RU2670622C1 - Method for obtaining 2-alkyl-substituted semicarbazides - Google Patents

Abstract

FIELD: chemistry.SUBSTANCE: invention relates to the field of organic chemistry, namely a process for the preparation of 2-alkyl-substituted semicarbazides of formula (I) or their hydrochlorides of formula (II), wherein R = alkyl or substituted alkyl. Method consists in indirect alkylation of unsubstituted semicarbazide at the nitrogen atom N2 and includes steps a) to e). In step a), the reaction of semicarbazide hydrochloride with acetone is carried out in the presence of sodium acetate in water to obtain the acetone semicarbazone, which precipitates during the reaction and is isolated by the filtration operation. In step b) the acetone semicarbazone is deprotonated by the action of an equivalent amount of sodium hydride with stirring in dry acetonitrile for 1 hour at room temperature. In step c), the resulting sodium salt of semicarbazone acetone without isolation and in the same solvent, acetonitrile, is alkylated at the nitrogen atom N2 by suitable alkylating reagents, wherein: (i) an equivalent amount of dimethyl sulphate is used to introduce a methyl group and the reaction is carried out for 17 hours at room temperature; (ii) for the introduction of other alkyl groups, in addition to the methyl group, a 5–10-fold molar excess of the corresponding alkyl bromide is used, and the reaction is carried out by boiling in acetonitrile for 9 hours; (iii) an equivalent amount of the corresponding bromide is used to introduce the substituted alkyl group and the reaction is carried out by boiling in acetonitrile for 9 hours. In step d), the resulting 2-alkyl-substituted semicarbazones without intermediate isolation and purification are subjected to acid hydrolysis, for which the reaction mass after the alkylation filtered from the precipitation of salts, the solvent is removed in vacuo at a bath temperature of up to 40 °C, 17–36 % hydrochloric acid is added to the residue in an amount of 5–10 equivalents of HCl per 1 equivalent of semicarbazone and the resulting solutions are immediately evaporated in vacuo at a bath temperature of up to 60 °C. Solid residues, that are the hydrochlorides of the 2-alkyl substituted semicarbazides of formula (II), are triturated with isopropyl alcohol, the precipitates are filtered off and dried. In step e), the hydrochlorides of the 2-alkyl-substituted semicarbazides of the formula (II) are treated to form the 2-alkyl-substituted semicarbazides of the formula (I), obtained in the previous step, with a small excess of sodium carbonate in water, followed by extraction of the product with ethyl acetate, distilling off the solvent from the combined extract, trituration of the residue with petroleum ether until crystallization.EFFECT: proposed method is universal, simple and allows, under mild conditions, to obtain the desired products in high yield.1 cl, 6 ex

Description

The invention relates to the field of organic chemistry, namely to a method for producing 2-alkyl-substituted semicarbazides of the formula (I) or their hydrochlorides of the formula (II):

где R = алкил или замещенный алкил,

where R = alkyl or substituted alkyl,

which are important multipurpose reagents and are used as starting materials in organic synthesis to produce a variety of acyclic and heterocyclic nitrogen-containing compounds, in particular, semicarbazones, hydantoins, pyrazoles, 1,2,4-triazoles, 1,2,4-triazines, 1 , 2,4-triazepins, pyrimidines, 1,3,4-oxadiazoles, azamacrocycles, etc. In addition, these compounds are used in the synthesis of many biologically active substances containing the semicarbazide fragment, including analogues of furacilin and nitrofurantoin, which have a pronounced antimicrobial effect [Mashkovsky MD. Medicines. 16th ed. - M .: New Wave, 2012. - 1216 s; Vass, M. et al. Nitrofuran antibiotics: a review on the application, prohibition and residual analysis / Veterinarni Medicina, 2008, V. 53, N. 9, pp. 469-500], selective peroxisome proliferator-activated receptor agonists PPARα [Xu Y. et al. Design and Synthesis of a Potent and Selective Triazolone-Based Peroxisome Proliferator-Activated Receptor α Agonist / Journal of Medicinal Chemistry, 2003, V. 46, N. 24, 5121-5124], MALT1 inhibitor protease [patent application WO 2014086478 A1, publ. 12.06.2014], etc.

