CN109369638B - Preparation process of dasatinib - Google Patents
Preparation process of dasatinib Download PDFInfo
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- CN109369638B CN109369638B CN201811388270.9A CN201811388270A CN109369638B CN 109369638 B CN109369638 B CN 109369638B CN 201811388270 A CN201811388270 A CN 201811388270A CN 109369638 B CN109369638 B CN 109369638B
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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Abstract
The invention relates to a preparation process of dasatinib, which comprises the following steps: heating and refluxing 3-oxo ethyl propionate and 2-chloro-6-methylaniline under an alkaline condition, adding copper bromide, heating and refluxing, adding thiourea and a catalyst heteropolyacid salt, and stirring at room temperature to react to obtain 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide; then carrying out one-pot reaction on 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, 4, 6-dichloro-2-methylpyrimidine and N-hydroxyethyl piperazine under the action of a catalyst to obtain the dasatinib. 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 process 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 Bezim America. 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 process of dasatinib is characterized by comprising the following operation steps:
1) heating and refluxing 3-oxo ethyl propionate and 2-chloro-6-methylaniline under an alkaline condition, adding a solvent dissolved with copper bromide, heating and refluxing, filtering, adding thiourea into the filtrate, and cyclizing under a catalyst to obtain 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide;
2) dissolving 4, 6-dichloro-2-methylpyrimidine in an organic solvent, sequentially adding N-hydroxyethyl piperazine and 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, and stirring to react at a certain temperature under the action of alkali and a catalyst to prepare dasatinib;
in the step 1), the solvent is tetrahydrofuran, and the alkali is sodium methoxide; the catalyst is heteropolyacid salt, and the cyclization reaction temperature is 20-25 ℃; the mass ratio of 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 to the catalyst is 1: 1.0-2.0: 0.05-0.1. Wherein the heteropolyacid salt is (NH)4)3[PMo12O40]Or H18N3O43PW12(ii) a The mass ratio of the ethyl 3-oxopropionate 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 to the catalyst is 1: 1.3-1.4: 0.08.
In the step 2), the organic solvent is dimethylformamide; the alkali is K3PO4Or K2CO3(ii) a The catalyst is CuI, and the ligand is N, N-dimethylglycine; the reaction temperature is 120 ℃; the mass ratio of the 4, 6-dichloro-2-methylpyrimidine, the N-hydroxyethyl piperazine and the 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide is 1: 1.0-1.2; the mass ratio of the 4, 6-dichloro-2-methylpyrimidine, the alkali, the CuI and the N, N-dimethylglycine is 1: 1.5-2.5: 0.05-0.15: 0.1-0.5. Wherein, 4, 6-dichloro-2-methylpyrimidine and K3PO4The mass ratio of CuI to N, N-dimethylglycine is 1: 1.9-2.1: 0.09-0.11: 0.2-0.3. Preferably, the mass ratio of 4, 6-dichloro-2-methylpyrimidine, N-hydroxyethylpiperazine, 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide is 1:1.1: 1.1; 4, 6-dichloro-2-methylpyrimidine, K3PO4The mass ratio of CuI to N, N-dimethylglycine is 1:2.0:0.10: 0.25.
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. the heteropolyacid salt is used as a catalyst during the synthesis of the 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, the catalyst can be removed by simple filtration, the catalytic activity is high, the treatment is convenient, the catalyst can be repeatedly used, the catalytic activity is still stable, and the green chemical concept is met;
4. the dasatinib is synthesized by the 4, 6-dichloro-2-methylpyrimidine, the N-hydroxyethyl piperazine and the 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide in a one-pot method under the action of CuI and a ligand N, N-dimethylglycine, and the dasatinib is high in synthesis yield, high in purity and short in reaction time.
Detailed Description
The technical solution of the present invention is further described in the following non-limiting examples.
