IL46953A - Triazolo-quinolines and their preparation - Google Patents

Description

Novel triazolo-quinolines and their pxepaxation The present invention relates to certain novel 1 substituted 5-pbenyl-s-triaolo ( ,3-a) quinoline of iormula ITs wherein 1 is selected from the group consisting of hydrogen and alfcyl of 1 to 3 carbon atoms, inclusive; wherein Bg, are hydrogen, or chlorine and B3 and B5 are hydrogen, and to a process for the preparation of these. he process of the invention comprises t 1. Refluxing a 2-chloro- -phenylquinoline (II) with hydrazine hydrate to give a 2-hydrezino«- - phenylquinoline (III); 2. Befluxing the 2*hydrasino* ->ph6nylquinoline (III) with a trialkyl orthoacylate e.g. with triethyl ortho ormate, triethyl orthoacetate, triethyl orthopropionate or trimethyl orthobutyrate, in an inert organic solvent to give the corresponding 1- substituted -5*phenyl-e»triazolo»( ,3a) quinoline (IV).

She novel compounds and the process of production therefore can be illustratively represented as follows: The novel quinolines are valuable intermediates in the production of various benzophenone derivatives and especially in the production of triazolobenzodiazepines described and claimed in our copending patent application No. 38505, from which the present patent application has been divided out.

The starting materials of formula II of this invention, substituted and unsubstituted 2-chloro-4-phenylquinolines, are partially known in the art e.g. G.A. Reynolds and C.R. Hauser, J.Am. Chem. Soc. 72, 1852 (1950) or are prepared according to the methods shown in the Preparations.

In carrying out the process of the present invention, a 2-hydraaino-4-pheny1quino1ine II is heated with hydrazine hydrate.

In the preferred embodiment of this invention, the reaction is carried out at the reflux temperature of the mixture; however, temperatures between 25 and 118°C. with a reaction time of 1 to 18 hours are opera 1- and 2-propanol can be used but is not necessary. In the preferred embodiment of the invention, one hour reflux under nitrogen is sufficient. At the termination of the reaction, the mixture is concentrated, poured into water and the insoluble product collected on a filter. Purification is carried out by conventional means such as extraction, chromatography or more commonly recrystallization to obtain the corresponding 2-hydrazino-4-phenylquinoline III.

Compound III is converted to the corresponding 1-substituted -5-phenyl-s-triazolo £"4,3-§7 quinoline (IV) by heating with an ortho lower alkanol ester of a carboxylic acid e.g. trimethyl or triethyl orthoacetate. Temperatures between 80-170*C are operative in this reaction. Solvents such as heptane, octane, methylcyclohexane, benzene, toluene, xylene (o,m, or p) can be used but are not necessary. In the preferred embodiment of this invention, the reaction is carried out in a nitrogen atmosphere with a higher boiling solvent e.g. xylene, at the reflux temperature of the reaction mixture. Lower alkanols, produced during the reaction by decomposition of the ortho ester, can be removed by distillation. The product IV is recovered and purified by conventional procedures e.g. concentration of the reaction mixture to dryness, extraction, chromatography and/or recrystallization.

The following examples are illustrative of the processes and products of the present invention, but are not to be construed as limiting: Preparation 1 - 2' -Benzoyl-4' -chloroacetanilide Acetyl chloride (81.3 g., 1037 mole)was added to a stirred solution of 2-amino-S-chlorobenzophenone (200.0g., 0.864 mole) and pyridine (68/4 g., 0.864 mole) in dry ether (4 1.); the mixture was kept at ambient temperature for 2 hours and treated with 500 ml. of water. The layers were separated and the ether layer was dried over anhydrous sodium sulfate and concentrated. Crystallization of the residue from ethyl acetate-Skellysolve B hexanes gave: 124.0 g. of 21-benzoyl-41 -chloroacetanilide of melting point 114-115°C. TWo more crops of 2'-benzoyl-4* -chloroacetanilide also were obtained: 67.8 g. of melting point 113.5-114.5*C and 33.0 g. of melting point 113-114*C.

/" Preparation 2 6-Chloro-4-phenyl-2(lH)-quinoline The procedure (reaction of 21-benzoyl-5'-chloroacetanilide with sodium hydroxide) of A.E. Drukker and C.I. Judd, J., Heterocyclic Chem. 3, 359 (1966) was used for this preparation. The yield was 77% . Two other preparations have been described: S.C. Bell, T.S. Sulkowski, C.Gochman and S.J. Childress, J.Org. Chem.27, 562 (1962); G.A. Reynolds and C.R. Hauser, J.Amer. Chem.Soc. 72, 1852 (1950).

Preparation 3 2,6-Dichloro-4-phen lquinol ne The procedure of A.E. Drukker and C.I. Judd , J. Heterocyclic Chem 3, 359 (1966) was used for this preparation. The yield was 62%.

Example 1 6-Chloro-2-hydrazino-4-phenylqulnoline A stirred mixture of 2,6-dichloro-4-phenylquinollne (2.7 g. , P.01 mole) was refluxed with hydrazine hydrate (6.8 g.) under nitrogen for 1 hour and concentrated in vacuo. The residue was suspended in warm water, and the solid was collected by filtration, dried and re- crystallized from ethyl acetate-Skelly B hexanes to give 1.81 g. (67% yield) of 6-chloro-2-hydrazino-4-phenylquinoline of melting point 156.S-.S7*C.

