CN109503568B - Preparation method of dasatinib - Google Patents
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Abstract
The invention relates to a preparation method of dasatinib, which comprises the following steps: reacting ethyl 3-oxopropionate with 2-chloro-6-methylaniline under an alkaline condition, adding a solvent in which copper bromide is dissolved for reaction, adding thiourea, and cyclizing under a catalyst to obtain 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide; and then synthesizing the dasatinib by the 4, 6-dichloro-2-methylpyrimidine, N-hydroxyethyl piperazine and 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide in a one-pot method under the action of alkali and ionic liquid 1-butyl-3-methylimidazole glycinate. The method has the advantages of mild conditions, simple steps, environmental friendliness and high yield, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of drug synthesis, and in particular relates to a preparation method of dasatinib.
Background
Dasatinib (Dasatinib, trade name is Sprycel), the chemical name is N- (2-chloro-6-methylphenyl) -2- [6- [4- (2-hydroxyethyl) -1-piperazinyl ] -2-methyl-4-pyrimidinyl ] amino-5-thiazolecarboxamide, and the Dasatinib is an oral tyrosine kinase inhibitor developed by Behcet MeishiGuibao company. The medicine is approved by FDA in 2006 for marketing, and can be used for treating chronic myelogenous leukemia and Philadelphia chromosome positive acute lymphocytic leukemia. The product has inhibition effect on various mutants of Bcr-Ab1 kinase, has greatly improved inhibition intensity compared with Imatinib (Imatinib), and has no drug resistance. The structural formula is as follows:
many domestic and foreign literatures report about the synthesis of dasatinib, and most of dasatinib is prepared by synthesizing intermediate 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide by different methods and then performing a series of substitution reactions. The synthetic route is as follows:
(1) document j.med.chem.2004,47, 6658-; the routes provided in j.med.chem.2006,49,6819-6832 are as follows:
the route requires n-butyllithium to react at minus 78 ℃, sodium hydride is required to be used for many times, the reaction condition is harsh, the route is not suitable for industrial production, and the price of the 2-methyl-4-amino-6-chloropyrimidine is higher and the route is not suitable for purchase.
(2) Patent CN200580011916.6 discloses two routes. The synthetic route is as follows:
route one:
and a second route:
the total yield of the route is lower, only 36 percent, the price of the 2-methyl-4-amino-6-chloropyrimidine is higher, the raw material is not suitable for purchase, the intermediate 14(E) -3-ethoxyacryloyl chloride has high volatility, is not easy to store and is difficult to purchase, the raw material is prepared by self, and vinyl ether with high risk is required to be used as a starting raw material for reacting with triphosgene, so that the method is not very beneficial to industrial production. The overall yield of route two was 55%, but expensive Pd (OAc) was used2And BINAP (binaphthyl diphenyl phosphate) is used as a catalyst, so that the method does not accord with the concepts of environmental friendliness, low cost, simple and convenient operation and the like, and the reaction condition is harsh, the yield is not high, and the large-scale production is not easy to realize.
(3) CN1348370A discloses a preparation method of dasatinib, which takes 2-aminothiazole-5-carboxylic acid ethyl ester as a starting material, and the specific synthetic route is as follows:
the methods have the defects of long circuit, harsh multistep conditions, requirement of anhydrous, oxygen-free, low temperature and the like, repeated use of a lithium metal reagent and NaH, unsuitability for industrial production, low yield and poor selectivity. And the intermediate 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazole formamide can easily generate a bipyrimidine ring compound by-product in the reaction process with 4, 6-dichloro-2-methylpyrimidine, the property of the by-product is similar to that of a target intermediate, the by-product is difficult to separate, the by-product is easy to be brought into the next reaction, and the by-product reacts with compounds such as N-hydroxyethyl piperazine in the next reaction to generate more by-products, so that the quality of the final product of dasatinib is greatly influenced.
And the synthesis of 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide in addition to the above method, there are the following synthesis methods:
US200737978 uses mucochloric acid as starting material, which is hydrolyzed to 2, 3-dichloroacrylic acid, then treated with thionyl chloride to form acyl chloride, then grafted with 2-chloro-6-methylaniline, then treated with methanol-sodium methoxide to form dimethyl acetal, finally deprotected under acidic conditions and in situ cyclized with thiourea to obtain the target compound, the synthetic route is as follows:
the reaction process involves multi-step reduced pressure distillation, has high energy consumption and equipment requirements, and uses a chlorinated reagent such as thionyl chloride which is volatile and has large environmental pollution.