Example 1: preparation of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide
Dissolving 30mmol of ethyl 3-oxopropionate and 36mmol of sodium methoxide in 80mL of tetrahydrofuran, stirring at room temperature for 10min, adding 27mmol of 2-chloro-6-methylaniline, heating and refluxing for 45min, after the reaction is finished, adding 60mL of tetrahydrofuran in which 78mmol of copper bromide is dissolved, heating and refluxing for 1h, filtering while hot, collecting filtrate, adding 39mmol of thiourea and 2.4mmol (NH) of thiourea into the filtrate4)3[PMo12O40]Stirring and reacting at 20-25 ℃ for 15min, and monitoring the reaction by TLC (tracking the reaction to the original state)Materials disappear), after the reaction is finished, the catalyst is filtered, the filtrate is decompressed and evaporated to remove the solvent, 50mL of ether is added for stirring and crystallization for 20min, and 6.58g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide is obtained after suction filtration and drying, the yield is 90.94% and the purity is 99.88%.
Example 2: preparation of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide
Dissolving 30mmol of ethyl 3-oxopropionate and 39mmol of sodium methoxide in 80mL of tetrahydrofuran, stirring at room temperature for 10min, adding 27mmol of 2-chloro-6-methylaniline, heating and refluxing for 45min, after the reaction is finished, adding 60mL of tetrahydrofuran dissolved with 84mmol of copper bromide, heating and refluxing for 1h, filtering while hot, collecting filtrate, adding 42mmol of thiourea and 2.4mmol of H into the filtrate18N3O43PW12Stirring and reacting for 15min at 20-25 ℃, monitoring the reaction by TLC (tracking the reaction until the raw materials disappear), filtering the catalyst after the reaction is finished, evaporating the filtrate under reduced pressure to remove the solvent, adding 50mL of 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 99.86%.
Example 3: preparation of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide
Dissolving 30mmol of ethyl 3-oxopropionate and 30mmol of sodium methoxide in 80mL of tetrahydrofuran, stirring at room temperature for 10min, adding 24mmol of 2-chloro-6-methylaniline, heating and refluxing for 45min, after the reaction is finished, adding 60mL of tetrahydrofuran in which 60mmol of copper bromide is dissolved, heating and refluxing for 1h, filtering while hot, collecting filtrate, adding 30mmol of thiourea and 1.5mmol (NH) of thiourea into the filtrate4)3[PMo12O40]Stirring and reacting for 15min at 20-25 ℃, monitoring the reaction by TLC (tracking the reaction until the raw materials disappear), filtering the catalyst after the reaction is finished, evaporating the filtrate under reduced pressure to remove the solvent, adding 50mL of diethyl ether, stirring and crystallizing for 20min, filtering, and drying to obtain 5.50g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide with the yield of 85.31% and the purity of 99.69%.
Example 4: preparation of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide
30mmol of ethyl 3-oxopropionate and 60mmol of methylDissolving sodium alkoxide in 80mL tetrahydrofuran, stirring at room temperature for 10min, adding 30mmol of 2-chloro-6-methylaniline, heating and refluxing for 45min, adding 60mL tetrahydrofuran dissolved with 90mmol of copper bromide after the reaction is finished, heating and refluxing for 1h, filtering while hot, collecting filtrate, adding 60mmol of thiourea and 3.0mmol of H into the filtrate18N3O43PW12Stirring and reacting for 15min at 20-25 ℃, monitoring the reaction by TLC (tracking the reaction until the raw materials disappear), filtering the catalyst after the reaction is finished, evaporating the filtrate under reduced pressure to remove the solvent, adding 50mL of diethyl ether, stirring and crystallizing for 20min, filtering, and drying to obtain 6.96g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide with the yield of 86.47% and the purity of 99.72%.
