Processes for the preparation of Tasimelteon and intermediates thereof

Patent metadata

Field	Value
Publication number	US-9944616-B2
Application number	US-201715615020-A
Country	US
Kind code	B2
Filing date	Jun 6, 2017
Priority date	Jun 8, 2016
Publication date	Apr 17, 2018
Grant date	Apr 17, 2018

Abstract

The present invention provides processes for the preparation of Tasimelteon (1), as well as processes for the preparation of intermediates of Formulas (2), (3) and (4) useful in the preparation of Tasimelteon (1).

First claim

What is claimed is:

1. A process for preparing a compound of Formula (1)

the process comprising:
(i) reacting a compound of Formula (3)

with (S)-(+)-camphorsulfonic acid in a suitable solvent to form a salt of Formula (2-A)

(ii) isolating the salt of Formula (2-A) formed in step (i);
(iii) treating the salt of Formula (2-A) with a first base to produce a compound of Formula (3), wherein the purity of the compound of Formula (3) formed in step (iii) is greater than the purity of the compound of Formula (3) used in step (i); and
(iv) reacting the compound of Formula (3) prepared in step (iii) with a compound of Formula (A)

wherein G is a leaving group.

2. The process of claim 1 , wherein the purity in step (iii) is chemical purity.

3. The process of claim 1 , wherein the purity in step (iii) is chiral purity.

4. The process of claim 1 , wherein the solvent comprises toluene.

5. The process of claim 1 , wherein the solvent comprises a mixture of toluene and a second solvent.

6. The process of claim 5 , wherein the second solvent is selected from the group consisting of diglyme, 2-propanol and methanol.

7. The process of claim 1 , wherein the salt of Formula (2-A) obtained in step (ii) is further purified prior to step (iii).

8. The process of claim 7 , wherein the salt of Formula (2-A) obtained in step (ii) is purified by stirring a slurry of the salt of Formula (2-A) in a solvent comprising a C 1 -C 3 alcohol prior to isolating the salt of Formula (2-A) by filtration.

9. The process of claim 1 , wherein the reaction of the compound of Formula (3) with the compound of Formula (A) occurs in the presence of a second base.

10. The process of claim 9 , wherein the second base is the same as the first base used in step (iii), and is a tertiary amine or a metal hydroxide.

11. The process of claim 1 , wherein the compound of Formula (A) is propionic anhydride.

12. The process of claim 1 , wherein the compound of Formula (3) is prepared by a process comprising reducing a compound of Formula (4):

with sodium borohydride in the presence of aluminum trichloride and diglyme.

13. The process of claim 12 , wherein diglyme is used with a co-solvent.

14. The process of claim 13 , wherein tetrahydrofuran is used as the co-solvent.

15. The process of claim 12 , wherein the compound of Formula (4) is prepared by a process comprising reacting a compound of Formula (5):

wherein R is a C 1 -C 4 alkyl chain, with either of:
(a) methanolic ammonia; or
(b) a mixture of formamide and metal alkoxide.

16. The process of claim 15 , wherein the compound of Formula (5) is reacted with a mixture of formamide and metal alkoxide.

17. The process of claim 16 , wherein the metal alkoxide is sodium methoxide.

18. The process of claim 15 , wherein R in the compound of Formula (5) is ethyl.

19. The salt of Formula (2-A):

20. A process for preparing a salt of Formula (2-A)

the process comprising the steps of:
(i) reacting a compound of Formula (3)

with (S)-(+)-camphorsulfonic acid in a suitable solvent; and
(ii) isolating a salt of Formula (2-A) formed between the compound of Formula (3) and (S)-(+)-camphorsulfonic acid.

Assignees

• Apotex Inc

Inventors

• Zhao Yajun
• Kondamreddy Murali
• Blazecka Peter Garth
• Weeratunga Gamini
• Stewart Craig
• Nagireddy Nalini
• Johansen Michael B
• Kotipalli Uma

Classifications

• C07C13/04

  with a three-membered ring · CPC title

• C07B41/06

  of carbonyl groups · CPC title

• C07D307/79 Primary

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring · CPC title

• C07C2602/02

  the rings having only two atoms in common · CPC title

• C07C233/05

  having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms · CPC title