CN103058991A - Preparation method of alpha-crystal form imatinib mesylate - Google Patents

Preparation method of alpha-crystal form imatinib mesylate Download PDF

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Publication number
CN103058991A
CN103058991A CN2012105857642A CN201210585764A CN103058991A CN 103058991 A CN103058991 A CN 103058991A CN 2012105857642 A CN2012105857642 A CN 2012105857642A CN 201210585764 A CN201210585764 A CN 201210585764A CN 103058991 A CN103058991 A CN 103058991A
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China
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crystal form
imatinib mesylate
preparation method
reaction
alpha
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CN2012105857642A
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Chinese (zh)
Inventor
王雪根
何凌云
郭莉芹
周磊
吴邵嘉
卢向阳
赵国新
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南京艾德凯腾生物医药有限责任公司
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Publication of CN103058991A publication Critical patent/CN103058991A/en

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Abstract

The invention discloses a preparation method of alpha-crystal form imatinib mesylate. The preparation method comprises the following steps that 1, 4-[(4-methyl piperazine-1-yl)methyl]benzoic acid dihydrochloride shown in the formula II is converted into an acyl chloride shown in the formula III by an acylating chlorination reagent; 2, the acyl chloride shown in the formula III and N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-aminopyrimidin undergo a condensation reaction in the presence of an alkali to produce a compound shown in the formula IV; and 3, the compound shown in the formula IV and methylsulfonic acid undergo a salt forming reaction in the presence of an organic solvent to produce a compound shown in the formula I. The preparation method can realize preparation of stable alpha-crystal form imatinib mesylate and allows mild process conditions. The stable alpha-crystal form imatinib mesylate can be after-treated simply and has high purity. The preparation method has a low reaction cost and is suitable for industrial production.

Description

A kind of preparation method of alpha-crystal form imatinib mesylate

Technical field

The invention belongs to the chemicals synthesis technical field, relate to the preparation method of alpha-crystal form 4-(4-methyl isophthalic acid-piperazine) methyl-N-4-methyl-3-4-(3-pyridine)-2-pyrimdinyl-amino phenyl-aniline mesylate (imatinib mesylate).

Background technology

Imatinib mesylate (Imatinib Mesylate), chemistry 4-(4-methyl isophthalic acid-piperazine) methyl by name-N-4-methyl-3-4-(3-pyridine)-2-pyrimdinyl-amino phenyl-aniline mesylate compound, structural formula is as follows:

Imatinib mesylate is the derivative of aniline pyrimidine by the exploitation of Switzerland Novartis Co.,Ltd, is a specific tyrosine kinase inhibitor, is used for the treatment of chronic lymphocytic leukemia and gastrointestinal stromal tumors.Imatinib mesylate all can suppress the Bcr-Abl Tyrosylprotein kinase at cell levels in vivo and in vitro, can selectivity suppress the chronic myelocytic leukemia of Bcr-Abl positive cell line cell, PH chromatin-positive and acute lymphoblastic leukemia patient new fresh cell propagation and induce its apoptosis.In addition, imatinib mesylate also can suppress platelet derived growth factor (PDGF) acceptor, STEM CELL FACTOR (SCF), the Tyrosylprotein kinase of c-Kit acceptor, thus inhibition is by the cell behavior of PDGF and STEM CELL FACTOR mediation.

The synthetic method of imatinib mesylate is a lot, and the method summary of related documents report is as follows:

(1) prepare the method for imatinib among the PCT patent WO 03/066613 as follows:

The method is carried out first condensation reaction successively take 4-methyl-3-nitro aniline as starting raw material, and reduction generates guanidine with cyanamide again, carries out ring-closure reaction again and obtains imatinib.The ring-closure reaction yield that the shortcoming of the method is to generate pyrimidine ring is very low, and long and reaction of reaction times not exclusively.

Chinese patent CN1630648A discloses a kind of method for preparing imatinib, the method used amide condensed dose of chemical that trimethyl aluminium is easy spontaneous combustion in preparation process, there is potential danger during scale operation, be not suitable for suitability for industrialized production, and building-up process has been used catalyzer and BINAP part, and production cost is too high.

European patent EP 564409 discloses a kind of method for preparing imatinib, take 3-nitrophenyl nitroguanidine and dimethylamino-1-(3-pyridyl)-the 2-propylene is as starting raw material, obtain at last imatinib through pass ring, reduction, condensation, final step will through column chromatography purification, be not suitable for suitability for industrialized production.

Less for the document of imatinib mesylate crystal formation research in the prior art, relate to alpha-crystal form imatinib mesylate preparation technology's document still less, therefore, be very important by the preparation method who researchs and develops a kind of safe and manageable alpha-crystal form imatinib mesylate.

