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

Patent metadata

Field	Value
Publication number	US-2016347769-A1
Application number	US-201414900976-A
Country	US
Kind code	A1
Filing date	Jun 24, 2014
Priority date	Jun 24, 2013
Publication date	Dec 1, 2016
Grant date	—

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

1 . 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”):

under conditions sufficient to form (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 reacting comprises contacting the HYDZ with a thiophosphetane compound.

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

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

5 . The method of claim 2 further comprising contacting Compound A with a water-rich solvent having a pH of at least 7 under conditions sufficient to form the monohydrate form of Compound A.

6 . The method of claim 1 , wherein the reacting comprises contacting the HYDZ with a phosphorus (V) dehydrating agent.

7 . The method of claim 6 , 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.

8 . The method of claim 7 , 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.

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

10 . The method of claim 9 , 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.

11 . The method of claim 1 further comprising crystallizing Compound A in a solution comprising alcohol and water, under conditions sufficient to form a monohydrate form of Compound A:

12 . 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-1H-pyrazl-4-yl)pyridine (“PYRH”):

and a coupling reagent, and under conditions sufficient to form HYDZ:

13 . The method of claim 12 , wherein NAPA is a salt comprising HCl, HBr, sulfonic acid, diisopropylamine, or potassium.

14 . The method of claim 13 , 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.

15 . The method of claim 12 , 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.

16 . The method of claim 12 , 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.

17 . The method of claim 12 , wherein the NAPA is formed by admixing 3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (“NAPH”):

and a base, under conditions sufficient 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.

18 . The method of claim 17 , wherein R 2 is COOH.

19 . The method of claim 17 , 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.

20 . The method of claim 12 , wherein the PYRH is formed by
(i) admixing

 and a catalyst, under conditions sufficient 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:

21 . The method of claim 20 , wherein the catalyst comprises palladium (0), palladium (II), nickel, copper, iron, or combinations thereof.

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

23 . The method of claim 20 , wherein Y is Cl, Br, I, or OTf, and Z comprises boron, magnesium, zinc, zirconium, tin, or silicon.

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

25 . The method of claim 20 , wherein Y comprises boron, magnesium, zinc, zirconium, tin, or silicon, and Z is Cl, Br, I, or OTf.

26 . The method of claim 25 , wherein Y comprises boronic acid, boronic ester, or boronate.

27 . The method of claim 20 , wherein the admixing in step (i) occurs in the presence of a phase transfer catalyst.

28 . The method of claim 17 , 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 a

Assignees

• 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