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Synthesis method of vorapaxar sulfate intermediate aldehyde group compound

A synthesis method and technology of intermediates, applied in the field of medicinal chemical synthesis, can solve the problems of not using industrialized production and the like

Inactive Publication Date: 2019-11-22
TIANJIN LISHENG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method needs column chromatographic purification to obtain the pure intermediate aldehyde 2, and does not utilize industrial production

Method used

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  • Synthesis method of vorapaxar sulfate intermediate aldehyde group compound
  • Synthesis method of vorapaxar sulfate intermediate aldehyde group compound
  • Synthesis method of vorapaxar sulfate intermediate aldehyde group compound

Examples

Experimental program
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Embodiment 1

[0048]Add 339 mg (0.001 mol) of Vorapasar sulfate intermediate carboxylic acid 1, 10 ml of tetrahydrofuran, and 164 mg (0.0012 mol) of isobutyl chloroformate to a three-necked flask equipped with a thermometer and magnetic stirring, and cool to 0 °C, then slowly added 310 mg (0.0024 mol) of diisopropylethylamine to the reaction system, and continued to stir for 10 min. Subsequently, 275 mg (0.0025 mol) of thiophenol was added to the reaction system, and after the addition was completed, the temperature was raised to 25 °C, and stirring was continued for 1 h. After the reaction was completed, 10 ml of dichloromethane was added to the reaction system, the reaction solution was washed with aqueous sodium bicarbonate solution, and the reaction solution was washed with aqueous sodium chloride solution, dried, and concentrated to obtain vorapaxer sulfate intermediate 7. Intermediate 7 was transferred to a three-necked flask with magnetic stirring, a thermometer, and a reflux condens...

Embodiment 2

[0051] Add 339 mg (0.001 mol) of Vorapasar sulfate intermediate carboxylic acid 1, 10 ml of tetrahydrofuran, and 164 mg (0.0012 mol) of isobutyl chloroformate to a three-necked flask equipped with a thermometer and magnetic stirring, and cool to 0 °C, then slowly added 310 mg (0.0024 mol) of diisopropylethylamine to the reaction system, and continued to stir for 10 min. Subsequently, 350 mg (0.0025 mol) of p-methoxythiophenol was added to the reaction system, and after the addition was completed, the temperature was raised to 25 °C, and stirring was continued for 1 h. After the reaction was completed, 10 ml of dichloromethane was added to the reaction system, the reaction solution was washed with aqueous sodium bicarbonate solution, and the reaction solution was washed with aqueous sodium chloride solution, dried, and concentrated to obtain vorapaxer sulfate intermediate 7. Intermediate 7 was transferred to a three-necked flask with magnetic stirring, a thermometer, and a refl...

Embodiment 3

[0054] Add 339 mg (0.001 mol) of Vorapasar sulfate intermediate carboxylic acid 1, 10 ml of tetrahydrofuran, and 164 mg (0.0012 mol) of isobutyl chloroformate to a three-necked flask equipped with a thermometer and magnetic stirring, and cool to 0 °C, then slowly added 310 mg (0.0024 mol) of diisopropylethylamine to the reaction system, and continued to stir for 10 min. Subsequently, 388 mg (0.0025 mol) of p-nitrothiophenol was added to the reaction system, and after the addition was completed, the temperature was raised to 25 °C, and stirring was continued for 1 h. After the reaction was completed, 10 ml of dichloromethane was added to the reaction system, the reaction solution was washed with aqueous sodium bicarbonate solution, and the reaction solution was washed with aqueous sodium chloride solution, dried, and concentrated to obtain vorapaxer sulfate intermediate 7. Intermediate 7 was transferred to a three-necked flask with magnetic stirring, a thermometer, and a reflux...

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Abstract

The invention discloses a synthetic method of a vorapaxar sulfate intermediate aldehyde group compound. The method comprises the following steps: by taking a vorapaxar sulfate intermediate carboxylicacid as a starting raw material, firstly synthesizing thioester from the vorapaxar sulfate intermediate carboxylic acid and mercaptan or thiophenol under an alkaline condition, and then performing a reaction under the combined action of palladium catalysis and silane serving as a reducing agent to finish conversion of a functional group, namely, converting carboxyl into an aldehyde group, therebysynthesizing the vorapaxar sulfate intermediate aldehyde group compound. The synthesis method has the characteristics of simple synthesis process, mild reaction conditions, convenience in operation, high yield and the like, and the obtained intermediate can be directly used for subsequent reaction without purification and avoids use of high-pressure hydrogen.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and relates to a method for synthesizing aldehydes of vorapaxar sulfate intermediates, more specifically, the aldehydes of vorapaxar sulfate intermediates [(1R, 3aR, 4aR, 6R, 8aR, 9S ,9aS)-9-formyl-1-methyl-3-oxododechydronaphthalene[2,3-c]furan-6-yl]carbamate ethyl ester. Background technique [0002] Vorapaxar sulfate chemical name: N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(1E)-2-[5-(3-fluorobenzene) Chemistry of -2-pyridyl]vinyl]dodecahydro-1-methyl-3-oxonaphth[2,3-c]furan-6-yl]urethane sulfate, vorapaxar sulfate The structural formula is as follows: [0003] [0004] Vorapaxar Sulfate (Zontivity) is a new small molecule antiplatelet drug developed by Merck & Co. It is clinically used for the treatment of coronary artery disease. On May 8, 2014, it was approved by the FDA for marketing in the United States, and on January 19, 2015, it was approved by the EMA for marketi...

Claims

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Application Information

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IPC IPC(8): C07D307/92
CPCC07D307/92
Inventor 石亮亮张瑜张杰霍志甲姜根华
Owner TIANJIN LISHENG PHARM CO LTD
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