Salts of 2-fluoro-N-methyl-4-[7-(quinolin-6-yl-methyl)-imidazo[1,2-B][1,2,4]triazin-2-yl]benzamide and processes related to preparing the same

Patent metadata

Field	Value
Publication number	US-10245265-B2
Application number	US-201615355630-A
Country	US
Kind code	B2
Filing date	Nov 18, 2016
Priority date	May 21, 2008
Publication date	Apr 2, 2019
Grant date	Apr 2, 2019

Abstract

The present invention is directed to dihydrochloric acid and dibenzenesulfonic acid salts of the c-Met kinase inhibitor 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)-imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, and pharmaceutical compositions thereof, useful in the treatment of cancer and other diseases related to the dysregulation of kinase pathways. The present invention further relates to processes and intermediates for preparing 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide, and salts thereof.

First claim

What is claimed is:

1. A process of preparing a compound of Formula I:

or salt thereof;
comprising reacting a compound of Formula II:

with a compound of Formula III:

at a temperature from about 120° C. to about 150° C. to form a compound of Formula I, or salt thereof;
wherein X 1 is chloro, bromo, or iodo.

2. The process according to claim 1 , further comprising reacting said compound of Formula I, or salt thereof, with a strong acid to form a compound of Formula IV:

or salt thereof.

3. The process according to claim 2 , wherein said acid is concentrated hydrochloric acid.

4. The process according to claim 2 , further comprising reacting the compound of Formula IV, or salt thereof, with CH 3 NH 2 in the presence of a coupling agent to form a compound of Formula V:

or salt thereof.

5. The process according to claim 4 , wherein said coupling agent is selected from 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N-hydroxybenzotriazole, (benzotriazol-1-yloxyl)tripyrrolidinophosphonium hexaflurophosphate, and salts thereof.

6. The process according to claim 2 , further comprising:
a) reacting the compound of Formula IV:

or salt thereof, with a halogenating agent, to form a compound of Formula VI:

or salt thereof; and
b) reacting said compound of Formula VI, or salt thereof, with CH 3 NH 2 to form a compound of Formula V:

or salt thereof, wherein X 2 is halogen.

7. The process of claim 6 , wherein said halogenating agent is thionyl chloride.

8. The process of claim 1 , further comprising preparing the compound of Formula II:

by a process comprising reacting a compound of Formula IIa:

with a compound of Formula IIb:

in the presence of a base,
wherein X 1 is chloro, bromo, or iodo.

9. The process of claim 8 , wherein the reacting of the compound of Formula IIa with the compound of Formula IIb is carried out in the presence of proline.

10. The process of claim 8 , wherein X 1 is chloro.

11. The process of claim 8 , further comprising preparing the compound of Formula IIa:

by a process comprising reacting a compound of Formula IIc:

with prop-2-en-1-ol in the presence of a palladium catalyst and a base;
wherein X 3 is chloro, bromo, or iodo.

12. The process of claim 11 , further comprising preparing the compound of Formula IIa:

by a process comprising reacting a compound of Formula IId:

with an acid of formula HX;
wherein X′ is chloro, bromo, or iodo.

13. A process of claim 12 , further comprising preparing a compound of Formula IId:

by a process comprising reducing a compound of Formula IIe:

with hydrogen gas in the presence of a hydrogenation catalyst.

14. A process of claim 13 , wherein the hydrogenation catalyst is palladium-on-carbon.

15. A process of claim 13 , further comprising preparing a compound of Formula IIe by a process comprising reacting a compound of Formula IIc with a compound of Formula IIf:

in the presence of a coupling catalyst and a base.

16. A process of claim 15 , wherein the catalyst is a mixture of palladium acetate and CuI.

17. A process of claim 13 , further comprising preparing a compound of Formula IId:

by a process comprising reacting a compound of Formula IIg:

with 9-borabicyclo[3.3.1]nonane, followed by reacting with a compound of Formula IIc:

in the presence of a coupling catalyst to form the compound of Formula IId;
wherein X 3 is chloro, bromo, or iodo.

18. The process of claim 17 , wherein the coupling catalyst is palladium(II)diacetate.

19. The process of claim 1 , further comprising preparing the compound of Formula III by a process comprising reacting a compound of Formula IIIa:

with a compound of Formula IIIb:

in the presence of a palladium catalyst and a base; wherein:
X 4 is chloro, bromo or iodo; and
each R a is, independently, C 1-6 alkyl; or
each R a , along with the two oxygen atoms and boron atom form a 5- or 6-membered heterocyclic ring; wherein said heterocyclic ring is optionally substituted with 1, 2, 3, or 4 independently selected C 1-4 alkyl groups.

20. The process of claim 19 , wherein the compound of Formula IIIb has formula IIIb-1.

21. The process of claim 19 , further comprising preparing the compound of Formula IIIa by reacting 1,2,4-triazine-3-amine with a halogenating agent.

22. The process of claim 20 , further comprising preparing the compound of Formula IIIb-1 by a process comprising:
a) reacting a compound of Formula IIIc:

a reagent of formula R 1 MgY, followed by reacting with a compound of formula B(OR 2 ) 3 to form a compound of Formula IIId:

and
b) after the reacting in s

Assignees

• Incyte Corp
• Incyte Holdings Corp
• Incyte Inc

Inventors

• Weng Lingkai
• Qiao Lei
• Zhou Jiacheng
• Liu Pingli
• Pan Yongchun

Classifications

• A61P43/00

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

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P35/04

  specific for metastasis · CPC title