Process for the preparation of 2-pyrazolo[1,5-a]pyrazin-2-ylpyrido[1,2-a]pyrimidin-4-one compounds

Patent metadata

Field	Value
Publication number	US-10538536-B2
Application number	US-201816171936-A
Country	US
Kind code	B2
Filing date	Oct 26, 2018
Priority date	Apr 28, 2016
Publication date	Jan 21, 2020
Grant date	Jan 21, 2020

Abstract

The present invention relates to a process for the preparation of 2-pyrazolo[1,5-a]pyrazin-2-ylpyrido[1,2-a]pyrimidin-4-one derivatives useful as pharmaceutically active compounds.

First claim

The invention claimed is:

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

which comprises reacting compound of formula (II):

with a compound of formula (III):

wherein
R 1 is hydrogen, C 1-7 -alkyl, or C 3-8 -cycloalkyl;
R 2 is hydrogen, halo, C 1-7 -alkyl, C 1-7 -haloalkyl or C 3-8 -cycloalkyl;
R 3 is hydrogen or C 1-7 -alkyl;
R 4 is C 1-7 -alkoxy;
A is

R 5 to R 8 are each independently selected from hydrogen and C 1-3 -alkyl.

2. A process according to claim 1 , which further comprises the preparation of the compound of formula (II):

which comprises reacting compound of formula (IV)

with a compound of formula (V)

wherein,
R 1 is hydrogen, C 1-7 -alkyl, or C 3-8 -cycloalkyl;
R 2 is hydrogen, halo, C 1-7 -alkyl, C 1-7 -haloalkyl or C 3-8 -cycloalkyl;
R 3 is hydrogen or C 1-7 -alkyl;
A is

R 5 to R 8 are each independently selected from hydrogen and C 1-3 -alkyl.

3. A process according to claim 2 , which further comprises the preparation of the compound of formula (V):

which comprises reacting a compound of formula (VII)

wherein
R 2 is hydrogen, halo, C 1-7 -alkyl, C 1-7 -haloalkyl or C 3-8 -cycloalkyl;
R 3 is hydrogen or C 1-7 -alkyl;
with a reducing agent.

4. A compound of formula (II):

wherein,
R 1 is hydrogen, C 1-7 -alkyl, or C 3-8 -cycloalkyl;
R 2 is hydrogen, halo, C 1-7 -alkyl, C 1-7 -haloalkyl or C 3-8 -cycloalkyl;
R 3 is hydrogen or C 1-7 -alkyl;
A is

R 5 to R 8 are each independently selected from hydrogen and C 1-3 -alkyl.

5. A compound of formula (V):

wherein
R 2 is hydrogen, halo, C 1-7 -alkyl, C 1-7 -haloalkyl or C 3-8 -cycloalkyl;
R 3 is hydrogen or C 1-7 -alkyl.

6. A process according to claim 1 , wherein R 4 is methoxy.

7. A process according to claim 3 , wherein the reducing agent is a hindered organoborane, an organo-aluminium hydride or inorgano-aluminium hydride.

8. A process according to claim 3 , wherein the reducing agent is sodium bis-(2-methoxyethoxy)aluminium hydride.

9. A process according to claim 1 , wherein R 1 is methyl.

10. A process according to claim 1 , wherein R 2 is ethyl.

11. A process according to claim 1 , wherein R 3 is methyl.

12. A process according to claim 1 , wherein
A is

R 5 , R 6 , R 7 and R 8 are hydrogen.

13. A compound of formula (II′):

14. A compound of formula (IV′):

15. A compound of claim 5 of formula (V′)

16. A solid form of a compound of formula (I′) or a salt thereof

characterized by an XRPD diffraction pattern comprising an XRPD peak at an angle of diffraction 2Theta at about 10.3°, 12.3°, 13.3°, and 15.4° (±0.2°).

17. The solid form according to claim 16 , characterized by the XRPD diffraction pattern comprising XRPD peaks at angles of diffraction 2Theta at about 8.5°, 10.3°, 12.3°, 13.3°, 15.4°, 17.7°, 18.1°, 19.1°, 19.6°, 19.9°, 21.1°, 21.3°, 21.5°, 22.8°, 24.0° and 25.0°.

18. A solid form of a compound of formula (I′) or a salt thereof

characterized by an XRPD diffraction pattern comprising an XRPD peak at an angle of diffraction 2Theta at about 8.0°, 9.1°, 15.0°, and 23.7° (±0.2°).

19. The solid form according to claim 17 , characterized by the XRPD diffraction pattern comprising XRPD peaks at angles of diffraction 2Theta at about 8.0°, 8.3°, 9.1°, 11.7°, 12.5°, 13.5°, 14.7°, 15.0°, 15.4°, 16.0°, 16.1°, 16.6°, 17.0°, 19.3°, 20.6°, 21.0°, 21.5° 23.0°, 23.1°, 23.6°, 23.7°, 23.9°, 27.0°, 27.3° and 28.3°.

Assignees

• Hoffmann La Roche

Inventors

• Dott Pascal
• Feyen Fabian
• Hildbrand Stefan
• Hoffmann Ursula
• Hoffmann-Emery Fabienne
• Meier Roland
• Moine Gerard
• Rege Pankaj
• Wuitschik Georg

Classifications

• A61P43/00

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

• C07D401/04

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

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title