des nitrosamines /Rec. Trav. Chim., 1913, V. 32, N. 2, pp. 39-47; Backer H.J. Quelques

du 1,2,4-Triazol /Rec. Trav. Chim., 1925, V. 44, N. 12, pp. 1113-1117].One of the known methods for producing the claimed compounds of formula (I) and (II) is the nitrosation of N-alkylureas by the action of nitrous acid in situ or its anhydride, followed by reduction of the nitroso group in the synthesized N-alkyl-N-nitrosoureas under the action of metallic zinc in aqueous acetic acid, hydrogen over a catalyst or electrochemically [Gabriel S. Uber einige Hydrazin-Derivate / EurJIC, 1914, V. 47, N. 3, pp. 3028-3033; Vogelesang C. Methylated semicarbazides / Rec. Trav. Chim., 1943, V. 62, N. 1, pp. 5-11; Smith PAS et al. Preparation of Alkyl Azides from Hydrazine Derivatives / The Journal of Organic Chemistry, 1958, V. 23, N. 11, pp. 1595-1599; patent US 2959615 And publ. 08/11/1960; Young G. et al. Contribution to the chemistry of the triazoles. 1-Methyl-5-hydroxytriazoles / Journal of the Chemical Society, Transactions, 1901, V. 79, pp. 659-668; Backer hj

des nitrosamines / Rec. Trav. Chim., 1913, V. 32, N. 2, pp. 39-47; Backer hj quelques

du 1,2,4-Triazol / Rec. Trav. Chim., 1925, V. 44, N. 12, pp. 1113-1117].

The prior art describes a method for producing 2- (2-hydroxyethyl) semicarbazide by reacting (2-hydroxyethyl) hydrazine with urea [patent application WO 9706250 A1, publ. 20.02.1997].

There are also known methods for producing some 2-alkyl semicarbazides based on the interaction of alkyl hydrazines with trimethylsilyl isocyanate [Szimhardt N. Methylsemicarbazide as a Ligand in Late 3d Transition Metal Complexes / Chemistry European Journal, 2018, V. 24, N. 11, pp. 2687-2698; patent applications: WO 2014086478 Al (publ. 12.06.2014), WO 2014154828 Al (publ. 02.10.2014), WO 2012002096 Al (publ. 05.01.2012), WO 2011036280 Al (publ. 03/31/2011), US 20030119670 Al (published on 06.26.2003)] or with cyanic acid generated by the action of Brønsted acids on alkali metal cyanates [Ottersbach R.А. et al. Induction of chirality: experimental evidence of atropisomerism in azapeptides / Chemical Communication, 2012, V. 48, pp. 5772-5774; Argentine M.D. et al. Agonoist LY518674 / Organic Process Research & Development, 2009, V. 13, pp. 131-143; Gever G. et al. Chemotherapeutic Nitrofurans. I. Some Derivatives of 3-Amino-2-oxazolidone / Journal of the American Chemical Society, 1955, V. 77, N. 8, pp. 2277-2281; Bruning G. Ann., 1889, V 253, pp. 10-11; Hale W.J. et al. Four-membered cyclic ureas. Iii. The Chemical Chemical Society, 1920, V. 42, N. 1, pp. 107-116; patent applications: WO 2011018454 Al (publ. 02/17/2011), WO 9847869 Al (publ. 10/29/1998), US 20030119670 Al (publ. 06/26/2003); patents: DE 4416868 Al (publ. 11.11.1994), GB 757822 A (publ. 26.09.1956), US 2779786 Al (publ. 01.29.1957)].

2-Methylsemicarbazide was synthesized by reacting benzaldehyde methylhydrazone with phosgene and then with ammonia, followed by removal of the benzylidene protection by acid hydrolysis [Patent GB 898419 A, publ. 06.06.1962].

There is also known a method of producing a single 2-benzylsemicarbazide derivative based on alkylation of the tert-butoxycarbonylhydrazine amino group, followed by sequential processing of the obtained product with triphosgene, ammonia, HCl solution in methanol (for removal of Vos-protection), aqueous NaHCO ₃ [patent application WO 2016096936 A1 , publ. 06/23/2016]

A method for the synthesis of 2- (4-methylbenzyl) semicarbazide methanesulfonate, including the transformation of tert-butoxycarbonylhydrazine by reaction with 4-methylbenzaldehyde to the corresponding Boc-protected hydrazone, which is reduced by hydrogen over platinum to disubstituted hydrazine, is also described, is treated with trimethylsilicyl isocyanate, and the yanthropes are used. the action of methanesulfonic [Braden T.M. et al. Kilogram-Scale Synthesis of the PPARα Agonist LY518674: Discovery of a Novel Acid-Mediated Triazolone Synthesis / Organic Process Research & Development, 2007, V. 11, N. 3, pp. 431-440; patent application WO 2002038553 A2, publ. May 16, 2002].

