Methods and compounds useful in the synthesis of orexin-2 receptor antagonists

Patent metadata

Field	Value
Publication number	US-9416109-B2
Application number	US-201314379063-A
Country	US
Kind code	B2
Filing date	Feb 14, 2013
Priority date	Feb 17, 2012
Publication date	Aug 16, 2016
Grant date	Aug 16, 2016

Abstract

The present disclosure provides compounds and methods that are useful for the preparation of compounds useful as orexin-2 receptor antagonists.

First claim

That which is claimed is:

1. A process for making a compound of Formula IX:

wherein:
Ar is phenyl, which phenyl may be unsubstituted, or substituted 1-3 times with substituents independently selected from the group consisting of: halo, C 1-6 alkyl, C 1-6 alkoxy, and haloC 1-6 alkyl;
R 2 and R 3 are each independently selected from the group consisting of: hydrogen, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, and hydroxyC 1-6 alkyl; and
Ar′ is a pyridine group:

wherein:
R 4 is selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, and (C 1-6 alkoxy)C 1-6 alkyl;
R 5 is selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, and haloC 1-6 alkyl; and
R 6 is selected from the group consisting of: hydrogen, halo, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, (C 1-6 alkoxy)C 1-6 alkyl, and cyano,

comprising the step of reacting a compound of Formula VII:

wherein Ar, R 2 and R 3 are as given above,

with a compound of Formula X:

wherein R 4 , R 5 , and R 6 are as given above,

said reacting carried out in an organic solvent in the presence of an organic amine and an amide coupling agent,
to prepare said compound of Formula IX,
wherein said amide coupling agent is an alkyl phosphonic anhydride.

2. The process of claim 1 , wherein Ar is unsubstituted or substituted 1-3 times with a halo independently selected from the group consisting of: chloro, fluoro, bromo, and iodo, and
R 2 and R 3 are each independently selected from the group consisting of: hydrogen and C 1-6 alkyl.

3. The process of claim 1 , wherein said organic solvent is selected from the group consisting of ethyl acetate, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), acetone, toluene, acetonitrile, and dichloromethane.

4. The process of claim 1 , wherein said amide coupling agent is a propyl phosphonic anhydride or tri-n-propyl phosphonic anhydride.

5. The process of claim 1 , wherein said compound of Formula IX is:

6. The process of claim 1 , wherein said compound of Formula VII,

wherein Ar, R 2 and R 3 are as given in claim 1 , is produced by a process comprising: oxidizing a compound of Formula V:

wherein Ar, R 2 and R 3 are as given above,
with sodium hypochlorite and sodium chlorite,
to thereby make said compound of Formula VII.

7. The process of claim 6 , wherein said oxidizing with sodium hypochlorite and sodium chlorite is carried out simultaneously.

8. The process of claim 6 , wherein said oxidizing is catalyzed with an effective amount of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO).

9. The process of claim 1 , wherein said compound of Formula VII:

wherein Ar, R 2 and R 3 are as given in claim 1 ,
is produced by a process comprising the steps of:
a) oxidizing a compound of Formula V:

 wherein Ar, R 2 and R 3 are as given above,
with a first oxidizing agent, to form an aldehyde of Formula VIII:

 wherein Ar, R 2 and R 3 are as given above; and then
b) oxidizing the aldehyde of Formula VIII with a second oxidizing agent,
to thereby make said compound of Formula VII.

10. The process of claim 9 , wherein the first oxidizing agent is sodium hypochlorite.

11. The process of claim 9 , wherein said oxidizing of step a) is catalyzed with an effective amount of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO).

12. The process of claim 9 , wherein the second oxidizing agent is sodium chlorite.

13. The process of claim 6 , wherein said compound of Formula V,

wherein Ar, R 2 and R 3 are as given in claim 6 , is produced by a process comprising the steps of:
a) stirring a mixture of:
i) a compound of Formula IV:

 wherein Ar is as given above, and R 1 is a leaving group;
ii) a substituted pyrimidine of Formula VI:

 wherein R 2 and R 3 are as given above;
iii) a base; and
iv) an organic solvent,
at a temperature of from 65-70° C., for 1 to 12 hours; and then
b) reacting the mixture with an aqueous base for a time of from 2 to 20 hours,
to thereby make said compound of Formula V.

14. The process of claim 13 , wherein said compound of Formula IV:

wherein Ar is as given in claim 13 , and R 1 is a sulfonate ester leaving group,
is produced by a process comprising reacting a compound of Formula III:

wherein Ar is as given above,
with a compound selected from the group consisting of: tosyl chloride, mesyl chloride, nosyl chloride, toluenesulfonyl chloride, toluenesulfonic anhydride and methanesulfonic anhydride, wherein said reacting is carried out in an organic solvent in the presence of a base,
to thereby make said compound of Formula IV.

15. The process of claim 14 , wherein the base is an organic amine or potassium carbonate.

16. The process of claim 14 , wherein the organic solvent is selected from the group consisting of: dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, and ethyl acetate.

17. The process of claim 14 , wherein said compound of Formula III is:

18. The process of claim 14 , wherein said compound of Formula IV has the absolute stereochemistry of Formula IVa:

wherein the compound has an enantiomeric excess (ee) of the Formula IVa stereoisomer of at least 80%.

19. The process of claim 14 , wherein said compound of Formula IV is:

20. The process of claim 14 , wherein said compound of Formula III:

Assignees

• Eisai R&D Man Co Ltd

Inventors

• Moniz George Anthony
• Wilcoxen Annie Zhu
• Benayoud Farid
• Lee Jaemoon
• Zhang Huiming
• Terauchi Taro
• Takemura Ayumi
• Yoshida Yu
• Tanaka Toshiaki
• Sorimachi Keiichi
• Naoe Yoshimitsu
• Kazuta Yuji

Classifications

• C07C303/28

  by reaction of hydroxy compounds with sulfonic acids or derivatives thereof · CPC title

• C07C29/147 Primary

  of carboxylic acids or derivatives thereof · CPC title

• C07C67/03

  by reacting an ester group with a hydroxy group · CPC title

• C07C309/73 Primary

  to carbon atoms of non-condensed six-membered aromatic rings · CPC title

• C07C2601/02

  with a three-membered ring · CPC title