Lactams as Antiproliferative Agents

Winkler etal, US Patent 6,451,785 (September 17, 2002) Assignee SmithKline Beecham Corporation Utility Cell Anti-Proliferation Agent in Mammals 

A mixture of 4-benzoyloxy-azetidin-2-one (80 mmol) dissolved in 150 ml toluene was treated with isobutyl alcohol (O.lbmmol), NEt3 (O.lbmol) and Pd(OAc)2 (16mmol), stirred in an ice bath several hours, and at ambient temperature for hours. The mixture was filtered through Supercel, concentrated, and the residue purified by chromatography 

The product from Step 1 (33 mmol) was dissolved in 50 ml THE containing NEtj (66 mmol), cooled in an ice bath, and t-butyldimethylsilyl chloride (43 mmol) dissolved in 15 ml THE added dropwise. The cooled reaction mixture was stirred 5 hours then stored in a refrigerator 64 hours. The cooled mixture was poured into ice- cold water, extracted with EtOAc, and the extract washed with brine and dried. The residue was purified by chromatography using EtOAc/hexane, 1 9, and the product isolated in 79% yield. 

N-Isopropylcyclohexylamine (10 mmol) was dissolved in 18 ml THE, cooled to — 15°C, and 48 ml 2M n-butyllithium added dropwise. The mixture was stirred 40 minutes, the temperature lowered to — 78°C, and the product from Step 2 (7 mmol) dissolved in 7 ml THE added. The reaction mixture was stirred an additional hour and p-toluenesulfonylazide (9 mmol) dissolved in 8 ml THE containing 2 ml HMPA added over 40 minutes. The mixture was stirred one hour at —50°C and 16 hours at —28°C. Thereafter, 5 ml trimethylsilyl chloride was added and the mixture stirred at ambient temperature for 45 minutes. The mixture was diluted with water, extracted with EtOAc, purified as in Step 2, and the product isolated in 30% yield. 

The product from Step 3 (0.67 mmol) was dissolved in I5CH2CI2 containing NEtj (0.7 mmol), cooled on an ice bath, and H2S bubbled gently through the solution for 10 minutes. The mixture was stirred while cold 4 hours, concentrated, and the desired product isolated. 

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