Patent GB-808045-A (GB)
Title: Novel pyridones and process for the manufacture thereof
Inventor: COHEN AARON
Filed: 1955-12-13
Abstract: The invention comprises 4-methyl-5-alkyl pyridones of the general formula <FORM:0808045/IV (b)/1> wherein R represents an alkyl group and their preparation by heating a 2,6-dichloro-4-methyl-5-alkyl pyridine with a molecular proportion of an alkali metal derivative of an alcohol <FORM:0808045/IV (b)/2> wherein R1 and R2 represent hydrogen, an alkyl group or the phenyl group and, when the group in the 2-position of the resulting product is an aralkoxy group, catalytically hydrogenating the product so as to replace the 6-chloro substituent therein by a hydrogen atom and convert the aralkoxy group to a keto-group or, when the group in the 2-position of the product is an alkoxy group, replacing the 6-chloro substituent therein by a hydrogen atom by catalytic hydrogenation and converting the alkoxy group to a keto-group by acid hydrolysis, these two steps being carried out in either sequence; any isomeric 3-alkyl 4-methyl compound formed in appreciable quantity in the process is separated off after any stage, for example by crystallization, distillation or chromatography.  The catalytic hydrogenation may be effected with hydrogen and a palladium catalyst or with zinc and nickel in the presence of water.  It is stated that the formation of the pyridones by reaction of the appropriate 3-alkyl-4-methyl pyridine with an alkali metal amide followed by treatment of the resulting amines with nitrous acid yields predominantly the 3-alkyl-4-methylpyridone - 2 isomers. The 4 - methyl 4 - alkyl pyridones may be used in the synthesis of compounds having the structure of emetine (see Specification 808,046).  In examples: (1) 2 : 6-dichloro - 4 - methyl - 5 - ethyl pyridine is refluxed with sodium in dry benzyl alcohol; the resulting 2-benzyloxy-6-chloro-4-methyl-5-ethyl pyridine is isolated in admixture with some of its isomer by ethereal extraction and fractional distillation and is reduced in methanol by hydrogen and a palladium catalyst; the desired 4-methyl - 5 - ethyl pyridone - 2 is precipitated in the form of its hydro chloride by addition of ethyl acetate, the isomeric compound present remaining in solution, and is converted into the free base; (2) the pyridino reagent used in (1) is refluxed with a xylene solution of the potassium salt of benzhydrol and 6-chloro-2-(a -phenyl-benzoxy) 4 - methyl - 5 - ethyl pyridine free from its isomer is obtained on crystallization of the product from methanol; the desired isomer is then reduced as in (1) in ethanol and the product is partitioned between benzene and dilute aqueous NaOH to recover 4-methyl-5-ethyl pyridone; (3) the pyridino reagent of (1) is refluxed with sodium isopropoxide in xylene yielding 2 - isopropoxy - 6 - chloro - 4 - methyl-5-ethyl pyridine and some of its isomer and the product is hydrogenated as in (1) and the resultidine is heated with concentrated HCl at 118 DEG  C. in a sealed tube or refluxed with aqueous HBr and the product is extracted with chloroform and crystallized from ethyl acetate to recover the desired pyridone free from its isomer; alternatively, the isopropoxy-chloro-pyridine intermediate is first subjected to the acid hydrolysis and the resulting 6-chloro-pyridone is separated from the unwanted isomer by crystallization from ethyl acetate and alcohol and is then hydrogenated using hydrogen and palladium catalyst in the presence of sodium acetate or using zinc and Raney nickel in refluxing aqueous NH4Cl.