Method for preparing (s)-1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline compound

Patent metadata

Field	Value
Publication number	US-2021087595-A1
Application number	US-202016805742-A
Country	US
Kind code	A1
Filing date	Feb 29, 2020
Priority date	Sep 20, 2019
Publication date	Mar 25, 2021
Grant date	—

Abstract

This application relates to biological pharmacy and biochemical engineering, and more particularly to a method of preparing a (S)-1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline compound. This method includes: subjecting a 1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline raceme as a substrate to selective oxidation in the presence of a monoamine oxidase and the non-selective reduction to prepare the (S)-1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline compound, where the monoamine oxidase has an amino acid sequence as shown in SEQ ID NO: 1 or an amino acid sequence having an identity of more than 80% with SEQ ID NO: 1. The kinetic resolution is carried out in the presence of the monoamine oxidase as a catalyst and a reductant, and the resulting product has a high chiral purity.

First claim

What is claimed is:

1 . A method of preparing a (S)-1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline compound of formula (I)

comprising: subjecting a 1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline raceme as a substrate to the kinetic resolution in the presence of the monoamine oxidase as a catalyst and a non-selective reductant to prepare the (S)-1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline compound;
wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl and cycloalkyl, C 1 -C 6 alkoxyl, halogen, cyano, nitro, hydroxyl, amino, methylthio, C 1 -C 6 ester group and trifluoromethyl.

2 . The method of claim 1 , wherein the monoamine oxidase is obtained using an E. coli expression system.

3 . The method of claim 1 , wherein the monoamine oxidase has an amino acid sequence shown as SEQ ID NO:1 or an amino acid sequence having an identity of more than 80% with SEQ ID NO:1.

4 . The method of claim 1 , wherein the non-selective reductant is for reducing an amine.

5 . The method of claim 1 , wherein the non-selective reductant is selected from the group consisting of boranamine and sodium borohydride.

6 . The method of claim 1 , wherein a molar equivalent ratio of the non-selective reductant to the 1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline raceme is 1-10:1.

7 . The method of claim 1 , wherein the 1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline raceme has a concentration of 0.1%-5% (w/v).

8 . The method of claim 1 , wherein the monoamine oxidase, calculated as wet cells, is 300%-1000% by weight of the 1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline raceme.

9 . The method of claim 1 , wherein a reaction temperature is 15-50° C.; a reaction time is 6-72 h; and a pH of the reaction mixture is 6-10.

10 . The method of claim 1 , wherein the monoamine oxidase is in a form of a genetically-engineered whole cell, a crude enzyme solution, a pure enzyme or an immobilized enzyme.

11 . The method of claim 1 , further comprising: purifying the the (S)-1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline compound.

12 . The method of claim 11 , the purifying step comprises:
terminating the reaction with 1-6 M hydrochloric acid; adjusting pH of the reaction mixture to 10-11 with 1-10 M sodium hydroxide; extracting the reaction mixture with ethyl acetate 3-5 times by high-speed centrifugation and collecting and combining organic phases; and drying the combined organic phase with anhydrous sodium sulfate; and purifying the dried organic phase by column chromatography to give the purified (S)-1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline compound.

Assignees

• Univ Fudan

Inventors

• Chen Fener
• Huang Zedu
• Li Zhining
• Wang Jiaqi

Classifications

• C12Y104/03004

  Monoamine oxidase (1.4.3.4) · CPC title

• C12P41/006

  by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C12P17/12 Primary

  containing a six-membered hetero ring · CPC title

• C12N9/0022

  with oxygen as acceptor (1.4.3) · CPC title