CN102617552A - Crystallizing method for preparing alpha crystal form methanesulfonic acid imatinib - Google Patents

Crystallizing method for preparing alpha crystal form methanesulfonic acid imatinib Download PDF

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Publication number
CN102617552A
CN102617552A CN2012100990498A CN201210099049A CN102617552A CN 102617552 A CN102617552 A CN 102617552A CN 2012100990498 A CN2012100990498 A CN 2012100990498A CN 201210099049 A CN201210099049 A CN 201210099049A CN 102617552 A CN102617552 A CN 102617552A
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CN
China
Prior art keywords
imatinib
methanesulfonic acid
sti571
crystal form
ethyl alcohol
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CN2012100990498A
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Chinese (zh)
Inventor
陆杰
汪晶
李义平
林青
舒亮
曾德利
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江南大学
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Priority to CN2012100990498A priority Critical patent/CN102617552A/en
Publication of CN102617552A publication Critical patent/CN102617552A/en

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Abstract

The invention discloses a simple preparation method for alpha crystal form methanesulfonic acid imatinib, which belongs to the technical field of drug crystal form discovery and preparation. The method includes four steps of (A) dripping methanesulfonic acid into suspension of imatinib and absolute ethyl alcohol at normal temperature and reacting to generate methanesulfonic acid imatinib; (B) performing micropore filtration for solution so as to obtain clear solution; (C) growing crystals for 1-2 hours at the same temperature; and (D) washing obtained solid by ethyl acetate and performing vacuum drying. The prepared alpha crystal form methanesulfonic acid imatinib crystals are determined as high-crystal-form-purity alpha crystal form methanesulfonic acid imatinib via X-ray powder diffraction, infrared spectrum and thermal analysis. A defined amount of seed crystals are added in a crystallization process, so that crystallization speed is increased obviously, and crystallization can be finished after about 3 hours.

Description

A kind of crystallization method for preparing the alpha-crystal form STI571

Technical field

The present invention relates to a kind of preparation method of alpha-crystal form STI571 of high crystal formation purity, in particular, the present invention relates to the imatinib is the method for feedstock production alpha-crystal form STI571, belongs to the medicine crystal formation and finds and preparing technical field.

Background technology

STI571 (Imatinib Mesylate; Structural formula is shown below); Chemistry 4-[(4-methyl isophthalic acid-piperazinyl methyl)-N-[4-methyl-3-[4-(3-pyridyl)-2-pyrimidyl] amino] phenyl] BM mesylate by name is a kind of tyrosine kinase inhibitor class medicine.This medicine is researched and developed by Switzerland Novartis Co.,Ltd; May calendar year 2001; Having breakthrough antitumor mechanism acquisition U.S. FDA express train with it examines; Be used for alpha-interferon administration failure protoblast crisis stadium, chronic stadium, quicken the treatment of the granulocyte leukemia (CML, Chmnic Myelogenous Leukemia) of stadium, commodity are called imatinib mesylate (G1ivec); In February, 2002, U.S. FDA is ratified these article again and is used to treat the gi tract Leydig's cell tumor.

 

According to document and patent report, STI571 has multiple crystal formation, comprises amorphous, α type, β type, IV type, V-type, VI, VII type, VIII type, IX type, X type and XI type.Each crystal formation has than big-difference aspect physico-chemical property, and for example, the β type is compared with the α type, and good stability is prone to preparation, and anti-wettability power is good, but its solubleness is poor than the α type.The existing method for preparing α type STI571 mainly contains two kinds: first kind is with imatinib and methylsulfonic acid reaction, i.e. reaction-crystallization method; Second kind is to change into alpha-crystal form from other crystal formations of STI571, promptly starches the attitude rotating crystal method.But the STI571 crystal that is obtained by the preparation method of present reported in literature is the β type often, even the α type, its crystal formation purity is not high, and being prone to during storage change crystalline substance is the β type, and the moisture-sensitive moisture absorption.

Patent US7732601, US20070265288 and WO2006048890A disclose the method that reaction-crystallization method prepares the alpha-crystal form STI571, and the solvent of use comprises absolute ethyl alcohol, absolute ethyl alcohol-Virahol, absolute ethyl alcohol-ETHYLE ACETATE, Virahol, propyl carbinol and methanol-water.But in these systems, step such as all need heat, reflux, concentrate, required equipment is complicated, and duration disappears.The amorphous STI571 of the general employing of slurry attitude rotating crystal method is a raw material, and the solvent of employing mainly contains anhydrous methanol-Virahol, absolute ethyl alcohol-Virahol etc.But the normally mixed crystal or the beta crystal that obtain, and required equipment is more in producing, and step is more.

Summary of the invention

Main purpose of the present invention is to overcome problems such as existing α type STI571 preparation process is complicated, product crystal formation purity is not high, period of storage is short, and a kind of preparation method of α type STI571 of high crystal formation purity is provided.

