CN102146073A - New preparation method of alpha crystal form of imatinib mesylate - Google Patents
New preparation method of alpha crystal form of imatinib mesylate Download PDFInfo
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- CN102146073A CN102146073A CN2011100441918A CN201110044191A CN102146073A CN 102146073 A CN102146073 A CN 102146073A CN 2011100441918 A CN2011100441918 A CN 2011100441918A CN 201110044191 A CN201110044191 A CN 201110044191A CN 102146073 A CN102146073 A CN 102146073A
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- mixed solvent
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- 239000013078 crystal Substances 0.000 title claims abstract description 61
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 229960003685 imatinib mesylate Drugs 0.000 title abstract 3
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 title abstract 3
- 239000012046 mixed solvent Substances 0.000 claims abstract description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000003960 organic solvent Substances 0.000 claims abstract description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 98
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 87
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 57
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims description 41
- 150000002576 ketones Chemical class 0.000 claims description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 29
- 150000002148 esters Chemical class 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 13
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 12
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- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 11
- 238000001291 vacuum drying Methods 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 9
- 230000008025 crystallization Effects 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 8
- 238000012423 maintenance Methods 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
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- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 6
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- 150000002191 fatty alcohols Chemical class 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 claims description 4
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- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 3
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 3
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 3
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 3
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 3
- 229940090181 propyl acetate Drugs 0.000 claims description 3
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 12
- 239000005517 L01XE01 - Imatinib Substances 0.000 abstract 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 abstract 1
- 229960002411 imatinib Drugs 0.000 abstract 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 abstract 1
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- RGFNRWTWDWVHDD-UHFFFAOYSA-N isobutyl butyrate Chemical compound CCCC(=O)OCC(C)C RGFNRWTWDWVHDD-UHFFFAOYSA-N 0.000 description 3
- JSLCOZYBKYHZNL-UHFFFAOYSA-N isobutyric acid butyl ester Natural products CCCCOC(=O)C(C)C JSLCOZYBKYHZNL-UHFFFAOYSA-N 0.000 description 3
- WDAXFOBOLVPGLV-UHFFFAOYSA-N isobutyric acid ethyl ester Natural products CCOC(=O)C(C)C WDAXFOBOLVPGLV-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 3
- -1 2,2-dimethyl-1-propyl Chemical group 0.000 description 2
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- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- FFOPEPMHKILNIT-UHFFFAOYSA-N Isopropyl butyrate Chemical compound CCCC(=O)OC(C)C FFOPEPMHKILNIT-UHFFFAOYSA-N 0.000 description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
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- XUPYJHCZDLZNFP-UHFFFAOYSA-N butyl butanoate Chemical compound CCCCOC(=O)CCC XUPYJHCZDLZNFP-UHFFFAOYSA-N 0.000 description 2
