NL7907633A - PROCESS FOR PREPARING 2-PHENYL-S-TRIAZOLO / 5,1-ALPHA / ISOQUINOLINES AND COMPOUNDS CONTAINING PHARMACEUTICAL PREPARATIONS PREPARED THEREOF. - Google Patents

Description

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Process for the preparation of 2-phenyl-s-triazolo / 5,1-alpha-isoquinoline and thus prepared compounds containing pharmaceutical preparations.

The invention relates to a new process for the preparation of 2-phenyl-s-triazolo / 5,1-a-Tiisoquinolines.

2-Phenyl-3-triazolo / 5,1-a-7-isoquinoline and a process for its preparation are described in U.S. Pat. No. 3,758,480.

U.S. Patent 4,075,341 discloses 2-phenyl-s-triazolo / 5,1-a-isoquinolines substituted in the 2-phenyl group and a process for preparing them from the corresponding 5,6-dihydro compounds .

2-Phenyl-s-triazolo / 5,1-a / isoquinoline and the 5,6-dihydroderivates can be used as an antifertility agent (U.S. Patent 3,985,113). 2- (Substituted phenyl) -s-triazolo / 5,1-a-7-isoquinolines and the corresponding 5,6-dihydroderivatives are particularly suitable for controlling fertility in mammals (U.S. Patent 4,075,341).

The known methods of preparing 2-phenyl-s-triazolo / 5,1-a / isoquinolines are cumbersome and give poor yields, making them unsuitable for technical scale implementation.

According to the invention, a new process is provided for preparing 2-phenyl-s-triazolo / ~ 5,1-a / isuhinolines of the formula I, wherein R and Rj are each separately a hydrogen atom, fluorine atom, chlorine atom, bromine atom, lower alkyl group, lower alkylamino group, di-lower alkylamino group, trifluoromethyl group or a group 0R4 wherein a lower alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group or benzyl group, or together represent a group -OCHjO-, and R ^ and each separately a hydrogen atom, 790 76 33 2 fluorine atom, chlorine atom, bromine atom or alkoxy group with 1-4 carbon atoms.

By "lower alkyl" is meant a straight or branched chain alkyl group of 1 to 5 carbon atoms, preferably the methyl group and the ethyl group.

By "low alkenyl" is meant an alkenyl group with 3-5 carbon atoms, preferably allyl.

By "lower alkynyl" is meant an alkynyl group with 3-5 carbon atoms, preferably propargyl.

By "cycloalkyl" is meant a 3-6 membered cycloalkyl group.

The compounds of the formula I are prepared according to the invention by reacting a compound of the formula 2 and a nitrile of the formula 3, wherein R, R 1, R 2 and R 2 above have the meaning indicated, preferably in the presence of a catalyst.

The reaction of the compounds of formulas 2 and 3 can be carried out in the absence of a solvent by mixing, preferably with ± ghe ± d of a catalyst present.

When the reaction is carried out on a large scale, it is recommended to use solvent to reduce the viscosity of the reaction mixture and to facilitate mixing. Examples of suitable solvents are alkanols such as methanol, ethanol, propanol and butanol, lower alkoxy alkanols such as methoxyethanol, ethoxyethanol and propoxyethanol, chlorinated low hydrocarbons, ethylene glycol, benzene, chlorobenzene, toluene, nitrobenzene, tetrahydrofuran, dioxane dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide and mixtures thereof.

The reaction can be carried out at room temperature to the boiling point of the reaction mixture using a solvent. Preferably, the reaction temperature is 60-160 ° C because the reaction proceeds sufficiently quickly at this temperature and no undesired by-products are formed.

The reactants are generally used in about 35 equimolecular amounts. However, when the reaction is carried out without solvent, it is recommended to use an excess of nitrile of 1-20 mole% over the compound of formula II to facilitate mixing.

The reaction is preferably carried out in the presence of a catalyst. Good results are obtained with basic catalysts such as alkali metal hydroxides, alkoxides and hydrides. Furthermore, tertiary organic amines as well as transition metal salts and elemental sulfur can be used. Of the transition metal salts, iron (III) chloride and zinc acetate are particularly preferred.

The 2-amino-1- (2H) isoquinolinone of the formula 2 can be prepared in various ways. The most suitable includes, as the last step, the reaction of isocumarin (formula 4) and hydrazine.

The preparation of isocumarin has been described in detail and core suitably are carried out by bromination with the corresponding i-isochromanone, followed by dehydrobromination with triethylamine in 1,2-dichloroethane.