Example 5: preparation of dasatinib
5mmol of N, N-dimethylglycine, 2mmol of CuI, 20mmol of 4, 6-dichloro-2-methylpyrimidine are dissolved in 100mL of DMF, 22mmol of N-hydroxyethyl piperazine, 40mmol of K are added with stirring3PO4After stirring at room temperature for 40min, 22mmol of 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide was added under stirring. General formula (N)2Reacting at 120 deg.C for 6h, dissolving copper salt with 50mL ammonia water, extracting with 50mL × 3 ethyl acetate, mixing ethyl acetate phases, washing with saturated saline solution, and collecting organic layer with anhydrous Na2SO4Drying to obtain a crude product. Adding the crude product into 100mL of 80% ethanol aqueous solution, adding 2g of activated carbon while stirring, refluxing for 30min, filtering while hot, refrigerating and crystallizing the filtrate overnight, filtering, washing the filter cake with ice 80% ethanol aqueous solution, and drying to obtain 8.64g of white solid with yield of more than 88.41% and purity of more than 99.92%.
Example 6: preparation of dasatinib
4mmol of N, N-dimethylglycine, 1.8mmol of CuI and 20mmol of 4, 6-dichloro-2-methylpyrimidine are dissolved in 100mL of DMF, 20mmol of N-hydroxyethyl piperazine and 38mmol of K are added with stirring3PO4After stirring at room temperature for 40min, 20mmol of 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide was added under stirring. General formula (N)2Reacting at 120 deg.C for 6h, dissolving copper salt with 50mL ammonia water, extracting with 50mL × 3 ethyl acetate, mixing ethyl acetate phases, washing with saturated saline solution, and collecting organic layerWater Na2SO4Drying to obtain a crude product. Adding the crude product into 100mL of 80% ethanol aqueous solution, adding 2g of activated carbon while stirring, refluxing for 30min, filtering while hot, refrigerating and crystallizing the filtrate overnight, filtering, washing the filter cake with ice 80% ethanol aqueous solution, and drying to obtain 8.48g of white solid with yield of more than 86.72% and purity of more than 99.77%.
Example 7: preparation of dasatinib
6mmol of N, N-dimethylglycine, 2.2mmol of CuI and 20mmol of 4, 6-dichloro-2-methylpyrimidine are dissolved in 100mL of DMF, and 24mmol of N-hydroxyethyl piperazine and 42mmol of K are added with stirring2CO3After stirring at room temperature for 40min, 24mmol of 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide was added under stirring. General formula (N)2Reacting at 120 deg.C for 6h, dissolving copper salt with 50mL ammonia water, extracting with 50mL × 3 ethyl acetate, mixing ethyl acetate phases, washing with saturated saline solution, and collecting organic layer with anhydrous Na2SO4Drying to obtain a crude product. Adding the crude product into 100mL of 80% ethanol aqueous solution, adding 2g of activated carbon while stirring, refluxing for 30min, filtering while hot, refrigerating and crystallizing the filtrate overnight, filtering, washing the filter cake with ice 80% ethanol aqueous solution, and drying to obtain 8.52g of white solid with yield of more than 87.14% and purity of more than 99.82%.
Example 8: preparation of dasatinib
Dissolving 2mmol of N, N-dimethylglycine, 1mmol of CuI and 20mmol of 4, 6-dichloro-2-methylpyrimidine in 100mL of DMF, adding 22mmol of N-hydroxyethyl piperazine and 22mmol of K under stirring3PO4After stirring at room temperature for 40min, 30mmol of 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide was added under stirring. General formula (N)2Reacting at 120 deg.C for 6h, dissolving copper salt with 50mL ammonia water, extracting with 50mL × 3 ethyl acetate, mixing ethyl acetate phases, washing with saturated saline solution, and collecting organic layer with anhydrous Na2SO4Drying to obtain a crude product. Adding the crude product into 80% ethanol water solution 100mL, stirring, adding 2g activated carbon, refluxing for 30min, filtering while hot, cold preserving the filtrate for crystallization overnight, filtering, washing the filter cake with ice 80% ethanol water solution, and drying to obtain white solid 8.17g with yield over 83.38%, pureThe degree is more than 99.57%.
