RU2554004C1 - N,n-bis(1-adamantyl-1-ethylamine) hydrochloride and method for production thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound - N,N-bis(1-adamantyl-1-ethylamine) hydrochloride of the structural formula I

and a method for production thereof. Compound has biological activity and can be used as a component of a medicinal agent or as an impurity label of a medicinal agent as a standard sample in analytical chemistry of pharmaceutical preparations. A method of producing a compound of formula I includes a) obtaining 1-adamantyl-1-ethylamine from 1-adamantyl-1-ethylamine hydrochloride, b) obtaining a Schiff base of structural formula III

by treating with a compound obtained at step (a) with acetyl adamantane, c) treating the Schiff base of formula III with a reducing agent to obtain bis(1-adamantyl-1-ethylamine) hydrochloride of formula I. The compound is characterised by a boiling point, IR, NMR and a mass spectrum data.

EFFECT: improved method.

2 cl, 8 dwg, 1 tbl, 3 ex

Description

The claimed invention relates to organic chemistry, and in particular to methods for producing N, N-bis (1-adamantyl-1-ethylamine) hydrochloride of the general formula I:

The compound of formula I may find application as a component of antiviral agents, as well as as an impurity marker in a drug sample.

A known method for producing 1-aminoethyl-adamantane, formula II, which is the biologically active basis of the substance of the influenza drug, widely used as a medicine for combating type A influenza viruses [1, 2].

As a result of the analysis of the industrial synthesis of 1-aminoethyl-adamantane [3], it was found that during the synthesis of 1-aminoethyl-adamantane a side reaction may occur with the formation of a Schiff base, and with the further action of reducing agents, a product of structural formula I is formed. Product formation structural formula I was confirmed by the analysis of a number of samples of the substance 1-aminoethyl-adamantane hydrochloride obtained by an industrial method using chromatography-mass spectrometry and NMR.

An admixture with R _t = 2.35 (Fig. 1) was detected on the chromatogram of the substance 1-aminoethyl-adamantane hydrochloride, an ion with a molecular mass of 342.34 g / mol, which with an error of 0.03, was present in the mass spectrum of the impurity (Fig. 2) g / mol can be interpreted as a quasimolecular ion with a gross formula of C ₂₄ H ₄₁ N.

In order to ensure the possibility of quantitative determination of the content of the compounds of structural formula I in the samples under study, a method for the synthesis of compounds of structural formula I was developed and its counter synthesis was carried out.

The technical result of the invention is a method for producing a new compound N, N-bis (1-adamantyl-1-ethylamine) hydrochloride.

Brief Description of the Drawings:

FIG. 1. Chromatogram of the substance 1-aminoethyl-adamantane hydrochloride.

FIG. 2. The mass spectrum of the impurity found in the substance 1-aminoethyl adamantane hydrochloride R _t = 2,35.

FIG. 3. Mass spectrum of an impurity detected in the substance 1-aminoethyl adamantane in the mode of dissociation activated by collision (MS-MS by m / z 342 ⁺ ).

FIG. 4. NMR spectrum of ¹ H bis (1-adamantyl-1-ethylamine) hydrochloride in CDCl ₃ .

FIG. 5. NMR spectrum of ¹³ With bis (1-adamantyl-1-ethylamine) hydrochloride in CDCl ₃ .

FIG. 6. NMR spectrum of ¹ H bis (1-adamantyl-1-ethylamine) hydrochloride in D ₂ O.

FIG. 7. IR spectrum of bis (1-adamantyl-1-ethylamine) hydrochloride.

FIG. 8. The order of numbering of carbon atoms in the compound of formula I for identification on the NMR spectra. FIG. 8 is for illustrative purposes only, for readability of ¹ H-NMR spectrum.

The claimed invention is illustrated by the following examples:

Example 1. Obtaining 1-adamantyl-1-ethylamine (intermediate stage)

10 g of 1-adamantyl-1-ethylamine hydrochloride is dissolved in 40 ml of water, then a solution of 4.07 g of sodium hydroxide in 20 ml of water is added to the resulting solution.

The reaction mass is kept for 1 h at a temperature of 65 ° C and vigorous stirring on a magnetic stirrer. The resulting emulsion was cooled to room temperature over 0.5 h. Then extracted with two portions of 30 ml of methylene chloride and the organic layer is separated on a separatory funnel. The extract was dried over anhydrous sodium sulfate for 0.5 h. To separate the precipitate of the desiccant, the organic solution was filtered through a Schott filter under vacuum. Methylene chloride is distilled off on a rotary evaporator. 7.40 g of 1-adamantyl-1-ethylamine are obtained, which, without purification, is taken into the next step.

Example 2. Obtaining a Schiff base of structural formula III (intermediate stage)

A mixture of 3.56 g (0.02 mol) of acetyladamantane and 3.58 g (0.02 mol) of 1-adamantyl-1-ethylamine is heated to boiling and maintained at this temperature for 1 hour. The resulting alloy is treated with 60 ml of methanol and the resulting solid precipitate is dried under vacuum on a Schott filter. 6.21 g of a Schiff base of structural formula III are obtained, which are involved in the next step without purification.

