KR20120047342A - New method for synthesiging imatinib - Google Patents

Abstract

PURPOSE: A method for synthesizing imatinib is provided to enhance yield by aminolysis reaction of ester. CONSTITUTION: A method for synthesizing imatinib comprises a step of reacting 4-(4-methyl-N-3-(4-pyridin-2-ye)-1, 3-benzenediamine of structural formula I and 4-(4-methy)-piperazin-1-methyl)-benzoic ester of general formula II in a base and organic solvent. The organic solvent is tetrahydrofuran, ether, dichloromethane, 1,2-dichloroethane, acetonitrile, C1-4 alcohol, toluene, ethyl, acetate, dimethyl formamide, dimethyl sulfoxide, or dimethyl benzene.

Description

New method for synthesis of imatinib {New method for Synthesiging Imatinib}

The present invention relates to a new method of synthesizing imatinib.

 Imatinib mesylate, a signal transduction inhibitor developed by Novartis over seven years, is the world's first approved cancer signal transduction inhibitor. Imatinib mesylate has been certified as a rare disease drug in the United States, Europe, and Japan, and chronic myelogenous leukemia in the blast, or blast, accelerator, and chronic phases by the US Food and Drug Administration (FDA) on May 10, 2001. It has been recognized as a treatment for patients.

The chemical name of imatinib is

4- (4-methyl-piperazin-1-ylmethyl) -N- [4-methyl-3- [4- (3-pyridinyl) -pyrimidin-2-ylamino] -benzamide], and the chemical formula is shown below.

There are two ways to industrially synthesize imatinib. The first method is reacting 2-methyl-5-nitro-phenylamine with cyanamide to form guanidine and 3-dimethylamino-l- (3-pyridinyl) -2-propylene-1-ketone Cyclization was carried out to reduce the nitro group to an amino group, and condensed p-chloromethyl-benzoyl chloride and N-methyl-piperazine sequentially to prepare imatinib using 2-methyl-5-nitro-phenylamine as a starting material. (See WO 2004/108699).

In the second method, p-chloromethyl-benzoyl chloride and N-methyl-piperazine are sequentially condensed to reduce the nitro group to an amino group, and then react with cyanamide to obtain guanidine, which is 3-dimethyllamino-l- ( Imatinib is prepared using 4-methyl-3-nitro-phenylamine obtained by crystallization in 3-pyridinyl) -2-propylene-I-ketone as a starting material (see WO 03/066613).

The main difference between these two methods is the continuous pyrimidine cyclization. However, both methods have the following disadvantages: 1) Guanidine is unstable with low yield because it is synthesized using a low boiling point and highly volatile cyanamide; 2) Synthesis of pyrimidine ring has low yield, long production time and incomplete reaction of raw materials.

Another method of synthesizing imatinib is also disclosed in Chinese Patent No. CN1630648A. In this method, 2-bromo-4-methyl-phenylamine is used as a raw material, and to obtain N- (4-methyl-3-bromo-phenyl) -4- (4-methyl-piperazin-1-ylmethyl) -benzamide Aminolysis of 4- (4-methyl-piperazin-l-ylmethyl) -benzoic acid methyl ester is carried out using trimethylaluminum to obtain imatinib, which is then reacted with pyrimithamine using a precious metal palladium catalyst. The disadvantages of this method are that 1) the trimethylaluminium used here is a flammable chemical and reacts violently with water and 2) contains about 10% of the isomers which are difficult to remove in the final product.

Another method of synthesizing imatinib is disclosed in Chinese Patent No. CN101016293A. In this method, N- (4-methyl-3-3-amino-phenyl) -4- (4-methyl-piperazin-1-ylmethyl) -benzamide is used as a raw material, and 2-halogeno-4-methyl- (3 reacts with -pyridin-3-yl) -pyrimidine Halogenated reagents used to synthesize 2-halogeno-4-methyl- (3-pyridin-3-yl) -pyrimidine, such as phosphorus oxychloride, are highly toxic and have a very serious environmental impact.

An object of the present invention is to provide a high yield of imatinib synthesis method in an environmentally friendly way by using a low toxicity raw materials under mild reaction conditions.

