GB2034709A

GB2034709A - Preparing 2-phenyl-s- triazolo[5,1-a]isoquinoline Derivatives

Info

Publication number: GB2034709A
Application number: GB7937384A
Authority: GB
Original assignee: Gruppo Lepetit SpA; Lepetit SpA
Current assignee: Gruppo Lepetit SpA
Priority date: 1978-10-30
Filing date: 1979-10-29
Publication date: 1980-06-11
Also published as: GB2034709B

Abstract

A 2-Phenyl-s-triazolo(5,1- a]isoquinoline compound is prepared by reacting a 2-amino-1(2H)- isoquinolinone with a benzonitrile.

Description

SPECIFICATION Preparing 2-Phenyl-s-triazolo-[5,1 -a]isoquinoline Derivatives This invention relates to a new process for preparing 2-phenyl-s-triazolo[5,1-a]isoquinoline derivatives. 2-Phenyl-s-triazolo[5,1-a]isoquinoline derivatives and a method for their manufacture are described in U.S. Patent 3,758,480.

A series of 2-phenyl-s-triazolo[5,1-a]isoquinolines substituted on the 2-phenyl portion and a method for their production from the corresponding 5,6-dihydro compounds is described in U.S. Patent 4,075,341. 2-Phenyl-s-triazolo[5,1-a]isoquinoline and its 5,6-dihydro derivative are useful as antifertility agents (U.S. Patent 3,985,1 13). 2-(Substituted -phenyl)-s-triazolo[5,1-a]isoquinolines and their corresponding 5,6-dihydro derivatives are particularly suitable for use in controlling fertility in mammals (U.S. Patent 4,075,341).

The methods described in the prior literature for preparing said 2-phenyl-s-triazolo[5,1a]isoquinoline derivatives are tedious and give poor yields making the overall procedure uneconomical for commercial production.

The object of this invention is to provide a novel and useful method for the manufacture of 2-phenyl-s-triazolo[5, 1 -a]isoquinoline derivatives of the general formula

wherein R and R, independently represent hydrogen, chloro, fluoro, bromo, lower alkyl, lower alkylamino, di-lower alkylamino, trifluoromethyl, or a group OR4 wherein R4 is lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, and benzyl; or R and Ri taken together represent a group -OCH2O-; R2 and R3 are independently hydrogen, chloro, fluoro, bromo or C14 alkoxy.

The term, and the portion "lower alkyl" designates a branched or linear 1 to 5 carbon alkyl group, preferably methyl or ethyl.

The term "lower alkenyl" identifies a 3 to 5 carbon atoms alkenyl group, preferably allyl. The term "lower alkynyl" designates a 3 to 5 carbon atoms alkynyl, preferably propargyl. The term "cycloalkyl" designates a 3 to 6 membered cycloalkyl.

The process of this invention consists in contacting a compound of the formula 11 with a nitrile of the formula Ill,

wherein R, R1, R2 and R3 have the same meanings as before, preferably in the presence of a catalyst.

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

When the reaction is carried out in large batches, it is however desirable to add some solvent to lower the viscosity of the reaction mass and to facilitate the mixing of the reactants. A wide variety of solvents may be used. Suitable solvents are for instance the alkanols such as methanol, ethanol, propanol and butanol, the lower alkoxy-alkanols such as methoxy-ethanol, ethoxy-ethanol and propoxy-ethanol, the chlorinated lower hydrocarbons, ethylene glycol, benzene, chlorobenzene, toluene, nitrobenzene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide and hexamethylphosphoric triamide and their mixtures.

The temperature of the reaction may range between the room temperature and the boiling temperature of the mixture when it is carried out in a solvent. In general, temperatures between 60 and 1 600C are preferred since under these conditions the reaction rate is sufficiently rapid and the formation of undesired side product is prevented.

The two reactants are generally used in about equimolecular amounts, although in some cases a 1 to 20 per cent molar excess of the nitrile over the compound II may be added, in particular to facilitate the mixing when the reaction is carried out in the absence of solvents. The reaction is generally carried out in the presence of a catalyst. Basic catalysts such as alkali metal hydroxides, alkoxides and hydrides, were found to give satisfactory results. Tertiary organic amines may also be suitably employed as the catalyst, as well as transition metal salts and elemental sulfur. Among the transition metal salts ferric chloride and zinc acetate are particularly preferred.