Thus, all the above-described methods for producing 2-alkyl semicarbazides include forming the semicarbazide moiety from either alkylureas by forming an N-N bond or from alkyl hydrazines or their derivatives by forming a C-N bond using an acylation reaction.

The closest analogue to the claimed method, which is selected as a prototype, is [patent BE 821084 R, publ. 03.02.1975] the method of obtaining 2- {3- [4- (3-chlorophenyl) piperazin-1-yl] prop-1-yl} semicarbazide - intermediate of the synthesis of pharmacologically active derivative 1,2,4-triazolin-5-one. The method consists in the introduction of the corresponding alkyl group in the second position of the semicarbazide. According to this method, in the first stage, semicarbazide benzaldehyde is obtained, which is then deprotonated under the action of sodium amide in refluxing 1,4-dioxane for 1 hour and alkylated using 3- [4- (3-chlorophenyl) piperazin-1-yl] propyl chloride ( 1,4-dioxane, boiling, 18 hours). At the last stage, the resulting N2-substituted semicarbazone is subjected to acid hydrolysis (water, oxalic acid, boiling) with distillation of the resulting benzaldehyde with water vapor.

It should be noted that the cited patent does not provide the reaction time at the last stage, as well as the conditions for the isolation and purification of the target semicarbazide. In addition, there is no yield of the alkylation product of semicarbazone and the yield of the final semicarbazide. It can be assumed that these outputs are quite small.

Indeed, it is known that acid-catalyzed hydrolysis of semicarbazones of aromatic aldehydes proceeds with great difficulty and is accompanied by the formation of hydrazines, products of the subsequent hydrolysis of semicarbazides. So, in [Hale W.J. et al. Four-membered cyclic ureas. Iii. The Chemical Chemical Society, 1920, V. 42, N. 1, pp. 107-116] failed to obtain 2-benzylsemicarbazide by hydrolysis of 2-benzylsemicarbazone benzaldehyde (water, HCl, boiling, stripping of banzaldehyde with water vapor). Instead of the expected compound, only benzylhydrazine hydrochloride was isolated from the reaction mass.

In addition to the incompleteness and uncertainty of the description, the shortcomings of the prototype method also include the harsh conditions of alkylation and hydrolysis reactions, the significant time consuming and laboriousness of the synthesis process, the use of toxic sodium amide as a base. In addition, this method was used to synthesize only one 2-alkyl-substituted semicarbazide, which leaves open the question of its universality.

The present invention claims an approach to the synthesis of 2-alkyl-substituted semicarbazides of formula (I) or their hydrochlorides of formula (II), based on alkylation of semicarbazide in the second position, with a significant positive technical result, consisting in the universality of this approach, ease of implementation of individual stages of the process, low labor-intensive, mild reaction conditions, sufficiently high product yields at all stages of the process, using sodium hydride as the base, which is more convenient to use Hovhan and less toxic than the sodium amide.

This technical result is achieved by a method that includes the following stages:

a) the reaction of commercially available semicarbazide hydrochloride with acetone in the presence of sodium acetate in water at room temperature to obtain semicarbazone acetone (III), which precipitates during the reaction and is easily isolated in 83% filtration operation in a pure form;

b) carry out the deprotonation of the N2-H group of semicarbazone acetone (III) under the action of bases in various solvents while stirring at room temperature. Among the tested bases (DBU, K ₂ CO ₃ , EtONa, NaH, etc.) and solvents (EtOH, MeCN, THF, toluene). The most effective is the use of an equivalent amount of sodium hydride in dry acetonitrile. Under optimal conditions, the deprotonation is completed within 1 hour at room temperature with the formation of the sodium salt of semicarbazone acetone (IV);

c) the obtained sodium salt of semicarbazone acetone (IV) without isolation and in the same solvent (acetonitrile) is subjected to alkylation at the nitrogen atom N2 under the action of suitable alkylating reagents. So, for the introduction of the methyl group, the best result is achieved using an equivalent amount of dimethyl sulfate as an alkylating agent, and the reaction is carried out for 17 hours at room temperature. For the introduction of other alkyl groups (ethyl, propyl, butyl, etc.), a 5–10 fold molar excess of the corresponding alkyl bromide should be used; for the introduction of a substituted alkyl group (for example, a benzyl), it is advisable to use an equivalent amount of the corresponding bromide; the reaction is carried out by boiling in acetonitrile for 9 hours;