In order to solve the problems of the technologies described above, the present invention realizes through following technical scheme:

(1), at room temperature; With imatinib (Suzhou Lixin Pharmacy Co., Ltd.; Chemical purity 99.9%) mixes with an amount of absolute ethyl alcohol; She counts 0.5:13 ~ 27 with g/mL by Ma Ti Ni ︰ absolute ethyl alcohol, and in suspension-s, drips the methanesulfonic acid solution that diluted through absolute ethyl alcohol, stirs solid is dissolved fully;

(2), with the solution millipore filtration of step (1) gained, remove solid impurity, obtain clear filtrate;

(3), in step (2) the gained settled solution, add crystal seed, growing the grain 1 ~ 2 h under the normal temperature;

(4), ETHYLE ACETATE washing step (3) gained solid 2 times, and vacuum-drying 24 h under vacuum tightness 50 mbar, 50 ~ 55 ℃ of conditions obtain alpha-crystal form STI571 product.

Above-mentioned methanesulfonic acid solution is meant that the dense methylsulfonic acid with mass concentration 99% is diluted to 12% methylsulfonic acid ethanolic soln with absolute ethyl alcohol, and the mol ratio of methylsulfonic acid dripping quantity and imatinib is 1:1.

The above-mentioned condition of crossing millipore filtration is meant that normal temperature, decompression, membrane pore size are 0.22 μ m.

Above-mentioned crystal seed is meant α type STI571, and its add-on is 1% of a theoretical yield.

Beneficial effect of the present invention: the present invention adopts easy reaction process and seed technology, can effectively improve crystallization velocity and purity.Compared with prior art, the present invention has following characteristics: be easy to suitability for industrialized production, product crystal formation purity height, efficient.

Description of drawings

The α type STI571 X-ray powder diffraction that Fig. 1 embodiment 1 obtains.

The α type STI571 IR collection of illustrative plates that Fig. 2 embodiment 1 obtains.

Fig. 3 β type STI571 X-ray powder diffraction.

Fig. 4 β type STI571 IR collection of illustrative plates.

The amorphous STI571 X-of Fig. 5 ray powder diffraction.

The amorphous STI571 IR of Fig. 6 collection of illustrative plates.

Embodiment

Further present invention is described through specific embodiment: at room temperature; Imatinib is mixed with an amount of absolute ethyl alcohol; Imatinib: absolute ethyl alcohol is counted 0.5:13 ~ 27 with g/mL; Ratio according to the mol ratio 1:1 of methylsulfonic acid and imatinib drips the methanesulfonic acid solution that diluted through absolute ethyl alcohol in suspension-s, stir solid is dissolved fully.The solution of gained descended millipore filtration in normal temperature, reduced pressure, removed solid impurity, obtained clear filtrate.In settled solution, add an amount of α crystal seed (theoretical yield 1%), growing the grain 1 ~ 2 h under the normal temperature.Filter and with ETHYLE ACETATE wash solids product 2 times, product obtains α type STI571 at 50 ~ 55 ℃ of following vacuum-drying 24 h.

Embodiment 1:

At room temperature, 0.5g (0.001mol) imatinib and 13mL absolute ethyl alcohol are mixed, in suspension-s, drip 0.07mL methylsulfonic acid (0.001mol) solution that diluted through the 1mL absolute ethyl alcohol, stirring is dissolved solid fully.The solution of gained descended millipore filtration in normal temperature, reduced pressure, removed solid impurity, obtained clear filtrate.In settled solution, add 0.006g α crystal seed, growing the grain 2h under the normal temperature.Filter and with 10mL ETHYLE ACETATE wash solids product 2 times, product obtains 0.55g α type STI571 at 50 ~ 55 ℃ of following vacuum-drying 24 h, yield is 92.0%.PXRD and IR detect its crystal formation purity>95%.

Embodiment 2:

At room temperature, 0.5g (0.001mol) imatinib and 20mL absolute ethyl alcohol are mixed, in suspension-s, drip 0.07mL methylsulfonic acid (0.001mol) solution that diluted through the 1mL absolute ethyl alcohol, stirring is dissolved solid fully.The solution of gained descended millipore filtration in normal temperature, reduced pressure, removed solid impurity, obtained clear filtrate.In settled solution, add 0.006g α crystal seed, growing the grain 2h under the normal temperature.Filter and with 10mL ETHYLE ACETATE wash solids product 2 times, product obtains 0.54g α type STI571 at 50 ~ 55 ℃ of following vacuum-drying 24 h, yield is 90.3%.PXRD and IR detect its crystal formation purity>95%.

