JPS6129949B2 - - Google Patents

Description

Detailed Description of the Invention The present invention provides a novel 5-(4-
Aminomethylbicyclo[2,2,2]octane
1-yl)tetrazole and its salts.

The target compound of the present invention has strong anti-plasmin activity and can be produced, for example, according to the following reaction formula.

(In the formula, R is a protecting group for an amino group, such as a carbobenzoxy group, a tertiary amyloxycarbonyl group,
In other words, the compound represented by the formula () is reacted with ammonia to form an acid amide (), which is then converted into an oxychloride in the presence of tertiary amines such as pyridine and dimethylaniline. After reacting with a dehydrating agent such as phosphorus or thionyl chloride to form a nitrile derivative represented by the formula (), reacting with an azide alkali metal salt such as sodium azide or lithium azide in a solvent such as dimethylformamide or dimethyl sulfoxide yields the formula () A tetrazole derivative represented by can be prepared. In addition, by adding ammonium chloride, aluminum chloride, etc. to this reaction, the reaction can be accelerated and the yield can be improved. The compound of formula () thus prepared can be prepared using conventional methods such as hydrobromic acid-acetic acid when the protecting group R is a carbobenzoquine group, and hydrogen chloride in ethyl acetate when the protecting group R is a tertiary amyloxycarbonyl group. When the protecting group is removed by treatment with , the desired compound () can be obtained.

The target compound of the present invention can be converted into an acid addition salt if necessary, and examples of the acid used include inorganic acids and organic acids such as hydrochloric acid, hydrobromic acid, tartaric acid, and citric acid.

The target compound of the present application has strong anti-plasmin activity and is useful as a medicine, but the effects of its hydrobromide salt have been investigated with tranexamic acid, which is currently widely used as an anti-plasmin agent, and serum fibrinolysis ( Serum Fibrinolysis) showed a relative activity ratio of 1.48 times.

Example 7.2 g of 4-benzyloxycarbonylaminomethylbicyclo[2,2,2]octane-1-carboxylic acid chloride is dissolved in 50 ml of benzene, and 60 ml of concentrated aqueous ammonia is added dropwise to this solution while stirring on ice. Thereafter, the mixture was stirred at room temperature for 2.5 hours, the benzene was distilled off, water was added, and the mixture was extracted with chloroform. After washing the chloroform solution with water and drying, the chloroform is distilled off to obtain colorless crystals. When a portion is recrystallized from alcohol-water, the melting point
Colorless plate-like crystals of 4-benzyloxycarbonylaminomethylbicyclo[2,2,2]octane-1-carboxamide are obtained at 63-64°C.

Elemental analysis value Calculated value (%) as C ₁₈ H ₂₄ N ₂ O ₃ :
C 68.33, H 7.65, N 8.85 Experimental values (%):
C 68.28, H 7.62, N 8.98 The 4-benzyloxycarbonylaminomethylbicyclo[2,2,2]octane-1-carboxamide obtained in the above reaction was dissolved in 25 ml of pyridine, cooled with ice-salt, and stirred. Phosphorus oxychloride 3
ml and 15 ml of dichloromethane are added dropwise. Thereafter, the mixture was stirred at the same temperature for 1 hour, cold water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate solution was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate solution, and water, and after drying, the ethyl acetate was distilled off to give 5.3 g of colorless crystals with a melting point of 137-139°C.
get. A portion is recrystallized from ethyl acetate-hexane to obtain colorless prismatic crystals of 4-benzyloxycarbonylaminomethylbicyclo[2,2,2]octane-1-carbonitrile with a melting point of 138-139°C.

Elemental analysis value Calculated value (%) as C ₁₈ H ₂₂ N ₂ O ₂ :
C 72.45, H 7.43, N 9.39 Experimental values (%):
C 72.43, H 7.21, N 9.14 Add 2.1 g of 4-benzyloxycarbonylaminomethylbicyclo[2,2,2]octane-1-carbonitrile, 2.3 g of sodium azide and 1.9 g of ammonium chloride to 40 ml of dimethylformamide,
Heat and stir at 140-150°C for 24 hours. Dimethylformamide was distilled off under reduced pressure, water was added to the residue, and the mixture was made alkaline with 2N sodium hydroxide. Insoluble materials were removed by filtration, and the filtrate was acidified with concentrated hydrochloric acid and extracted with chloroform. After washing the chloroform solution with water and drying, the chloroform is distilled off. The residue was recrystallized from acetone-petroleum ether, melting point 191-192℃.
1.28 g of colorless prism crystals of 5-(4-benzyloxycarbonylaminomethylbicyclo[2,2,2]octan-1-yl)tetrazole were obtained.

Elemental analysis value Calculated value (%) as C ₁₈ H ₂₃ N ₅ O ₂ :
C 63.32, H 6.79, N 20.52 Experimental values (%):
C 63.12, H 6.67, N 20.82 1.2 g of 5-(4-benzyloxycarbonylaminomethylbicyclo[2,2,2]octan-1-yl)tetrazole in 30% hydrobromic acid and acetic acid solution
Add to 50 ml and stir at room temperature for 3 hours. Add ether and collect the precipitated crystals by filtration, wash with ether, and recrystallize from ethanol ether to obtain a decomposition point of 262 ~
5-(4-aminomethylbicyclo[2,
0.60 g of 2,2]octan-1-yl)tetrazole hydrobromide is obtained as colorless prismatic crystals.

Elemental analysis value Calculated value (%) as C ₁₀ H ₁₇ N ₅ HBr:
C 41.67, H 6.30, N 24.30 Experimental values (%):
C 41.66, H 6.18, N 24.44 This hydrobromide salt is made into an aqueous solution, a calculated amount of dilute sodium hydroxide solution is added, and the precipitate is collected by filtration to obtain the free form as crystals with a decomposition point of 273-274°C.

Claims (1)

[Claims] 1 formula 5-(4-Aminomethylbicyclo[2,2,2]octan-1-yl)-tetrazole and its salts.