Patent GB-646198-A (GB)
Title: Improvements in or relating to the preparation of antispasmodic agents
IPC: C07D295/088
Filed: 1947-01-24
Abstract: Compounds of the formula R1R2C(OH)-Y-NR3R4, where R1 is aryl, cycloalkyl or heterocyclic, R2 is aryl or cycloalkyl (but R1 and R2 are not both aryl), Y is an a  : b -alkylene group and R3 and R4 are alkyl groups which may form a heterocyclic ring with the nitrogen atom, are prepared by reacting a ketone R1-CO-Y-NR3R4 with an organo-metallic compound R2M, where M is an alkali metal or halomagnesium, and hydrolysing the resulting complex.  The reactants are mixed at a temperature around 0 DEG  C., the mixture warmed to room temperature or higher and then treated with a strong acid around 0 DEG  C.  The products may be converted into salts, especially water-soluble non-toxic salts such as sulphates, phosphates, citrates, tartrates, sulphamates, hydrochlorides and hydrobromides. The products are antispasmodic agents having a high musculotropic action but little neurotropic action.  Examples show the preparation of the following 1 - phenyl - 1 - cyclohexyl - 1 - propanols: - 3 - N - piperidino, 2 - methyl - 3 - N-piperidino -, 2 - ethyl - 3 - N - piperidino -, 3-dimethylamino-, and 3-di-n-butylamino-, and also of 1 - phenyl - 1 - (2 - thienyl) - 2 - methyl-3 - N - piperidino - 1 - propanol and 1 - (2-thienyl) - 1 - cyclohexyl - 2 - methyl - 3 - di-ethylamino - 1 - propanol.  Specified radicals for R1 are phenyl, naphthyl, furyl, thienyl, pyridyl, cyclohexyl and cyclopentyl, and for R2 are phenyl, naphthyl, cyclohexyl and cyclopentyl; these may carry alkyl, alkoxy, halogen or amino-substituents, as for example methylcyclohexyl and veratryl. The heterocyclic ring formed by R3, R4 and the nitrogen atom may be that of morpholine, pyrrolidine, piperazine or thiomorpholine in addition to piperidine mentioned above.  M may be sodium, potassium, lithium or bromo-magnesium. Specification 307,304, [Class 2 (iii)], is referred to. Amino-ketones of the above formula can be obtained by (1) the Mannich reaction, e.g. a -(diethylaminomethyl) - 2 - propiothienone from ethyl 2-thienyl ketone, formaldehyde and di-ethylamine hydrochloride; (2) reaction of b -(tertiary-amino)-acyl halides with aromatic compounds, e.g. b -dimethylamino-butyric acid is converted into its acid chloride hydrochloride with thionyl chloride, and this is condensed with benzene in the presence of aluminium chloride to give b -dimethylamino-butyrophenone; (3) addition of amines of a  : b -unsaturated ketones, e.g. piperidine and crotonophenone give b -piperidino-butyrophenone.  The Specification as open to inspection under Sect. 91 refers to the production of compounds R1R2C(OH)-Y-NR3R4, where R1 and R2 may both be aryl, R2 may be heterocyclic, R3 and R4 may be cycloalkyl, and R4 may be hydrogen or benzyl, in addition to the groups defined above.  These compounds may be prepared as defined above, and in the case where R4 is hydrogen, they may be obtained by catalytic hydrogenation of the corresponding compound where R4 is benzyl (see below). Examples show the preparation of 1 : 1-diphenyl - 3 - piperidino - 1 - propanol and the 2 - methyl derivative and 1 : 1 - diphenyl - 2-methyl - 3 - diethylamino - 1 - propanol.  The following 1 : 1-diphenyl-1-propanols are mentioned: 2 - methyl - 3 - morpholino -, 2 - ethyl-3 - piperidino -, 3 - methylamino -, 3 - methyl-3 - dimethylamino -, 3 : 3 - dimethyl - 3 - di-ethylamino - and 2 - ethyl - 3 - thiamorpholino-, and also the following 1-propanols: 1-phenyl-1 - p - anisyl - 3 - dimethylamino -, 1 - phenyl-1 - cyclohexyl - 2 - 2 - dimethyl - 3 - piperidino-, 1 - phenyl - 1 - a  - naphthyl - 2 - methyl - 2-morpholino -, 1 - phenyl - 1 - p - xenyl - 2-methyl - 3 - morpholino-, 1 - phenyl - 1 - p-tolyl - 2 - methyl - 3 - morpholino -, 1 - phenyl-1 - o - tolyl - 2 - methyl - 3 - morpholino -, 1-b  - naphthyl - 1 - cyclohexyl - 3 - dimethylamino -, 1 - veratryl - 1 - cyclohexyl - 3 - di-ethylamino -, 1 : 1 - dicyclohexyl - 3 - piperidino -, 1 - a  - furyl - 1 - cyclohexyl - 3 - di-methylamino - and 1 - b  - pyridyl - 1 - cyclohexyl-3-dimethylamino.  Amino-ketones of the above formula where R4 is hydrogen can be prepared by the Mannich reaction, e.g. b -methylamino-propiophenone from acetophenone, formaldehyde and methylamine hydrochloride, or from b -alkyl-benzylamino-acid halides as in method (2) above, the benzyl group being removed, e.g. by catalytic hydrogenation, before or after reaction of the ketone with the organometallic compound.  Amines of the formula R1R2CH-Y-NR3R4 are obtained from the amino-propanols by (1) reduction with phosphorus and hydrogen iodide; (2) dehydration to an unsaturated amine with acetic anhydride, benzoyl chloride, hydrochloric acid in acetic acid, or sulphuric acid, and catalytic hydrogenation of the product, or (3) replacing the hydroxyl group by a halogen with acetyl chloride, thionyl chloride or phosphorus tribromide, and reductively clearing the product, e.g. by catalytic hydrogenation.  The production of the following 1-cyclohexyl-propanes is mentioned: 1-phenyl-2 - butyl - 3 - dibutylamino -, 1 - phenyl - 3-methylamino -, 1 - b  - naphthyl - 3 - dimethylamino -, 1 - phenyl - 2 : 2 - dimethyl - 3 - piperidino -, 1 - (2 - thienyl) - 2 - methyl - 3 - diethylamino -, 1 - a  - furyl - 3 - dimethylamino - and 1 - veratryl - 3 - diethylamino-.  This subject-matter does not appear in the Specification as accepted.