The Impact of a tert-Butyl Group

Ming Guo from Pfizer described the rapid development of a multi kilo scale synthesis of AG 3433, a third generation MMP inhibitor, and in particular the impact a t-butyl group had on the stereoselectivity of an alkylation step and the improved chemical selectivity and chemical stability in subsequent steps.  The first two stages of the synthesis are shown in Scheme 1, 4-cyano-4’-aminobiphenyl (prepared by nitration of 4-cyanobiphenyl, with the 2’-isomer being removed by crystallisation) is reacted with the substituted THF (3-MTHF) derivative to form the pyrrole acetic acid (45% overall yield from 3-MTHF), which was coupled with the oxazolidinone auxiliary.

Scheme 1
The success of the subsequent alkylation of the oxazolidinone with bromoacetate in THF depended on the choice of base and the ester used for the alkylation.  A survey of bases showed sodium hexamethyldisilazide gave the best ee, but the choice of ester had a significant effect on the outcome.  The tert-butyl ester gave product with the highest ee followed by the ethyl ester and then the benzyl ester (see table).

The final stages of the synthesis are shown in Scheme 2 – hydrolysis of the auxiliary, which proceeded without any racemisation when the tert-butyl ester was used.  The intermediate was purified as the dicyclohexylamine salt and then coupled with the aminolactone to give AG3433 after removal of the tert-butyl ester group.

A preliminary polymorph screen (acetonitrile, ethyl acetate, acetone, dichloromethane/methyl tert-butyl ether, heptane in various ratios) had been carried out, but only one form had been found.  During the cGMP campaign a problem was encountered with he level of an impurity.  The amount of impurity could be reduced to acceptable levels by treatment with toluene, but the subsequent crystallisation (the same procedure that had been used in the pilot runs) revealed a new polymorphic form.  Polymorph screening was resumed and a third form was found as well as an acetonitrile solvate.  Further work showed form II to the most stable form when crystallisation was carried out from alcoholic solutions and a robust crystallisation process was developed.  Various grades of ethanol and other alcohols were examined along with the rate of cooling, the diastereomers content of the crude product, but the crystallisation consistently gave form II.  Form I could generally be obtained from ethyl acetate, and form III was produced in acetone.