Patent GB-716901-A (GB)
Title: Improvements relating to the preparation of substituted quinazolones
IPC: C07D401/06
Filed: 1952-03-04
Abstract: The invention comprises (1) the preparation of quinazolones of the formula <FORM:0716901/IV (b)/1> where R is hydrogen or at least one substituent and R1 is hydrogen or at least one substituent attached to the nucleus via an oxygen atom, by catalytic hydrogenation of the tetrahydro pyridine derivatives of the formula <FORM:0716901/IV (b)/2> with not more than 1.4 molar equivalents of hydrogen in an inert solvent containing at least one molar equivalent of a non-oxidizing acid having a dissociation constant of at least 1 X 10-2; and (2) the products of the formula I excluding febrifugine (R=H, R1=3-hydroxyl) and the compounds of Specification 713,767 (R1=3-hydroxyl, R=one or more of halogen, alkoxy, aralkoxy, aryloxy, hydroxy, alkyl, aryl, acyl and carboxyl).  The starting materials (II) are obtained by acid hydrolysis of 3-(2 : 4-dioxo-8-acylamino-octyl)-4-quinazolones to give salts of the corresponding 8-amino compounds and treating the latter with bases. Suitable reaction conditions are given for the various steps.  In the examples: (1) N-(3-bromopropyl)-phthalimide is condensed with methyl acetoacetate to give 1-phthalimido-5-hexanone (isolated as sodium bisulphite compound), which in turn is condensed with ethyl 4-quinazolone - 3 - acetate to yield 3 - (2 : 4 - dioxo - 8 - phthalimido - octyl) - 4 - quinazolone; treatment of the latter first with hydrochloric acid and then with ammonia produces 3-(2-oxo-3-tetrahydropyridyl-propyl)-4-quinazolone, reduced by the process of the invention to 3 - [2 - oxo - 3 - (21 p  - piperidyl) - propyl] - 4 - quinazolone (dihydrochloride); (2) N-(3-iodo-2-methoxypropyl)-phthalimide is made from N-allylphthalimide by treatment with methanolic mercuric acetate, aqueous potassium iodide and iodine; this is condensed with methyl acetoacetate to give 1-phthalimido-2-methoxy-5-hexanone (isolated as 2 : 4-dinitrophenylhydrazone), which is hydrolysed to the free 1-amino compound (hydrochloride) and re-acylated to yield 1-benzamido-2-methoxy-5-hexanone (isolated as 2 : 4-dinitrophenylhydrazone); this ketone is reacted with ethyl 4 - quinazolone - 3 - acetate, yielding 3 - (2 : 4 - dioxo - 7 - methoxy - 8 - benzamido - octyl) - 4 - quinazolone, which forms a copper derivative; from the latter successive treatments with sulphuric acid-, ammonia and hydrobromic acid produce 3 - [2 - oxo - 3 - (51 - hydroxy - tetrahydropyridyl) - propyl] - 4 - quinazolone; reduction of the latter by the process of the invention gives 3 - [2 - oxo - 3 - (51 - hydroxy - 21 - piperidyl) - propyl] - 4 - quinazolone (dihydrochloride); (3) ethyl 5-methyl-4-quinazolone-3-acetate (from 5-methyl-4-quinazolone and ethyl chloroacetate) is condensed with the intermediate of (2) and reduced to 3-[2-oxo-3-(51-hydroxy-21 - piperidyl) - propyl] - 5 - methyl - 4 - quinazolone (dihydrochloride); (4) 5-chloro-4-quinazolone (from 6-chloranthranilic acid and formamide) is reacted with ethyl chloracetate to yield ethyl 5-chloro-4-quinazolone-3-acetate; the latter by condensation with the intermediate of (2) and reduction gives 3-[2-oxo-3-(51 - hydroxy - 21 - piperidyl) - propyl] - 5 - chloro - 4 - quinazolone (dihydrochloride).  The reduction step is preferably carried out at 0-140 DEG  C. (especially 20-35 DEG  C.) at a pressure of 1-3 atmospheres with a platinum or palladium catalyst. Suitable solvents are water, alcohol, dioxane, glycol ethers and acetic acid.  The non-oxidizing acid may be hydrochloric, hydrobromic, sulphuric, phosphoric or toluenesulphonic, in a concentration between N and 21N, especially 4N-8N.  In the above formul  R may be hydrogen, chlorine, bromine, fluorine, methoxy, ethoxy, benzyloxy, phenoxy, hydroxy, methyl, ethyl, propyl, butyl, phenyl, acyl, acyloxy, carboxylic acid, amide or ester; R1 may be hydrogen, hydroxy, methoxy, ethoxy, propoxy, phenoxy, benzyloxy, acetoxy, or benzoyloxy.