Literature Synthesis, 2001, 2: 239-242 and WO2005077945A2 take oxalyl chloride and vinyl ethyl ether as starting materials, firstly produce 4-ethoxy-3-oxobutenoyl chloride, then are thermally degraded into 3-ethoxyacryloyl chloride, the 3-ethoxyacryloyl chloride reacts with 2-chloro-6-methylaniline to obtain N- (2-chloro-6-methylphenyl) -3-ethoxyacrylamide, and then react with NBS and thiourea to obtain a target compound, wherein the reaction route is shown as follows.
The synthetic route is short, and is a good synthetic idea, but the method has the following defects: in the first step, vinyl ether with high risk is used as a starting raw material to react with trichloroacetyl chloride, and the synthesized (E) -3-ethoxy acryloyl chloride has high volatility and is difficult to store; the second step is to degrade and decarboxylate at high temperature, under the condition, the product 3-ethoxy acryloyl chloride in the second step is easy to polymerize, so that the yield is reduced, the intermediate product is impure, reduced pressure distillation purification is needed, and the requirement of energy consumption on equipment is high; in addition, the third step and the fourth step use solvents of tetrahydrofuran and dioxane respectively, so the cost is also higher, the fourth step uses a large amount of NBS, the cost is greatly increased, the NBS reaction needs to be carried out at low temperature, the conditions are harsh, and in addition, the workload of post-treatment is also increased.
Patent WO2010/144338 reports alkaline hydrolysis of ethyl 3-ethoxyacrylate to sodium 3-ethoxyacrylate, which is directly treated with thionyl chloride to give 3-ethoxyacryloyl chloride, the starting ethyl 3-ethoxyacrylate being prepared from trichloroacetyl chloride and vinyl ethyl ether, the entire synthetic route being as follows:
the method improves the synthesis of 3-ethoxy acryloyl chloride, but the synthesis route becomes long, the operation is complicated, and a chlorinated reagent which is easy to volatilize and has large environmental pollution is used in the reaction process.
Therefore, there is still a need in the art for a method for synthesizing dasatinib, which is simple, mild in conditions, environmentally friendly and high in yield.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide a preparation process of dasatinib, which is high in yield, green and environment-friendly. The technical scheme of the invention is as follows:
the preparation method of dasatinib is characterized by comprising the following operation steps:
1) reacting ethyl 3-oxopropionate with 2-chloro-6-methylaniline under an alkaline condition, adding a solvent in which copper bromide is dissolved for reaction, adding thiourea, and cyclizing under a catalyst to obtain 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, namely a compound 2;
2) dissolving 4, 6-dichloro-2-methylpyrimidine and alkali in a solvent, adding N-hydroxyethyl piperazine for reaction, adding 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, and stirring for reaction at a certain temperature to obtain a compound 1, namely dasatinib;
in the step 1), a reaction solvent is tetrahydrofuran, and the amount ratio of the alkali to the 3-oxo ethyl propionate to the alkali to the 2-chloro-6-methylaniline is 1: 1.0-2.0: 0.8-1.0; the mass ratio of the ethyl 3-oxopropionate to the copper bromide is 1: 2.0-3.0; the mass ratio of the ethyl 3-oxopropionate to the thiourea is 1: 1.0-2.0; the mass ratio of the ethyl 3-oxopropionate to the catalyst is 1: 0.1-1.0, the catalyst is ionic liquid [ Bmim ] Br, and the cyclization reaction temperature is 20-25 ℃. Wherein the mass ratio of the 3-oxo ethyl propionate to the alkali to the 2-chloro-6-methylaniline is 1: 1.2-1.3: 0.9; the mass ratio of the ethyl 3-oxopropionate to the copper bromide is 1: 2.6-2.8; the mass ratio of the ethyl 3-oxopropionate to the thiourea is 1: 1.2-1.6; the mass ratio of the ethyl 3-oxopropionate to the catalyst is 1: 0.1-0.4. Preferably, the mass ratio of the ethyl 3-oxopropionate to the base to the 2-chloro-6-methylaniline is 1:1.25: 0.9; the mass ratio of the ethyl 3-oxopropionate to the copper bromide is 1:2.7, and the mass ratio of the ethyl 3-oxopropionate to the thiourea is 1: 1.4; the mass ratio of ethyl 3-oxopropionate to catalyst was 1: 0.15.
In the step 2), the solvent is 1-butyl-3-methylimidazole glycinate; the alkali is K3PO4Or K2CO3(ii) a The reaction temperature is 80 ℃, and the mass ratio of 4, 6-dichloro-2-methylpyrimidine, N-hydroxyethyl piperazine, 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide is 1: 1.0-1.1: 1.0 ℃1.1; the mass ratio of the 4, 6-dichloro-2-methylpyrimidine, the alkali and the 1-butyl-3-methylimidazole glycinate is 1: 1.0-3.0: 0.5-2.0. Wherein the mass ratio of 4, 6-dichloro-2-methylpyrimidine, base, 1-butyl-3-methylimidazolyl glycinate is 1: 1.5-2.0: 0.6-1.0, preferably the mass ratio of 4, 6-dichloro-2-methylpyrimidine, N-hydroxyethylpiperazine, 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide is 1:1.05: 1.05; the mass ratio of 4, 6-dichloro-2-methylpyrimidine, alkali and 1-butyl-3-methylimidazolium glycinate is 1:1.75: 0.8.
