Patent EA-001761-B1 (EA)
Title: Process for preparing eprosartan
Inventor: MATSUOKA RICHARD T
IPC: A61K31/4164
Filed: 1998-02-13
Abstract: 1. A process for the preparation of eprosartan, a compound of formula (I)   or a pharmaceutically acceptable salt thereof, which process comprises the steps of: (i) treating a compound of formula (II):   with base, followed by reaction with a regioselective nitrogen-protecting reagent; (ii) reacting the compound of formula (E):   wherein R1 is a nitrogen protecting group either consisting of (1) an ethylene bridge connecting the nitrogen to an electron-withdrawing group, such as an ester (COOR", where R" = C1-4alkyl), acid, carbonyl, nitrile, sulfone, or sulfoxide, or (2) a methylene bridge connecting the nitrogen to a pivalate, 2-(trimethylsilyl)ethoxy, methoxy, tert-butoxy, or benzyloxy, with a compound of formula (IV):   wherein R' is C 1-4alkyl, in the presence of a catalyst; and (iii) reacting the compound of formula (V):   wherein R' and R1 are as defined above, with a compound of formula (VI):   wherein R"' is C1-4alkyl and X is halo or OR*, in which R* is CH3SO2- or p-CH3C6H4SO2-, at elevated temperatures; and thereafter hydrolyzing the R' and R"' ester groups and removing the N-3 protecting group, and optionally forming a pharmaceutically acceptable salt. 2. The process according to Claim 1 for the preparation of eprosartan, a compound of formula (I):   or a pharmaceutically acceptable salt thereof, which process comprises the steps of: (i) treating a compound of formula (II):   with base, followed by reaction with a C1-4alkyl ester derivative of acrylic acid; (ii) reacting the compound of formula (IIIb):   wherein R'' is C1-4alkyl, with a compound of formula (IV):   wherein R' is C1-4alkyl, in the presence of a catalyst; and (iii) reacting the compound of formula (Vb):   wherein R' and R'' are as defined above, with a compound of formula (VI):   wherein R''' is C1-4alkyl and X is halogen, at elevated temperatures; and thereafter hydrolyzing the R' and R''' ester groups and removing the N-3 protecting group, and optionally forming a pharmaceutically acceptable salt. 3. The process according to Claim 1 for the preparation of eprosartan, a compound of formula (I):   or a pharmaceutically acceptable salt thereof, which process comprises the steps of: (i) treating a compound of formula (II):   with 1,8-diazabicyclo[5.4.0]undec-7-ene, followed by reaction with methyl acrylate; (ii) reacting the compound of formula (IIIa):   with a compound of formula (IVa):   in the presence of piperidine; and (iii) reacting the compound of formula (Va):   with a compound of formula (VIa):   at elevated temperatures; and thereafter hydrolyzing the ester groups and removing the N-3 protecting group, and optionally forming a pharmaceutically acceptable salt. 4. A process for the preparation of eprosartan, a compound of formula (I):   or a pharmaceutically acceptable salt thereof, which process comprises the steps of: (i) reacting a compound of formula (II):   with a compound of formula (IV):   wherein R' is C1-4alkyl, in the presence of a catalyst; (ii) treating the compound of formula (VII):   with base, followed by reaction with a regioselective nitrogen-protecting reagent; and (iii) reacting the compound of formula (V):   wherein R' is as defined above and R1 is a nitrogen-protecting group either consisting of (1) an ethylene bridge connecting the nitrogen to an electron-withdrawing group, such as an ester (COOR'', where R''=C1-4alkyl), acid, carbonyl, nitrile, sulfone or sulfoxide, or (2) a methylene bridge connecting the nitrogen to a pivalate, 2-(trimethylsilyl)ethoxy, methoxy tert-butoxy or benzyloxy, with a compound of formula:   wherein R'' is C1-4alkyl and X is halogen or OR*, in which R* is CH3SO2- or p-CH3C6H4SO2-, at elevated temperatures; and thereafter hydrolyzing the R' and R''' ester groups and removing the N-3 protecting group, and optionally forming a pharmaceutically acceptable salt. 5. A compound which is   wherein R'' is C1-4alkyl. 6. The compound according to Claim 5 which is   7. A compound which is   wherein R' and R'' independently of one another are C1-4alkyl. 8. The compound according to Claim 7 which is   9. A compound which is   10. The compound according to Claim 9 which is