Processes for the preparation of pyrimidinylcyclopentane compounds

Patent metadata

Field	Value
Publication number	US-9862689-B2
Application number	US-201415036741-A
Country	US
Kind code	B2
Filing date	Nov 13, 2014
Priority date	Nov 15, 2013
Publication date	Jan 9, 2018
Grant date	Jan 9, 2018

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 preparation of a compound of formula (I)

or a salt thereof, comprising coupling a compound of formula (II)

with a deprotected 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; and
M is a metal ion selected from the list of alkali metal ion, alkaline earth metal ion and transition metal ion;
to provide the compound of formula (I) or a salt thereof.

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

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

4. The process according to claim 1 , wherein M is Na + .

5. The process according to claim 1 , 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.

6. The process according to claim 5 , wherein the deprotection in step a) is performed using hydrochloric acid.

7. The process according to claim 5 , wherein the solvent used for the deprotection in step a) is selected from n-propanol and isopropanol.

8. The process according to claim 5 , 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.

9. The process according to claim 5 , wherein the solvent in step c) is selected from n-propanol and isopropanol.

10. The process according to claim 5 , wherein the coupling agent used in step d) is propylphosphonic anhydride (T3P).

11. The process according to claim 5 , wherein the solvent used in step d) is a mixture of n-propanol and toluene.

12. The process according to claim 1 , further comprising preparing the compound of formula (II)

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

using a metal complex catalyst (C);
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,
to provide the compound of formula (II).

13. The process according to claim 1 , further comprising deprotecting the compound of formula I or a salt thereof to provide a compound of formula (VI)

or a pharmaceutically acceptable salt thereof.

14. The process according to claim 13 , comprising the following reaction steps:
i) Deprotection of the compound of formula (I) in a solvent under acidic conditions;
ii) Adjustment of the pH using a base in a solvent;
iii) Optionally crystallizing the compound of formula (VI).

15. The process according to claim 14 , wherein the deprotection in step i) is performed using hydrochloric acid, sulfuric acid, trifluoro acetic acid or hydrobromic acid.

16. The process according to claim 14 , wherein the solvent used for the deprotection in step i) is selected from n-propanol and isopropanol.

17. The process according to claim 14 , wherein the base in step ii) is ammonia.

18. The process according to claim 14 , wherein the solvent in step ii) is selected from n-propanol and isopropanol.

19. The process according to claim 14 , wherein the crystallization in step iii) is performed by a solvent switch to a crystallization solvent selected from toluene, heptane, tetrahydrofuran, 2-propanone, 2-butanone, ethylene glycol dimethyl ether, ethyl acetate, butyl acetate, isopropyl acetate and mixtures thereof.

20. A mixture comprising a compound of formula (VI) or a pharmaceutically acceptable salt thereof as described in claim 13 and between 1 ppb and 100 ppm of a compound of formula (I) or a salt thereof.

21. A mixture comprising a compound of formula (VI) or a pharmaceutically acceptable salt thereof as described in 13 and between 1 ppb and 1 ppm of a compound of formula (I) or a salt thereof.

22. A mixture comprising a compound of formula (I) or a salt thereof as described in claim 1 and between 1 ppb and 100 ppm of a compound of formula (II).

23. A mixture comprising a compound of formula (I) or a salt thereof as described in claim 1 and between 1 ppb and 1 ppm of a compound of formula (II).

24. A mixture comprising a compound of formula (I) or a salt thereof as described in claim 1 and between 1 ppb and 100 ppm of a compound of formula (III).

25. A mixture comprising a compound of formula (I) or a salt thereof as described in claim 1 and between 1 ppb and 1 ppm of a compound of formula (III).

26. A mixture comprising a compound of formula (I) or a salt thereof as described in claim 1 and between 1 ppb and 100 ppm of a compound of formula (II) and between 1 ppb and 100 ppm of a compound of formula (III).

27. A mixture comprising a compound of formula (I) or a salt thereof as described in claim 1 and between 1 ppb and 1 ppm of a compound of formula (II) and between 1 ppb and 1 ppm of a compound of formula (III).

Assignees

• 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

• C12P17/165

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

• C07B2200/07

  Optical isomers · CPC title

• C07C269/06

  by reactions not involving the formation of carbamate groups · CPC title