- NMJJFJNHVMGPGM-UHFFFAOYSA-N butyl formate Chemical compound CCCCOC=O NMJJFJNHVMGPGM-UHFFFAOYSA-N 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- NGAZZOYFWWSOGK-UHFFFAOYSA-N heptan-3-one Chemical compound CCCCC(=O)CC NGAZZOYFWWSOGK-UHFFFAOYSA-N 0.000 description 2
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- QNVRIHYSUZMSGM-UHFFFAOYSA-N hexan-2-ol Chemical compound CCCCC(C)O QNVRIHYSUZMSGM-UHFFFAOYSA-N 0.000 description 2
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- BHIWKHZACMWKOJ-UHFFFAOYSA-N methyl isobutyrate Chemical compound COC(=O)C(C)C BHIWKHZACMWKOJ-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
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- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 1
- HFZLSTDPRQSZCQ-UHFFFAOYSA-N 1-pyrrolidin-3-ylpyrrolidine Chemical compound C1CCCN1C1CNCC1 HFZLSTDPRQSZCQ-UHFFFAOYSA-N 0.000 description 1
- UHOPWFKONJYLCF-UHFFFAOYSA-N 2-(2-sulfanylethyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCS)C(=O)C2=C1 UHOPWFKONJYLCF-UHFFFAOYSA-N 0.000 description 1
- QNVRIHYSUZMSGM-LURJTMIESA-N 2-Hexanol Natural products CCCC[C@H](C)O QNVRIHYSUZMSGM-LURJTMIESA-N 0.000 description 1
- AVMSWPWPYJVYKY-UHFFFAOYSA-N 2-Methylpropyl formate Chemical compound CC(C)COC=O AVMSWPWPYJVYKY-UHFFFAOYSA-N 0.000 description 1
- MHNNAWXXUZQSNM-UHFFFAOYSA-N 2-methylbut-1-ene Chemical compound CCC(C)=C MHNNAWXXUZQSNM-UHFFFAOYSA-N 0.000 description 1
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical class CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 1
- PFCHFHIRKBAQGU-UHFFFAOYSA-N 3-hexanone Chemical compound CCCC(=O)CC PFCHFHIRKBAQGU-UHFFFAOYSA-N 0.000 description 1
- MXLMTQWGSQIYOW-UHFFFAOYSA-N 3-methyl-2-butanol Chemical class CC(C)C(C)O MXLMTQWGSQIYOW-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
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- HYTRYEXINDDXJK-UHFFFAOYSA-N Ethyl isopropyl ketone Chemical compound CCC(=O)C(C)C HYTRYEXINDDXJK-UHFFFAOYSA-N 0.000 description 1
- WVRPFQGZHKZCEB-UHFFFAOYSA-N Isopropyl 2-methylpropanoate Chemical compound CC(C)OC(=O)C(C)C WVRPFQGZHKZCEB-UHFFFAOYSA-N 0.000 description 1
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- 206010028980 Neoplasm Diseases 0.000 description 1
- AZFUASHXSOTBNU-UHFFFAOYSA-N Propyl 2-methylpropanoate Chemical compound CCCOC(=O)C(C)C AZFUASHXSOTBNU-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- OJCKJHHYVUPUSJ-UHFFFAOYSA-N benzamide;methanesulfonic acid Chemical class CS(O)(=O)=O.NC(=O)C1=CC=CC=C1 OJCKJHHYVUPUSJ-UHFFFAOYSA-N 0.000 description 1
- VPSLGSSVPWVZFG-UHFFFAOYSA-N butan-2-yl propanoate Chemical compound CCC(C)OC(=O)CC VPSLGSSVPWVZFG-UHFFFAOYSA-N 0.000 description 1
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a new preparation method of an alpha crystal form of imatinib mesylate. The method comprises the following steps: suspending imatinib in the mixed solvent of organic solvent and water, and then adding methylsulphonic acid to obtain the alpha crystal form of imatinib mesylate.
Description
Technical field
The present invention's design relates to the polymorph medicine preparing technical field, more specifically for relating to the preparation method that a kind of her agate replaces Buddhist nun's methane sulfonates alpha-crystal form
Background of invention
Yi Ma is 4-[(4-methyl isophthalic acid-piperazinyl again for Buddhist nun's methane sulfonates) methyl]-N-[4-methyl-3-[4-(3-pyridyl)-2-pyrimidyl] amino]-phenyl] the benzamide methane sulfonates, its structural formula is suc as formula shown in the I:
Formula I
Yi Ma is a kind of protein-tyrosine kinase inhibitor of being developed by Switzerland Novartis Co.,Ltd for Buddhist nun's methane sulfonates, it is effective especially in all types of treatment for cancer, is widely used in the chronic phase patient after treatment chronic myelocytic leukemia (CML) acute transformation phase, acceleration period or alpha-interferon treatment are failed at present; Can not excision or malignant gastrointestinal mesenchymal neoplasm (GIST) patient that shifts is taken place, with oral form administration, the market requirement is bigger usually.
