JPH0570429A - Production of 3-azabicyclo(3,3,0)octane - Google Patents

Abstract

PURPOSE:To easily obtain the title compound in an industrially advantageous way through, so called, one-pot process. CONSTITUTION:A 2-cyano-1-cyclopentenecarboxylic ester is first put to catalytic hydrogenation in an inert solvent in the presence of a Raney catalyst followed by filtering off the catalyst. Thence, the product is further put to catalytic hydrogenation in the same solvent as the above in the presence of copper chromite and an alkali metal oxide or alkaline earth metal oxide to obtain the objective 3-azabicyclo[3,3,0] octane.

Description

Detailed Description of the Invention

[0001]

The present invention relates to 3-azabicyclo [3,3,3] which is useful as a raw material for pharmaceuticals such as diabetes and angina.
0] Octane

[0002]

[Chemical 1]

The manufacturing method of

[0004]

2. Description of the Related Art For example, as described in JP-A No. 50-62971, 2-cyano-1-cyclopentenecarboxylic acid ester in isopropanol in the presence of ammonia using a Raney nickel catalyst at a temperature of 60.
1st under the condition of -100 ℃ and hydrogen pressure of 17-20Kg / cm ² .
3-azabicyclo [3,3,3,3
0] octane-2-one, and after taking it out and purifying it, dioxane was used in the presence of a Cu—Ba—CrO 2 catalyst at a temperature of
^Second under the condition of 00 ℃, hydrogen pressure 130 ~ 140Kg / cm 2.
3-azabicyclo [3,3,3,3
A method is known for obtaining [0] octane with a yield of 39%.

However, this method is
The product is taken out from the reaction mixture, purified, and then catalytically hydrogenated again in another solvent. Furthermore, in the above method, when the reaction mixture obtained in the first-stage catalytic hydrogenation is used as it is in the second-stage catalytic hydrogenation, an N-alkylated product may be produced. In the catalytic hydrogenation of the stage, the solvent in the first stage, isopropanol, cannot be used.

The above publication also describes a method of reducing 3-azabicyclo [3,3,0] octane-2-one with diborane in tetrahydrofuran. However, diborane is expensive and requires special handling, such as ignition due to contact with moisture.

[0007]

DISCLOSURE OF INVENTION Problems to be Solved by the Invention The present inventors have earnestly studied to solve the problems in the conventional production of 3-azabicyclo [3,3,0] octane as described above, and as a result, 2-cyano- After catalytic hydrogenation of 1-cyclopentenecarboxylic acid ester in an inert solvent in the presence of a Raney catalyst, the catalyst is filtered off, and subsequently, in the same inert solvent as above, with copper chromite, Industrially advantageous and easy production of 3-azabicyclo [3,3,0] octane by further catalytic hydrogenation in the presence of an alkali metal oxide or an alkaline earth metal oxide. That is, the present invention has been achieved.

[0008]

The method for producing 3-azabicyclo [3,3,0] octane according to the present invention comprises a 2-cyano-1-cyclopentenecarboxylic acid ester in an inert solvent in the presence of a Raney catalyst. After catalytic hydrogenation, the catalyst is filtered off, followed by further catalytic hydrogenation in the presence of copper chromite and an alkali metal oxide or alkaline earth metal oxide in the same inert solvent as above. It is characterized by

2-cyano-used in the method of the present invention
The 1-cyclopentenecarboxylic acid ester is usually preferably an alkyl ester, and particularly preferably a methyl ester or an ethyl ester. In the method of the present invention, 2-
Catalytic hydrogenation of cyano-1-cyclopentenecarboxylic acid ester (first stage catalytic hydrogenation) is carried out in an inert solvent such as dioxane or cyclohexane.

This first-stage catalytic hydrogenation is carried out in such an inert solvent as ammonia, alkali metal hydroxides such as sodium hydroxide or calcium hydroxide, or alkaline earth metal hydroxides. In the presence of a base, using a Raney catalyst such as Raney nickel or Raney cobalt, a temperature of 50 to 280 ° C., a pressure of 10 to 200 Kg / cm ² , preferably a temperature of 100 to 200 ° C., a pressure of 20 to 100 Kg / cm.
^It is performed under the conditions of ² .

According to the method of the present invention, in this way,
After carrying out the first-stage catalytic hydrogenation, the catalyst used is filtered off and subsequently the second-stage catalytic hydrogenation is carried out in the same inert solvent as described above. In this second stage catalytic hydrogenation, in the presence of alkali metal oxides or alkaline earth metal oxides such as sodium oxide, calcium oxide, etc.,
Using a copper chromite catalyst, a temperature of 150 to 280 ° C., a pressure of 100 to 250 kg / cm ² , preferably a temperature of 200 to
It is carried out under the conditions of 250 ° C. and a pressure of 150 to 200 kg / cm ² .

