The initial discovery route to saxagliptin was a 15-step, convergent synthesis focused on the production and use of compounds 109
and 113 (Schemes a and b). While the strategy of early
drug delivery involved rapid synthesis to support preclinical
activities and Phase I clinical trials, as saxagliptin entered Phase
II, a greater emphasis was placed on defining and demonstrating
a commercially viable synthetic process. Scheme a describes a
more expedient route to the preparation of adamantylamino acid
109. Commercially available 1-adamantoic acid (106) was first
converted to the corresponding acid halide through the use of
thionyl chloride prior to a Grignard addition reaction utilizing
iodomethane and magnesium metal to furnish ketone 107. This
ketone was then subjected to oxidizing conditions involving potassium
permanganate to provide the hydroxylated ketoacid 108.
The amino acid 109 was furnished through the use of phenylalanine
dehydrogenase in near-quantitative yield in 99% enantioselectivity.
The synthesis of 113 began with commercially available ethyl
N-tert-butoxycarbonylpyroglutamate (110) (Scheme b). Selective
reduction of the amide carbonyl within 110 through the use
of lithium triethylborohydride followed by acylation and baseinduced
elimination of the resulting aminal and careful hydrolysis gave rise to dihydropyrrole 111 with full retention of stereochemical
configuration in 95% yield. Amidation followed by Simmons¨C
Smith cyclopropanation employing methylene iodide converted
111 to the cyclopropanated product 112, which was then converted
to the key coupling partner 113.
The core of saxagliptin was formed by the amide coupling of
amino acid 109 and methanoprolinamide 113 to give amide 114
in 95% yield (Scheme c). Subsequent dehydration of the primary
amide 114 using trifluoroacetic acid anhydride and ethyl nicotinate
gave nitrile 115 in 98% yield. Removal of both the alcohol
and amine protecting groups with HCl afforded saxagliptin (XVIII)
in 88% yield.