Imatinib synthesis in the present invention is represented by the 4- (4-methyl-piperzazin-l-methyl) -benzoic acid ester represented by the following general formula (II) and the following structural formula (I) 4-methyl-N-3- (4-pyridin-3-yl-pyrimidin-2-yl) -1,3-benzenediamine is reacted to synthesize a compound represented by the following structural formula (III).

It said general formula, R represents an aliphatic alkyl of C ₁ ~ ₁₀ with a phenyl, substituted phenyl, benzyl or substituted benzyl.

In the present invention, C ₁ ~ ₁₀ aliphatic alkyl is p-methoxy-phenyl, benzyl substituent is p-methoxy-benzyl, the base may be an organic base or an inorganic base. The organic base may be selected from one or more of sodium alcoholate, potassium alcoholate, butyl lithium, isobutyl lithium, tert-butyl lithium, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and potassium carbonate. do. Sodium alcoholate is selected from one or more of sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, sodium tert-butoxide and sodium benzoxide. Potassium alcoholate is selected from one or more of potassium methoxide, potassium ethoxide, potassium propoxide, potassium butoxide, potassium tert-butoxide and potassium benzoxide. The base concentration is preferably 0.1-10M, preferably 1-2M.

Organic solvent in the present invention include tetrahydrofuran, ether, dichloromethane, 1,2-dichloroethane, acetonitrile, C ₁ ~ ₄ alcohols, toluene, ethyl acetate, dimethylformamide (dimethyl formamide), dimethyl sulfoxide, and one of the dimethylbenzene Or choose more.

The molar ratio of the compound represented by formula (I) to the compound represented by formula (II) is preferably 1: 1 to 1:10, and more preferably 1: 1.5 to 1: 4.

The reaction temperature is preferably 0-100 ° C, more preferably 25-50 ° C. The reaction continues until no reduction of the raw material is detected. Methods of synthesizing the compounds represented by formula (I) are described in WO 2004/108699.

n- (2-methyl-5-nitro-phenyl) -guanidine is formed by the reaction of 2-methyl-5-nitro-phenylamine with cynamide. The pyrimidine compound is obtained by reaction with n- (2-methyl-5-nitro-henyl) -guanidine reacted with 3-dimethylamino-l-pyridin-3-yl-propenone, and the compound represented by formula (I) is a nitro group. Obtained by reduction.

The method for synthesizing the compound represented by formula (II) is described in "Synthetic Compound 2003,3597" (syn. Comm. 2003.3597), and synthesized as follows. First, a P-halomethyl-benzonitrile or p-hydroxymethyl-benzonitrile sulfonic acid ester is reacted with methylpiperazine, and then the acid is reacted with the alcohol to form the ester, i.e., a compound represented by formula (II).

In the above chemical structures, R is phenyl, substituted phenyl, represents a benzyl ttoeun replace benzyl substituent of the aliphatic alkyl, C ₁ ~ ₁₀ having, X represents a Cl, Br, I, or of OM OT.

Raw materials or reagents used in the present invention can be obtained commercially unless otherwise specified.

The method of the present invention has a high yield because the aminolysis reaction of ester can be completed completely, and the dispersion of the aminolisis reaction is suitable for commercial production since the reaction can proceed under environmentally friendly and mild reaction conditions in alcohol. Has an effect.

The applications are presented below, but the invention is not limited to these applications. In the applications below, the experiment is conducted under normal conditions or as recommended by the manufacturer.

[ Example  One]

In 500 ml of dried four-necked flask, 250 ml of tetrahydrofuran, 27.7 g of 4-methyl-N-3- (4-pyridin-3-yl-pyrimidin-2-yl) -1, 3-benzenediamine and 25 g of 4- (4-methyl-piperazin-1-methyl) -benzoic acid methyl ester was added. Stir to dissolve the mixture and add 10 g sodium methoxide. The mixture was then heated to 70 ° C. to reflux and react overnight until the reaction was complete and concentrated to remove tetrahydrofuran. The residual solid was washed with water and dried to give 45 g of imatinib with a yield of 91%.

