CN109503511B

CN109503511B - Preparation method of dasatinib intermediate

Info

Publication number: CN109503511B
Application number: CN201811388251.6A
Authority: CN
Inventors: 高红军; 李兆文; 程明
Original assignee: Shandong Luoxin Pharmaceutical Group Hengxin Pharmaceutical Co ltd; Shandong Yuxin Pharmaceutical Co ltd; Shandong Luoxin Pharmaceutical Group Co Ltd
Current assignee: Shandong Luoxin Pharmaceutical Group Hengxin Pharmaceutical Co ltd; Shandong Yuxin Pharmaceutical Co ltd; Shandong Luoxin Pharmaceutical Group Co Ltd
Priority date: 2018-11-21
Filing date: 2018-11-21
Publication date: 2021-01-01
Anticipated expiration: 2038-11-21
Also published as: CN109503511A

Abstract

The invention relates to a preparation method of a dasatinib intermediate, which comprises the following steps: heating and refluxing 3-oxo ethyl propionate and 2-chloro-6-methylaniline under an alkaline condition, adding copper bromide, and heating and refluxing to obtain a compound 2; cyclizing the compound 2 and thiourea in a solvent PEG 400 to obtain the target product 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide. The method has the advantages of mild conditions, simple steps, environmental friendliness and high yield, and is suitable for industrial production.

Description

Preparation method of dasatinib intermediate

Technical Field

The invention relates to the field of drug synthesis, and particularly relates to a preparation method of a dasatinib intermediate.

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.

2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide is a key intermediate for the synthesis of dasatinib, and is represented by the following formula:

according to literature reports, the following synthetic methods are mainly used for 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, and the following methods are introduced.

(1) Using thiazole ring compounds as starting materials, for example j.med.chem.,2004,6658 reports a route for the synthesis of dasatinib, as follows:

and 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.

(2) The preparation method comprises the following steps of preparing a thiazole intermediate by condensing non-thiazole raw materials, hydrolyzing chlorous acid serving as a starting material to obtain 2, 3-dichloroacrylic acid, treating the raw material to obtain acyl chloride by using thionyl chloride, grafting the acyl chloride with 2-chloro-6-methylaniline, treating the acyl chloride with methanol-sodium methoxide to generate dimethyl acetal, deprotecting under an acidic condition, and performing in-situ cyclization with thiourea to obtain a target compound, wherein 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 fourth step uses NBS in a large amount, so that the cost is greatly increased, the NBS reaction must be carried out at low temperature, the conditions are harsh, and the workload of post-treatment is 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 intermediates, which is simple, mild in conditions, environmentally friendly and high in yield.

Disclosure of Invention

The invention aims to overcome the defects of the existing method for preparing the dasatinib intermediate 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, and provides a synthetic method of the dasatinib intermediate, which has the advantages of mild conditions, simple steps, environmental friendliness and high yield. The technical scheme of the invention is as follows:

a preparation method of a dasatinib intermediate 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, and reacting to obtain a compound 2;

2) reacting the compound 2 with thiourea at room temperature, and performing post-treatment to obtain a target product 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide;

in the step 1), the solvent is tetrahydrofuran, and the alkali is sodium methoxide, sodium carbonate or sodium bicarbonate; 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 post-treatment steps are as follows: and after the reaction is finished, filtering while the reaction is hot, washing, combining the filtrate with a washing solution, washing to be neutral by water, distilling under reduced pressure to remove the solvent, pouring the residue into ice water, stirring, filtering under reduced pressure, washing a filter cake by the ice water, and drying to obtain the compound 2. 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.

In the step 2), the reaction solvent is PEG-400; the mass of the compound 2 and the volume of the organic solvent are 1g: 8-14 mL; the mass ratio of the compound 2 to the thiourea is 1: 1.0-2.0; the purification steps are as follows: after the reaction is finished, adding ethyl acetate, separating out solids and filtering; adding the filter cake into a mixed solvent of water and ethyl acetate, dropwise adding ammonia water to adjust the pH value, standing for layering, extracting with ethyl acetate, drying an organic phase, concentrating under reduced pressure to obtain an oily substance, adding diethyl ether, cooling to 0-5 ℃, preserving heat, stirring for crystallization, performing suction filtration, and drying to obtain a target product. Wherein the mass ratio of the compound 2 to the thiourea is 1: 1.4-1.6; the mass of the compound 2 and the volume of the organic solvent are 1g: 10-11 mL; the volume ratio of water to ethyl acetate in the mixed solvent is 1:1, the pH value adjusted by ammonia water is 8.5-9.0, the stirring speed in stirring crystallization is 60 revolutions per minute, and the stirring time is 30 min.