Summary of the invention

In view of the deficiencies in the prior art, it is shorter that technical problem to be solved by this invention provides a kind of synthesis step, be easy to purifying, simple to operate, the preparation method of the 4-of the alpha-crystal form that yield is higher (4-methyl isophthalic acid-piperazine) methyl-N-4-methyl-3-4-(3-pyridine)-2-pyrimdinyl-amino phenyl-aniline mesylate (imatinib mesylate).

In order to realize purpose of the present invention, the inventor studies by lot of experiments, has finally obtained following technical scheme:

A kind of preparation method of alpha-crystal form imatinib mesylate comprises the following steps:

(1) with formula II compound 4-[(4-methylpiperazine-1-yl) methyl] the phenylformic acid dihydrochloride is converted into the acyl chlorides compound of formula III with chloride reagent:

(2) the formula III compound obtains the formula IV compound with N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine condensation in the presence of alkali:

(3) formula IV compound and methylsulfonic acid salt-forming reaction obtain the formula I compound:

Be the alpha-crystal form imatinib mesylate behind the gained formula I compound crystallization.

Preferably, the preparation method of above-mentioned alpha-crystal form imatinib mesylate, wherein the temperature of reaction of step (1) is 80-110 ℃, and the reaction times is 4-6 hour, and reaction solvent is selected from one or more in toluene, DMF and the pyridine; Described chloride reagent is selected from one or more of sulfur oxychloride, oxalyl chloride and phosphorus trichloride.

Further preferably, the preparation method of above-mentioned alpha-crystal form imatinib mesylate, wherein the reaction solvent in the step (1) is toluene, described chloride reagent is sulfur oxychloride.

Preferably, the preparation method of above-mentioned alpha-crystal form imatinib mesylate, wherein the temperature of reaction of step (2) is 20-30 ℃, and the reaction times is 4-6 hour, and reaction solvent is selected from one or more in DMF, DMSO, toluene, pyridine and the tetrahydrofuran (THF); Described alkali is selected from one or more of salt of wormwood, yellow soda ash, cesium carbonate, sodium hydride, triethylamine, sodium methylate and sodium ethylate, and the consumption of alkali is 1.0-1.5 times (M/M mol ratio) of N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine consumption.M/M herein is mol ratio.

Further preferably, the preparation method of above-mentioned alpha-crystal form imatinib mesylate, wherein the reaction solvent in the step (2) is pyridine or/and tetrahydrofuran (THF), described alkali is triethylamine.

Preferably, the preparation method of above-mentioned alpha-crystal form imatinib mesylate, wherein the salt-forming reaction temperature of step (3) is 80-90 ℃, and the reaction times is 4-6 hour, and reaction solvent is selected from one or more of methyl alcohol, ethanol, n-propyl alcohol, Virahol and amylalcohol; Recrystallization temperature is 20-30 ℃, and the crystallization time is 16-20 hour.

Further preferably, the preparation method of above-mentioned alpha-crystal form imatinib mesylate, wherein the reaction solvent in the step (3) is the mixed solvent of ethanol and Virahol.

Again further preferably, the preparation method of above-mentioned alpha-crystal form imatinib mesylate, wherein the reaction solvent in the step (3) is ethanol: the mixed solvent of Virahol=2:8(v:v), the consumption of mixed solvent are the 10-15 doubly (v/w) of compound (IV) weight.

Imatinib mesylate has multiple crystal formation, wherein mainly is that alpha-crystal form and beta crystal are used for clinical treatment.The inventor has found a kind of novel method for preparing the alpha-crystal form imatinib mesylate in research process.Compare with existing method, it is shorter that the method has synthesis step, simple to operate, is easy to purifying, and yield is high, the advantage that finished product is stable.In addition, the present invention has effectively avoided using inflammable, deadly poisonous compound, greatly dwindled reactions steps simultaneously, thereby reduced the reaction difficulty, and then simplified aftertreatment, the reaction cost that improved yield and decrease, be beneficial to industrialized production.

Embodiment

Form is described in further detail foregoing of the present invention again by the following examples, but this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment, all technology that realizes based on foregoing of the present invention all belong to scope of the present invention.

The preparation of embodiment alpha-crystal form imatinib mesylate

(1) 4-[(4-methylpiperazine-1-yl) methyl] Benzoyl chloride (formula III) synthetic

In the four-hole round-bottomed flask of 1000mL, mechanical stirring is installed, reflux condensing tube, thermometer, in round-bottomed flask, add 200mL toluene, open and stir, add sour (4-[(4-methylpiperazine-1-yl) methyl of her horse of 50g] the phenylformic acid dihydrochloride), stir the lower 25 mL sulfur oxychlorides that slowly add, be warming up to 80~90 ℃, insulated and stirred reaction 4 hours is closed the heating nature and is down to room temperature, vacuum concentration gets oily matter.Be directly used in next step.

