benzene oxygen) -7- methoxyl group -6- quinolinecarboxamideas
Mesylate dimethyl sulfoxide closes in object crystallization and n-butyl acetate is added, and stirring and crystallizing obtains crystal form C；Method (2), by 4- (3-
Chloro- 4- (cyclopropylaminocarbonyl) amino-benzene oxygen) -7- methoxyl group -6- quinolinecarboxamideas mesylate acetic acid close object in be added
Ethyl alcohol obtains crystal form C after needing to stir 36h；Method (3), by 4- (3- chloro- 4- (cyclopropylaminocarbonyl) amino-benzene oxygen)-
7- methoxyl group -6- quinolinecarboxamideas is added acetic acid and mixes with methanesulfonic acid, needs to be added crystal form C (crystal seed) and acetic acid after dissolution
Isopropyl ester etc. needs repeatedly to adjust temperature in preparation process, and different solvents etc. are repeatedly added；Method (4), by 4- (the chloro- 4- of 3-
(cyclopropylaminocarbonyl) amino-benzene oxygen) acetic acid mixing is added in -7- methoxyl group -6- quinolinecarboxamideas, then first is added thereto
2- propyl alcohol is added in sulfonic acid thereto after dissolution, and crystal form C (crystal seed) is added, and 14 addition 2- propyl alcohol, mistake are divided in subsequent process
Filter, agitation and filtration dries to obtain crystal form C in ethyl alcohol after washing.
The preparation process of the crystal form C of the patent report is lengthy and tedious, and reaction process is more difficult to control, technique is not easy to repeat, and is easy hair
The problems such as raw mixed crystal phenomenon, there are stirring and crystallizing overlong times.Therefore it is significantly limited in course of industrialization, no
Large-scale production and drug safety conducive to crystal form C.
Summary of the invention:
In view of the above-mentioned deficiencies in the prior art, it is an object of the present invention to which it is simple to provide a kind of preparation process, it is more suitable for industrializing
The pleasure of production is cut down for the preparation method of Buddhist nun's Mesylate Form C.
Pleasure provided by the invention is cut down for the preparation method of Buddhist nun's Mesylate Form C, it is characterised in that: the 4- (chloro- 4- (ring of 3-
Propylaminocarbonyl) amino-benzene oxygen) -7- methoxyl group -6- quinolinecarboxamideas and methanesulfonic acid reacted in specific organic solvent at
Salt obtains pleasure and cuts down for Buddhist nun's Mesylate Form C.
Further, by 4- (3- chloro- 4- (cyclopropylaminocarbonyl) amino-benzene oxygen) -7- methoxyl group -6- quinolinecarboxamideas
It is added in specific organic solvent, is heated to 40~55 DEG C, methanesulfonic acid is added and stirs into salt, cool to 0~10 DEG C, filtration drying,
Pleasure is obtained to cut down for Buddhist nun's Mesylate Form C.
Further, the specific organic solvent is selected from methanol, ethyl alcohol, 2- methyltetrahydrofuran, acetone, acetonitrile, acetic acid
Ethyl ester, isopropyl acetate, glycol dimethyl ether or their mixture, preferred alcohol.
The beneficial effects of the present invention are preparation provided by the invention pleasures to cut down for the method for Buddhist nun's Mesylate Form C, technique
Refining effect is significant, easy to operate, can steadily obtain target crystal form, low in cost, the optimization and exploitation to the following drug
With important value.
Detailed description of the invention
Pleasure prepared by Fig. 1 embodiment 1 cuts down the X-ray powder diffraction figure (XPRD) for Buddhist nun's Mesylate Form C
Pleasure prepared by Fig. 2 embodiment 2 cuts down the X-ray powder diffraction figure (XPRD) for Buddhist nun's Mesylate Form C
Pleasure prepared by Fig. 3 embodiment 3 cuts down the X-ray powder diffraction figure (XPRD) for Buddhist nun's Mesylate Form C
Pleasure prepared by Fig. 4 embodiment 4 cuts down the X-ray powder diffraction figure (XPRD) for Buddhist nun's Mesylate Form C
Pleasure prepared by Fig. 5 embodiment 5 cuts down the X-ray powder diffraction figure (XPRD) for Buddhist nun's Mesylate Form C
Pleasure prepared by Fig. 6 embodiment 6 cuts down the X-ray powder diffraction figure (XPRD) for Buddhist nun's Mesylate Form C
Pleasure prepared by Fig. 7 embodiment 7 cuts down the X-ray powder diffraction figure (XPRD) for Buddhist nun's Mesylate Form C
Specific embodiment
Technology contents of the invention are further elaborated combined with specific embodiments below, its purpose is to better
Understand the contents of the present invention, but the scope of the present invention is not limited thereto.
