CN103570674A - Preparation method of imatinib mesylate alpha crystal form - Google Patents
Preparation method of imatinib mesylate alpha crystal form Download PDFInfo
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- CN103570674A CN103570674A CN201210276326.8A CN201210276326A CN103570674A CN 103570674 A CN103570674 A CN 103570674A CN 201210276326 A CN201210276326 A CN 201210276326A CN 103570674 A CN103570674 A CN 103570674A
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- butyl alcohol
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- C—CHEMISTRY; METALLURGY
- 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
- C07D401/02—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 two hetero rings
- C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention relates to the field of drug synthesis and discloses a preparation method of an imatinib mesylate alpha crystal form. In the preparation method, imatinib alkali is mixed with sec-butyl alcohol, and the mixture reacts with the methanesulfonic acid-sec-butyl alcohol mixed liquid to obtain the imatinib mesylate alpha crystal form. The preparation method disclosed by the invention realizes high yield and stable process and is suitable for industrial production of the imatinib mesylate alpha crystal form.
Description
Technical field
The present invention relates to the synthetic field of medicine, relate to specifically a kind of preparation method of imatinib mesylate alfa crystal form.
Background technology
Imatinib mesylate, English name: Imatinib Mesilate, chemical name: 4-[(4-methyl isophthalic acid-piperazine) methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl]-aniline mesylate, molecular formula is C
29h
31n
7oCH
4sO
3, molecular weight is 589.71, structural formula is as follows:
A signal transduction inhibitor of company of Ta Shi Switzerland Novartis (Novartis) research and development, in 10 U.S. Initial Public Offering in May calendar year 2001, the Yi U.S., European Union, Japan and China are in more than 60 interior country's listings at present.
Research is found, imatinib mesylate all can suppress Bcr-Abl Tyrosylprotein kinase in vivo and in vitro on cell levels, can selectivity suppress Bcr-Abl positive cell line cell and the chronic myelocytic leukemia of Ph chromatin-positive, the propagation of acute lymphoblastic leukemia patient's new fresh cell and induce its apoptosis.In addition, it also can suppress platelet derived growth factor (PDGF) acceptor, STEM CELL FACTOR (SCF), the Tyrosylprotein kinase of c-Kit acceptor, thus suppress the cell behavior by PDGF and STEM CELL FACTOR mediation.Imatinib mesylate belongs to small molecules targeting anti-tumor medicine, is applicable to chronic phase patient after chronic myelocytic leukemia (CML) acute transformation phase, acceleration period or alpha-interferon therapy failure and can not excision or malignant gastrointestinal mesenchymal neoplasm (GIST) patient that shifts occurs.
US Patent No. 5521184 has been described imatinib and salt form thereof the earliest.International Patent Application WO 99/03854, WO2005/077933, WO2004/106326, WO2006/054314 and WO2007/023182 disclose imatinib mesylate α, β, α 2, H1, I, II, δ, ε crystal formation.
WO99/03854 discloses the preparation method of imatinib mesylate alfa crystal form and beta crystal.Wherein, alpha-crystal form is made solvent with ethanol, is mixed into suspension with imatinib alkali, adds methylsulfonic acid, after through a series of post-processing operation, prepare.But the alpha-crystal form that the method prepares is unstable, under state of nature, easily moisture absorption and be unformed, is unsuitable for medicinal application.
WO2005095379 discloses in the mixing solutions of alkyl alcohols or alkyl alcohol and alkyl acid esters and has prepared imatinib mesylate alfa crystal form, uses like this mixing solutions of alkyl alcohol and alkyl acid esters to be unfavorable for generating alpha-crystal form, causes on the contrary generating mixed crystal.