Compared with the prior art, the beneficial technical effects of the invention are as follows:
1. according to the invention, 3-oxo ethyl propionate is used as a starting material, the reaction steps are simple, the target product 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide can be synthesized by only one step, and the synthesis of the intermediate (E) -3-ethoxy acryloyl chloride which has high volatility and is difficult to store is avoided;
2. copper bromide is used as a brominating reagent, so that NBS is prevented from being used in a large amount, the condition is mild, the yield is effectively improved, the pollution of bromine to the environment is reduced, and meanwhile, cheap raw material thiourea is used, so that the production cost is reduced;
3. when synthesizing 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, the traditional synthesis method needs to react under an acidic condition, the reaction time is longer, and the yield is not ideal;
4. the method dissolves 4, 6-dichloro-2-methylpyrimidine, N-hydroxyethyl piperazine, 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide in ionic liquid 1-butyl-3-methylimidazole glycinate, and synthesizes the dasatinib by a one-pot method, wherein the 1-butyl-3-methylimidazole glycinate can be used as a solvent and a catalyst, the synthesis yield is high, the purity is high, the reaction time is short, and meanwhile, the ionic liquid is easy to recover and can be reused.
Detailed Description
In the following, the technical scheme of the invention is further illustrated by combining with a plurality of preferred embodiments without limitation, wherein the brominated 1-butyl-3-methylimidazole ([ Bmim ] Br) ionic liquid is prepared by weighing 0.1mol of N-methylimidazole 8m L in a three-necked flask, heating in water bath to 70 ℃, slowly dripping 0.12mol of 1-bromobutane 13m L under stirring at 300r/min, refluxing and reacting for 20h at 70 ℃ to obtain a light yellow liquid, washing with ethyl acetate for 2 times, shaking, standing and layering, putting the lower layer liquid into a single-necked flask, distilling under reduced pressure to remove ethyl acetate, and drying at 80 ℃ for 20h to obtain purified [ Bmim ] Br.
The 1-butyl-3-methylimidazole ([ Bmim ] OH) hydroxide ionic liquid is prepared by weighing 13g of an intermediate [ Bmim ] Br in a wide-mouth bottle, slowly adding 20m L KOH methanol solution, reacting for 10h under constant-temperature stirring, carrying out suction filtration, washing for several times with methanol during the reaction, carrying out reduced pressure distillation on the filtrate, and removing the methanol to obtain the target product 1-butyl-3-methylimidazole ([ Bmim ] OH).
1-butyl-3-methylimidazolidine salt ([ Bmim ] [ Gly ] is prepared by titrating [ Bmim ] [ OH ] solution with 0.1 mol/L hydrochloric acid, adding the titrated solution into aminoacetic acid (Gly) aqueous solution with a slightly excessive molar ratio, stirring at room temperature for 24h, removing excessive water by rotary evaporation of the obtained product (temperature 70 ℃, 50-60 r/min, RE-52AA rotary evaporator), placing the obtained product into a vacuum oven, drying in vacuum for 48h (80 ℃), cooling to room temperature, taking out, adding anhydrous methanol (10M L)/acetonitrile (90M L), sealing and stirring with PARAFI L M for 12h to separate out unreacted amino acid, filtering, removing methanol/acetonitrile by rotary evaporation (RE-52AA rotary evaporator, 60 ℃, 50-60 r/min), vacuum drying [ Bmim ] [ Gly ] for 2d, setting the temperature to 80 ℃, repeating for 3 times, and placing the obtained sample in a dryer for standby.
Example 1: preparation of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide
Dissolving 30mmol of ethyl 3-oxopropionate and 37.5mmol of sodium methoxide in 80m L tetrahydrofuran, stirring at room temperature for 10min, adding 27mmol of 2-chloro-6-methylaniline, heating and refluxing for 45min, cooling to room temperature after the reaction is finished, adding 60m L tetrahydrofuran in which 81mmol of copper bromide is dissolved, heating and refluxing for 1h, filtering while hot, reserving filtrate, adding 42mmol of thiourea and 4.5mmol of [ Bmim ] Br into the filtrate, stirring and reacting at 20-25 ℃ for 30min, monitoring the reaction by T L C (tracking the reaction until the raw material disappears), pouring into ice water after the reaction is finished, extracting with dichloromethane, concentrating an organic phase, washing with water, adding 50m L diethyl ether, stirring and crystallizing for 20min, filtering and drying to obtain 6.68g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, wherein the yield is 92.31%, and the purity is 99.91%.
