CN114634421A - Preparation method of dasatinib intermediate - Google Patents
Preparation method of dasatinib intermediate Download PDFInfo
- Publication number
- CN114634421A CN114634421A CN202210184505.2A CN202210184505A CN114634421A CN 114634421 A CN114634421 A CN 114634421A CN 202210184505 A CN202210184505 A CN 202210184505A CN 114634421 A CN114634421 A CN 114634421A
- Authority
- CN
- China
- Prior art keywords
- chloro
- ethoxy
- methylphenyl
- temperature
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
- C07C51/62—Preparation of carboxylic acid halides by reactions not involving the carboxylic acid halide group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention relates to a synthetic method of a drug intermediate, in particular to a preparation method of a dasatinib intermediate, which comprises the following steps: reacting oxalyl chloride with vinyl ether at low temperature, removing hydrogen chloride at room temperature, removing carbon monoxide at high temperature, and performing vacuum distillation to obtain 3-ethoxy-2-acryloyl chloride; the 3-ethoxy-2-acryloyl chloride and 2-chloro-6-methylaniline react at low temperature to prepare the N- (2-chloro-6-methylphenyl) -3-ethoxy acrylamide. Compared with the prior art, the invention has the following technical and benefit advantages: the raw materials are cheap and easy to purchase, corresponding equipment is greatly reduced, the low-room temperature-high temperature condition of the reaction is easy to realize in mass production, the reaction is stable and controllable, and the yield is high; compared with the traditional catalyst, the high-efficiency catalyst is used with a small dosage, and the N- (2-chloro-6-methylphenyl) -3-ethoxy acrylamide with better quality is obtained at low temperature.
Description
Technical Field
The invention relates to a synthetic method of a drug intermediate, in particular to a synthetic method of N- (2-chloro-6-methylphenyl) -3-ethoxy acrylamide and 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, wherein the compounds are key intermediates for synthesizing dasatinib.
Background
Dasatinib is an oral tyrosine kinase inhibitor developed by Bezime Misge company, and has the chemical name of N- (2-chloro-6-methylphenyl) -2- [6- [4- (2-hydroxyethyl) -1-piperazinyl) -2-methyl-4-pyrimidinyl ] amino-5-thiazolecarboxamide monohydrate. The drug is approved by FDA to be marketed in 2006 and 6 months, and is used for treating chronic myelocytic leukemia patients resistant or intolerant to imatinib; also, it is useful for treating adult patients with philadelphia chromosome positive acute lymphocytic leukemia who are resistant or intolerant to other therapies. The product has inhibition effect on various mutants of Bcr-Abl kinase, has greatly improved inhibition intensity compared with Imatinib (Imatinib), and has no drug resistance. The medicine has good development trend and huge market potential.
2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide is a key intermediate for synthesizing dasatinib, and is shown as the following formula.
The literature reports that there are mainly two synthetic methods for 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide, namely 1): firstly preparing thiazole ring, and then condensing with 2-chloro-6-methylaniline; 2) the side chain acyl chloride or ester and 2-chloro-6-methylaniline are condensed first and then closed to form a thiazole ring. Now separately described are the following:
the patent W02005077945A1 and the document J Med Chem,2006,49(23):6819-6832 report that the target product is obtained by taking 2-aminothiazole-5-ethyl formate as a raw material, performing N-Boc protection, hydrolyzing the raw material into acid, performing acyl chloride to form amide, and removing Boc protection groups, and the method is as follows:
generally, the method for synthesizing the target 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide by firstly preparing the thiazole ring and then condensing the thiazole ring with 2-chloro-6-methylaniline has the defects of long route, complex operation and high cost.
The synthesis method of condensing side chain acyl chloride or ester with 2-chloro-6-methylaniline and then closing ring to form thiazole ring has many related patents, and the specific contents are as follows:
patent US200737978 reports that mucochloric acid is used as a starting material, and is hydrolyzed into 2, 3-dichloroacrylic acid, then reacts with thionyl chloride to generate acyl chloride, and then is condensed with 2-chloro-6-methylaniline, then is treated with methanol-sodium methoxide to generate dimethyl acetal, and finally under an acidic condition, deprotection and in-situ thiourea cyclization are carried out to obtain a target compound, wherein the synthetic route is as follows:
the method has the advantages of high price of raw material mucochloric acid, high production cost, multi-step reduced pressure distillation in the reaction process, and high energy consumption and equipment requirement.
