RU2487117C1 - Method of producing 1,3-disubstituted urea derivatives of 1,3-dimethyladamantane - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 1,3-disubstituted urea derivatives of 1,3-dimethyladamantane of general formula:

,

where n=0, 1

. The method involves reacting an isocyanate of general formula:

, where n=0, 1; with amines selected from: 1,2-ethylenediamine, piperidine, 1-aminomethyladamantane, 2-amino-2-cyanoadamantane and 2-aminoethanol at temperature of 0-25°C, for 3-8 hours in dimethyl formamide with molar ratio isocyanate:amine:dimethyl formamide=1:1.1-7.2:65-107.

EFFECT: invention enables to obtain novel 1,3-disubstituted ureas of the disclosed structural formula with a low melting point.

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Description

The invention relates to the chemistry of adamantane derivatives, and in particular to a new method for producing 1,3-disubstituted ureas of 1,3-dimethyladamantane derivatives of the general formula:

where n = 0, 1

which may find application in the pharmaceutical industry.

It is known that 1,3-disubstituted urea having the structural formula:

where R = -NHCH ₂ CH ₂ OH, -NHCH ₂ CH ₂ Br, -NH (CH ₂ ) ₅ O (CH ₂ ) ₃ CH ₃ , -NH (CH ₂ ) ₅ O (CH ₂ ) ₃ O (CH ₂ ) ₂ CH ₃ , -NH (CH ₂ ) ₅ O (CH ₂ ) ₂ O (CH ₂ ) ₂ OPhCH ₂ CH ₃ , obtained from 1-isocyanatoadamantane are actively studied as intermediates for the synthesis of inhibitors of soluble hydrolase epoxide. They are used as neurotransmitters that affect blood pressure and inflammatory processes. One of the most important parameters of the studied compounds is their melting point and solubility, which affect the bioavailability of the compounds, which was quite high for many tested substances [In-Hae Kim, Hsing-Ju Tsai, and Bruce D. Hammock. 1,3-Disubstituted Ureas Functionalized with Ether Groups are Potent Inhibitors of the Soluble Epoxide Hydrolase with Improved Pharmacokinetic Properties, J. Med. Chem. 2007, 50, p. 5217-5226].

Similar properties are possessed by 1,1 ′ - (adamant-1,3-diyl) bis [3- (naphthalen-2-yl) urea] [Vesna Blazek, Nikola Bregovic, Nikola Basaric, Tetrahedron 2011, 67, 3846-3857].

However, these methods do not allow to obtain compounds of the claimed structural formulas.

The technical result of the invention is the development of a technologically advanced method for producing new 1,3-disubstituted ureas of 1,3-dimethyladamantane derivatives with high yield according to the initial isocyanate.

The technical result is achieved by the proposed method for producing 1,3-disubstituted urea derivatives of 1,3-dimethyladamantane of the general formula:

where n = 0, 1

consisting in the interaction of an isocyanate of the General formula:

where n = 0, 1,

with amines selected from the series: 1,2-ethylenediamine, piperidine, 1-aminomethyladamantane, 2-amino-2-cyanoadamantane and 2-aminoethanol, at a temperature of 0-25 ° C, for 3-8 hours in dimethylformamide at a molar ratio isocyanate: amine: dimethylformamide (1: 1.1-7.2: 65-107) with the release of the target product.

The yield of the target product by the proposed method is 94-97%.

The introduction of methyl groups into the adamantane molecule lowers the melting point of the compounds. Thus, methyladamantane has a melting point of 104 ° C, which is 165 ° C lower than that of adamantane, and 1,3-dimethyladamantane is generally a liquid substance. The same patterns hold for adamantane derivatives. In this regard, the use of isocyanates containing a 1,3-dimethyl (adamant-5-yl) fragment in their structure eliminates the existing disadvantages of 1,3-disubstituted ureas. The use of such isocyanates significantly reduces the melting point and, consequently, the bioavailability of 1,3-disubstituted ureas obtained on their basis.