Example 9: preparation of dasatinib
10mmol of N, N-dimethylglycine, 3mmol of CuI and 20mmol of 4, 6-dichloro-2-methylpyrimidine are dissolved in 100mL of DMF, and 22mmol of N-hydroxyethyl piperazine and 50mmol of K are added with stirring3PO4After stirring at room temperature for 40min, 22mmol of 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide was added under stirring. General formula (N)2Reacting at 120 deg.C for 6h, dissolving copper salt with 50mL ammonia water, extracting with 50mL × 3 ethyl acetate, mixing ethyl acetate phases, washing with saturated saline solution, and collecting organic layer with anhydrous Na2SO4Drying to obtain a crude product. Adding the crude product into 100mL of 80% ethanol aqueous solution, adding 2g of activated carbon while stirring, refluxing for 30min, filtering while hot, refrigerating and crystallizing the filtrate overnight, filtering, washing the filter cake with ice 80% ethanol aqueous solution, and drying to obtain 8.37g of white solid with yield of more than 85.49% and purity of more than 99.71%.
Comparative example 1: preparation of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide
Dissolving 30mmol of ethyl 3-oxopropionate and 36mmol of sodium methoxide in 80mL of methanol, stirring at room temperature for 10min, adding 27mmol of 2-chloro-6-methylaniline, heating and refluxing for 45min, after the reaction is finished, adding 60mL of methanol in which 78mmol of copper bromide is dissolved, heating and refluxing for 1h, filtering while hot, collecting filtrate, adding 39mmol of thiourea and 2.4mmol (NH) of thiourea into the filtrate4)3[PMo12O40]Stirring and reacting for 15min at 20-25 ℃, monitoring the reaction by TLC (tracking the reaction until the raw materials disappear), filtering the catalyst after the reaction is finished, evaporating the filtrate under reduced pressure to remove the solvent, adding 50mL of diethyl ether, stirring and crystallizing for 20min, filtering and drying to obtain 5.47g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, wherein the yield is 74.36 percent and the purity is 98.28 percent.
Comparative 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 80mL of tetrahydrofuran, stirring at room temperature for 10min, adding 27mmol of 2-chloro-6-methylaniline, heating and refluxing for 45min, after the reaction is finished, adding 60mL of tetrahydrofuran in which 78mmol of copper bromide is dissolved, heating and refluxing for 1h, filtering while hot, reserving filtrate, adding 39mmol of thiourea in the filtrate, stirring and reacting at 20-25 ℃ for 15min, monitoring the reaction by TLC (tracking the reaction until the raw material disappears), filtering the catalyst after the reaction is finished, evaporating the filtrate under reduced pressure to remove the solvent, adding 50mL of diethyl ether, stirring and crystallizing for 20min, carrying out suction filtration and drying to obtain 4.40g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, wherein the yield is 59.42% and the purity is 97.65%.
Comparative example 3: preparation of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide
Dissolving 30mmol of ethyl 3-oxopropionate and 36mmol of sodium methoxide in 80mL of tetrahydrofuran, stirring at room temperature for 10min, adding 27mmol of 2-chloro-6-methylaniline, heating and refluxing for 45min, after the reaction is finished, adding 60mL of tetrahydrofuran in which 30mmol of copper bromide is dissolved, heating and refluxing for 1h, filtering while hot, collecting filtrate, adding 39mmol of thiourea and 2.4mmol (NH) of thiourea into the filtrate4)3[PMo12O40]Stirring and reacting for 15min at the temperature of 30-35 ℃, monitoring the reaction by TLC (tracking the reaction until the raw materials disappear), filtering the catalyst after the reaction is finished, evaporating the filtrate under reduced pressure to remove the solvent, adding 50mL of diethyl ether, stirring and crystallizing for 20min, performing suction filtration and drying to obtain 5.34g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, wherein the yield is 72.75% and the purity is 98.40%.
