Biocatalytic Transamination Process

Patent metadata

Field	Value
Publication number	US-2017335359-A1
Application number	US-201715665572-A
Country	US
Kind code	A1
Filing date	Aug 1, 2017
Priority date	Dec 7, 2012
Publication date	Nov 23, 2017
Grant date	—

Abstract

A novel process is provided for the efficient preparation of an asymmetric compound of structural formula I:

employing dynamic kinetic resolution (DKR). The DKR process involves an enzymatic enantioselective amination reaction catalyzed by transaminases. The process can be used to manufacture key intermediates in the preparation of poly (ADP-ribose) polymerase (PARP) inhibitors which may be useful for the treatment of cancer.

First claim

1 . A process for preparing an asymmetric compound of Formula I:

wherein:
R 1 is a leaving group, a protected amino group, NO 2 , or OH or its protected form;
R 2 is hydrogen;
R 3 is (C═O)OR 5 , CH 2 R 6 , or a protected aldehyde; or,
R 2 and R 3 are combined to form a nitrogen containing heterocyclyl selected from

R 4 is hydrogen or an amino protecting group;
R 5 is C 1-6 alkyl, C 3-10 cycloalkyl, C 4-10 heterocyclyl, aryl, or heteroaryl; and,
R 6 is a leaving group or OH or its protected form;

comprising a biocatalytic transamination of a compound of Formula II:

wherein:
R 1 is as defined above;
R 2′ is an aldehyde or an aldehyde equivalent; and,
R 3′ is R 3 ; or
RT and R 3′ are combined to form

in the presence of a transaminase polypeptide, a coenzyme, and an amino donor; wherein the transaminase polypeptide is selected from the group consisting of an amino acid sequence as set forth in SEQ ID NO: 6, 8, 10, 12, 14, 16, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, and 206.

2 . The process of claim 1 , wherein the biocatalytic transamination provides a compound of Formula I having an enantiomeric excess of at least 95%.

3 . (canceled)

4 . The process of claim 3 , wherein the transaminase polypeptide is SEQ ID NO: 180.

5 . The process of claim 1 , wherein the coenzyme is pyridoxal-phosphate (PLP)

6 . The process of claim 1 , wherein the amino donor is isopropylamine.

7 . The process of claim 1 , wherein the transaminase polypeptide is SEQ ID NO: 180, the coenzyme is PLP, and the amino donor is isopropyl amine.

8 . The process of claim 1 , wherein R 1 is Br.

9 . The process of claim 1 , wherein R 2 and R 3 are combined to form a nitrogen containing heterocyclyl selected from

and R 4 is hydrogen.

and R 4 is hydrogen.

11 . The process of claim 1 , wherein R 1 is Br, R 2 and R 3 are combined to form

and R 4 is hydrogen.

12 . The process of claim 1 , wherein R 2 is hydrogen, R 3 is CH 2 R 5 , R 4 is hydrogen, and R 5 is OH.

13 . A process for preparing an asymmetric compound of Formula III:

comprising a biocatalytic transamination of a compound of Formula IV or a compound of Formula V:

in the presence of a transaminase polypeptide, a coenzyme, and an amino donor.

14 . The process of claim 13 , wherein the biocatalytic transamination provides the compound of Formula III having an enantiomeric excess of at least 95%.

15 . The process of claim 14 , wherein the transaminase polypeptide is selected from SEQ ID NO: 18 or SEQ ID NO: 180.

16 . The process of claim 15 , wherein the transaminase polypeptide is SEQ ID NO: 180, the coenzyme is PLP, and the amino donor is isopropylamine.

17 . A process form preparing an asymmetric compound of Formula VI:

comprising:
(a) a biocatalytic transamination of a compound of Formula IV or a compound of Formula V:

in the presence of a transaminase polypeptide, a coenzyme, and an amino donor, forming the compound of Formula III:

(b) reducing the lactam of the compound of Formula III, forming the compound of Formula VII:

and,
(c) protecting the piperidine nitrogen of the compound of Formula VII to form the compound of formula VI.

Assignees

• Merck Sharp & Dohme

Inventors

• Bulger Paul Gerard
• Kosjek Birgit
• Rivera Nelo

Classifications

• C12Y206/01

  Transaminases (2.6.1) · CPC title

• C12N9/1096

  transferring nitrogenous groups (2.6) · CPC title

• C12P13/001

  Amines; Imines · CPC title

• C07D211/02 Primary

  Preparation by ring-closure or hydrogenation · CPC title

• C12P17/12 Primary

  containing a six-membered hetero ring · CPC title