Picolinic acid derivatives and their use as intermediates

Patent metadata

Field	Value
Publication number	US-10633341-B2
Application number	US-201716470778-A
Country	US
Kind code	B2
Filing date	Dec 18, 2017
Priority date	Dec 19, 2016
Publication date	Apr 28, 2020
Grant date	Apr 28, 2020

Abstract

The present invention relates to new picolinic acid derivatives of formula (I) and their use as intermediates in the process of making pyridine derivatives, including (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide that are useful for the treatment of respiratory disorders.

First claim

The invention claimed is:

1. A compound according to formula (I) or a salt thereof:

wherein
R 1 is C 1-10 alkyl, C 2-10 alkenyl or C 2-10 alkynyl;
R 2 is H, C 1-10 alkyl or benzyl; and
R 3 is bromo or iodo.

2. The compound according to claim 1 , wherein R 1 is C 1-10 alkyl.

3. The compound according to claim 1 , wherein R 2 is C 1-10 alkyl.

4. The compound according to claim 1 , wherein R 2 is C 1-3 alkyl.

5. The compound according to claim 1 , wherein R 2 is methyl.

6. The compound according to claim 1 , wherein R 2 is H.

7. The compound according to claim 1 , wherein R 3 is bromo.

8. The compound 3-bromo-6-methoxy-5-(trifluoromethyl)picolinic acid or a salt thereof.

9. The compound methyl 3-bromo-6-methoxy-5-(trifluormethyl)picolinate or a salt thereof.

10. A process for the preparation of a compound of formula (I) or a salt thereof:

the process comprising reacting a compound of formula (II) or a salt thereof

with TMPMgCl.LiCl, TMPLi, dicyclohexylamine-MgCl.LiCl, or dicyclohexylamine-Li and a reactive electrophile to obtain a compound of formula (I) or a salt thereof, wherein
R 1 is C 1-10 alkyl, C 2-10 alkenyl or C 2-10 alkynyl;
R 2 is H, C 1-10 alkyl or benzyl; and
R 3 is bromo, chloro or iodo.

11. A compound (S)-3-bromo-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide or a salt thereof.

12. The process according to claim 10 , wherein a compound of formula (II) is reacted with TMPMgCl.LiCl and a reactive electrophile to obtain a compound of formula (I).

13. The process according to claim 12 , wherein the reactive electrophile is CO 2 , CO(O—C 1-10 alkyl) 2 , Cl—COO—C 1-10 alkyl or Cl—COOCH 2 -phenyl.

14. The process according to claim 13 , wherein the reactive electrophile is CO 2 or CO(O—C 1-10 alkyl) 2 .

15. The process according to claim 12 , wherein the amount of TMPMgCl.LiCl is about 1 mole equivalent to about 5 mole equivalents based on the amount of the compound of formula (II).

16. The process according to claim 10 , wherein the process is performed in the presence of an aprotic solvent.

17. The process according to claim 10 , wherein the process is performed at a temperature between about −50° C. and about 50° C.

18. The process according claim 10 , wherein R 1 is methyl, R 2 is H or methyl and R 3 is bromo.

19. A process for the preparation of a compound according to formula (VII)

or a salt thereof, the process comprising
(a) reacting a compound of formula (III) or a salt thereof with TMPMgCl.LiCl and CO 2

to obtain a compound of formula (IV) or a salt thereof

(b) under Ullmann amination conditions, converting a compound of formula (IV) or a salt thereof to a compound of formula (V) or a salt thereof

and
(c) reacting a compound of formula (V) or a salt thereof with a compound of formula (VI) or a salt thereof

to obtain a compound of formula (VII) or a salt thereof, and
(d) optionally converting a compound of formula (VII) to a pharmaceutically acceptable salt thereof.

20. A process for the preparation of a compound according to formula (VII)

or a salt thereof, the process comprising
(a) reacting a compound of formula (III) or a salt thereof with TMPMgCl.LiCl and CO(OCH 3 ) 2

to obtain a compound of formula (VIII) or a salt thereof

(b) converting a compound of formula (VIII) or a salt thereof to a compound of formula (IV) or a salt thereof

(c) under Ullmann amination conditions, converting a compound of formula (IV) or a salt thereof to a compound of formula (V) or a salt thereof

and
(d) reacting a compound of formula (V) or a salt thereof with a compound of formula (VI) or a salt thereof

to obtain a compound of formula (VII) or a salt thereof, and
(e) optionally converting a compound of formula (VII) to a pharmaceutically acceptable salt thereof.

21. A process for the preparation of a compound according to formula (VII)

or a salt thereof, the process comprising
(a) reacting a compound of formula (III) or a salt thereof with TMPMgCl.LiCl and a reactive electrophile

to obtain a compound of formula (X) or a salt thereof

wherein R 2 is C 1-10 alkyl or benzyl;
(b) reacting a compound of formula (X) or a salt thereof with a compound of formula (VI) or a salt thereof

to obtain a compound of formula (IX) or a salt thereof

(c) converting a compound of formula (IX) or a salt thereof to a compound of formula (VII) or a salt thereof; and
(d) optionally converting a compound of formula (VII) to a pharmaceutically acceptable salt thereof.

Assignees

• Novartis Ag

Inventors

• Heinz Thomas
• Martin Benjamin
• Rampf Florian Andreas
• Zaugg Werner

Classifications

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D213/79 Primary

  Acids; Esters · CPC title

• C07D213/81

  Amides; Imides · CPC title

• A61K31/435

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title