Chemoenzymatic preparation of the novel antifolate thymidylate synthase inhibitor N-(4-{N-[(6S )-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}benzoyl)-L-glutamic acid and its glutamyl cleavage product

Antifolate chemistry: synthesis of 4-{N-[(6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}benzoic acid via a (propargyl)Co2(CO)6+ complex

“…This methodology differs significantly from the published route to 3. 7,8 The oxo-functionality, required for the formation of the C 6 -N 10 bond via a reductive amination reaction, was introduced in the initial steps of the synthesis whereas the cyclopenta[g]quinazoline ring was constructed after the formation of the C 6 -N 10 bond making this route simpler and more flexible. Most significantly, the propargyl group was introduced in the penultimate step under mild conditions utilising the (propargyl)Co 2 (CO) 6 ϩ complex as the electrophilic propargyl synthon.…”

“…7 4-{N-[(6RS)-2-Methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta-[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino}benzoic acid 3, the key intermediate for the synthesis of this class of compounds, was prepared from N-(4-{N-[(6RS)-2-methyl-4-oxo-3,4,7,8tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)-amino}benzoyl)--glutamic acid by the enzymatic cleavage of its glutamyl residue. 7, 8 We now report an improved route to this key intermediate 3 in which the propargyl group was introduced in the penultimate step using the (propargyl)Co 2 (CO) 6 ϩ complex as the electrophilic propargyl reagent.…”

Synthesis of Bromoaminoindane and Bromoaminoindanone Derivatives

“…141-142°C (dichloromethane/hexane) (lit. 21 140-142 °C). 1 reflux was added to a solution of N-(5-bromo-2,3-dihydro-1H-inden-6-yl)acetamide 8 (0.25 g, 1.0 mmol) in CCl 4 (25 mL) was added.…”

Preparative biotransformations

“…Prolonged exposure of amide 37 to the same enzyme gave the (6S)-carboxylic acid, an anti-folate. 57 The amide CH 3 CH 2 CH(CH 2 OH)NHCOCH 2 Ph has been resolved using penicillin-G acylase immobilised on Eupergit C. The (S)-amine is isolated (35% yield, >99% ee) at 40% conversion. 58 The resolution of the γ-lactam 38 has been accomplished on a scale of five metric tonnes using a lactamase from Comamonas acidovorans.…”