CH650779A5 - Process for the preparation of 2-phenyl-s-triazolo[5,1-a]iso- quinoline derivatives - Google Patents

Description

650779

2

CLAIMS 1. Process for preparing derivatives of 2-phenyl-s - traizole [5, l-a] isokinoline of formula I

7. Preparation process for the 5,6-dihydroderivatives of 2-phenyl-s-triazole [5, the] isochinoline of formula I characterized in that the 2-phenyl-s-triazole [5, the] isochinolines obtained according to the process of claim 1 are subjected to catalytic hydrogenation.

8. Compounds obtained by the process according to claim 1.

where R and Rx independently represent hydrogen, chlorine, fluorine, bromine, lower alkyl, lower alkylamino, lower di-alkylamino, trifluoromethyl, or an OR4 group where R4 is lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl and benzyl; or R and Rx taken together represent a group -0CH20-; R2 and Rs independently represent hydrogen, chlorine, fluorine, bromine and (CH) -alkoxy; which includes contacting a compound of formula II

II

with a nitrile of formula III

This invention relates to a process for preparing 2-phenyl-s-triazole [5, 1-a] isokinolinic derivatives.

Some 2-phenyl-s-triazole [5, 1-a] isokinolinic derivatives and a method for their preparation are described in U.S. Pat. No. 3 758 480.

A series of 2-phenyl-s-triazole [5, la] isochinolines substituted on the 2-phenyl portion and a method for their production from the corresponding hydrogenated compounds in position 5,6 is disclosed in the American patent 4 075 341. 20 La 2 -phenyl-s-triazole [5, the] isokinoline and its $, 6-dihydro derivative are useful as agents for the control of fertility (American patent 3 985 113). The 2-phenyl-s-triazole [5, 1-a] -isochinolines substituted on the phenyl and their corresponding 5,6-dihydroderivatives are particularly useful for controlling the 25 fertility in mammals (American patent 4 075 341).

The methods described in the previous literature for the preparation of such 2-phenyl-s-triazole [5, 1-a] isokinol-nene derivatives are tedious and give rise to low yields making the whole procedure non-economic for commercial production.

The object of this invention is to provide a convenient method for the preparation of 2-phenyl-s-triazole- [5, 1-a] isokinolinic derivatives of general formula I

R

III

where R, Rj, Rjj and R3 have the same meanings as before, in the presence of a catalyst.

2. Process as in claim 1 wherein the catalyst is selected from the group consisting of alkali metal alkoxides, alkali metal hydroxides, alkali metal hydrides, tertiary organic cores, transition metal salts and sulfur.

3. Process as in claim 1 wherein the reaction is carried out in the presence of a solvent.

4. Process as in claim 3 where the solvent is selected from the alkanols, the lower alkoxy-alkanols, the lower chlorinated hydrocarbons, the ethylene glycol, the benzene, the chlorobenzene, the tuoluene, the nitrobenzene, the tetra-hydrophurane, the dioxane , dimethylformamide, dimethylsulphoside, phosphoric acid hexamethyltriamide and their mixtures.

5. Process as in claim 1 wherein a molar excess of 1 to 20% of the nitrile is used.

6. Process as in claims 1, 2, 3, 4, 5 where the reaction is carried out at a temperature between 60 and 160 ° C.

where R and Rj independently represent hydrogen, chlorine, fluorine, bromine, lower alkyl, lower alkylamino, lower di-alkylamino, trifluoromethyl or an OR4 grappa where R4 is lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl and benzyl; or R and Rj taken together represent a group -0CH20-; R2 and R3 independently represent hydrogen, chlorine, fluorine, bromine and (Cj_4) alkoxy.

The term and the "lower alkyl" portion defines a linear or branched alkyl of 1 to 5 preferably methyl and ethyl carbon atoms.

60 The term "lower alkenyl" identifies an alkenyl group containing from 3 to 5 carbon atoms, preferably allyl. The term "lower alkynyl" defines an alkynyl containing from 3 to 5 carbon atoms, preferably propargyl. The term "cycloalkyl" defines a "cycloalkyl ring having 3 to 6 members.

The process of this invention consists in contacting a compound of formula II with a nitrile of formula III

3

650779

where R, Rj, R2 and R3 have the same meanings as before, in the presence of a catalyst.

