Patent GB-719237-A (GB)
Title: The manufacture of basic ketones
IPC: C07D277/44
Filed: 1952-02-08
Abstract: The invention comprises basic ketones of the formula <FORM:0719237/IV (b)/1> p  in which R1 and R2 each represent an alkyl radical having up to 6 carbon atoms or together represent a four- or five-membered divalent residue, R3 represents a methylene group or a methylene group containing as a substituent an alkyl radical having up to 6 carbon atoms, R4 represents the residue of pyridine, thiazole or pyrimidine a ring carbon atom of which is directly bound to the central C-atom, R5 represents a phenyl, hydroxy-phenyl or alkoxy-phenyl radical and R7 represents an alkyl radical containing up to 6 carbon atoms, and salts of such basic ketones.  Such compounds are obtained by reacting a carboxylic acid ester of the formula <FORM:0719237/IV (b)/2> with an alkyl magnesium halide, and, if desired, converting the free base so obtained into a salt.  The carboxylic acid esters are produced by reacting an ester of the formula R4R5CH.COO.Alkyl with a basically substituted alkyl halide. Better yields are generally obtained when "Alkyl" in the ester is a branched alkyl radical.  Salts of the above compounds mentioned are those with sulphuric, hydrochloric, phosphoric, acetic, propionic, benzoic and ethane sulphonic acids, and (for identification purposes) the succinic and maleic acid salts.  In an example: (1) a  - phenyl - a  - pyridyl - (2) - g  - N - pyrrolidino-butyric acid ethyl ester (prepared by reacting phenyl-pyridyl-(2)-acetic acid ethyl ester and N-b -chlorethyl-pyrrolidine in the presence of sodamide) is reacted with ethyl magnesium bromide to give 1-N-pyrrolidino-3-phenyl-3-pyridyl-(2)-hexanone, which is converted to its succinate.  Similarly prepared are (2) 1 - dimethylamino - 3 - phenyl - 3 - pyridyl - (21) - hexanone - (4) from a  - phenyl - a  - pyridyl - (2) - g  - dimethylamino - butyric acid ethyl ester; (3) 1-N-morpholino-3-phenyl-3-pyridyl-(21)-hexanone-(4) from a -phenyl-a -pyridyl-(2)-g -N-morpholino-butyric acid ethyl or isopropyl ester; (4) an isomeric mixture of 2-dimethylamino-4-phenyl-4-pyridyl-(21)-heptanone-(5) and 1 - dimethylamino - 2 - methyl - 3 - phenyl - 3-pyridyl-(21)-hexanone-(4) from an isomeric mixture of a -phenyl-a -pyridyl-(2)-g -dimethylamino-valeric acid and a -phenyl-a -pyridyl-(2)-b  - methyl - g  - dimethylamino - butyric acid ethyl ester; (5) 1-dimethylamino-3-phenyl-3-pyridyl - (41) - hexanone - (4) from phenyl - pyridyl-(4)-acetic acid ethyl ester; (6) 1-dimethylamino - 3 - phenyl - 3 - thiazolyl - (21) - hexanone-(4) from a -phenyl-a -thiazolyl-(2)-g -dimethylamino-butyric acid ethyl ester; (7) 1-N - pyrrolidino - 3 - phenyl - 3 - thiazolyl - (21) - hexanone-(4) from a -phenyl-a -thiazolyl-(2)-g -N-pyrrolidino-butyric acid methyl ester; (8) 1 - N - piperidino - 3 - phenyl - 3 - thiazolyl - (21) - hexanone - (4) from a  - phenyl - a  - thiazolyl - (2) - g  - N - piperidino - butyric acid methyl ester; (9) 1-N-morpholino-3-phenyl-3-thiazolyl-(21)-hexanone-(4) from a -phenyl-a -thiazolyl-(2)-g -N-morpholino-butyric acid methyl ester; (10) 1 - diethylamino - 3 - phenyl - 3 - thiazolyl-(21) - hexanone - (4) from a  - phenyl - a  - thiazolyl - (2) - g  - diethylamino - butyric acid ethyl ester; (11) 1-dimethylamino-3-(31-methoxy - phenyl) - 3 - thiazolyl - (21) - hexanone - (4) from a  - (31 - methoxy - phenyl) - a  - thiazolyl - (21) - g  - dimethylamino - butyric acid methyl ester.  The product is converted to the corresponding 31-hydroxy-phenyl derivative by boiling with hydrobromic acid; (12) 1-dimethylamino - 3 - phenyl - 3 - pyrimidyl - (21) - hexanone - (4) from a  - phenyl - a  - pyrimidyl - (2) - butyric acid ethyl ester.  Most of the products are converted to their succinate or maleate.  In example (4) the product is separated into its isomers by fractional crystallization of the maleates.  In each example the preparation of the specified starting material by a method analogous to that employed in the corresponding stage in example (1) is described.