Phenylacetonitrile → HCID 21217075, compound

Process for preparing norbenzomorphan of general formula 1 wherein R1 is defined as in claim 1, according to claim 2, characterised in that a) a benzylcyanide of general formula 2 is reacted with ethyl bromoisobutylbutyrate (3) in the presence of a trialkylhalosilane and zinc power in an ether and a haloalkane, the reaction mixture is heated, allowed to cool once the reaction has ended, the zinc powder is removed and the reaction mixture is combined with a complex alkali metal borohydride derivative which is selective with regard to the reduction of imino functions, and the reaction mixture is diluted with a C1-4 -alcohol and then with an aqueous ammonia solution, the organic phase is separated and evaporated down, the residue is taken up in an aliphatic or aromatic hydrocarbon, the solution obtained is extracted with the aqueous solution of an inorganic acid, the combined aqueous extracts are made alkaline with aqueous ammonia solution, this alkaline solution is extracted with a halohydrocarbon and the resulting ether 3-amino-2,2-dimethylbutanoate derivative of general formula 4 is isolated ##STR34## and b) the ethyl 3-amino-2,2-dimethylbutanoate derivative of general formula 4 is subjected to a Michael addition reaction with ethyl acrylate in a straight-chained or branched C1-4 -alcohol, after the reaction has ended the reaction medium is eliminated and the resulting ethyl 3-(2-ethoxycarbonylethyl)-amino-2,2-dimethylbutanoate derivative of general formula 5 is isolated ##STR35## and c) the ethyl 3-(2-ethoxycarbonylethyl)amino-2,2-dimethylbutanoate derivative of general formula 5 thus prepared is subjected to the conditions of a Dieckmann ester condensation in an aliphatic or aromatic hydrocarbon in the presence of an alkali metal alkoxide of a straight-chained or branched C1-4 -alcohol, the volatile components of the reaction mixture resulting from the reaction of cyclisation are eliminated by distillation, then the mixture is hydrolysed and mixed with the aqueous solution of an inorganic acid, the resulting mixture is combined with a water-immiscible dialkylether and with aqueous ammonia solution, the combined organic extracts are evaporated down and the resulting piperidone derivative of general formula 6 is isolated ##STR36## and d) the piperidone derivative 6 is saponified in a mixture of a straight-chained or branched C1-4 -alcohol and water in the presence of an alkali metal hydroxide or an inorganic acid, with heating, and decarboxylated to obtain the corresponding 3,3-dimethylpiperidone derivative of general formula 7, the product is isolated and optionally the corresponding acid addition salt is prepared with a proton acid ##STR37## and e) the mixture of stereoisomers thus obtained is dissolved, optionally after liberation of the enantiomeric free bases, in a straight-chained or branched C1-4 -alcohol, mixed with the corresponding enantiomers of malic, tartaric, mandelic or camphor sulphonic acid, the desired stereoisomer is isolated in the form of its salt of addition with the optically active acid, the mother liquor containing the unwanted isomer is heated and in this way the unwanted enantiomer is thermally converted into the desired stereoisomer, mixed with an optically active, enantiomerically pure organic acid capable of forming an acid addition salt and the desired stereoisomer occurring as an acid addition salt is optionally crystallised by the addition of a C3-8 -alcohol and then isolated and this procedure is repeated as necessary ##STR38## and f) the pure stereoisomer thus obtained is liberated from the enantiomerically pure acid addition salt and then subjected to a Wittig reaction, in an optionally cyclic ether with a methyl triphenylphosphonium halide in the presence of an alkali metal alkoxide in a temperature range from 20 to 60° C., then after the reaction has taken place the reaction mixture is mixed with water and with a haloalkane, the aqueous phase is extracted exhaustively, the reaction product of type 9 or optionally the corresponding stereoisomer is isolated in the form of its acid addition salt after the addition of a proton acid ##STR39## and g) the alkene 9 obtained from the Wittig reaction is optionally first liberated from its acid addition salt and the free base of type 9 is dissolved in an alkyl aromatic compound as solvent and subjected, with an alkyl formate, to a formylation reaction at the piperidine nitrogen and the reaction product of type 10 or the corresponding stereoisomer thereof is isolated ##STR40## and h) the formyl compound 10 thus obtained, or the corresponding stereoisomer, is dissolved in a halogenated hydrocarbon and reacted with an aluminium(III)halide and the cyclisation product of type 11 resulting from this reaction is isolated ##STR41## and i) the benzomorphan derivative 11 resulting from the reaction of cyclisation is dissolved in an alkanol and reacted with the aqueous solution of a hydrohalic acid and the deformylated norbenzomorphan of type 12 resulting from this reaction is isolated optionally after the addition of a proton acid, in the form of the acid addition salt thereof ##STR42## and j) if desired, after liberation of the free benzomorphan base, the substituent R2, if it denotes an alkoxy group, is converted into a free hydroxy function by the method of ether splitting and the reaction product is isolated, optionally in the form of the acid addition salt thereof of type 13, in which the base corresponds to general formula 1 ##STR43##

1. temperatureto cool once the reaction
2. customthe zinc powder is removed
3. additionthe reaction mixture is diluted with a C1-4 -alcohol
4. customwith an aqueous ammonia solution, the organic phase is separated
5. customevaporated down
6. customthe solution obtained
7. extractionis extracted with the aqueous solution of an inorganic acid
8. extractionthis alkaline solution is extracted with a halohydrocarbon

ORD record

ord-3ff984689b1a4b009421dcf629d8a3f1

Source dataset

uspto-grants-1999_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05945535