The data values are as follows:

1 H NMR (500M, DMSO) δ: 10.2 (s, 1H), 9.30 (s, 1H), 8.99 (s, 1H), 8.72 (d, J = 4.0Hz, 1H), 8.57 (s, 1H), 8.53 (s, 1H), 8.11 (s, 1H), 8.00 (s, 1H), 7.58-7.51 (m, 4H), 7.44 (d, J = 4.3Hz, 1H), 7.22 (d, J = 8.1Hz, 1H), 3.70 (s, 2H), 3.50-3.25 (m, 2H), 3.20-2.90 (m, 4H), 2.81 (s, 3H), 2.40 (s, 3H), 2.24 (s, 3H), 13C NMR (125M, DMSO) δ: 164.9, 161.3, 161.1, 159.4, 150.8, 147.7, 137.7, 137.1, 134.9, 134.3, 132.3, 129.9, 129.1, 127.7, 127.6, 123.9, 117.2, 116.8, 107.5, 59.9, 52.1, 48.9, 42.2, 17.5

MS (M ++ 1): 494.3

[ Example  2]

3L dichloromethane, 277g 4-methyl-N-3- (4-pyridin-3-yl-pyrimidin-2-yl) -1, 3-benzenediamine and 270g 4- (4) in 5,000ml dried sand dune flask -methyl-piperazin-1-methyl) -benzoic acid methyl ester was added. Stir to dissolve the mixture and add 100 g sodium methoxide. The mixture was then heated to 40 ° C. to reflux and react overnight until the reaction was complete and concentrated to remove toluene. The residual solid was washed with water and dried to give 455 g of imatinib with a yield of 92%. The data values are the same as in Example 1.

[ Example  3]

In a 5 L dried sand dune flask, 3 L toluene, 277 g 4-methyl-N-3- (4-pyridin-3-yl-pyrimidin-2-yl) -1, 3-benzenediamine and 450 g 4- (4- Methyl-piperazin-1-methyl) -benzoic acid benzyl ester was added. Stir to dissolve the mixture and add 100 g sodium methoxide. The mixture was then heated to 50 ° C. to reflux and react overnight until the reaction was complete and concentrated to remove toluene. The residual solid was washed with water and dried to give 445 g of imatinib with a yield of 90.0%. The data values are the same as in Example 1.

[ Example  4]

3L toluene, 2.77kg 4-methyl-N-3- (4-pyridin-3-yl-pyrimidin-2-yl) -1, 3-benzenediamine and 3.50kg 4- (4-methyl in 50L reactor -piperazin-1-methyl) -benzoic acid benzyl ester was added. Stir to dissolve the mixture and add 3 kg potassium butoxide. The mixture was then heated to 50 ° C. to react overnight until the reaction was complete and placed in water to separate the solids. The residual solid was centrifuged and dried to yield 445 g of imatinib with a yield of 90.0%. The data values are the same as in Example 1.

[ Example  5]

In a 5 L dried dune flask, 3 L acetonitrile, 277 g 4-methyl-N-3- (4-pyridin-3-yl-pyrimidin-2-yl) -1, 3-benzenediamine and 450 g 4- (4 -Methyl-piperazin-1-methyl) -benzoic acid 4-methoxy-benzyl ester was added. After stirring to dissolve the mixture, 400 mL (2.5 M) butyl lithium was added. The mixture was then heated to 20 ° C. to react overnight until the reaction was complete and concentrated to remove acetonitrile. The obtained solid was washed with water and dried to obtain 445 g of imatinib, with a yield of 90.0%. The data values are the same as in Example 1.

[ Example  6]

3 L propanol, 277 g 4-methyl-N-3- (4-pyridin-3-yl-pyrimidin-2-yl) -1, 3-benzenediamine and 2.25 kg 4- (4-methyl- in 5 L flask piperazin-1-methyl) -benzoic acid 4-methoxy-phenyl ester was added. After stirring to dissolve the mixture, 1.5 kg of cesium hydroxide was added. The mixture was then heated to 80 ° C. to react overnight until the reaction was complete and concentrated to remove propanol. The obtained solid was washed with water and dried to obtain 450 g of imatinib, with a yield of 90.5%. The data values are the same as in Example 1.

