CN105017222A - Preparation method of imatinib impurity - Google Patents
Preparation method of imatinib impurity Download PDFInfo
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- CN105017222A CN105017222A CN201510387465.1A CN201510387465A CN105017222A CN 105017222 A CN105017222 A CN 105017222A CN 201510387465 A CN201510387465 A CN 201510387465A CN 105017222 A CN105017222 A CN 105017222A
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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 preparation method of an imatinib impurity. The preparation method comprises: using 1,4-bi(4-carboxybenzyl)piperazine as a raw material, and at presence of N,N- diisopropylcarbodiimide, 1-hydroxy benzotriazole and N,N-diisopropylethylamine, reacting with imaamine to obtain the imatinib impurity 1,4-bi[4-[4-methyl-3-[[4-(pyridine-3-group)pyrimidyl-2group]amino]phenyl]carbamoyl radical]benzyl piperazine. The preparation method provided by the invention is simple, low in requirement on reaction conditions, high in product purity, high in yield, and suitable for industrial production. The synthesized impurity can be used for qualitative and quantitative analysis of the impurity, thus improving drug safety of the imatinib.
Description
Technical field
The invention belongs to medical art, relate to the preparation method of the impurity that a kind of imatinib preparation process produces in particular.
Background technology
Imatinib (Imatinib) is called " imatinib mesylate " in Chinese commodity name, and it is that a kind of development by Novartis Co., Ltd of Switzerland is sold, the oral pharmaceutical of the target medicine of cancer such as treatment chronic lymphocytic leukemia, gastrointestinal stromal tumors etc.This medicine is ratified in calendar year 2001 by U.S. food Drug Administration FDA, and by 2011, this medicine was used for the treatment of 10 different cancers by FDA approval.Imatinib make 10 years survival rates of chronic particulate cell leukaemic from before less than 50%, increase present about 90%, and most patient can normally work and live, and therefore has good market outlook.In order to ensure drug safety and the quality of imatinib, with regard to needing, rigorous research is carried out to relevant impurity, by Control of Impurities within safety, reasonably limits.
1; 4-two [4-[4-methyl-3-[[4-(pyridin-3-yl) pyrimidine-2 base] is amino] phenyl] formamyl] benzyl diethylenediamine (is popularly at present called imatinib impurity E; hereafter be called for short by this), CAS:1365802-18-1, molecular formula: C
52h
48n
12o
2, molecular weight: 873.02; Chemical structural formula is as follows.
The generation of imatinib impurity E is the product that the hydrogen on the piperazine owing to producing in the building-up process of imatinib on two nitrogen is all substituted.This kind of impurity due to molecular structure large, and reaction raw materials precursor compound must all can connect her horse amine in two carboxylic acid molecules, therefore on synthesizing, has very high technical difficulty.Found there is no the concrete synthetic method of this compound of bibliographical information by Literature Consult.
Summary of the invention
The object of the invention is the blank filling up imatinib impurity E synthesis aspect, a kind of preparation method of this impurity is provided.The method is without the need to the reaction conditions of harshness, and product purity is high, and suitability for industrialized is produced.The impurity E of synthesis may be used for the Qualitative and quantitative analysis of impurity, thus can improve the drug safety of imatinib.
Imatinib impurity E has very high technical difficulty in synthesis.By the general method of synthesizing amide, to react with her horse amine with acyl chlorides and can not obtain corresponding impurity.Exploration by experiment we take to be obtained by reacting impurity E with her horse amine after carboxylic acid activated.Reaction equation is as follows.
Technical scheme of the present invention is: a kind of preparation method of imatinib impurity, it is characterized in that, it is with 1, two (4-carboxybenzyl) piperazine (compound 4) of 4-is raw material, at N, N-DIC (DIC), I-hydroxybenzotriazole (HOBT), N, carry out being obtained by reacting imatinib impurity E (1 with her horse amine (compound 5) under N-diisopropylethylamine (DIPEA) existent condition, 4-two [4-[4-methyl-3-[[4-(pyridin-3-yl) pyrimidine-2 base] is amino] phenyl] formamyl] benzyl diethylenediamine).
The reaction solvent of described reaction is dimethyl sulfoxide (DMSO), acetonitrile, methyl alcohol, DMF, preferred dimethyl sulfoxide (DMSO).