Up to the present, according to bibliographical information, Yi Ma is for Buddhist nun's methane sulfonates total α, β, δ, ε, α 2, H1, I, II, F, G, K, H, I, K, IV, V, VI, VII, VIII, IX, X, XI, XIII, XIV, XV, XVI, amorphous, totally 27 kinds of crystal formations.Wherein beta crystal is that the listing crystal formation is subjected to Novartis Co.,Ltd's patent protection, and all the other crystal formation patents are new or be solvate, and alpha-crystal form has not had patent protection at present, and had similar physico-chemical property with beta crystal, so be studied more as one of crystal formation of discovery early.In W09903854, her agate is suspended in the ethanol for the Buddhist nun, drips methanesulfonic, the high temperature reflux cooling crystallization makes, but this method yield is low, and dissolvent residual exceeds national standard; CN101573350A mentions multiple her special agate and replaces Buddhist nun's methane sulfonates preparation method, and product is separated out soon in these method salification process, can't filter purification, and controllability is bad, concurrent existing mixed crystal phenomenon.WO2005095379 replaces the Buddhist nun to be suspended in the mixed solvent of ethanol and C1～C6 alcoholic solvent her agate, and high temperature drips methanesulfonic, drips ester badness solvent then, cooling crystallization, this method solvent load is excessive, and the salification process product is separated out soon, can't filter purification.Patent WO2006024863 is suspended in the single alcohol kind solvent of C3～C5 with her agate for the Buddhist nun, drips methanesulfonic, the high temperature reflux cooling crystallization, and this method also is to have the problem that dissolvent residual can't be qualified.WO2006048890 is that her agate that will prepare replaces Buddhist nun's methane sulfonates to be dissolved in the mixed solvent of C1～C4 alcohol and water, and by Rotary Evaporators concentrating under reduced pressure evaporate to dryness, this method has mixed crystal phenomenon, and is not easy to industrialization.More than the methods introduced of five pieces of patent applications, mainly have mixed crystal phenomenon, problem such as repeatability is bad, and dissolvent residual is defective, and reaction volume is excessive, and reaction process is uncontrollable is so cause it to be subjected to certain limitation in course of industrialization.
Summary of the invention
The present invention improves on the basis of WO2005095379 and WO2006048890, by replacing her agate the optimum solvent and the poor solvent of Buddhist nun's methane sulfonates to be mixed with mixed solvent with certain proportion, reaction cumulative volume and the solubleness of product in mother liquor have effectively been regulated by the water that adds certain ratio again, add methanesulfonic one step salify then, add a small amount of α crystal seed again and induce crystallization to make her agate for Buddhist nun's methane sulfonates alpha-crystal form.This method has well solved the problem that alcoholic solvent exceeds standard, and whole salification process controllability, favorable reproducibility, and strong operability has good industrial application value.
The reaction that the present invention relates to is suc as formula shown in the II:
Formula II
Her agate is suspended in the mixed solvent of organic solvent and water for the Buddhist nun, adds methanesulfonic then, obtain the alpha-crystal form that above-mentioned her agate replaces Buddhist nun's methane sulfonates.
Further, the concrete scheme of taking is as follows:
Her agate is suspended in the mixed solvent of organic solvent and water for the Buddhist nun, make temperature maintenance at 20 ℃～80 ℃, add methanesulfonic or methanesulfonic solution then, continue to keep 20 ℃～80 ℃ reactions, add her agate of alpha-crystal form and make to cause crystal seed for Buddhist nun's methane sulfonates, the cooling crystallization.The volume ratio of water is 1%～10% in the mixed solvent of described organic solvent and water, and it is one of following that organic solvent is selected from: a) two or more Fatty Alcohol(C12-C14 and C12-C18) mixed solvent; B) mixed solvent of methyl alcohol or ethanol and ester, described ester can be single ester solvent, also can be the blending ratio mixed solvent of two or more ester arbitrarily; C) mixed solvent of methyl alcohol or ethanol and ketone, described ketone can be single ketone solvent, also can be the blending ratio mixed solvent of two or more ketone arbitrarily.