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 two steps, 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. because the traditional synthesis method needs to react under an acidic condition, adopts a polar solvent, has long reaction time and unsatisfactory yield, the invention adopts cheap and easily-obtained nontoxic polyethylene glycol (PEG 400) as a green solvent, has less environmental pollution and high yield and purity, and the PEG 400 can be recycled.

Detailed Description

The technical solution of the present invention is further described in the following non-limiting examples.

Example 1: synthesis of Compound 2

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 1h, cooling to room temperature after the reaction is finished, adding 60mL of tetrahydrofuran in which 78mmol of copper bromide is dissolved, heating and refluxing for 2h, filtering while hot, washing a filter cake with 50mL of hot tetrahydrofuran, combining a filtrate and a washing solution, washing to neutrality by water, distilling under reduced pressure to remove the solvent, pouring the residue into 50mL of ice water, stirring for 0.5h, carrying out suction filtration under reduced pressure, washing the filter cake with ice water, and drying to obtain 7.19g of compound 2, wherein the yield is 91.60%, and the purity is 99.92%.

Example 2: synthesis of Compound 2

Dissolving 30mmol of ethyl 3-oxopropionate and 39mmol of sodium carbonate in 80mL of tetrahydrofuran, stirring at room temperature for 10min, adding 27mmol of 2-chloro-6-methylaniline, heating and refluxing for 1h, cooling to room temperature after the reaction is finished, adding 60mL of tetrahydrofuran dissolved with 84mmol of copper bromide, heating and refluxing for 2h, filtering while hot, washing a filter cake with 50mL of hot tetrahydrofuran, combining a filtrate and a washing solution, washing to neutrality by water, distilling under reduced pressure to remove the solvent, pouring the residue into 50mL of ice water, stirring for 0.5h, carrying out suction filtration under reduced pressure, washing the filter cake with ice water, and drying to obtain 7.10g of compound 2, wherein the yield is 90.43%, and the purity is 99.90%.

Example 3: synthesis of Compound 2

Dissolving 30mmol of ethyl 3-oxopropionate and 30mmol of sodium bicarbonate in 80mL of tetrahydrofuran, stirring at room temperature for 10min, adding 24mmol of 2-chloro-6-methylaniline, heating and refluxing for 1h, cooling to room temperature after the reaction is finished, adding 60mL of tetrahydrofuran dissolved with 40mmol of copper bromide, heating and refluxing for 2h, filtering while hot, washing a filter cake with 50mL of hot tetrahydrofuran, combining a filtrate and a washing solution, washing to neutrality by water, distilling under reduced pressure to remove a solvent, pouring a residue into 50mL of ice water, stirring for 0.5h, carrying out suction filtration under reduced pressure, washing the filter cake with ice water, and drying to obtain 5.99g of compound 2, wherein the yield is 85.72%, and the purity is 99.82%.

Example 4: synthesis of Compound 2

Dissolving 30mmol of ethyl 3-oxopropionate and 60mmol of sodium methoxide in 80mL of tetrahydrofuran, stirring at room temperature for 10min, adding 30mmol of 2-chloro-6-methylaniline, heating and refluxing for 1h, cooling to room temperature after the reaction is finished, adding 60mL of tetrahydrofuran in which 90mmol of copper bromide is dissolved, heating and refluxing for 2h, filtering while hot, washing a filter cake with 50mL of hot tetrahydrofuran, combining a filtrate and a washing solution, washing to neutrality by water, distilling under reduced pressure to remove a solvent, pouring a residue into 50mL of ice water, stirring for 0.5h, carrying out suction filtration under reduced pressure, washing the filter cake with ice water, and drying to obtain 7.75g of compound 2, wherein the yield is 88.68%, and the purity is 99.71%.