According to the method of the present invention, a so-called one
The 3-azabicyclo [3,3,0] octane can be obtained by the pot reaction.

[0013]

The present invention will be described below with reference to examples.
The present invention is not limited to these examples. Example 1 Methyl 2-cyano-1-cyclopentenecarboxylate 5.0
g was dissolved in a mixture of 5.0 g of dioxane and 2.15 g of concentrated aqueous ammonia, and the temperature was adjusted to 20 in the presence of Raney nickel.
The mixture was stirred at 0 ° C. and hydrogen pressure of 50 kg / cm ² for 4 hours while distilling off by-produced methanol. After completion of the reaction, the catalyst was filtered off to obtain a reaction solution.

Then, a solution prepared by suspending 2.50 g of copper chromite and 5.32 g of calcium oxide in 21.0 g of dioxane was added to the above reaction solution, and the temperature was 250 ° C. and the hydrogen pressure was 150 kg /.
The mixture was stirred under cm ² for 4 hours. The catalyst was filtered off from the resulting reaction solution, the solvent was distilled off, and the reaction mixture was distilled to give 1.69 g of 3-azabicyclo [3,3,0] octane.
(Yield 39.7%) was obtained. Boiling point: 97 ℃ / 143mmHg GC-MS: m / z = 111 λ _max (cm ^-1 ): 3250 (NH), 2910, 1445, 1080, 855, 8
30 Example 2 Methyl 2-cyano-1-cyclopentenecarboxylate 4.5
g of cyclohexane 60.0 g and liquid ammonia 0.45 g
The mixture was dissolved in a mixture of and, and the mixture was stirred for 5 hours in the presence of Raney cobalt at a temperature of 200 ° C. and a hydrogen pressure of 80 kg / cm ² while distilling off by-produced methanol. After completion of the reaction, the catalyst was filtered off to obtain a reaction solution.

Then, copper chromite 1.
Add 35 g and 1.00 g of sodium oxide, and add 250
The mixture was stirred for 4 hours under the condition of ℃ and hydrogen pressure of 160 kg / cm ² .
After the catalyst was filtered off from the obtained reaction solution and the solvent was distilled off,
The reaction mixture was distilled to give 3-azabicyclo [3,3,0]
1.12 g of octane (yield 30.6%) was obtained. Example 3 Ethyl 2-cyano-1-cyclopentenecarboxylate 7.0
g was dissolved in a mixture of dioxane 70.0 g and 40% sodium hydroxide aqueous solution 4.12 g, and in the presence of Raney nickel at a temperature of 190 ° C. and a hydrogen pressure of 50 kg / cm ² ,
The mixture was stirred for 8 hours while distilling off by-product ethanol.
After completion of the reaction, the catalyst was filtered off to obtain a reaction solution.

Next, a solution prepared by suspending 2.81 g of copper chromite and 4.59 g of calcium oxide in 30.0 g of dioxane was added to the above reaction solution, and the temperature was 250 ° C. and the hydrogen pressure was 170 kg /.
The mixture was stirred for 6 hours under the condition of cm ² . The catalyst was filtered off from the resulting reaction solution, the solvent was distilled off, and the reaction mixture was distilled to obtain 1.82 g of 3-azabicyclo [3,3,0] octane.
(Yield 33.8%) was obtained.

[0017]

According to the method of the present invention, 2-cyano-1
-Cyclopentenecarboxylic acid ester in an inert solvent,
After catalytic hydrogenation in the presence of a Raney catalyst, the catalyst is filtered off, then in the same solvent as above, with copper chromite,
By further catalytic hydrogenation in the presence of alkali metal oxides or alkaline earth metal oxides, 3-azabicyclo [3,3,0] octane can be obtained. Therefore, according to the method of the present invention, 3-azabicyclo [3,3,0] octane can be easily obtained by the so-called one-pot reaction.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Haruo Kasamatsu Inventor, 563 Nagayama, Kishigawa-cho, Naga-gun, Wakayama Prefecture (72) Yoshiaki Iwasaki 3-39 Usu, Wakayama City, Wakayama Prefecture

Claims (2)

[Claims] 1. A 2-cyano-1-cyclopentenecarboxylic acid ester is catalytically hydrogenated in an inert solvent in the presence of a Raney catalyst, then the catalyst is filtered off, and subsequently in the same inert solvent as described above. Copper chromite and further catalytic hydrogenation in the presence of an alkali metal oxide or an alkaline earth metal oxide, 3-azabicyclo [3,3,3]
0] A method for producing octane. 2. The method for producing 3-azabicyclo [3,3,0] octane according to claim 1, wherein the inert solvent is dioxane or cyclohexane.