Preferably her agate is suspended in the mixed solvent of organic solvent and water for the Buddhist nun, make temperature maintenance at 30 ℃～80 ℃, add methanesulfonic or methanesulfonic solution then, continue to keep 30 ℃～80 ℃ reactions, add her agate of 0.1%～2% alpha-crystal form and do to cause crystal seed, be cooled to-10 ℃～20 ℃ insulated and stirred crystallizatioies, filter for Buddhist nun's methane sulfonates, drying obtains her agate and replaces Buddhist nun's methane sulfonates alpha-crystal form.Described drying is dry or 20 ℃～60 ℃ vacuum-dryings of common heating.The volume ratio of water is 1%～10% in the mixed solvent of described organic solvent and water, and it is one of following that organic solvent is selected from: a) two or three or four kind C
1-6The Fatty Alcohol(C12-C14 and C12-C18) mixed solvent; B) mixed solvent of methyl alcohol or ethanol and ester, described ester are R
1C (O) OR
2, R wherein
1Be C
1-4Alkyl, R
2Be C
1-4Alkyl, described ester can be single ester solvent, also can be the blending ratio mixed solvent of two or three ester arbitrarily; C) mixed solvent of methyl alcohol or ethanol and ketone, described ketone are R
3C (O) R
4, R wherein
3Be C
1-4Alkyl, R
4Be C
1-4Alkyl, described ketone can be single ketone solvent, also can be the blending ratio mixed solvent of two or three ketone arbitrarily.
More preferably her agate is suspended in the mixed solvent of organic solvent and water for the Buddhist nun, make temperature maintenance at 40 ℃～80 ℃, add methanesulfonic or methanesulfonic solution then, continue to keep 40 ℃～80 ℃ reaction 0.1h～2h, add her agate of 0.1%～2% alpha-crystal form and do to cause crystal seed, slowly be cooled to-10 ℃～20 ℃ for Buddhist nun's methane sulfonates, then with rotating speed insulated and stirred 1h～24h crystallization of 0rpm～300rpm, filter, drying obtains her agate and replaces Buddhist nun's methane sulfonates alpha-crystal form.Described drying is 30 ℃～50 ℃ vacuum-dryings.The volume ratio of water is 1%～10% in the mixed solvent of described organic solvent and water, and it is one of following that organic solvent is selected from: a) two kinds of C
1-6The Fatty Alcohol(C12-C14 and C12-C18) mixed solvent; B) mixed solvent of methyl alcohol or ethanol and ester, the volume ratio of methyl alcohol or ethanol and ester are 1: 0.5～1: 2, and described ester is R
1C (O) OR
2, R wherein
1Be C
1-4Alkyl, R
2Be C
1-4Alkyl, described ester are single ester solvent; C) mixed solvent of methyl alcohol or ethanol and ketone, the volume ratio of methyl alcohol or ethanol and ketone are 1: 0.5～1: 2, and described ketone is R
3C (O) R
4, R wherein
3Be C
1-4Alkyl, R
4Be C
1-4Alkyl, described ketone are single ketone solvent.
Further preferably her agate is suspended in the mixed solvent of organic solvent and water for the Buddhist nun, make temperature maintenance at 50 ℃～80 ℃, add methanesulfonic or methanesulfonic solution then, continue to keep 50 ℃～80 ℃ reaction 0.1h～2h, add her agate of 0.1%～2% alpha-crystal form and do to cause crystal seed, slowly be cooled to-10 ℃～20 ℃ for Buddhist nun's methane sulfonates, then with rotating speed insulated and stirred 4h～16h crystallization of 0rpm～300rpm, filter, drying obtains her agate and replaces Buddhist nun's methane sulfonates alpha-crystal form.Described drying is 40 ℃～50 ℃ vacuum-dryings.The volume ratio of water is 1%～10% in the mixed solvent of described organic solvent and water, and it is one of following that organic solvent is selected from: a) two kinds in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, sec-butyl alcohol, isopropylcarbinol, the Pentyl alcohol; B) mixed solvent of methyl alcohol or ethanol and ester, wherein the volume ratio of methyl alcohol or ethanol and ester is 1: 0.5～1: 1.5, and described ester is selected from a kind of in ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, the isobutyl acetate; C) mixed solvent of methyl alcohol or ethanol and ketone, the volume ratio of methyl alcohol or ethanol and ketone are 1: 0.5～1: 1.5, and described ketone is selected from a kind of in acetone, butanone, methyl isopropyl Ketone, methyl butyl ketone, the methyl iso-butyl ketone (MIBK).
