RU2767540C1 - METHOD FOR PRODUCING 1,9-N,N'-DIETHYL-ETHYLENEDIAMINO-1,9-DIHYDRO-(C60-Ih)[5,6]FULLERENE - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry of heterocyclic compounds, particularly to a method of producing 1,9-N,N'-diethyl-ethylenediamino-1,9-dihydro-(C₆₀-I_h)[5,6]fullerene of formula (1), which can be used as a synthon for synthesis of a number of drugs: analgesics, antispasmodics, psychotropic, anticancer, antirheumatic, antihistamines. Method of producing 1,9-N,N'-diethyl-ethylenediamino-1,9-dihydro-(C₆₀-I_h)[5,6]fullerene of formula (1) by reacting fullerene C₆₀ with Ν,Ν'-diethylethylenediamine is characterized by that the reaction is carried out in molar ratio C₆₀:N,N'-diethylethylenediamine, equal to 1:2–10, in air, at room temperature, in a medium toluene: DMF = 5:1 (volume ratio), with ultrasound for 1 hour and further stirring on a magnetic mixer for 20–48 hours.

EFFECT: technical result: previously unknown method for selective production of 1,9-N,N'-diethylethylenediamino-1,9-dihydro-(C₆₀-I_h)[5,6]fullerene (1) with output of 45 %.

1 cl, 1 tbl, 1 ex

Description

The invention relates to the organic synthesis of heterocyclic compounds of C ₆₀ fullerene, specifically to a method for obtaining 1,9-N,N'-diethyl-ethylenediamino-1,9-dihydro-(C ₆₀ -I _h )[5,6]fullerene of the formula (1 ).

The compound of formula (1) can be used as a precursor for the production of a number of drugs: analgesics, antispasmodics, psychotropic, antitumor, antirheumatic, antihistamines [A.K. Rathi, R. Syed, H.-S. Shin, R.V. Patel, Expert Opinion on Therapeutic Patents, 2016, 26.; A.F. Brito, L.K.S. Moreira, R. Menegatti, E.A. Costa, Fundamental Clinical Pharmacology, 2018, 13; M.A. Bhat, M.A. Al-Omar, H.A. Ghabbour, A.M. Naglah, Molecules, 2018, 23(7), 1559].

The known method [M. Maggini, G. Scorrano, A. Bianco, C. Toniolo, M. Prato, Tetrahedron Letters, 1995, 36, 2845.] to obtain 1,4-dimethyl-2,3-fullero[60]de-cahydroquinoxaline of formula (2) reaction of C ₆₀ with N ¹ ,N ² -dimethyl-1,2-cyclohexanediamine in a solution of toluene at the boiling point of the solvent (~110°C) for a week in a nitrogen atmosphere with a yield of 10%.

The known method does not allow to obtain 1,9-N,N'-diethyl-ethylenediamino-1,9-dihydro-(C ₆₀ -I _h )[5,6]fullerene (1).

Catalytic cycloamination of 1,2-diaminopropane in the presence of a Cp ₂ TiCl ₂ catalyst in toluene at room temperature (~20°C) for 44-52 h leads to the formation of adduct (3) with a yield of the target product of 73-90%. [MIND. Dzhemilev, A.G. Ibragimov, A.R. Tuktarov, M. Pudas, Z.S. Muslimov, Method for obtaining 5-methyl-2,3-fullero[60]piperazine, patent RU 2307832C1.].

The known method does not allow to obtain 1,9-N,N'-diethyl-ethylenedia-mino-1,9-dihydro-(C ₆₀ -I _h )[5,6]fullerene (1).

A number of substituted and unsubstituted Ν,Ν'-ethylenediamines, upon thermal activation, are attached to C ₆₀ fullerene in an inert atmosphere [K.-D. Kampe, N. Egger, Reaktionen von Diaminen rnit Fulleren C ₆₀ , Liebigs Ann. 1995, 115-124] with the formation of the corresponding cycloadducts (4-7,1) with maximum yields of 12.5% for (4), 35.9% - (5), 3.8% - (6), 40.8% - (7), 3.5% -(one).

The disadvantage of the known method for obtaining 1,9-N,N'-diethyl-ethylenediamino-1,9-dihydro-(C ₆₀ -I _h )[5,6]fullerene (1) are: a) elevated reaction temperature (85°C ); b) the duration of the reaction (14 days); c) small yield (1) -3.5%.

The objective of the present invention is to develop a new method for the selective production of 1,9-N,N'-diethyl-ethylenediamino-1,9-dihydro-(C ₆₀ -I _h )[5,6]fullerene (1) with a high yield in softer conditions - room temperature, air.

