Patent GB-681102-A (GB)
Title: Aryl esters of acid phosphorus compounds
IPC: C07F9/38
Filed: 1950-01-30
Abstract: The invention comprises basically substituted aryl esters of acid derivatives of phosphorus, of the general formula <FORM:0681102/IV (b)/1> (wherein Ar represents phenyl or naphthyl carrying as substituent at least one dialkylamino, dialkylaminoalkyl, piperidino, piperidinoalkyl, morpholino or morpholinoalkyl group, n is 1, 2 or 3, and X represents halogen, amino, substituted amino, hydroxy, substituted hydroxy, alkyl, cycloalkyl, aralkyl or aryl, X being absent when n is 3 and the two X's being identical or different when n is 1), and salts of such esters, and the manufacture thereof by reacting a basically substituted phenol or naphthol, ArOH, or an alkali metal derivative thereof, with a halide of an acid derivative of phosphorus, of the formula <FORM:0681102/IV (b)/2> (wherein Y represents halogen), advantageously in a relatively inert solvent or diluent, and, if desired, reacting the product, if it still contains halogen, with ammonia or a primary or secondary amine, or with an alkali, or with ammonium or alkali metal fluoride, or with an alkyl or aryl magnesium halide.  When the free phenol or naphthol is used, the product is obtained in the form of a hydrohalide unless, as is preferred, the reaction is carried out in the presence of an acid acceptor (advantageously a tertiary amine).  The products have therapeutic utility as cholinesterase inhibitors.  In examples: (1) phosphorus oxychloride is reacted with 3 molecular proportions of m-dimethylaminophenol in benzene in the presence of triethylamine or pyridine to produce tri-(m-dimethylaminophenyl) phosphate, which may be converted into its methiodide, picrate, methomethyl sulphate, hydrochloride, sulphate, perchlorate and oxalate; (2) phosphorus oxychloride is reacted with 3 molecular proportions of m-diethylaminophenol in aqueous caustic soda; (3) phosphorus oxychloride is reacted with o-dimethylaminophenol as in (1), or with a benzene suspension of sodium o-dimethylaminophenate; (4)-(9) the o-dimethylaminophenol in (3) is replaced by p-dimethylamino-or o- or p-dimethylaminomethyl-phenol, 1-dimethylaminomethyl- or 1-piperidinomethyl-2-naphthol, or 2-piperidinomethyl-1-naphthol; (10) phosphorus trichloride is reacted with 3 molecular proportions of m-dimethylaminophenol is benzene in the presence of triethylamine, or with a suspension of sodium m-dimethylaminophenate in ether, producing tri-(m-dimethylaminophenyl) phosphite; (11) the m-dimethylaminophenol in (10) is replaced by the p-isomer; (12) phosphorus thiochloride is reacted with 2 molecular proportions of p-dimethylaminophenol in benzene in the presence of triethylamine to form di-(p-dimethylaminophenyl)-thiophosphoryl chloride; (13) the p-dimethylaminophenol in (12) is replaced by the m-isomer; (14) the phosphorus thiochloride in (13) is replaced by the oxychloride, and the resulting di - (m - dimethylaminophenyl) - phosphoryl chloride is reacted with ammonium fluoride to give the corresponding phosphoryl fluoride; (15) the product of (12) is treated with ammonium or sodium fluoride in isopropanol; (16) the product of (12) is reacted with sodium p-dimethylaminophenate in isopropanol to produce tri-(p-dimethylaminophenyl) thiophosphate; the same product is obtained by reacting phosphorus thiochloride with 3 molecular proportions of p-dimethylaminophenol in toluene in the presence of triethylamine and phosphorus trichloride; (17)-(20) the product of (12) is reacted with a solution of sodium in isopropanol, aqueous ammonia, aqueous methylamine or a solution of dimethylamine in benzene, producing respectively di - (p - dimethylaminophenyl) - isopropyl thiophosphate and the di-(p-dimethylaminophenyl) esters of amino-, methylamino-and dimethylamino-thiophosphonic acids; (21) the di-(m-dimethylaminophenyl) ester of dimethylaminophosphonic acid is prepared by reacting di - (m - dimethylaminophenyl) - phosphoryl chloride with excess dimethylamine in benzene, or by reacting dimethylaminophosphonyl chloride with 2 molecular proportions of sodium m-dimethylaminophenate, or of m-dimethylaminophenol in the presence of triethylamine; (22) dimethylaminophosphonyl chloride is reacted with an equimolecular proportion of m-dimethylaminophenol in benzene in the presence of triethylamine to yield the m - dimethylaminophenyl ester of chlorodimethylaminophosphinic acid; (23) the product of (22) is reacted with dimethylamine in benzene to produce the m-dimethylaminophenyl ester of di-(dimethylamino)-phosphinic acid; (24) the phosphorus thiochloride in (12) is replaced by phosphorus thiobromide; (25) di-(m-dimethylaminophenyl)-thiophosphoryl chloride and sodium m-dimethylaminophenate are reacted as in (16); (26) and (27) the o-dimethylaminophenol in (3) is replaced by p-dimethylaminocarvacrol or p-(3-dimethylaminobutyl)-phenol; (28) a solution of di-(m-dimethylaminophenyl)-phosphoryl chloride in isopropanol is treated with aqueous caustic soda to give di-(m-dimethylaminophenyl) sodium phosphate; (29) the di - (m p  - dimethylaminophenyl) - phosphonyl chloride in (21) is replaced by the diethylamino compound; (30) tri-(m-diethylaminophenyl) thiophosphate is prepared by the method of (16); (31) and (32) di-(p-dimethylaminophenyl)-thiophosphoryl chloride is heated with di-n-butylamine or aniline; (33)-(36) benzene phosphorus oxydichloride is reacted in benzene in the presence of triethylamine with two molecular proportions of m-, o- or p-dimethylamino-or m-diethylamino-phenol to produce diaryl esters of benzenephosphonic acid; (37)-(39) the di-(m-dimethylaminophenyl) esters of heptane- and cyclohexane-phosphonic acids and the di-(o-dimethylaminomethylphenyl) ester of benzenephosphonic acid are analogously prepared; (40) the m-diethylaminophenyl ester of (p)-benzene-(p)-dimethylaminophosphinic acid is prepared by reacting benzene phosphorus oxydichloride successively with equimolecular proportions of m-diethylaminophenol and di-methylamine; (41) and (42) benzene phosphorus thiodichloride is reacted in benzene and isopropanol with sodium m-diethylaminophenate or o-dimethylaminomethylphenate to form esters of benzenethiophosphonic acid.