In the prior art, in the production of N- (2-chloro-6-methylphenyl) -3-ethoxy acrylamide, the decarboxylation is decomposed at high temperature, and under the condition, the product 3-ethoxy acrylic acid chlorine is easy to polymerize and form carbonization, so that the yield is reduced, the intermediate product is impure, reduced pressure distillation and purification are needed, and the requirement of energy consumption on equipment is high; or the synthesis route is long, the operation is complicated, and the thionyl chloride and the trichloroacetyl chloride which are volatile and have large pollution to the environment are used in the reaction process.
In conclusion, none of the methods reported in the literature is an optimal synthetic process suitable for scale-up production.
Therefore, the method for synthesizing the dasatinib intermediate is simple, mild in condition, environment-friendly and high in yield, and the requirement on equipment is simplified as much as possible to meet the production requirement.
Disclosure of Invention
The invention aims to overcome the defects of the existing method for preparing the dasatinib intermediate and provides the method for preparing the dasatinib intermediate, which is mild in condition, simple in step, environment-friendly and high in yield.
In order to achieve the purpose, the technical scheme adopted by the invention comprises the following steps: a preparation method of a dasatinib intermediate comprises the following steps:
1) reacting oxalyl chloride with vinyl ether at low temperature, removing hydrogen chloride at room temperature, removing carbon monoxide at high temperature, and performing vacuum distillation to obtain 3-ethoxy-2-acryloyl chloride;
2) the 3-ethoxy-2-acryloyl chloride and 2-chloro-6-methylaniline react at low temperature to prepare the N- (2-chloro-6-methylphenyl) -3-ethoxy acrylamide.
The N- (2-chloro-6-methylphenyl) -3-ethoxyacrylamide (which is also an intermediate for synthesizing dasatinib) is prepared above, and can be used as a raw material for preparing 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, wherein the 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide is a key intermediate for synthesizing dasatinib.
Further, the method also comprises the step 3): the N- (2-chloro-6-methylphenyl) -3-ethoxy acrylamide is subjected to bromination and then reacts with thiourea under the alkaline condition to obtain the 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide through ring closure (namely, after the bromination reaction, thiourea is added for reaction, and the ring closure is carried out under the alkaline condition).
Preferably, the step 1) is a step of preparing 3-ethoxy-2-acryloyl chloride by a one-pot method, wherein the molar ratio of oxalyl chloride to vinyl ethyl ether is (1.2-1.6): 1, reaction temperature control: slowly dripping vinyl ether at the low temperature of-10 to-5 ℃; slowly raising the temperature; removing carbon monoxide at the high temperature of 100-125 ℃ for 30-60 min; colorless 3-ethoxy-2-acryloyl chloride was obtained by vacuum distillation. Wherein "one-pot" means that the whole step 1) is completed in one reaction apparatus (e.g., a reaction flask).
The slow temperature rise specifically means: firstly, 10 ℃ below zero/1 h (-10 ℃ for 1h), then 5 ℃ below zero/1 h (-5 ℃ for 1 h); then 0 ℃/1h (0 ℃ for 1 h); then 5 ℃/1h (5 ℃ for 1 h); then 10 ℃/1h (10 ℃ for 1 h); then 15 ℃/1h (15 ℃ for 1 h); and finally, the temperature is kept for 12-18 h at 20-25 ℃/12-18 h (the temperature is kept for 12-18 h at 20-25 ℃), and the hydrogen chloride is removed in the process.
More preferably, in the step 1), the molar ratio of oxalyl chloride to vinyl ethyl ether is (1.5-1.6): 1, reaction temperature control: slowly dripping vinyl ether at the low temperature of-10 to-5 ℃; slowly raising the temperature: -10 ℃/1 h; -5 ℃/1 h; 0 ℃/1 h; 5 ℃/1 h; 10 ℃/1 h; 15 ℃/1 h; 20-25 ℃/15-16 h; removing carbon monoxide at a high temperature of 105-115 ℃ for 45-60 min; colorless 3-ethoxy-2-acryloyl chloride was obtained by vacuum distillation.
