Method for the preparation of [1,2,4]-triazolo[4,3-a]pyridines

Patent metadata

Field	Value
Publication number	US-9643984-B2
Application number	US-201414900976-A
Country	US
Kind code	B2
Filing date	Jun 24, 2014
Priority date	Jun 24, 2013
Publication date	May 9, 2017
Grant date	May 9, 2017

Abstract

Disclosed herein are methods for preparing [1,2,4]triazolo[4,3-a]pyridines, particularly (R)-6-(1-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one, and precursors thereof, such as a method comprising reacting (R)—N-(3-fluoro-5-(1methyl-1H-pyrazol-4-yl) pyridin-2-yl)-2-(3-(2-methoxyethoxy)-5-oxo-1,6-naphthyridin-6(5H)yl) propanehydrazide (“HYDZ”): (HYDZ) under conditions sufficient to form (R)-6-(1-(8-fluoro-6-(1-methyl-IH-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (“A”): (A)

First claim

We claim:

1. A method comprising;
subjecting (R)—N′-(3-fluoro-5-(1methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(3-(2-methoxyethoxy)-5-oxo-1,6-naphthyridin-6(5H)yl)propanehydrazide (“HYDZ”):

to a dehydration reaction with either a thiophosphetane compound or a phosphorus (V) dehydrating agent thereby forming (R)-6-(1-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (“A”):

2. The method of claim 1 , wherein the thiophosphetane compound comprises a 2,4-bis(aryl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide compound.

3. The method of claim 2 , wherein the 2,4-bis(aryl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide compound is:

4. The method of claim 1 further comprising contacting Compound A with a water-rich solvent having a pH of at least 7 to form the monohydrate form of Compound A.

5. The method of claim 1 , wherein the dehydrating agent comprises a compound having a structure:

wherein each L independently is C 1-6 alkyl, O—C 1-6 alkyl, aryl, O-aryl, Br, Cl, or I; and R 1 is Cl, Br, or I.

6. The method of claim 5 , wherein each L is selected from the group consisting of Me, Et, t-Bu, O-Me, O-Et, O-t-Bu, phenyl, O-phenyl, Br, and Cl.

7. The method of claim 1 , further comprising contacting Compound A with an acid under conditions sufficient to form a salt of Compound A.

8. The method of claim 7 , wherein the acid is selected from the group consisting of hydrochloric acid, phosphoric acid, camphorsulfonic acid, 2-naphthylsulfonic acid, methansulfonic acid, benzenesulfonic acid and derivatives thereof, succinic acid, tartaric acid, fumaric acid, maleic acid, and combinations thereof.

9. The method of claim 1 further comprising crystallizing Compound A in a solution comprising alcohol and water to form a monohydrate form of Compound A:

10. The method of claim 1 , wherein the HYDZ is formed by reacting (R)-2-(3-(2-methoxyethoxy)-5-oxo-1,6-naphthyridin-6(5H)-yl)propanoic acid (“NAPA”):

with 3-fluoro-2-hydrazinyl-5-(1-methyl-/H-pyrazl-4-yl)pyridine (“PYRH”):

and a coupling reagent to form HYDZ:

11. The method of claim 10 , wherein NAPA is a salt comprising HCl, HBr, sulfonic acid, diisopropylamine, or potassium.

12. The method of claim 11 , wherein the sulfonic acid salt is selected from the group consisting of 2-naphthalenesulfonic acid, 1-naphthalenesulfonic acid, m-xylenesulfonic acid, p-toluene sulfonic acid, benzene sulfonic acid, 2-nitrobenzenesulfonic acid, 2,5-dichlorobenzene sulfonic acid, (−)-10-camphorsulfonic acid, (+)-camphor-10-sulfonic acid, p-chlorobenzene sulfonic acid, methanesulfonic acid, and combinations thereof.

13. The method of claim 10 , wherein the coupling reagent comprises a reagent selected from the group consisting of a carbodiimide reagent, a phosphonium reagent, a uronium reagent, an immonium reagent, an imidazolium reagent, an organophosphorus reagent, an acid chloride reagent, a chloroformate reagent, a pyridinium reagent, and combinations thereof.

14. The method of claim 10 , wherein the reacting occurs in the presence of a tertiary amine base selected from the group consisting of N,N-diisopropylethylamine (“DIEA”), triethylamine (“TEA”), N-methylmorpholine (“NMM”), and combinations thereof.

15. The method of claim 10 , wherein the NAPA is formed by admixing 3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (“NAPH”):

and a base to form NAPA:

wherein R 1 is Br, Cl, I, or OTf and
R 2 is COOH or C 1-3 alkyl ester, and
when R 2 is C 1-3 alkyl ester, the method of forming the NAPA further comprises hydrolyzing the C 1-3 alkyl ester to form an acid.

16. The method of claim 15 , wherein R 2 is COOH.

17. The method of claim 15 , wherein the base is selected from the group consisting of KOtBu, NaOtBu, LiOtBu, Mg(OtBu) 2 , Al(OtBu) 3 , NaOSiMe 3 , Cs 2 CO 3 , potassium bis(trimethylsilyl)amide (“KHMDS”), sodium bis(trimethylsilyl)amide (“NaHMDS”), lithium bis(trimethylsilyl)amide (“LiHMDS”), and combinations thereof.

18. The method of claim 10 , wherein the PYRH is formed by
(i) admixing

and a catalyst to form an intermediate:

wherein:
(a) Y is F, Cl, Br, I, or OTf, and Z comprises boronic acid, boronic ester, magnesium, zinc, zirconium, tin, or silicon; or
(b) Y comprises boronic acid, boronic ester, magnesium, zinc, zirconium, tin, or silicon, and Z is F, Cl, Br, I, or OTf; and

(ii) admixing

and H 2 NNH 2 , under conditions sufficient to form PYRH:

19. The method of claim 18 , wherein the catalyst comprises palladium (0), palladium (II), nickel, copper, iron, or combinations thereof.

20. The method of claim 18 , wherein the admixing in step (i) occurs in the presence of a base.

21. The method of claim 18 , wherein Y is Cl, Br, I, or OTf, and Z comprises boron, magnesium, zinc, zirconium, tin, or silicon.

22. The method of claim 21 , wherein Z comprises boronic acid, boronic ester, or boronate.

23. The method of claim 18 , wherein Y comprises boron, magnesium, zinc, zirconium, tin, or silicon, and Z is Cl, Br, I, or OTf.

24. The method of claim 23 , wherein Y comprises boronic acid, boronic ester, or boronate.

25. The method of claim 18 , wherein the admixing in step (i) occurs in the presence of a phase transfer catalyst.

26. The method of claim 15 , wherein the NAPH is formed by
(i) admixing a methylnicotinate of Formula (I):

wherein R 3 is Cl, Br, or I, and R 4 is alkyl;
with 1,3,5-triazine, and a base to form a naphthyridinone of Formula (II):

and
(ii) admixing the naphthyridinone of Formula (II) with methoxyethanol, a base, and a copper (I) catalyst, under conditions sufficient to form NAPH:

Assignees

• Amgen Inc
• Amgen Inc

Inventors

• Bio Matthew
• Fang Eric
• Milne Jacqueline E
• Wiedemann Sean
• Wilsily Ash

Classifications

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title