Example 2: preparation of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide
Dissolving 30mmol of ethyl 3-oxopropionate and 36mmol of sodium methoxide in 80m L tetrahydrofuran, stirring at room temperature for 10min, adding 27mmol of 2-chloro-6-methylaniline, heating and refluxing for 45min, cooling to room temperature after the reaction is finished, adding 60m L tetrahydrofuran in which 78mmol of copper bromide is dissolved, heating and refluxing for 1h, filtering while hot, reserving filtrate, adding 36mmol of thiourea and 3mmol of [ Bmim ] Br in the filtrate, stirring and reacting at 20-25 ℃ for 30min, monitoring the reaction by T L C (tracking the reaction until the raw materials disappear), pouring into ice water after the reaction is finished, extracting with dichloromethane, concentrating an organic phase, washing with water, adding 50m L of diethyl ether, stirring and crystallizing for 20min, carrying out suction filtration and drying to obtain 6.53g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, wherein the yield is 90.17%, and the purity is 99.86%.
Example 3: preparation of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide
Dissolving 30mmol of ethyl 3-oxopropionate and 39mmol of sodium methoxide in 80m L tetrahydrofuran, stirring at room temperature for 10min, adding 27mmol of 2-chloro-6-methylaniline, heating and refluxing for 45min, cooling to room temperature after the reaction is finished, adding 60m L tetrahydrofuran in which 84mmol of copper bromide is dissolved, heating and refluxing for 1h, filtering while hot, reserving filtrate, adding 48mmol of thiourea and 12mmol of [ Bmim ] Br in the filtrate, stirring and reacting at 20-25 ℃ for 30min, monitoring the reaction by T L C (tracking the reaction until the raw materials disappear), pouring into ice water after the reaction is finished, extracting with dichloromethane, concentrating an organic phase, washing with water, adding 50m L of diethyl ether, stirring and crystallizing for 20min, carrying out suction filtration and drying to obtain 6.65g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, wherein the yield is 91.87%, and the purity is 99.88%.
Example 4: preparation of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide
Dissolving 30mmol of ethyl 3-oxopropionate and 30mmol of sodium methoxide in 80m L tetrahydrofuran, stirring at room temperature for 10min, adding 24mmol of 2-chloro-6-methylaniline, heating and refluxing for 45min, cooling to room temperature after the reaction is finished, adding 60m L tetrahydrofuran in which 60mmol of copper bromide is dissolved, heating and refluxing for 1h, filtering while hot, reserving filtrate, adding 30mmol of thiourea and 3mmol of [ Bmim ] Br in the filtrate, stirring and reacting at 20-25 ℃ for 30min, monitoring the reaction by T L C (tracking the reaction until the raw materials disappear), pouring into ice water after the reaction is finished, extracting with dichloromethane, concentrating an organic phase, washing with water, adding 50m L of diethyl ether, stirring and crystallizing for 20min, carrying out suction filtration and drying to obtain 5.49g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, wherein the yield is 85.24%, and the purity is 99.76%.
Example 5: preparation of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide
Dissolving 30mmol of ethyl 3-oxopropionate and 60mmol of sodium methoxide in 80m L tetrahydrofuran, stirring at room temperature for 10min, adding 30mmol of 2-chloro-6-methylaniline, heating and refluxing for 45min, cooling to room temperature after the reaction is finished, adding 60m L tetrahydrofuran in which 90mmol of copper bromide is dissolved, heating and refluxing for 1h, filtering while hot, reserving filtrate, adding 60mmol of thiourea and 30mmol of [ Bmim ] Br in the filtrate, stirring and reacting at 20-25 ℃ for 30min, monitoring the reaction by T L C (tracking the reaction until the raw material disappears), pouring into ice water after the reaction is finished, extracting with dichloromethane, concentrating an organic phase, washing with water, adding 50m L of diethyl ether, stirring and crystallizing for 20min, carrying out suction filtration and drying to obtain 6.86g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, wherein the yield is 85.19% and the purity is 99.72%.
Example 6: preparation of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide
Dissolving 30mmol of ethyl 3-oxopropionate and 37.5mmol of sodium methoxide in 80m L tetrahydrofuran, stirring at room temperature for 10min, adding 27mmol of 2-chloro-6-methylaniline, heating and refluxing for 45min, cooling to room temperature after the reaction is finished, adding 60m L tetrahydrofuran in which 78mmol of copper bromide is dissolved, heating and refluxing for 1h, filtering while hot, reserving filtrate, adding 48mmol of thiourea and 4.5mmol of [ Bmim ] Br in the filtrate, stirring and reacting at 20-25 ℃ for 30min, monitoring the reaction by T L C (tracking the reaction until the raw material disappears), pouring into ice water after the reaction is finished, extracting with dichloromethane, concentrating an organic phase, washing with water, adding 50m L diethyl ether, stirring and crystallizing for 20min, filtering and drying to obtain 6.59g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, wherein the yield is 91.07% and the purity is 99.89%.