WO2011099039 discloses take imatinib alkali as raw material, and the trimethyl carbinol is the method that solvent is prepared imatinib mesylate alfa crystal form.Be specially: imatinib alkali is dissolved into suspension with the trimethyl carbinol, and at 30～60 ℃ of mixing solutionss that drip methylsulfonic acids and the trimethyl carbinol, heated mixt is to refluxing cooling, filtration, crystallization, dry.In this preparation method, require the purity of imatinib alkali to be greater than 99%, the moisture content of solvent is greatly about 0.01 to 0.015, and dripping methylsulfonic acid and trimethyl carbinol mixing solutions time is 1～4 hour, and alkali is 2～10 times of methylsulfonic acid quality.The method is high to the purity requirement of raw material, also needs to control solvent water content, and complicated operation, is unsuitable for suitability for industrialized production.
In view of the series of problems existing in prior art, be necessary the preparation method of imatinib mesylate alfa crystal form to be further improved, development yield is high, process stabilizing, be applicable to the preparation method of the imatinib mesylate alfa crystal form of suitability for industrialized production.
Summary of the invention
The preparation method who the invention provides a kind of imatinib mesylate alfa crystal form, the method is simple to operate, and yield is high, is suitable for suitability for industrialized production.
The technical solution used in the present invention is:
After imatinib alkali mixes with sec-butyl alcohol, react with the mixing solutions of methylsulfonic acid and sec-butyl alcohol, make imatinib mesylate alfa crystal form.
After imatinib alkali mixes with sec-butyl alcohol, along with the dosage of sec-butyl alcohol increases, imatinib alkali can become and is dissolved in sec-butyl alcohol completely from being not exclusively dissolved in sec-butyl alcohol.Through contriver's experiment, when the mass ratio of sec-butyl alcohol and imatinib alkali is greater than 20 times, imatinib can be dissolved in sec-butyl alcohol completely; When the mass ratio of sec-butyl alcohol and imatinib alkali is 8～20:1, imatinib mesylate can form suspendible shape in sec-butyl alcohol, is more conducive to separate out imatinib mesylate alfa crystal form.
As preferably, imatinib alkali mixes with sec-butyl alcohol, and the mass ratio of sec-butyl alcohol and imatinib alkali is 8～20:1.
As preferably, in the mixing solutions of methylsulfonic acid and sec-butyl alcohol, the mass ratio of sec-butyl alcohol and methylsulfonic acid is 15:1.
As preferably, after sec-butyl alcohol mixes with imatinib alkali, be heated to 60～102 ℃.
Through contriver's experiment, after sec-butyl alcohol mixes with imatinib alkali, the temperature of heating is higher, and the solubleness of imatinib alkali is higher, reacts faster with the mixing solutions of methylsulfonic acid and sec-butyl alcohol, and the imatinib mesylate alfa crystal form color of generation is pure.
Preferred, sec-butyl alcohol is heated to reflux temperature after mixing with imatinib alkali.
One embodiment of the present invention are: imatinib alkali is heated to reflux temperature after mixing with sec-butyl alcohol, react with the mixing solutions of methylsulfonic acid and sec-butyl alcohol, after simple aftertreatment, obtain imatinib mesylate alfa crystal form.
Simple aftertreatment of the present invention is for filtering the imatinib mesylate alfa crystal form making, wash, being dried.
Filtration is preferably and is cooled to 25 ℃, and drying nitrogen protection is lower filters, and due to the stable chemical nature of nitrogen, is difficult for reacting with other materials, is commonly used for protection gas, and dry nitrogen does not have moisture, makes crystal formation more stable.
Washing is preferably sec-butyl alcohol drip washing.
Be dried and be preferably vacuum-drying at 65 ℃.
The invention provides a kind of method of imatinib mesylate alfa crystal form of preparing as solvent with sec-butyl alcohol, the method has utilized imatinib alkali can be dissolved in sec-butyl alcohol, and imatinib mesylate is not soluble in the character of sec-butyl alcohol, prepared imatinib mesylate alfa crystal form yield is high, crystal formation is pure, and simple to operate, be applicable to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 shows the imatinib mesylate alfa crystal form x-ray diffractogram of powder spectrum of the embodiment of the present invention 1 preparation.
Fig. 2 shows the imatinib mesylate alfa crystal form DSC collection of illustrative plates of the embodiment of the present invention 1 preparation.
