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

Patent metadata

Field	Value
Publication number	US-9828336-B2
Application number	US-201615158687-A
Country	US
Kind code	B2
Filing date	May 19, 2016
Priority date	Feb 17, 2012
Publication date	Nov 28, 2017
Grant date	Nov 28, 2017

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 compound of Formula IV:

or a salt thereof,
wherein Ar is aryl optionally substituted with 1-3 substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkoxy, and haloC 1-6 alkyl; and
R 1 is a leaving group.

2. The compound of claim 1 , wherein Ar is phenyl.

3. The compound of claim 1 , wherein Ar is substituted 1-3 times with a halo independently selected from the group consisting of chloro, fluoro, bromo, and iodo.

4. The compound of claim 1 , wherein the leaving group is a sulfonate ester leaving group selected from the group consisting of mesylate, tosylate, nosylate, benzene sulfonate, and brosylate.

5. The compound of claim 4 , wherein the leaving group is mesylate.

6. The compound of claim 4 , wherein the leaving group is tosylate.

7. The compound of claim 4 , wherein said compound is:

8. The compound of claim 1 , wherein the compound of Formula IV is a compound of Formula IVa:

9. The compound of claim 8 , wherein the compound has an enantiomeric excess (ee) of the Formula IVa stereoisomer of at least 80%.

10. The compound of claim 8 , wherein the compound has an enantiomeric excess (ee) of the Formula IVa stereoisomer of at least 85%.

11. The compound of claim 8 , wherein the compound has an enantiomeric excess (ee) of the Formula IVa stereoisomer of at least 90%.

12. The compound of claim 8 , wherein the compound has an enantiomeric excess (ee) of the Formula IVa stereoisomer of at least 95%.

13. The compound of claim 8 , wherein the compound has an enantiomeric excess (ee) of the Formula IVa stereoisomer of at least 98%.

14. A composition comprising a compound of Formula IV, or a pharmaceutically acceptable salt thereof:

wherein Ar is aryl optionally substituted with 1-3 substituents independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkoxy, and haloC 1-6 alkyl; and
R 1 is a leaving group; and
an acceptable carrier.

15. The composition of claim 14 , wherein said compound of Formula IV is:

or a pharmaceutically acceptable salt thereof.

Assignees

• Eisai R&D Man Co Ltd

Inventors

• Moniz George Anthony
• Wilcoxen Annie Zhu
• Benayoud Farid
• Tanaka Toshiaki
• Sorimachi Keiichi

Classifications

• C07C67/03

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

• C07C303/28

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

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07C69/16

  of dihydroxylic compounds · CPC title

• C07C33/36

  Polyhydroxylic alcohols containing six-membered aromatic rings and other rings · CPC title