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
Life of this patent
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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).
Claims23
A method of making a compound of Formula (VII), or a stereoisomer or a salt thereof:
- wherein Ra is —N(C1-4 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.
A method of making a compound of Formula (IX), or a stereoisomer or a salt thereof:
- wherein Ra is —N(C1-4 alkyl)2;
- comprising contacting a compound of Formula (VII) or a salt thereof:
- wherein Ra is —N(C1-4 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.
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 R7—OH solution, wherein R7 are independently C1-6 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.
A method of making a compound of Formula (XII), 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;
- and
- R11 is independently Br, Cl or I;
- comprising contacting a compound of Formula (XIII) or a salt thereof:
- wherein:
- R8, R9, R10 and R11 are the same as above in the Formula (XII) and R1la 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.
A method of making a compound of Formula (XIVc), 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;
- and
- R12 is C1-4 alkyl;
- comprising (1) contacting a compound of Formula (I):
- wherein R1 is C1-6 alkyl;
- and R2 and R2a are halogen;
- with an organometallic reagent and with or without an inorganic reagent in Solvent 8 that is a polar aprotic, or nonpolar solvent, or a solvent mixture thereof;
- for a time and at a temperature sufficient for metal-halogen exchange;
- then
- (2) contacting a compound of Formula (XII) or a stereoisomer or a salt:
- wherein:
- R8 and R9 are independently N, CH or C(C1-6 alkyl);
- R10 is independently C1-4 alkyl or halogen;
- and
- R11 is Br or Cl;
- with the metal-halogen exchanged product and a Palladium catalyst in Solvent 8;
- for a time and at a temperature sufficient for C—C coupling;
- and
- (3) contacting a metal binding agent in Solvent 8;
- for a time and at a temperature sufficient for reaction quench to produce the compound of Formula (XIVc) or a stereoisomer or a salt thereof.
A compound of Formula (VII), or a salt thereof:
- wherein Ra is —N(C1-4 alkyl)2.
A compound of Formula (IX) or a stereoisomer or a salt thereof:
- wherein Ra is —N(C1-4 alkyl)2.
A compound of Formula (XII) 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;
- and
- R11 is independently Br, Cl or I.
Dependencies are inferred from the claim text.