Phenylacetonitrile → Ethyl 3-amino-2,2-dimethylbutanoate

a benzylcyanide of general formula 2 is subjected to the conditions of a Reformatsky reaction with ethyl bromoisobutylbutyrate (3) in the presence of an alkylhalosilane and zinc powder in an inert solvent in the presence of a reducing agent which is selective with regard to the reduction of imino functions, and the resulting ethyl 3-amino-2,2-dimethylbutanoate derivative of general formula 4 is isolated ##STR14## and b) the ethyl 3-amino-2,2-dimethylbutanoate derivative of general formula 4 is subjected to the conditions of a Michael addition reaction with ethyl acrylate and the resulting ethyl 3-(2-ethoxycarbonylethyl)amino-2,2-dimethylbutanoate derivative of general formula 5 is isolated ##STR15## c) the ethyl 3-(2-ethoxycarbonylethyl)amino-2,2-dimethylbutanoate of general formula 5 thus prepared is subjected to the conditions of a Dieckmann ester condensation in an inert solvent in the presence of a basically reacting compound and the resulting piperidone derivative of general formula 6 is isolated ##STR16## and d) the piperidone derivative 6 is saponified under acid or alkaline conditions in a polar solvent or solvent mixture, with heating, then decarboxylated, to obtain the corresponding 3,3-dimethylpiperidone derivative of general formula 7, isolated and if desired the corresponding acid addition salt is prepared using an acid and isolated ##STR17## and e) the stereoisomer mixture thus obtained is dissolved, optionally after release of the enantiomeric free bases, in a reaction medium which is inert with respect to enantiomer separation, then combined with a suitable stereoisomer of an organic acid suitable for salt formation with a stereoisomer of the mixture of enantiomers, the desired stereoisomer is isolated in the form of its addition salt with the optically active acid, the mother liquor containing the unwanted isomer is heated and in this way the unwanted enantiomer is converted thermally into the desired stereoisomer, mixed with an optically active enantiomerically pure organic acid capable of forming an acid addition salt and the desired stereoisomer thus present as an acid addition salt is optionally added, with the addition of a medium which behaves as a nonsolvent relative to the desired salt, and then isolated and this process is repeated as necessary □ ##STR18## and f) the pure stereoisomer thus obtained, after release from the enantiomerically pure acid addition salt, is reacted in an inert solvent with a Wittig reagent generating a methylene group in the presence of a basically reacting compound and the reaction product of type 9 or the corresponding stereoisomer is isolated, optionally in the form of the acid addition salt thereof ##STR19## and g) the alkene 9 obtained from the Wittig reaction is optionally first freed from its acid addition salt and the free base of type 9 is dissolved in an organic solvent and subjected, with a formylating agent, to a formylating reaction at the piperidine nitrogen and the reaction product of type 10 or the corresponding stereoisomer thereof is isolated ##STR20## and h) the formyl compound 10 thus obtained, or the corresponding stereoisomer, is dissolved in an inert solvent and reacted with a Lewis acid and the cyclising product of type 11 resulting from this reaction is isolated ##STR21## i) the benzomorphan derivative resulting from the cyclising reaction is dissolved in a polar solvent and reacted with an acidically reacting compound and the deformylated norbenzomorphan of type 12 resulting from this reaction is optionally isolated in the form of its acid addition salt ##STR22## and j) if desired, after liberation of the free benzomorphan base, the substituent R2, if it constitutes an alkoxy group, is converted by ether splitting into a free hydroxy function and the reaction product is isolated, optionally in the form of the acid addition salt thereof of type 13, the base corresponding to general formula 1. ##STR23##

ORD record

ord-511faed810b740fda0f597e12e7bbe33

Source dataset

uspto-grants-1999_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05945535