Processes for the preparation of pyrimidinylcyclopentane compounds

Patent metadata

Field	Value
Publication number	US-10858324-B2
Application number	US-201916555842-A
Country	US
Kind code	B2
Filing date	Aug 29, 2019
Priority date	Nov 15, 2013
Publication date	Dec 8, 2020
Grant date	Dec 8, 2020

Abstract

The present invention relates to a process for the preparation of a compound of formula (I)

wherein R 1 is as defined herein, which is useful as an intermediate in the preparation of active pharmaceutical compounds.

First claim

The invention claimed is:

1. A process for the manufacture of compounds of formula (III)

comprising the asymmetric reduction of the compound of formula (V)

catalyzed by an oxidoreductase, selected from the group consisting of KRED-X1.1.P1B06, and KRED-X1.1-P1F01, or a variant thereof, in the presence of a cofactor using a substrate coupled cofactor regeneration system with 2-propanol as final reductant in the absence of glucose dehydrogenase (GDH) wherein:
R 2 is an amino-protecting group selected from the group consisting of benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ), 9-Fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and trifluoroacetyl.

2. The process according to claim 1 , wherein the oxidoreductase catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) with a diastereoselectivity of at least 99% diastereomeric excess (de).

3. The process according to claim 1 , wherein the oxidoreductase catalyzes the asymmetric reduction of a compound of formula (V) to a compound of formula (III) with a diastereoselectivity of at least at least 98% de.

4. The process according to claim 1 , wherein the cofactor which is oxidized in the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is NADH or NADPH.

5. The process according to claim 1 , wherein the catalysis further comprises continuous removal of acetone formed by the coupled cofactor regeneration-system.

6. The process according to claim 1 , wherein the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is performed in an aqueous medium in the presence of one or more organic cosolvents.

7. The process according to claim 6 , wherein the organic cosolvents are present in a total concentration from 1 to 50% V.

8. The process according to claim 6 , wherein the organic cosolvents are present in a total concentration from 5 to 30% V.

9. The process according to claim 6 , wherein the organic cosolvent is 2-propanol.

10. The process according to claim 1 , wherein the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is performed in an aqueous buffer.

11. The process according to claim 10 , wherein the buffer is 2-(N-morpholino)ethanesulfonic acid (MES) or potassium dihydrogen phosphate (PBS).

12. The process according to claim 1 , wherein the asymmetric reduction of a compound of formula (V) to a compound of formula (III) is performed at a reaction temperature between 20° C. and 45° C.

Assignees

• Genentech Inc

Inventors

• Iding Hans
• Reents Reinhard
• Scalone Michelangelo
• Gosselin Francis

Classifications

• C07D239/70 Primary

  condensed with carbocyclic rings or ring systems · CPC title

• Y02P20/55

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

• C12P17/165

  Heterorings having nitrogen atoms as the only ring heteroatoms · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07C271/22

  to carbon atoms of hydrocarbon radicals substituted by carboxyl groups · CPC title