(2) 4-(4-methyl isophthalic acid-piperazine) methyl-N-4-methyl-3-4-(3-pyridine)-2-pyrimdinyl-amino phenyl-aniline (formula IV) is synthetic

In the 1000mL there-necked flask, she is horse amine (N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine) 37g, add 150mL pyridine and 35ml triethylamine, drip the 4-[(4-methylpiperazine-1-yl under the stirring at room) methyl] tetrahydrofuran solution (oily matter obtained above is dissolved in the 100mL tetrahydrofuran (THF)) of Benzoyl chloride, keep 20~30 ℃, stirring reaction 6 hours.Add the 200mL purified water, then add strong aqua and regulate pH value 8-9.Stirring and crystallizing 4 hours, suction filtration get 4-(4-methyl isophthalic acid-piperazine) methyl-N-4-methyl-3-4-(3-pyridine)-2-pyrimdinyl-amino phenyl-aniline solid, and solid has the washing of 400mL purified water.Suction filtration gets 4-(4-methyl isophthalic acid-piperazine) methyl-N-4-methyl-3-4-(3-pyridine)-2-pyrimdinyl-amino phenyl-aniline.60 ℃ of lower vacuum-dryings 12 hours, get 4-(4-methyl isophthalic acid-piperazine) methyl-N-4-methyl-3-4-(3-pyridine)-2-pyrimdinyl-amino phenyl-aniline dry product 50.2g.Yield: 64%, be directly used in next step.

(3) 4-(4-methyl isophthalic acid-piperazine) methyl-N-4-methyl-3-4-(3-pyridine)-2-pyrimdinyl-amino phenyl-aniline mesylate (formula I) is synthetic

Get the compound 50g in step, add the mixing solutions 500mL(ethanol of ethanol and Virahol: the Virahol volume ratio is 2:8), drip the 10g methylsulfonic acid, drip off in the 30min.Regulate temperature, be warming up to 80 ℃ of-85 ℃ of backflows, reacted 4 hours.Reaction is cooled to 20-30 ℃, stirring and crystallizing 16 hours after finishing.Suction filtration, filter cake 100mL washed with isopropyl alcohol dry 12 hours of 60 ℃ of lower vacuum drying ovens, gets the off-white color solid.Obtain 40.3g, yield: 67%.HPLC:99.7%。The compound that obtains is the alpha-crystal form imatinib mesylate, and is very stable.

Relevant physico-chemical property, the spectroscopy data of compound (formula I) are as follows:

Fusing point: 222-225 ℃; 1H NMR(300MHz, D 2O) δ (ppm): 10.3 (s, 1H), 9.8 (s, 11H), 9.4 (s, 1H) 9.0 (d, 1H), 8.8 (d, 1H), 7.5 (q, 5H) 7.3 (d, 1H), 3.8 (s, 2H) 3.6 (s, 2H,), 2.8 (s, 5H), (2.2 s, 5H), 2.0 (s, 3H); MS (ES) m/z 494.1 ([M-CH 3SO 3H+H] +). compound (formula I) X-ray diffracting spectrum is that its refraction angle of alpha-crystal form characteristic peak 2 θ are as follows: 4.9 ° (18), 10.5 ° (100), among 28.6 ° (25) and the former patent CN98807303.X of the unit of grinding in the α spectrogram characteristic peak data basically identical.

The instrument and the reagent that adopt in the various embodiments described above are as follows:

X-4 type micro-meldometer; Varian Mercury plus-500 MHz type nuclear magnetic resonance analyser, AGILENT LC-MSD-Trap-SL mass spectrograph, D 8X-ray diffractometer (German Bruker-axs company).

Used other reagent is commercially available analytical pure or chemical pure, and is not purified before the use.

Claims (8)