The reaction of isocumarin and hydrazine is performed at room temperature using aqueous hydrazine-20 hydrate in ethanol. Afterwards, an acid is added to the reaction mixture to convert the intermediate 2-amino-3,4-dihydro-3-hydroxy-1 (2h) isoquinolinone into the desired 2-amino-1 (2H) isoquinolinone with the formula 2.

Examples of compounds which can be prepared by the process according to the invention are: 2- (4-Chloro-enyl) -s-triazolo / 5,1-α / isoquinoline.

2- (4-Fluorophenyl) -s-triazolo (5.1-alpha / isoquinoline.

2- (3-Methoxyphenyl) -s-triazolo / 5.1-alpha / isoquinoline.

2- (4-Dimethylaminophenyl) -s-triazolo / 5,1-alpha / isoquinoline.

2- (4-Chloro-3-methoxyphenyl) -s-triazolo / 5,1-a-7-isoquinoline.

2- (3-Ethoxyphenyl) -s-triazolo / -3,1-a / isoquinoline.

2- (3-Allyloxyphenyl) -s-triazolo / 5,1-α / isoquinoline.

2- (3-Propargyloxyphenyl) -s-triazolo / 5,1-a / isoquinoline.

2- (3-Cyclopentyloxphenyl) -s-triazolo / 5,1-a / isoquinoline.

2- (4-Bromophenyl) -s-triazolo / 5,1-alpha / isoquinoline.

790 76 33 * 4 2- (3-Propyloxyphenyl) -s-triazolo 5.1-isoquinoline.

2- (3-Benzyloxyphenyl) -s-triazolo / 5,1-α / s-soquinoline.

2- (4-Trifluoromethylphenyl) -s-triazolo / 5.1-a-5 / isoquinoline.

The yields achieved by the process of the invention are unusually high for a synthesis of a condensed s-triazolo system such as s-triazolo / 5,1-a / isoquinoline. Moreover, the process according to the invention lends itself very well for implementation on a technical scale, because no special precautions are required with regard to the reactants.

The process according to the invention is particularly applicable for the preparation of 2-phenyl-s-triazolo / 5,1-a / iso-quinolines of the formula 1 in which R and R1 are in the 3 and 4 positions are present in the phenyl ring.

The 2-phenyl-s-triazolo / 5,1-a-5-isoquinolines obtained by the process of the invention can be converted to the corresponding 5,6-dihydro compounds by catalytic hydrogenation as described, for example, in the U.S. Pat. Nos. 3,775,417 and 3,758,480.

--— Example-ΐ ............................................ 20 2- (4-chlorophenyl) -s-triazolo / 5,1-a-isoquinoline.

To a solution of sodium ethoxide (0.68 g, 0.01 mol) in absolute ethanol (150 ml) were added 2-amino-1 (2H) isoquinolinone (8 g, 0.05 mol) and 4-chlorobenzonitrile (7, 24 g, 0.05 mol) was added and the mixture was heated at reflux temperature for 1 hour with stirring. Amidrazone intermediate crystallized thereby. The ethanol was distilled off and replaced with 2-ethoxyethanol under heating. After the vapor temperature reached 135 ° C, heating at reflux temperature was continued for an additional 5 hours. Afterwards, the reaction mixture was cooled with the title compound crystallizing out. The product was collected by filtration, washed with water and 95% ethanol and then dried in vacuo. Thus, 13.43 g (96%) of the title product, mp 250-251 ° C, were obtained.

35 790 76 33 ie5

Example II

2- (3-Ethoxyphenyl) -s-triazolo / 5,1-alpha / isoquinoline.

A mixture of 2-amino-1 (2H) -isoquinolinone (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 for 30 min, at room temperature under nitrogen and then for an additional 30 min at 60 ° C. After this, 2 portions of 0.044 g of sodium methoxide each were added successively in about 90 min, after which the temperature slowly warmed to reflux temperature. increased. The solvent was distilled off in vacuo after which the residue was taken up in water (20 ml) followed by acidification with dilute hydrochloric acid to pH 2. The crude product was collected by filtration under reduced pressure. After crystallization in 85% ethanol (120 ml), 5.18 g (89.5%) of pure title compound, mp 140-141 ° C, were obtained.

Example III

2-amino-1 (2H) isoquinolinone.

To a solution of isocumarin (26 g, 0.16 mol) in 95% ethanol (200 ml) was added a solution of 25 wt% hydrazine hydrate in water (64 ml, 0.32 mol) and the mixture was stirred at room temperature for 1 hour. The precipitated 2-amino-3,4-dihydro-3-hydroxy-1- (2H) isoquinolinone was dissolved and dehydrated by adding 10% hydrochloric acid (150 ml) at room temperature. After 3 hours, the mixture was neutralized with sodium carbonate and the ethanol was distilled off in vacuo. The title compound was collected by filtration and extracted with chloroform. Thus, 27.92 g (98%) of the title compound, mp 103-104 ° C, were obtained.

