Patent GB-800695-A (GB)
Title: Improvements in and relating to diquaternary compounds and the manufacture thereof
Inventor: COKER GEOFFREY GEORGE
IPC: C07D295/13
Filed: 1955-08-18
Abstract: The invention comprises compounds of the general formula <FORM:0800695/IV (b)/1> and a process for the manufacture thereof by treating a diamine of the general formula <FORM:0800695/IV (b)/2> with a quaternizing agent.  In the general formul  R1 and R2 are the same or different and are each a cycloalkyl group, a phenyl group which may be substituted by halogen atoms, lower alkyl group or a lower alkoxy group ("lower" indicating 1-4 C atoms); m is 0 to 4; n is 1 to 9 (m+n is not greater than 10); X is -COO.CH2- or -O.CO-; <FORM:0800695/IV (b)/3> is a quaternary nitrogen atom carrying two alkyl groups (total up to 5 C atoms); <FORM:0800695/IV (b)/4> is a quaternary nitrogen atom carrying at least one alkyl group (1 to 4 C atoms) and either carrying two further alkyl groups (total up to 9 C atoms) or forming part of a pyrrolidino, piperidino or morpholino ring; Y is an alkylene chain (2 to 10 C atoms) or <FORM:0800695/IV (b)/5> may be a piperazine in which <FORM:0800695/IV (b)/6> and <FORM:0800695/IV (b)/7> are quaternary atoms, <FORM:0800695/IV (b)/8> carrying one alkyl group (1 to 4 C atoms) and <FORM:0800695/IV (b)/9> carrying two alkyl groups (total up to 4C atoms, the total for the three groups not exceeding 6 C atoms); A- is an anion of an inorganic or organic base; N3 is a secondary or tertiary and N4 is a tertiary nitrogen atom carrying substituents such that with those provided by the quaternizing agent the desired substitution in the general formula (I) is obtained.  Examples are given of the preparation of N1:N1:N2-trimethyl-N1-R-ethylene - 1 - ammonium - 2 - piperidinium diiodide, where R is (2-diphenylacetoxyethyl), [3-di - (4 - methylphenyl) acetoxypropyl], (4-dicyclo-hexylacetoxybutyl),[4-di-)4-methylphenyl) acetoxybutyl], (6 - diphenylacetoxyhexyl), [2 - (3:3 - diphenylpropionoxy) ethyl], [2 - (4:4 - diphenylbutyroxy) ethyl], (2:2 - diphenylethoxycarbonylmethyl), (3:3 - diphenylpropoxycarbonylmethyl), [4 - (2:2 - diphenylethoxycarbonyl) butyl], [4 - (3:3 - diphenylpropoxycarbonyl) butyl], (5 - diphenylmethoxycarbonylpentyl), [5 - (2:2 - diphenylethoxycarbonyl) pentyl], [5 - (3:3 - diphenylpropoxycarbonyl) pentyl] and [4-di-(4-methoxyphenyl) acetoxybutyl]; of N1:N2:N2-trimethyl-N1-R-piperazinium di-iodide where R is (2-diphenylacetoxyethyl), [2 - di - (4 - chlorophenyl) acetoxyethyl], [3 - di - (4 - methylphenyl) acetoxypropyl], and [4 - di - (4 - methylphenyl) acetoxybutyl]; of N2:N2-di-n-butyl-N1:N1:N2-trimethyl - N1 - (2 - diphenylacetoxyethyl) - ethylene-1:2-diammonium di-iodide and N2:N2-diethyl - N1:N1:N2 - trimethyl - N1 - R - ethylene-1:2-diammonium di-iodide, where R is (6-diphenylacetocyhexyl), [6 - (3:3 - diphenylpropionoxy) - hexyl], (2:2 - diphenylethoxycarbonylmethyl), and (3:3-diphenylpropoxycarbonylmethyl); of N1:N1:N2-trimethyl-N1-(4 - diphenylacetoxybutyl) - hexamethylene - 1 - ammonium - 6 - morpholinium di - iodide, N1:N1:N2 - trimethyl - N1 - (4 - diphenylacetoxybutyl)- and N1:N1:N2 - trimethyl - N1 - [2 - (3:3 - diphenylpropionoxy) - ethyl] - tri - methylene - 1 - ammonium - 3 - morpholinium di-iodides and N1:N1:N2-trimethyl-N1-R-ethylene - 1 - ammonium - 2 - morpholinium diiodide, where R is [4-di-(4-methylphenyl)-acetoxybutyl], (3-diphenylmethoxycarbonylpropyl), [3 - (2:2 - diphenylethoxycarbonyl) - propyl] and [3 - (3:3 - diphenylpropoxycarbonyl) - propyl]; and of N1:N1:N2-trimethyl-N1-(4-diphenyl acetoxybutyl)- and N1:N1:N2-trimethyl-N1-[4 - di - (4 - methylphenyl) - acetoxybutyl] - ethylene - 1 - ammonium - 2 - pyrrolidinium diiodides, by treating the corresponding bases of formula II (N3 being in each case a tertiary nitrogen atom) with methyl iodide.  