Patent GB-798320-A (GB)
Title: The preparation of 3-pyridinols and intermediates thereof
IPC: C07D213/66
Filed: 1954-11-30
Abstract: The invention comprises compounds of the formula <FORM:0798320/IV (b)/1> (wherein R is alkyl, hydroxyalkyl, alkoxyalkyl or cycloalkyl and contains at most 6 carbon atoms, R2 and R4 are each hydrogen or alkyl and Y is hydrogen or CH2OR1, R1 being hydrogen or acyl, provided that when R4 and Y are hydrogen R2 is alkyl), and the N-acylates, carbamates and N-mono- and N-di-carbamoyl derivatives thereof; the preparation of the free or protected amines by oxidation of compounds of the formula <FORM:0798320/IV (b)/2> (wherein R2, R4 and Y have the above meanings and the amino group may be protected) electrolytically in solution in an alcohol ROH in presence of an electrolyte soluble therein; or by oxidation of these compounds with chlorine or bromine in the anhydrous alcohol ROH; the preparation of the free amines (I) by oxidation of the free amines (II) with chlorine or bromine in aqueous alcohol ROH at a temperature between about room temperature and - 80 DEG  C.; and a process wherein the free or protected amines (II) are oxidized in solution in the alcohol ROH to the free or protected amines (I) and these are then hydrolysed, with or without a previous saponification to remove any groups protecting hydroxy groups and/or any groups protecting the amino group, by being stored or heated in an acid medium or heated in a neutral medium to give 3-pyridinols of the formula <FORM:0798320/IV (b)/3> (wherein Z is hydrogen or CH2OH), the limitation on the values of Y, R2 and R4 not applying in these last 3 processes.  Suitable soluble electrolytes for use in the first process are ammonium and lithium bromides or mixtures thereof, sulphuric acid, boron trifluoride or an organic complex thereof such as the etherate or the acetic acid complex, a nitrate, a thiocyanate, a formate or a salt of a halogen hydracid with an organic base, e.g. pyridine hydrochloride. Suitable alcohols are methanol, ethanol and 2-ethoxyethanol and the electrolysis may be performed with the apparatus described in Acta. Chem. Scand. 6, 1952, page 531, or 7, 1953, page 234, advantageously at between 0 DEG  and - 30 DEG  C. and at a terminal voltage of 3 to 20 volts, the current strength preferably being from 0.1 to 10 amperes.  In the oxidation with chlorine or bromine in an anhydrous alcohol, which is preferably performed at - 10 DEG  to - 80 DEG  C., a neutralizing agent, e.g. an alkali metal hydroxide or a salt of an inorganic base with a weak acid, may be added simultaneously or subsequently.  In examples: (1) to (4) 2-(alpha - acetamidoethyl) - 3 : 4 - bis - (acetoxymethyl)-furan (hereinafter called compound A) is electrolytically oxidized in methanol containing ammonium bromide, the resulting solution is poured into sodium methylate and evaporated in vacuo leaving a mixture of 2-(alpha-acetamidoethyl) - 3 : 4 - bis - (hydroxymethyl) - 2 : 5 - dimethoxy-2 : 5-dihydrofuran with the mono- and di-acetoxymethyl derivatives thereof, this mixture on refluxing with sodium hydroxide gives 2 - (alpha - aminoethyl) - 3 : 4 - bis - (hydroxymethyl) - 2 : 5 - dimethoxy - 2 : 5 - dihydrofuran and this on refluxing with hydrochloric acid gives pyridoxine hydrochloride; (5) compound A is oxidized with bromine in anhydrous methanol, potassium acetate is added and the mixture is then worked up and hydrolysed as in (1) to yield pyridoxine hydrochloride; (6) compound A is refluxed with sodium methoxide in methanol, acetic acid is added and the mixture is then oxidized as in (5) and hydrolysed as in (1) to give pyridoxine hydrochloride; (7) the procedure is as in (5) except that the potassium acetate is added initially; (8) 2 - (alpha - aminoethyl) - 3 : 4 - bis-(hydroxymethyl)-furan is oxidized in aqueous methanol with chlorine and the reaction mixture is boiled with water and evaporated to dryness, giving pyridoxine hydrochloride directly; (9) 2-acetamidomethyl-2 : 5-dimethoxy-2 : 5-dihydrofuran is refluxed with sodium hydroxide to give 2-aminomethyl-2 : 5-dimethoxy-2 : 5-dihydrofuran and this on refluxing with hydrochloric acid gives 3-pyridinol hydrochloride; (10) 2-acetamidomethyl-2 : 5-dimethoxy-2 : 5-dihydrofuran is refluxed with hydrochloric acid and the resulting solution is evaporated to dryness and made alkaline to give 3-pyridinol; (11) furfurylamine and urea are refluxed together, the product is electrolytically oxidized in methanol containing ammonium bromide and the electrolysate is evaporated with sodium methoxide and then boiled with hydrochloric acid to give, on neutralization, 3-pyridinol; (12) 2-acetylfuranoxime is catalytically reduced in the presence of acetyl chloride to 2-(alpha-aminoethyl)-furan, this on refluxing with urea and hydrochloric acid gives 2-(alpha-ureidoethyl)-furan and this on electrolytic oxidation, evaporation of the electrolysate with sodium methylate and refluxing with hydrochloric acid gives 2-methyl-3-pyridinol hydrochloride; (13) furfurylamine and methyl chloroformate give 2 - (carbomethoxyamidomethyl)-furan which on electrolytic oxidation in methanol gives 2 : 5-dimethoxy-2-carbomethoxyamidomethyl-2 : 5-dihydrofuran and this on refluxing with hydrochloric acid gives 3-pyridinol; (14) 2-acetylfuranoxime is hydrogenated as in (12), the product is condensed with methyl chloroformate to give 2-(alpha-carbomethoxyamidoethyl) - furan, this is electrolytically oxidized in methanol to 2 : 5-dimethoxy-2-(alphacarbomethoxyamidoethyl) - 2 : 5 - dihydrofuran and this on refluxing with hydrochloric acid gives 2-methyl-3-pyridinol hydrochloride; (15) 2-acetylfuranoxime is catalytically reduced in the presence of acetic anhydride to 2-(alpha-acetamidoethyl)-furan (also obtainable by acetylation of the free amine), this is electrolytically reduced in methanol to 2 : 5-dimethoxy-2 - (alpha - acetamidoethyl) - 2 : 5 - dihydrofuran, this is saponified to 2 : 5-dimethoxy-2-(alpha-aminoethyl)-2 : 5-dihydrofuran and this on acid hydrolysis gives 2-methyl-3-pyridinol hydrochloride; (16) 2-acetamidomethyl-furan, prepared by acylation of furfurylamine, is oxidized with bromine in anhydrous methanol containing potassium acetate to 2 : 5-dimethoxy-2-(acetamidomethyl)-2 : 5-dihydrofuran which is then converted to 3-pyridinol as in (9); (17) the reaction product of furfurylamine and urea is oxidized as in (16) and the product is refluxed with hydrochloric acid to give 3-pyridinol; (18) furfurylamine is oxidized with chlorine in aqueous methanol and the product is heated and then treated with potassium carbonate giving 3-pyridinol; (19) bromine replaces the chlorine of (18), the 3-pyridinol being obtained via its hydrobromide; (20) ethanol replaces the methanol of (19); (21) 2-carbomethoxy-5-isopropyl-furan is electrolytically oxidized in methanol containing sulphuric acid, the product is evaporated with sodium methylate to give 2 : 5 - dimethoxy - 2 - carbomethoxy - 5 - isopropyl-2 : 5-dihydrofuran, this is stood with ammonia in aqueous methanol, the resulting solution is worked up and then reduced with lithium aluminium hydride giving 2:5 - dimethoxy - 2 - aminomethyl - 5 - isopropyl - 2:5 - dihydrofuran and this is refluxed with hydrochloric acid to give on neutralization, 6-isopropyl-3-pyridinol. Starting material. 2-(Alpha-aminoethyl)-3:4-bis-(hydroxymethyl)-furan may be prepared by reductive amination of 2-acetyl-3:4-bis-(hydroxymethyl or acetoxymethyl)-furan. Specifications 682,735 and 798,319 are referred to.