Yi Ma is 1: 4～1: 50 for the mass ratio of the mixed solvent of Buddhist nun and organic solvent and water, is preferably 1: 4～1: 40; More preferably 1: 4～1: 35, more preferably 1: 6～1: 30.
Yi Ma is 1: 0.9～1: 1 for the molar ratio example of Buddhist nun and methanesulfonic, is preferably 1: 0.95～1: 1.05, more preferably is 1: 0.98～1: 1.02.
C described in the application
1-6Fatty Alcohol(C12-C14 and C12-C18) includes but not limited to: methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, sec-butyl alcohol, isopropylcarbinol, the trimethyl carbinol, 1-amylalcohol, 2-amylalcohol, 3-amylalcohol, 2-methyl-1-butene alcohol, 2-methyl-2-butanols, 3-methyl-2-butanols, 3-methyl isophthalic acid-butanols, 2,2-dimethyl-1-propyl alcohol, 1-hexanol, 2-hexanol, 3-hexanol.
Formula described in the application is R
1C (O) OR
2Ester (R
1Be C
1-4Alkyl or cycloalkyl, R
2Be C
1-4Alkyl or cycloalkyl); Include but not limited to methyl-formiate, ethyl formate, propyl formate, isopropyl formate, butyl formate, sec.-butyl formate, tetryl formate, t-butyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, sec-butyl acetate, isobutyl acetate, tert.-butyl acetate, methyl propionate, ethyl propionate, propyl propionate, isopropyl propionate, butyl propionate, sec-butyl propionate, isobutyl propionate, the propionic acid tert-butyl ester, methyl-butyrate, ethyl butyrate, propyl butyrate, isopropyl butyrate, butyl butyrate, the secondary butyl ester of butyric acid, isobutyl butyrate, tert-butyl acetate, methyl isobutyrate, ethyl isobutyrate, propyl isobutyrate, isopropyl isobutyrate, butyl isobutyrate, the secondary butyl ester of isopropylformic acid, isobutyl isobutyrate, tert-butyl isobutyrate.
Formula described in the application is R
3C (O) R
4Ketone (R
3Be C
1-4Alkyl or C
1-4Cycloalkyl, R
4Be C
1-4Alkyl or C
1-4Cycloalkyl); Include but not limited to acetone, butanone, methyl isopropyl Ketone, methyl butyl ketone, methyl iso-butyl ketone (MIBK), 1,1,1-trimethylammonium acetone, metacetone, 3-hexanone, 2-methyl-propione, 3-heptanone.
Problems such as there was mixed crystal phenomenon in patent before the present invention had overcome when her agate of preparation replaces Buddhist nun's methane sulfonates alpha-crystal form, and repeatability is bad, and dissolvent residual is defective, and reaction volume is excessive, and reaction process is uncontrollable, thus the feasibility of operating increased; This invention yield height in addition, technology is simple, is fit to very much suitability for industrialized production, therefore has good economic worth.
Description of drawings
Fig. 1 produces the XRPD collection of illustrative plates that her agate replaces Buddhist nun's methane sulfonates alpha-crystal form for embodiment 1.
Fig. 2 produces the XRPD collection of illustrative plates that her agate replaces Buddhist nun's methane sulfonates alpha-crystal form for embodiment 2.
Fig. 3 produces the XRPD collection of illustrative plates that her agate replaces Buddhist nun's methane sulfonates alpha-crystal form for embodiment 3.
Fig. 4 produces the XRPD collection of illustrative plates that her agate replaces Buddhist nun's methane sulfonates alpha-crystal form for embodiment 4.