The reaction between compound II and compound III can be carried out in a suitable solvent system but it can also be carried out in the absence of solvent simply by mixing the two reactants, preferably with a catalyst.

When the reaction is carried out on large quantities, it is however desirable to add solvent to lower the viscosity of the reaction mass and facilitate mixing of the reactants. A wide variety of solvents can be used. For example solvents that are conveniently used are alkanols such as methanol, propanol and butanol, lower alkoxy-alkanols such as methoxy-ethanol, ethoxy-ethanol and propoxy-ethanol, the chlorinated lower hydrocarbons, the ethylene glycol, benzene, chloroben-zene, toluene, nitrobenzene, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulphoxide, Pesamethyl-triamide of phosphoric acid and their mixtures.

The reaction temperature can vary between the ambient temperature and the boiling temperature of the mixture when the reaction is carried out in a solvent. In general, temperatures between 60 and 160 ° C are preferred since in these conditions the reaction rate is sufficiently rapid and the formation of unwanted collateral products is prevented.

The two reagents are generally used in approximately equimolecular quantities although in some cases a molecular excess of I to 20% of the nitrile with respect to compound II can be added, in particular to facilitate mixing when the reaction is carried out in absence of solvents. The reaction is generally carried out in the presence of a catalyst. Basic catalysts such as hydroxides, alkoxides and alkali metal hydrides have been found to provide satisfactory results. Tertiary organic amines can also be usefully used as catalysts, as well as the salts of transition metals and elemental sulfur. Among the salts of the transition metals, ferric chloride and zinc acetate are particularly preferred.

The reagent II, 2-amino-1 (2H) -isoquinolinone can be prepared according to various methods. The most convenient procedure involves the reaction between hydrazine and isocumarin IV as the final step

The preparation of compound IV is well documented in the literature and can be conveniently carried out by brominating with Br2 of the corresponding 1-iso-15 chromomanone followed by de-brominating with triethylamine in 1,2-dichloroethane.

The reaction between hydrazine and isocumarin is carried out at room temperature using hydrazine aqueous hydrate in ethanol as solvent. The subsequent addition of acids to the 20 reaction mixture allows the transformation of the desired 2-amino-3,4-dihydro-3-hydroxy- (2H) -isoquinolinone into the desired 2-amino-1 (2H) -isoquinolinone II.

Examples of types of compounds which can be prepared with the step of this invention are the following: 25 2- (4-Chlorophenyl) -s-triazole [5, la] isochinoline 2- (4-Fluorof enyl) -s-triazole [5 , 1 -a] isochinoline 2- (3-Methoxyphenyl) -s-triazole [5, la] isochinoline 2- (4-Dimethylaminophenyl) -s-triazole [5, la] isochinoline 2- (4-Chloro-3-methoxyphenyl) ) -s-triazole [5, la] isochinoline 30 2- (3-ethoxyphenyl) -s-triazole [5, la] isochinoline 2- (3-allyloxyphenyl) -s-triazole [5, la] isochinine 2- (3 -Propargyloxyphenyl) -s-triaozlo [5, la] isochinoline 2- (3-Cyclopentyloxyphenyl) -s-triazole [5, la] isochinoline 2- (4-Bromophenyl) -s-triazole [5, la] isochinoline 35 2- 2- (3-Propyloxyphenyl) -s-triazole [5, la] isochinoline 2- (3-Benzyloxyphenyl) -s-triazole [5, la] isochinoline 2- (4-Trifluoromethylphenyl) -s-triazole [5,1-a] isoquinoline.

The process of this invention results in unusually high yields in the synthesis of fused s-triazole systems 40 such as Ps-triazole [5, 1-a] isokinoline. Furthermore, the process is carried out very easily in large-scale preparations, because it does not require the use of reagents which require particular care for their use in industrial plants.

45 The process is particularly useful for the preparation of 2-phenyl-s-triazole [5, 1-a] isochinolines of formula I indicated above where R and Rx are in positions 3 and 4 of the phenyl ring.

The 2-phenyl-s-triazole [5, la] isokinolinic derivatives obtained 50 according to the process of this invention can also be used for their conversion into the corresponding 5,6-dihydro compounds through catalytic hydrogenation using for example the methods of the American patents No. 3 775 417 and 3 758 480.