Embodiment
In order further to understand the present invention, below in conjunction with embodiment, the preparation method of a kind of imatinib mesylate alfa crystal form provided by the invention is elaborated.It will be appreciated that, it is just further description feature of the present invention that these embodiment describe, rather than the restriction to the scope of the invention or the claims in the present invention scope.
Embodiment 1:
In the four-hole reaction flask of 500ml, drop into 25g imatinib alkali and 200g sec-butyl alcohol, be heated to 102 ℃, insulation.To splashing into the mixing solutions of methylsulfonic acid (4.875g) with sec-butyl alcohol (75g) in reaction flask; dropwise; insulation 0.5h; naturally cool to 25 ℃; suction filtration under nitrogen protection, with the drip washing of 25ml sec-butyl alcohol, drains in the vacuum drying oven that is placed on 65 ℃ and dries 12h; obtain imatinib mesylate alfa crystal form 28.37g, yield 95.0%.Utilize powder x-ray diffraction method and dsc (DSC) to measure the imatinib mesylate alfa crystal form of preparation.Fig. 1 is shown in by XRPD collection of illustrative plates, and reflection angle 2 θ are: 4.940,10.495,11.285,11.916,12.227,12.935,13.885,14.946,16.506,17.746,18.118,18.651,19.105,19.864,21.310,21.566,22.688,23.181,23.769,25.011,26.372,27.395,28.064,28.536,28.871,30.033,30.412,32.060,32.635.Fig. 2 is shown in by DSC collection of illustrative plates, and peak value is 229.4 ℃.
Embodiment 2:
In the four-hole reaction flask of 500ml, drop into 25g imatinib alkali and 300g sec-butyl alcohol, be heated to 102 ℃, insulation.To splashing into the mixing solutions of methylsulfonic acid (4.875g) with sec-butyl alcohol (75g) in reaction flask; dropwise; insulation 0.5h; naturally cool to 25 ℃; suction filtration under nitrogen protection, with the drip washing of 25ml sec-butyl alcohol, drains in the vacuum drying oven that is placed on 65 ℃ and dries 12h; obtain imatinib mesylate alfa crystal form 28.26g, yield 94.6%.Utilize differential heat scanning method (DSC) to measure the imatinib mesylate alfa crystal form of preparation.Dsc figure spectrum peak is 226.5 ℃.
Embodiment 3:
In the four-hole reaction flask of 1000ml, drop into 25g imatinib alkali and 500g sec-butyl alcohol, be heated to 102 ℃, insulation.To splashing into the mixing solutions of methylsulfonic acid (4.875g) with sec-butyl alcohol (75g) in reaction flask; dropwise; insulation 0.5h; naturally cool to 25 ℃; suction filtration under nitrogen protection, with the drip washing of 25ml sec-butyl alcohol, drains in the vacuum drying oven that is placed on 65 ℃ and dries 12h; obtain imatinib mesylate alfa crystal form 28.24g, yield 94.5%.Utilize differential heat scanning method (DSC) to measure the imatinib mesylate alfa crystal form of preparation.Dsc figure spectrum peak is 227.2 ℃.
Embodiment 4:
In the four-hole reaction flask of 500ml, drop into 25g imatinib alkali and 200g sec-butyl alcohol, be heated to 60 ℃, insulation.To splashing into the mixing solutions of methylsulfonic acid (4.875g) with sec-butyl alcohol (75g) in reaction flask; dropwise; insulation 0.5h; naturally cool to 25 ℃; suction filtration under nitrogen protection, with the drip washing of 25ml sec-butyl alcohol, drains in the vacuum drying oven that is placed on 65 ℃ and dries 12h; obtain imatinib mesylate alfa crystal form 28.27g, yield 94.6%.Utilize differential heat scanning method (DSC) to measure the imatinib mesylate alfa crystal form of preparation.Dsc figure spectrum peak is 227.2 ℃.
