Patent GB-948730-A (GB)
Title: Substituted cyclopropanes and related compounds
IPC: C07D487/10
Filed: 1959-04-08
Abstract: The invention comprises a salt containing an ammonium cation of the formula: <FORM:0948730/C2/1> (wherein Ar is a phenyl, halophenyl, alkylphenyl or alkoxyphenyl group, the alkyl and alkoxy groups each containing at most 4 carbon atoms, or Ar2 is an o,o1-biphenylene group, R1 and R2 are hydrogen atoms or alkyl groups of at most 4 carbon atoms, W is a hydrogen atom or an alkyl group of at most 6 carbon atoms which may be substituted other than on the a -carbon atom with a dialkylamino group, the whole dialkylaminoalkyl group containing at most 12 carbon atoms, or an aralkyl group of 7 to 9 carbon atoms, X is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, or W and X together with the nitrogen atom may form a saturated cyclic amino group having 4 to 6 carbon atoms, Y is a hydrogen atom or an alkyl group of at most 4 carbon atoms, Z is an a -hydroxyalkyl group of at most 5 carbon atoms or an O-aryl derivative thereof, or an aryl group of 2 to 5 carbon atoms, or Z may be a hydrogen atom if the amine is a cyclic amine, or Y and Z together form a methylene group) and, unless the cation is quaternary, the secondary or tertiary amine corresponding thereto; and their preparation by (1) reduction with lithium aluminium hydride of a compound of the formula: <FORM:0948730/C2/2> (wherein W1 is as W but is not a hydrogen atom, X1 is as X, and Z1 is a hydrogen atom, a carboxyl group or its ester or an acyl group, or X1 and Z1 together form a carbonyl group in which event W1 may also be a carbamyl group), which reduction may be followed, if desired, by acylation of the a -hydroxyalkyl group, or by oxidation to an acyl group, or by N-quaternization or, when W is benzyl, by hydrogenative N-debenzylation; or (2) for preparing the bicyclic compounds by treating a compound of the formula: <FORM:0948730/C2/3> (wherein neither W nor X is a hydrogen atom) with p-toluene-sulphonyl chloride in the presence of a tertiary aliphatic amine. If W1 is a carbamyl group, W in the product is a hydrogen atom. In examples (1) 1,1-diphenylcyclopropane -2- carbonyl chloride (prepared from the acid and thionyl chloride) and pyrrolidine give 1,1-diphenyl -2- pyrrolidino carbonyl - cyclopropane and this on reduction gives 1,1-diphenyl -2-pyrrolidinomethylcyclopropane hydrochloride; (2) 1, 1-diphenyl -2- methyl -2- pyrrolidinocarbonyl cyclopropene is similarly prepared and reduced; (3) 1,1-diphenylcyclopropane -2,3-cis-dicarboxylic anhydride and dimethylamine give 1,1-diphenyl-cyclopropane -2,3-dicarboxylic acid mono-dimethylamide, this is reduced to 1,1-diphenyl -2-dimethylaminomethyl -3- hydroxymethylcyclopropane and this is converted to the acetate; (4) 1,1-diphenyl -2- piperidino carbonyl -3- ciscarboxy - cyclopropane is prepared similarly and is reduced to the piperidinomethyl compound which is converted to the acetate, cirramate and to the quaternary metho-p-toluene-sulphonate; (5) and (6) similarly are prepared 1,1-diphenyl -2-morpholinocarbonyl -3- cis-carboxycyclopropane and the corresponding pyrrolidide, which are reduced and the products converted into esters and quaternary salts; (7) The acid-amide of (4) is converted to the corresponding acid chloride, this with ethyl magnesium bromide gives 1,1-diphenyl -2- piperidinocarbonyl -3- cis-propionylcyclopropane and this is reduced to 1,1-diphenyl -2- piperidinomethyl -3- cis-(1-hydroxypropyl)-cyclopropane which is converted to the acetate and is also oxidized to 1,1-diphenyl -2- piperidinomethyl -3- cis-propionylcyclopropane; (8) to (11) 1,1-diphenyl -2- dimethylaminocarbonyl -3- cis-carboxy -3- trans - methylcyclopropane, the corresponding di-nbutyamino compound and