Described compound 4 is 1:2 ~ 3 with the mol ratio of her horse amine.
Described with the use gauge of compound 4, the consumption of N, N-DIC is 0.5 ~ 0.8g/g; The consumption of I-hydroxybenzotriazole is 0.5 ~ 0.8g/g; The consumption of DIPEA is 0.8 ~ 1.2g/g.
Described temperature of reaction is 35 ~ 80 DEG C.
The described reaction times is preferably 7 ~ 15h.
Described compound 4 can obtain by the following method: p-chloromethyl benzoic acid methyl esters (compound 1) reacts with piperazine (compound 2) under triethylamine existent condition, then purifying obtains sterling Isosorbide-5-Nitrae-bis-(4-(methoxycarbonyl) benzyl) piperazine (intermediate 3); Intermediate 3 obtains compound 4 by hydrolysis.
Method of the present invention specifically comprises the following steps: add in reaction vessel by compound 4 and reaction solvent, add I-hydroxybenzotriazole, N, N-DIC, N is added under agitation condition, N-diisopropylethylamine, heats up and is stirred to whole dissolving, then adds her horse amine constant temperature stirring reaction to no longer changing, after being down to room temperature, be poured into by reaction solution in frozen water, separate out yellow solid, suction filtration obtains yellow solid; By the solid dispersal of gained in water, add salt acid for adjusting pH to 3 ~ 5, suction filtration, dry, obtain impurity E by methyl alcohol making beating.
The invention has the beneficial effects as follows: preparation method of the present invention is simple, reaction conditions requires low, and the purity of product is high, and yield is high, and suitability for industrialized is produced.The impurity E of synthesis may be used for the Qualitative and quantitative analysis of impurity, thus can improve the drug safety of imatinib.
Embodiment
Embodiment 1
26.0g p-chloromethyl benzoic acid methyl esters is dissolved in 400ml methylene dichloride, under stirred at ambient temperature condition, adds 55g triethylamine, after finishing, slowly add 6.1g piperazine, finish and be slowly warming up to back flow reaction 4h afterwards.Cooling, purify with 200ml and wash system three times, be spin-dried for after anhydrous sodium sulfate drying, be separated and obtain 24g intermediate 3 respectively.Be dissolved in 480ml water by 25.2g sodium hydroxide, add 24g intermediate 3, the 60 DEG C of stirring reactions that heat up are clearly molten to system, regulate pH=2 ~ 3 to separate out white solid, and suction filtration drying obtains the compound 4 of 19.2g, carries out the next step by purity 100%.
Embodiment 2
9.6g compound 4 and 150ml dimethyl sulfoxide (DMSO) are added in round-bottomed flask, adds I-hydroxybenzotriazole 6.6g, N, N-DIC 7.0g, add DIPEA 10.5g under agitation condition, be warming up to 60 DEG C, be stirred to whole dissolving, add her horse amine constant temperature stirring reaction of 15.8g more extremely no longer to change, after being down to room temperature, reaction solution is poured in frozen water, separate out yellow solid, suction filtration obtains yellow solid.By the solid dispersal of gained in water, add salt acid for adjusting pH to 3 ~ 5, suction filtration, dry.18.2g impurity E is obtained, molar yield 76.8%, purity 96.4% by methyl alcohol making beating.
Embodiment 3
9.6g compound 4 and 150ml dimethyl sulfoxide (DMSO) are added in round-bottomed flask, adds I-hydroxybenzotriazole 4.8g, N, N-DIC 5.3g, add DIPEA 8.6g under agitation condition, be warming up to 60 DEG C, be stirred to whole dissolving, add her horse amine constant temperature stirring reaction of 17.8g more extremely no longer to change, be down to room temperature, reaction solution be poured in frozen water, separate out yellow solid, suction filtration obtains yellow solid.By the solid dispersal of gained in water, add salt acid for adjusting pH to 3 ~ 5, suction filtration, dry.17.2g impurity E is obtained, molar yield 72.6%, purity 96.1% by methyl alcohol making beating.
