Kilogram Synthesis of a LFA-1/ICAM Inhibitor

Abstract

The process development and the kilogram-scale synthesis of BMS-587101 (1) are described. The synthesis features a [3 + 2] azomethine ylide cycloaddition to efficiently build the spirocyclic core in a diastereoselective fashion followed by a classical resolution which affords the desired enantiomer in >98% enantiomeric excess. The target was prepared in four steps in an overall yield of 22%.

Kilogram Synthesis of a Second-Generation LFA-1/ICAM Inhibitor

“…The free base spirocyclic hydantoin 4a was initially utilized in the Discovery synthesis for the synthesis of gram-scale quantities of API. We planned to ultimately use the hemi (+)-di- p -toluyl- d -tartaric acid ((+)-DTTA) salt 4b directly as it was readily available from a prior large-scale synthesis . However, to simplify our initial lab development work, we initially used the free base spirocyclic hydantoin 4a.…”

A New and Efficient Synthesis of 6-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl]nicotinic Acid, a Potent LFA-1/ICAM Inhibitor

“…Reaction of 3 with tert -butanol afforded the tert -butyl ester 4 in 70% yield. Heating of 4 with spirocyclic hydantoin intermediate 5 at 112 °C in dimethylacetamide (DMA) in the presence of diisopropylethylamine (DIPEA) provided the coupling product 6 in 77% yield. The tert -butyl ester group in 6 was subsequently deprotected with trifluoroacetic acid to give 1 in 86% yield.…”

Recent Advances in the Synthesis of Hydantoins: The State of the Art of a Valuable Scaffold

“…After the cycloaddition, further steps enable the desired spirohydantoins BMS-587101 and derivatives to be accessed. 14,15,460,461 12.6.2. From Other Substrates.…”

“…The key step in the preparation of this spirohydantoin relied on the cycloaddition of N- (methoxymethyl)- N- (trimethylsilylmethyl)­benzylamine on the suitable arylidene hydantoin, obtained from the reaction between 3,5-dichlorophenylisocyanate and sarcosine methyl ester followed by the Knoevenagel condensation of 4-cyanobenzaldehyde (Scheme ). After the cycloaddition, further steps enable the desired spirohydantoins BMS-587101 and derivatives to be accessed. ,,, …”