Specific implementation method
To help to understand the present invention by following examples of implementation, but not limit content of the present invention
Embodiment 1: her agate replaces the preparation of Buddhist nun's methane sulfonates alpha-crystal form
Take by weighing her agate and replace Buddhist nun 10g (2.02mmol, 1.0eq), be suspended in the mixed solvent of 100mL methanol/isopropanol/water (V%:49: 49: 2), be warming up to 70 ℃, speed with 1mL/min drips 1.3mL (2.0mmol, 0.99eq) methanesulfonic solution, dropwise reaction solution and be the clarification shape, keep 70 ℃ and continue stirring reaction 0.5h, the reaction filtered while hot, filtrate is warming up to 70 ℃ again, add her agate of 0.1g (1%) and make to cause crystal seed for Buddhist nun's methane sulfonates alpha-crystal form, slowly be cooled to 10 ℃,, filter with 50rpm rotating speed insulated and stirred 8h, filter cake 50mL ethyl acetate rinse, 45 ℃ of vacuum-dryings obtain her agate and replace Buddhist nun's methane sulfonates alpha-crystal form 10.5g, yield 88%.
Embodiment 2: her agate replaces the preparation of Buddhist nun's methane sulfonates alpha-crystal form
Take by weighing her agate and replace Buddhist nun 10g (2.02mmol, 1.0eq), be suspended in the mixed solvent of 200mL ethanol/isopropanol (V%:48: 48: 4), be warming up to 70 ℃, speed with 1mL/min drips 1.3mL (2.0mmol, 0.99eq) methanesulfonic solution, dropwise the reaction solution system and be the clarification shape, keep 70 ℃ and continue stirring reaction 0.5h, the reaction filtered while hot, filtrate is warming up to 70 ℃ again, add her agate of 0.1g (1%) and make to cause crystal seed for Buddhist nun's methane sulfonates alpha-crystal form, slowly be cooled to 10 ℃,, filter with 50rpm rotating speed insulated and stirred 8h, filter cake 50mL ethyl acetate rinse, 45 ℃ of vacuum-dryings obtain her agate and replace Buddhist nun's methane sulfonates alpha-crystal form 10.8g, yield 90%.
Embodiment 3: her agate replaces the preparation of Buddhist nun's methane sulfonates alpha-crystal form
Take by weighing her agate and replace Buddhist nun 10g (2.02mmol, 1.0eq), be suspended in the mixed solvent of 250mL ethanol/ethyl acetate/water (V%:49: 49: 2), be warming up to 70 ℃, speed with 1mL/min drips 1.3mL (2.0mmol, 0.99eq) methanesulfonic solution, dropwise the reaction solution system and be the clarification shape, keep 70 ℃ and continue stirring reaction 0.5h, the reaction filtered while hot, filtrate is warming up to 70 ℃ again, add her agate of 0.1g (1%) and make to cause crystal seed for Buddhist nun's methane sulfonates alpha-crystal form, slowly be cooled to 0 ℃,, filter with 50rpm rotating speed insulated and stirred 12h, filter cake 50mL ethyl acetate rinse, 45 ℃ of vacuum-dryings obtain her agate and replace Buddhist nun's methane sulfonates alpha-crystal form 11.5g, yield 96%.
Embodiment 4: her agate replaces the preparation of Buddhist nun's methane sulfonates alpha-crystal form
Take by weighing her agate and replace Buddhist nun 10g (2.02mmol, 1.0eq), be suspended in the mixed solvent of 250mL ethanol/methyl iso-butyl ketone (MIBK)/water (V%:47: 47: 6), be warming up to 70 ℃, speed with 1mL/min drips 1.3mL (2.0mmol, 0.99eq) methanesulfonic solution, dropwise the reaction solution system and be the clarification shape, keep 70 ℃ and continue stirring reaction 0.5h, the reaction filtered while hot, filtrate is warming up to 70 ℃ again, add her agate of 0.1g (1%) and make to cause crystal seed for Buddhist nun's methane sulfonates alpha-crystal form, slowly be cooled to 0 ℃,, filter with 50rpm rotating speed insulated and stirred 12h, filter cake 50mL ethyl acetate rinse, 45 ℃ of vacuum-dryings obtain her agate and replace Buddhist nun's methane sulfonates alpha-crystal form 11.3g, yield 95%.
Claims (10)
1. her agate replaces the new preparation method of Buddhist nun's methane sulfonates alpha-crystal form, it is characterized in that: her agate is suspended in the mixed solvent of organic solvent and water for the Buddhist nun, add methanesulfonic or methanesulfonic solution then, obtain the alpha-crystal form that her agate replaces Buddhist nun's methane sulfonates.
