# US 2022/0033344 A1 · Method for preparing (2s,3s)-3-amino-bicyclo[2.2.2]octane-2-carboxylate

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- Number: US 2022/0033344 A1
- Document ID: US20220033344A1
- Status: Published application
- Kind: A1
- Application number: 17/262,079
- Filed: 2020-06-30
- Published: 2022-02-03
- Earliest claimed: 2019-12-30
- Assignees: Guangdong Raffles Pharmatech Co., Ltd
- Applicants: Guangdong Raffles Pharmatech Co., Ltd
- Inventors: Zhangtao ZHOU; Zhining HUANG; Weiping YE; Andrew Toroa PHILLIS
- Web page: https://patentgrep.com/patent/US20220033344A1

## CPC

- C07C 227/18: by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C 227/16: by reactions not involving the amino or carboxyl groups
- C07C 227/32: by stereospecific synthesis
- C07B 2200/07: Optical isomers
- C07C 2602/44: the bicyclo ring system containing eight carbon atoms
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

A method for preparing (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate is in the field of pharmaceutical intermediate synthesis. The method uses 3-carbonyl-bicyclo[2.2.2]octane-2-carboxylate as the starting material and performs reductive amination, alkalinity configuration flip, and hydrogenation to remove the protecting group in sequence to obtain the target product. This synthesis method of (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate is characterized by a novel route, mild reaction conditions and low cost, with a yield of more than 65%.

## Claims

### Claim 1

Method for preparing (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate, wherein, the method comprises: using 3-carbonyl-bicyclo[2.2.2]octane-2-carboxylate as raw material, carrying out reductive amination, flip of ester group conformation and removal of protecting group to obtain the (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate, and reaction process is shown below,
wherein, X, Y and R are all organic substituents.

### Claim 2 (depends on 1)

The method according to claim 1, wherein, the method comprises:
S1, reacting 3-carbonyl-bicyclo[2.2.2]octane-2-carboxylate with chiral amines in presence of acid to give 3-amino-bicyclo[2.2.2]octene-2-carboxylate;
S2, carrying out reduction with a reducing agent or metal-catalyzed hydrogenation of the 3-amino-bicyclo[2.2.2]octene-2-carboxylate to give (2R,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate;
S3, under strong base conditions, carrying out ester configuration flip of the (2R,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate to give (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate;
S4, carrying out hydrogenation of the (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate to remove the protecting group to give the (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate.

### Claim 3 (depends on 1)

The method according to claim 1, wherein,
the R is methyl, ethyl, propyl, butyl, phenyl or benzyl, preferably ethyl;
the X is methyl, ethyl, phenyl or 1-naphthyl, the Y is methyl, ethyl, phenyl or 1-naphthyl, and the X and the Y are not identical, the X group is larger than the Y group;
preferably, the X is phenyl, the Y is methyl.

### Claim 4 (depends on 2)

The method according to claim 2, wherein, in the S2, the metal-catalyzed hydrogenation is carried out using a metal catalyst, the metal catalyst comprising at least one selected from the group consisting of platinum carbon, platinum dioxide and ruthenium metal catalyst; the reducing agent comprising at least one selected from the group consisting of sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride and sodium trifluoroacetoxy borohydride; preferably, the metal catalyst is platinum dioxide; the reducing agent is sodium triacetoxy borohydride.

### Claim 5 (depends on 2)

The method according to claim 2, wherein, in the S3, the strong base comprises at least one selected from the group consisting of sodium tert-butoxide, sodium tert-amylate, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide; preferably, the strong base is sodium tert-butoxide.

### Claim 6 (depends on 2)

The method according to claim 2, wherein, in the S1, the acid is organic acid or inorganic acid; preferably, the acid is strong organic acid; further preferably, the acid comprises p-toluenesulfonic acid or trifluoroacetic acid.

### Claim 7

A compound of formula V, wherein, the R is methyl, ethyl, propyl, butyl, phenyl or benzyl, preferably ethyl; the X is methyl, ethyl, phenyl or 1-naphthyl, and the Y is methyl, ethyl, phenyl or 1-naphthyl, and the X and the Y are not identical and the X is larger than the Y, preferably, the X is phenyl, the Y is methyl,

### Claim 8 (depends on 7)

Use of the compound V according to claim 7 for preparation of (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate.

### Claim 9

A compound of formula VI, wherein, the R is methyl, ethyl, propyl, butyl, phenyl or benzyl, preferably ethyl; the X is methyl, ethyl, phenyl or 1-naphthyl, and the Y is methyl, ethyl, phenyl or 1-naphthyl, and the X and the Y are not identical and the X is larger than the Y,
preferably, the X is phenyl, the Y is methyl,

### Claim 10 (depends on 9)

Use of the compound VI according to claim 9 for preparation of (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate.