CN107043375B - Novel method for preparing dasatinib and intermediate thereof - Google Patents
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Abstract
The invention discloses a novel method for preparing dasatinib and an intermediate thereof, which comprises the step of carrying out substitution, hydroxymethylation, oxidative amidation, positioned chlorination and amination on 2-aminothiazole (2) to obtain dasatinib (1). The method has the advantages of short synthetic route, high reaction yield, cheap and easily-obtained raw materials, greatly reduced production cost, mild reaction conditions, suitability for industrial scale production, avoidance of acyl chloride and reduced environmental pollution.
Description
The technical field is as follows:
the invention relates to a novel method for manufacturing dasatinib and an intermediate thereof, belonging to the field of pharmaceutical chemistry manufacturing processes.
Background art:
dasatinib (Dasatinib), a second-generation tyrosine kinase inhibitor developed by Bristol-Myers Squibb, was approved by the U.S. Food and Drug Administration (FDA) to be marketed in 2006 under the trade name of sedaxane (Sprycel), is mainly used for the treatment of Chronic Myelogenous Leukemia (CML) and Acute Lymphocytic Leukemia (ALL), and can also treat other types of cancers such as prostate cancer. The chemical name of the compound is N- (2-chloro-6-methylphenyl) -2- [ [6- [4- (2-hydroxyethyl) -1-piperazinyl ] -2-methyl-4-pyrimidinyl ] amino ] -5-thiazolecarboxamide, and the chemical structure is as follows:
the literature reports that the synthetic methods of dasatinib mainly include:
(1) (J Med Chem), 2004, 47 (27): 6658 Discovery of N- (2-chloro-6-methylphenyl) -2- (6- (4- (2-hydroxyethyl) -piperazin-1-yl) -2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with reactive groups in a cationic assay, reported by 6661, by using 2-chlorothiazole as a starting material, to obtain dasatinib with a total yield of 61.1% by acylation, amino protection, substitution, deprotection and amination, which uses extremely strong isocyanates which are toxic and reactive, and by using N-butyllithium and sodium hydride several times in the reaction, which is required to be carried out under anhydrous, oxygen-free and low temperature conditions. The synthetic route is as follows:
(2) disclosed in a Chinese patent (CN 101812060B) at 17.2011.08, a new method for simply preparing high-purity dasatinib and an intermediate compound thereof, 2-chlorothiazole-5-methyl formate is used as a starting raw material, and dasatinib is obtained through substitution, hydrolysis, chlorination and twice amination, wherein the total yield is 41.8%. The synthetic route is as follows:
(3) the cyclic protein tyrosine kinase inhibitor disclosed in the Chinese patent No. CN 1348370A at 05/08/2002 is prepared by using 2-aminothiazole-5-ethyl formate as a starting material, performing amino protection, and performing hydrolysis, chlorination, amination, deprotection and amination to obtain dasatinib with a total yield of 46.0 percent, wherein the synthetic route of the method is long. The synthetic route is as follows:
(4) the Chinese patent (CN 1980909B) at 25 th 2007 (CN 1980909B) (preparation method of 2-aminothiazole-5-aromatic formamide as kinase inhibitor), the world patent at 20 th 2007 at 09 th.09 th.2007 (WO 2007/106879A2) (Process for preparing N- (2-chloro-6-methylphenyl) -2- [ [6- [4- (2-hydroxyphenyl-1-piperazinyl) -2-methyl-4-pyrimidinyl ] amino ] -5-thiazole and related metabolites thermal of), the Chinese patent at 19 th.12 th.2012 (CN 102827156A) (a new industrial synthesis method of Dasatinib), and the world patent at 03 th.2014.03 th. 2014/102759A2 (Process for preparing the Dasatinib and intermediates) as starting materials, i.e. 2-chloro-6-methyl aniline, after acylation with (E) -3-ethoxy acryloyl chloride, the dasatinib is obtained through bromination, cyclization, substitution and amination, the total yield is 50.2%, the method is short in synthetic route and high in yield, but the raw materials are expensive and are not easy to source; or firstly reacting the 4, 6-dichloro-2-methylpyrimidine with N-hydroxyethyl piperazine, and then reacting with 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide to prepare the dasatinib with the total yield of 41.7 percent; or acylating with chloracetyl chloride, cyclizing with substituted thiourea, removing protecting group, substituting and aminating to obtain dasatinib with total yield of 49.2%, wherein the substituted thiourea used in the method needs to be prepared by self; or after the reaction with magnesium metal to prepare an organic magnesium compound, directly reacting with ethyl 2- ((6- (4- (2-hydroxyethyl) piperazin-1-yl) -2-methylpyrimidin-4-yl) amino) thiazole-5-carboxylate to obtain dasatinib. The synthetic route is as follows:
(5) 6-chloro-2-methyl-4-aminopyrimidine is used as a starting material to prepare N-substituted thiourea, and then cyclization and amination are carried out to obtain the dasatinib, wherein the synthetic method is disclosed in Chinese patent No. 25/08 (CN 1980909B) in 2007 (a preparation method of 2-aminothiazole-5-aromatic formamide used as a kinase inhibitor) and Chinese patent No. 04/12/2013 (CN 103420999A) (a synthetic method suitable for industrial production of dasatinib), and the total yield is 36.6%; or preparing the N-substituted thiourea into N, N-disubstituted thiourea, cyclizing and aminating to obtain the dasatinib, wherein the total yield is only 31.1 percent although acyl chloride is avoided. The synthetic route is as follows:
the invention content is as follows:
the invention aims to solve the technical problem of providing a novel method for preparing dasatinib and an intermediate thereof, wherein the preparation method takes cheap and easily-obtained 2-aminothiazole (2) as a starting material, and synthesizes dasatinib (1) through substitution, hydroxymethylation, oxidative amidation, positioned chlorination and amination reactions, and the total yield reaches 63.8%. Compared with the literature method, the synthesis method has the advantages that the used raw materials of the 2-aminothiazole (2) and the o-toluidine (6) are cheap and easy to obtain, the total reaction yield is high, the production cost is greatly reduced, the reaction condition is mild, and the method is suitable for industrial mass production.
The invention is realized by the following technical scheme:
a novel process for the preparation of dasatinib and its intermediates comprising the steps of:
(1) dissolving 2-aminothiazole (2) and 4, 6-dichloro-2-methylpyrimidine (3) in a molar ratio of 1: 1-2 in an organic solvent in a three-necked bottle, adding alkali under stirring, reacting for 10-20 h under stirring at 10-30 ℃, precipitating, and filtering to obtain a white solid 2- (6-chloro-2-methylpyrimidine-4-yl) aminothiazole (4);
(2) dissolving the obtained intermediate 4 in an organic solvent, adding a catalyst and trioxymethylene, and heating the obtained mixture at 100-130 ℃ for reaction for 10 min-1 h. And cooling the reaction liquid to room temperature, adding ammonia water, stirring at room temperature for 10-20 min, and extracting with ethyl acetate. The organic phases were combined and anhydrous Na2SO4Drying, vacuum concentrating, and recrystallizing the residue with methanol to obtain white solid 2- (6-chloro-2-methylpyrimidin-4-yl) amino-5-hydroxymethyl thiazole (5);
(3) adding the intermediate 5 and 2-methylaniline (6) in a mol ratio of 1: 1-2, an oxidant, a catalyst and a polar solvent into a three-necked flask under the protection of nitrogen at room temperature, and stirring and reacting for 3-6 h at 60-100 ℃. Cooling the reaction liquid to room temperature, extracting with ethyl acetate, drying an organic phase by using anhydrous sodium sulfate, evaporating in vacuum, and recrystallizing residues by using ethanol to obtain a white solid 2- (6-chloro-2-methylpyrimidin-4-yl) amino-N- (2-methylphenyl) thiazole-5-formamide (7);
(4) and (3) adding a chlorinating agent, a catalyst and a solvent into a three-neck flask, dissolving, adding the intermediate 7, heating to 80-100 ℃, and stirring for reaction for 10-15 hours. Cooling the reaction liquid to room temperature, distilling under reduced pressure to remove the solvent, and recrystallizing the residue with ethanol to obtain white crystals of 2- (6-chloro-2-methylpyrimidin-4-yl) amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide (8);
(5) adding 1-1.5 mol of N-hydroxyethyl piperazine (9)/mol of intermediate 8, alkali and an organic solvent into a three-necked bottle, stirring for 10-30 min at 10-50 ℃, adding the intermediate 8, and stirring and reacting for 8-12 h at 10-50 ℃ under the protection of nitrogen. And (4) carrying out suction filtration, washing the solid with distilled water and ethanol, and carrying out vacuum drying to obtain the dasatinib (1).