Example XV

2- (3-Ethoxyphenyl) -5,6-dihydro-s-triazolo / 5,1-a-/ isoquinoline.

2- (3-Ethoxyphenyl) -s-triazolo / 5,1-a / isoquinoline (3.9 g, 0.013 mol) prepared according to example II was dissolved in a mixture of 150 ml ethanol and 108 ml acetic acid which 2.2 ml of 790 76 33 6 contained 22% HCl in ethanol. The mixture was hydrogenated in a Parr bomb at 90 ° C under a pressure of 1010 kPa (10 atm.) In the presence of 0.5 g of 10% palladium on carbon. Afterwards, the catalyst was removed by filtration, after which the solvent was evaporated and the residue was taken up in water. The aqueous solution was extracted four times with 60 ml of dichloromethane each time. After removal of the dichloromethane by evaporation, the residue was recrystallized from 50 ml of 70% ethanol. Thus, 3.5 g (90%) of the title product, mp 102-103 ° C, were obtained.

10 Example V

2 - / - 4- (Trifluoromethyl) phenyl / - s-triazolo / - 5,1-a / / isoquinoline.

To a solution of sodium ethoxide (0.136 g, 0.002 mol) in absolute ethanol (30 ml) was added 4-trifluoromethylbenzo-15 nitrile (1.71 g, 0.01 mol) and 2-amino-1 (2H) isoquinolinone (1 , 6 g, 0.01 mol). The mixture was heated at reflux temperature for 1.5 hours with most of the ethanol distilled off and replaced with 35 ml of 2-ethoxyethanol with heating. When the vapor temperature had reached a value of 135 ° C, heating at reflux temperature was continued for an additional 5 hours. Afterwards, the reaction mixture was cooled to 0 ° C with the title compound crystallizing out. The product was collected by filtration, washed with 95% ethanol and water and then dried in vacuo at 50 ° C. Thus, 2.97 g (95%) of the title compound, mp 211-212 ° C, were obtained.

790 76 33

Claims (9)

A process for the preparation of 2-phenyl-s-triazolo- / 5,1-a / isoquinolines of the formula 1 wherein R and Rj are each separately a hydrogen atom, fluorine atom, chlorine atom, bromine atom, lower alkyl group, lower alkylamino group, di-lower alkylamino group, trifluoro-methyl group or a group -OR4 in which R4 represents a lower alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group or benzyl group, or together represent a group -OCHjO-, and and R ^ each separately a hydrogen atom, fluorine atom, chlorine atom, bromine atom 10 or alkoxy group with 1-4 carbon atoms, characterized in that a compound of the formula 2 and a nitrile of the formula 3 in which R, R 1, R 1 and R 1 have the aforementioned meanings are reacted with each other preferably in the presence of a catalyst. 2. Process according to claim 1, characterized in that the catalyst used is an alkali metal alkoxide, alkali metal hydroxide, alkali metal hydride, tertiary organic amine, transition metal salt and / or sulfur. 3. Process according to claim 1, characterized in that the reaction is carried out in a solvent. 4. Process according to claim 3, characterized in that the solvent consists of an alkanol, low alkoxyalkanol, chlorinated low hydrocarbon, ethylene glycol, benzene, chlorobenzene, toluene, nitrobenzene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide or mixtures thereof. Process according to claim 1, characterized in that the nitrile is used in a molar excess of 1-20%. 6. Process according to claims 1, 2, 3, 4 and 6, characterized in that the reaction is carried out at a temperature of 60-160 ° C. 7. A process for preparing a compound suitable for use in the process according to any one of the preceding claims, characterized in that a compound is prepared according to formula 2, wherein R 2 and R 3 are each a hydrogen atom, 790 76 33 * *. r represent fluorine atom, chlorine atom, bromine atom or alkoxy group with 1-4 carbon atoms, by reaction of isocumarin of the formula IV wherein 01 R3 have the above meaning, and hydrazine hydrate. A process for preparing the 5,6-dihydro-5 derivatives of the compounds of the formula 1 as defined in claim 1 by catalytic hydrogenation, characterized in that the compounds of the formula 1 are prepared according to the process of one of claims 1-6. 9. Compounds and process for preparing them as described in the description and examples. 790 76 33 -3 ». ι ^ Γ ^ "'N R1 ex'Y R5 · R, 0 JL ^, ΝΗ * UJk ^ J 2 R» nc_GT 3 XR Ri 0 W ^ o ^ JU 4 R * 790 7 6 33