CN105017222B - A kind of preparation method of Imatinib impurity - Google Patents
A kind of preparation method of Imatinib impurity Download PDFInfo
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- CN105017222B CN105017222B CN201510387465.1A CN201510387465A CN105017222B CN 105017222 B CN105017222 B CN 105017222B CN 201510387465 A CN201510387465 A CN 201510387465A CN 105017222 B CN105017222 B CN 105017222B
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- imatinib
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- 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
- C07D401/14—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 three or more hetero rings
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Abstract
The invention discloses a kind of preparation method of Imatinib impurity.This method is with 1; 4 pairs of (4 carboxybenzyl) piperazines are raw material; in N; N DICs, 1 hydroxybenzotriazole, N; N diisopropylethylamine with Imatinib amine react under conditions of existing obtains double [4 [4 methyl 3 [[base of 4 (base of the pyridine 3) pyrimidine 2] amino] phenyl] carbamoyl] benzyl diethylenediamines of Imatinib impurity Isosorbide-5-Nitrae.The preparation method of the present invention is simple, and reaction condition requires low, and the purity of product is high, high income, suitable industrialized production.The impurity of synthesis can be used for the Qualitative and quantitative analysis of impurity, so as to improve the drug safety of Imatinib.
Description
Technical field
The invention belongs to pharmaceutical technology field, the impurity that more specifically to a kind of Imatinib preparation process is produced
Preparation method.
Background technology
Imatinib (Imatinib) is entitled " Gleevec " in Chinese commodity, and it is that one kind is developed by Novartis Co., Ltd of Switzerland
Sale, treats the oral drugs of the target medicines of cancer such as chronic myelogenous leukemia, gastrointestinal stromal tumors.The medicine in
Ratified by food and medicine Surveillance Authority of U.S. FDA within 2001, by 2011, the medicine ratified to be used to treat 10 not by FDA
Same cancer.Imatinib makes 10 years survival rates of chronic particulate cell leukaemic from former less than 50%, increase
Present 90% or so has been arrived, and most patients can be with normal work and life, therefore there are good market prospects.
In order to ensure the drug safety and quality of Imatinib, it is necessary to rigorous research is carried out to related impurity, by impurity control
System is within safety, rational limits.
Double [4- [4- methyl -3- [[4- (pyridin-3-yl) pyrimidines -2 base] amino] phenyl] carbamoyl] benzyls of 1,4-
Piperazine (popular at present to be referred to as Imatinib impurity E, hereafter by this referred to as), CAS：1365802-18-1, molecular formula：
C52H48N12O2, molecular weight：873.02；Chemical structural formula is as follows.
The generation of Imatinib impurity E, is due on the piperazine produced in the building-up process of Imatinib on two nitrogen
Hydrogen substituted product.Such a impurity is big due to molecular structure, and reaction raw materials precursor compound is allowed at two
An Imatinib amine can be connected in carboxylic acid molecules, therefore with very high technical difficulty in synthesis.Pass through Literature Consult
It was found that, the specific synthetic method without this compound of document report.
The content of the invention
The purpose of the present invention is that there is provided a kind of preparation side of the impurity for the blank of filling up in terms of Imatinib impurity E synthesis
Method.This method is without harsh reaction condition, and product purity is high, suitable industrialized production.The impurity E of synthesis can be used for impurity
Qualitative and quantitative analysis, so as to improve the drug safety of Imatinib.
Imatinib impurity E has very high technical difficulty in synthesis.By the conventional method of synthesizing amide, acyl chlorides is used
Corresponding impurity can not be accessed with Imatinib amine reaction.By the exploration of experiment we take will it is carboxylic acid activated after and Imatinib amine
Reaction has obtained impurity E.Reaction equation is as follows.
The technical scheme is that：A kind of preparation method of Imatinib impurity, it is characterized in that, it is with Isosorbide-5-Nitrae-bis-
(4- carboxybenzyls) piperazine (compound 4) is raw material, in N, N- DICs (DIC), I-hydroxybenzotriazole
(HOBT) with Imatinib amine (compound 5) react under conditions of, DIPEA (DIPEA) is present obtaining her horse and replacing
Buddhist nun's impurity E (double [4- [4- methyl -3- [[4- (pyridin-3-yl) pyrimidines -2 base] amino] phenyl] carbamoyl] benzyls of 1,4-
Piperazine).
The reaction dissolvent of the reaction is dimethyl sulfoxide (DMSO), acetonitrile, methanol, DMF, preferably dimethyl
Sulfoxide.
The mol ratio of the compound 4 and Imatinib amine is 1:2~3.
The use gauge with compound 4, N, the consumption of N- DICs is 0.5~0.8g/g；1- hydroxyls
The consumption of BTA is 0.5~0.8g/g；The consumption of N, N- diisopropylethylamine is 0.8~1.2g/g.