Anal. Calcd. for C, 66.79; H, 4.49; CI, 13.15; N, 15.58 Found: C, 67.15, H, 4.65, CI, 13.19; N, 15.32 Example 2 7-Chloro-l-methyl-5-phenyl-s-triazolo 4,3-a7-quinoline.

A stirred mixture of 6-chloro-2-hydrazino-4-phenyl-quinoline (1.4g., 0.0052 mole), triethyl orthoacetate (0.925 g.t 0.0057 mole) and xylene (100 ml) was refluxed, under nitrogen for 2 hours 40 minutes. During this period the ethanol formed in the reaction was removed by distillation through a short, glass helix-packed column. The mixture was concentrated to dryness in vacuo and the residue was crystallized from methanol-ethyl acetate to give: 1.02 g. of 7-chloro-l-methyl-5-phenyl-s-triazolo- _4,3-a^7quinoline of melting point 253.5-255*C. and 0.26 g. of melting point 253.5-2S5*C. (83.9% yield). The analytical sample was crystallized from methylene chloride : methanol and had a melting point 252.5-253*C.

Anal. Calcd. for C17H12C1 3 C, 69.50; H, 4.12; CI, 12.07; N, 14.31 Found: C, 69.39; H, 4.02; CI, 12.10; N, 14.49.

The o-chlerophenyl analogue of the compound of example 2, 1.e. 7-chloro-l-methyl-S-(o-chlorophenyl)-s-triazolo£"4,3-a7 quinoline was prepared in a similar manner; M.P. = 257-259*C.

Example 3 6-Chloro-4-(2,6-difluorophenyl) -2-hydrazino-quinolino In the manner given in Example 1, 2,6-dichloro-4-(2,6-difluorophenyl)quinoline was reacted at reflux with hydrazine hydrate to give 6-chloro-4- (2,6-difluorophenyl)-2-hydrazinoquinoline.

Example 4 7-Chloro-l-methyl-5-(2,6-difluorophenyl)-s-triazolo T4,3-§7 quinoline.

In the manner given in Example 2, 6-chloro-4-(2,6-difluorophenyl)-2-hydrazinoquinoline and triethyl orthoacetate are refluxed -1-in xylene to give 7-chloro½ethyl-5-(2,6-difluorophenyl)-s-triazolo- },3-a/ quinoline.

- S - Example S 6-Chloro-4-(o-chlorophenyl)-2-hydrazinoquinoline In the manner given in Example 1, 2,6-dichloro-4-(o-chlorophenyl)quinoline was reaeted at reflux with hydrazine hydrate to give 6-chloro-4-(o-chlorophenyl)-2-hydrazinoquinoline.

Example 6 7-Chloro-l-methyl-5-(o-chlorophenyl)-s-triazolo/J"4,3-a quinoline.

In the manner given in Example 2, 6-chloro-4-(o-chlorophenyl)-2-hydrazinoquinoline and triethyl orthoacetate were refluxed in xylene to give 7-chloro-l-mothyl-5-(o-chlorophenyl)-s-triazolo £H,3-a_ quinoline.

Example 7 5-Nitro-6-propyl-4-(m-trifluoromethylphenyl)-2-hydrazino quinoline.

In the manner given in Example 1, 2-chloro-5-nitro-6-propy1-4-(m-trifluoromethylphenyl)quinoline was reacted at reflux with hydrazine hydrate to give 5-nitro-6-propyl-4-(m-trifluoroinethyl phenyl)-2-hydrazinoquinoline.

Example 8 6-Nitro-7-propyl-l-ethyl-5-(m-trifluoromethylphenyl)-s- triazolo ~4,3-a^7quinoline.

In the manner given in Example 2, S-nitro-6-propyl-4-(m-trifluoromethylphenyl)-2-hydrazinoquinoline, and triethyl ortho-propionat© were refluxed in xylene to give 6-nitro-7- propyl-1-ethyl S-(m-tri luoromethylphenyl)-s-triazolo-^4,3-¾7quinoline.

Claims (1)

1. wherein B ia selected from the group coneleting of and alkyl of to carbon inclusivej wherein and are or and are She compound of claim 1 wherein B is and are hydrogen and is so that the pound is quinolines as defined in claim 1 substantially as hereinbefore scribed and with reference to the process fo quinolines defined in claim which comprises Befluxing a as herein with hydrazine hydrate to give a phenylquinoline as herein Befluxing the as herein with a trialkyl orthoacylate with triethyl triethyl orthopropionate or trimethyl in an inert organic solvent to give the corresponding n A process according to claim wherein the reaction with hydrazine hydrate is effected at a temperature between ambient temp erature and between the reflux temperature of the reaction A process according to claim 4 or wherein the reaction time is between 1 to 18 A process according to claim wherein the compound of Formula III is converted to the final product by heating with an ortho lower alkanol ester of q carbox lic acid at a temperature of between A process according to any of claims 4 to wherein the reaction is effected in an inert A process for the production of compounds defined in claim substantially as hereinbefore described and with reference to the Box 33110 for Applicant insufficientOCRQuality