Patent ID: 7910774

Claim:
A method for preparing a compound of the formula (A) wherein R 1 is halogen, C 1-6 halogenalkyl, C 1-6 alkoxy-C l-6 alkyloxy or C 1-6 alkoxy-C 1-6 alkyl; R 2 is halogen, C l-4 alkyl or C l-4 alkoxy; R 3 and R 4 are independently branched C 3-6 alkyl; and R 5 is cycloalkyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkanoyloxy-C 1-6 alkyl, C 1-6 aminoalkyl, C 1-6 alkylamino-C 1-6 alkyl, C 1-6 dialkylamino-C 1-6 alkyl, C 1-6 alkanoylamino -C 1-6 alkyl, HO(O)C—C 1-6 alkyl, C 1-6 alkyl-O—(O)C—C 1-6 alkyl, H 2 N—C(O)—C 1-6 alkyl, C 1-6 alkyl-HN—C(O)—C 1-6 alkyl or (C 1-6 alkyl) 2 N—C(O)—C 1-6 alkyl; or a pharmaceutically acceptable salt thereof; which method comprises at least one of the following steps: (i) Lactam ring opening of the N- and O-protected 5-hydroxymethyl-3-substituted pyrrolidinone of formula (IV) with an organometallic compound of formula (XIIc) to afford the substituted benzoyl compound of formula (V); wherein R 3 is as defined above, R 7 is an O-protecting group and R 8 is an N-protecting group; with an organometallic compound of formula (XIIc) wherein R1 and R2 are defined above; to afford the substituted benzoyl compound of formula (V) wherein R 1 , R 2 , R 3 , R 7 and R 8 are defined above; (ii) reduction of the benzylic carbonyl group of compound of formula (V) followed by selective removal of the O-protecting group to afford the compound of formula (VI) with a free hydroxyl group; wherein R 1 , R 2 , R 3 and R 8 are defined above; (iii) oxidation of the hydroxyl group of the compound of formula (VI) to a carboxylic acid group to afford the compound of formula (VII); wherein R 1 , R 2 , R 3 and R 8 are defined above; (iv) activation of the carboxylic acid of formula (VII) to obtain the corresponding activated derivative of formula (VIIIa) wherein R 1 , R 2 , R 3 and R 8 are defined above and X is halogen, R 10 OC(O)O- in which R 10 is C 1-20 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkyl-C 1-6 alkyl, C 6-10 aryl or C 6-10 aryl-C 1-6 alkyl; Me(MeO)N—; or imidazolyl; (v) coupling the activated derivative of formula (VIIIa) with a chiral malonate derivative (VIIIb) wherein R4 is defined above, E is C(O))R 9 and R 9 is C 1-20 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkyl-C 1-6 alkyl, C 6-10 aryl , C 2-20 alkenyl or C 6-10 aryl-C 1-6 alkyl to obtain the compound of formula (IX); wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 9 and E are as defined above (vi) decarboxylation of the carboxylic ester groups E and simultaneous ester hydrolysis of the carboxylic ester to afford the carboxylic acid of formula (X); wherein R 1 , R 2 , R 3 , R 4 , R 8 are defined above and R′ is hydrogen or R 9 ; and (vi) conversion of the carboxylic acid of formula (X) to the compound of formula (A).