55 The following examples illustrate the process of this invention without limiting its purpose:

Example 1

60

2- (4-Chlorophenyl) -s-triazole [5,1 -a] isokinoline

To a solution of sodium ethoxide (0.68 g, 0.01 mol) in absolute ethanol (150 ml), 2-amino-1 (2H) -isoquinolinone (8 g, 0.05 mol) and 4- were added chlorobenzonitrile 65 (7.24 g, 0.05 mol) and the mixture was heated under reflux under stirring for 1 hour. The intermediate amidrazone crystallized; the ethanol was distilled off and replaced with 2-ethoxyethanol while maintaining heating. When the

650779

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vapor temperature reached 135 ° C and continued to heat under reflux for 5 hours.

The title compound crystallized by cooling and was recovered by filtration. After washing the solid with water, 95% ethanol and drying under vacuum, 13.43 g (96%) of the title product were obtained; mp 250-251 ° C.

Example 2

2- (3-ethoxyphenyl) -s-triazolo [5, l-a] isoquinoline

A mixture of 2-amino-1 (2H) isokinolinone (3.2 g, 0.02 mol), 3-ethoxybenzonitrile (3.09 g, 0.021 mol) and sodium methoxide (0.044 g) in toluene (20 ml ) was stirred under nitrogen at room temperature for 30 minutes and at 60 ° C for another 30 minutes. Subsequently, two additions were made, each of 0.044 g of sodium methoxide, in about 90 minutes and the temperature was gradually increased until reflux. The solvent was distilled under vacuum, the residue was taken up with water (20 ml) and acidified to pH 2 with diluted hydrochloric acid. The crude product was filtered under vacuum and crystallized from 85% ethanol (120 ml) giving 5.18 g (89.5%) of pure title compound; mp 140-141 ° C.

Example 3 2-Amino-1 (2H) -isoquinolinone

An isocumarin solution (26 g, 0.16 mol) in 95% ethanol (200 ml) was treated with 25% hydrazine hydrate in water (64 ml, 0.32 mol) and kept under stirring at room temperature for 1 Now. The 2-amino-3,4-dihydro-3-hydroxy-1 (2H) -isoquinolinone precipitate was dissolved and dehydrated by addition of 10% hydrochloric acid (150 ml) at room temperature.

After 3 hours the mixture was neutralized with sodium carbonate and the ethanol was recovered by distillation under vacuum. The title compound was isolated by filtration and extraction with chloroform to give 27.92 g (98%) of the title product; mp 103-4 ° C.

5 Example 4

2- (3-ethoxyphenyl) -5,6-dihydro-s-triazolo [5, l-a] isoquinoline

2- (3-ethoxyphenyl) -s-triazole [5, 1-a] isokinoline (3,9 g, 0,013 mol) obtained according to the process of Example 4

10 was dissolved in a mixture of 150 ml of ethanol and 108 ml of acetic acid containing 2.2 ml of 22% HCl acid in ethanol. The mixture was hydrogenated in a Parr autoclave at 90 ° C under 10 atmospheres pressure in the presence of 0.5 g of 10% palladium carbon.

15 After filtering the catalyst, the solvent was evaporated and the residue was taken up in water.

By extraction with 4 portions of 60 ml of dichloro-methane and evaporation of the solvent, a residue was obtained which was recrystallized from 50 ml of 70% ethanol.

20 Yield 3.5 g (90%) of the title product. M.P. 102-103 ° C.

Example 5

2- [4- (Trifluoromethyl) phenyl] -s-triazolo [5, l-a] isoquinoline

25 A solution of sodium ethoxide (0.136 g, 0.002 mol) in absolute ethanol (30 ml), 4-trifluoromethylbenzonitrile (1.71 g, 0.01 mol) and 2-amino-l (2H) -isoquinolinone (1, 6 g, 0.01 mol) was heated to reflux for 1.5 hours. Most of the ethanol was then distilled off and removed.

30 placed with 35 ml of 2-ethoxyethanol keeping the heating. When the vapor temperature reached 135 ° C, heating continued for 5 hours.

The title compound crystallized by cooling to 0 ° C and was recovered by filtration.

35 After washing with 95% ethanol and water, the solid was dried under vacuum at 50 ° C. 2.97 g (95%) of the title product was obtained which melts at 211-12 ° C.

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