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

a benzylcyanide of general formula 2 is reacted with ethyl bromoisobutylbutyrate (3) in the presence of an alkyl halosilane and zinc powder in an inert solvent, the reaction mixture is heated, allowed to cool after the reaction has ended, the zinc powder is separated off and the reaction mixture is mixed with a reducing agent which is selective with regard to the reduction of imino functions and the reaction mixture is diluted with an alkanol and then mixed with an aqueous solution of a basically reacting compound, the organic phase is removed and evaporated down, the residue is taken up in an inert solvent, the resulting solution is extracted with the aqueous solution of an acid, the combined aqueous extracts are made alkaline with a basically reacting compound, this alkaline solution is extracted with a water-immiscible organic solvent and the resulting ethyl 3-amino-2,2-dimethylbutanoate derivative of general formula 4 is isolated ##STR24## and b) the ethyl 3-amino-2,2-dimethylbutanoate derivative of general formula 4 is subjected with ethyl acrylate to a Michael addition reaction in an inert solvent, the reaction medium is eliminated once the reaction has ended and the resulting ethyl 3-(2-ethoxycarbonylethyl)amino-2,2-dimethylbutanoate derivative of general formula 5 is isolated ##STR25## and 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, 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 acidically reacting compound, the resulting mixture is combined with a water-immiscible organic solvent and an aqueous solution of a basically reacting compound, the combined organic extracts are evaporated down and the resulting piperidone derivative of general formula 6 is isolated ##STR26## and d) the piperidone derivative 6 is saponified under acid or alkaline conditions in a polar solvent or mixture of solvents, with heating, then decarboxylated, to obtain the corresponding 3,3-dimethylpiperidone derivative of general formula 7 and isolated and if desired the corresponding acid addition salt is prepared using an acid and then isolated □ ##STR27## and e) the mixture of stereoisomers thus obtained is dissolved, optionally after liberation of the enantiomeric free bases, in a reaction medium which is inert relative to the enantiomer separation, mixed with a suitable stereoisomer of an organic acid which is suitable for salt formation with a stereoisomer of the enantiomer mixture, the desired stereoisomer is isolated in the form of the acid addition salt thereof with the optically active acid, the mother liquor containing the unwanted isomer is heated and the unwanted enantiomer is thereby 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 the salt is isolated and this process is repeated as necessary ##STR28## and f) the pure stereoisomer thus obtained, after liberation from the enantiomerically pure acid addition salt, is subjected to a Wittig reaction in an inert solvent with a Wittig reagent generating a methylene group in the presence of a basically reacting compound and in a temperature range from 0 to 80° C., after the reaction the mixture is combined with water and a water-immiscible organic solvent, the aqueous phase is extracted exhaustively, the reaction product of type 9 is isolated or, after the addition of a proton acid, the corresponding stereoisomer is isolated in the form of the acid addition salt thereof □ ##STR29## 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 ##STR30## 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 □ ##STR31## and 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, after the addition of the inorganic acid ##STR32## 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. ##STR33##

1. temperaturethe reaction mixture is heated
2. temperatureto cool after the reaction
3. customthe zinc powder is separated off
4. additionthe reaction mixture is mixed with a reducing agent which
5. additionthe reaction mixture is diluted with an alkanol
6. additionmixed with an aqueous solution of a basically reacting compound
7. customthe organic phase is removed
8. customevaporated down
9. extractionthe resulting solution is extracted with the aqueous solution of an acid
10. extractionthis alkaline solution is extracted with a water-immiscible organic solvent

ORD record

ord-8627ad5b79a2455583b6a0f5690d9817

Source dataset

uspto-grants-1999_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05945535