The step 2) is specifically as follows: mixing 3-ethoxy-2-acryloyl chloride, a solvent, a catalyst and 2-chloro-6-methylaniline, reacting under the ice salt bath condition, controlling the internal temperature to be-5-0 ℃, reacting for 0.5-2h, heating to 20-25 ℃ and continuously stirring for reacting for 2-3 h; washing, drying, and concentrating by rotary evaporation to obtain brown solid; cooling the distillation residue to 0-5 ℃, stirring for 0.5-2h, filtering, and washing to obtain a light yellow sandy solid crude product, wherein the light yellow sandy solid crude product is N- (2-chloro-6-methylphenyl) -3-ethoxy acrylamide; the mass ratio of the 3-ethoxy-2-acryloyl chloride to the 2-chloro-6-methylaniline is 1: (0.7-1); the mass ratio of the 3-ethoxy-2-acryloyl chloride to the catalyst is (5-40): 1.
in the step of preparing the N- (2-chloro-6-methylphenyl) -3-ethoxy acrylamide by reacting the 3-ethoxy-2-acryloyl chloride with the 2-chloro-6-methylaniline at a low temperature, a solvent is one or more of dichloromethane, trichloromethane, tetrahydrofuran and carbon tetrachloride; the catalyst is one or more of pyridine, triethylamine, 4-dimethylaminopyridine (4-DMAP), 4-pyrrolidinylpyridine (4-PPY), N-Dimethylformamide (DMF) and Dimethylacetamide (DMAC). More preferably, the catalyst is 4-DMAP or 4-PPY (0.05 to 0.10 eq).
The method comprises the following steps of (1) brominating N- (2-chloro-6-methylphenyl) -3-ethoxy acrylamide, then reacting with thiourea under an alkaline condition, and carrying out ring closure to obtain 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide, wherein a solvent is one or more of dioxane, water, toluene and ammonia water; controlling the temperature to be 75-95 ℃; controlling the pH value to be between 9 and 11; more preferably, the temperature is controlled between 80 and 90 ℃; the pH value is controlled to be between 10 and 10.5. The mass ratio of the brominating agent to the N- (2-chloro-6-methylphenyl) -3-ethoxy acrylamide is (0.4-1) to 1; the mass ratio of the N- (2-chloro-6-methylphenyl) -3-ethoxy acrylamide to the thiourea is (2-5): 1.
the step 3) is specifically as follows: dissolving N- (2-chloro-6-methylphenyl) -3-ethoxyacrylamide in a solvent, adding a brominating agent (such as NBS (N-bromosuccinimide)), reacting in a salt-ice bath for 0.4-1h, and then moving to room temperature for reaction for 0.5-2 h; adding thiourea, heating to 80-90 ℃, continuing to react for 1-2 h, cooling to room temperature, adjusting the pH to 10-10.5, and performing rotary evaporation and concentration to obtain slurry; dissolving, filtering, washing and drying to obtain a brown yellow solid (namely 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide).
Compared with the prior art, the invention has the following obvious technical and benefit advantages:
oxalyl chloride and vinyl ether react at low temperature, hydrogen chloride is removed at room temperature, carbon monoxide is removed at high temperature, 3-ethoxy-2-acryloyl chloride is prepared by high vacuum distillation in a one-pot method, raw materials are cheap and easily available, corresponding equipment is greatly reduced, the low-room temperature-high temperature condition of the reaction process is easy to realize in mass production, the reaction is stable and controllable, and the yield is high;
the freshly prepared 3-ethoxy-2-acryloyl chloride and 2-chloro-6-methylaniline react at low temperature to prepare N- (2-chloro-6-methylphenyl) -3-ethoxy acrylamide, and an efficient catalyst is selected, so that compared with the traditional catalyst, the dosage is very small, and the N- (2-chloro-6-methylphenyl) -3-ethoxy acrylamide with better quality is obtained at high yield under the low-temperature condition;
the N- (2-chloro-6-methylphenyl) -3-ethoxy acrylamide is subjected to bromination and then reacts with thiourea under an alkaline condition to obtain 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide through ring closure, the process is mature, and the 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide is obtained through two-step reaction in one pot.
Detailed Description
The present invention will be described in detail with reference to examples, but the present invention is not limited to the following specific examples.
EXAMPLE 1 Synthesis of the Compound 3-ethoxy-2-propenoyl chloride
Adding 94.6g/1.6eq oxalyl chloride into a 250ml reaction bottle, controlling the temperature to be 10 ℃ below zero, slowly adding 33.6g vinyl ethyl ether into the reaction bottle by a dropping funnel, after the dropwise addition is finished, maintaining the reaction liquid at 10 ℃ below zero for 1.0h, and then gradually and slowly increasing the temperature: -5 ℃/1 h; 0 ℃/1 h; 5 ℃/1 h; 10 ℃/1 h; 15 ℃/1 h; controlling the temperature to be 20-22 ℃, finishing the reaction for 15h, transferring the reaction flask into an oil bath for heating, and carrying out reduced pressure distillation to remove oxalyl chloride to obtain a black residual solution. Then the oil bath is continuously heated to 112 ℃, and the reaction is kept for 45 min. And (3) ending heating, cooling, starting oil pump high vacuum reduced pressure distillation when the temperature is about 80 ℃, continuously heating the oil bath to 112 ℃ to collect fractions until no fractions are distilled, thus obtaining 45.5g of colorless liquid with the yield of 72.5%. The obtained 3-ethoxy-2-acryloyl chloride immediately carries out the next reaction feeding.