Example 7: preparation of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide
Dissolving 30mmol of ethyl 3-oxopropionate and 37.5mmol of sodium methoxide in 80m L tetrahydrofuran, stirring at room temperature for 10min, adding 27mmol of 2-chloro-6-methylaniline, heating and refluxing for 45min, cooling to room temperature after the reaction is finished, adding 60m L tetrahydrofuran in which 81mmol of copper bromide is dissolved, heating and refluxing for 1h, filtering while hot, reserving filtrate, adding 48mmol of thiourea and 12mmol of [ Bmim ] Br in the filtrate, stirring and reacting at 20-25 ℃ for 30min, monitoring the reaction by T L C (tracking the reaction until the raw materials disappear), pouring the mixture into ice water after the reaction is finished, extracting with dichloromethane, concentrating an organic phase, washing with water, adding 50m L of diethyl ether, stirring and crystallizing for 20min, carrying out suction filtration and drying to obtain 6.53g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, wherein the yield is 90.25%, and the purity is 99.86%.
Example 8: preparation of dasatinib
20mmol of 4, 6-dichloro-2-methylpyrimidine and 35mmol of K3PO4Dissolving in 16mmol of 1-butyl-3-methylimidazolium glycinate, stirring, adding 21mmol of N-hydroxyethyl piperazine, reacting at 80 ℃ for 1.5h, cooling to room temperature, adding 21mmol of 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide, continuing to react at 80 ℃ for 2h, after the reaction is finished, cooling to room temperature, extracting the mixture with diethyl ether for 3 times (3 × 50m L), combining the extracts, concentrating to obtain a crude product (the ionic liquid is extracted with dichloromethane, drying in vacuum to remove a small amount of solvent in the ionic liquid, washing the residual viscous ionic liquid with diethyl ether, directly using the residual viscous ionic liquid for the following reaction without further purification), adding 80% ethanol water solution 100m L into the crude product, stirring, adding 2g of activated carbon, refluxing for 30min, filtering while hot, refrigerating the filtrate overnight, filtering, washing the filter cake with ice 80% ethanol water solution, and drying to obtain 9.01g of white solid with the yield of 92.27% and the purity of 99.94%.
Example 9: preparation of dasatinib
20mmol of 4, 6-dichloro-2-methylpyrimidine and 30mmol of K2CO3Dissolving in 12mmol of 1-butyl-3-methylimidazolium glycinate, stirring, adding 21mmol of N-hydroxyethyl piperazine, reacting at 80 ℃ for 1.5h, cooling to room temperature, adding 21mmol of 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide, continuing to react at 80 ℃ for 2h, after the reaction is finished, cooling to room temperature, extracting the mixture with diethyl ether for 3 times (3 × 50m L), combining the extracts, concentrating to obtain a crude product (the ionic liquid is extracted with dichloromethane, vacuum drying is carried out to remove a small amount of solvent in the ionic liquid, the residual viscous ionic liquid is fully washed with diethyl ether and then directly used for the following reaction without further purification), adding 80% ethanol water solution 100m L into the crude product, stirring, adding 2g of activated carbon, refluxing for 30min, filtering while hot, refrigerating and crystallizing overnight, filtering, washing a filter cake with ice 80% ethanol water solution, and drying to obtain 8.73g of a white solid with yield of 89.32% and purity of 99.90%.
Example 10: preparation of dasatinib
20mmol of 4, 6-dichloro-2-methylpyrimidine and 40mmol of K3PO4Dissolving in 20mmol of 1-butyl-3-methylimidazolium glycinate, stirring, adding 21mmol of N-hydroxyethyl piperazine, reacting at 80 ℃ for 1.5h, cooling to room temperature, adding 21mmol of 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide, continuing to react at 80 ℃ for 2h, after the reaction is finished, cooling to room temperature, extracting the mixture with diethyl ether for 3 times (3 × 50m L), combining the extracts, concentrating to obtain a crude product (the ionic liquid is extracted with dichloromethane, drying in vacuum to remove a small amount of solvent in the ionic liquid, washing the residual viscous ionic liquid with diethyl ether, directly using the residual viscous ionic liquid for the following reaction without further purification), adding 80% of ethanol aqueous solution 100m L into the crude product, stirring, adding 2g of activated carbon, refluxing for 30min, filtering while hot, refrigerating the filtrate overnight, filtering, washing the filter cake with ice 80% of ethanol aqueous solution, and drying to obtain 8.87g of white solid with yield of 90.86% and purity of 99.93%.