Embodiment 1
At room temperature by 1.0g 4- (3- chloro- 4- (cyclopropylaminocarbonyl) amino-benzene oxygen) -7- methoxyl group -6- quinoline carboxylic
Amide and 10mL ethyl alcohol are added in reaction flask, are heated to 50 DEG C.0.24g methanesulfonic acid is added dropwise in reaction solution and stirs 1h.Drop
Temperature is filtered to 0~10 DEG C, dry, is obtained pleasure and is cut down for the crystallization 1.13g of Buddhist nun's Mesylate Form C.
Embodiment 2
At room temperature by 10g 4- (3- chloro- 4- (cyclopropylaminocarbonyl) amino-benzene oxygen) -7- methoxyl group -6- quinoline carboxylic acyl
Amine and 100mL ethyl alcohol are added in reaction flask, are heated to 55 DEG C.2.4g methanesulfonic acid is added dropwise in reaction solution and stirs 1h.Cooling
To 0~10 DEG C, filter, it is dry, it obtains pleasure and cuts down for the crystallization 11.6g of Buddhist nun's Mesylate Form C.
Embodiment 3
At room temperature by 10g 4- (3- chloro- 4- (cyclopropylaminocarbonyl) amino-benzene oxygen) -7- methoxyl group -6- quinoline carboxylic acyl
Amine and 100mL methanol are added in reaction flask, are heated to 45 DEG C.2.4g methanesulfonic acid is added dropwise in reaction solution and stirs 1h.Cooling
To 0~10 DEG C, filter, it is dry, it obtains pleasure and cuts down for the crystallization 10.1g of Buddhist nun's Mesylate Form C.
Embodiment 4
At room temperature by 1.0g 4- (3- chloro- 4- (cyclopropylaminocarbonyl) amino-benzene oxygen) -7- methoxyl group -6- quinoline carboxylic
Amide and 100mL methyltetrahydrofuran are added in reaction flask, are heated to 50 DEG C.2.4g methanesulfonic acid is added dropwise in reaction solution and is stirred
Mix 1h.It is cooled to 0~10 DEG C, is filtered, it is dry, it obtains pleasure and cuts down for the crystallization 12.5g of Buddhist nun's Mesylate Form C.
Embodiment 5
At room temperature by 10g 4- (3- chloro- 4- (cyclopropylaminocarbonyl) amino-benzene oxygen) -7- methoxyl group -6- quinoline carboxylic acyl
Amine and 100mL acetone are added in reaction flask, are heated to 50 DEG C.2.4g methanesulfonic acid is added dropwise in reaction solution and stirs 0.5h.Drop
Temperature is filtered to 0~10 DEG C, dry, is obtained pleasure and is cut down for the crystallization 11.1g of Buddhist nun's Mesylate Form C.
Embodiment 6
At room temperature by 10g 4- (3- chloro- 4- (cyclopropylaminocarbonyl) amino-benzene oxygen) -7- methoxyl group -6- quinoline carboxylic acyl
Amine and 100mL ethyl acetate are added in reaction flask, are heated to 50 DEG C.2.4g methanesulfonic acid is added dropwise in reaction solution and is stirred
0.5h.It is cooled to 0~10 DEG C, is filtered, it is dry, it obtains pleasure and cuts down for the crystallization 11.5g of Buddhist nun's Mesylate Form C.
Embodiment 7
At room temperature by 10g 4- (3- chloro- 4- (cyclopropylaminocarbonyl) amino-benzene oxygen) -7- methoxyl group -6- quinoline carboxylic acyl
Amine and 100mL isopropyl acetate are added in reaction flask, are heated to 50 DEG C.2.4g methanesulfonic acid is added dropwise in reaction solution and is stirred
0.5h.It is cooled to 0~10 DEG C, is filtered, it is dry, it obtains pleasure and cuts down for the crystallization 11.4g of Buddhist nun's Mesylate Form C.