Example 2 Synthesis of Compound 3-ethoxy-2-propenoyl chloride
87.9g/1.5eq oxalyl chloride is added into a 250ml reaction bottle, the temperature is controlled to be minus 10 ℃, 33.6g vinyl ethyl ether is slowly added into the reaction bottle by a dropping funnel, and the material liquid is yellow after the dropping is finished. The reaction solution is maintained at-10 ℃ for 1.0h, and then gradually and slowly heated: -5 ℃/1 h; 0 ℃/1 h; 5 ℃/1 h; 10 ℃/1 h; 15 ℃/1 h; controlling the temperature to be 21-22 ℃, finishing the reaction for 15h, transferring the reaction flask into an oil bath for heating, and carrying out reduced pressure distillation to remove oxalyl chloride to obtain a black residual solution. Then the oil bath is continuously heated to 108 ℃, and the reaction is carried out for 60min under the condition of heat preservation. And (3) finishing heating, cooling, starting oil pump high vacuum reduced pressure distillation when the temperature is about 80 ℃, continuously heating the oil bath to 108 ℃ to collect fractions until no fractions are distilled, thus obtaining 46g of colorless liquid with the yield of 73.5%. The obtained 3-ethoxy-2-acryloyl chloride immediately carries out the next reaction feeding.
Comparative example 3 Synthesis of Compound 3-ethoxy-2-propenoyl chloride
Adding 71.0g/1.2eq oxalyl chloride into a 250ml reaction bottle, controlling the temperature to be 0-5 ℃, slowly adding 33.6g vinyl ethyl ether into the reaction bottle by a dropping funnel, and after the dropwise addition is finished, the feed liquid is yellow. Maintaining the reaction liquid at 0-5 ℃ for 1.0h, gradually and slowly heating to the internal temperature of 20-22 ℃, ending the reaction for 12h, transferring the reaction bottle into an oil bath for heating, and distilling under reduced pressure to remove oxalyl chloride to obtain a black residual solution. Then the oil bath is continued to heat to 120 ℃ and the temperature is kept for 30 min. And (3) ending heating, cooling, starting oil pump high vacuum reduced pressure distillation when the temperature in the reaction flask is about 80 ℃, continuously heating the oil bath to 120 ℃ to collect fractions until no fractions are distilled off, and obtaining 20g of colorless liquid with the yield of 32%. The obtained 3-ethoxy-2-acryloyl chloride immediately carries out the next reaction feeding.
EXAMPLE 4 Synthesis of the Compound N- (2-chloro-6-methylphenyl) -3-ethoxyacrylamide
33.7g of 2-chloro-6-methylaniline and 150ml of dry methylene chloride were put into a 500ml reaction flask to replace N2Then, 1.45g/0.05eq 4-DMAP was added to the reaction flask. The reaction flask was placed in a salt-ice bath and 40g of 3-ethoxy-2-propenoyl chloride diluted with 50ml of dry dichloromethane was added dropwise over a half hour using a dropping funnel. Controlling the internal temperature of the reaction to be-5-0 ℃ under the ice salt bath condition, reacting for 1h (the internal temperature refers to the temperature of the reaction solution), transferring the reaction flask into a water bath, heating to the internal temperature of 22 ℃, continuously stirring for reacting for 2h, and monitoring the complete reaction of the raw material 2-chloro-6-methylaniline by TLC. Washing the mixture three times by using 100ml of saturated sodium bicarbonate until the pH value is 7-8. Then washed once with 100ml of pure water and once with 100ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated by rotary evaporation to give a brown solid. And (3) adding 100ml of toluene into the distillation residue (namely the brown solid), stirring at room temperature for 15min, then cooling to 0-5 ℃, stirring for 1h, filtering, and washing with cold toluene to obtain a light yellow sandy solid crude product 45.5g, wherein the yield is 80%, and the HPLC (high performance liquid chromatography) 99.3%.
