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Preparation methods of imrecoxib intermediate and imrecoxib

A technology for erecoxib and intermediates, which is applied in the preparation of erecoxib and the field of erecoxib intermediates, can solve the problems of high toxicity in the operation process and waste water, difficulty in controlling and researching impurities of raw materials, and difficult purification. , to achieve the effect of being conducive to industrialized large-scale production, avoiding heavy metal oxidizing reagents, and optimizing the reaction process

Active Publication Date: 2018-10-26
江苏美迪克化学品有限公司
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  • Summary
  • 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 methods of imrecoxib intermediate and imrecoxib
  • Preparation methods of imrecoxib intermediate and imrecoxib
  • Preparation methods of imrecoxib intermediate and imrecoxib

Examples

Experimental program
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Effect test

Embodiment 1

[0055] A) Preparation of 2-propylamino-1-p-methylsulfonylacetophenone (compound (II)):

[0056] 2-Amino-1-p-methylsulfonylacetophenone (25.6g, compound (I)) was dissolved in N,N-dimethylformamide (150mL), potassium carbonate (41.5g) was added, stirred and cooled in an ice bath To 5~10°C, add 1-chloropropane (10.4g, R is chlorine) dropwise, rise to 100°C and react for 6h until the reaction is complete, then cool down to room temperature, adjust to neutral with 1N hydrochloric acid, remove the organic solvent by rotary evaporation under reduced pressure , added ethyl acetate and water for extraction, separated the organic phase, 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 2-propylamino-1 - p-methylsulfonylacetophenone, off-white solid 29.2g, yield 95.3%, purity 98.7%.

[0057] B) Preparation o...

Embodiment 2

[0062] A) Preparation of 2-propylamino-1-p-methylsulfonylacetophenone (compound (II)):

[0063] 2-Amino-1-p-methylsulfonylacetophenone (100.0g, compound (I)) was dissolved in tetrahydrofuran (550mL), cesium carbonate (306g) was added, stirred and cooled to 5-10°C in an ice bath, and 1 -Bromopropane (69.5g, R is bromine), rise to 50°C and react for 24h until the reaction is complete, cool down to room temperature, adjust to neutral with 1N hydrochloric acid, remove the organic solvent by rotary evaporation under reduced pressure, add 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 2-propylamino-1-p-methylsulfonylacetophenone, Off-white solid 108.8g, yield 90.9%, purity 98.2%.

[0064] B) Preparation of N-n-propyl-N-[2-oxo-2-...

Embodiment 3

[0069] A) Preparation of 2-propylamino-1-p-methylsulfonylacetophenone (compound (II)):

[0070] 2-Amino-1-p-methylsulfonylacetophenone (131.0g, compound (I)) was dissolved in toluene (700mL), added sodium hydroxide (73.7g), stirred and cooled to 5-10°C in an ice bath, dropwise Add 1-bromopropane (151.1g, R is bromine), rise to 70°C and react for 12h until the reaction is complete, cool down to room temperature, adjust to neutral with 1N hydrochloric acid, remove the organic solvent by rotary evaporation under reduced pressure, add ethyl acetate and water Extract, separate the organic phase, wash with water and saturated brine successively, dry over anhydrous sodium sulfate, concentrate to dryness by rotary evaporation under reduced pressure, and recrystallize the obtained crude product with ethanol to obtain 2-propylamino-1-p-methylsulfonylphenethyl Ketone, off-white solid 144.3g, yield 92%, purity 98.3%.

[0071] B) Preparation of N-n-propyl-N-[2-oxo-2-(4-methylsulfonylpheny...

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Abstract

The invention discloses preparation methods of an imrecoxib intermediate and imrecoxib. The preparation method of N-propyl-N-[2-oxo-2-(4-mesylphenyl)]ethyl-4-methyl phenyl acetamide as the imrecoxib intermediate comprises the following steps of performing substitution reaction on 2-amino-1-p-methylsulfonyl acetophenone and 1-halopropane in a system of an acid binding agent and a solvent to obtain2-propylamino-1-p-methylsulfonyl acetophenone; and enabling 2-propylamino-1-p-methylsulfonyl acetophenone and p-methyl phenylacetyl halide to perform amidation in the system of the acid binding agentand the solvent to obtain N-propyl-N-[2-oxo-2-(4-mesylphenyl)] ethyl-4-methyl phenyl acetamide. The preparation method of the imrecoxib comprises the following step of performing condensation and cyclization reaction on N-propyl-N-[2-oxo-2-(4-mesylphenyl)] ethyl-4-methyl phenyl acetamide in a system of an alkaline matter and a solvent on the basis. The synthetic route provided by the invention enables the reaction process to be more simple and post-treatment separation to be easier and is capable of acquiring ideal yield.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to an Erecoxib intermediate and a preparation method of Erecoxib. 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 prepa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/38C07C315/04C07C317/32
CPCC07C315/04C07C317/32C07D207/38
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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