Example 5: synthesis of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide

20mmol (5.81g) of compound 2 and 28mmol of thiourea were dissolved in 60mL of PEG 400, the reaction was stirred at room temperature for 1 hour, the reaction was monitored by TLC (following the reaction until the starting material disappeared), after the reaction was completed, 50mL of ethyl acetate was added, a solid precipitated, and the reaction was filtered (water was added to the filtrate, extraction was performed with ethyl acetate, and the aqueous phase was dried to recover PEG-400). Adding the filter cake into 50mL of water and 50mL of ethyl acetate, dropwise adding ammonia water to adjust the pH value to 8.5-9.0, standing for layering, extracting with ethyl acetate, drying the organic phase, concentrating under reduced pressure to obtain an oily substance, adding 50mL of diethyl ether, cooling to 0-5 ℃, keeping the temperature, stirring for crystallization for 30min, stirring at the speed of 60 r/min, performing suction filtration and drying to obtain 5.14g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, wherein the yield is 95.94%, and the purity is 99.86%.

Example 6: synthesis of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide

Dissolving 20mmol of compound 2 and 32mmol of thiourea in 60mL of PEG 400, stirring at room temperature for reaction for 1h, monitoring the reaction by TLC (tracking the reaction until the raw material disappears), adding 50mL of ethyl acetate after the reaction is finished, separating out a solid, and filtering (adding water into the filtrate, extracting with ethyl acetate, drying the water phase, and recovering PEG-400). Adding the filter cake into 50mL of water and 50mL of ethyl acetate, dropwise adding ammonia water to adjust the pH value to 8.5-9.0, standing for layering, extracting with ethyl acetate, drying the organic phase, concentrating under reduced pressure to obtain an oily substance, adding 50mL of diethyl ether, cooling to 0-5 ℃, keeping the temperature, stirring for crystallization for 30min, stirring at the speed of 60 r/min, performing suction filtration and drying to obtain 5.07g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, wherein the yield is 94.41 percent, and the purity is 99.76 percent.

Example 7: synthesis of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide

Dissolving 20mmol of compound 2 and 20mmol of thiourea in 80mL of PEG 400, stirring at room temperature for reaction for 1h, monitoring the reaction by TLC (tracking the reaction until the raw material disappears), adding 50mL of ethyl acetate after the reaction is finished, separating out a solid, and filtering (adding water into the filtrate, extracting with ethyl acetate, drying the water phase, and recovering PEG-400). Adding the filter cake into 50mL of water and 50mL of ethyl acetate, dropwise adding ammonia water to adjust the pH value to 8.5-9.0, standing for layering, extracting with ethyl acetate, drying the organic phase, concentrating under reduced pressure to obtain an oily substance, adding 50mL of diethyl ether, cooling to 0-5 ℃, keeping the temperature, stirring for crystallization for 30min, stirring at the speed of 60 r/min, performing suction filtration and drying to obtain 4.92g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, wherein the yield is 91.47%, and the purity is 99.61%.

Example 8: synthesis of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide

Dissolving 20mmol of compound 2 and 40mmol of thiourea in 50mL of PEG 400, stirring at room temperature for reaction for 1h, monitoring the reaction by TLC (tracking the reaction until the raw material disappears), adding 50mL of ethyl acetate after the reaction is finished, separating out a solid, and filtering (adding water into the filtrate, extracting with ethyl acetate, drying the water phase, and recovering PEG-400). Adding the filter cake into 50mL of water and 50mL of ethyl acetate, dropwise adding ammonia water to adjust the pH value to 8.5-9.0, standing for layering, extracting with ethyl acetate, drying the organic phase, concentrating under reduced pressure to obtain an oily substance, adding 50mL of diethyl ether, cooling to 0-5 ℃, keeping the temperature, stirring for crystallization for 30min, stirring at the speed of 60 r/min, performing suction filtration and drying to obtain 5.03g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, wherein the yield is 93.42% and the purity is 99.37%.

Comparative example 1: synthesis of Compound 2

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 1h, cooling to room temperature after the reaction is finished, adding 60mL of methanol in which 78mmol of copper bromide is dissolved, heating and refluxing for 2h, filtering while hot, washing a filter cake with 50mL of hot tetrahydrofuran, combining a filtrate and a washing solution, washing to neutrality by water, distilling under reduced pressure to remove the solvent, pouring a residue into 50mL of ice water, stirring for 0.5h, carrying out suction filtration under reduced pressure, washing the filter cake with ice water, and drying to obtain 5.83g of compound 2, wherein the yield is 72.48%, and the purity is 97.47%.