EXAMPLE 5 Synthesis of the Compound N- (2-chloro-6-methylphenyl) -3-ethoxyacrylamide
33.7g of 2-chloro-6-methylaniline and 150ml of dry methylene chloride were put into a 500ml reaction flask to replace N2Then, 3.54g/0.10eq4-PPY was added to the reaction flask. The reaction flask was placed in a salt-ice bath and 40g of 3-ethoxy-2-propenoyl chloride diluted with 50ml of dry dichloromethane was added dropwise over a half hour using a dropping funnel. Controlling the internal temperature of the reaction to be-5-0 ℃ under the ice salt bath condition, reacting for 1h, transferring the reaction bottle into a water bath, heating to the internal temperature of 25 ℃, continuously stirring for reacting for 3h, and monitoring the complete reaction of the raw material 2-chloro-6-methylaniline by TLC. Washing the mixture three times by using 100ml of saturated sodium bicarbonate until the pH value is 7-8. Then washed once with 100ml of pure water and once with 100ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated by rotary evaporation to give a brown solid. And adding 100ml of toluene into the distillation residue, stirring at room temperature for 30min, then cooling to 0-5 ℃, stirring for 1h, filtering, and washing with cold toluene to obtain a light yellow sandy solid crude product 45.5g, the yield being 80% and the HPLC being 99.4%.
Comparative example 6 Synthesis of Compound N- (2-chloro-6-methylphenyl) -3-ethoxyacrylamide
33.7g of 2-chloro-6-methylaniline and 150ml of dry methylene chloride were put into a 500ml reaction flask to replace N2Then, 28.2g/1.50eq of dry pyridine was added to the reaction flask. The reaction flask was placed in a salt-ice bath and 40g of 3-ethoxy-2-propenoyl chloride diluted with 50ml of dry dichloromethane was added dropwise over a half hour using a dropping funnel. Controlling the internal temperature of the reaction to be-5-0 ℃ under the ice salt bath condition, reacting for 1h, transferring the reaction bottle into a water bath, heating to the internal temperature of 22 ℃, continuously stirring for reacting for 2h, and monitoring the complete reaction of the raw material 2-chloro-6-methylaniline by TLC. The reaction solution was washed with 100ml of 1M HCl to adjust the pH of the reaction solution to 5-6, and excess pyridine was removed. And then washed three times by 100ml of saturated sodium bicarbonate until the pH is 7-8. Then washed once with 100ml of pure water and once with 100ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated by rotary evaporation to give a brown solid. And adding 100ml of toluene into the distillation residue, stirring at room temperature for 15min, cooling to 0-5 ℃, stirring for 1h, filtering, and washing with cold toluene to obtain 38.5g of a yellow sandy solid crude product, wherein the yield is 67.5%, and the HPLC (high performance liquid chromatography) is 98.5%.
Comparative example 7 Synthesis of Compound N- (2-chloro-6-methylphenyl) -3-ethoxyacrylamide
33.7g of 2-chloro-6-methylaniline and 150ml of dry methylene chloride were put into a 500ml reaction flask to replace N2Then 48.2g/2.00eq of dry triethylamine was added to the reaction flask. The reaction flask was placed in a salt-ice bath and 40g of 3-ethoxy-2-propenoyl chloride diluted with 50ml of dry dichloromethane was added dropwise over a half hour using a dropping funnel. Controlling the internal temperature of the reaction to be-5-0 ℃ under the ice salt bath condition, reacting for 1h, transferring the reaction bottle into a water bath, heating to the internal temperature of 25 ℃, continuously stirring for reacting for 3h, and monitoring the complete reaction of the raw material 2-chloro-6-methylaniline by TLC. And (3) adjusting the pH of the washing reaction solution to 5-6 by using 100ml of 1MHCl, and removing the redundant triethylamine. And then washing the mixture for three times by using 100ml of saturated sodium bicarbonate until the pH value is 7-8. Then washed once with 100ml of pure water and once with 100ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated by rotary evaporation to give a brown solid. And adding 100ml of toluene into the distillation residue, stirring at room temperature for 30min, cooling to 0-5 ℃, stirring for 1h, filtering, and washing with cold toluene to obtain 35g of crude yellow sandy solid, wherein the yield is 61.5%, and HPLC 96%.
