Patent GB-1039450-A (GB)
Title: Piperidine derivatives and their preparation
IPC: C07D211/70
Filed: 1964-11-09
Abstract: The invention comprises substituted piperidines of the general formula <FORM:1039450/C2/1> wherein Z represents -(CH2)n- or S, n is 1, 2 or 3, <FORM:1039450/C2/2> represents <FORM:1039450/C2/3> wherein R and R1 represent hydrogen, C1-C4 alkyl or benzyl and R3 represents C1-C4 alkyl or benzyl and in which any or all of the aromatic rings therein may be substituted by from 1 to 3 alkyl, alkoxy or alkylthio groups containing 1 to 4 carbon atoms, a methylenedioxy or trifluoromethyl group or 1 or 2 fluorine, chlorine, bromine or iodine atoms up to a maximum of 3 of these substituents in all the aromatic rings put together, and acid addition and quaternary ammonium salts thereof and N-oxides thereof and acid addition salts of the N-oxides, and the preparation of an alcohol of the general formula <FORM:1039450/C2/4> wherein Z, R1 and possible substitution on any or all of the aromatic rings have the above significance and R2 represents hydrogen, C1-C4 alkyl or benzyl or substituted benzyl such as an o-, m- or p-methoxy (or methyl)-benzyl or a naphthyl methyl radical, by reacting compounds of the formulae <FORM:1039450/C2/5> wherein R1, R2 and Z have the above significance and Y represents an alkali metal, -MgX, -CdX or -ZnX and X represents Cl, Br or I, and hydrolysing the reaction product and, when required, replacing the R2 group when it is other than hydrogen with hydrogen by hydrogenolysis or by indirect replacement by reaction with a chloroformic ester and subsequent hydrolysis of the resulting ester.  Prior or subsequent to this replacement, the invention also includes a process for dehydrating the alcohols of the general formulae <FORM:1039450/C2/6> to form compounds of the respective formulae <FORM:1039450/C2/7> wherein R1, R3, Z and the aromatic rings have the above significance. The above replacement by hydrogenolysis and the dehydration may take place simultaneously.  Dehydration also takes place if the first process referred to above involving the organo-metal reagent is carried out under more forcing reaction conditions-particularly as regards reaction temperature and hydrolysis.  In a product of the first general formula above in which R represents hydrogen, the hydrogen may be replaced by a C1-C4 alkyl or benzyl group by reaction with a suitable alkylating agent.  The N-oxides of all the compounds of the first general formula above are formed by reaction with a suitable reagent such as hydrogen peroxide, a per-acid or Caro's acid.  A racemate of an alcohol of the first general formula above may be separated by fractional crystallization or by reaction with an optically active acid.  Pharmaceutical compositions useful in human and veterinary medicine having a narcosis potentiating effect or a central-depressive, thymoleptic, spasmolytic, anti - histaminic, stimulating or analeptic effect contain as the active ingredient substituted piperidines of the first general formula above.  The compositions may be in a form suitable for parenteral, enteral or topical application.  2 - Methyl - 2 - phenyl - 2,3 - dihydrothionaphthen-3-one (admixed with 1-methoxy-2-phenyl-thionaphthene) is prepared by reacting 2-phenyl - 2,3 - dihydro - thionaphthen - 3 - one, potassium t-butylate and methyl iodide.  Ketones of the general formula <FORM:1039450/C2/8> wherein R1 and Z have the above significance, are prepared as follows: (a) when Z has the above significance, by intramolecular cyclization of a ,b -diphenyl-propionic acid, a ,g -diphenylbutyric acid, a ,d -diphenyl-valeric acid or a -phenyl-mercaptophenylaceti acid or a functional derivative thereof; (b) when Z is -CH2- and R1 is H, by cyclisation of hydroxymethyl desoxy benzoin or methylene desoxy benzoins; (c) when Z is S and R1 is H, by intramolecular ester condensation of S-carbalkoxy-benzyl-thiosalicylic acid alkyl esters followed by saponification and decarboxylation of the cyclization products; (d) when R1 is alkyl or aralkyl, by alkylation or aralkylation of the corresponding compound wherein R1 is H.