1. the preparation method of an alpha-crystal form imatinib mesylate is characterized in that comprising the following steps:
(1) with formula II compound 4-[(4-methylpiperazine-1-yl) methyl] the phenylformic acid dihydrochloride is converted into the acyl chlorides compound of formula III with chloride reagent:
(2) the formula III compound obtains the formula IV compound with N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine condensation in the presence of alkali:
(3) formula IV compound and methylsulfonic acid salt-forming reaction obtain the formula I compound:
Be the alpha-crystal form imatinib mesylate behind the gained formula I compound crystallization.
2. the preparation method of described alpha-crystal form imatinib mesylate according to claim 1, it is characterized in that: the temperature of reaction of step (1) is 80-110 ℃, reaction times is 4-6 hour, and reaction solvent is selected from one or more in toluene, DMF and the pyridine; Described chloride reagent is selected from one or more of sulfur oxychloride, oxalyl chloride and phosphorus trichloride.
3. the preparation method of described alpha-crystal form imatinib mesylate according to claim 2, it is characterized in that: the reaction solvent in the step (1) is toluene, described chloride reagent is sulfur oxychloride.
4. the preparation method of described alpha-crystal form imatinib mesylate according to claim 1, it is characterized in that: the temperature of reaction of step (2) is 20-30 ℃, reaction times is 4-6 hour, and reaction solvent is selected from one or more in DMF, DMSO, toluene, pyridine and the tetrahydrofuran (THF); Described alkali is selected from one or more of salt of wormwood, yellow soda ash, cesium carbonate, sodium hydride, triethylamine, sodium methylate and sodium ethylate, and the consumption of alkali is 1.0-1.5 times (M/M) of N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine consumption.
5. the preparation method of described alpha-crystal form imatinib mesylate according to claim 4 is characterized in that: the reaction solvent in the step (2) is pyridine or/and tetrahydrofuran (THF), and described alkali is triethylamine.
6. the preparation method of described alpha-crystal form imatinib mesylate according to claim 1, it is characterized in that: the salt-forming reaction temperature of step (3) is 80-90 ℃, reaction times is 4-6 hour, and reaction solvent is selected from one or more of methyl alcohol, ethanol, n-propyl alcohol, Virahol and amylalcohol; Recrystallization temperature is 20-30 ℃, and the crystallization time is 16-20 hour.
7. the preparation method of described alpha-crystal form imatinib mesylate according to claim 6, it is characterized in that: the reaction solvent in the step (3) is the mixed solvent of ethanol and Virahol.
8. the preparation method of described alpha-crystal form imatinib mesylate according to claim 6, it is characterized in that: the reaction solvent in the step (3) is ethanol: the mixed solvent of Virahol=2:8(v:v), the consumption of mixed solvent are the 10-15 doubly (v/w) of compound (IV) weight.
CN2012105857642A 2012-12-28 2012-12-28 Preparation method of alpha-crystal form imatinib mesylate CN103058991A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103483314A (en) * 2013-09-16 2014-01-01 南京优科生物医药研究有限公司 Method for preparing imatinib mesylate in alpha crystal form conveniently and rapidly
CN104072477A (en) * 2013-07-26 2014-10-01 江苏豪森药业股份有限公司 Refining method for imatinib
US20150299164A1 (en) * 2014-04-04 2015-10-22 F.I.S. - Fabbrica Italiana Sintetici S.P.A. Process for preparing imatinib and salts thereof, free of genotoxic impurity f
CN106905296A (en) * 2017-03-02 2017-06-30 南京优科制药有限公司 A kind of preparation method of imatinib mesylate

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* Cited by examiner, † Cited by third party
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
US20070265288A1 (en) * 2004-09-02 2007-11-15 Pathi Srinivas L 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
WO2012004801A1 (en) * 2010-07-07 2012-01-12 Hetero Research Foundation Process for imatinib mesylate
WO2012131711A1 (en) * 2011-03-31 2012-10-04 Ind-Swift Laboratories Limited Improved process for preparation of imatinib and its mesylate salt

Patent Citations (5)

* Cited by examiner, † Cited by third party
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
US20070265288A1 (en) * 2004-09-02 2007-11-15 Pathi Srinivas L 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
WO2012004801A1 (en) * 2010-07-07 2012-01-12 Hetero Research Foundation Process for imatinib mesylate
WO2012131711A1 (en) * 2011-03-31 2012-10-04 Ind-Swift Laboratories Limited Improved process for preparation of imatinib and its mesylate salt

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104072477A (en) * 2013-07-26 2014-10-01 江苏豪森药业股份有限公司 Refining method for imatinib
CN103483314A (en) * 2013-09-16 2014-01-01 南京优科生物医药研究有限公司 Method for preparing imatinib mesylate in alpha crystal form conveniently and rapidly
US20150299164A1 (en) * 2014-04-04 2015-10-22 F.I.S. - Fabbrica Italiana Sintetici S.P.A. Process for preparing imatinib and salts thereof, free of genotoxic impurity f
US9630944B2 (en) * 2014-04-04 2017-04-25 F.I.S.—Fabbrica Italiana Sintetici S.p.A. Process for preparing Imatinib and salts thereof, free of genotoxic impurity F
CN106905296A (en) * 2017-03-02 2017-06-30 南京优科制药有限公司 A kind of preparation method of imatinib mesylate
CN106905296B (en) * 2017-03-02 2019-07-19 南京优科制药有限公司 A kind of preparation method of imatinib mesylate

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Application publication date: 20130424