Embodiment 3:

At room temperature, 0.5g (0.001mol) imatinib and 27mL absolute ethyl alcohol are mixed, in suspension-s, drip 0.07mL methylsulfonic acid (0.001mol) solution that diluted through the 1mL absolute ethyl alcohol, stirring is dissolved solid fully.The solution of gained descended millipore filtration in normal temperature, reduced pressure, removed solid impurity, obtained clear filtrate.In settled solution, add 0.006g α crystal seed, growing the grain 2h under the normal temperature.Filter and with 10mL ETHYLE ACETATE wash solids product 2 times, product obtains 0.52g α type STI571 at 50 ~ 55 ℃ of following vacuum-drying 24 h, yield is 87.0%.PXRD and IR detect its crystal formation purity>95%.

Embodiment 4:

At room temperature, 1.0g (0.002mol) imatinib and 26mL absolute ethyl alcohol are mixed, in suspension-s, drip 0.13mL methylsulfonic acid (0.002mol) solution that diluted through the 2mL absolute ethyl alcohol, stirring is dissolved solid fully.The solution of gained descended millipore filtration in normal temperature, reduced pressure, removed solid impurity, obtained clear filtrate.In settled solution, add 0.012g α crystal seed, growing the grain 2h under the normal temperature.Filter and with 20mL ETHYLE ACETATE wash solids product 2 times, product obtains 1.14g α type STI571 at 50 ~ 55 ℃ of following vacuum-drying 24 h, yield is 95.3%.PXRD and IR detect its crystal formation purity>95%.

The above content is merely the basic explanation of the present invention under conceiving, and according to any equivalent transformation that technical scheme of the present invention is done, all should belong to protection scope of the present invention.

Claims (2)

1. the preparation method of a high-purity alpha crystal formation STI571 is characterized in that this method steps is:
(1), at room temperature, imatinib is mixed imatinib with an amount of absolute ethyl alcohol: absolute ethyl alcohol is counted 0.5:13 ~ 27 with g/mL, and in suspension-s, drips the methanesulfonic acid solution that diluted through absolute ethyl alcohol, stirs solid is dissolved fully;
(2), with the solution millipore filtration of step (1) gained, remove solid impurity, obtain clear filtrate;
(3), in step (2) gained settled solution, add an amount of crystal seed, growing the grain 1 ~ 2h under the normal temperature;
(4), ETHYLE ACETATE washing step (3) gained solid 2 times, and vacuum-drying 24 h under vacuum tightness 50 mbar, 50 ~ 55 ℃ of conditions obtain alpha-crystal form STI571 product;
In the step (1), said methanesulfonic acid solution is meant that the dense methylsulfonic acid with mass concentration 99% is diluted to 12% methylsulfonic acid ethanolic soln with absolute ethyl alcohol, and the mol ratio of methylsulfonic acid dripping quantity and imatinib is 1:1;
In the step (3), an amount of crystal seed of said adding is meant and adds alpha-crystal form STI571 crystal seed that add-on is controlled to be 1% of STI571 theoretical yield.
2. the preparation method of high-purity alpha crystal formation STI571 according to claim 1 is characterized in that step (2), and the said condition of crossing millipore filtration is meant that normal temperature, decompression, membrane pore size are 0.22 μ m.
CN2012100990498A 2012-04-06 2012-04-06 Crystallizing method for preparing alpha crystal form methanesulfonic acid imatinib CN102617552A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103570676A (en) * 2012-08-04 2014-02-12 正大天晴药业集团股份有限公司 Preparation of imatinib mesylate alpha crystal and pharmaceutical composition thereof

Citations (4)

* Cited by examiner, † Cited by third party
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
WO2006048890A1 (en) * 2004-11-04 2006-05-11 Sun Pharmaceutical Industries Limited Imatinib mesylate crystal form and process for preparation thereof
US20070197545A1 (en) * 2004-04-02 2007-08-23 Instytut Farmaceutyczny Crystalline Polymorphs Of Methanesulfonic Acid Addition Salts Of Imatinib
CN102190649A (en) * 2011-03-28 2011-09-21 齐鲁天和惠世制药有限公司 Method for preparing alpha-imatinib mesylate

Patent Citations (4)

* Cited by examiner, † Cited by third party
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
US20070197545A1 (en) * 2004-04-02 2007-08-23 Instytut Farmaceutyczny Crystalline Polymorphs Of 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
CN102190649A (en) * 2011-03-28 2011-09-21 齐鲁天和惠世制药有限公司 Method for preparing alpha-imatinib mesylate

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103570676A (en) * 2012-08-04 2014-02-12 正大天晴药业集团股份有限公司 Preparation of imatinib mesylate alpha crystal and pharmaceutical composition thereof
CN103570676B (en) * 2012-08-04 2016-03-16 正大天晴药业集团股份有限公司 The preparation of imatinib mesylate α crystallization and pharmaceutical composition thereof

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Application publication date: 20120801