d) the obtained 2-alkyl-substituted semicarbazones (V), without intermediate isolation and purification, are subjected to acid hydrolysis. To this end, after the alkylation is completed, the reaction masses are filtered from the salt deposits, the solvent is removed in vacuum at a bath temperature up to 40 ° C, 17-36% hydrochloric acid in the amount of 5-10 equivalents of HCl per 1 equivalent of semicarbazone is added to the residue and the resulting solutions evaporated in vacuum at a bath temperature up to 60 ° C. The solid residues, which are the hydrochlorides of 2-alkyl-substituted semicarbazides of formula (II), are triturated with isopropyl alcohol, the precipitates are filtered off and dried;

d) to isolate the free bases of formula (I), the hydrochlorides of 2-alkyl-substituted semicarbazides of formula (II) obtained in the previous step are treated with a slight excess of sodium carbonate (Na ₂ CO ₃ ) in water, followed by extraction of the product with ethyl acetate, distilling off the solvent from the combined extract, trituration of the residue with petroleum ether before crystallization.

The implementation of the present invention and the achievement of the technical result is illustrated by examples 1-6.

Example 1. Hydrochloride of 2-methylsemicarbazide (II, R = CH ₃ ).

To a suspension of NaH (0.319 g, 13.28 mmol) in dry MeCN (10 ml) add (1.458 g, 12.67 mmol) of semicarbazone acetone (III). The resulting suspension is stirred for 40 minutes, a solution of dimethyl sulfate (1.692 g, 13.41 mmol) in dry MeCN (10 ml) is added and stirred at room temperature for 17 hours. Then the precipitate is filtered off, the mother solution is evaporated, and 8 ml of 36% is added to the residue. hydrochloric acid solution, the resulting solution is evaporated in vacuum at a bath temperature up to 60 ° C. The solid residue is triturated with isopropyl alcohol to form a suspension, cooled to 0 ° C, the precipitate is filtered off, washed with chilled isopropyl alcohol, petroleum ether, and dried. 1.150 g (72%) of 2-methylsemicarbazide hydrochloride are obtained. Analytically pure sample obtained by recrystallization from a mixture of i-PrOH-EtOH (2: 1). T. pl. 135.5-136 ° C (with decomposition.).

Calculated,%: C 19.13, H 6.42, N 33.47. C ₂ H ₈ ClN ₃ O. Found,%: C 19.41, H 6.69, N 33.72.

Spectrum ¹ H NMR (300.13 MHz, DMSO-d ₆ ) δ, ppm: 10.26 (3H, br s, NH ₃ ⁺ ), 6.95 (2H, s, NH ₂ ), 3.13 (3H, s, CH ₃ ).

¹³ C NMR spectrum (75.48 MHz, DMSO-d ₆ ) δ, ppm: 158.7 (C = O), 36.6 (CH ₃ ).

IR spectrum (liquid paraffin), ν, cm ^-1 : 3355 (br. S), 3197 (br. S), 3176 (br. S), 2729 (br. S), 2654 (br. S), 2540 ( Bw), 1689 (s), 1613 (Bhp), 1592 (Bhc), 1573 (Bhc), 1533 (Bhc), 1515 (Bhc), 1293 (Wed), 1245 (Wed), 1097 (s), 1020 (s), 762 (Wed), 610 (Wed), 565 (br. S), 537 (br. S), 458 (s).

Example 2. Hydrochloride 2-ethylmetikarbazid (II, R = C ₂ H ₅ ).

To a suspension of NaH (0.092 g, 3.84 mmol) in dry MeCN (10 ml) add (0.421 g, 3.66 mmol) of semicarbazone acetone (III). The resulting suspension is stirred for 1 hour, a solution of ethyl bromide (4,100 g, 37.63 mmol) in MeCN (5 ml) is added and boiled with stirring for 9 hours. Next, the precipitate is filtered off, the mother liquor is evaporated, 3 ml of 17% hydrochloric acid solution is added to the residue, the resulting solution is evaporated in vacuo at a bath temperature of up to 60 ° C. The solid residue is triturated in a mixture of isopropyl alcohol and diethyl ether to form a suspension, cooled to 0 ° C, the precipitate is filtered, washed with cold isopropyl alcohol, cold diethyl ether, petroleum ether, and dried. This gives 0.326 g (71%) of 2-ethyl semicarbazide hydrochloride. Analytically pure sample obtained by recrystallization from a mixture of i-PrOH-EtOH (2: 1). T. pl. 127-127.5 ° C (with decomposition.).