Example 11: preparation of dasatinib
20mmol of 4, 6-dichloro-2-methylpyrimidine and 20mmol of K3PO4Dissolved in 10mmol of 1-butyl-3-methylimidazolium glycinate is stirred, 20mmol of N-hydroxyethyl piperazine is added firstly, the mixture reacts for 1.5h at 80 ℃, then the mixture is cooled to room temperature, 20mmol of 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide is added, the reaction is continued for 2h at 80 ℃, after the reaction is finished, the mixture is cooled to room temperature, the mixture is extracted for 3 times by diethyl ether (3 × 50m L), the extract liquor is combined and concentrated to obtain a crude product (the ionic liquid is extracted by dichloromethane, a small amount of solvent is removed by vacuum drying, the residual viscous ionic liquid is fully washed by diethyl ether and then directly used for the following reaction without further purification). The crude product is added into 80% ethanol water solution 100m L, the active carbon is added under stirring, the reflux is carried out for 30min, the hot filtration is carried out, the filtrate is refrigerated and crystallized overnight, the filtration is carried out, the filter cake is washed by 80% ethanol water solution of ice, and the drying is carried out, thus obtaining 8.19g of white solid with 83.45 percent yield.
Example 12: preparation of dasatinib
20mmol of 4, 6-dichloro-2-methylpyrimidine and 60mmol of K3PO4Dissolving the raw materials in 40mmol of 1-butyl-3-methylimidazolium glycinate, stirring, adding 22mmol of N-hydroxyethyl piperazine, reacting at 80 ℃ for 1.5h, cooling to room temperature, adding 22mmol of 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide, continuing to react at 80 ℃ for 2h, after the reaction is finished, cooling to room temperature, extracting the mixture with diethyl ether for 3 times (3 × 50m L), combining the extracts, concentrating to obtain a crude product (the ionic liquid is extracted with dichloromethane, drying in vacuum to remove a small amount of solvent in the ionic liquid, washing the residual viscous ionic liquid with diethyl ether fully, and then directly using the residual viscous ionic liquid for the following reaction without further purification). The crude product is added with 100m L of 80% aqueous ethanol solution, stirred, added with 2g of activated carbon, refluxed for 30min, filtered while hot, refrigerated for crystallization overnight, filtered, a filter cake is washed with 80% aqueous ethanol solution of ice, and dried to obtain 8.59g of white solid with the yield of 87.87% and the purity of 99.88%.
Example 13: preparation of dasatinib
20mmol of 4, 6-dichloro-2-methylpyrimidine and 30mmol of K3PO4Dissolving in 1mmol of 1-butyl-3-methylimidazolium glycinate, stirring, adding 20mmol of N-hydroxyethyl piperazine, reacting at 80 deg.C for 1.5h, and collecting the solutionCooling to room temperature, adding 20mmol 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide, continuing to react for 2h at 80 ℃, after the reaction is finished, cooling to room temperature, extracting the mixture for 3 times by using diethyl ether (3 × 50m L), combining the extract liquor and concentrating to obtain a crude product (the ionic liquid is extracted by using dichloromethane, vacuum drying is carried out to remove a small amount of solvent in the ionic liquid, the residual viscous ionic liquid is fully washed by using diethyl ether and then directly used for the following reaction without further purification), adding the crude product into 80% ethanol water solution 100m L into the crude product, stirring, adding 2g of activated carbon, refluxing for 30min, filtering while hot, carrying out cold crystallization on the filtrate overnight, filtering, washing a filter cake by using ice 80% ethanol water solution, and drying to obtain 8.40g of a white solid, wherein the yield is 85.87% and the purity is 99.72%.
