US 12,227,477 B2
Method for preparing single isomer of 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine in high-purity
Kwang Ho Kim, Daejeon (KR); Ji Sang Yoo, Daejeon (KR); Chi Jang Moon, Daejeon (KR); Shin Young Park, Daejeon (KR); You Na Moon, Daejeon (KR); and So Hee Kim, Gyeonggi-do (KR)
Assigned to VSPHARMTECH, Daegu (KR)
Appl. No. 17/782,171
Filed by VSPHARMTECH, Daegu (KR)
PCT Filed May 17, 2022, PCT No. PCT/KR2022/007010
§ 371(c)(1), (2) Date Jun. 3, 2022,
PCT Pub. No. WO2023/101115, PCT Pub. Date Jun. 8, 2023.
Claims priority of application No. 10-2021-0169203 (KR), filed on Nov. 30, 2021.
Prior Publication US 2024/0174609 A1, May 30, 2024
Int. Cl. C07D 211/22 (2006.01)
CPC C07D 211/22 (2013.01) 9 Claims
 
1. A method for preparing a single isomer from a mixture of 2 or more types of isomers among 4 types of isomers of 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine having two chirality centers, as a phosphate with a purity of 99% or more, the method comprising:
Step 1 of preparing a mixture comprising 2 or more types of isomers of 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine comprising an isomer of interest by reacting (R)- or (S)-1-(2-benzylphenoxy)propan-2-ol in which a hydroxyl group is activated with a racemic mixture of 2-methylpiperidine;
Step 2 of obtaining a hydrochloride of 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine in a solid form by treating a solution in which the mixture comprising 2 or more types of 1-(1-(2-benzylphenoxy)propan-2-yl)-2-methylpiperidine is dissolved in acetone with hydrochloric acid;
Step 2-a of obtaining a hydrobromide of the compound by recrystallizing a filtrate recovered from Step 2 with hydrobromic acid once or more than once, optionally, in the case where the isomer of interest is an (S,S) form or an (R,R) form, and
Step 3 of substituting the hydrochloride or hydrobromide of the compound obtained in the previous step with a phosphate of the compound by adding phosphoric acid to a solution in which the hydrochloride or hydrobromide of the compound is dissolved in ethanol.