JPH0116836B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to the production of 1-azabicycloalkane represented by the following formula, and involves deammonization and intramolecular ring closure of 2-(ω-aminoalkyl)-1-azacycloalkane represented by the following formula in the presence of a catalyst. It is by reacting. 1-Azabicycloalkane (hereinafter abbreviated as ABA), which is the object of the present invention, is the basic skeleton of an alkaloid, and is a compound useful as an intermediate raw material for medicines and agricultural chemicals. As there are many types of natural alkaloids with this type of cyclic structure, various methods for synthesizing ABA have been proposed for a long time (Supervised by Fujio Kotake, "Great Organic Chemistry" Vol. 17) , 325~
423 pages, published by Hirokawa Shoten (1959)). However, all of these known methods have too many limitations for industrial implementation, such as extremely long reaction steps, the use of special starting materials, and generally harsh reaction conditions.
Moreover, the yield of the target product is also low. For example, in the reductive ring-closing reaction of oxime dicarboxylic acid esters or nitrodicarboxylic acid esters, not only is the synthesis of starting materials complicated, but the ring-closing reaction is also carried out under hydrogen pressure of 300 ml.
It requires harsh conditions of over atmospheric pressure and 250℃.
Even if the overall yield is high, it will only be a few percent (for example, N,
J., Leonard, LRHruda, F.W.Long, J.Am.
Chem.Soc., 69 , 690 (1947); N.J. Leonard,
WEGoode, J.Am.Chem.Soc., 72 , 5404
(1950)) Furthermore, known methods are usually only effective for the synthesis of specific ABA;
There are limitations to its universal use in ABA synthesis. The present inventors use compounds that are easily obtained from industrially available raw materials as starting materials.
As a result of investigating various methods for the purpose of providing a general method for synthesizing ABA, the method of the present invention was arrived at. That is, the present invention provides 2-
(ω-Aminoalkyl)-1-azacycloalkane (m, n are integers of 3, 4, and 5, respectively) is intramolecularly deammoniated and ring-closing in the presence of a catalyst to obtain ABA. It is. The starting material of the present invention, 2-(ω-aminoalkyl)-1-azacycloalkane, is obtained by single decarboxylation condensation or cross decarboxylation condensation of industrially easily available α-pyrrolidone, α-piperidone, or ε-caprolactam. It is a compound that can be synthesized with high yield by hydrogenation.
Described in No. 18096. As described above, the starting material of the present invention is a compound that is much easier to synthesize than in conventional production methods, and is therefore advantageous both technically and economically. Thus, in the method of the present invention, the starting material 2-(ω-aminoalkyl)-1-azacycloalkane is subjected to a deammonia ring closure reaction. This reaction can be carried out in either a gas phase reaction or a liquid phase reaction, and the raw material 2-(ω-aminoalkyl)-1-azabicycloalkane may be heated under normal pressure in the presence of a catalyst. The heating temperature may be 50 to 250°C, and the heating time may be several hours to several tens of hours. Although the reaction in the present invention can be carried out without a solvent, the following formula In order to suppress the intermolecular condensation reaction represented by , it is preferable to carry out the reaction in an inert solvent, and more preferably to carry out the reaction in a dilute solution in which the concentration of the reactant is 50% or less. Examples of such inert solvents include aromatic hydrocarbons, aliphatic hydrocarbons, alicyclic hydrocarbons, alcohols, and ethers, but specifically benzene,
Examples include toluene, xylene, chlorobenzene, cyclohexane, decalin, methanol, ethanol, tetrahydrofuran, dioxane, and the like.
When using an inert solvent, the reaction is preferably carried out below the boiling point of the inert solvent. A catalyst is used to accelerate the reaction. The catalyst used is a compound with deammonization activity or hydrogenation activity, such as a compound containing a group metal of the periodic table, such as a Raney catalyst such as Raney nickel or Raney cobalt, or a noble metal catalyst such as palladium charcoal or platinum black. is preferred. The amount of the catalyst used may be several percent or more, and may be determined as appropriate based on various reaction conditions. Since the ring-closing reaction ends once ammonia has been produced, the reaction rate can be adjusted by adjusting the amount of catalyst by detecting the amount of ammonia produced as the reaction progresses. The target product can be separated from the reactant by conventional separation means such as distillation. The obtained target product, 1-azabicycloalkane, is useful as a starting material for synthesizing agricultural chemicals and concentrated drugs. EXAMPLES The present invention will be explained below with reference to Examples, but the present invention is not limited thereto. Example 1 Starting material, 2-(3-aminopropyl)-1-
