Patent GB-797042-A (GB)
Title: New benzoic acid alkamine esters and a process for their manufacture
IPC: C07D295/088
Filed: 1954-10-01
Abstract: The invention comprises compounds of the general formula <FORM:0797042/IV (b)/1> (wherein R1 is an alkyl radical of 1 to 6 carbon atoms or a cycloalkyl or aralkyl radical, R2 and R3 are hydrogen atoms or alkyl, aralkyl or cycloalkyl radicals or together with the nitrogen atom represent the radical of a hydrogenated heterocyclic ring system, n is zero or 1 and X is a hydrogen atom or a hydroxyl group), and their preparation either by treating an ester or salt of 2-chloro-4-amino-benzoic acid with an alkylating, aralkylating or cycloalkylating agent to form the corresponding N-substituted compound and esterifying this with the appropriate basically substituted amino-alcohol or a hydrohalic acid ester thereof, or by treating an ester of 2-chloro-4-aminobenzoic acid with the appropriate basically substituted amino-alcohol or a hydrohalic acid ester thereof and then alkylating, aralkylating or cycloalkylating the nitrogen atom on the aromatic ring of the ester reaction product.  The re-esterification in either process is carried out at elevated temperatures and in the presence of a metal alcoholate condensing agent.  Alkylating agents referred to are alkyl halides, dialkyl sulphates or, preferably, aldehydes and hydrogen in the presence of a hydrogenation catalyst.  In examples: (1) a mixture of 2-chloro-4-amino-benzoic acid ethyl ester, butyraldehyde and methanol is hydrogenated at 35 DEG  C. in presence of Raney nickel to give 2-chloro-4-n-butylamino-benzoic acid ethyl ester, which is then heated at 120 DEG  C. with dimethylamino-ethanol and sodium methylate solution to give 2 - chloro - 4 - n - butylamino - benzoic acid dimethylamino-ethyl ester, isolated as the hydrochloride; replacement of the dimethylamino - ethanol by 1 - dimethylamino - propane-diol-(2:3) gives 2-chloro-4-n-butylaminobenzoic acid - gamma - dimethylamino - beta - hydroxy-propyl ester hydrochloride; (2) replacement of butyraldehyde by propionaldehyde in the first stage of (1) gives 2-chloro-4-n-propylamino-benzoic acid ethyl ester which with dimethylamino-ethanol and, separately, 1-dimethylamino-propane-diol-(2:3) then gives the corresponding basic esters, isolated as hydrochlorides; (3) 2-chloro-4-n-butylamino-benzoic acid methyl ester, obtained as in (1), and morpholino-ethanol give 2-chloro-4-n-butylamino-benzoic acid morpholino-ethyl ester hydrochloride; (4) the corresponding piperidino compound is prepared similarly; (5) sodium in isopropanol is added to a solution of 2-chloro-4-n-butylamino-benzoic acid (prepared as the ethyl ester in (1)) in isopropanol, then n-butylamino-ethyl chloride is added and the whole is boiled, giving, on working up, 2-chloro-4-n-butylamino-benzoic acid n-butylaminoethyl ester hydrochloride; (6) 2-chloro-4-n-butylamino-benzoic acid dimethylaminoethyl ester hydrochloride is prepared as in (5); (7) dimethylaminoethanol and sodium methylate are heated under reduced pressure at 120 DEG  C. with 2-chloro-4-amino-benzoic acid methyl ester giving 2-chloro-4-amino-benzoic acid dimethylaminoethyl ester, the hydrochloride of which on hydrogenation with butyraldehyde in presence of palladium gives the product of (6). A list of further starting materials, in which R1 has the additional values of methyl, ethyl, n-hexyl, cyclohexyl and benzyl and -NR1R2 has the additional values of amino, methylamino, mono- and di-n-propylamino, di - n - butylamino, n - hexylamino, cyclohexylamino, mono- and di-benzylamino, mono- and di-ethylamino and 1-pyrrolidino is given, and further salt-forming acids, including inorganic and organic acids, are also referred to.  Specification 321,968, [Class 2 (iii)], is referred to.