Embodiment 5:
In the four-hole reaction flask of 500ml, drop into 25g imatinib alkali and 200g sec-butyl alcohol, be heated to 80 ℃, insulation.To splashing into the mixing solutions of methylsulfonic acid (4.875g) with sec-butyl alcohol (75g) in reaction flask; dropwise; insulation 0.5h; naturally cool to 25 ℃; suction filtration under nitrogen protection, with the drip washing of 25ml sec-butyl alcohol, drains in the vacuum drying oven that is placed on 65 ℃ and dries 12h; obtain imatinib mesylate alfa crystal form 28.31g, yield 94.8%.Utilize differential heat scanning method (DSC) to measure the imatinib mesylate alfa crystal form of preparation.Dsc figure spectrum peak is 226.5 ℃.
Embodiment 6:
In the four-hole reaction flask of 1000ml, drop into 25g imatinib alkali and 500g sec-butyl alcohol, be heated to 100 ℃, insulation.To splashing into the mixing solutions of methylsulfonic acid (4.875g) with sec-butyl alcohol (75g) in reaction flask; dropwise; insulation 0.5h; naturally cool to 25 ℃; suction filtration under nitrogen protection, with the drip washing of 25ml sec-butyl alcohol, drains in the vacuum drying oven that is placed on 65 ℃ and dries 12h; obtain imatinib mesylate alfa crystal form 28.28g, yield 94.7%.Utilize differential heat scanning method (DSC) to measure the imatinib mesylate alfa crystal form of preparation.Dsc figure spectrum peak is 226.1 ℃.
The explanation of above embodiment is just for helping to understand method of the present invention and core concept thereof.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of the claims in the present invention.
Claims (5)
1. a preparation method for imatinib mesylate alfa crystal form, is characterized in that, after imatinib alkali is mixed with sec-butyl alcohol, reacts with the mixing solutions of methylsulfonic acid and sec-butyl alcohol, prepares imatinib mesylate alfa crystal form.
2. preparation method according to claim 1, is characterized in that, comprises following two steps:
A) drop into imatinib alkali and sec-butyl alcohol, heating;
B) react with the mixing solutions of methylsulfonic acid and sec-butyl alcohol.
3. preparation method according to claim 2, is characterized in that, in described step a, the mass ratio of sec-butyl alcohol and imatinib alkali is 8～20:1.
4. preparation method according to claim 2, is characterized in that, in the mixed solution of described step b methylsulfonic acid sec-butyl alcohol, the mass ratio of sec-butyl alcohol and methylsulfonic acid is 15:1.
5. preparation method according to claim 2, is characterized in that, described temperature need be heated to 60 ℃～102 ℃.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005095379A2 (en) * | 2004-04-02 | 2005-10-13 | Instytut Farmaceutyczny | Crystalline methanesulfonic acid addition salts of imatinib |
| WO2006024863A1 (en) * | 2004-09-02 | 2006-03-09 | Cipla Limited | Stable crystal form of imatinib mesylate and process for the preparation thereof |
| WO2011099039A1 (en) * | 2010-02-15 | 2011-08-18 | Reliance Life Sciences Pvt. Ltd. | Process for the preparation of alpha form of imatinib mesylate |
| CN102321070A (en) * | 2011-07-27 | 2012-01-18 | 江苏先声药物研究有限公司 | Method for preparing imatinib methylolsulfonate alpha crystal through inverse solvent recrystallization method |
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- 2012-08-04 CN CN201210276326.8A patent/CN103570674A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005095379A2 (en) * | 2004-04-02 | 2005-10-13 | Instytut Farmaceutyczny | Crystalline methanesulfonic acid addition salts of imatinib |
| WO2006024863A1 (en) * | 2004-09-02 | 2006-03-09 | Cipla Limited | Stable crystal form of imatinib mesylate and process for the preparation thereof |
| WO2011099039A1 (en) * | 2010-02-15 | 2011-08-18 | Reliance Life Sciences Pvt. Ltd. | Process for the preparation of alpha form of imatinib mesylate |
| CN102321070A (en) * | 2011-07-27 | 2012-01-18 | 江苏先声药物研究有限公司 | Method for preparing imatinib methylolsulfonate alpha crystal through inverse solvent recrystallization method |
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