Processes for the preparation of pyrimidinylcyclopentane compounds

Patent metadata

Field	Value
Publication number	US-2016297773-A1
Application number	US-201415036741-A
Country	US
Kind code	A1
Filing date	Nov 13, 2014
Priority date	Nov 15, 2013
Publication date	Oct 13, 2016
Grant date	—

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

1 . A process for the preparation of a compound of formula (I)

or salts thereof, which comprises the coupling reaction of a compound of formula (II)

with a compound of formula (III)

wherein
R 1 is an amino-protecting group selected from the list of benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ), 9-Fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and trifluoroacetyl.
R 2 is an amino-protecting group selected from the list of benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ), 9-Fluorenylmethyloxycarbonyl (Fmoc), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and trifluoroacetyl.
M is a metal ion selected from the list of alkali metal ion, alkaline earth metal ion and transition metal ion.

2 . The process according to claim 1 , wherein R 1 is tert-butoxycarbonyl (BOC).

3 . The process according to any of claim 1 or 2 , wherein R 2 is tert-butoxycarbonyl (BOC).

4 . The process according to any of claims 1 to 3 , wherein M is an alkali metal ion.

5 . The process according to any of claims 1 to 4 , wherein M is Na + .

6 . The process according to any of claims 1 to 5 , comprising the following reaction steps:
a) Deprotection of the compound of formula (III) in a solvent under acidic conditions;
b) adjustment to an alkaline pH using a base;
c) Addition of a solution comprising the compound of formula (II) in a solvent;
d) Addition of a solution comprising a coupling agent in a solvent.

7 . The process according to any of claims 1 to 6 , wherein the deprotection in step a) is performed using hydrochloric acid.

8 . The process according to any of claims 1 to 7 , wherein the solvent used for deprotection in step a) is selected from n-propanol or isopropanol.

9 . The process according to any of claims 1 to 8 , wherein the base in step b) is selected from N-ethyl morpholine (NEM), triethylamine (TEA), tri(n-propyl)amine (TPA), diisopropylethylamine (DIPEA), pyridine and lutidine.

10 . The process according to any of claims 1 to 9 , wherein the base in step b) is N-ethyl morpholine (NEM).

11 . The process according to any of claims 1 to 10 , wherein the solvent in step c) is selected from n-propanol or isopropanol.

12 . The process according to any of claims 1 to 11 , wherein the coupling agent used in step d) is propylphosphonic anhydride (T3P).

13 . The process according to any of claims 1 to 12 , wherein the solvent used in step d) is a mixture of n-propanol and toluene.

14 . The process according to any of claims 1 to 13 , wherein after step d) the product is worked up by aqueous extraction.

15 . The process according to any of claims 1 to 14 , further comprising a process for the manufacture of compounds of formula (II)

comprising the asymmetric hydrogenation of a compound of formula (IV)

using a metal complex catalyst (C) wherein R 1 and M are as defined in any of claims 1 to 5 .

16 . A process for the manufacture of compounds of formula (II)

comprising the asymmetric hydrogenation of a compound of formula (IV)

using a metal complex catalyst (C) wherein R 1 and M are as defined in any of claims 1 to 5 .

17 . The process according to claim 15 or 16 , wherein the metal complex catalyst (C) is a ruthenium complex catalyst selected from a compound of formula (C1), (C2) or (C3):
Ru(Z) 2 D  (C1)

[Ru(Z) 2-p (D)(L) m ](Y) p   (C2)

Ru(E)(E′)(D)(F)  (C3)

wherein:
D is a chiral phosphine ligand;
L is a neutral ligand selected from C 2-7 alkene, cyclooctene, 1,3-hexadiene, norbornadiene, 1,5-cyclooctadiene, benzene, hexamethylbenzene, 1,3,5-trimethylbenzene, p-cymene, tetrahydrofuran, dimethylformamide, acetonitrile, benzonitrile, acetone, toluene and methanol;
Z is an anionic ligand selected from hydride, fluoride, chloride, bromide, η 5 -2,4-pentadienyl, η 5 -2,4-dimethyl-pentadienyl or the group A-COO − , with the proviso that when two Z are attached to the Ru atom they can either be the same or different;
A is C 1-7 alkyl, C 1-7 haloalkyl, aryl, or haloaryl;
Y is a non-coordinating anion selected from fluoride, chloride, bromide, BF 4 − , ClO 4 − , SbF 6 − , PF 6 − , B(phenyl) 4 , B(3,5-di-trifluoromethyl-phenyl) 4 − , CF 3 SO 3 —, and C 6 H 5 SO 3 − ;
F is an optionally chiral diamine;
E and E′ are both halogen ions, or E is hydride and E′ is BH 4 − ;
m is 1, 2, 3 or 4; and
p is 1 or 2.

18 . The process according to any of claims 15 to 17 , wherein the ruthenium complex catalysts is Ru(Z) 2 D, wherein Z and D are as defined in claim 17 .

19 . The process according to any of claims 15 to 18 , wherein the anionic ligand (Z) is independently selected from chloride, bromide, iodide, OAc, and TFA.

20 . The process according to any of claims 15 to 19 , wherein the anionic ligand (Z) is trifluoroacetate (TFA).

21 . The process according to any of claims 15 to 17 , wherein the neutral ligand (L) is independently selected from benzene (C 6 H 6 ), p-cymene (pCym), and acetonitrile (AN).

22 . The process according to any of claims 15 to 17 , wherein the neutral ligand (L) is benzene (C 6 H 6 ).

23 . The process according to any of claims 15 to 17 , wherein the non-coordinating anion (Y) is selected from chloride, bromide, iodide and BF 4 − .

24 . The process according to any of claims 15 to 17 , wherein the non-coordinating anion (Y) is BF 4 − .

25 . The process according to any of claims 15 to 17 , wherein m is 1 or 4.

26 . The process according to any of claims 15 to 17 , wherein E and E′ are both chloride;

27 . The process according to any of claims 15 to 17 , wherein the chiral diamine F is (1S,2S)-1,2-diphenylethylenediamine (S,S-DPEN).

28 . The process according to any of claims 15 to 17 , wherein the chiral phosphine ligand D is selected from a compound of formula (D1) to (D12):

wherein:
R 11 is C 1-7 alkyl, C 1-7 alkoxy, hydroxy or C 1-7 alkyl-C(O)O—;
R 12 and R 13 are each independently hydrogen, C 1-7 alkyl, C 1-7 alkoxy or di(C 1-7 alkyl)amino; or
R 11 and R 12 which are attached to the same phenyl group, or R 12 and R 13 which are attached to the same phenyl group taken together are —X—(CH 2 ) r —Y—, wherein X is —O—, or —C(O)O—, Y is —O—, —N(lower-alkyl)-, or —CF 2 — and r is an intege

Assignees

• Hoffmann La Roche
• Genentech Inc

Inventors

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

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07C271/22

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

• C07B2200/07

  Optical isomers · CPC title

• C07D239/70 Primary

  condensed with carbocyclic rings or ring systems · CPC title