Comparative example 1: preparation of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide
Dissolving 30mmol of ethyl 3-oxopropionate and 37.5mmol of sodium methoxide in 80m L methanol, stirring at room temperature for 10min, adding 27mmol of 2-chloro-6-methylaniline, heating and refluxing for 45min, cooling to room temperature after the reaction is finished, adding 60m L methanol in which 81mmol of copper bromide is dissolved, heating and refluxing for 1h, filtering while hot, taking the filtrate, adding 42mmol of thiourea and 4.5mmol of [ Bmim ] Br into the filtrate, stirring and reacting at 20-25 ℃ for 30min, monitoring the reaction by T L C (tracking the reaction until the raw materials disappear), pouring into ice water after the reaction is finished, extracting with dichloromethane, concentrating the organic phase, washing with water, adding 50m L diethyl ether, stirring and crystallizing for 20min, performing suction filtration and drying to obtain 5.51g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, wherein the yield is 74.89%, the purity is 98.17% [ 267.73 ]
Comparative example 2: preparation of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide
Dissolving 30mmol of ethyl 3-oxopropionate and 37.5mmol of sodium methoxide in 80m L tetrahydrofuran, stirring at room temperature for 10min, adding 27mmol of 2-chloro-6-methylaniline, heating and refluxing for 45min, cooling to room temperature after the reaction is finished, adding 60m L tetrahydrofuran in which 81mmol of copper bromide is dissolved, heating and refluxing for 1h, filtering while hot, reserving filtrate, adding 42mmol of thiourea into the filtrate, stirring and reacting at 20-25 ℃ for 30min, monitoring the reaction at T L C (tracking the reaction until the raw material disappears), pouring into ice water after the reaction is finished, extracting with dichloromethane, concentrating an organic phase, washing with water, adding 50m L of diethyl ether, stirring and crystallizing for 20min, performing suction filtration and drying to obtain 4.57g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, wherein the yield is 61.85% and the purity is 97.86%.
Comparative example 3: preparation of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide
Dissolving 30mmol of ethyl 3-oxopropionate and 37.5mmol of sodium methoxide in 80m L tetrahydrofuran, stirring at room temperature for 10min, adding 27mmol of 2-chloro-6-methylaniline, heating and refluxing for 45min, cooling to room temperature after the reaction is finished, adding 60m L tetrahydrofuran in which 30mmol of copper bromide is dissolved, heating and refluxing for 1h, filtering while hot, collecting filtrate, adding 42mmol of thiourea and 4.5mmol of [ Bmim ] into the filtrate]BH4Stirring and reacting for 30min at the temperature of 30-35 ℃, monitoring the reaction by T L C (tracking the reaction until the raw materials disappear), pouring into ice water after the reaction is finished, extracting by dichloromethane, concentrating and washing an organic phase, adding 50m of L diethyl ether, stirring and crystallizing for 20min, and performing suction filtration and drying to obtain 5.48g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, wherein the yield is 74.52% and the purity is 98.27%.
Comparative example 4: preparation of dasatinib
20mmol of 4, 6-dichloro-2-methylpyrimidine and 35mmol of K3PO4Dissolving the raw materials in 16mmol of 1-butyl-3-methylimidazolium tetrafluoroborate, stirring, adding 21mmol of N-hydroxyethyl piperazine, reacting at 80 ℃ for 1.5h, cooling to room temperature, adding 21mmol of 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide, continuing to react at 80 ℃ for 2h, after the reaction is finished, cooling to room temperature, extracting the mixture with diethyl ether for 3 times (3 × 50m L), combining the extracts, concentrating to obtain a crude product (the ionic liquid is extracted with dichloromethane, drying in vacuum to remove a small amount of solvent in the ionic liquid, washing the residual viscous ionic liquid with diethyl ether fully, and then directly using the residual viscous ionic liquid for the following reaction without further purification). The crude product is added with 100m L of 80% aqueous ethanol solution, stirring, added with 2g of activated carbon, refluxed for 30min, filtered while hot, refrigerated for crystallization overnight, filtering, washing a filter cake with 80% aqueous ethanol solution of ice, and drying to obtain 7.54g of a white solid with yield of 98.76.94%.
Comparative example 5: preparation of dasatinib
20mmol of 4, 6-dichloro-2-methylpyrimidine and 35mmol of K3PO4Dissolving the raw materials in 16mmol of 1-N-butyl-3-methylimidazolium bromide, stirring, adding 21mmol of N-hydroxyethyl piperazine, reacting at 80 ℃ for 1.5h, cooling to room temperature, adding 21mmol of 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide, continuing to react at 80 ℃ for 2h, after the reaction is finished, cooling to room temperature, extracting the mixture with diethyl ether for 3 times (3 × 50m L), combining the extracts, concentrating to obtain a crude product (the ionic liquid is extracted with dichloromethane, drying in vacuum to remove a small amount of solvent in the ionic liquid, washing the residual viscous ionic liquid with diethyl ether fully, and then directly using the residual viscous ionic liquid for the following reaction without further purification). The crude product is added with 100m L of 80% aqueous ethanol solution, stirred, added with 2g of activated carbon, refluxed for 30min, filtered while hot, refrigerated for crystallization overnight, filtered, a filter cake is washed with 80% aqueous ethanol solution of ice, and dried to obtain 7.37g of white solid with yield of 74.86% and purity of 99.09%.
