Patent GB-660381-A (GB)
Title: Improvements in or relating to the production of nitrobenzyl ªÏ-amido acetophenones and derivatives thereof
Filed: 1949-02-15
Abstract: A compound <FORM:0660381/IV (b)/1> is hydrolysed with an inorganic mineral acid to yield <FORM:0660381/IV (b)/2> which is simultaneously neutralized and acylated by treatment with an acylating agent in the presence of a weakly alkaline substance to yield an acylamido ketone of formula <FORM:0660381/IV (b)/3> wherein R1 and R2 are the same or different and are hydrogen, halogen, lower alkyl or lower alkoxy radicles, X is halogen, HY is one equivalent of an inorganic mineral acid and "acyl" represents lower aliphatic acyl, halogen-substituted lower aliphatic acyl, benzoyl, substituted benzoyl and araliphatic acyl radicles.  The expression "lower" denotes radicles containing not more than four carbon atoms.  Mineral acids specified are hydrochloric, hydrobromic, hydriodic, sulphuric and phosphoric acids. The use of an alcoholic medium is preferred, alcohols specified being methanol, ethanol, n-propanol, isopropanol and n-butanol. Temperatures specified for the hydrolysis are about 0-110 DEG  C., preferably 20-30 DEG  C.  Weakly alkaline substances such as an alkali metal salt of an organic acid, an alkali or alkaline earth metal carbonate or bicarbonate, a tertiary organic base, a hydroxide of an amphoteric metal, and calcium, magnesium and ammonium hydroxides are mentioned and those specified are sodium acetate, carbonate and bicarbonate, potassium bicarbonate, calcium and magnesium carbonates, pyridine, quinoline, triethylamine and aluminium hydroxide.  Acyl halides or anhydrides are mentioned as acylating agents and may be used in aqueous or non-aqueous reaction media over a wide range of temperatures, 0-110 DEG  C. being specified.  The products are useful as intermediates in the synthesis of antibiotics, see, e.g., Specifications 652,272-652,280 and 688,023.  In examples: (1) the p-nitro-o -bromoacetophenone hexamethylene tetramine complex prepared by treating p - nitro - o  - bromoacetophenone with hexamethylene tetramine in chloroform solution is hydrolysed with absolute ethanol conc. HCl mixture to the hydrochloride of p-nitro-o -aminoacetophenone which on treatment with acetic anhydride and sodium bicarbonate, whilst water and ice is optionally added, reaches about 70 DEG  C. and on dilution with water yields p-nitro-o -acetamidoacetophenone, alternatively the above hydrochloride is treated with benzoic anhydride and sodium acetate at 45 DEG  C. whilst ice and water is added and the product p-nitro-o -benzamidoacetophenone isolated after an hour's heating, with p-nitrobenzoyl chloride and sodium bicarbonate in a similar fashion at below 75 DEG  C. to yield p-nitro-o -p1-nitrobenzamidoacetophenone and dichloroacetyl chloride and pyridine at below about 5 DEG  C. to yield p-nitro-o -dichloroacetamidoacetophenone; (2) o-methyl-p - nitro - o  - chloroacetophenone - hexamethylene tetramine complex is hydrolysed with methanol-conc. HCl mixture to give o-methyl-p-nitro-o -amino-acetophenone hydrochloride which is treated with acetic anhydride and sodium acetate at about 70 DEG  C., whilst ice and water are added, and the product o-methyl-p-nitro-o -acetamidoacetophenone isolated after dilution with water, by substituting propionic for acetic anhydride the corresponding propiono derivative is made; (3) m-methoxy-p-nitro-o -bromoacetophenone hexamethylene tetramine complex is hydrolysed with isopropanol-conc. HBr mixture to yield m-methoxy-p-nitro-o -aminoacetophenone hydrobromide which is acylated with p-toluyl anhydride and potassium carbonate at about 40 DEG  C., whilst iced water is added, and the product m-methoxy-p-nitro-o -p1-toluylamidoacetophenone isolated after dilution with water and pH adjustment to about 8 with sodium hydroxide; (4) 2-nitro-4,5-dimethyl-o -chloroacetophenone hexamethylene tetramine complex is hydrolysed with ethanol-conc. HCl mixture at 40 DEG  C. to yield 2-nitro-4,5-dimethyl-o -aminoacetophenone hydrochloride which on acylation with phenyl-acetyl chloride and pyridine at below about 5 DEG  C. yields 2-nitro-4,5-dimethyl-o -phenylacetamidoacetophenone on dilution; and in (5) m-nitro-p-chloro-o -bromoacetophenone hexamethylene tetramine complex is hydrolysed with ethanol-conc. HCl mixture to yield m-nitro-p-chloro-o -aminoacetophenone hydrochloride (sulphuric acid may be used instead of HCl and the o -iodoinstead of the o -bromocomplex) which on acylation with a -chloropropionyl chloride and dimethylaniline at below about 5 DEG  C., yields m-nitro-p-chloro-o -a 1-chloropropionamido-acetophenone on dilution with cold dil. HCl.  The hexamethylene tetramine complex used as starting material is prepared by adding the amine to p - nitro - o  - bromoacetophenone in chloroform when the complex separates and is isolated.