Example 3. Obtaining bis (1-adamantyl-1-ethylamine) hydrochloride (final stage)

The Schiff base obtained in the previous step is placed in 100 ml of methanol and sodium borohydride is added in small portions with vigorous stirring. To initiate the process, a working surface temperature of 80 ° C is set on a magnetic stirrer. The reaction mass is maintained under these conditions for 3 hours. Next, the reaction mass is transferred into 500 ml of water. The precipitate was filtered on a Schott filter and dried. The dry residue is dissolved in 50 ml of chloroform and dry hydrogen chloride is passed through the chloroform solution for 1 hour. The chloroform solution of the compound of formula I is evaporated to dryness to give a product, which is then recrystallized from 5 ml of methylene chloride.

The result is 4.5 g of N, N-bis (1-adamantyl-1-ethylamine) hydrochloride. The final yield of the compound of structural formula I, taking into account three stages, is 59%.

The obtained N, N-bis (1-adamantyl-1-ethylamine) hydrochloride has the following characteristics:

1. melting point 276 ° C (with decomposition);

2. ¹ H NMR spectrum in CDCl ₃ (1.413 (6H, br.s, C ₍₂₄₎ H ₃ , C ₍₂₅₎ H ₃ ), 1.72 (12H, br.s, C ₍₄₎ H ₂ , С ₍₆₎ Н ₂ , С ₍₁₀₎ Н ₂ , С ₍₁₇₎ Н ₂ , С ₍₁₉₎ Н ₂ , С ₍₂₃₎ Н ₂ ), 1,79 (6Н, br.s, C ₍₂₎ Н, С ₍₈₎ Н, С ₍₉₎ Н, C ₍₁₅₎ H, C ₍₂₁₎ H, С ₍₂₂₎ Н), 2,092 (6Н, br.s, С ₍₃₎ Н, С _{(5 )} Н, С ₍₇₎ Н, С ₍₁₆₎ Н, С ₍₁₈₎ Н, С ₍₂₀₎ Н), 2,708 (2Н, m, С ₍₁₁₎ Н, С ₍₁₃₎ Н), 7, 31 (1H, s., NH));

3. ¹³ C NMR spectrum in CDCl ₃ (11.946 (2C, C ₍₂₄₎ , C ₍₂₅₎ ), 28.159 (6C, C ₍₃₎ , C ₍₅₎ , C ₍₇₎ , C ₍₁₆₎ , C ₍₁₈₎ , С ₍₂₀₎ ), 35,936 (2С, С ₍₁₎ , С ₍₁₄₎ ), 36,373 (6С, С ₍₄₎ , С ₍₆₎ , С ₍₁₀₎ , С ₍₁₇₎ , C ₍₁₉₎ , С ₍₂₃₎ ), 38,496 (6С, С ₍₂₎ , С ₍₈₎ , С ₍₉₎ , С ₍₁₅₎ , С ₍₂₁₎ , С ₍₂₂₎ ), 67,421 (2С, С ₍₁₁₎ , C ₍₁₃₎ ));

4. ¹ H NMR spectrum in D ₂ O;

5. mass spectrum with a molecular ion weighing 342.34 g / mol;

6. IR spectrum.

The peak table of FIG. 7 Position Intensity 459.17 88.640 600.89 85.889 668.68 87.591 752.06 91.711 812.87 90.802 850.77 90.485 933.64 88.254 970.06 89.506 983.47 89.361 1026.04 84.545 1049.73 81.943 1070.48 59.729 1094.34 84.531 1177.11 80.551 1198.76 86.298 1254.60 88.423 1317.58 81.187 1349.45 73.971 1375.14 70.414 1394.47 60.908 1419.19 67.208 1447.09 51.743 1598.25 58.742 2342.05 76.195 2360.66 70.788 2478.97 78.389 2681.59 64.633 2846.29 27.276 2901.37 17.156 3357.59 72.734

References

1. Ershov F.I., Chizhov N.P., Tazulakhova E.B. Antiviral agents. SPb .: Science. 1993.104 p.

2. Yakhontov L.N., Glushkov R.G. Synthetic Medicines. / M. Medicine. 1983, pp. 54-57.

3. Makareev S. M., Kaliteevsky V. V., Sheludyakov V. D., Lebedev A. V., Lebedeva A. B., Ustinova O. L. The method of obtaining 1- (1′-adamantyl) ethylamine. RF patent №2118313 for Application No. 97106700 dated May 6, 1997

Claims (2)

1. The compound of structural formula I

2. A method of obtaining a compound of structural formula I according to claim 1, which includes 3 stages, namely: a) obtaining 1-adamantyl-1-ethylamine from 1-adamantyl-1-ethylamine hydrochloride, b) treating the compound obtained in stage a) acetyladamantane to obtain the Schiff base of structural formula III

c) treating a Schiff base of formula III with a reducing agent to obtain a bis (1-adamantyl-1-ethylamine) hydrochloride of formula I.

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