2. preparation method according to claim 1, its feature may further comprise the steps: her agate is suspended in the mixed solvent of organic solvent and water for the Buddhist nun, make temperature maintenance at 20 ℃～80 ℃, add methanesulfonic or methanesulfonic solution then, continue to keep 20 ℃～80 ℃ reactions, add her agate of alpha-crystal form and make to cause crystal seed for Buddhist nun's methane sulfonates, the cooling crystallization.
3. preparation method according to claim 1, its feature may further comprise the steps: her agate is suspended in the mixed solvent of organic solvent and water for the Buddhist nun, make temperature maintenance at 30 ℃～80 ℃, add methanesulfonic or methanesulfonic solution then, continue to keep 30 ℃～80 ℃ reaction 0.1h～2h, add her agate of 0.1%～2% alpha-crystal form and make to cause crystal seed for Buddhist nun's methane sulfonates, be cooled to-10 ℃～20 ℃ insulated and stirred 1h～24h crystallizatioies, filter, drying obtains her agate and replaces Buddhist nun's methane sulfonates alpha-crystal form; Described drying is dry or 20 ℃～60 ℃ vacuum-dryings of common heating; Wherein her agate is 1:0.9～1:1.1 for the molar ratio example of Buddhist nun and methanesulfonic.
4. preparation method according to claim 1, its feature may further comprise the steps: her agate is suspended in the mixed solvent of organic solvent and water for the Buddhist nun, make temperature maintenance at 40 ℃～80 ℃, add methanesulfonic or methanesulfonic solution then, continue to keep 40 ℃～80 ℃ reaction 0.1h～2h, add her agate of 0.1%～2% alpha-crystal form and make to cause crystal seed for Buddhist nun's methane sulfonates, slowly be cooled to-10 ℃～20 ℃, then with rotating speed insulated and stirred 4h～16h crystallization of 0rpm～300rpm, filter, drying obtains her agate and replaces Buddhist nun's methane sulfonates alpha-crystal form; Described drying is dry or 20 ℃～60 ℃ vacuum-dryings of common heating; Wherein her agate is 1:0.95～1:1.05 for the molar ratio example of Buddhist nun and methanesulfonic.
5. preparation method according to claim 4 is characterized in that described drying is 30 ℃～50 ℃ vacuum-dryings.
6. according to each described preparation method in the claim 1 ~ 5, it is characterized in that the volume ratio of water in the mixed solvent of described organic solvent and water is 1% ~ 10%, it is one of following that organic solvent is selected from:
A) two or more Fatty Alcohol(C12-C14 and C12-C18) mixed solvent;
B) mixed solvent of methyl alcohol or ethanol and ester, described ester can be single ester solvent, also can be the blending ratio mixed solvent of two or more ester arbitrarily;
C) mixed solvent of methyl alcohol or ethanol and ketone, described ketone can be single ketone solvent, also can be the blending ratio mixed solvent of two or more ketone arbitrarily.
7. according to each described preparation method in the claim 1 ~ 5, it is characterized in that the volume ratio of water in the mixed solvent of her described organic solvent and water is 1% ~ 10%, it is one of following that organic solvent is selected from:
A) two or three or four kind C
1-6The Fatty Alcohol(C12-C14 and C12-C18) mixed solvent;
B) mixed solvent of methyl alcohol or ethanol and ester, described ester are R
1C (O) OR
2, R wherein
1Be C
1-4Alkyl or C
1-4Cycloalkyl, R
2Be C
1-4Alkyl or C
1-4Cycloalkyl can be single ester solvent, also can be the blending ratio mixed solvent of two or three ester arbitrarily;
C) mixed solvent of methyl alcohol or ethanol and ketone, described ketone are R
3C (O) R
4, R wherein
3Be C
1-4Alkyl or C
1-4Cycloalkyl, R
4Be C
1-4Alkyl or C
1-4Cycloalkyl can be single ketone solvent, also can be the blending ratio mixed solvent of two or three ketone arbitrarily.
