US 6,982,335 B2
Synthesis of substituted thiazoline carboxylic acids
Mukund S. Chorghade, Natick, Mass. (US); Rayomand H. Gimi, Chelmsford, Mass. (US); Peter D. McDonnell, Edmunds (United Kingdom); and Paul Wolstenholme-Hogg, Haverhill (United Kingdom)
Assigned to Genzyme Corporation, Cambridge, Mass. (US)
Filed on May 15, 2003, as Appl. No. 10/439,263.
Claims priority of provisional application 60/392833, filed on Jun. 27, 2002.
Claims priority of provisional application 60/381012, filed on May 15, 2002.
Claims priority of provisional application 60/381021, filed on May 15, 2002.
Claims priority of provisional application 60/380894, filed on May 15, 2002.
Claims priority of provisional application 60/380910, filed on May 15, 2002.
Claims priority of provisional application 60/380880, filed on May 15, 2002.
Claims priority of provisional application 60/381017, filed on May 15, 2002.
Claims priority of provisional application 60/380895, filed on May 15, 2002.
Claims priority of provisional application 60/380903, filed on May 15, 2002.
Claims priority of provisional application 60/381013, filed on May 15, 2002.
Claims priority of provisional application 60/380878, filed on May 15, 2002.
Claims priority of provisional application 60/380909, filed on May 15, 2002.
Prior Publication US 2004/0082796 A1, Apr. 29, 2004
Int. Cl. C07D 277/56 (2006.01)
U.S. Cl. 548—201 30 Claims
 
1. A method of preparing an alkylated thiazoline carboxylic acid or a derivative thereof represented by Structural Formula (I):
OG Complex Work Unit Drawing
or a salt thereof,wherein R1 is a substituted or unsubstituted alkyl group;
each R2 is, independently, —H or a substituted or unsubstituted alkyl group;
R3 is —H, a substituted or unsubstituted alkyl group or a carboxyl protecting group; and
n is an integer from 1 to 5,
the method comprising:
(a) coupling a compound represented by Structural Formula (II):
OG Complex Work Unit Drawing
 wherein each R4 is, independently, a substituted or unsubstituted alkyl group
and n is an integer from 1 to 5,
 with a cysteine ester represented by Structural Formula (III):
OG Complex Work Unit Drawing
wherein A is an anion and R5 is a substituted or unsubstituted alkyl group,
 thereby forming a substituted thiazoline carboxylic acid ester represented by Structural Formula (IV):
OG Complex Work Unit Drawing
(b) optionally, hydrolyzing the substituted thiazoline carboxylic acid ester to form a substituted thiazoline carboxylic acid represented by Structural Formula (V):
OG Complex Work Unit Drawing
(c) optionally, protecting the carboxyl group of the substituted thiazoline carboxylic acid to form a protected thiazoline carboxylic acid represented by Structural Formula (VI):
OG Complex Work Unit Drawing
wherein R6 is a carboxyl protecting group;
(d) alkylating the optionally protected thiazoline carboxylic acid represented by Structural Formula (VII):
OG Complex Work Unit Drawing
wherein R4 and n are as defined above and R7 is —H, R5 or R6,
 with a compound having the formula R1-L, wherein R1 is defined as above and L is a leaving group, in the presence of a phase transfer catalyst to form an alkylated optionally protected thiazoline carboxylic acid represented by Structural Formula (VIII):
OG Complex Work Unit Drawing
(e) optionally, hydrolyzing the optionally protected alkylated thiazoline carboxylic acid and cleaving ether groups,
thereby forming the compound represented by Structural Formula (I).