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US 2026/0184685 A1Published application
Process for preparing carbamoyloxymethyl triazole cyclohexyl acid compounds
AssigneeBristol-Myers Squibb Company
InventorsRICHARD J. FOX, CARLOS A. GUERRERO, MICHAEL DUMMELDINGER, DIMITRI SKLIAR, HARSHKUMAR PATEL, YICHEN TAN, DAVID THOMAS GEORGE, SHANE MCKENNA, CANDICE LEE JOE, MICHAEL J. SMITH
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Abstract
Improved methods and intermediates thereof for preparing carbamoyloxymethyl triazole cyclohexyl acid compounds are described. These compounds are useful as LPA antagonists.
Claims22
A method of making a compound of Formula (I):
- wherein R1 is C1-6 alkyl;
- and R2 and R2a are halogen;
- comprising contacting a compound of Formula (III):
- wherein R1 is C1-6 alkyl;
- R2 is halogen;
- and R3 is halogen;
- with Reagent 2 that is an organolithium, in Solvent 2 that is a polar aprotic or nonpolar aprotic solvent, or a solvent mixture thereof;
- for a time and at a temperature sufficient for lithium halogen exchange;
- followed by an alkylating agent in Solvent 3 that is a polar, polar aprotic, or nonpolar aprotic solvent, or a solvent mixture thereof;
- for a time and at a temperature sufficient for alkylation;
- followed by a strong acid to produce the compound of Formula (I).
8 more elements
A method of making a compound of Formula (IV) or a salt thereof:
- wherein Ra is —N(C1-4 alkyl)2;
- comprising contacting a compound of Formula (V):
- wherein R6 is halogen;
- with a compound of Formula (VI) or a salt thereof:
- wherein Ra is —N(C1-4 alkyl)2;
- in presence of an inorganic base and a phase-transfer catalyst in Solvent 4 that is a polar aprotic solvent, or a solvent mixture thereof;
- for a time and at a temperature sufficient for reaction completion to produce the compound of Formula (IV) or a salt thereof.
4 more elements
A method of making a compound of Formula (IVb):
- comprising contacting a compound of Formula (Va):
- with a compound of Formula (VIa):
- in presence of KHCO3 and (Et)4NBr in DMF;
- for 4 to 72 hours and at 25 to 35° C. sufficient for reaction completion to produce the compound of Formula (IVb).
1 more element
A method of making a compound of Formula (XVI), or a stereoisomer or a salt thereof:
- wherein:
- R8 and R9 are independently N, CH or C(C1-6 alkyl);
- R10 is independently C1-4 alkyl or halogen;
- R12 is C1-4 alkyl;
- and
- R14 and R14a are independently C1-6 alkyl;
- comprising contacting a compound of Formula (XV) or a stereoisomer or a salt thereof:
- with a compound of Formula (XVII) or a salt thereof:
- wherein R14 and R14a are independently C1-6 alkyl;
- in presence of a metal alkoxide in Solvent 9 that is a polar protic or polar aprotic solvent, or a solvent mixture thereof;
- for a time and at a temperature sufficient for carbamate formation to produce the compound of Formula (XVI) or a stereoisomer or a salt thereof.
8 more elements
The method of claim 10, for making a compound of Formula (XVIb) or a salt thereof:
- comprising contacting a compound of Formula (XVb) or a salt thereof:
- with a compound of Formula (XVIIa) or a salt thereof:
- in presence of KOtBu (20 wt % in THF) in Solvent 9 selected from t-AmOH, DMF, THF, CH3CN, MEK and a solvent mixture thereof;
- for a time and at 20-75° C. sufficient for carbamate formation to produce the compound of Formula (XVIb) or a salt thereof.
1 more element
A compound of Formula (IVa) or a salt thereof:
A compound of Formula (XIV) or a stereoisomer or a salt thereof:
- wherein:
- R8 and R9 are independently N, CH or C(C1-6 alkyl);
- R10 is independently C1-4 alkyl or halogen;
- R12 is C1-4 alkyl;
- and
- R13 is independently H, C1-4 alkyl or benzyl.
3 more elements
A compound of Formula (XVIIa):
A method of making a compound of Formula (XVII), or a salt thereof:
- wherein R14 and R14a are independently C1-6 alkyl;
- comprising contacting a compound of Formula (XVIII):
- with NHR14R14a in presence of Solvent 10 that is a polar protic, aprotic, or nonpolar solvent or a solvent mixture thereof;
- for a time and at −5 to 25° C. sufficient for carboxamide formation to produce the compound of Formula (XVII).