Examples are also given of the preparation of N1-methyl-N1 - (6 - diphenylacetoxyhexyl) - N1:N2 - di - n - propyl - ethylene - 1 - ammonium - 2 - piperidinium di-iodide by quaternization of the corresponding base with n-propyl iodide and of N1:N2 - diethyl - N1 - (4 - dicyclohexylacetoxybutyl) - N1 - methyl - ethylene - 1 - ammonium - 2-piperidinium di-iodide by the use of ethyl iodide and the appropriate base.  Starting materials.  N2 - Methyl - N1 - (2 - diphenylacetoxyethyl) - piperazine; 2 - (N - methyl - N - 2 - piperidinoethyl) - and 2 - (N - methyl - N - 2 - di - n - butylaminoethyl) - amino - 1 - diphenylacetoxyethanes; 4 - (N - methyl - N - 3 - morpholinopropyl) -, 4 - (N - methyl - N - 6 - morpholinohexyl) - and 6 - (N - methyl - N - 2 - piperidinoethyl) - amino - 1 - diphenylacetoxybutanes; and 4 - (N - methyl - N - 2 - piperidinoethyl) - amino - 1-dicyclohexylacetoxybutane are prepared by reacting a compound of the general formula <FORM:0800695/IV (b)/100> with a hydroxyamine HO[CH2]n+1.N3-Y-N4 3 - (N - methyl - N - 2 - piperidinoethyl) - amino - 1 - [di - (4 - methylphenyl) - acetoxy] - propane; N2 - methyl - N1 - [3 - di - (4 - methylphenyl) - acet oxypropyl] - piperazine; N2 - methyl - N1 - [4 - di-(4 - methylphenyl) - acetoxybutyl] - piperazine; 4 - (N - methyl - N - 2 - pyrrolidinoethyl) - amino - 1 - diphenyl - acetoxybutane; 4 - (N - methyl - N - 2 - pyrrolidinoethyl) - amino - 1 - [di - (4 - methylphenyl) - acetoxy] - butane; 4 - (N - methyl - N - 2-piperidinoethyl) - amino - 1 - [di - (4 - methylphenyl) - acetoxy] - butane; 4 - (N - methyl - N - 2 - morpholinoethyl) - amino - 1 - [di - (4 - methylphenyl) - acetoxy] - butane; 6 - (N - 2 - diethylaminoethyl - N - methyl) - amino - 1 - diphenyl - acetoxyhexane; and 4 - (N - methyl - N - 2 - piperidinoethyl) - amino - 1 - [di - (4 - methoxyphenyl) - acetoxy] - butane, are prepared by reacting with a halohydrin HO[CH2]n+1-Z to form a compound <FORM:0800695/IV (b)/111> and then reacting (V) with a diamine N5-Y-N4 (In the above Z is a halogen atom and N5 a secondary nitrogen atom.) N1-[2-Di-(4-chlorophenyl) - acetoxyethyl] - N2 - methylpiperazine is prepared by reacting the potassium salt of di-(4-chlorophenyl)-acetic acid with N1-2-chloroethyl - N2 - methylpiperazine.  1 - (N - Methyl - N - 2 - piperidinoethyl) - amino - 2 - (3:3 - diphenylpropionoxy) - ethane; 1 - (N - methyl - N - 3 - morpholinopropyl) - amino - 2 - (3:3 - diphenylpropionoxy) - ethane; 1 - (N - methyl - N - 2 diethylaminoethyl) - amino - 6 - (3:3 - diphenylpropionoxy) - hexane; 1 - (N - methyl - N - 2 - piperidinoethyl) - amino - 2 - (4:4 - diphenyl butyroxy)-ethane, are prepared by reacting an ester of formula <FORM:0800695/IV (b)/122> with a diaminoalcohol HO(CH2)n+1.N3-Y-N4 (R3 being a lower alkyl group).  N-(2-Hydroxyethyl) - N - methyl - N - (2 - piperidinoethyl) - amine is prepared by reacting ethylene bromohydrin with N - methyl - N - (2 - piperidinoethyl)-amine.  2 : 2 - Diphenylethyl and 3 : 3-diphenylpropyl N - (2 - diethylaminoethyl) - N - methylaminoacetates; 2 : 2 - diphenylethyl and 3 : 3 - diphenylpropyl - N - methyl - N - 2 - piperidinoethylaminoacetates; diphenylmethyl, 2 : 2-diphenylethyl and 3 : 3-diphenylpropyl 4 - (N - methyl - N - 2 - morpholinoethylamino) - butyrates; 2 : 2 - diphenylethyl and 3 : 3 - diphenylpropyl 5 - (N - methyl - N - 2 - piperidinoethylamino)-pentanoates; and diphenylmethyl, 2 : 2-diphenylethyl and 3 : 3-diphenylpropyl 6 - N - methyl - N - 2 - piperidinoethylamino) - hexanoates are prepared by reacting an alcohol <FORM:0800695/IV (b)/133> with a diamino-ester <FORM:0800695/IV (b)/144> (where R is a lower alkyl group).  Ethyl - N - (2 - diethylaminoethyl) - N - methylaminoacetate is prepared by reacting ethyl bromoacetate with N-(2-diethylaminoethyl)-methylamine.