The isocyanate react with amines selected from the series: 1,2-ethylenediamine, piperidine, 1-aminomethyladamantane, 2-amino-2-cyanoadamantane, is carried out for 3-4 hours. By reducing the reaction time, a high yield of the main product is not achieved. The increase in the duration of the reaction is impractical and economically disadvantageous.

It was found that the optimal condition for the reaction of the interaction of isocyanate with amines selected from the series: 1,2-ethylenediamine, piperidine, 1-aminomethyladamantane, 2-amino-2-cyanoadamantane in dimethylformamide, is its implementation at a molar ratio of isocyanate: amine: dimethylformamide ( 1: 1.1-2: 65-78). The use of a larger excess of amine did not affect the yield of the target products, but only complicated the isolation process and therefore was not practical. A smaller excess of dimethylformamide led to a slight decrease in the yield of the target products. A further increase in the excess of dimethylformamide did not affect the yield of the target products and was impractical.

It was found that the optimal condition for the reaction of the interaction of isocyanate with amines selected from the series 1,2-ethylenediamine, piperidine, 1-aminomethyladamantane, 2-amino-2-cyanoadamantane is its implementation at room temperature. Carrying out the reaction at a lower temperature led to a significant increase in the reaction time, and a further increase in temperature is associated with high energy costs and is impractical.

The reaction of isocyanate with 2-aminoethanol is carried out for 7-8 hours. By reducing the reaction time, a high yield of the main product is not achieved. The increase in the duration of the reaction is impractical and economically disadvantageous.

It was found that the optimal condition for the reaction of the interaction of isocyanate with 2-aminoethanol in dimethylformamide is its implementation at a molar ratio of isocyanate: 2-aminoethanol: dimethylformamide (1: 5.4-7.2: 80-107). The use of a larger excess of 2-aminoethanol did not affect the yield of the target products, but only complicated the isolation process and therefore was impractical. A smaller excess of dimethylformamide led to a slight decrease in the yield of the target products. A further increase in the excess of dimethylformamide did not affect the yield of the target products and was impractical.

It was found that the optimal condition for the reaction of the interaction of isocyanate with 2-aminoethanol in dimethylformamide is its implementation at a temperature of 0 ° C. Carrying out the reaction at a higher temperature led to a significant decrease in the selectivity of the reaction and to the formation of urethanes, and a further decrease in temperature is associated with large energy expenditures and is impractical.

The method is as follows.

To the corresponding isocyanate from the series: 1-isocyanato-3,5-dimethyladamantane, 1-isocyanatomethyl-3,5-dimethyladamantane, add an amine from the series: ethylenediamine, piperidine, 2-amino-2-cyanoadamantane, 1-aminomethyladamantane and dimethylforamide, in a ratio of 1: 1.1-2: 65-78 and stirred at room temperature for 3-4 hours or 2-aminoethanol and dimethylformamide in a ratio of 1: 5.4-7.2: 80-107 and stirred at a temperature of 0 ° C for 7-8 hours. Then the precipitated white precipitate is filtered off, dried and recrystallized from ethanol.

The invention is illustrated by the following examples.

Example 1

Preparation of 1- [3,5-Dimethyl (adamant-1-yl)] - 3- (2-hydroxyethyl) urea

To a solution of 500 mg (2.43 mmol) of 1-isocyanato-3,5-dimethyladamantane (n = 0) in 10 ml of dimethylformamide was added a solution of 800 mg (13.11 mmol) of 2-aminoethanol in 5 ml of dimethylformamide (molar ratio 1: 5.4: 80) at a temperature of 0 ° C. After stirring for 8 hours, the crystalline precipitate was filtered off and washed with 50 ml of water and then 30 ml of ethyl acetate. The resulting solid was dried in vacuo. Received 620 mg (2.36 mmol, 97%), white solid. Mp 125 ° C. Mass spectrum, m / z ( _Irel ,%): 266 (1%, [M] ⁺ ), 249 (2%, [M-OH] ⁺ ), 163 (100%, [Ad (CH ₃ ) ₂ ] ⁺ ).

Example 2

Preparation of 1 - {[3,5-dimethyl (adamant-1-yl)] methyl} -3- (2-hydroxyethyl) urea

To a solution of 400 mg (1.82 mmol) of 1-isocyanatomethyl-3,5-dimethyladamantane (n = 1) in 10 ml of dimethylformamide was added a solution of 800 mg (13.11 mmol) of 2-aminoethanol in 5 ml of dimethylformamide (molar ratio 1: 7.2: 107) at a temperature of 0 ° C. After stirring for 7 hours, the crystalline precipitate was filtered off and washed with 50 ml of water and then 30 ml of ethyl acetate. The resulting solid was dried in vacuo. Received 480 mg (1.71 mmol, 94%), a white solid. Mp 118 ° C. Mass spectrum, m / z ( _Irel ,%): 280 (1%, [M] ⁺ ), 263 (2%, [M-OH] ⁺ ), 163 (100%, [Ad (CH ₃ ) ₂ ] ⁺ ).

Example 3

Preparation of N- [3,5-Dimethyl (adamant-1-yl)] piperidino-1-carboxyamide

To a solution of 510 mg (2.50 mmol) of 1-isocyanato-3,5-dimethyladamantane (n = 0) in 10 ml of dimethylformamide was added a solution of 240 mg (2.80 mmol) of piperidine in 5 ml of dimethylformamide (molar ratio 1: 1, 1:78) at a temperature of 15-25 ° C. After stirring for 4 hours, the crystalline precipitate was filtered off and washed with 50 ml of water and then 30 ml of ethyl acetate. The resulting solid was dried in vacuo. Received 700 mg (2.41 mmol, 96.5%), a white solid. Mp 120-122 ° C. Mass spectrum, m / z ( _Irel ,%): 290 (65%, [M] ⁺ ), 205 (19%, [M- (CH ₂ ) ₅ N] ⁺ ), 178 (2%, [ Ad (CH ₃ ) ₂ NH] ⁺ ), 163 (70%, [Ad (CH ₃ ) ₂ ] ⁺ ), 127 (20%, [M-Ad (CH ₃ ) ₂ ] ⁺ ), 107 (33%) 84 (100%, [(CH ₂ ) ₅ N] ⁺ ). 1 H NMR spectrum, ppm: 0.80 s (6H, 2CH ₃ ); 1.20-1.60 (19H, Ad + 3CH ₂ ); 2.73 s (1H, NH); 3.17-3.20 t (4H, 2CH ₂ ).

Example 4

Preparation of 1- (2-aminoethyl) -3- [3,5-dimethyl (adamant-1-yl) 1-urea

To a solution of 615 mg (3.0 mmol) of 1-isocyanato-3,5-dimethyladamantane (n = 0) in 10 ml of dimethylformamide was added a solution of 360 mg (6.00 mmol) of 1,2-ethylenediamine in 5 ml of dimethylformamide (molar ratio 1: 2: 65) at a temperature of 15-25 ° C. After stirring for 3 hours, the crystalline precipitate was filtered off and washed with 50 ml of water and then 30 ml of ethyl acetate. The resulting solid was dried in vacuo. Received 755 mg (2.85 mmol, 95%), white solid. Mp 250-252 ° C. Mass spectrum, m / z ( _Irel ,%): 265 (1%, [M] ⁺ ), 248 (12%, [M-NH ₂ ] ⁺ ), 236 (25%, [M-CH ₂ NH ₂ ] ⁺ ), 223 (64%, [M- (CH ₂ ) ₂ NH ₂ ] ⁺ ), 208 (35%, [(CH ₃ ) ₂ AdNHC (O)] ⁺ ), 179 (46%, [ Ad (CH ₃ ) ₂ NH] ⁺ ), 163 (100%, [Ad (CH ₃ ) ₂ ] ⁺ ) 122 (61%), 108 (61%), 107 (42%), 93 (35%). 1Н NMR spectrum δ, ppm: 0.79-1.29 m (19Н, Ad (СН ₃ ) ₂ ); 1.46-1.52 q (2H, 2NH); 2.03-2.05 t (2H, NH ₂ ); 2.73 s (2H, CH ₂ ); 2.89 s (2H, CH ₂ ).

