US 12,304,889 B2
Method for producing cis-(-)-flocino piperidol
Hiroto Tatamidani, Osaka (JP); Shinjiro Tsuyumine, Osaka (JP); and Yoko Takahashi, Osaka (JP)
Assigned to Sumitomo Pharma Co., LTD., Osaka (JP)
Appl. No. 17/603,536
Filed by SUMITOMO PHARMA CO., LTD., Osaka (JP)
PCT Filed Apr. 17, 2020, PCT No. PCT/JP2020/016885
§ 371(c)(1), (2) Date Oct. 13, 2021,
PCT Pub. No. WO2020/213714, PCT Pub. Date Oct. 22, 2020.
Claims priority of application No. 2019-079299 (JP), filed on Apr. 18, 2019.
Prior Publication US 2022/0220072 A1, Jul. 14, 2022
Int. Cl. C07D 211/42 (2006.01); C07B 57/00 (2006.01)
CPC C07D 211/42 (2013.01) [C07B 57/00 (2013.01)] 14 Claims
 
1. A manufacturing method of cis-(−)-flocinopiperidol represented by formula (I):

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or a salt thereof or a solvate thereof, comprising the following steps:
(b) forming (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone (+)-dibenzoyl-D-tartrate represented by formula (5):

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or a solvate thereof by:
(i) reacting (+)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone represented by formula (3):

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or a salt thereof or a solvate thereof with (+)-dibenzoyl-D-tartrate represented by formula (4):

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or a salt thereof or a solvate thereof in a reaction solvent;
(ii) precipitating (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone (+)-dibenzoyl-D-tartrate represented by formula (5) by adding a poor solvent to a reaction solution of step (i), wherein the poor solvent is an ether-based solvent selected from diisopropyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 2-methyltetrahydrofuran and cyclopentyl methyl ether;
(c) reacting (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone (+)-dibenzoyl-D-tartrate represented by formula (5):

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or a solvate thereof with an organic base in a solvent to manufacture (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone represented by formula (6):

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or a salt thereof or a solvate thereof, wherein the organic base is a tertiary amine; and
(d) reacting (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone represented by formula (6):

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or a salt thereof or a solvate thereof with a compound of formula (7):

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or a solvate thereof, in a solvent, to manufacture cis-(−)-flocinopiperidol represented by formula (I):

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or a salt thereof or a solvate thereof, wherein M in formula (7) is lithium, sodium, or potassium.