Patent GB-762184-A (GB)
Title: Improvements in or relating to the production of cinnoline derivatives
Inventor: BARBER HARRY JAMES
IPC: C07D237/28
Filed: 1953-08-13
Abstract: The invention comprises (1) a method of preparing 4-hydroxycinnoline-3-carboxylic acids and 4-hydroxycinnolines by ring closing a compound of formula <FORM:0762184/IV(b)/1> in the presence of a Friedel-Crafts type catalyst, converting the products into 4-hydroxycinnoline-3-carboxylic acids by hydrolysis and if desired, decarboxylating said acids, X being a chlorine or bromine atom and Y a carboxylic halide or ester group, while the benzene ring may contain substituents (e.g. halogen, alkyl, aryl, alkoxy, aryloxy, alkylsulphonyloxy, arylsulphonyloxy and groups convertible into amino groups by methods known per se) provided at least one of the positions ortho to the hydrazone group remains unsubstituted; (2) as new compounds methoxy- and halogeno-4-hydroxycinnoline-3-carboxylic acids, 6-methyl-4 - hydroxycinnoline - 3 - carboxylic acid and 6 - nitro - 4 - hydroxycinnoline - 3 - carboxylic acid.  The catalyst is preferably titanium tetrachloride, stannic chloride, antimony pentachloride, ferric chloride or aluminium trichloride.  The reaction is preferably conducted at a temperature of 80-120 DEG  C. in an inert steam - volatile medium, e.g. nitrobenzene. Hydrolysis and separation may be achieved simultaneously by subjecting the reaction mixture to either (1) steam-distillation under acid conditions, followed by aqueous alkali extraction and subsequent re-precipitation of the desired cinnolinecarboxylic acid; or (2) steam-distillation under alkaline conditions, followed by separation of insolubles and precipitation of the desired cinnolinecarboxylic acid.  The 4-hydroxycinnoline-3-carboxylic acids may be decarboxylated to 4-hydroxycinnolines by heating to 200-215 DEG  C. in an inert solvent such as benzophenone.  The examples describe the preparation of 6-methoxy-4 - hydroxy - and 6 : 8 - dichloro - 4 - hydroxycinnoline-3-carboxylic acids; 4-hydroxy-, 6-chloro - 4 - hydroxy -, 6 - methyl - 4 - hydroxy -, 6 - bromo - 4 - hydroxy -, 5 : 8 - dichloro - 4-hydroxy -, 7 : 8 - dichloro - 4 - hydroxy -, 8-chloro - 4 - hydroxy -, 6 - nitro - 4 - hydroxy -, 8 - methoxy - 4 - hydroxy -, 5 (or 7) - chloro-4-hydroxy-, 5 (or 7)-bromo-4-hydroxy- and 5 : 6 (or 6 : 7)-dichloro-4-hydroxycinnolines and -cinnoline-3-carboxylic acids.  Starting materials of the formula shown above are prepared by coupling an appropriate diazotized aniline or substituted aniline with a dialkyl malonate to give a dialkyl mesoxalate phenylhydrazone, partially hydrolysing this latter compound by boiling it in ethanol with one molecular equivalent of 2N-alkali metal mesoxalate phenylhydrazone and either (1) treating the above half-ester with thionyl chloride in a dry non-hydroxylic solvent to give an a  - alkoxycarbonyl glyoxylylchloride phenylhydrazone; or (2) completely hydrolysing said half-ester with excess alkali to give a mesoxalic acid phenylhydrazone which is converted to a mesoxalyl chloride phenylhydrazone by treatment with phosphorus pentachloride or thionyl chloride in a dry non-hydroxylic solvent.  The following intermediates are described: sodium ethyl mesoxalate para-chlorophenylhydrazone, ethyl hydrogen mesoxalate para-methylphenylhydrazone, a  - ethoxycarbonyl glyoxylylchloride para-methylphenylhydrazone and compounds of the formula <FORM:0762184/IV(b)/2> wherein X is -COOEt, -COOH or -COCl; R2 is H, Cl or methoxy; R3 is H, Cl or Br; R4 is H, Cl, Br, methyl, methoxy or nitro; and R5 is H or Cl.  Specifications 663,095, 663,096 and 702,664 are referred to.