the corresponding piperidide and pyrrolidide are prepared and reduced as in (3) and one of the products is converted to various esters; (12) diphenyldiazomethane (from benzophenone hydrazone) and methyl N-pentamethylenemaleamate give a pyrazoline, this on heating gives 1,1-diphenyl -2-piperidinocarbonyl -3- trans - methoxycarbonylcyclopropane and this is reduced; (13) p,p1-dimethylbenzophenone hydrazone is reacted with mercuric oxide and XOH and then with maleic anhydride to give 1,1-bis-p-tolylcyclopropane -2, 3-cis-dicarboxylic anhydride and this with piperidine gives a mono-piperidide which is then reduced and the product converted to a methiodide; (14) to (16) the corresponding monopyrrolidide and morpholide are similarly prepared and reduced; (17) bis-p-tolyldiazomethane and citraconic anhydride give 1,1-bis-p-tolyl -3-methylcyclopropane -2, 3-cis-dicarboxylicanhydride, this is converted to the corresponding mono-dimethylamide and this is reduced and then acetylated; (18) the corresponding mono-piperidide is similarly prepared and reduced; (19) p, p1-dimethoxybenzophenone hydrazone is oxidized to the diazo compound and this reacted with maleic anhydride to give 1,1-bis-p-methoxyphenylcyclopropane -2,3-cis-dicarboxylic anhydride, this is converted to the mono-dimethylamide, this is converted to the methyl ester and this is reduced; (20) to (23) by the above described methods 1,1-bisp - chlorophenylcyclopropane -2, 3 - cis - dicarboxylic anhydride and the corresponding mono-piperidide, and the corresponding monopyrrolidide and mono-isopropylamide are prepared and reduced; (24) 9-diazofluorene (from fluorenone hydrazone) and maleic anhydride give 1,1 -obiphenylenecyclopropane -2, 3 - cis - dicarboxylic anhydride, this is converted to the mono-piperidide and this reduced; (25) to (28) the corresponding dimethylamide, diethylamide, pyrrolidide and morpholide are similarly prepared and reduced; (29) diazofluorene and citraconic anhydride give 1,1-o-biphenylene -3- methylcyclopropane -2, 3 - cis - dicarboxylic anhydride, this converted to the mono-pyrrolidide and this reduced and the product esterified; (30) to (38) other products of the invention are prepared similarly; (39) diphenyldiazomethane and N-methylmaleimide give 6,6-diphenyl -2, 4- dioxo - 3-methyl -3- azabicyclo [3.1.0]-hexane and this is reduced and the product converted to the methiodide, and, via the quaternary hydroxide, to the methopicrate; (40) the corresponding 3-ethyl compound is similarly prepared and reduced; (41) 6,6-diphenyl 2, 4 - dioxo -1- methyl -3- b -diethylaminoethyl -3- azabicyclo [3.1.0] hexane is prepared from the appropriate anhydride and diamine and then reduced and the product converted to a bis-methiodide; (42) and (43) diphenyldiazomethane and N-benzylmaleimide give a pyrazoline, this on heating gives 6,6-diphenyl -2,4-dioxo -3- benzyl -3- azabicyclo - [3.1.0] hexane and this is reduced 6,6-diphenyl -3- benzyl -3- azabicyclo- [3.1.0]-hexane which is then debenzylated; (44) 6,6-diphenyl 2,4-dioxo-3-carbamyl -3- azabicyclo [3.1.0] hexane is similarly prepared and reduced; (45) the pyrazoline of the formula: <FORM:0948730/C2/4> is similarly prepared, heated to form the azabicyclo compound and this reduced and the product quaternized; (46) the corresponding N-n-butylpyrazoline is similarly prepared and heated to give the azabicyclo compound and the latter reduced; (47) and (48) 9-diazofluorene and N-methylmaleimide give 6,6-o-biphenylene -2, 4-dioxo -3- methyl -3- azabicyclo [3.1.0] hexane and this is reduced and the product quaternized; (49) the corresponding 3-ethyl compound is similarly prepared and reduced; (50) to (63) process (2) of the invention is illustrated. Some of these processes are also described in more general terms.