Comparative example 4: preparation of dasatinib
5mmol of N, N-dimethylethylenediamine, 2mmol of CuI and 20mmol of 4, 6-dichloro-2-methylpyrimidine were dissolved in 100mL of DMF and 22mmol of N-hydroxyethylpiperazine, 40mmol of K, were added with stirring3PO4After stirring at room temperature for 40min, 22mmol of 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide was added under stirring. General formula (N)2Reacting at 120 deg.C for 6h, dissolving copper salt with 50mL ammonia water, extracting with 50mL × 3 ethyl acetate, mixing ethyl acetate phases, washing with saturated saline solution, and collecting organic layer with anhydrous Na2SO4Drying to obtain a crude product. Adding the crude product into 80% ethanol water solution 100mL, stirring, adding 2g active carbon, refluxing for 30min, filtering while hot, cold preserving the filtrate for crystallization overnight, filtering, washing the filter cake with ice 80% ethanol water solution, and drying to obtain white solid 7.20g with yield of 72More than 58% and purity more than 98.42%.
Comparative example 5: preparation of dasatinib
Adding 5mmol of N, N-dimethylglycine and 2mmol of Cu2O, 20mmol of 4, 6-dichloro-2-methylpyrimidine in 100mL of DMF, 22mmol of N-hydroxyethyl piperazine, 40mmol of K are added with stirring2CO3After stirring at room temperature for 40min, 22mmol of 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide was added under stirring. General formula (N)2Reacting at 120 deg.C for 6h, dissolving copper salt with 50mL ammonia water, extracting with 50mL × 3 ethyl acetate, mixing ethyl acetate phases, washing with saturated saline solution, and collecting organic layer with anhydrous Na2SO4Drying to obtain a crude product. Adding the crude product into 100mL of 80% ethanol aqueous solution, adding 2g of activated carbon while stirring, refluxing for 30min, filtering while hot, refrigerating and crystallizing the filtrate overnight, filtering, washing a filter cake with ice 80% ethanol aqueous solution, and drying to obtain 7.52g of white solid, wherein the yield is more than 75.94%, and the purity is more than 98.59%.
Comparative example 6: preparation of dasatinib
Dissolving 5mmol of N-methylglycine, 2mmol of CuI and 20mmol of 4, 6-dichloro-2-methylpyrimidine in 100ml of DMF, adding 22mmol of N-hydroxyethyl piperazine and 40mmol of K under stirring3PO4After stirring at room temperature for 40min, 22mmol of 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide was added under stirring. General formula (N)2Reacting at 120 deg.C for 6h, dissolving copper salt with 50mL ammonia water, extracting with 50mL × 3 ethyl acetate, mixing ethyl acetate phases, washing with saturated saline solution, and collecting organic layer with anhydrous Na2SO4Drying to obtain a crude product. Adding the crude product into 100mL of 80% ethanol aqueous solution, adding 2g of activated carbon while stirring, refluxing for 30min, filtering while hot, refrigerating and crystallizing the filtrate overnight, filtering, washing the filter cake with ice 80% ethanol aqueous solution, and drying to obtain 7.71g of white solid with yield over 78.36% and purity over 99.17%.
Comparative example 7: preparation of dasatinib
Dissolving 5mmol of N, N-dimethylglycine, 2mmol of CuI and 20mmol of 4, 6-dichloro-2-methylpyrimidine in 100mL of absolute ethanol, adding 22mmol of N-hydroxyethyl piperazine and 40mmol of N, N-dimethylglycine and copper chloride under stirringl K3PO4After stirring at room temperature for 40min, 22mmol of 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide was added under stirring. General formula (N)2Reacting at 120 deg.C for 6h, dissolving copper salt with 50mL ammonia water, extracting with 50mL × 3 ethyl acetate, mixing ethyl acetate phases, washing with saturated saline solution, and collecting organic layer with anhydrous Na2SO4Drying to obtain a crude product. Adding the crude product into 100mL of 80% ethanol aqueous solution, adding 2g of activated carbon while stirring, refluxing for 30min, filtering while hot, refrigerating and crystallizing the filtrate overnight, filtering, washing a filter cake with ice 80% ethanol aqueous solution, and drying to obtain 7.36g of white solid, wherein the yield is over 74.68%, and the purity is over 99.03%.
