Patent GB-791804-A (GB)
Title: Improvements in or relating to substituted benz-indoles, intermediates therefor, andprocess for preparing the same
Inventor: KORNFELD EDMUND CARL
IPC: C07D209/90
Filed: 1955-04-05
Abstract: The invention comprises (1) benz-indoles of formula X where R is an aliphatic radical of 1-8 carbon atoms, a monocarbocyclic aromatic radical or monocarbocyclic aromatic substituted C1-C4 alkyl radical, R1 is C1-C8 alkyl, R2 is hydroxymethyl or acyloxymethyl (1-4 C atoms in the acyl group) and R3 and R4 are each C1-C4 alkyl or together represent an alkylene chain having 2 or 3 carbon atoms; also, acid addition salts thereof; (2) the production from (1) of the corresponding 5-keto compounds by oxidation, e.g. with lead tetraacetate or periodic acid; and (3) the various steps in the synthesis of (1) set out below.  <PICT:0791804/IV (b)/1> <PICT:0791804/IV (b)/2> The compounds (2) are useful in the synthesis of lysergic acid. The compounds are prepared from an N-acyl-5-formyl-tetrahydro-benz-indole of formula I by reduction to the 5-methylol compound (e.g. with sodium borohydride), epoxidation with a per-acid and reaction with an alkylamino-acetone ketal. Acylation of the hydroxymethyl group may be carried out if desired before or after epoxidation, and the latter (using hydrogen peroxide) may precede reduction of the formyl group.  The acyloxymethyl group can be hydrolysed to hydroxymethyl in the product.  In the examples: (1) 1 - benzoyl - 5 - keto - 1 : 2 : 2a : 3 : 4 : 5 - hexahydro - benz - [cd] - indole (see Specification 791,805) is condensed with ethyl chloracetate and potassium t-butoxide and the resulting glycidic ester hydrolysed to the 1-benzoyl - 5 - carboxymethyl - 5 : a  - epoxy compound (sodium salt); the latter is oxidized with pyridine hydrobromide perbromide and the product treated with semicarbazide to give the semicarbazone of 1-benzoyl-5-formyl-1 : 2 : 2a : 3 - tetrahydro - benz - [cd] - indole, from which the free aldehyde is obtained by the action of pyruvic acid; the aldehyde is then epoxidized with hydrogen peroxide; (2) the aldehyde of (1) is reduced with sodium borohydride to 1-benzoyl - 5 - hydroxymethyl - 1 : 2 : 2a : 3 - tetrahydro - benz - [cd] - indole which is epoxidized with perbenzoic acid; (3) methylaminoacetone ethylene ketal (from chloroacetone ketal and methylamine) is reacted with the epoxide of (2) to give 1-benzoyl-5-hydroxy-5 - hydroxymethyl - 4 - (N - methyl - N - acetonyl - amino) - 1 : 2 : 2a : 3 : 4 : 5 - hexahydrobenz - [cd] - indole ethylene ketal (hydrochloride described); the corresponding 5-acetoxymethyl compound is made similarly; (4) the hydroxymethyl product of (3) is oxidized to the 5-keto compound with periodic acid; (5) the hydroxymethyl compound of (2) is acetylated and then epoxidized; (6) the epoxyaldehyde of (1) is reduced with sodium borohydride to give 1 - benzoyl - 4 : 5 - epoxy - 5 - hydroxymethyl - 1 : 2 : 2a : 3 : 4 : 5 - hexahydrobenz-[cd]-indole; (7) the product of (6) is acetylated; (8) the acetoxymethyl product of (3) is hydrolysed to the hydroxymethyl compound.  It is stated that R can also be methyl, ethyl, pentyl, hexyl and benzyl, R1 can be ethyl, isopropyl, butyl, amyl and heptyl, and R2R3 can be propylene, diethyl or dipropyl.