1 more element
A method of making a compound of Formula (Xa) or a salt thereof:
- comprising (1) contacting a compound of Formula (XIX) or a salt thereof:
- with an ene reductase biocatalyst in the presence of an aqueous phosphate buffer, GDH, NADPH and glucose with or without an organic cosolvent selected from DMSO, IPA, dioxane, acetone and a mixture thereof;
- for a time and at a temperature sufficient to produce the compound of Formula (XX);
- followed by (2) addition of a keto reductase biocatalyst with or without an organic solvent selected from DMSO, IPA, dioxane, acetone and a mixture thereof;
- for additional time and at a temperature sufficient to produce the compound of Formula (Xa) or a salt thereof.
2 more elements
A method of making a compound of Formula (Xa) or a salt thereof:
- comprising contacting a compound of Formula (XIX) or a salt thereof:
- with a combination of an ene reductase biocatalyst with a keto reductase biocatalyst in the presence of an aqueous phosphate buffer, GDH, NADPH and glucose with or without an organic solvent selected from DMSO, IPA, dioxane, acetone and a mixture thereof;
- for a time and at a temperature sufficient to produce the compound of Formula (Xa) or a salt thereof.
A method of making a compound of Formula (Xa) or a salt thereof:
- comprising (1) contacting a compound of Formula (XXI) thereof:
- with a sulfonyl chloride reagent in an aprotic polar solvent and an inorganic or organic base;
- for a time and at a temperature sufficient for O-sulfonylation to produce the compound of Formula (XXII);
- (2) either (a) contacting the compound of Formula (XXII) with a transition-metal catalyst, a phosphine ligand and an organic or inorganic base in the presence of (C1-4 alkyl)-OH purged with carbon monoxide;
- for a time, at a temperature and pressure sufficient for carbonylation to produce the compound of Formula (XXIII);
- then followed by contacting a compound of Formula (XXIII) with an aqueous base to produce a compound of Formula (XIX) or a salt thereof:
- or (b) contacting the compound of Formula (XXII) with a transition-metal catalyst, a phosphine ligand in presence of an inorganic or organic base, in water and another polar aprotic solvent;
- purged with carbon monoxide;
- for a time, at a temperature and pressure sufficient for carbonylation to produce the compound of Formula (XIX) or a salt thereof;
- (3) contacting the compound of Formula (XIX) or a salt thereof with an ene reductase biocatalyst in the presence of an aqueous phosphate buffer, GDH, NADPH and glucose with or without an organic cosolvent selected from DMSO, IPA, dioxane, acetone and a mixture thereof;
- for a time and at a temperature sufficient to produce the compound of Formula (XX);
- followed by (4) addition of a keto reductase biocatalyst with or without an organic solvent selected from DMSO, IPA, dioxane, acetone and a mixture thereof;
- for additional time and at a temperature sufficient to produce the compound of Formula (Xa) or a salt thereof.
10 more elements
A method of making a compound of Formula (Xa) or a salt thereof:
- comprising (1) contacting a compound of Formula (XXI) thereof:
- with a sulfonyl chloride reagent in an aprotic polar solvent and an inorganic or organic base;
- for a time and at a temperature sufficient for O-sulfonylation to produce the compound of Formula (XXII);
- (2) either (a) contacting the compound of Formula (XXII) with a transition-metal catalyst, a phosphine ligand and an organic amine base in the presence of (C1-4 alkyl)-OH purged with carbon monoxide;
- for a time, at a temperature and pressure sufficient for carbonylation to produce the compound of Formula (XXIII);
- then followed by contacting a compound of Formula (XXIII) with an aqueous base to produce a compound of Formula (XIX) or a salt thereof:
- or (b) contacting the compound of Formula (XXII) with a transition-metal catalyst, a phosphine ligand in presence of an inorganic or organic base, in water and another polar aprotic solvent;
- purged with carbon monoxide;
- for a time and at a temperature and carbon monoxide pressure sufficient for carbonylation to produce the compound of Formula (XIX) or a salt thereof;
- (3) contacting a compound of Formula (XIX) or a salt thereof, with a combination of an ene reductase biocatalyst with a keto reductase biocatalyst in the presence of an aqueous phosphate buffer, GDH, NADPH and glucose with or without an organic solvent selected from DMSO, IPA, dioxane, acetone and a mixture thereof;
- for a time and at a temperature sufficient to produce the compound of Formula (Xa) or a salt thereof.
8 more elements
Dependencies are inferred from the claim text.