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Method of synthesizing benzhydryl quinuclidone through Michael addition

A technology of benzhydrylquinuclidine ketone and benzylidene quinine is applied in the field of organic synthesis, and can solve the problems of environmental protection pressure, undisclosed yield, unfriendly environment and the like in scaled production, and achieve no environmental protection pressure, Low price and low environmental impact

Active Publication Date: 2018-11-16
SICHUAN QINGMU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The third method is another production method disclosed in the patent US2005075473, using cuprous bromide dimethyl sulfide as a catalyst, but the yield is not disclosed
Because this catalyst is a sulfur-containing compound, it has a strong odor and is not friendly to the environment. The scale-up production has environmental protection pressure

Method used

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  • Method of synthesizing benzhydryl quinuclidone through Michael addition
  • Method of synthesizing benzhydryl quinuclidone through Michael addition
  • Method of synthesizing benzhydryl quinuclidone through Michael addition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Weigh (Z)-2-benzylidene quinine-3-one (9.0g) into a 250mL beaker, add tetrahydrofuran (110mL), stir and dissolve to obtain solution A, and transfer to the dropping funnel. Add 2.0M phenylmagnesium chloride tetrahydrofuran solution (36mL) into a 250mL three-necked flask, add cuprous bromide (602mg), cool down to -5°C under nitrogen protection, add solution A dropwise, and return to 25°C naturally after adding, react for 15 hours, Slowly pour the reaction solution into saturated ammonium chloride solution (40mL), stir for 10 minutes, separate the liquids, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash with water, wash with saturated sodium chloride solution, and dry over anhydrous sodium sulfate , concentrated in vacuo to obtain a crude product, which was crystallized from absolute ethanol to obtain 2-(benzhydryl)quinuclidin-3-one (10.5g), yield: 85%, HPLC: 99.6%. 1 HNMR (400MHz, CDCl 3 ): δ (ppm) = 7.394-7.133, (m, 10H, Ar-H), 4.524...

Embodiment 2

[0035] Weigh (Z)-2-benzylidene quinine-3-one (10.0g) into a 250mL beaker, add tetrahydrofuran (80mL), stir and dissolve to obtain solution A, and transfer to the dropping funnel. Add 2.0M phenylmagnesium chloride tetrahydrofuran solution (28mL) into a 250mL three-necked flask, add cuprous bromide (674mg), cool down to -5°C under nitrogen protection, add solution A dropwise, and return to 25°C naturally after adding, react for 12 hours, Slowly pour the reaction solution into saturated ammonium chloride solution (45mL), stir for 10 minutes, separate the liquids, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash with water, wash with saturated sodium chloride solution, and dry over anhydrous sodium sulfate , concentrated in vacuo to obtain the crude product, crystallized with absolute ethanol to obtain 2-(benzhydryl)quinuclidin-3-one (10.9g), yield: 80%, HPLC: 99.2%, NMR and MS data were the same Example 1.

Embodiment 3

[0037] Weigh (Z)-2-benzylidene quinine-3-one (10.0 g) into a 500 mL beaker, add tetrahydrofuran (200 mL), stir and dissolve to obtain solution A, and transfer to the dropping funnel. Add 2.0M phenylmagnesium chloride tetrahydrofuran solution (70mL) into a 500mL three-necked flask, add cuprous bromide (674mg), cool down to -5°C under nitrogen protection, add solution A dropwise, return to 25°C naturally after adding, and react for 24 hours. Slowly pour the reaction solution into saturated ammonium chloride solution (55mL), stir for 10 minutes, separate the liquids, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash with water, wash with saturated sodium chloride solution, and dry over anhydrous sodium sulfate , concentrated in vacuo to obtain the crude product, crystallized with absolute ethanol to obtain 2-(benzhydryl)quinuclidin-3-one (11.2g), yield: 82%, HPLC: 99.2%, NMR and MS data were the same Example 1.

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Abstract

The invention discloses a method of synthesizing benzhydryl quinuclidone through Michael addition and belongs to the field of organic synthesis. In the invention, with (Z)-2-benzylidenequinine-3-one being a raw material, a Michael addition reaction is carried out to prepare a 2-(diphenylmethyl)-3-quinuclidone product in the presence of a cuprous catalyst. Under preferable reaction conditions, yield can reach 85% and purity is higher than 99%. The preparation method solves the problems of low yield and selectivity and poor environment-friendly property of methods in the prior art.

Description

technical field [0001] The invention relates to a synthesis method of benzhydryl quinuclidone, wherein the Michael addition synthesis method used belongs to the technical field of organic synthesis. Background technique [0002] The benzhydrylquinuclidinone system is named 2-(benzhydryl)quinuclidin-3-one, the English name is 2-benzhydrylquinuclidin-3-one, which is the key intermediate of the veterinary drug Maropitant, and its structural formula is as follows : [0003] [0004] Currently on the market, Cerenia, whose active ingredient is maropitant citrate, is an antiemetic drug for large animals produced and sold by Pfizer. Maropitant is a type 1 neurokinin (NK1) receptor anti-blocking agent, which can act on the central nervous system by inhibiting substance P (the key neurotransmitter that causes vomiting), and can inhibit peripheral and central vomiting . [0005] The synthetic report about benzhydryl quinuclidinone has following several methods at present: [00...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/02
CPCC07D453/02
Inventor 李晓迅张勇胡同军王颖
Owner SICHUAN QINGMU PHARMA CO LTD
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