Processes for preparing dihydropyrimidine derivatives and intermediates thereof

A compound having Formula (V), or a tautomer thereof having Formula (V1), or a salt thereof, or a combination thereof,

• wherein each R1 is independently F;
• R2 is Cl or Br;
• R3b is C1-6alkoxy, C1-6alkylamino, C3-6cycloalkoxy, C3-6cycloalkylamino, C1-6 alkyl-C3-6-cycloalkoxy, C6-10arylamino, benzylamino, or benzyloxy;
• R3a is H or C1-3 alkyl;
• each R9 is independently H, halo, C1-4 alkyl, C1-4alkylthio, C1-4haloalkyl, C3-6cycloalkyl, —(CR7R7a)m—C(═O)—N(R8R8a), or —(CR7R7a)m—C(═O)O—R8;
• each R7a and R7 is independently H, halo, C1-4 alkyl, C1-4haloalkyl, —(CH2)m—OH, or —(CH2)m—C(═O)O—R8;
• or R7 and R7a, together with the carbon atom to which they are attached, form a C3-6cycloalkyl group, C2-9 heterocyclylgroup, or —(C═O)—;
• each R8 and R8a is independently H, C1-4 alkyl, amino-C1-4-alkyl, C1-4alkoxy, C1-6 alkyl-S(═O)q—, C6-10 aryl, C1-9heteroaryl, C3-6cycloalkyl, C2-9heterocyclyl, C6-10 aryl-C1-6-alkyl, C1-9 heteroaryl-C1-6-alkyl, C3-6 cycloalkyl-C1-4-alkyl, C2-9 heterocyclyl-C1-6-alkyl, C2-9heterocyclyl-S(═O)q—, C1-9heteroaryl-S(═O)q—, C3-6cycloalkyl-S(═O)q—, C6-10 aryl-S(═O)q—, —(CH2)m—OH, —(CH2)m—C(═O)O—(CH2)m—H, or —(CH2)m—OC(═O)—(CH2)m—H;
• each m is independently 0, 1, 2, 3, or 4;
• R10 is H or deuterium;
• f is 1, 2, 3, or 4;
• Z is —O—, —S—, —S(═O)t, or —N(R4)—;
• each of j and t is independently 0, 1, or 2;
• and
• R4 is H or C1-4 alkyl.

A process for preparing adihydropyrimidine compound having Formula (I), or a tautomer thereof having Formula (Ia),

• wherein each R1 is F;
• R2 is Cl or Br;
• R3 is C1-4 alkyl;
• Z is —O—, —S—, —S(═O)t—, or —N(R4)—;
• Y is —O—, —S—, —S(═O)t—, —(CH2)q—, or —N(R5)—;
• each t and q is independently 0, 1, or 2;
• each of R4 and R5 is independently H or C1-4 alkyl;
• each R6 is independently H, deuterium, halo, C1-4 alkyl, C1-4haloalkyl, amino, C1-4alkylamino, C1-4alkoxy, nitro, triazolyl, tetrazyl, —(CR7R7a)m—OH, —(CR7R7a)m—C(═O)O—R8, —(CR7R7a)t—N(R8a)2, —S(═O)qOR8a, —(CR7R7a)m—S(═O)qN(R8a)2, —(CR7R7a)m—C(═O)O—(CR7R7a)m—OC(═O)O—R8, —(CR7R7a)m—C(═O)O—(CR7R7a)m—OC(═O)—R8, —(CR7R7a)m—C(═O)O—(CR7R7a)m—C(═O)O—R8, —(CR7R7a)m—OC(═O)—R8, or —(CR7R7a)m—C(═O)—N(CR8R8a);
• each R7a and R7 is independently H, halo, C1-4 alkyl, C1-4haloalkyl, —(CH2)m—OH, or —(CH2)m—C(═O)O—R8, or R7a and R7, together with the carbon atom to which they are attached, form a C3-6cycloalkyl group, C2-9 heterocyclylgroup, or —(C═O)—;
• each R8 and R8a is independently H, C1-4 alkyl, amino-C1-4-alkyl, C1-4alkoxy, C1-6 alkyl-S(═O)q—, C6-10 aryl, C1-9heteroaryl, C3-6cycloalkyl, C2-9heterocyclyl, C6-10 aryl-C1-6-alkyl, C1-9 heteroaryl-C1-6-alkyl, C3-6 cycloalkyl-C1-4-alkyl, C2-9 heterocyclyl-C1-6-alkyl, C2-9heterocyclyl-S(═O)q—, C1-9heteroaryl-S(═O)q—, C3-6cycloalkyl-S(═O)q—, C6-10 aryl-S(═O)q—, —(CH2)m—OH, —(CH2)m—C(═O)O—(CH2)m—H, or —(CH2)m—OC(═O)—(CH2)m—H;
• each R9 is independently H, halo, C1-4 alkyl, C1-4 alkylthio, C1-4haloalkyl, C3-6cycloalkyl, —(CR7R7a)m—C(═O)—N(R8R8a), or —(CR7R7a)m—C(═O)O—R8;
• R10 is H or deuterium;
• n is 0, 1, 2, 3, 4, or 5;
• each m is independently 0, 1, 2, 3, or 4;
• f is 1, 2, 3, or 4;
• and
• j is 0, 1, or 2;
• wherein the process comprises the steps of:
• step (1):
• reacting an amidine compound of Formula (II), or a salt thereof
• with an aldehyde compound of Formula (III)
• and a compound of Formula (IV)
• to obtain a compound of Formula (V),
• step(2):
• forming a compound of Formula (X) from the compound of Formula (V) by means of a transesterification,
• wherein R3b is C1-6alkoxy, C1-6alkylamino, C3-6cycloalkoxy, C3-6-cycloalkylamino, C1-6 alkyl-C3-6-cycloalkoxy, C6-10arylamino, benzylamino, or benzyloxy;
• and
• R3a is H or C1-3 alkyl;
• and
• step (3):
• halogenating the compound of Formula (X) to form a halide;
• and then reacting the halide with a compound of Formula (VI), or a salt thereof to obtain a compound of Formula (I) or Formula (Ia),