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Novel method for preparing etoricoxib intermediate 1-(6-methylpyridyl-3-yl)-2-[4-(mesyl)-phenyl]-ethyl-one

A technology of methylsulfonyl and picoline, applied in the field of preparation of etoricoxib intermediate 1--2-[4-phenyl]ethanone, can solve the problems of high cost, difficult removal, expensive palladium catalyst, etc. , to achieve the effect of good product quality and low cost

Active Publication Date: 2014-09-17
CHENGDU CLIMB PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] CN102731374A has reported the following synthetic route: this route uses expensive palladium catalyst, and the cost is high
Verification shows that its content is greater than 1.5%; this impurity is difficult to remove during the subsequent synthesis of etoricoxib

Method used

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  • Novel method for preparing etoricoxib intermediate 1-(6-methylpyridyl-3-yl)-2-[4-(mesyl)-phenyl]-ethyl-one
  • Novel method for preparing etoricoxib intermediate 1-(6-methylpyridyl-3-yl)-2-[4-(mesyl)-phenyl]-ethyl-one
  • Novel method for preparing etoricoxib intermediate 1-(6-methylpyridyl-3-yl)-2-[4-(mesyl)-phenyl]-ethyl-one

Examples

Experimental program
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Effect test

Embodiment 1

[0040] Example 1: Preparation of Compound C (M=H, R=Me, Compound A:t-BuMgCl=1:3)

[0041]

[0042] 11 g of (4-methylthio)phenylacetic acid, 200 mL of anhydrous THF were added to the reaction flask, and the mixture was heated to 65-70°C. While maintaining T=65-70°C, 175ml of 1.0M t-BuMgCl solution in THF and 5.7g of methyl 6-picoline-3-carboxylate in 50ml of THF were added dropwise. Add dropwise to complete the incubation reaction for 1 hour. Cool down to room temperature, add 50ml of 4M hydrochloric acid dropwise to quench the reaction, separate layers, extract the organic layer with 50ml of 4M hydrochloric acid, combine the aqueous layer, add 50g of sodium hydroxide to the aqueous layer, heat to 40-50°C and stir for 3 hours, cool to room temperature, and filter 6.9 g of a light yellow solid was obtained, with a yield of 72.0% and a purity of 97.3%.

Embodiment 2

[0043] Example 2: Preparation of Compound C (M=Na, R=Me, Compound A:t-BuMgCl=1:1.5)

[0044] 11 g of sodium (4-methylthio)phenylacetate, 200 mL of anhydrous THF were added to the reaction flask, and the mixture was heated to 65-70°C. While maintaining T=65-70°C, 88ml of 1.0M t-BuMgCl solution in THF and 5.7g of methyl 6-picoline-3-carboxylate in 50ml of THF were added dropwise. Add dropwise to complete the incubation reaction for 1 hour. Cool down to room temperature, add 50ml of 4M hydrochloric acid dropwise, separate layers, extract the organic layer with 50ml of 4M hydrochloric acid, combine the aqueous layer, add 50g of sodium hydroxide to the aqueous layer, heat to 40-50°C and stir for 3 hours, cool to room temperature, filter to obtain light yellow The solid was 7.4g, the yield was 78.5%, and the purity was 98.1%.

Embodiment 3

[0045] Example 3: Preparation of Compound C (M=Li, R=Me, Compound A:t-BuMgCl=1:1.5)

[0046] 11 g of lithium (4-methylthio)phenylacetate, 200 mL of anhydrous THF were added to the reaction flask, and the mixture was heated to 65-70°C. While maintaining T=65-70°C, 88ml of 1.0M t-BuMgCl solution in THF and 5.7g of methyl 6-picoline-3-carboxylate in 50ml of THF were added dropwise. Add dropwise to complete the incubation reaction for 1 hour. Cool down to room temperature, add 50ml of 4M hydrochloric acid dropwise, separate layers, extract the organic layer with 50ml of 4M hydrochloric acid, combine the aqueous layer, add 50g of sodium hydroxide to the aqueous layer, heat to 40-50°C and stir for 3 hours, cool to room temperature, filter to obtain light yellow The solid is 8.3g, the yield is 87.7%, and the purity is 98.6%.

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Abstract

The invention provides a preparation method of 1-(6-methylpyridyl-3-yl)-2-[4-(mesyl)-phenyl]-ethyl-one, which is characterized by comprising the following steps: (1) adding a compound B and an organic metal reagent into (4-dimethylsulfido)phenylacetic acid or metal salt (A) thereof to perform condensation reaction to obtain a compound C disclosed in the specification, wherein M is selected from H or metals and is preferably H or an alkali metal, and R is selected from H or C1-C6 alkyl groups; and (2) oxidizing the compound C with oxydol to obtain a compound D disclosed in the specification. In the two-step synthesis process, the yield from the compound A to the compound C is about 85%, the yield from the compound C to the compound D is about 90%, and the total mole yield is 65-80%; and the HPLC (high performance liquid chromatography) purity of the compound D is higher than 98%.Compared with the prior art, the method provided by the invention has the advantages of higher product quality and lower cost.

Description

technical field [0001] The invention relates to a preparation method of etoricoxib intermediate 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone. Background technique [0002] Etoricoxib, whose chemical name is 5-chloro-6-methyl-3[4-(methylsulfonyl)phenyl]-2,3-bipyridine, is a highly selective epoxy compound developed and produced by Merck. Catase-2-(COX-2) Inhibitors. Drugs for the treatment of acute gouty arthritis, osteoarthritis (OA) and rheumatoid arthritis. Etoricoxib is an analgesic drug whose performance is improved compared with traditional non-steroidal anti-inflammatory drugs (NSAIDs). It is the only coxib drug that has been proven effective in the treatment of acute gouty arthritis. [0003] 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone is an intermediate used in the preparation of etoricoxib, which is disclosed in prior art documents The preparation process of its precursor 1-(6-methylpyridin-3-yl)-2-[4-(methylthio)phenyl]ethanone...

Claims

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Application Information

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IPC IPC(8): C07D213/50
CPCC07D213/50
Inventor 龚义叶丁徐建超郭瑞
Owner CHENGDU CLIMB PHARMA TECH
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