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Process for preparing 1-(6-methylpyridin-3-yl)-2-[4-methylthio-phenyl]ethanone

A technology of picoline and methylthio, which is applied in the field of preparation of intermediates, can solve problems such as falling off and the reaction system is prone to explosion, and achieve the effect of reducing the risk of explosion and avoiding the effect of easily decomposing and generating gas when heated

Active Publication Date: 2016-05-25
SHANGHAI JIAOTONG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The amide reagent contains N, O-dimethylhydroxylamine fragments. During the reaction, this fragment will fall off, and the generated N, O-dimethylhydroxylamine is highly irritating and will cause irritation to the eyes, respiratory tract and skin. Stimulating effect, if heated, it will decompose and generate dangerous gases such as carbon monoxide, carbon dioxide, nitrogen oxides, etc., causing the reaction system to be explosive

Method used

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  • Process for preparing 1-(6-methylpyridin-3-yl)-2-[4-methylthio-phenyl]ethanone
  • Process for preparing 1-(6-methylpyridin-3-yl)-2-[4-methylthio-phenyl]ethanone
  • Process for preparing 1-(6-methylpyridin-3-yl)-2-[4-methylthio-phenyl]ethanone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Synthesis of isoxazolidin-2-yl-(6-methylpyridin-3-yl)-methanone of formula (Ⅲ)

[0052] synthetic route:

[0053]

[0054] Under nitrogen protection, 150 g of 6-methylnicotinic acid methyl ester (V) and 120 g of isoxazole hydrochloride (IV) were added into 500 ml of toluene, and the solution was cooled to -20°C. Slowly add 2.2 mol / L tetrahydrofuran solution of isopropylmagnesium chloride into the cooled solution. The reaction temperature is controlled between -20°C to -10°C, after stirring for 0.5 hours, add 500ml20% acetic acid solution, separate and remove the water phase, and evaporate the organic solvent under reduced pressure to obtain the formula (Ⅲ) compound (152g , 80%). 1 HNMR (300MHz, CDCl 3)δ2.36(t, 2H, J=7.8Hz), 2.59(s, 3H), 3.94(m, 4H), 7.19(d, 1H, J=8.1Hz), 8.01(dd, 1H, J=7.8 Hz, 1.2Hz), 8.94(s, 1H).

[0055] Synthesis of 1-(6-methylpyridin-3-yl)-2-[4-methylthio-phenyl]ethanone of formula (Ⅰ)

[0056] synthetic route:

[0057]

[0058] Under n...

Embodiment 2

[0060] Synthesis of isoxazolidin-2-yl-(6-methylpyridin-3-yl)-methanone of formula (Ⅲ)

[0061] synthetic route:

[0062]

[0063] Add 230g of sodium carbonate to 600ml of water and cool to 15°C. 120 g of isoxazole hydrochloride (IV) was added thereto. Suspend and disperse 155g of 6-methylnicotinoyl chloride (VI) uniformly in dichloromethane, and then add it to an aqueous sodium carbonate solution at 15-25°C. The mixed solution was stirred for 0.5 hour, the aqueous phase was separated and removed, and the organic phase was washed with water and dried over anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure to obtain the compound of formula (III) (123 g, 65%) as a yellow liquid.

[0064] Synthesis of 1-(6-methylpyridin-3-yl)-2-[4-methylthio-phenyl]ethanone of formula (Ⅰ)

[0065] synthetic route:

[0066]

[0067] Under nitrogen protection, 191 g of isoxazolidin-2-yl-(6-methylpyridin-3-yl)-methanone (III) was dissolved in 350 ml of tolu...

Embodiment 3

[0069] A kind of new method for preparing 1-(6-methylpyridin-3-yl)-2-[4-methylthio-phenyl]ethanone, will comprise the Grignard reagent of formula (II) and formula (III) The isoxazolidin-2-yl-(6-methylpyridin-3-yl)-methanone is reacted in the solvent toluene at a molar ratio of 1:1 between -10°C and 0°C to obtain the product;

[0070] The structural formula of described Grignard reagent is:

[0071]

[0072] Wherein X is a chlorine atom;

[0073] Described isoxazolidin-2-base-(6-methylpyridin-3-yl)-methanone: it is to comprise the isoxazole salt of formula (IV) and the 6-methyl smoke of formula (V) Methyl acid is prepared by reacting in the solvent toluene in the presence of sodium hydroxide at a molar ratio of 1.5:1.

[0074] The molecular formula of described isoxazole salt is:

[0075]

[0076] Wherein Y is hydrochloric acid.

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Abstract

The invention relates to a new method for preparing 1-(6-methylpyridine-3-yl)-2-[4-(methylsulfanyl)phenyl]acetone. The method comprises the step of reacting Grignard reagent of formula (II) with isoxazole-2-yl-(6-methylpyridine-3-yl)-ketone of formula (III) at minus 20 to 0 DEG C to obtain the 1-(6-methylpyridine-3-yl)-2-[4-(methylsulfanyl)phenyl]acetone of formula (I). Compared with the prior art, the method has the advantage of lowering the explosive risk of the reaction system.

Description

technical field [0001] The present invention relates to a method for preparing an intermediate of etoricoxib, in particular to a method for preparing an intermediate of etoricoxib 1-(6-methylpyridin-3-yl)-2-[4-methylthio-phenyl ] A new approach to ethyl ketone. Background technique [0002] 1-(6-methylpyridin-3-yl)-2-[4-methylthio-phenyl]ethanone (I) is a highly selective cyclooxygenase-2 (COX-2) inhibitor— —An important intermediate of Etoricoxib. Its performance has been improved compared with traditional non-steroidal anti-inflammatory drugs (NSAIDs), and it has been approved by the China Food and Drug Administration (sFDA) for the treatment of symptoms and signs of osteoarthritis in the acute and chronic phases, as well as for the treatment of acute gouty arthritis. [0003] [0004] The synthesis method of compound (I) is described in many patents and literatures, among which patents WO01 / 07410A1 and US2003 / 0088107A1 describe the synthesis route (1): [0005] ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/50
CPCC07D213/50
Inventor 毛振民詹晓平刘增路兰天隆艳
Owner SHANGHAI JIAOTONG UNIV
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