In the invention, the alkali in the step (1) is used for neutralizing HCl generated in the reaction to promote the completion of the substitution reaction; the base is organic base Triethylamine (TEA), or Diisopropylethylamine (DIEA), or 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), or inorganic base cesium carbonate, or potassium carbonate, preferably DIEA; the amount of the alkali used is 1.2 to 2.0mol/mol 2, preferably 1.3 to 1.6mol/mol 2. The organic solvent is isopropanol/Dichloromethane (DCM) (the volume ratio is 2-3: 1), or 1, 4-dioxane, or N, N-Dimethylformamide (DMF), or acetonitrile, and preferably isopropanol/DCM (the volume ratio is 2-3: 1); the amount of the organic solvent is 3000-4000 mL/mol 2, preferably 3200-3800 mL/mol 2.
The organic solvent in the step (2) is Tetrahydrofuran (THF) or 1, 4-dioxane, preferably THF; the amount of the organic solvent is 1600-1900 mL/mol 4, preferably 1600-1700 mL/mol 4. The catalyst is Triethylamine (TEA) or piperidine, preferably TEA; the dosage of the catalyst is 600-800 mL/mol 4, preferably 650-700 mL/mol 4. The trioxymethylene is an aqueous solution with the mass fraction of 30% -50%, and the using amount is 1500-1800 mL/mol 4, preferably 1650-1750 mL/mol 4. The heating mode is conventional heating or microwave heating, and the microwave heating is preferred because the microwave heating reaction time is short, the obtained reaction liquid has high purity, few side reactions and high yield; the reaction can be completed after microwave heating for 10-20 min.
The oxidant in the step (3) is a tert-butyl hydroperoxide (t-BuOOH) aqueous solution or a hydrogen peroxide aqueous solution, preferably a t-BuOOH aqueous solution; the concentration of the oxidant is 50-70% (mass fraction), preferably 60-70% (mass fraction); the amount of the oxidant is 6-9 mol/mol 5, preferably 7-8 mol/mol 5. The catalyst is sodium iodide, or zinc iodide, or tetra-n-butylammonium iodide [ (n-Bu)4NI]Preferably sodium iodide; the amount of the catalyst is 0.05 to 0.2mol/mol 5, preferably 0.1 to 0.15mol/mol 5. The polar solvent is acetonitrile, DMF or dimethyl sulfoxide (DMSO), preferably acetonitrile; the dosage of the polar solvent is 3000-5000 mL/mol 5, preferably 3500-4500 mL/mol 5.
The chlorinating agent in the step (4) is N-chlorosuccinimide (NCS) or sulfonyl chloride (SO)2Cl2) Preferably NCS; the amount of the chlorinating agent is 1 to 1.5mol/mol 7, preferably 1.1 to 1.3mol/mol 7. The catalyst is 2, 2, 6, 6-tetramethyl piperidine or PdCl2Or Pd (OAc)2Using Pd (OAc)2When used as a catalyst, the catalyst is preferably PdCl because acetoxylation by-products are formed2(ii) a The dosage of the catalyst is 0.02-0.1 mol/mol 7, preferably 03 to 0.6mol/mol 7. The solvent is acetonitrile, or benzonitrile, or toluene, and the acetonitrile can also be used as a ligand of the catalyst to promote the reaction and improve the selectivity of the ortho-position chlorination product, so the acetonitrile is preferably selected; the amount of the solvent is 7-10L/mol 7, preferably 8-9L/mol 7.
