General process for the preparation of 6-substituted or 5,6-disubstituted derivatives of 2-amino-isonicotinic acid

Patent metadata

Field	Value
Publication number	US-10106506-B2
Application number	US-201615738632-A
Country	US
Kind code	B2
Filing date	Jul 1, 2016
Priority date	Jul 2, 2015
Publication date	Oct 23, 2018
Grant date	Oct 23, 2018

Abstract

This invention relates to a novel synthetic method for the preparation of 6-substituted or 5,6-disubstituted derivatives of 2-amino-isonicotinic acid.

First claim

The invention claimed is:

1. A process for preparing 2-amino-isonicotinic acid derivatives of formula I

in which
R1 is C 1 -C 6 -alkyl- or C 6 -C 10 -aryl-;
R2 is H—, C 1 -C 6 -alkyl- or C 6 -C 10 -aryl-;
or
R1 and R2 together form a C 2 -C 5 -alkyl-group such that a ring is formed;
R3 is C 1 -C 4 -alkyl-;
R4 is C 1 -C 4 -alkyl-;
comprising the reaction of compound (1)

with a compound of formula II

in which R1, R2, R3 and R4 have the meaning as in formula I,
in which water is eliminated.

2. The process according to claim 1 , further comprising hydrolyzing the ester groups —COOR3 and —COOR4 of the 2-amino-isonicotinic acid derivatives of formula I to give intermediate compound of formula III

in which R1 and R2 have the meaning as in formula I.

3. The process according to claim 2 , further comprising reacting the intermediate compound of formula III under conditions facilitating decarboxylation to give a compound of formula IV

in which R1 and R2 have the meaning as in formula I.

4. The process according to claim 1
in which
R1 is methyl-, ethyl-, iso-propyl-, tert-butyl- or phenyl-;
R2 is H— or methyl-;
or
R1 and R2 together form a —CH 2 —CH 2 —CH 2 — or —CH 2 —CH 2 —CH 2 —CH 2 — group such that a ring is formed;
R3 is ethyl- or methyl-;
R4 is ethyl- or methyl-.

5. The process according to claim 1
in which
R1 is methyl-, ethyl-, iso-propyl-, tert-butyl- or phenyl- and R2 is H—;
or
R1 is ethyl- and R2 is methyl-;
or
R1 and R2 together form a —CH 2 —CH 2 —CH 2 — group such that a ring is formed;
R3 is ethyl-;
R4 is ethyl-.

6. The process according to claim 1 , wherein the reaction comprises NaOEt in EtOH for elimination of water.

7. The process according to claim 2 , wherein an inorganic base is used for hydrolysis of the ester groups.

8. The process according to claim 2 , wherein NaOH, LiOH, KOH or Ba(OH) 2 is used for hydrolysis of the ester groups.

9. The process according to claim 2 , wherein the reaction mixture is adjusted to a pH in the range of 5-6 with an acid after hydrolysis of the ester groups.

10. The process according to claim 2 , wherein the reaction mixture is adjusted to a pH in the range of 5-6 with hydrochloric acid or H 2 SO 4 after hydrolysis of the ester groups.

11. The process according to claim 3 , wherein concentrated H 2 SO 4 is used for decarboxylation.

12. The process according to claim 3 , wherein decarboxylation is conducted in the presence of LiCl, NaCl or MgCl 2 .

13. The process according to claim 3 , wherein decarboxylation is conducted at a temperature of 120 to 150° C.

Assignees

• Boehringer Ingelheim Int

Inventors

• Dong Weitong
• Deng Da
• Fu Yan
• Jin Xiangle
• Xing Lidong
• Yan Jun

Classifications

• C07D213/80

  in position 3 · CPC title

• C07D213/803 Primary

  Processes of preparation · CPC title

• C07D213/12

  from unsaturated compounds · CPC title