Comparative example 6: preparation of dasatinib
20mmol of 4, 6-dichloro-2-methylpyrimidine and 35mmol of K3PO4Dissolving the raw materials in 16mmol of 1-butyl-3-methylimidazolium hexafluorophosphate, stirring, adding 21mmol of N-hydroxyethyl piperazine, reacting at 80 ℃ for 1.5h, cooling to room temperature, adding 21mmol of 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide, continuing to react at 80 ℃ for 2h, after the reaction is finished, cooling to room temperature, extracting the mixture with diethyl ether for 3 times (3 × 50m L), combining the extracts, concentrating to obtain a crude product (the ionic liquid is extracted with dichloromethane, drying in vacuum to remove a small amount of solvent in the ionic liquid, washing the residual viscous ionic liquid with diethyl ether fully, and then directly using the residual viscous ionic liquid for the following reaction without further purification), adding 80% of ethanol aqueous solution 100m L into the crude product, stirring, adding 2g of activated carbon, refluxing for 30min, filtering while hot, refrigerating the filtrate overnight, filtering, washing a filter cake with ice 80% of ethanol aqueous solution, and drying to obtain 6.99g of white solid with the yield of 70.73% and the purity of 98.81%.
It should be noted that the above-mentioned embodiments are only for illustrating the technical concept and features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the content of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (10)
1. The preparation method of dasatinib is characterized by comprising the following operation steps:
1) reacting ethyl 3-oxopropionate with 2-chloro-6-methylaniline under an alkaline condition, adding a solvent in which copper bromide is dissolved for reaction, adding thiourea, and cyclizing under a catalyst to obtain 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide; the catalyst is ionic liquid [ Bmim ] Br;
2) dissolving 4, 6-dichloro-2-methylpyrimidine and alkali in a solvent, adding N-hydroxyethyl piperazine for reaction, adding 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, and stirring for reaction at a certain temperature to obtain a compound 1, namely dasatinib;
2. the method for preparing dasatinib according to claim 1, wherein in step 1), the reaction solvent is tetrahydrofuran, and the base is sodium methoxide.
3. The method for preparing dasatinib according to claim 1, wherein in step 1), the cyclization reaction temperature is 20-25 ℃.
4. The method for preparing dasatinib according to claim 1, wherein in step 1), the mass ratio of ethyl 3-oxopropionate to base to 2-chloro-6-methylaniline is 1: 1.0-2.0: 0.8-1.0; the mass ratio of the ethyl 3-oxopropionate to the copper bromide is 1: 2.0-3.0; the mass ratio of the ethyl 3-oxopropionate to the thiourea is 1: 1.0-2.0; the mass ratio of the ethyl 3-oxopropionate to the catalyst is 1: 0.1-1.0.
5. The process of claim 1, wherein in step 2), the solvent is 1-butyl-3-methylimidazolium glycinate; the alkali is K3PO4Or K2CO3(ii) a The reaction temperature was 80 ℃.
6. The method for preparing dasatinib according to claim 5, wherein in step 2), the mass ratio of 4, 6-dichloro-2-methylpyrimidine, N-hydroxyethylpiperazine, and 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide is 1: 1.0-1.1; the mass ratio of the 4, 6-dichloro-2-methylpyrimidine, the alkali and the 1-butyl-3-methylimidazole glycinate is 1: 1.0-3.0: 0.5-2.0.
7. The method for preparing dasatinib according to claim 4, wherein in step 1), the mass ratio of ethyl 3-oxopropionate to base to 2-chloro-6-methylaniline is 1:1.2 to 1.3: 0.9; the mass ratio of the ethyl 3-oxopropionate to the copper bromide is 1: 2.6-2.8; the mass ratio of the ethyl 3-oxopropionate to the thiourea is 1: 1.2-1.6; the mass ratio of the ethyl 3-oxopropionate to the catalyst is 1: 0.1-0.4.
8. The method for preparing dasatinib according to claim 7, wherein in step 1), the mass ratio of ethyl 3-oxopropionate to base to 2-chloro-6-methylaniline is 1:1.25: 0.9; the mass ratio of the ethyl 3-oxopropionate to the copper bromide is 1:2.7, and the mass ratio of the ethyl 3-oxopropionate to the thiourea is 1: 1.4; the mass ratio of ethyl 3-oxopropionate to catalyst was 1: 0.15.
9. The method for preparing dasatinib according to claim 6, wherein in step 2), the mass ratio of 4, 6-dichloro-2-methylpyrimidine, base and 1-butyl-3-methylimidazolium glycinate is 1: 1.5-2.0: 0.6-1.0.
10. The process of claim 6, wherein in step 2), the mass ratio of 4, 6-dichloro-2-methylpyrimidine, N-hydroxyethylpiperazine, 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide is 1:1.05: 1.05; the mass ratio of 4, 6-dichloro-2-methylpyrimidine, alkali and 1-butyl-3-methylimidazolium glycinate is 1:1.75: 0.8.
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