Patent GB-1117259-A (GB)
Title: Dibenzocycloheptatriene derivatives and their preparation
Inventor: FOUCHE JEAN CLEMENT LOUIS
IPC: C07D211/14
Filed: 1966-05-25
Abstract: Novel dibenzo - [a,d] cycloheptatriene derivatives of the general formula <FORM:1117259/C2/1> wherein one of the two symbols X is a hydrogen atom and the other is a hydrogen or halogen atom, or an alkyl, alkoxy, alkylthio, alkanesulphinyl or alkanesulphonyl radical of up to 5 carbon atoms and R is a hydrogen atom or an alkyl, alkenyl, alkynyl, hydroxyalkyl or hydroxyalkoxyalkyl radical in which each hydrocarbon chain is of up to 5 carbon atoms or a phenylalkyl or phenylalkenyl radical of up to 11 carbon atoms in which the phenyl nucleus may be substituted by one or more halogen, alkyl or alkoxy of up to 5 carbon atoms, amino or trifluoromethyl radicals, and acid addition and quaternary ammonium salts thereof are prepared (a) when R is not alkenyl, alkynyl or phenylalkenyl, by dehydrating a hydroxy compound of the general formula <FORM:1117259/C2/2> wherein R is as defined above with the exception of alkenyl, alkynyl or phenyl-alkenyl; (b) when R is a hydrogen atom, by treating a dibenzo-[a,d] cycloheptatriene derivative of the first formula above in which R is a radical as defined for the first formula above, but easily replaceable by hydrogen, so as to replace the said radical by a hydrogen atom, (c) when R is other than a hydrogen atom, by reacting a dibenzo-[a,d] cycloheptatriene derivative of the first formula above in which R is a hydrogen atom with a reactive ester of the formula Y-R, wherein Y is a reactive ester residue and R is as defined for the first formula above with the exception of hydrogen; (d) when one of the symbols X is a hydrogen atom and the other is an alkanesulphonyl or alkanesulphinyl radical, but in which R is not alkenyl, alkynyl or phenylalkenyl radical, by oxidizing the corresponding compound of the first formula above in which one of the symbols X is a hydrogen atom and the other is an alkylthio group followed by optional conversion to an acid addition or quaternary ammonium salt of the product.  Pharmaceutical compositions having an effect on the central nervous system and acting as antihistaminic, antiserotonine, analgesic, spasmolytic or antiemetic agents, comprise as active ingredient at least one dibenzo-[a,d] cycloheptatriene derivative of the first formula above or an acid addition or quaternary ammonium salt thereof in association with a pharmaceutical carrier or coating.  Hydroxy compounds of the second formula above are prepared (a) when R is hydrogen, by debenzylating the corresponding N-benzyl compound, or (b) when R is other than hydrogen, by reacting 4-pyridyl lithium with a dibenzo-[a,d] cycloheptadiene of the general formula <FORM:1117259/C2/3> to form a dibenzo - [a,d] cycloheptadiene of the general formula <FORM:1117259/C2/4> quaternizing this compound with an ester of the formula Z-R1, wherein Z is an anion and R is as defined for the first formula above with the exception of hydrogen, and reducing the resulting quaternary compound.  Dibenzo-[a,d] cycloheptadienes of the third general formula above are prepared (a) when one X is hydrogen and the other is alkanesulphinyl or alkanesulphonyl, by oxidizing the corresponding alkylthio compound, or (b) when one X is hydrogen and the other is other than alkanesulphinyl or alkanesulphonyl, by esterifying substituted benzoic acids of the general formula <FORM:1117259/C2/5> wherein X1 has the same significance as X immediately above, reducing the resulting methyl esters to form alcohols of the general formula <FORM:1117259/C2/6> converting these alcohols successively to the corresponding halo-compounds and cyano-compounds, hydrolysing the latter to the carboxylic acids of the general formula <FORM:1117259/C2/7> and cyclizing the carboxylic acids as such or converting them to the corresponding acid chlorides and then cyclizing.  Substituted benzoic acids of the fifth general formula above are prepared (a) by reacting the required phthalic anhydride and benzene derivative according to Friedel-Crafts and reducing the resulting o-aroylbenzoic acid of the general formula <FORM:1117259/C2/8> or (b) by reducing phthalides of the general formula <FORM:1117259/C2/9> which are obtainable from the required o-formyl-benzoic acid and phenyl magnesium halide.  3 - Bromo - 7 - chlorophthalide is prepared by the action of bromine on 7-chlorophthalide. 2-Formyl-6-chlorobenzoic acid is prepared by the action of caustic soda on 3-bromo-7-chlorophthalide.