Process for preparing carbamoyloxymethyl triazole cyclohexyl acid compounds

Patent metadata

Field	Value
Publication number	US-12459904-B2
Application number	US-202017603659-A
Country	US
Kind code	B2
Filing date	Apr 14, 2020
Priority date	Apr 16, 2019
Publication date	Nov 4, 2025
Grant date	Nov 4, 2025

Abstract

Improved methods and intermediates thereof for preparing carbamoyloxy methyl triazole cyclohexyl acid compounds are described. These compounds are useful as LPA antagonists. Formula (I).

First claim

What is claimed is:

1 . A method of making a compound of Formula (VII), or a stereoisomer or a salt thereof:

wherein R a is —N(C 1-4 alkyl) 2 ,
comprising contacting a compound of Formula (VIII) or a salt thereof:

in presence of

and a co-catalyst selected from

and 4-DMAP, with or without an aqueous base, in Solvent 5 that is a nonpolar solvent, or a solvent mixture thereof;
for a time and at a temperature sufficient for reaction completion to produce the compound of Formula (VII) or a stereoisomer or a salt thereof.

2 . The method of claim 1 , for making a compound of Formula (VIIa) or a salt

comprising contacting a compound of Formula (VIII) or a salt thereof;
in presence of

with or without aqueous KOH, in Solvent 5 selected from toluene, CH 2 Cl 2 , trifluorotoluene, 1,2-dichlorobenzene, and a solvent mixture thereof;
for a time and at 25 to 35° C. sufficient for reaction completion to produce the compound of Formula (VIIa) or a salt thereof.

3 . The method of claim 2 , for making a compound of Formula (VIIb):

comprising contacting a compound of Formula (VIII) or a salt thereof;
in presence of

with or without aqueous KOH, in toluene;
for 24 to 48 hours and at 25 to 35° C. sufficient for reaction completion to produce the compound of Formula (VIIb).

4 . A method of making a compound of Formula (IX), or a stereoisomer or a salt thereof:

wherein R a is —N(C 1-4 alkyl) 2 ;
comprising contacting a compound of Formula (VII) or a salt thereof:

wherein R a is —N(C 1-4 alkyl) 2 ;
with a transition-metal catalyst in presence of a diprotic acid in Solvent 6 that is a protic or polar aprotic solvent or a solvent mixture thereof;
for a time and at a temperature sufficient for ketone reduction to produce the compound of Formula (IX) or a stereoisomer or a salt thereof.

5 . The method of claim 4 , for making a compound of Formula (IXa) or a salt thereof:

comprising contacting a compound of Formula (VIIa) or a salt thereof:

with a transition-metal catalyst selected from IrCl 4 , IrCl 4 *hydrate or [Ir(COD)Cl] 2 in presence of phosphorous acid in Solvent 6 selected from IPA, MeOH, EtOH, t-AmOH, H 2 O, NMP, DMF, DMAc, sulfolane, and a solvent mixture thereof;
for a time and at 65 to 100° C. sufficient for ketone reduction to produce the compound of Formula (IXa) or a salt thereof.

6 . The method of claim 5 , for making a compound of Formula (IXb):

comprising contacting a compound of Formula (VIIb):

with IrCl 4 *hydrate or [Ir(COD) Cl] 2 in presence of phosphorous acid in IPA/H 2 O or a solvent mixture thereof;
for 24 to 96 hours and at 80 to 85° C. sufficient for ketone reduction to produce the compound of Formula (IXb).

7 . A method of making a compound of Formula (Xa) or a salt thereof:

comprising (1) contacting a compound of Formula (IXa) or a salt thereof:

with Reagent 3 selected from NaOH, KOH, LiOH, tetraalkylammonium hydroxide, and a mixture thereof, in an aqueous R 7 —OH solution, wherein R 7 are independently C 1-6 alkyl;
for up to 48 hours at 80 to 85° C. sufficient for hydrolysis of all three ester moieties to produce the compound of Formula (XI);

wherein M is selected from a metal element selected from Li, Na, and K, and tetraalkylammonium;
(2) contacting an acid in a protic solvent; and
(3) contacting periodic acid in a protic solvent;
for up to 48 hours at 20-25° C. sufficient for oxidation to produce the compound of Formula (Xa) or a salt thereof.

8 . The method of claim 7 , for making a compound of Formula (Xa):

comprising (1) contacting a compound of Formula (IXb) or a salt thereof:

with NaOH in an aqueous IPA solution for at least 12 hours at 80 to 85° C. sufficient to produce the compound of Formula (XIa);

(2) contacting aqueous HCl; and
(3) contacting periodic acid in an aqueous IPA solution;
for up to 48 hours at 20-25° C. sufficient for oxidation to produce the compound of Formula (Xa).

9 . A method of making a compound of Formula (XII), or a stereoisomer or a salt thereof:

wherein: R 8 and R 9 are independently N, CH or C(C 1-6 alkyl);
R 10 is independently C 1-4 alkyl or halogen; and
R 11 is independently Br, Cl or I;
comprising contacting a compound of Formula (XIII) or a salt thereof:

wherein: R 8 , R 9 , R 10 and R 11 are the same as above in the Formula (XII) and R 1la is halogen;
with the compound of Formula (X) or a stereoisomer or a salt thereof:

in presence of a metal alkoxide in Solvent 7 that is a polar aprotic or nonpolar solvent, or a solvent mixture thereof;
for a time and at a temperature sufficient for reaction completion to produce the compound of Formula (XII) or a stereoisomer or a salt thereof.

10 . The method of claim 9 , for making a compound of Formula (XIIa) or a salt thereof:

comprising contacting a compound of Formula (XIIIa) or a salt thereof:

with the compound of Formula (Xa) or a salt thereof:

Assignees

• Bristol Myers Squibb Co

Inventors

• Fox Richard J
• Guerrero Carlos A
• Dummeldinger Michael
• Skliar Dimitri
• Patel Harshkumar
• Tan Yichen
• George David Thomas
• Mckenna Shane
• Joe Candice Lee
• Smith Michael J

Classifications

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D233/60

  with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms · CPC title

• C07C51/29

  with halogen-containing compounds which may be formed in situ · CPC title

• C07C51/12

  on an oxygen-containing group in organic compounds, e.g. alcohols · CPC title

• C07C51/09

  from carboxylic acid esters or lactones · CPC title