EXAMPLE 8 Synthesis of the Compound 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide
In a 500ml flask equipped with a magnetic stirring device, 100ml of water and 100ml of dioxane were added and then 10.0g of N- (2-chloro-6-methylphenyl) -3-ethoxyacrylamide was added and dissolved at room temperature. Cooling at 0-5 ℃, adding 7.50g of NBS (N-bromosuccinimide) in three batches within 30 minutes, reacting for half an hour in a salt ice bath, and moving to room temperature for reaction for 1 hour. The completion of the reaction of N- (2-chloro-6-methylphenyl) -3-ethoxyacrylamide was checked by TLC. Then adding 3.24g of thiourea, slowly heating the mixed solution to 85 ℃, continuing to react for 1.5h, cooling to room temperature, adding concentrated ammonia water to adjust the pH value to 10.5, and performing rotary evaporation and concentration to obtain slurry. Dissolving in 300ml of water, filtering, washing the filter cake with water, and drying in vacuum to obtain 9.62g of brown yellow solid, the yield is 86%, and HPLC 98.5%.
Comparative example 9 Synthesis of Compound 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide
100ml of water and 150ml of dioxane followed by 10.0 ml of 10.0g N- (2-chloro-6-methylphenyl) -3-ethoxyacrylamide were placed in a 500ml flask equipped with a magnetic stirring apparatus and dissolved at room temperature. After cooling at the temperature of 0-5 ℃, 7.50g of NBS is added in three batches within 30 minutes, and the mixture is reacted for half an hour in a salt ice bath and then is moved to room temperature for reaction for 1 hour. The completion of the reaction of N- (2-chloro-6-methylphenyl) -3-ethoxyacrylamide was checked by TLC. Then adding 3.24g of thiourea, slowly heating the mixed solution to 70 ℃, continuing to react for 4h, cooling to room temperature, adding concentrated ammonia water to adjust the pH value to 9.5, and concentrating by rotary evaporation to be slurry. Dissolving in 300ml of water, filtering, washing the filter cake with water, and drying in vacuum to obtain 8.38g of brown yellow solid with the yield of 75 percent and the HPLC of 97.5 percent.
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 (9)
1. A preparation method of a dasatinib intermediate is characterized by comprising the following steps:
1) reacting oxalyl chloride with vinyl ether at low temperature, removing hydrogen chloride at room temperature, removing carbon monoxide at high temperature, and performing vacuum distillation to obtain 3-ethoxy-2-acryloyl chloride;
2) the 3-ethoxy-2-acryloyl chloride and 2-chloro-6-methylaniline react at low temperature to prepare the N- (2-chloro-6-methylphenyl) -3-ethoxy acrylamide.
2. The method for preparing the dasatinib intermediate according to claim 1, further comprising step 3): after bromination, N- (2-chloro-6-methylphenyl) -3-ethoxy acrylamide reacts with thiourea under alkaline condition to obtain 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-formamide through ring closure.
3. The preparation method of the dasatinib intermediate as claimed in claim 1, wherein step 1) is a step of preparing 3-ethoxy-2-acryloyl chloride by a one-pot method, wherein the molar ratio of oxalyl chloride to vinyl ethyl ether is 1.2-1.6: 1, reaction temperature control: slowly dripping vinyl ether at the low temperature of-10 to-5 ℃; slowly raising the temperature: -10 ℃/1 h; -5 ℃/1 h; 0 ℃/1 h; 5 ℃/1 h; 10 ℃/1 h; 15 ℃/1 h; 20-25 ℃/12-18 h; removing carbon monoxide at the high temperature of 100-125 ℃ for 30-60 min; colorless 3-ethoxy-2-acryloyl chloride was obtained by vacuum distillation.
4. The preparation method of the dasatinib intermediate according to claim 1, characterized in that step 2) specifically comprises: mixing 3-ethoxy-2-acryloyl chloride, a solvent, a catalyst and 2-chloro-6-methylaniline, reacting for 0.5-2h under the condition of ice salt bath at an internal temperature of-5-0 ℃, heating to an internal temperature of 20-25 ℃, and continuously stirring for reacting for 2-3 h; washing, drying, and performing rotary evaporation and concentration to obtain a brown solid; cooling the distillation residue to 0-5 ℃, stirring for 0.5-2h, filtering, and washing to obtain a light yellow sandy solid crude product, wherein the light yellow sandy solid crude product is N- (2-chloro-6-methylphenyl) -3-ethoxy acrylamide; the mass ratio of the 3-ethoxy-2-acryloyl chloride to the 2-chloro-6-methylaniline is 1: 0.7 to 1; the mass ratio of the 3-ethoxy-2-acryloyl chloride to the catalyst is 5-40: 1.
