Syntheses Du S 9490‐3: Sel De Terbutylamine De l'Acide {[Carbethoxy‐1 (1S) Butyl Amino] OXO‐1 (2S) Propyl} (2S, 3aS, 7aS) Perhydro Indole ‐ Carboxylique‐2 [Cyclohexyl ‐ 14 C‐U], du S 9780 : Acide {[Carboxy‐1 (1S) Butyl Amino] OXO‐1 (2S) Propyl} (2S, 3aS, 7aS) Perhydro Indole‐Carboxylique‐2 [Cyclohexyl‐ 14 C‐U], du S 9490‐3 [Butyl‐( 3 H‐3,4) Amino] et du S 9780 [Butyl‐( 3 H‐3,4)‐Amino] A Hautes Radioactivites Specifiques

Synthesis of S 9490‐3 [U‐ 14 C‐cyclohexyl] 1‐{[(2S) 2 ‐ [(1S) 1‐(carbethoxybutyl) amino] 1‐oxopropyl} (2S, 3aS, 7aS) perhydroindole‐2‐carboxylic acid terbutylamine salt 1 and S 9780 [U‐ 14 C‐cyclohexyl]1‐ {[(2S) 2 ‐ [(1S)1‐ carbethoxybutyl] amino]1‐ oxopropyl} (2S, 3aS, 7aS) perhydroindole‐2‐carboxylic acid and of [3,4‐ 3 H‐butylamino] S 9490‐3 and [(3,4‐ 3 H‐) butylamino] S 9780, potent inhibitors of angiotensin converting enzyme at very high specific radioactivities. [U‐ 14 C] Aniline 3 with a specific activity of 120 mCi / mM was converted in a one pot reaction into the [U‐ 14 C] phenyl hydrazone of ethyl pyruvate 6 via [U‐ 14 C] phenyl diazonium chloride 4 in a 66% overall yield. Cyclization of 6 with PPA in xylene gave [U‐ 14 C] phenyl 2‐carbethoxy indole 7 in a 39.5% yield. Catalytic hydrogenation of 7 in the presence of platinum gave [U‐ 14 C‐cyclohexyl] (RS) ‐ 2 ‐ carbethoxy perhydroindole 8 which was saponified to the corresponding acid 10 which was reesterified to the benzylester 11 . Racemic 11 was condensed with N‐ [(S) 1‐ carbethoxybutyl] (S) alanine in presence of DCC and 1 ‐ hydroxy ‐ 1 benzotriazole. The resulting 12 was separated from the mixture of isomers by a silicagel column chromatography. [U‐ 14 C‐Cyclohexyl] S 9490‐3 1 was obtained from 12 by hydrogenolysis in a 1.7% overall yield from [U‐ 14 C] aniline. [U‐ 14 C Cyclohexyl]‐ S 9780 2 was made in a 50% yield by mild saponification of : 1 . Cyanoborohydride reductive amination of pyruvic acid with ethyl (S) C‐ allylglycinate gave a mixture of epimers 15 and 16 from which [ N ‐ (S) 1 ‐ ethoxycarbonyl ‐ 3 ‐ butenyl ] ‐ (S) alanine 15 was isolated. The latter condensed with 2 ‐ t ‐ butyloxycarbonyl (25, 3aS, 7aS) perhydroindole 17 gave 18 , which on hydrochloric acid hydrolysis gave 1 ‐{[ (25)] 2 ‐ [ (1S) 1 ‐ carbethoxy ‐ 3 ‐ butenyl] amino]‐1 ‐ oxopropyl} (2S, 3aS, 7aS) perhydroindole ‐ 2 ‐ carboxylic acid 13 a dehydro analog of S 9490. Tritiation of 13 with tritium gas in the presence of PdIc in THF gave [ 3,4 ‐ 3 H ‐ butylamino] (S) 9490‐3 with a specific activity of 52 Curies ImM. Saponification of a fraction of [ 3 H] S 9490‐3 gave [3,4 ‐ 3 H ‐ butylamino] S 9780 with a specific activity of 52 Curies/mM in low yield.