JPH021146B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides 2-phenyl-s-triazolo[5,
1-a] A novel method for producing isoquinoline derivatives. 2-Phenyl-s-triazolo[5,1-
a] Isoquinoline derivatives and methods for their preparation are described in US Pat. No. 3,758,480. A series of 2 substituted on the 2-phenyl moiety
Its preparation from -phenyl-s-triazolo[5,1-a]isoquinoline and its corresponding 5,6-dihydro compounds is described in US Pat. No. 4,075,341. 2-phenyl-s-triazolo[5,1-a]
Isoquinoline and its 5,6-dihydro derivatives have been used effectively as antifertilization agents. (See US Pat. No. 3,895,113). 2-(Substituted-phenyl)-s-triazolo[5,1-a]isoquinolines and their corresponding 5,6-dihydro derivatives are particularly suitable for controlling fertility in mammals. (See US Pat. No. 4,075,341). The method for producing such a 2-phenyl-s-triazolo[5,1-a]isoquinoline derivative described in the prior literature is complicated and has a low yield;
This entire operation is uneconomical for commercial production. The purpose of the present invention is to [In the formula, R and R ₁ are independently hydrogen, chloro,
fluoro, bromo, lower alkyl, lower alkylamino, di-lower alkylamino, trifluoromethyl, or OR ₄ group (wherein R ₄ is lower alkyl,
lower alkenyl, lower alkynyl, cycloalkyl and benzyl), or R and R ₁ together represent an _-OCH2O- group, and R ₂ and R ₃ independently represent hydrogen, chloro, fluoro, bromo. and alkoxy having 1 to 4 carbon atoms]
2-phenyl-s-triazolo[5,1
-a] To provide a new and useful method for producing isoquinoline derivatives. The term "lower alkyl" and the moiety refers to branched or linear alkyl groups having 1 or 5 carbon atoms, preferably methyl and ethyl groups. The term "lower alkenyl" refers to alkenyl groups having 3 to 5 carbon atoms, preferably allyl groups. The term "lower alkynyl" refers to an alkynyl group having 3 to 5 carbon atoms, preferably a propargyl group. The term "cycloalkyl" refers to a 3- to 6-membered cycloalkyl group. The method of the invention comprises combining a compound of formula and a nitrile of formula