5. the method for preparing dasatinib intermediate according to claim 4, characterized in that in the step of preparing N- (2-chloro-6-methylphenyl) -3-ethoxyacrylamide by reacting 3-ethoxy-2-acryloyl chloride with 2-chloro-6-methylaniline at low temperature, the solvent is one or more of dichloromethane, trichloromethane, tetrahydrofuran and carbon tetrachloride; the catalyst is one or more of pyridine, triethylamine, 4-dimethylaminopyridine (4-DMAP), 4-pyrrolidinylpyridine (4-PPY), N-Dimethylformamide (DMF) and Dimethylacetamide (DMAC).
6. The method for preparing the dasatinib intermediate according to claim 2, characterized in that in the step of ring closure to obtain 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide, N- (2-chloro-6-methylphenyl) -3-ethoxyacrylamide is subjected to bromination and then reacted with thiourea under alkaline conditions, the solvent is one or more of dioxane, water, toluene and ammonia water; controlling the reaction temperature to be 75-95 ℃; controlling the pH value to be between 9 and 11; the mass ratio of the brominating agent to the N- (2-chloro-6-methylphenyl) -3-ethoxy acrylamide is 0.4-1: 1; the mass ratio of the N- (2-chloro-6-methylphenyl) -3-ethoxy acrylamide to the thiourea is 2-5: 1.
7. the method for preparing the dasatinib intermediate according to claim 1, wherein in step 1), the molar ratio of oxalyl chloride to vinyl ethyl ether is 1.5-1.6: 1, reaction temperature control: slowly dripping vinyl ether at the low temperature of-10 to-5 ℃; slowly raising the temperature: -10 ℃/1 h; -5 ℃/1 h; 0 ℃/1 h; 5 ℃/1 h; 10 ℃/1 h; 15 ℃/1 h; 20-25 ℃/15-16 h; removing carbon monoxide at a high temperature of 105-115 ℃ for 45-60 min; colorless 3-ethoxy-2-acryloyl chloride was obtained by vacuum distillation.
8. The method for preparing the dasatinib intermediate according to claim 6, characterized in that in step 3), the reaction temperature is controlled to be 80-90 ℃; the pH value is controlled to be between 10 and 10.5.
9. The method for preparing a dasatinib intermediate according to claim 2, characterized in that step 3) specifically comprises: dissolving N- (2-chloro-6-methylphenyl) -3-ethoxy acrylamide in a solvent, adding a brominating agent, reacting in a salt ice bath for 0.4-1h, and then moving to room temperature for reaction for 0.5-2 h; adding thiourea, heating to 80-90 ℃, continuing to react for 1-2 h, cooling to room temperature, adjusting the pH to 10-10.5, and performing rotary evaporation and concentration to obtain slurry; dissolving, filtering, washing and drying to obtain a brown yellow solid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210184505.2A CN114634421A (en) | 2022-02-24 | 2022-02-24 | Preparation method of dasatinib intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210184505.2A CN114634421A (en) | 2022-02-24 | 2022-02-24 | Preparation method of dasatinib intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114634421A true CN114634421A (en) | 2022-06-17 |
Family
ID=81947225
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210184505.2A Pending CN114634421A (en) | 2022-02-24 | 2022-02-24 | Preparation method of dasatinib intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114634421A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005077945A2 (en) * | 2004-02-06 | 2005-08-25 | Bristol-Myers Squibb Company | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
| CN102827156A (en) * | 2012-09-11 | 2012-12-19 | 湖南欧亚生物有限公司 | Novel industrial synthetic method of dasatinib |
| CN103739550A (en) * | 2014-01-02 | 2014-04-23 | 中国药科大学 | 2, 3-dimethyl-6-urea-2H-indazole compound and preparation method and application thereof |
| CN104334543A (en) * | 2013-04-09 | 2015-02-04 | 广州慧柏瑞生物医药科技有限公司 | Anti-angiogenesis compound, intermediate and use thereof |
| CN104703991A (en) * | 2012-06-08 | 2015-06-10 | 吉利德科学公司 | Macrocyclic inhibitors of flaviviridae viruses |
-
2022