Azacyclopentane was synthesized by the following method. 85 g (1 mol) of α-pyrrolidone is thoroughly mixed with 100 g of calcium oxide, placed in a retort, heated gradually, and finally heated to 400-450° C. while collecting the distillate. Caustic soda is added to the distillate to make it strongly alkaline, and the base component to be separated is vacuum distilled.58-62
Obtain 25 g of fraction at °C/0.1 mmHg. Analysis result 4-
It was an intramolecular Schiff base of oxo-1,7-heptamethylenediamine. 70g of this Schizuf base
% acetic acid, add 0.5 g of platinum oxide in an autoclave, and stir at room temperature under a hydrogen pressure of 50 Kg/cm ² ·G. Hydrogen absorption will stop in about 40 minutes.
Separate the catalyst, make it strong alkaline with caustic soda, extract with ether, and vacuum distillate to obtain a boiling point of 52-54.
A fraction of 18 g was obtained at a temperature of 0.4 mmHg. 2-(3-aminopropyl)-1- by spectral analysis
It was confirmed that it was azacyclopentane. 6.34 g (0.0495 mol) of 2-(3-aminopropyl)-1-azacyclopentane was placed in a 100 ml flask equipped with a stirrer, nitrogen inlet, and reflux condenser.
Dissolve in 60 ml of xylene. Ranney Nickel 15g
(wet), stir while heating from the outside, and slowly introduce nitrogen gas. As the reaction mixture boils, the presence of ammonia is observed in the nitrogen gas stream from the top of the reflux condenser, so it is brought into contact with dilute sulfuric acid of known concentration to collect the generated ammonia. After 3 hours, when 0.0442 mol of ammonia was distilled out, the heating was stopped, the catalyst was cooled, the catalyst was transferred to a separate distillation flask, the benzene was distilled off, and the benzene was distilled off under reduced pressure, resulting in a fraction of 1.6 with a boiling point of 39 to 41°C at 16 mmHg. g
(Gas chromatography analysis purity 98%) was obtained. The obtained fraction has a refractive index of 1.4680 (20℃) and a boiling point of
Both NMR spectra were completely consistent with literature values for pyrrolizidine (1-azabicyclo[3,3,0]octane). The conversion rate of the starting azacyclopentane was 89.2%, and the yield of pyrrolidine was 33%. Example 2 6.07 g (0.0389 mol) of 2-(4-aminobutyl)-1-azacyclohexane, 60 ml of toluene, and 15 g of Raney nickel (wet) were reacted in the same manner as in Example 1, until no ammonia formation was observed. From then on (after 2 hours and 30 minutes), catalyst separation and distillation were performed. 2.29 g of a fraction at 60-61°C (10 mmHg) was obtained. The refractive index (1.4768), boiling point, boiling point of picrate (198-200°C) and infrared spectrum completely matched the literature values for quinolizidine (1-azabicyclo[4,4,0]decane. The yield of quinolizidine was that of azacyclohexane. Example 3 100 g (0.54 mol) of 2-(5-aminopentyl)-1-azacycloheptane was mixed with Raney Nickel 35
The mixture is heated to reflux in 330 ml of xylene under a nitrogen atmosphere with stirring in the presence of 100 g (wet). After about 6 hours, when the production of ammonia stopped, the catalyst was separated and distilled to obtain 32.5 g of a fraction at 110-114°C (19 mmHg) and 58.2 g of a residue. Refractive index of distillate 1.4936 (20℃), picrate (1
-Melting point of azabicyclo[5,5,0]dodecane
The temperature of 142-143°C was consistent with the literature value. Yield from starting substituted azacycloheptane is 36%
It was hot. Examples 4 to 9 Table 1 shows the results of the same reaction as in Example 3, changing the ratio of 2-(5-aminopentyl)-1-azacycloheptane to Raney nickel and xylene. In Table 1, the reaction rate and yield are values determined by gas chromatography analysis of the reaction mixture.

【table】

[Table] Examples 10 to 11 Table 2 shows the results when 2-(5-aminopentyl)-1-azacycloheptane was reacted in the same manner as in Example 3 by changing the type of metal catalyst in xylene. Shown below.

【table】

Claims (1)

[Scope of Claims] 1 A 2-(ω-aminoalkyl)-1-azacycloalkane represented by the following formula is subjected to intramolecular deammonia ring closure in the presence of a metal catalyst containing at least one metal of Group Group of the Periodic Table. A method for producing 1-azabicycloalkane represented by the following formula, which comprises carrying out a reaction. (m and n are integers of 3, 4, and 5, respectively) (m, n are integers of 3, 4, and 5, respectively) 2. Claim 1, characterized in that the intramolecular deammonia ring-closing reaction is carried out in an inert solvent.
The method for producing 1-azabicycloalkane described in Section 1.