The reactant 11, a 2-amino-1 (2H)-isoquinolinone, may be prepared by several methods. The most convenient procedure involves as the final step the reaction between hydrazine and the isocoumarin IV

The preparation of the compound IV is well documented in the literature and may be conveniently performed through bromination with Br2 of the corresponding 1-isochromanone followed by dehydrobromination with triethylamine in 1 ,2-dichloroethane.

The reaction between hydrazine and isocoumarine is carried out at room temperature by utilizing aqueous hydrazine hydrate in ethanol, as the solvent. Subsequent addition of acid to the reaction mixture allows the transformation of the intermediate 2-amino-3,4-di-hydro-3-hydroxy-1 (2H)isoquinolinone into the desired 2-amino-1 (2H)-isoquinolinone II.

Typical examples of compounds which may be prepared by the process of this invention are the following: 2-(4-Chlorophenyl)-s-triazolo[5, 1 -a]isoquinoline 2-(4-Fluorophenyl)-s-triazolo[5, 1 -a]isoquinoline 2-(3-Methoxyphenyl)-s-triazolo[5, -a]isoquinoline 2-(4-Dimethylaminophenyl)-s-triazolo[5, 1 -a] isoquinoline 2-(4-Chloro-3-methoxyphenyl)-s-triazolo[5, 1 -a]isoquinoline 2-(3-Ethoxyphenyl)-s-triazolo[5,1 -a]isoquinoline 2-(3-Allyloxyphenyl)-s-triazolo[5,1 -a]isoquinoline 2-(3-Propargyloxyphenyl)-s-triazolo[5,1 -a] isoquinoline 2-(3-Cyclopentyloxyphenyl)-s-triazolo[5,1 -a]isoquinoline 2-(4-Bromophenyl)-s-triazolo[5, 1 -a]isoquinoline 2-(3-Propyloxyphenyl)-s-triazolo[5, 1 -a]isoquinoline 2-(3-Benzyloxyphenyl)-s-triazolo[5,1 -ajisoquinoline 2-(4-Trifluoromethylphenyl)-s-triazolo[5, 1 -a]isoquinoline The process of this invention gives unusually high yields in the synthesis of fused s-triazolo systems such as s-triazolo[5,1 -a]isoquinoline. Moreover, the process is very easily carried out for large scale preparations, since it does not require reagents needing particuiar care for their use in industrial plants.

The new process is particularly useful for the preparation of 2-phenyl-s-triazolo[5, 1 a]isoquinolines of the formula I above wherein R and R1 are in the positions 3 and 4 of the phenyl group.

The 2-phenyl-s-triazolo[5, l-a]isoquinoline derivatives obtained through the process of this invention may be utilized also for their conversion into the corresponding 5,6-dihydro compounds through catalytic hydrogenation by using, for instance, the methods of US Patents 3,775,417 and 3,758,480. The following Examples illustrate the process of this invention without limiting its scope.

Example 1 2-(4-Chlorophenyl)-s-triazolo[5,1 isoquinoline To a solution of sodium ethoxide (0.68 g, 0.01 mole) in absolute ethanol (150 ml), 2-amino1 (2H)isoquinolinone (8 g, 0.05 mol) and 4-chlorobenzonitrile (7.24 g, 0.05 mol) were added and the mixture was refluxed under stirring for one hour. The intermediate amidrazone crystallized out; ethanol was distilled and repiaced with 2-ethoxyethanol while heating. As the temperature of the vapors reached 1350C, heating was continued at reflux for five hours.

The title compound crystallized out by cooling and was recovered by filtration. After washing the solid with water, 95% ethanol and then drying under vacuum, 1 3.43 g t96%) of the title product were obtained, m.p. 250-251 00.

Example 2 2-(3-Ethoxyphenyl)-s-t?iazolo5,l -a]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 under nitrogen at room temperature for 30 minutes and at 60CC for further 30 minutes. Two successive additions, each of 0.044 g of sodium methoxide, were done in about 90 minutes and the temperature was gradually increased until reflux. The solvent was distilled in vacuo, the residue was taken up with water (20 ml) and acidified to pH 2 with dilute hydrochloric acid.

The crude product was filtered under vacuum and crystallization from 85% ethanol (120 ml) afforded 5.18 g (89.5% of the pure title compound, m.p. 140--141 OC.