- 2022-02-24 CN CN202210184505.2A patent/CN114634421A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005077945A2 (en) * | 2004-02-06 | 2005-08-25 | Bristol-Myers Squibb Company | Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors |
| CN104703991A (en) * | 2012-06-08 | 2015-06-10 | 吉利德科学公司 | Macrocyclic inhibitors of flaviviridae viruses |
| CN102827156A (en) * | 2012-09-11 | 2012-12-19 | 湖南欧亚生物有限公司 | Novel industrial synthetic method of dasatinib |
| CN104334543A (en) * | 2013-04-09 | 2015-02-04 | 广州慧柏瑞生物医药科技有限公司 | Anti-angiogenesis compound, intermediate and use thereof |
| CN103739550A (en) * | 2014-01-02 | 2014-04-23 | 中国药科大学 | 2, 3-dimethyl-6-urea-2H-indazole compound and preparation method and application thereof |
Non-Patent Citations (9)
| Title |
|---|
| YOUNGHEE KIM ET AL.: "Synthesis and Biological Evaluation of 2-Substituted Quinoline 6-Carboxamides as Potential mGluR1 Antagonists for the Treatment of Neuropathic Pain", 《CHEM. PHARM. BULL.》, vol. 62, no. 6, pages 508 - 518 * |
| 何小兵: "2-氨基噁唑和 2-氨基噻唑类化合物的合成及其抗肿瘤活性的研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》, pages 1 - 86 * |
| 侯巍 等: "抗肿瘤药物达沙替尼的合成工艺研究", 《精细化工中间体》, vol. 44, no. 6, pages 37 - 39 * |
| 李虎: "抗肿瘤药物达沙替尼类似物的合成及抗肿瘤活性研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》, pages 079 - 2 * |
| 柴星星: "2-氨基噁唑和2-氨基噻唑类达沙替尼类似物的合成及抗慢性白血病活性研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》, pages 079 - 7 * |
| 臧佳良 等: "达沙替尼的合成", 《中国医药工业杂志》, vol. 40, no. 5, pages 321 - 323 * |
| 蔡志萍: "２-氨基噁唑和２-氨基噻唑类达沙替尼类似物的合成及抗慢性髓性白血病活性研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》, pages 1 - 81 * |
| 陈磊祥: "达沙替尼类似物的合成与胃漂浮剂的制备", 《中国优秀硕士学位论文全文数据库 工程科技I辑》, pages 1 - 75 * |
| 黄睿 等: "达沙替尼的合成研究", 《化学与生物工程》, vol. 30, no. 10, pages 48 - 50 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5581401B2 (en) | Synthesis method of dasatinib and its intermediate | |
| CN108947884B (en) | Preparation method of ereoxib and intermediate thereof | |
| CN109320474B (en) | Preparation method of febuxostat | |
| CN103755688A (en) | Preparation method for afatinib compound | |
| CN107365275B (en) | High purity celecoxib | |
| CN114805314B (en) | Synthesis method of Entecavir | |
| CN103664912B (en) | A kind of synthesis technique of prucalopride | |
| CN107857743A (en) | A kind of method for preparing hydrochloric acid roxatidine acetate and intermediate | |
| US20230278960A1 (en) | Novel acridinium salt and method for producing same | |
| CN101531654B (en) | Preparation method for Rupatadine | |
| CN114634421A (en) | Preparation method of dasatinib intermediate | |
| CN108707115B (en) | Synthetic method of acrylic acid derivative | |
| WO2016061718A1 (en) | Compound and preparation method therefor, and method for preparing maytansine dm1 | |
| TW200904811A (en) | Use of 4-bromo-3-methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester for preparing the tryptase inhibitor [4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-(4-bromo-3-methyl-5-propoxy-thiophen-2-yl)-methanone | |
| JP4136024B2 (en) | 2-aminothiazol derivative or salt thereof | |
| CN110684028B (en) | Preparation method of 2, 6-diazabicyclo [3,3,0] octane compound | |
| CN110294734A (en) | A kind of preparation method of 2- aminothiophene -3,4- dicarboxylic acid derivatives | |
| CN104151299B (en) | Compound, crystal-form compound and preparation method thereof | |
| CN111233857B (en) | Synthetic method for continuously producing pexidininib | |
| CN108658931A (en) | A kind of preparation method of Raltitrexed key intermediate | |
| CN109796448B (en) | Preparation process of dasatinib | |
| CN109265455A (en) | A kind of preparation method of Dasatinib | |
| CN114736186B (en) | Method for synthesizing Violet Luo Zhongjian body from tert-butyl carbamate | |
| CN111825593B (en) | Synthetic method of 3-aminopyrrole-2-formamide compound | |
| CN117551093B (en) | Preparation method of maleic acid atorvastatin (4-chloro-2-thienyl) -2-thiazole amine) as starting material |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |