Preparation method of imrecoxib and intermediate thereof

A technology of intermediates and compounds, applied in the field of drug synthesis, can solve the problems of difficult control and research of raw material impurities, high toxicity of operation process and waste water, and increased difficulty of separation of target products, so as to avoid heavy metal oxidizing reagents and no pollutants The effect of producing and reducing production costs

Active Publication Date: 2018-12-07
江苏美迪克化学品有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] where R 1 , R 2 It is Cl or Br. However, in this route, firstly, the raw material n-propylamine used is a highly toxic chemical, and its operation process and waste water are highly toxic, and the waste water is nitrogenous waste water that is difficult to treat. Second, the intermediate reaction product It is a liquid oily substance, which is not easy to purify. The impurities in this step will be carried into the final product produced by the subsequent reaction and may continue to cause side reactions. The separation of the target product is more difficult, which brings difficulties to the control and research of impurities in raw materials.

Method used

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  • Preparation method of imrecoxib and intermediate thereof
  • Preparation method of imrecoxib and intermediate thereof
  • Preparation method of imrecoxib and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] A) Preparation of N-[2-oxo-2-(4-methylsulfonylphenyl)]ethyl-4-methylphenylacetamide (compound (Ⅲ)):

[0052] 2-Amino-1-p-methylsulfonylacetophenone (10.0g, compound (I)) was dissolved in acetonitrile (60mL), added triethylamine (7.1g), stirred and cooled to 5-10°C in an ice bath, dropwise Add p-methylphenylacetyl chloride (9.5g, compound (Ⅱ), X 1 Chlorine) in acetonitrile (15mL) solution, warmed up to 40°C and reacted for 12h until the reaction was complete, cooled to room temperature, adjusted to neutral with 1N hydrochloric acid, removed the organic solvent by rotary evaporation under reduced pressure, added ethyl acetate and water for extraction, and separated The organic phase was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, concentrated to dryness by rotary evaporation under reduced pressure, and the obtained crude product was recrystallized with ethanol to obtain N-[2-oxo-2-(4-methylsulfonylphenyl )] Ethyl-4-methylpheny...

Embodiment 2

[0058] A) Preparation of N-[2-oxo-2-(4-methylsulfonylphenyl)]ethyl-4-methylphenylacetamide (compound (Ⅲ)):

[0059] 2-Amino-1-p-methylsulfonylacetophenone (18.0g, compound (I)) was dissolved in methyl tert-butyl ether (100mL), N,N-diisopropylethylamine (27.3g) was added, Stir and cool in an ice bath to 5-10°C, add p-methylphenylacetyl bromide (27.0g, compound (II), X 1 bromine) in methyl tert-butyl ether (50mL) solution, heated to 20°C, reacted for 16h until the reaction was complete, adjusted to neutral with 1N hydrochloric acid, removed the organic solvent by rotary evaporation under reduced pressure, added ethyl acetate and water for extraction, The organic phase was separated, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, concentrated to dryness by rotary evaporation under reduced pressure, and the obtained crude product was recrystallized with ethanol to obtain N-[2-oxo-2-(4-methylsulfonyl Phenyl)]ethyl-4-methylphenylacetamide, ...

Embodiment 3

[0065] A) Preparation of N-[2-oxo-2-(4-methylsulfonylphenyl)]ethyl-4-methylphenylacetamide (compound (Ⅲ)):

[0066] 2-Amino-1-p-methylsulfonylacetophenone (20.0g, compound (I)) was dissolved in chloroform (110mL), added pyridine (14.8g), stirred and cooled to 5-10°C in an ice bath, and added dropwise to Toluyl acetyl chloride (20.6g, compound (Ⅱ), X 1 Chloroform (30 mL) solution of chlorine) was raised to 60°C for 6 hours until the reaction was complete, then cooled to room temperature, adjusted to neutrality with 1N hydrochloric acid, removed the organic solvent by rotary evaporation under reduced pressure, added ethyl acetate and water for extraction, and separated The organic phase was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, concentrated to dryness by rotary evaporation under reduced pressure, and the obtained crude product was recrystallized with ethanol to obtain N-[2-oxo-2-(4-methylsulfonylphenyl )] Ethyl-4-methylphenylac...

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Abstract

The invention discloses a preparation method of imrecoxib and an intermediate thereof. the preparation methoc comprises the following steps: 1) carrying out an amidation reaction between 2-amino-1-p-methylsulfonyl acetophenone and p-methylphenylacetyl halide so as to obtain N-[2-oxo-2-(4-methylsulfonylphenyl)]ethyl-4-methyl phenylacetamide; 2) carrying out a condensation and cyclization reaction on N-[2-oxo-2-(4-methylsulfonylphenyl)]ethyl-4-methyl phenylacetamide so as to obtain 3-p-methyl phenyl-4-p-methylsulfonylphenyl-3-pyrrolidine-2-ketone; and 3) carrying out a substitution reaction between 3-p-methyl phenyl-4-p-methylsulfonylphenyl-3-pyrrolidine-2-ketone and 1-halopropane or hydrocarbon sulfoacid propyl ester derivative so as to obtain imrecoxib; and preparing the intermediate of imrecoxib: N-[2-oxo-2-(4-methylsulfonylphenyl)]ethyl-4-methyl phenylacetamide or 3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidine-2-ketone. The reaction process is optimized by the synthetic route. Separation in each step is simpler, purity is higher, and ideal yield of the product also can be achieved.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of Erecoxib and an intermediate thereof. Background technique [0002] The new COX-2 selective inhibitor Imrecoxib (Imrecoxib) is a national 1.1 innovative drug, which is used to treat and relieve the pain symptoms of osteoarthritis and postoperative inflammation, and has been approved by the National FDA for marketing. Its chemical name is N-n-propyl-3-p-methylphenyl-4-p-methylsulfonylphenyl-3-pyrrolidin-2-one, and its chemical structure is: [0003] [0004] The first-line medication for osteoarthritis will change somewhat in the future, and specific inhibitors of COX-2 (a cyclooxygenase that causes joint pain and inflammation) may replace the current acetaminophen as an osteoarthritis drug. first-line medication. [0005] At present, there are many patent reports on the preparation method of Erecoxib. For example, a synthetic route for prepar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/38C07C317/40
CPCC07C317/40C07D207/38
Inventor 杨盟徐肖洁景亚婷
Owner 江苏美迪克化学品有限公司
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