The alkali in the step (5) is organic alkali TEA, or DIEA, or DBU, or inorganic alkali cesium carbonate, or potassium carbonate, preferably TEA; the amount of the alkali is 1 to 3mol/mol 8, preferably 1.5 to 2mol/mol 8. The organic solvent is isopropanol, or 1, 4-dioxane, or DMF, or acetonitrile, preferably DMF or acetonitrile; the organic solvent is used in an amount of 4000-6000 mL/mol8, preferably 4500-5500 mL/mol 8.
The chemical reaction formula of the invention is as follows:
in the invention, DIEA is used as a catalyst, isopropanol and DCM are used as a mixed solvent, and 2 and 3 can better perform substitution reaction to obtain an intermediate 4, wherein the yield is 88.7%. When the intermediate 5 is prepared, the microwave heating reaction time is short, the obtained reaction liquid has high purity and few side reactions, and the yield is as high as 94.8%. Sodium iodide is used as a catalyst, tert-butyl hydroperoxide is used as an oxidant, 5 and 6 are directly amidated, an intermediate 7 is obtained with the yield of 91.1%, and the method is high in reaction atom economy and environment-friendly. In PdCl2Under the catalysis, NCS can ensure that 7 is subjected to oriented chlorination at the ortho position of a benzene ring, the generated para-position chlorination product is less, and the yield of the intermediate 8 is as high as 96.8%. In the presence of triethylamine, amination is carried out on 8 and 9 to obtain a target product 1, the yield is 86.1%, and the purity is 99.3%.
Compared with the literature method, the method has the advantages of short synthetic route, high reaction yield, cheap and easily-obtained raw materials, greatly reduced production cost, mild reaction conditions, suitability for industrial mass production, avoidance of acyl chloride and reduction of environmental pollution. The invention provides an efficient and novel method for preparing dasatinib and an intermediate thereof, and has a good industrial application prospect.
The specific implementation mode is as follows:
example 1: preparation of 2- (6-chloro-2-methylpyrimidin-4-yl) aminothiazole (4)
In a three-necked flask, 2-aminothiazole (2) (2.0g, 20mmol), 4, 6-dichloro-2-methylpyrimidine (3) (5.9g, 36mmol) were dissolved in isopropanol (50mL) and Dichloromethane (DCM) (20mL), Diisopropylethylamine (DIEA) (4.8mL) was added with stirring, the reaction was stirred at room temperature for 20h to precipitate, and the precipitate was filtered to give 2- (6-chloro-2-methylpyrimidin-4-yl) aminothiazole (4) (4.02g, 88.7%) as a white solid.
Example 2: preparation of 2- (6-chloro-2-methylpyrimidin-4-yl) aminothiazole (4)
In a three-necked flask, 2-aminothiazole (2) (2.0g, 20mmol) and 4, 6-dichloro-2-methylpyrimidine (3) (3.9g, 24mmol) were dissolved in N, N-Dimethylformamide (DMF) (20mL), potassium carbonate (4.1g, 30mmol) was added thereto with stirring, and the mixture was stirred at room temperature for 10 hours to precipitate a precipitate, which was then filtered to obtain 2- (6-chloro-2-methylpyrimidin-4-yl) aminothiazole (4) (3.28g, 72.3%) as a white solid.
Example 3: preparation of 2- (6-chloro-2-methylpyrimidin-4-yl) aminothiazole (4)
In a three-necked flask, 2-aminothiazole (2) (2.0g, 20mmol) and 4, 6-dichloro-2-methylpyrimidine (3) (4.6g, 28mmol) were dissolved in dioxane (70mL), cesium carbonate (13.0g, 40mmol) was added with stirring, and the reaction was stirred at room temperature for 12 hours to precipitate a precipitate, which was filtered to give 2- (6-chloro-2-methylpyrimidin-4-yl) aminothiazole (4) (2.88g, 63.5%) as a white solid.
