Processes for the Preparation of Dasotraline and Intermediates Thereof

Patent metadata

Field	Value
Publication number	US-2019390235-A1
Application number	US-201916438801-A
Country	US
Kind code	A1
Filing date	Jun 12, 2019
Priority date	Jun 25, 2018
Publication date	Dec 26, 2019
Grant date	—

Abstract

The present invention provides processes for the preparation of Dasotraline, as well as intermediates useful in the preparation thereof. In particular, processes are provided for the enzymatic transamination of a compound of Formula (2) to afford Dasotraline.

First claim

What is claimed is:

1 . A process for the preparation of Dasotraline (1):

or a salt thereof, comprising transamination of a compound of Formula (2):

with an (R)-selective ω-transaminase in the presence of an amine donor and a co-factor,
wherein
the carbon atom marked with “*” is racemic, substantially racemic, or enantiomerically enriched in the (S)-configuration.

2 . The process of claim 1 further comprising the step of purifying the product of the transamination to increase the chiral purity of the Dasotraline (1) obtained.

3 . The process of claim 2 , wherein the purification comprises formation and isolation of a salt formed between Dasotraline (1) and a chiral acid.

4 . The process of claim 3 , wherein the chiral acid is (1R)-(−)-10-camphorsulfonic acid.

5 . The process of claim 1 , wherein the (R)-selective ω-transaminase is selected from the group consisting of ATA-013, ATA-025, ATA-301, ATA-303, ATA-412, or structurally and functionally equivalent enzymes.

6 . The process of claim 5 , wherein the (R)-selective ω-transaminase is ATA-025 or a structurally and functionally equivalent enzyme.

7 . The process of claim 1 , wherein the (R)-selective ω-transaminase is derived from an organism selected from the group consisting of Arthrobacter sp., ArRmut 11, Aspergillus fumigates, Aspergillus oryzae, Aspergillus terreus, Gibberella zeae, Hyphomonas neptunium, Mycobacterium vanbaalienii, Neosartorya fischeri and Penicillium chrysogenum.

8 . The process of claim 5 , wherein the amine donor is selected from the group consisting of alanine, α-methylbenzylamine, glutamate, phenylalanine, isopropylamine, 2-aminobutane, 1,2-diaminopropane and salts thereof.

9 . The process of claim 8 , wherein the amine donor is isopropylamine.

10 . The process of claim 8 , wherein the transamination is conducted in an aqueous mixture comprising a solvent selected from the group consisting of dimethylsulfoxide and N,N-dimethylformamide.

11 . The process of claim 10 , wherein the solvent is dimethylsulfoxide.

12 . The process of claim 11 , wherein the concentration of dimethylsulfoxide in the mixture is from about 30% v/v to about 55% v/v.

13 . The process of claim 11 , wherein the aqueous mixture is buffered to a pH of from about 7 to about 11.5.

14 . The process of claim 13 , wherein the reaction is conducted at a temperature of from about 40° C. to about 65° C.

15 . The process of claim 1 , wherein the compound of Formula (2) is prepared by a process comprising:
(i) oxidation of a compound of Formula (4):

or a salt thereof, to provide a compound of Formula (3):

and
(ii) hydrolysis of the compound of Formula (3) to provide the compound of Formula (2),

wherein
R is a C 1 -C 6 alkyl group; and
the carbon atom marked with “*” is racemic, substantially racemic, or enantiomerically enriched in the (S)-configuration.

16 . The process of claim 15 , wherein R is methyl.

17 . The process of claim 15 , wherein the oxidation is conducted in the presence of an oxidizing agent selected from the group consisting of bromine, iodine, halosuccinimides, peroxides, hypervalent iodides, manganese oxides, oxygen/transition metal combinations, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and hypochlorites.

18 . The process of claim 15 , wherein the oxidation is conducted in the presence of bromine and a metal hydroxide.

19 . The process of claim 15 , wherein the hydrolysis is conducted in the presence of an aqueous acid.

20 . The process of claim 5 , wherein the carbon atom marked with “*” is enantiomerically enriched in the (S)-configuration and the compound of Formula (2) has a chiral purity in favor of the (4S)-configuration of at least about 90%.

Assignees

• Apotex Inc

Inventors

• Souza Fabio E S
• Bodhuri Prabhudas
• Cammisa Eduardo Gustavo
• Weeratunga Gamini
• Rey Allan W

Classifications

• 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

• C12Y206/01018

  Beta-alanine-pyruvate transaminase (2.6.1.18) · CPC title

• C12P13/001 Primary

  Amines; Imines · CPC title