RU2523463C1 - Method of 2-amino-2-cyanoadamantane transamination - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: method consists in an interaction of α-aminonitrile with amines with heating. As α-aminonitrile, 2-amino-2-cyanoadamantane is used, and as amines - cyclohexylamine, 3-aminopropanol and morpholine. The process is carried out in the presence of potassium carbonate at 80-100°C.

EFFECT: method makes it possible to increase the output of 2-amino-2-cyanoadamantane derivatives.

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Description

The invention relates to a process for the transamination of α-aminonitriles, in particular, to a new method for the transamination of 2-amino-2-cyanoadamantane, which finds application in the synthesis of derivatives of 2-amino-2-cyanoadamantane of the general formula

which are intermediates of probable biologically active amino acids, diamines and heterocyclic compounds.

The closest analogue of the invention is a method for producing α-aminonitriles by reamination at a temperature of 130-180 ° C, while the product yields are 13-80%. Aminonitriles that do not contain a free amino group act as initial reagents, and diethylamine, heptylamine, piperidine, morpholine, and aniline act as a transaminating agent [Transamination of α-aminonitriles / Shahidayatov X. // Zhork. 1973, 9 (7), 1373-1401].

The disadvantage of this method is usually a low yield of products, which is associated with the chemical equilibrium of the reaction, as a result of which large yields are achieved only by removing the products formed from the reaction mixture. Quite high (up to 180 ° С) temperatures are used, as a result of which the reaction mass is ground. The use of α-aminonitriles substituted at the amino group as starting reagents requires their preliminary preparation and, therefore, the method increases the stepwise synthesis of the target products. In addition, in some cases, the formation of by-products, enamines, was observed. The reaction of the transamination of 2-amino-2-cyanoadamantane under the conditions used in the prototype, leads to the derivation of 2-amino-2-cyanoadamantane with a yield not exceeding 30-45%).

The technical result of the proposed method is to increase the yield of derivatives of 2-amino-2-cyanoadamantane and the adaptability of the transamination process using α-aminonitrile with a free amino group and the use of a catalyst

The technical result is achieved in the method of transamination of 2-amino-2-cyanoadamantane, which consists in the interaction of α-aminonitrile with amines when heated, while 2-amino-2-cyanoadamantane is used as α-aminonitrile, cyclohexylamine is used as amines, 3- aminopropanol, morpholine, and the process is carried out in the presence of potassium carbonate at 80-100 ° C.

The essence of the method is the reaction of transamination of 2-amino-2-cyanoadamantane with amines from the series cyclohexylamine, 3-aminopropanol, morpholine in the presence of potassium carbonate, accompanied by the release of gaseous ammonia.

The method is as follows. A 2-amino-2-cyanoadamantane and an amine from the series: cyclohexylamine, 3-aminopropanol, morpholine in a molar ratio of 1: 1.5-3 and a catalytic amount of potassium carbonate are loaded into a round-bottom flask. The reaction mixture is heated to 80-100 ° C, while gaseous ammonia is released. Upon completion of the separation of ammonia from the reaction mass, the excess of amine is distilled off, then the reaction product is distilled in vacuum. The yield of 2-amino-2-cyanoadamantane derivatives is 67-86%. Thus, the proposed method is characterized by simplicity in the synthesis and isolation of reaction products.

The difference of the proposed method from the prototype is the use of α-aminonitrile 2-amino-2-cyanoadamantane containing a free amino group, which is easily obtained from 2-hydroxy-2-cyanoadamantane using available ammonia [Pat.2307123 RF, IPC C07D 295/033 C07C 255/58. A method of obtaining 2-amino-2-cyanoadamantane or its derivatives / Yu.V. Popov, V.M. Mokhov, M.V. Khammo, S.N. Bondarenko; Volgograd State Technical University. - 2007]. It is shown that the use of α-aminonitrile, unsubstituted at the nitrogen atom as the starting compound, in particular 2-amino-2-cyanoadamantane, allows the reaction temperature to be reduced by 20-30 ° C relative to the prototype, and the use of potassium carbonate as a catalyst that promotes separation cyano groups from the starting 2-amino-2-cyanoadamantane, allowed to reduce the reaction onset temperature to 80 ° C, which reduces the degree of resinification of the reaction mixture, simplifies the process of obtaining and subsequent purification of 2-amino-2-cyanoad derivatives amantana. The formation of gaseous ammonia as one of the reaction products shifts the reaction equilibrium towards the formation of products and makes the transamination process irreversible, which ensures the complete conversion of the starting 2-amino-2-cyanoadamantane.

