Patent GB-936074-A (GB)
Title: ªá-amino acid derivatives related to l-phenylalanine
IPC: C07D233/78
Filed: 1960-10-18
Abstract: The invention comprises: (A) compounds of the general formula <FORM:0936074/IV(a)/1> (wherein R1 represents a C15 alkyl radical, R2 represents a hydrogen atom or an alkyl radical, R3 and R4 each represent a hydrogen atom or a C1-6 alkanoyl radical, X represents a hydrogen atom, or a halogen atom or alkyl or trifluoromethyl radical in a position para to the aminoacid side chain, and n is 1, 2 or 3), the said compound being in the L absolute configuration at the a -carbon atom and being substantially free from (i.e. containing less than 5% of) the D enantiomorph; (B) the preparation of these compounds by (i) heating a compound of the general formula <FORM:0936074/IV(a)/2> (wherein m is 0 or 1 and must be less than n) with an ammonium halide and a watersoluble cyanide salt in aqueous solution to form a compound of the general formula <FORM:0936074/IV(a)/3> treating this with an aqueous acid to form a compound of the general formula, <FORM:0936074/IV(a)/4> and heating this with an aqueous hydrohalic acid under pressure to produce a compound of the general formula <FORM:0936074/IV(a)/5> or (ii) reacting the same starting material with ammonium carbonate and a watersoluble cyanide salt in aqueous solution to form a compound of the general formula <FORM:0936074/IV(a)/6> heating this with an aqueous concentrated hydrohalic acid to give the final product of (i), or with an aqueous base to produce a compound of the general formula <FORM:0936074/IV(a)/7> which is then demethylated, and then in all cases either (a) resolving the final product into its optically active forms by forming a salt with an optically active base, or (b) resolving a product of any earlier stage by microbiological means or by forming a salt with an optically active acid, and carrying out the subsequent steps with the L isomer; and further, if desired, carrying out one or both (in either order) of the following steps: (a) esterification of the carboxyl group by heating with an alkanol in the presence of a mineral acid (this being carried out after the resolution if this is effected by method (a)); (b) heating with a C1-6 alkanoic anhydride in the presence of a proton acceptor to acylate the amino group and/or the nuclear hydroxy groups (this being, if desired, carried out partly before and partly after the demethylation step of method (ii), whereby products in which R3 and R4 are different acyl groups can be obtained, a similar result being obtainable after the demethylation step by first acylating the nuclear hydroxy groups in the presence of a strong inorganic base and then the amino group in the presence of a weak organic base); (C) the preparation of L-a -methyl-b -(3,4-dihydroxyphenyl)-alanine substantially free from its D enantiomorph by heating the racemic compound with excess of acetic anhydride in the presence of a proton acceptor, agitating or heating the resulting DL-triacetyl derivative with quinine in acetone, cooling to precipitate the quinine salt of the L-triacetyl compound, and either heating this with aqueous acid to give the desired product or liberating the L-triacetyl compound by adding a solution of the quinine salt in methanol to an aqueous solution of sodium oxalate, removing the diquinine oxalate and removing the acetyl groups by hydrolysis, or by reacting DL-a -methyl-b - (3,4-dimethoxyphenyl)-alanine with acetic anhydride in the presence of a proton acceptor, reacting the resulting DL-triacetyl derivative with L-a -phenylethylamine in an organic solvent at elevated temperature, recovering crystalline L-L-salt and dissolving it in dilute aqueous alkali, extracting the liberated L-a -phenylamine with a water-immiscible organic solvent, acidifying the aqueous solution with a dilute aqueous mineral acid to form L-N-acetyl-a -methyl-b -(3,4-dimethoxyphenyl)-alanine and hydrolysing this with 30-50% (by weight) aqueous hydrobromic acid at a temperature between 90 DEG C. and reflux temperature; and (D) pharmaceutical compositions containing a compound (A) and an inert pharmaceutical diluent. Ketones of the second general formula above are prepared according to Scheme 1 (A) or (B) below:- <FORM:0936074/IV(a)/8> 4-Chloro-, 4-bromo-, 4-iodo- and 4-fluoro-2,3-dimethoxybenzaldehyde are prepared from 4-nitro-2,3-dimethoxybenzoic acid by reducing the nitro group to an amino group with sodium sulphide, replacing the amino group by halogen by a Sandmeyer or Sandmeyerlike reaction (using cuprous chloride, cuprous bromide, potassium iodide or fluoroboric acid to decompose the diazonium salt), and converting the carboxyl group to an aldehyde group either by oxidation of the hydrazide of the acid with potassium ferricyanide or by distillation of a mixture of the calcium salt and calcium formate.  4-Methyl-2,3-dimethoxybenzaldehyde is prepared by methylating 4-methyl-2,3-dihydroxybenzaldehyde with dimethyl sulphate in the presence of alkali. 4-Trifluoromethyl- 2,3-dimethoxybenzaldehyde is prepared from 4-methyl-2,3-dimethoxybenzaldehyde by oxidizing the aldehyde group to carboxyl with hydrogen peroxide, reacting the carboxyl group with sulphur tetrafluoride to convert it to CF3, oxidizing the methyl group to carboxyl with dichromate and reducing the carboxyl group to an aldehyde group. 4-Chloro- and 4-fluoro-3,5-dimethoxybenzaldehyde are prepared from 4-nitro-3,5-dihydroxytoluene by methylating the hydroxy groups, reducing the nitro group to an amino group, replacing this by chlorine or fluorine and converting the methyl group to an aldehyde group by side-chain chlorination followed by heating with hexamethylenetetramine and water. 4-Methyl-3,5-dimethoxybenzaldehyde is prepared from 3,5-dimethoxy-p-toluic acid by oxidizing its hydrazide with ferricyanide or distilling a mixture of its calcium salt and calcium formate. 4-Trifluoromethyl- 3,5-dimethoxybenzaldehyde is prepared from 4-nitro-3,5-dihydroxytoluene by methylating the hydroxy groups, reducing the nitro group to an amino group, replacing this by cyano by the Sandmeyer reaction, acid hydrolysis of the nitrile to the carboxylic acid, converting the carboxyl group to CF3 with sulphur tetrafluoride and converting the methyl group to an aldehyde group by side-chain chlorination followed by heating with hexamethylenetetramine and water. 4-Fluoro- and 4-iodo-3-methoxybenzaldehyde are prepared by methylating 4-nitro-3-hydroxybenzaldehyde, reducing the nitro group to an amino group and replacing this by fluorine or iodine. 4-Trifluoromethyl- 3-methoxybenzaldehyde is prepared from 2-methoxy-4-toluic acid by converting the carboxyl group to CF3 with sulphur tetrafluoride, and converting the methyl group to an aldehyde group by sidechain chlorination followed by heating with hexamethylenetetramine and water. The pharmaceutical preparations, which have anti-hypertensive activity, may be in forms suitable for oral or parenteral administration, e.g. tablets.