The reaction temperature is 35~80 DEG C.
The reaction time is preferably 7~15h.
The compound 4 can be prepared by the following：P-chloromethyl benzoic acid methyl esters (compound 1) is deposited in triethylamine
Under the conditions with piperazine (compound 2) react, then purifying obtain sterling Isosorbide-5-Nitrae-bis- (4- (methoxycarbonyl group) benzyls) piperazine (in
Mesosome 3)；Intermediate 3 obtains compound 4 by hydrolysis.
The method of the present invention specifically includes following steps：Compound 4 and reaction dissolvent are added in reaction vessel, 1- is added
DIPEA is added under hydroxybenzotriazole, N, N- DICs, stirring condition, heating is stirred to complete
Portion dissolves, and adds Imatinib amine constant temperature stirring reaction to no longer changing, is down to after room temperature, reaction solution is poured into frozen water, analyses
Go out yellow solid, suction filtration obtains yellow solid；The solid of gained is distributed in water, addition salt acid for adjusting pH to 3~5, suction filtration,
Dry, impurity E is obtained by methanol mashing.
The beneficial effects of the invention are as follows：The preparation method of the present invention is simple, and reaction condition requires low, and the purity of product is high,
High income, suitable industrialized production.The impurity E of synthesis can be used for the Qualitative and quantitative analysis of impurity, so as to improve
The drug safety of Imatinib.
Embodiment
Embodiment 1
26.0g p-chloromethyl benzoic acid methyl esters is dissolved in 400ml dichloromethane, 55g is added under stirring condition at room temperature
Triethylamine, is slowly added to 6.1g piperazines after finishing, back flow reaction 4h is to slowly warm up to after finishing.Cool, use 200ml pure respectively
Change be spin-dried for after washing system three times, anhydrous sodium sulfate drying, isolated 24g intermediates 3.25.2g sodium hydroxides are dissolved in
In 480ml water, 24g intermediates 3 are added, 60 DEG C of stirring reactions of heating to system dissolved clarification, regulation pH=2~3 separate out white solid,
Suction filtration is dried to obtain 19.2g compound 4, and the next step is carried out by purity 100%.
Embodiment 2
9.6g compounds 4 and 150ml dimethyl sulfoxide (DMSO)s are added in round-bottomed flask, I-hydroxybenzotriazole 6.6g is added,
DIPEA 10.5g is added under N, N- DIC 7.0g, stirring condition, 60 DEG C, stirring are warming up to
To whole dissolvings, 15.8g Imatinib amine constant temperature stirring reactions are added to no longer changing, is down to after room temperature, reaction solution is poured into
In frozen water, yellow solid is separated out, suction filtration obtains yellow solid.The solid of gained is distributed in water, salt acid for adjusting pH is added to 3
~5, suction filtration is dried.18.2g impurity Es, molar yield 76.8%, purity 96.4% are obtained by methanol mashing.
Embodiment 3
9.6g compounds 4 and 150ml dimethyl sulfoxide (DMSO)s are added in round-bottomed flask, I-hydroxybenzotriazole 4.8g is added,
DIPEA 8.6g is added under N, N- DIC 5.3g, stirring condition, 60 DEG C are warming up to, stirring is extremely
All dissolving, adds 17.8g Imatinib amine constant temperature stirring reactions to no longer changing, is down to room temperature, reaction solution is poured into frozen water
In, yellow solid is separated out, suction filtration obtains yellow solid.The solid of gained is distributed in water, salt acid for adjusting pH is added to 3~5,
Suction filtration, is dried.17.2g impurity Es, molar yield 72.6%, purity 96.1% are obtained by methanol mashing.
Embodiment 4
9.6g compounds 4 and 150ml dimethyl sulfoxide (DMSO)s are added in round-bottomed flask, I-hydroxybenzotriazole 6.6g is added,
DIPEA 10.5g is added under N, N- DIC 7.0g, stirring condition, 60 DEG C, stirring are warming up to
To whole dissolvings, 17.8g Imatinib amine constant temperature stirring reactions are added to no longer changing, room temperature is down to, reaction solution is poured into ice
In water, yellow solid is separated out, suction filtration obtains yellow solid.The solid of gained is distributed in water, addition salt acid for adjusting pH to 3~
5, suction filtration is dried.18.8g impurity Es, molar yield 79.6%, purity 98.4% are obtained by methanol mashing.
The spectral data of impurity E, MS-API：(M+2H)/2=437；1H NMR (600MHz, DMSO)：10.389 (s,
2H), 9.498 (s, 2H), 9.240 (s, 2H), 9.077 (d, J=8.4Hz, 2H), 8.955 (d, J=4.8Hz, 2H), 8.634
(d, J=5.4Hz, 2H), 8.166 (s, 2H), 8.078-8.025 (m, 6H), 7.828 (d, J=7.2Hz, 4H), 7.599 (d, J
=4.8Hz, 2H), 7.479 (d, J=7.8Hz, 2H), 7.236 (d, J=2.4,2H), 4.510 (s, 4H), 3.764-3.556
(m, 8H), 2.241 (s, 6H).