Comparative example 2: synthesis of Compound 2

Dissolving 30mmol of ethyl 3-oxopropionate and 36mmol of sodium methoxide in 80mL of chloroform, stirring at room temperature for 10min, adding 27mmol of 2-chloro-6-methylaniline, heating and refluxing for 1h, cooling to room temperature after the reaction is finished, adding 60mL of chloroform in which 78mmol of copper bromide is dissolved, heating and refluxing for 2h, filtering while hot, washing a filter cake with 50mL of hot tetrahydrofuran, combining the filtrate and a washing solution, washing to neutrality by water, distilling under reduced pressure to remove the solvent, pouring the residue into 50mL of ice water, stirring for 0.5h, carrying out suction filtration under reduced pressure, washing the filter cake with ice water, and drying to obtain 5.49g of compound 2, wherein the yield is 68.89%, and the purity is 98.46%.

Comparative example 3: synthesis of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide

20mmol (5.81g) of Compound 2 and 28mmol of thiourea were dissolved in 60mL of acetonitrile, the reaction was stirred at room temperature for 1 hour, the reaction was monitored by TLC (following the reaction until the starting material disappeared), after the reaction was completed, 50mL of ethyl acetate was added, a solid precipitated, and the mixture was filtered. Adding the filter cake into 50mL of water and 50mL of ethyl acetate, dropwise adding ammonia water to adjust the pH value to 8.5-9.0, standing for layering, extracting with ethyl acetate, drying the organic phase, concentrating under reduced pressure to obtain an oily substance, adding 50mL of diethyl ether, cooling to 0-5 ℃, keeping the temperature, stirring for crystallization for 30min, stirring at the speed of 60 r/min, performing suction filtration and drying to obtain 3.78g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, wherein the yield is 68.84%, and the purity is 97.43%.

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

1. A preparation method of a dasatinib intermediate is characterized by comprising the following operation steps:

2. the method for preparing dasatinib intermediate according to claim 1, wherein in step 1), the solvent is tetrahydrofuran, and the base is sodium methoxide, sodium carbonate or sodium bicarbonate.

3. The method for preparing the dasatinib intermediate according to claim 1, wherein in step 1), the mass ratio of the ethyl 3-oxopropionate to the base 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.

4. The preparation method of dasatinib intermediate according to claim 1, characterized in that in step 1), the post-treatment step is: and after the reaction is finished, filtering while the reaction is hot, washing, combining the filtrate with a washing solution, washing to be neutral by water, distilling under reduced pressure to remove the solvent, pouring the residue into ice water, stirring, filtering under reduced pressure, washing a filter cake by the ice water, and drying to obtain the compound 2.

5. The method for preparing the dasatinib intermediate according to claim 1, wherein in step 2), the reaction solvent is PEG-400; the mass of the compound 2 and the volume of the organic solvent are 1g: 8-14 mL; the mass ratio of the compound 2 to the thiourea is 1: 1.0-2.0.

6. The method for preparing the dasatinib intermediate according to claim 1, wherein in step 2), the purification step is: after the reaction is finished, adding ethyl acetate, separating out solids and filtering; adding the filter cake into a mixed solvent of water and ethyl acetate, dropwise adding ammonia water to adjust the pH value, standing for layering, extracting with ethyl acetate, drying an organic phase, concentrating under reduced pressure to obtain an oily substance, adding diethyl ether, cooling to 0-5 ℃, preserving heat, stirring for crystallization, performing suction filtration, and drying to obtain a target product.

7. The method for preparing the dasatinib intermediate according to claim 3, wherein in step 1), the mass ratio of the ethyl 3-oxopropionate to the base to the 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.

8. The method for preparing the dasatinib intermediate according to claim 5, wherein in the step 2), the mass ratio of the compound 2 to the thiourea is 1: 1.4-1.6; the mass of the compound 2 and the volume of the organic solvent are 1g: 10-11 mL.

9. The preparation method of the dasatinib intermediate according to claim 6, characterized in that in step 2), the volume ratio of water to ethyl acetate in the mixed solvent is 1:1, the pH value adjusted by ammonia water is 8.5-9.0, the stirring speed in stirring crystallization is 60 rpm, and the stirring time is 30 min.