The solution of this problem is achieved by the fact that the method of obtaining (1) is carried out by the interaction of Ν,N'-diethylethylenediamine with fullerene C ₆₀ at a molar ratio of C ₆₀ :N,N'-diethylethylenediamine=1:2-10, in air, at room temperature, in toluene:DMF=5:1 (volume ratio) under the influence of ultrasound (22 kHz, 20 W) for 1 h and further stirring on a magnetic stirrer for 20-48 h. The maximum yield of the target product is 45%.

The reaction proceeds according to the scheme:

Isolated and chromatographically purified (1) is a dark brown solid. Its structure was confirmed by ^1D and 2D 1H and ^13C NMR, UV, IR and MALDI TOF/TOF mass spectrometry. All spectral characteristics correspond to the literature data [K.-D. Kampe, N. Egger, Liebigs Ann. 1995, 115; K.-D. Kampe, N. Egger, M. Vogel, Angew. Chem. Inr. Ed. English 1993, 32, 1174].

With a decrease in the ratio of the initial reagents (C ₆₀ :N,N'-diethyl-ethylenediamine=1:2), the yield of the target product (1) sharply decreases. Increasing the reaction time to 48 h at the ratio of the initial reagents C ₆₀ :N,N'-diethylethylenediamine=1:10 leads to the addition of additional molecules of Ν,N'-diethylethylenediamine to the C ₆₀ molecule. Below room temperature (eg 10° C.) the reaction rate decreases. Without exposure to ultrasound, the yield of product (1) does not exceed 3%. Synthesis (1) was carried out in toluene:DMF=5:1 (volume ratio), because in the absence of DMF, the reaction does not proceed.

Significant differences of the proposed method:

1. The proposed method uses ultrasonic radiation (22 kHz, 20 W)

2. The reaction takes place at room temperature, while, in the known method, the reaction takes place using thermal activation at a temperature of 85°C.

3. The reaction takes place within 21 hours (1 hour of ultrasonic irradiation followed by stirring on a magnetic stirrer for 20 hours), which is significantly less than in the known method, where the reaction time is 14 days.

4. The yield of the reaction product (1) is 45%, while in the known method the yield of the reaction product is only 3.5%.

5. In the proposed method, a mixture of toluene:DMF in a volume ratio of 5:1 is used as a solvent.

The proposed method has the following advantages:

1. The developed method opens the way to the efficient production of 1,9-N,N'-diethyl-ethylenediamino-1,9-dihydro-(С ₆₀ -I _h )[5,6]fullerene (1), which has a wide spectrum of biological activity , which allows it to be used as a precursor for the production of a number of drugs: analgesics, antispasmodics, psychotropic, antitumor, antirheumatic, antihistamines (A.K. Rathi, R. Syed, H.-S. Shin, RV Patel, Expert Opinion on Therapeutic Patents, 2016, 26; AF Brito, LKS Moreira, R. Menegatti, EA Costa, Fundamental Clinical Pharmocology, 2018, 13; MA Bhat, MA Al-Omar, HA Ghabbour, AM Naglah, Molecules, 2018, 23(7), \559.)

2. The method provides selective production of the compound - 1,9-N,N'-diethyl-ethylenediamino-1,9-dihydro-(C ₆₀ -I _h )[5,6]fullerene (1) with a yield of up to 45%.

3. The reaction is carried out under mild conditions with a short reaction time: air, room temperature, 21-49 hours.

The method is illustrated by the following example:

Example 1

To 30 ml of a solution of C ₆₀ fullerene (90 mg, 0.125 mmol) in toluene is added Ν,Ν'-diethylethylenediamine (145.25 mg; 0.18 ml; 1.25 mmol) and 6 ml of DMF. The resulting mixture was placed in a jacketed reactor and sonicated (22 kHz, 20 W) in air at room temperature for 1 hour. The starting dark purple solution turned dark brown. Next, the solution was stirred on a magnetic stirrer for 20 h in air at room temperature. After the reaction, the solution is passed through a column filled with a small layer of silica gel (~4 cm). The reaction product is isolated using preparative high performance liquid chromatography (HPLC). Removal of the solvent in vacuo gave a dark brown powder. The yield of 1,9-N,N'-diethyl-ethylenediamino-1,9-dihydro-(C ₆₀ -I _h )[5,6]fullerene (1) is 47 mg (45%).

Other examples confirming the method are given in the table.

Claims (3)

Method for obtaining 1,9-N,N'-diethyl-ethylenediamino-1,9-dihydro-(С ₆₀ -I _h )[5,6]fullerene of formula (1)

interaction of C ₆₀ fullerene with Ν,N'-diethylethylenediamine, characterized in that the reaction is carried out at a molar ratio of C ₆₀ :N,N'-diethylethylenediamine equal to 1:2-10, in air, at room temperature, in toluene:DMF medium \u003d 5: 1 (volume ratio), when exposed to ultrasound for 1 h and further stirring on a magnetic stirrer for 20-48 h.