Example 4: preparation of 2- (6-chloro-2-methylpyrimidin-4-yl) amino-5-hydroxymethylthiazole (5)
2- (6-chloro-2-methylpyrimidin-4-yl) aminothiazole (4) (3.4g, 15mmol) was dissolved in THF (25mL), TEA (10mL) and an aqueous formaldehyde solution (mass fraction: 40%, 25mL) were added, and the resulting mixture was heated with a microwave at 120 ℃ for 10 min. The reaction solution was cooled to room temperature, and then ammonia (30mL) was added thereto, followed by stirring at room temperature for 10min, followed by extraction twice with ethyl acetate (60 mL). The organic phases were combined and anhydrous Na2SO4Drying, concentration in vacuo and recrystallization of the residue from methanol gave 2- (6-chloro-2-methylpyrimidin-4-yl) amino-5-hydroxymethylthiazole (5) (3.65g, 94.8%) as a white solid.
Example 5: preparation of 2- (6-chloro-2-methylpyrimidin-4-yl) amino-5-hydroxymethylthiazole (5)
2- (6-chloro-2-methylpyrimidin-4-yl) aminothiazole (4) (3.4g, 15mmol) was dissolved in THF (25mL), TEA (10mL) and an aqueous formaldehyde solution (mass fraction 40%, 25mL) were added, and the resulting mixture was allowed to react at 120 ℃ for 1 hour with tube sealing. The reaction solution was cooled to room temperature, and then ammonia (30mL) was added thereto, followed by stirring at room temperature for 10min, followed by extraction twice with ethyl acetate (60 mL). The organic phases were combined and anhydrous Na2SO4Drying, concentration in vacuo and recrystallization of the residue from methanol gave 2- (6-chloro-2-methylpyrimidin-4-yl) amino-5-hydroxymethylthiazole (5) (2.24g, 58.2%) as a white solid.
Example 6: preparation of 2- (6-chloro-2-methylpyrimidin-4-yl) amino-N- (2-methylphenyl) thiazole-5-carboxamide (7)
In a three-necked flask, under nitrogen protection and at room temperature, an aqueous solution (70% by mass, 14.6mL, 80mmol) of t-butylhydroperoxide (t-BuOOH), sodium iodide (150mg, 1mmol), 2- (6-chloro-2-methylpyrimidin-4-yl) amino-5-hydroxymethylthiazole (5) (2.6g, 10mmol), 2-methylaniline (6) (1.6g, 15mmol) and acetonitrile (40mL) were added, and the reaction was stirred at 80 ℃ for 4 hours. After the reaction was cooled to room temperature, it was extracted with ethyl acetate (3X 10mL), the organic phase was dried over anhydrous sodium sulfate, evaporated in vacuo, and the residue was recrystallized from ethanol to give 2- (6-chloro-2-methylpyrimidin-4-yl) amino-N- (2-methylphenyl) thiazole-5-carboxamide (7) (3.28g, 91.1%) as a white solid.
Example 7: preparation of 2- (6-chloro-2-methylpyrimidin-4-yl) amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide (8)
In a three-necked flask, N-chlorosuccinimide (NCS) (960mg, 7.2mmol), PdCl were added2(53mg, 0.3mmol) and CH3CN (50mL) was dissolved, and 2- (6-chloro-2-methylpyrimidin-4-yl) amino-N- (2-methylphenyl) thiazole-5-carboxamide (7) (2.2g, 6mmol) was added thereto, and the mixture was heated to 100 ℃ and stirred for reaction for 12 hours. The reaction solution was cooled to room temperature and then distilled under reduced pressureThe solvent was removed and the residue was recrystallized from ethanol to give 2- (6-chloro-2-methylpyrimidin-4-yl) amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide (8) (2.29g, 96.8%) as white crystals.
Example 8: preparation of dasatinib (1)
In a three-necked flask, N-hydroxyethylpiperazine (9) (470mg, 3.6mmol), triethylamine (0.8mL) and anhydrous acetonitrile (15mL) were added, stirred at room temperature for 10min, 2- (6-chloro-2-methylpyrimidin-4-yl) amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide (8) (1.2g, 3mmol) was added, and the reaction was stirred at room temperature under nitrogen for 9 h. Suction filtration, washing of the solid with distilled water and ethanol, and vacuum drying gave the title compound (1) (1.26g, 86.1%) with a purity of 99.3% (HPLC area normalization).