Calculated,%: C 25.81, H 7.22, N 30.10. C ₃ H ₁₀ ClN ₃ O. Found,%: C 25.57, H 7.25, N 30.12.

Spectrum ¹ H NMR (300.13 MHz, DMSO-d ₆ ) δ, ppm: 10.22 (3H, br s, NH ₃ ⁺ ), 6.91 (2H, s, NH ₂ ), 3.61 (2H, q, ³ J _{CH2, CH3} = 7.0 Hz, CH ₂ ), 1.10 (3H, t, ³ J _{CH3, CH2} = 7.0 Hz, CH ₃ ).

Spectrum ¹³ C NMR (75.48 MHz, DMSO-d ₆ ) δ, ppm: 157.6 (C = O), 43.7 (CH ₂ ), 11.5 (CH ₃ ).

IR spectrum (liquid paraffin), ν, cm ^-1 : 3357 (br. S), 3198 (br. S), 3176 (br. S), 3045 (br. S), 2679 (br. S), 2620 ( Bw), 2357 (Bcc), 1679 (s), 1620 (Bc.), 1592 (Bc.), 1530 (Bc.), 1197 (Wed), 1091 (c), 1039 ( (c), 948 (cf.), 799 (cf.), 762 (cf.), 605 (cf.), 536 (w. sr), 503 (w. sr.), 472 (w. sr.), 432 (b. sr.) .

Example 3. 2-propylsemicarbazide hydrochloride (II, R = n-C ₃ H ₇ ).

To a suspension of NaH (0.093 g, 3.88 mmol) in dry MeCN (10 ml) add (0.407 g, 3.53 mmol) of semicarbazone acetone (III). The resulting suspension is stirred for 1 hour, a solution of propyl bromide (2.171 g, 17.65 mmol) in MeCN (5 ml) is added and boiled with stirring for 9 hours. Next, the precipitate is filtered off, the mother liquor is evaporated, 2.9 ml of 17% hydrochloric acid solution is added to the residue, the resulting solution is evaporated in vacuo at a bath temperature of up to 60 ° C. The solid residue is triturated in a mixture of isopropyl alcohol and diethyl ether to form a suspension, cooled to 0 ° C, the precipitate is filtered, washed with cold isopropyl alcohol, cold diethyl ether, petroleum ether, and dried. Obtain 0.382 g (71%) of 2-propylsemicarbazide hydrochloride. Analytically pure sample obtained by recrystallization from a mixture of i-PrOH-EtOH (2: 1). T. pl. 129-129.5 ° C (with decomposition.).

Calculated,%: C 31.28, H 7.87, N 27.36. C ₄ H ₁₂ ClN ₃ O. Found,%: C 31.34, H 8.14, N 27.29.

Spectrum ¹ H NMR (300.13 MHz, DMSO-d ₆ ) δ, ppm: 10.24 (3H, br s, NH ₃ ⁺ ), 6.89 (2H, s, NH ₂ ), 3.49 (2H, t, ³ J = 7.7 Hz, NCH ₂ ), 1.47-1.65 (2H, m, CH ₂ CH ₃ ), 0.82 (3H, t, ³ J = 7.4 Hz, CH ₃ ).

¹³ C NMR spectrum (75.48 MHz, DMSO-d ₆ ) δ, ppm: 157.5 (C = O), 50.1 (NCH ₂ ), 19.4 (CH ₂ ), 10.5 (CH ₃ ).

IR spectrum (liquid paraffin), ν, cm ^-1 : 3327 (br. S), 3200 (br. S), 3105 (br. S), 2700 (br. S), 2644 (br. S), 2561 ( Bw), 1702 (s), 1613 (s), 1555 (bw), 1528 (bw), 1267 (cf), 1206 (c), 1082 (bs), 1065 (br. (c), 901 (cf.), 767 (s), 748 (s), 567 (br. s), 433 (cf.).

Example 4. 2-butyl semicarbazide hydrochloride (II, R = n C ₄ H ₉ ).

