Synthese du SL 75.212 (Betaxolol) Marque au Carbone 14 : [Cyclopropylmethoxy-2 Ethyl 14C-1)-4 Phenoxy] - 1 Isopropylamino-3 Propanol-2

✍ Scribed by F. Aubert; J.-P. Beaucourt; L. Pichat

• Publisher: John Wiley and Sons
• Year: 1982
• Tongue: French
• Weight: 364 KB
• Volume: 19
• Category: Article
• ISSN: 0022-2135
• DOI: 10.1002/jlcr.2580190409

✦ Synopsis

Abstract

The synthesis of SL‐75.212 (BETAXOLOL) labelled with carbon 14 : 1‐[4‐(2‐cyclopropyl methoxyethyl‐[1‐^14^C]) phenoxy]‐3‐isopropul amino‐2‐propanol : 13 was achieved by a twelve step sequence from [^14^C] carbon dioxide.

Carbonation with ^14^CO~2~ of the Grignard reagent 1 gave 4‐benzyloxy [carboxyl‐^14^C] benzoic acid: 2 (87 % yield). 2 was successively treated in diethyl ether solution with diazomethane and lithium aluminium hydride giving rise to [7‐^14^C] 4‐benzyloxybenzyl alcohol 4 (82 % yield). Alcohol 4 was transformed into the corresponding chloride 5 when exposed to thionylchloride in ether. 5 was condensed with NaCN in DMF to give the nitrile 6 which was hydrolysed into the acid 7 isolated in a 75% overall yield from Ba^14^CO~3~. 7 gave the alcohol 9 by successive treatments with diazomethane and LiAlH~4~ in ether. 9 with NaH gave the corresponding alkoxide which when condensed with bromomethylcyclopropane gave the ether 10 purified by silicagel column chromatography and isolated with an overall yield of 71 % from Ba^14^CO~3~. Hydrogenolysis of 10 gave the phenol 11. The epoxide 12 was secured by condensation with epichlorhydrin in presence of NaOH. After purification by silicagel column chromatography 10 was opened with isopropylamine leading to the target compound BETAXOLOL 13 isolated as the hydrochloride. After extensive purification by Sephadex G‐10 column chromatography, SL 75.212 [ethyl‐1‐^14^C] was obtained in an overall yield of 26% from barium [^14^C] carbonate and a radiochemical purity better than 99% (specific activity 57 mCi/mmole).