Example 3 2Amino-l (2H)-isoquinolinone A solution of isocoumarin (26 g, 0.16 mol) in 95% ethanol (200 ml) was treated with 25% hydrazine hydrate in water (64 ml, 0.32 mol) and stirred at room temperature for one hour. The precipitate of 2-amino-3,4-dihydro-3-hydroxy-1 (2H)-isoquinolinone was dissolved and dehydrated by addition of 10% hydrochloric acid (150 ml) at room temperature.

After three hours, the mixture was neutralized with sodium carbonate and the ethanol recovered by distillation in vacuo. The title compound was isolated by filtration and extraction with chloroform to give 27.92 g (98%) of the product of the title. M.p. 103-40C.

Example 4 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) obtained according to the process of Example 2 was dissolved in a mixture of t 50 ml of ethanol and 108 ml of acetic acid containing 2.2 ml of 22% HCI in ethanol. The mixture was hydrogenated in a Parr bomb at 900C under a pressure of 10 atmospheres, in the presence of 0.5 g of 10% palladiated charcoal.

After filtration of the catalyst, the solvent was evaporated off and the residue was taken up with water. Extraction with four 60 ml portions of dichloromethane and evaporation of the solvent yielded a residue which was re-crystallized from 50 ml of 70% ethanol. Yield 3.5 g (90%) of the product of the title. M.p. 102-30C.

Example 5 2-[4-(Trifluoromethyl)phenyl]-s-triazolo[5,1 -a] isoquinoline 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-amirio-l (2H)-isoquinolinone (1.6 g, 0.01 mol) was refluxed for 1.5 hours. Most of the ethanol was then distilled off and replaced with 35 ml of 2-ethoxyethanol while heating.

As the temperature of the vapours reached 1350C, heating was continued at reflux for five hours The title compound crystallized out by cooling at OOC and was recovered by filtration. After washing with 95% ethanol and water, the solid was dried under vacuum at 50"C. Yield 2.97 g (95%) of the title product melting at 1--120C.

Claims

1. A process for preparing a compound of the formula

wherein either R and R1 are independently selected from hydrogen, chlorine, fluorine, bromine, C15 alkyl, C15 alkylamino, di(C15 alkyl)amino, trifluoromethyl, C 1-5 alkoxy, C35 alkenyloxy, C35 alkynyloxy, C36 cycloalkyloxy and benzyloxy or R and R1 together are -0CH20-; and R2 and R3 are independently selected from hydrogen, chlorine, fluorine, bromine and C14 alkoxy; which comprises Contacting a compound of the formula

wherein R2 and R3 are as defined above, with a nitrile of the formula

wherein R and R1 are as defined above.

2. A process according to claim 1 in which is conducted in the presence of a catalyst.

3. A process according to claim 2 wherein the catalyst is selected from alkali metal alkoxides, alkali metal hydroxides, alkali metal hydrides, tertiary organic amines, transition metal salts and sulphur.

4. A process according to any preceding claim which is conducted in the presence of a solvent.

5. A process according to claim 4 wherein the solvent is selected from alkanols, (C15 alkoxy)alkanols, C15 chlorinated hydrocarbons, ethylene glycol, benzene, chlorobenzene, toluene, nitro benzene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, and mixtures thereof.

6. A process according to any preceding claim wherein a 1 to 20 per cent molar excess of the nitriie is used.

7. A process according to any preceding claim wherein the reaction is conducted at a temperature between 60 and 1 6O0C.

8. A process for preparing a compound of formula It as defined in claim 1 , which comprises reacting a compound of the formula

wherein R2 and R3 are as defined in claim 1, with hydrazine hydrate.

9. A compound of formula Il as defined in claim 1.

10. A process or compound according to any preceding claim wherein neither R nor R1 is trifluoromethyl.

11. A process or compound according to claim 10 wherein neither R2 nor R3 is hydrogen.

12. A process according to claim 1 substantially as described in Example 1 or Example 2.

13. A process according to claim 1 substantially as described in Example 5.

14. A process according to claim 8 substantially as described in Example 3.

1 5. A process for preparing a 5,6-dihydro derivative of a compound of formula I as described in claim 1, which comprises subjecting the product of any of claims 1 to 7, t2 and 13 to catalytic hydrogenation.

1 6. A process according to claim 1 5 substantially as described in Example 4.