Methods of making nicotinic acid derivatives

A process for preparing a compound of the formula

• wherein
• R1 is selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C10 aryl, wherein each hydrogen atom in C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C6-C10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bronco, OC1C8 alkyl, —N(C1-C8 alkyl)2, or SC1C8 alkyl;
• and
• each of R3 and R4 is independently selected from the group consisting of H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C10 aryl, wherein each hydrogen atom in C1C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C6-C10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC1C8 alkyl, —N(C1-C8 alkyl)2, or SC1C8 alkyl;
• comprising
• i. contacting a compound of the formula
• wherein each of R3 and R4 is independently selected from the group consisting of H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C10 aryl, wherein each hydrogen atom in C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C6-C10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bronco, OC1C8 alkyl, —N(C1-C8 alkyl)2, or SC1C8 alkyl;
• with a compound of the formula
• wherein
• R1 is selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C10 aryl, wherein each hydrogen atom in C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C6-C10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC1C8 alkyl, —N(C1-C8 alkyl)2, or SC1C8 alkyl;
• and
• R2 is a C1-C8 alkyl;
• in the presence of a base to provide a compound of the formula
• wherein
• R1 is selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C10 aryl, wherein each hydrogen atom in C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C6-C10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bronco, OC1C8 alkyl, —N(C1-C8 alkyl)2, or SC1C8 alkyl;
• R2 is a C1-C8 alkyl;
• and
• each of R3 and R4 is independently selected front the group consisting of H, deuterium, C1C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C10 aryl, wherein each hydrogen atom in C1C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C6-C10 aryl is independently optionally substituted with deuterium, fluoro, chloro, promo, OC1 C8 alkyl, —N(C1-C8 alkyl)2, or SC1C8 alkyl.

A process for preparing a compound of the formula

• wherein
• R1 is selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C10 aryl, wherein each hydrogen atom in C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C6-C10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC1C8 alkyl, —N(C1-C8 alkyl)2, or SC1C8 alkyl;
• and
• each of R3 and R4 is independently selected from the group consisting of H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C10 aryl, wherein each hydrogen atom in C1C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C6-C10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC1C8 alkyl, —N(C1-C8 alkyl)2, or SC1C8 alkyl;
• comprising
• ii. contacting a compound of the formula
• wherein
• R1 is selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C10 aryl, wherein each hydrogen atom in C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C6-C10 an is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC1C8 alkyl, —N(C1-C8 alkyl)2, or SC1C8 alkyl;
• R2 is a C1-C8 alkyl;
• and
• each of R3 and R4 is independently selected front the group consisting of H, deuterium, C1-C8 alkyl, C2 -C8 alkenyl, C2 -C8 alkynyl, and C6-C10 aryl, wherein each hydrogen atom in C1C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C6-C10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC1C8 alkyl, —N(C1-C8 alkyl)2, or SC1C8 alkyl;
• with an oxidizing agent and an additive to provide a compound of the formula
• wherein
• R1 is selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C10 aryl, wherein each hydrogen atom in C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C6-C10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC1C8 alkyl, —N(C1-C8 alkyl)2, or SC1C8 alkyl;
• R2 is a C1-C8 alkyl;
• and
• each of R3 and R4 is independently selected from the group consisting of H, deuterium, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C6-C10 aryl, wherein each hydrogen atom in C1C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C6-C10 aryl is independently optionally substituted with deuterium, fluoro, chloro, bromo, OC1C8 alkyl, —N(C1-C8 alkyl)2, or SC1C8 alkyl.