Comparative example 8: preparation of dasatinib
5mmol of N, N-dimethylglycine, 2mmol of CuI, 20mmol of 4, 6-dichloro-2-methylpyrimidine are dissolved in 100mL of DMF, 22mmol of N-hydroxyethyl piperazine, 40mmol of K are added with stirring3PO4After stirring at room temperature for 40min, 22mmol of 2-amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide was added under stirring. General formula (N)2Reacting at 80 deg.C for 6h, dissolving copper salt with 50mL ammonia water, extracting with 50mL × 3 ethyl acetate, mixing ethyl acetate phases, washing with saturated saline solution, and collecting organic layer with anhydrous Na2SO4Drying to obtain a crude product. Adding the crude product into 100mL of 80% ethanol aqueous solution, adding 2g of activated carbon while stirring, refluxing for 30min, filtering while hot, refrigerating and crystallizing the filtrate overnight, filtering, washing the filter cake with ice 80% ethanol aqueous solution, and drying to obtain 6.94g of white solid with yield of more than 70.25% and purity of more than 98.86%.
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 process of dasatinib is characterized by comprising the following operation steps:
1) heating and refluxing 3-oxo ethyl propionate and 2-chloro-6-methylaniline under an alkaline condition, adding a solvent dissolved with copper bromide, heating and refluxing, filtering, adding thiourea into the filtrate, and cyclizing under a catalyst to obtain 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide; the catalyst is heteropolyacid salt;
2) dissolving 4, 6-dichloro-2-methylpyrimidine in an organic solvent, sequentially adding N-hydroxyethyl piperazine and 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, and stirring to react at a certain temperature under the action of alkali and a catalyst to prepare dasatinib; the catalyst is CuI, and the ligand is N, N-dimethylglycine;
2. the process according to claim 1, wherein in step 1), the solvent is tetrahydrofuran and the base is sodium methoxide.
3. The process for preparing dasatinib according to claim 1, wherein in step 1), the cyclization reaction temperature is 20-25 ℃.
4. The process 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 to the catalyst is 1: 1.0-2.0: 0.05-0.1.
5. The process according to claim 1, wherein in step 2), the organic solvent is dimethylformamide; the alkali is K3PO4Or K2CO3(ii) a The reaction temperature was 120 ℃.
6. The process for preparing dasatinib according to claim 1, 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: 1.0-1.2; the mass ratio of the 4, 6-dichloro-2-methylpyrimidine, the alkali, the CuI and the N, N-dimethylglycine is 1: 1.5-2.5: 0.05-0.15: 0.1-0.5.
7. The process of claim 1, wherein in step 1), the heteropolyacid salt is (NH)4)3[PMo12O40]Or H18N3O43PW12。
8. The process for preparing dasatinib according to claim 4, wherein in step 1), the mass ratio of ethyl 3-oxopropanoate 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 to the catalyst is 1: 1.3-1.4: 0.08.
9. The process of claim 6, wherein 4, 6-dichloro-2-methylpyrimidine and K are used in step 2)3PO4The mass ratio of CuI to N, N-dimethylglycine is 1: 1.9-2.1: 0.09-0.11: 0.2-0.3.
10. The process for preparing dasatinib according to claim 9, characterized in that 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 1:1.1: 1.1; 4, 6-dichloro-2-methylpyrimidine, K3PO4The mass ratio of CuI to N, N-dimethylglycine is 1:2.0:0.10: 0.25.
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