Process for making isoquinoline compounds

Patent metadata

Field	Value
Publication number	US-9340511-B2
Application number	US-201314414879-A
Country	US
Kind code	B2
Filing date	Jul 15, 2013
Priority date	Jul 16, 2012
Publication date	May 17, 2016
Grant date	May 17, 2016

Abstract

The present invention relates to methods for making isoquinoline compounds and the intermediate compounds achieved thereby. Such compounds can be used to prepare compounds and compositions capable of decreasing HIF hydroxylase enzyme activity, thereby increasing the stability and/or activity of hypoxia inducible factor (HIF).

First claim

What is claimed is:

1. A method of making a compound of formula IV or a stereoisomer or mixture of stereoisomers thereof:

comprising contacting a compound of formula I:

with a compound of formula

followed by a compound of formula

a compound of formula R 12 —X 3 followed by a compound of formula

or a compound of formula V:

under reaction conditions sufficient to produce a compound of formula IV; wherein
Z is O, NR 1 or S;
R 1 is selected from the group consisting of hydrogen and alkyl;
R 2 is selected from the group consisting of hydrogen and alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R 3 and R 4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, —S(O) n —N(R 8 )—R 8 where n is 0, 1, or 2, —NR 8 C(O)NR 8 R 8 , —X 1 R 8 where X 1 is oxygen, —S(O) n — or —NR 9 — where n is 0, 1, or 2, or R 3 , R 4 together with the carbon atom pendent thereto, form a cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
R 5 and R 6 are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl and —X 2 R 10 where X 2 is oxygen, —S(O) n — or —NR 13 — where n is 0, 1, or 2, or when X 2 is —NR 13 —, then R 13 and R 10 , together with the nitrogen atom to which they are bound, can be joined to form a heterocyclyl or substituted heterocyclyl group;
each R 8 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl provided that when X 1 is —SO— or —SO 2 —, then R 8 is not hydrogen;
R 9 and R 13 are independently selected from the group consisting of hydrogen, alkyl, and aryl;
R 10 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl;
each R 11 is independently selected from alkyl, benzyl or aryl, or two R 11 together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl or a heteroaryl;
each R 12 is independently selected from the group consisting of alkyl, aryl, heteroaryl, and heterocyclyl, or when two R 12 are present, two R 12 together with the carbon atom to which they are attached form a 4-8 membered heterocyclyl; and
X 3 is halo.

2. The method of claim 1 , wherein Z is O.

3. The method of claim 1 , wherein the reaction conditions sufficient to produce a compound of formula IV comprise a compound of formula V.

4. The method of claim 1 , wherein the reaction conditions sufficent to produce a compound of formula IV comprise an inert atmosphere.

5. The method of claim 1 , wherein the reaction conditions sufficient to produce a compound of formula IV comprise a nitrogen atmosphere.

6. The method of claim 1 , wherein the reaction conditions sufficient to produce a compound of formula IV are anhydrous reaction conditions.

7. The method of claim 1 , wherein the reaction conditions sufficient to produce a compound of formula IV comprise at a temperature greater than about 30° C.

8. The method of claim 1 , wherein the reaction conditions sufficient to produce a compound of formula IV comprise at a temperature of about 100° C.

9. The method of claim 1 , wherein R 11 and R 12 are C 1 to C 4 alkyl.

10. The method of claim 1 , wherein R 11 and R 12 are methyl.

11. The method of claim 1 , wherein the reaction conditions sufficient to produce a compound of formula IV comprise a compound of formula V where R 12 is C 1 to C 4 alkyl; and wherein the reaction is conducted at a temperature of about 100° C.

12. The method of claim 11 , further wherein the reaction conditions sufficient to produce a compound of formula IV comprise under a nitrogen atmosphere.

13. The method of claim 1 , wherein the reaction conditions sufficient to produce a compound of formula IV further comprise converting a compound of formula VII to a compound of formula IV;

14. The method of claim 13 , wherein the reaction conditions sufficient to produce a compound of formula IV comprise an amine.

15. The method of claim 14 , wherein the amine is morpholine.

16. The method of claim 13 , wherein the reaction conditions sufficient to produce a compound of formula IV comprise dichloromethane.

17. The method of claim 13 , wherein the reaction conditions sufficient to produce a compound of formula IV comprise a temperature below 25° C.

18. The method of claim 13 , wherein the reaction conditions sufficient to produce a compound of formula IV comprise a temperature of from about 0° C. to about 10° C.

19. The method of claim 13 , wherein the reaction conditions sufficient to produce a compound of formula IV comprise morpholine; and
wherein the reaction is conducted in dichloromethane and at a temperature of from about 0° C. to about 10° C.

20. The method of claim 1 , wherein the method further comprises making a compound of formula VI or a stereoisomer or mixture of stereoisomers thereof:

comprising converting the compound of formula IV:

under reaction conditions sufficient to produce a compound of formula VI; wherein
Z is O, NR 1 or S;
R 1 is selected from the group consisting of hydrogen and alkyl;
R 2 is selected from the group consisting of hydrogen and alkyl which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl;
R 3 and R 4 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, halo, hydroxy, cyano, —S(O) n —N(R 8 )—R 8 where n is 0, 1, or 2, —NR 8 C(O)NR 8 R 8 , —X 1 R 8 where X 1 is oxygen, —S(O) n — or —NR 9 — where n is 0, 1, or 2, or R 3 , R 4 together with the carbon atom pendent thereto, form a cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;

Assignees

• Fibrogen Inc

Inventors

• Thompson Michael D
• Park Jung Min
• Arend Michael P

Classifications

• A61P7/06

  Antianaemics · CPC title

• A61P39/00

  General protective or antinoxious agents · CPC title

• C07D217/26 Primary

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title