Claims (2)
1. a kind of pleasure is cut down for the preparation method of Buddhist nun's Mesylate Form C, it is characterised in that: 4- (3- chloro- 4- (cyclopropylamino carbonyl
Base) amino-benzene oxygen) -7- methoxyl group -6- quinolinecarboxamideas and methanesulfonic acid react in specific organic solvent and obtain pleasure at salt and cut down
For Buddhist nun's Mesylate Form C, the specific organic solvent be selected from methanol, ethyl alcohol, 2- methyltetrahydrofuran, acetone, acetonitrile,
Ethyl acetate, isopropyl acetate, glycol dimethyl ether or their mixture.
2. preparation method as described in claim 1, which is characterized in that by 4- (3- chloro- 4- (cyclopropylaminocarbonyl) aminobenzene
Oxygroup) -7- methoxyl group -6- quinolinecarboxamideas is added in specific organic solvent, is heated to 40~55 DEG C, methanesulfonic acid is added and stirs into
Salt, cools to 0~10 DEG C, and filtration drying obtains pleasure and cuts down for Buddhist nun's Mesylate Form C.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910564696.3A CN110256341A (en) | 2019-06-27 | 2019-06-27 | A kind of pleasure is cut down for the preparation method of Buddhist nun's Mesylate Form C |
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| CN201910564696.3A CN110256341A (en) | 2019-06-27 | 2019-06-27 | A kind of pleasure is cut down for the preparation method of Buddhist nun's Mesylate Form C |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113999173A (en) * | 2020-07-28 | 2022-02-01 | 药源药物化学（上海）有限公司 | Preparation method of high-purity crystal |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1890220A (en) * | 2003-12-25 | 2007-01-03 | 卫材株式会社 | A crystalline of the salt form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide or the solvate of the salt and a process for preparing the same |
| WO2018196687A1 (en) * | 2017-04-25 | 2018-11-01 | 苏州科睿思制药有限公司 | New crystal form of lenvatinib methanesulfonate and preparation method thereof |
| CN109867626A (en) * | 2019-04-18 | 2019-06-11 | 安礼特（上海）医药科技有限公司 | A kind of methanesulfonic acid logical sequence is cut down for Buddhist nun's polymorph and preparation method thereof |
| WO2019111283A1 (en) * | 2017-12-09 | 2019-06-13 | Msn Laboratories Private Limited, R&D Center | Novel polymorphs of 4-[3-chloro-4-(n'-cyclopropyl ureido)phenoxy]-7-methoxyquinoline-6-carboxamide, its salts and process for the preparation thereof |
| CN111689897A (en) * | 2019-03-13 | 2020-09-22 | 齐鲁制药有限公司 | Preparation method of high-purity Levatinib mesylate crystal form C |
-
2019
- 2019-06-27 CN CN201910564696.3A patent/CN110256341A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1890220A (en) * | 2003-12-25 | 2007-01-03 | 卫材株式会社 | A crystalline of the salt form of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide or the solvate of the salt and a process for preparing the same |
| WO2018196687A1 (en) * | 2017-04-25 | 2018-11-01 | 苏州科睿思制药有限公司 | New crystal form of lenvatinib methanesulfonate and preparation method thereof |
| WO2019111283A1 (en) * | 2017-12-09 | 2019-06-13 | Msn Laboratories Private Limited, R&D Center | Novel polymorphs of 4-[3-chloro-4-(n'-cyclopropyl ureido)phenoxy]-7-methoxyquinoline-6-carboxamide, its salts and process for the preparation thereof |
| CN111689897A (en) * | 2019-03-13 | 2020-09-22 | 齐鲁制药有限公司 | Preparation method of high-purity Levatinib mesylate crystal form C |
| CN109867626A (en) * | 2019-04-18 | 2019-06-11 | 安礼特（上海）医药科技有限公司 | A kind of methanesulfonic acid logical sequence is cut down for Buddhist nun's polymorph and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113999173A (en) * | 2020-07-28 | 2022-02-01 | 药源药物化学（上海）有限公司 | Preparation method of high-purity crystal |
| WO2022022367A1 (en) * | 2020-07-28 | 2022-02-03 | 药源药物化学（上海）有限公司 | Method for preparing high-purity crystal |
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Application publication date: 20190920 |