Example 9: preparation of dasatinib (1)
In a three-necked flask, N-hydroxyethylpiperazine (9) (470mg, 3.6mmol), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) (0.9mL) and anhydrous acetonitrile (15mL) were added, stirred at room temperature for 10min, 2- (6-chloro-2-methylpyrimidin-4-yl) amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide (8) (1.2g, 3mmol) was added, and the reaction was stirred at room temperature under nitrogen for 8 h. Suction filtration, washing of the solid with distilled water and ethanol, and vacuum drying gave the title compound (1) (1.22g, 83.3%) with a purity of 99.1% (HPLC area normalization).
Example 10: preparation of dasatinib (1)
In a three-necked flask, N-hydroxyethylpiperazine (9) (470mg, 3.6mmol), Diisopropylethylamine (DIEA) (1.0mL) and N, N-dimethylformamide (18mL) were added, stirred at room temperature for 10min, 2- (6-chloro-2-methylpyrimidin-4-yl) amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide (8) (1.2g, 3mmol) was added, and the reaction was stirred at room temperature under nitrogen for 10 h. Suction filtration, washing of the solid with distilled water and ethanol, and vacuum drying gave the title compound (1) (1.21g, 82.7%) with a purity of 99.0% (HPLC area normalization).
Claims (1)
1. A novel process for the preparation of dasatinib, characterized in that it comprises the following steps:
(1) dissolving 2-aminothiazole (2) and 4, 6-dichloro-2-methylpyrimidine (3) in a molar ratio of 1: 1-2 in isopropanol/Dichloromethane (DCM), N-Dimethylformamide (DMF) or 1, 4-dioxane in a three-necked flask, adding Diisopropylethylamine (DIEA) or potassium carbonate or cesium carbonate while stirring, stirring and reacting for 10-20 h at 10-30 ℃, separating out a precipitate, and filtering to obtain a white solid 2- (6-chloro-2-methylpyrimidin-4-yl) aminothiazole (4);
(2) dissolving the obtained intermediate 4 in Tetrahydrofuran (THF), adding Triethylamine (TEA) and trioxymethylene, and heating the mixture at 100-130 ℃ for reaction for 10 min-1 h; cooling the reaction liquid to room temperature, adding ammonia water, stirring at room temperature for 10-20 min, and extracting with ethyl acetate; the organic phases were combined and anhydrous Na2SO4Drying, vacuum concentrating, and recrystallizing the residue with methanol to obtain white solid 2- (6-chloro-2-methylpyrimidin-4-yl) amino-5-hydroxymethyl thiazole (5);
(3) adding the intermediate 5 and 2-methylaniline (6) and tert-butyl hydroperoxide (t-BuOOH) aqueous solution, sodium iodide and acetonitrile in a molar ratio of 1: 1-2 into a three-necked bottle under the protection of nitrogen at room temperature, and stirring at 60-100 ℃ for reaction for 3-6 h; cooling the reaction liquid to room temperature, extracting with ethyl acetate, drying an organic phase by using anhydrous sodium sulfate, evaporating in vacuum, and recrystallizing residues by using ethanol to obtain a white solid 2- (6-chloro-2-methylpyrimidin-4-yl) amino-N- (2-methylphenyl) thiazole-5-formamide (7);
(4) adding N-chlorosuccinimide (NCS) and PdCl into a three-necked bottle2And acetonitrile, adding the intermediate 7 after dissolution, heating to 80-100 ℃, and stirring for reaction for 10-15 h; cooling the reaction liquid to room temperature, distilling under reduced pressure to remove the solvent, and recrystallizing the residue with ethanol to obtain white crystals of 2- (6-chloro-2-methylpyrimidin-4-yl) amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide (8);
(5) adding 1-1.5 mol of N-hydroxyethyl piperazine (9)/mol of intermediate 8, Triethylamine (TEA) or 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or Diisopropylethylamine (DIEA), anhydrous acetonitrile or N, N-Dimethylformamide (DMF) into a three-necked bottle, stirring for 10-30 min at 10-50 ℃, adding the intermediate 8, and stirring for reacting for 8-12 h at 10-50 ℃ under the protection of nitrogen; and (4) carrying out suction filtration, washing the solid with distilled water and ethanol, and carrying out vacuum drying to obtain the dasatinib (1).
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