It was found that the optimal molar ratio of 2-amino-2-cyanoadamantane: amine is 1: 1.5-3. Reducing the excess of amine to equimolar leads to incomplete conversion of 2-amino-2-cyanoadamantane, reduces the yield of the target products and greatly complicates their purification. Increasing the excess of aminonitriles above three times is impractical, since it does not lead to an increase in the yield of the target products. It was found that the optimum temperature for the synthesis of derivatives of 2-amino-2-cyanoadamantane is 80-100 ° C. Lowering the temperature to 60 ° C greatly slows down the reaction, and below 60 ° C - stops it. It was shown that a catalytic amount of potassium carbonate added to the reaction mixture significantly accelerates the process. The transamination of 2-amino-2-cyanoadamantane in the absence of potassium carbonate leads to the production of 2-amino-2-cyanoadamantane derivatives in a yield of not more than 30-45%.

The invention is illustrated by the following examples:

Example 1

2- (N-Morpholino) -2-cyanoadamantane.

A mixture of 3 g (0.017 mol) of 2-amino-2-cyanoadamantane, 4.3 g (0.05 mol) of morpholine and 0.05 g of potassium carbonate was heated in a flask under reflux at 80-100 ° C for 1 hour. In the initial reaction period, ammonia was released. At the end of the reaction, excess morpholine was distilled off at atmospheric pressure, the residue was distilled in vacuo, and 2.8 g (0.011 mol, 67%) of 2- (N-morpholino) -2-cyanoadamantane were obtained, boiling point. 219-221 ° C (20 mmHg). ¹ H NMR spectrum, δ, ppm: 1.38-2.13 m (14H, _2.2- Ad), 2.56 t (4H, (CH ₂ ) ₂ N), 3.72 t (4H, (CH ₂ ) ₂ O).

Example 2

2- (3-Hydroxypropylamino) -2-cyanoadamantane.

A mixture of 3 g (0.017 mol) of 2-amino-2-cyanoadamantane, 2.6 g (0.035 mol) of 3-aminopropanol and 0.05 g of potassium carbonate was heated in a flask under reflux at 80-100 ° C for 1 hour. In the initial reaction period, ammonia was released. At the end of the reaction, an excess of 3-aminopropanol was distilled off under reduced pressure, the residue was distilled in vacuo, 3.4 g (0.0146 mol, 86%) of 2- (3-hydroxypropylamino) -2-cyanoadamantane were obtained, boiling range 175-178 ° C (20 mmHg). ¹ H NMR spectrum, δ, ppm: 1.39-2.13 m (14H, _2.2- Ad, 2H, CH ₂ ), 2.84 t (2H, CH ₂ N), 2.76 br s (1H, NH ), 3.63 bs (1H, OH), 3.71 t (2H, CH ₂ O).

Example 3

2- (N-Cyclohexylamino) -2-cyanoadamantane.

); 2.62 м (1H, -CH-N).A mixture of 3.5 g (0.02 mol) of 2-amino-2-cyanoadamantane, 3 g (0.03 mol) of cyclohexylamine and 0.05 g of potassium carbonate was heated in a flask under reflux at 80-100 ° C for 1.5 hours. In the initial reaction period, ammonia was released. At the end of the reaction, an excess of cyclohexylamine was distilled off, the residue was distilled in vacuo, 3.8 g (0.0148 mol, 74%) of 2- (N-cyclohexylamino) -2-cyanoadamantane were obtained, boiling point. 170-172 ° C (20 mmHg). so pl. 93-94 ° C. ¹ H NMR spectrum, δ, ppm: 0.68 s (1H, NH); 1.05-2.25 m (14H, _2.2- Ad; 10H,

); 2.62 m (1H, -CH-N).

Thus, a new method was developed for the transamination of 2-amino-2-cyanoadamantane, which leads to the production of 2-amino-2-cyanoadamantane derivatives in high yield, which consists in the transamination of 2-amino-2-cyanoadamantane with amines from the series cyclohexylamine, 3-aminopropanol, morpholine in the presence of potassium carbonate at a temperature of 80-100 ° C for 1-1.5 hours.

Claims (1)

The method of transamination of 2-amino-2-cyanoadamantane, which consists in the interaction of α-aminonitrile with amines when heated, characterized in that 2-amino-2-cyanoadamantane is used as α-aminonitrile, cyclohexylamine, 3-aminopropanol, morpholine are used as amines , and the process is carried out in the presence of potassium carbonate at 80-100 ° C.