[ Example  7]

In a 5 L flask, 3 L ethyl acetate, 277 g 4-methyl-N-3- (4-pyridin-3-yl-pyrimidin-2-yl) -1, 3-benzenediamine and 450 g 4- (4-methyl- piperazin-1-methyl) -benzoic acid p-toly ester was added. After stirring to dissolve the mixture, 138 g of potassium carbonate was added. The mixture was then heated to 50 ° C. to react overnight until the reaction was complete and concentrated to remove ethyl acetate. The obtained solid was washed with water and dried to obtain 445 g of imatinib, with a yield of 90.0%. The data values are the same as in Example 1.

[ Example  8]

In a 5 L dried dune flask, 3 L dimethyl sulfoxide, 277 g 4-methyl-N-3- (4-pyridin-3-yl-pyrimidin-2-yl) -1, 3-benzenediamine and 450 g 4- ( 4-methyl-piperazin-1-methyl) -benzoic acid p-toly ester was added. After stirring to dissolve the mixture, 800 g of sodium hydroxide was added. The mixture was then heated to 70 ° C. to react overnight until the reaction was complete and concentrated to remove dimethyl sulfoxide. The obtained solid was washed with water and dried to obtain 445 g of imatinib, with a yield of 90.0%. The data values are the same as in Example 1.

[ Example  9]

In a 5 L flask, 3 L ether, 277 g 4-methyl-N-3- (4-pyridin-3-yl-pyrimidin-2-yl) -1, 3-benzenediamine and 1.5 kg 4- (4-methyl- piperazin-1-methyl) -benzoic acid benzyl ester was added. After stirring to dissolve the mixture, 1 kg (1 mol) of sodium benzoxide was added thereto. The mixture was then cooled to 0 ° C. to react overnight until the reaction was complete and concentrated to remove ether. The obtained solid was washed with water and dried to obtain 445 g of imatinib, with a yield of 90.0%. The data values are the same as in Example 1.

Claims (8)

In the method for synthesizing imatinib
4- (4-methyl-N-3- (4-pyridin-2-ye) -1, 3-benzenediamine represented by the following structural formula (I), and 4- (4-methy represented by the following general formula (II) ) -piperazin-1-methyl) -benzoic ester is reacted with a base in an organic solvent to form 4- (4-methyl-piperazin-1-ylmethyl) -N- [4-methyl-3- represented by the following structural formula (III): Method for synthesizing imatinib, 4- [4- (3-pyridinyl) -pyrimidin-2-ylamino] -benzamide]

In the general formula (II) R is an aliphatic alkyl of C ₁ ~ ₁₀ with a phenyl, substituted phenyl, benzyl or substituted benzyl.
The method of claim 1, wherein the aliphatic alkyl group of C ₁ ~ _10, and the phenyl substituents P-methy1-phenyl) will be selected from methyl, ethyl or propyl, a method of synthesizing a benzyl substituent imatinib the P-methoxy-benzyl
The method of synthesizing imatinib according to claim 1, wherein the compound represented by the general formula (II) is reacted at a molar ratio of 1: 1 to 1: 5 to react the compound represented by the structural formula (I).
The method of claim 1, wherein the base is selected from sodium alcoholate, potassium alcoholate, butyl lithium, iso-butyl lithium, tert-butyl lithium, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and potassium carbonate. How to Synthesize Imatinib of Choice
The method for synthesizing imatinib according to claim 1, wherein the concentration of the base is 0.1 to 10 moles.
The method of claim 1, wherein the organic solvent is tetrahydrofuran, ether, dichloromethane, 1, 2-ethane as a thickeners, acetonitrile, C ₁ ~ ₄ alcohol, toluene, ethyl acetate, dimethylformamide, dimethyl sulfoxide and dimethyl Method for synthesizing imatinib selected from one or more of benzene
The method for synthesizing imatinib according to claim 1, wherein the reaction temperature is 0 to 80 ° C.
The method for synthesizing imatinib according to claim 1, wherein the reaction proceeds until the compound represented by formula (I) and the compound represented by formula (II) are not detected.