Claims (10)
1. a kind of preparation method of Imatinib impurity, it is characterized in that, it be using Isosorbide-5-Nitrae-bis- (4- carboxybenzyls) piperazine as raw material,
In N, N- DICs, I-hydroxybenzotriazole, DIPEA enter under conditions of existing with Imatinib amine
Row reaction obtains double [4- [4- methyl -3- [[4- (pyridin-3-yl) pyrimidines -2 base] amino] phenyl] ammonia of Imatinib impurity 1,4-
Base formoxyl] benzyl diethylenediamine.
2. a kind of preparation method of Imatinib impurity as claimed in claim 1, it is characterized in that, the reaction dissolvent of the reaction
For dimethyl sulfoxide (DMSO), acetonitrile, methanol, N,N-dimethylformamide.
3. a kind of preparation method of Imatinib impurity as claimed in claim 2, it is characterized in that, the reaction dissolvent of the reaction
For dimethyl sulfoxide (DMSO).
4. a kind of preparation method of Imatinib impurity as claimed in claim 1, it is characterized in that, the Isosorbide-5-Nitrae-bis- (4- carboxyls
Benzyl) mol ratio of piperazine and Imatinib amine is 1:2~3.
5. a kind of preparation method of Imatinib impurity as claimed in claim 1, it is characterized in that, it is described with Isosorbide-5-Nitrae-bis- (4- carboxylics
Base benzyl) piperazine use gauge, N, the consumption of N- DICs is 0.5~0.8g/g.
6. a kind of preparation method of Imatinib impurity as claimed in claim 1, it is characterized in that, it is described with Isosorbide-5-Nitrae-bis- (4- carboxylics
Base benzyl) piperazine use gauge, the consumption of I-hydroxybenzotriazole is 0.5~0.8g/g.
7. a kind of preparation method of Imatinib impurity as claimed in claim 1, it is characterized in that, it is described with Isosorbide-5-Nitrae-bis- (4- carboxylics
Base benzyl) piperazine use gauge, the consumption of DIPEA is 0.8~1.2g/g.
8. a kind of preparation method of Imatinib impurity as claimed in claim 1, it is characterized in that, the reaction temperature is 35~
80℃。
9. a kind of preparation method of Imatinib impurity as claimed in claim 1, it is characterized in that, the reaction time is 7~
15h。
10. a kind of preparation method of Imatinib impurity as described in any one in claim 1-9, it is characterized in that, it is described
Double (4- carboxybenzyls) piperazines of 1,4- are prepared by the following：P-chloromethyl benzoic acid methyl esters is under conditions of triethylamine presence
Reacted with piperazine, then purifying obtains sterling Isosorbide-5-Nitrae-bis- (4- (methoxycarbonyl group) benzyls) piperazine；Double (4- (methoxycarbonyl group) benzyls of 1,4-
Base) piperazine obtains double (4- carboxybenzyls) piperazines of 1,4- by hydrolysis.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010133976A2 (en) * | 2009-05-22 | 2010-11-25 | Actavis Group Ptc Ehf | Substantially pure imatinib or a pharmaceutically acceptable salt thereof |
| WO2011095835A1 (en) * | 2010-02-02 | 2011-08-11 | Actavis Group Ptc Ehf | Highly pure imatinib or a pharmaceutically acceptable salt thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9439903B2 (en) * | 2012-10-25 | 2016-09-13 | Cadila Healthcare Limited | Process for the preparation of amorphous imatinib mesylate |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010133976A2 (en) * | 2009-05-22 | 2010-11-25 | Actavis Group Ptc Ehf | Substantially pure imatinib or a pharmaceutically acceptable salt thereof |
| WO2011095835A1 (en) * | 2010-02-02 | 2011-08-11 | Actavis Group Ptc Ehf | Highly pure imatinib or a pharmaceutically acceptable salt thereof |
Non-Patent Citations (2)
| Title |
|---|
| Identification of imatinib mesylate degradation products obtained under stress conditions;W.J. Szczepek et.al.;《Journal of Pharmaceutical and Biomedical Analysis》;20070112;第43卷;1682–1691 * |
| 甲磺酸伊马替尼有关物质的合成;吴立红等;《中国医药工业杂志》;20111123;第42卷(第11期);第730页图4，第729页图2，第731页右栏第2-3段 * |
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Effective date of registration: 20200302 Address after: No. 10678, Wenliang Road, Dongjia street, Licheng District, Jinan City, Shandong Province Patentee after: Shandong Anxin Pharmaceutical Co., Ltd Address before: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Patentee before: QILU TIANHE PHARMACEUTICAL Co.,Ltd. |
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