【formula】

[Formula] (In the formula, R, R ₁ , R ₂ and R ₃ have the same meanings as above) by contacting an alkali metal compound in the presence of a basic catalyst. The reaction between a compound of formula and a compound of formula can be carried out in a suitable solvent system, but can also be carried out in the absence of a solvent, preferably by simply mixing the two reactants together with a catalyst. You can also do that. However, when this reaction is carried out in large batches,
Add some solvent to reduce the viscosity of the reaction mass;
Moreover, it is desirable to facilitate mixing of the reactants.
A variety of solvents can be used. Suitable solvents include, for example, alkanols such as methanol, ethanol, propanol, and butanol, lower alkoxy-alkanols such as methoxy-ethanol, ethoxy-ethanol, and propoxy-ethanol, chlorinated lower hydrocarbons, ethylene glycol, benzene. , chlorobenzene, toluene, nitrobenzene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide and mixtures thereof. When the reaction is carried out in a solvent, the reaction temperature may range between room temperature and the boiling point of the mixture.
Generally, temperatures between 60 and 160°C are preferred as the reaction rate is sufficiently fast and the formation of undesirable by-products is prevented. Particularly when the reaction is carried out in the absence of a solvent, nitrile may be added in an excess of 1 to 20 mol% of the compound to facilitate mixing, but in general the two reactants are approximately equimolar. Use in quantity. This reaction is carried out in the presence of a basic catalyst, and basic catalysts of alkali metal hydroxides, alkali metal alkoxides and alkali metal hydrides have been found to give satisfactory results. The reactant 2-amino-1(2H)-isoquinoline can be prepared by several methods. The most suitable operation is to use hydrazine and isocoumarin as the final step. Including the reaction between The preparation of the compounds is well described in the literature and can be suitably carried out by bromination of the corresponding 1-isochromin with bromine followed by dehydrobromination with triethylamine in 1,2-dichloroethane. The reaction between hydrazine and isocoumarin is carried out at room temperature by using water-based hydrazine hydrate in ethanol as the solvent. The intermediate 2-amino-3,4-dihydro-
3-Hydroxy-1(2H)-isoquinolinone can be converted to the desired 2-amino-1(2H)-isoquinolinone. Typical examples of compounds that can be produced by the method of the invention are as follows. 2-(4-chlorophenyl)-s-triazolo[5,1-a]isoquinoline 2-(4-fluorophenyl)-s-triazolo[5,1-a]isoquinoline 2-(3-methoxyphenyl)- s-triazolo[5,1-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-bromphenyl)-s-triazolo[5,1-a]isoquinoline 2-(3-propyloxyphenyl)-s-triazolo[5,1-a] ] Isoquinoline 2-(3-benzyloxyphenyl)-s-triazolo[5,1-a]isoquinoline 2-(4-trifluoromethylphenyl)-s
-Triazolo[5,1-a]isoquinoline The method of the present invention generally uses s-triazolo[5,1-a]isoquinoline.
a] Provides high yields in the synthesis of condensed triazolo systems such as isoquinoline. Furthermore, the method does not require reagents that require special care when used in industrial plants, so it can be carried out very easily even in large-scale production. This new method is based on the above formula (wherein R and
R ₁ is in the 3- and 4-positions of the phenyl ring)
2-phenyl-s-triazolo[5,1-a]
It is particularly useful in the production of isoquinolines. 2-phenyl-s obtained by the method of the present invention
-triazolo[5,1-a]isoquinoline derivatives are also described, for example, in U.S. Pat.
It can also be used to convert to the corresponding 5,6-dihydro compound by catalytic hydrogenation using the method described in No. 3758480. The following examples illustrate the method of the invention without limiting its scope. Example 1 2-(4-Chlorphenyl)-s-triazolo[5,1-a]isoquinoline In a solution of sodium ethoxide (0.68 g, 0.01 mol) in absolute ethanol (150 ml), 2-amino- 1(2H)isoquinolinone (8g, 0.05mol)
and 4-chlorobenzonitrile (7.24 g, 0.05
mol) was added and the mixture was refluxed with stirring for 1 hour. The intermediate amidrazone is crystallized, ethanol is distilled off while heating, and 2-
It was replaced with ethoxyethanol. When the steam temperature reached 135°C, heating was continued with reflux for 5 hours. The title compound crystallized on cooling and was collected by filtration. The solid was washed with water and 95% ethanol and dried in vacuo to give 13.43 g (96%) of the title product. Melting point 250-251℃. Example 2 (Example) 2-(3-ethoxyphenyl)-s-triazolo[5,1-a]isoquinoline 2-amino-1(2H)isoquinolinone (3.2g,
0.02 mol), 3-ethoxybenzonitrile (3.09
g, 0.021 mol) and sodium methoxide (0.044 g) in toluene (20 ml) was stirred at room temperature under nitrogen for 30 min and further
Stirred at 60°C for 30 minutes. Two successive additions of 0.044 g each of sodium methoxide were added within about 90 minutes and the temperature was then slowly increased to reflux. The solvent was distilled under reduced pressure, and the residue was dissolved with water (20 ml) and then acidified to pH 2 with dilute hydrochloric acid. The crude product was filtered under reduced pressure and then crystallized from 85% ethanol (120ml) to yield 5.18g (89.5%) of pure title compound, mp 140-141°C. Example 3 (Reference example) 2-Amino-1(2H)-isoquinolinone A solution of isocoumarin (26 g, 0.16 mol) in 95% ethanol (200 ml) with 25% hydrazine hydrate in water (64 ml, 0.32 mol). The mixture was treated and stirred for 1 hour at room temperature. 10 at room temperature
Add % hydrochloric acid (150ml) to 2-amino-3,4-
The precipitate of dihydro-3-hydroxy-1(2H)-isoquinolinone was dissolved and dehydrated. After 3 hours, the mixture was neutralized with sodium carbonate and the ethanol was recovered by vacuum distillation. The title compound was isolated by filtration and extracted with chloroform to give 27.92 (98%) of the title product, mp 103-104°C. Example 4 (Reference example) 2-(3-ethoxyphenyl)-5,6-dihydro-s-triazolo[5,1-a]isoquinoline 2-(3-ethoxyphenyl) obtained by the method of Example 2 Enyl)-s-triazolo[5,1-a]isoquinoline (3.9 g, 0.013 mol) was dissolved in a mixture of 150 ml of ethanol and 108 ml of acetic acid containing 2.2 ml of 22% HCl in ethanol. This mixture was hydrogenated at 90° C. under a pressure of 10 atmospheres in a parboiler in the presence of 0.5 g of 10% palladized charcoal. After filtering the catalyst, the solvent was evaporated and the residue was dissolved in water. Extract 4 times with 60 ml of methylene chloride, evaporate the solvent, and add 50 ml of the residue.
Recrystallized from 70% ethanol. Yield 3.5g
(90%) of the title product, melting point 102-103°C, was obtained. Example 5 (Reference example) 2-[4-(trifluoromethyl)phenyl]
-s-Triazolo[5,1-a]isoquinoline Sodium ethoxide (0.136 g, 0.002 mol), 4-trifluoromethyl-benzonitrile (1.71 g, 0.01 mol) and 2-amino- in absolute ethanol (30 ml) A solution of 1(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. When the steam temperature reached 135°C, heating was continued under reflux for 5 hours. The title compound crystallized on cooling to 0°C and was collected by filtration. After washing with 95% ethanol and water, the solid was dried under vacuum at 50°C. yield
2.97% (95%) of the title biocompound, melting point 211-212
℃ was obtained.

Claims (1)

[Scope of Claims] 1. In the presence of a basic catalyst selected from the group consisting of alkali metal alkoxides, alkali metal hydroxides and alkali metal hydrides, the formula (In the formula, R ₂ and R ₃ are independently hydrogen, chloro,
fluoro, bromo, and alkoxy having 1 to 4 carbon atoms) and the formula [In the formula, R and R ₁ are independently hydrogen, chloro,
fluoro, bromo, lower alkyl, lower alkylamino, di-lower alkylamino, trifluoromethyl, or OR ₄ group (wherein R ₄ is lower alkyl,
lower alkenyl, lower alkynyl, cycloalkyl, and benzyl), or R and R ₁
together represent -OCH ₂ O-] with a nitrile,
formula (wherein R, R ₁ , R ₂ and R ₃ have the same meanings as above) 2-phenyl-s-triazolo[5,1-a]
A method for producing an isoquinoline derivative. 2. The method according to claim 1, wherein the method is carried out in the presence of a solvent. 3. The solvent is selected from alkanol, lower alkoxy-alkanol, chlorinated lower hydrocarbon, ethylene glycol, benzene, chlorobenzene, toluene, nitrobenzene, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide, and mixtures thereof. 2. The method according to claim 2, wherein: 4. Process according to claim 1, using a 1 to 20 mol% excess of nitrile. 5. The method according to any one of claims 1 to 4, wherein the reaction is carried out at a temperature of 60 to 160°C.