8. according to each described preparation method in the claim 1 ~ 5, it is characterized in that the volume ratio of water in the mixed solvent of described organic solvent and water is 1% ~ 10%, it is one of following that organic solvent is selected from:
A) two kinds of C
1-6The Fatty Alcohol(C12-C14 and C12-C18) mixed solvent;
B) mixed solvent of methyl alcohol or ethanol and ester, the volume ratio of methyl alcohol or ethanol and ester are 1:0.5 ~ 1:2, and described ester is R
1C (O) OR
2, R wherein
1Be C
1-4Alkyl or C
1-4Cycloalkyl, R
2For being C
1-4Alkyl or C
1-4Cycloalkyl is single ester solvent;
C) mixed solvent of methyl alcohol or ethanol and ketone, the volume ratio of methyl alcohol or ethanol and ketone are 1:0.5 ~ 1:2, and described ketone is R
3C (O) R
4, R wherein
3Be C
1-4Alkyl or C
1-4Cycloalkyl, R
4Be C
1-4Alkyl or C
1-4Cycloalkyl is single ketone solvent.
9. according to each described preparation method in the claim 1 ~ 5, it is characterized in that the volume ratio of water in the mixed solvent of described organic solvent and water is 1% ~ 10%, it is one of following that organic solvent is selected from:
A) two kinds in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, sec-butyl alcohol, isopropylcarbinol, the Pentyl alcohol;
B) mixed solvent of methyl alcohol or ethanol and ester, wherein the volume ratio of methyl alcohol or ethanol and ester is 1:0.5 ~ 1:1.5, and described ester is selected from a kind of in ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, the isobutyl acetate;
C) mixed solvent of methyl alcohol or ethanol and ketone, the volume ratio of methyl alcohol or ethanol and ketone are 1:0.5 ~ 1:1.5, and described ketone is selected from a kind of in acetone, butanone, methyl isopropyl Ketone, methyl butyl ketone, the methyl iso-butyl ketone (MIBK).
10. according to each described preparation method in the claim 1 ~ 5, it is characterized in that her agate replaces the molar ratio example of Buddhist nun and methanesulfonic to be 1:1, the volume ratio of water is 2% ~ 6% in the mixed solvent of described organic solvent and water, and it is one of following that organic solvent is selected from:
A) mixed solvent of the mixed solvent of methyl alcohol and Virahol or ethanol and Virahol;
B) mixed solvent of ethanol and ethyl acetate, wherein the volume ratio of ethanol and ethyl acetate is 1:1;
C) mixed solvent of ethanol and methyl iso-butyl ketone (MIBK), the volume ratio of ethanol and methyl iso-butyl ketone (MIBK) are 1:1.
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|---|---|---|---|---|
| CN103570677B (en) * | 2012-08-02 | 2017-03-01 | 广东东阳光药业有限公司 | A kind of preparation method of alpha-crystal form imatinib mesylate |
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|---|---|---|---|---|
| CN1264375A (en) * | 1997-07-18 | 2000-08-23 | 诺瓦提斯公司 | Crystal modification of N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
| WO2005095379A2 (en) * | 2004-04-02 | 2005-10-13 | Instytut Farmaceutyczny | Crystalline methanesulfonic acid addition salts of imatinib |
| WO2006048890A1 (en) * | 2004-11-04 | 2006-05-11 | Sun Pharmaceutical Industries Limited | Imatinib mesylate crystal form and process for preparation thereof |
-
2011
- 2011-02-23 CN CN2011100441918A patent/CN102146073A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1264375A (en) * | 1997-07-18 | 2000-08-23 | 诺瓦提斯公司 | Crystal modification of N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
| WO2005095379A2 (en) * | 2004-04-02 | 2005-10-13 | Instytut Farmaceutyczny | Crystalline methanesulfonic acid addition salts of imatinib |
| WO2006048890A1 (en) * | 2004-11-04 | 2006-05-11 | Sun Pharmaceutical Industries Limited | Imatinib mesylate crystal form and process for preparation thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103570677B (en) * | 2012-08-02 | 2017-03-01 | 广东东阳光药业有限公司 | A kind of preparation method of alpha-crystal form imatinib mesylate |
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