Example 5

Preparation of 1- [3,5-Dimethyl (adamant-1-yl)] - 3 - [(adamant-1-yl) methyl] -urea

To a solution of 510 mg (2.5 mmol) of 1-isocyanato-3,5-dimethyladamantane (n = 0) in 10 ml of dimethylformamide was added a solution of 410 mg (2.5 mmol) of 1-aminomethyladamantane in 5 ml of dimethylformamide (molar ratio 1: 1:78) at a temperature of 15-25 ° C. After stirring for 4 hours, the crystalline precipitate was filtered off and washed with 50 ml of water and then 30 ml of ethyl acetate. The resulting solid was dried in vacuo. Received 880 mg (2.4 mmol, 96%), a white solid. Mp > 300 ° C. Mass spectrum, m / z ( _Irel ,%): 370 (15%, [M] ⁺ ), 355 (100%, [M-CH ₃ ] ⁺ ), 265 (43%), 190 (26% ), 179 (30%, [Ad (CH ₃ ) ₂ NH] ⁺ ), 164 (41%), 163 (99%, [Ad (CH ₃ ) ₂ ] ⁺ ), 149 (26%, [AdCH ₂ ] ⁺ ), 135 (53%, [Ad] ⁺ ), 108 (85%), 107 (50%), 93 (44%), 78 (39%). 1Н NMR spectrum δ, ppm: 0.79-1.65 m (34Н, Ad, Ad (CH ₃ ) ₂ ); 2.04 q (2H, 2NH); 2.75 d (2H, CH ₂ ).

Example 6

Preparation of 1- [3,5-dimethyl (adamant-1-yl)] - 3- [2-nitrilo (adamant-2-yl)] - urea

To a solution of 510 mg (2.5 mmol) of 1-isocyanato-3,5-dimethyladamantane (n = 0) in 10 ml of dimethylformamide was added a solution of 440 mg (2.5 mmol) of 2-amino-2-cyanoadamantane in 5 ml of dimethylformamide ( molar ratio 1: 1: 78) at a temperature of 15-25 ° C. After stirring for 4 hours, the crystalline precipitate was filtered off and washed with 50 ml of water and then 30 ml of ethyl acetate. The resulting solid was dried in vacuo. Received 910 mg (2.4 mmol, 96%), a white solid. Mp 200-202 ° C. Mass spectrum, m / z ( _Irel ,%): 383 (4%, [M + 2H] ⁺ ), 355 (1%, [M-CN] ⁺ ), 205 (22%, [M-Ad (CN) NH] ⁺ ), 177 (26%, [Ad (CH ₃ ) ₂ NH] ⁺ ), 164 (36%), 163 (45%, [Ad (CH ₃ ) ₂ ] ⁺ ), 150 (100 %, [AdNH] ⁺ ), 134 (41%, [Ad-2H] ⁺ ), 107 (70%), 91 (78%), 80 (85%). 1Н NMR spectrum δ, ppm: 0.80-1.90 m (33Н, Ad, Ad (CH ₃ ) ₂ ); 2.00-2.06 t (2H, 2NH).

Thus, the above information indicates the fulfillment of the following set of conditions when using the claimed invention:

- a tool embodying the claimed invention in its implementation, is intended for use in various industries;

- for the claimed invention in the form as described in the independent clause of the claims below, the possibility of its implementation using the above or known means and methods is confirmed;

- a tool embodying the claimed invention in its implementation, is able to ensure the achievement of a technical result.

Therefore, the claimed invention meets the requirement of "industrial applicability".

Claims (1)

The method of obtaining 1,3-disubstituted urea derivatives of 1,3-dimethyladamantane of the General formula:

where n = 0, 1

consisting in the interaction of isocyanate of the General formula:

where n = 0, 1,
with amines selected from the series: 1,2-ethylenediamine, piperidine, 1-aminomethyladamantane, 2-amino-2-cyanoadamantane and 2-aminoethanol, at a temperature of 0-25 ° C for 3-8 hours in dimethylformamide at a molar ratio of isocyanate : amine: dimethylformamide 1: 1.1-7.2: 65-107 and the isolation of the target product.