Patent GB-1129718-A (GB)
Title: Derivatives of 10',11'-dihydrospiro[cyclopropane-1,5'-5'h-dibenzo(a,d)cycloheptene]and spiro [cyclopropane-1,9'-fluorene]
IPC: C07C17/00
Filed: 1966-10-10
Abstract: 1,129,718. Spirocyclopropane derivatives. SMITH KLINE & FRENCH LABORATORIES. 10 Oct., 1966 [19 Oct., 1965; 7 March, 1966], No. 45266/66. Heading C2C. [Also in Division C5] Novel compounds of the Formula I or their pharmaceutically acceptable acid addition salts wherein A represents a direct single valence bond or the radical -CH 2 CH 2 -; R represents a hydrogen or halogen atom or a trifluoromethyl, C 1-4 alkyl, C 1-4  alkoxy, C 1-4  alkylthio or C 1-4  alkylsulphonyl radical; n represents 0, 1 or 2 and each of R 1  and R 2  represents a hydrogen atom or a C 1-3  alkyl group or when taken together with the nitrogen atom to which they are attached, they represent a heterocyclic amino group of up to 15 carbon atoms are prepared (a), where n represents 0, by converting an acid of Formula II into an acid halide or a C 1-4 alkyl mixed anhydride (with a C 1-4  alkyl haloformate) converting the latter to the acid azide, rearranging the azide to the isocyanate and hydrolysing the isocyanate to give a primary amine or reacting said isocyanate with a C 1-2  alkylmagnesium halide or a C 1-3  alkanol to give an amine containing an N-C 2-3  acyl or N-C 2-4 carbalkoxy group respectively which is either reduced directly to give an N-C 2-3  alkylamine or a N-methylamine respectively or is further reacted with an alkyl iodide to give an N-alkyl-N-acyl or N-alkyl-N- carbalkoxyamine which is reduced to the N,N-dialkylamine or N-methyl-N-alkylamine respectively; (b) where n represents 1 by converting the acid of the Fomula II to its halide or C 1-4  alkyl mixed anhydride with thionyl chloride or a C 1-4 alkyl haloformate respectively, reacting with ammonia, a mono- or di-alkylamine or a heterocyclic amine and reducing the resulting amide; or (c) where n represents 2 by reacting the acid halide or C 1-4 alkyl mixed anhydride referred to above with diazomethane to give the corresponding 2-diazoacetyl derivative; rearranging the latter with silver benzoate to give the methyl 2-acetate, hydrolysing to the free acid, converting the latter to the appropriate amide via the acid chloride or C 1-4  alkyl mixed anhydride and reducing the amide or rearranging the above diazoketones with silver oxide in the presence of an amine to give carbamoyl methyl derivatives and reducing the latter; or (d) where R 1  and R 2  represent a heterocyclic amino group by reacting the appropriate primary amines with the appropriate bis-haloalkyl compounds. Acids of the Formula II, where A represents an ethylene group, may be prepared reacting a dibenzocyclohepten-5-one with methyllithium to give the 5-methyl-5-ol derivative, dehydrating and reacting the resulting 5-methylene derivative with ethyl diazoacetate to give the ethyl 10<SP>1</SP>,11<SP>1</SP> - dihydrospiro [cyclopropane - 1,5<SP>1</SP>- 5<SP>1</SP>H<SP>1</SP> - dibenzo(a,d)cyclohepten] - 2 - carboxylate and hydrolysing the latter or where A represents a direct bond by converting a 9-fluorenone to its hydrazone, converting the latter with mercuric oxide to the corresponding diazofluorene, reacting with ethyl acrylate to give an ethyl spiro [cyclopropane - 1,91 - fluorene] - 2 - carboxylate and hydrolysing said ester. Therapeutic compositions having antidepressant properties which may take forms suitable for oral or parenteral administration comprise compounds of the Formula I with a suitable carrier therefor.