Embodiment 4
9.6g compound 4 and 150ml dimethyl sulfoxide (DMSO) are added in round-bottomed flask, adds I-hydroxybenzotriazole 6.6g, N, N-DIC 7.0g, add DIPEA 10.5g under agitation condition, be warming up to 60 DEG C, be stirred to whole dissolving, add her horse amine constant temperature stirring reaction of 17.8g more extremely no longer to change, be down to room temperature, reaction solution be poured in frozen water, separate out yellow solid, suction filtration obtains yellow solid.By the solid dispersal of gained in water, add salt acid for adjusting pH to 3 ~ 5, suction filtration, dry.18.8g impurity E is obtained, molar yield 79.6%, purity 98.4% by methyl alcohol making beating.
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. the preparation method of an imatinib impurity; it is characterized in that; it is with 1; two (4-carboxybenzyl) piperazine of 4-is raw material; at N; carry out with her horse amine under N-DIC, I-hydroxybenzotriazole, DIPEA existent condition being obtained by reacting imatinib impurity Isosorbide-5-Nitrae-bis-[4-[4-methyl-3-[[4-(pyridin-3-yl) pyrimidine-2 base] is amino] phenyl] formamyl] benzyl diethylenediamine.
2. the preparation method of a kind of imatinib impurity as claimed in claim 1, is characterized in that, the reaction solvent of described reaction is dimethyl sulfoxide (DMSO), acetonitrile, methyl alcohol, DMF.
3. the preparation method of a kind of imatinib impurity as claimed in claim 2, is characterized in that, the reaction solvent of described reaction is dimethyl sulfoxide (DMSO).
4. the preparation method of a kind of imatinib impurity as claimed in claim 1, is characterized in that, the mol ratio of described Isosorbide-5-Nitrae-bis-(4-carboxybenzyl) piperazine and her horse amine is 1:2 ~ 3.
5. the preparation method of a kind of imatinib impurity as claimed in claim 1, is characterized in that, described with the use gauge of Isosorbide-5-Nitrae-bis-(4-carboxybenzyl) piperazine, the consumption of N, N-DIC is 0.5 ~ 0.8g/g.
6. the preparation method of a kind of imatinib impurity as claimed in claim 1, is characterized in that, described with the use gauge of Isosorbide-5-Nitrae-bis-(4-carboxybenzyl) piperazine, the consumption of I-hydroxybenzotriazole is 0.5 ~ 0.8g/g.
7. the preparation method of a kind of imatinib impurity as claimed in claim 1, is characterized in that, described with the use gauge of Isosorbide-5-Nitrae-bis-(4-carboxybenzyl) piperazine, the consumption of DIPEA is 0.8 ~ 1.2g/g.
8. the preparation method of a kind of imatinib impurity as claimed in claim 1, is characterized in that, described temperature of reaction is 35 ~ 80 DEG C.
9. the preparation method of a kind of imatinib impurity as claimed in claim 1, is characterized in that, the described reaction times is 7 ~ 15h.
10. as the preparation method of a kind of imatinib impurity in claim 1-9 as described in any one, it is characterized in that, described 1, two (4-carboxybenzyl) piperazine of 4-obtains by the following method: p-chloromethyl benzoic acid methyl esters reacts with piperazine under triethylamine existent condition, then purifying obtains sterling Isosorbide-5-Nitrae-bis-(4-(methoxycarbonyl) benzyl) piperazine; Isosorbide-5-Nitrae-bis-(4-(methoxycarbonyl) benzyl) piperazine obtains Isosorbide-5-Nitrae-bis-(4-carboxybenzyl) piperazine by hydrolysis.
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| CN201510387465.1A CN105017222B (en) | 2015-07-03 | 2015-07-03 | A kind of preparation method of Imatinib impurity |
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Citations (3)
| 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 |
| US20140121215A1 (en) * | 2012-10-25 | 2014-05-01 | Cadila Healthcare Limited | Process for the preparation of amorphous imatinib mesylate |
-
2015
- 2015-07-03 CN CN201510387465.1A patent/CN105017222B/en active Active
Patent Citations (3)
| 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 |
| US20140121215A1 (en) * | 2012-10-25 | 2014-05-01 | Cadila Healthcare Limited | Process for the preparation of amorphous imatinib mesylate |
Non-Patent Citations (2)
| Title |
|---|
| W.J. SZCZEPEK ET.AL.: "Identification of imatinib mesylate degradation products obtained under stress conditions", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 * |
| 吴立红等: "甲磺酸伊马替尼有关物质的合成", 《中国医药工业杂志》 * |
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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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