To a suspension of NaH (0.101 g, 4.21 mmol) in dry MeCN (13 ml) add (0.463 g, 4.02 mmol) of semicarbazone acetone (III). The resulting suspension is stirred for 1 hour, a solution of butyl bromide (5.506 g, 40.18 mmol) in MeCN (7 ml) is added and boiled with stirring for 9 hours. Next, the precipitate is filtered off, the mother liquor is evaporated, 3.2 ml of 17% hydrochloric acid solution is added to the residue, the resulting solution is evaporated in vacuo at a bath temperature of up to 60 ° C. The solid residue is triturated in a mixture of isopropyl alcohol and diethyl ether to form a suspension, cooled to 0 ° C, the precipitate is filtered, washed with cold isopropyl alcohol, cold diethyl ether, petroleum ether, and dried. 0.398 g (59%) of 2-butylsemicarbazide hydrochloride is obtained. Analytically pure sample obtained by recrystallization from i-PrOH. T. pl. 133.5-134 ° С (with decomposition).

Calculated,%: C 35.82, H 8.42, N 25.07. C ₅ H ₁₄ ClN ₃ O. Found,%: C 35.84, H 8.31, N 25.11.

Spectrum ¹ H NMR (300.13 MHz, DMSO-d ₆ ) δ, ppm: 10.20 (3H, br s, NH ₃ ⁺ ), 6.87 (2H, s, NH ₂ ), 3.53 (2H, t, ³ J = 7.7 Hz NCH ₂ ), 1.45-1.59 (2H, m, ³ J = 7.7 Hz, C ₍₂₎ H ₂ ), 1.16-1.32 (2H, m, ³ J = 7.3 Hz, C ( ₃ ) H ₂ ), 0.87 (3H, t, ³ J = 7.3 Hz CH ₃ ).

Spectrum ¹³ C NMR (75.48 MHz, DMSO-d ₆ ) δ, ppm: 157.6 (C = O), 48.4 (C ₍₁₎ H ₂ ), 28.1 (C ₍₂₎ H ₂ ), 19.0 (C ₍₃₎ H ₂ ), 13.7 (CH ₃ ).

IR spectrum (liquid paraffin), ν, cm ^-1 : 3342 (br. S), 3180 (br. S), 2730 (br. S), 2653 (br. S), 2594 (br. S), 2569 ( Bw), 1670 (s), 1626 (B-s), 1597 (B-s), 1560 (B-s), 1191 (Wed), 1108 (B-sr), 1086 (B-sr), 1061 (Wed), 941 (Wed), 759 (Wed), 738 (Wed), 609 (Wed), 542 (br. S), 462 (Wed).

Example 5.2-Octylsemicarbazide (I, R = C ₈ H ₁₇ ).

To a suspension of NaH (0.098 g, 4.06 mmol) in dry MeCN (13 ml) add (0.446 g, 3.87 mmol) of semicarbazone acetone (III). The resulting suspension is stirred for 1 hour, a solution of octyl bromide (3.741 g, 19.37 mmol) in MeCN (7 ml) is added and boiled with stirring for 9 hours. Next, the precipitate is filtered off, the mother liquor is evaporated, 3.2 ml of 17% hydrochloric acid solution is added to the residue, the resulting solution is evaporated in vacuo at a bath temperature of up to 60 ° C. 5 ml of H ₂ O are added to the residue and neutralized with Na ₂ CO ₃ (1.789 g, 21.29 mmol), the resulting suspension is stirred until the evolution of gas ceases. Then extracted with ethyl acetate (4 × 3 ml), the extract is evaporated to an oily residue, which is triturated in petroleum ether into suspension, the mixture is cooled to 0 ° C, the precipitate is filtered, washed with petroleum ether, dried, washed 2 times with Et ₂ O. Get 0.421 g (58%) 2-octyl semicarbazide. An analytically pure sample was obtained by recrystallization from a mixture of EtOH – H ₂ O (1: 3). T. pl. 72-72.5 ° C.

Calculated,%: C 57.72, H 11.30, N 22.44. C ₉ H ₂₁ N ₃ O. Found,%: C 57.73, H 11.47, N 22.55.

Spectrum^oneH NMR (300.13 MHz, DMSO-d₆) δ, ppm: 5.89 (2H, broadband, N_(one)H₂), 4.33 (2H, s, N₍₂₎H₂), 3.29 (2H, t,³J = 7.3 Hz, NCH₂), 1.40-1.54 (2H, tt,³J = 7.3 Hz³J = 7.0 Hz, C₍₂₎H₂), 1.13-1.35 (10H, m, С₍₃₎H₂, WITH_(four)H₂, WITH_(five)H₂, WITH₍₆₎H₂, WITH₍₇₎H_2,), 0.86 (3H, t,³J = 6.7 Hz, CH₃).

Spectrum ¹³ C NMR (75.48 MHz, DMSO-d ₆ ) δ, ppm: 160.0 (C = O), 48.2 (C ₍₁₎ H ₂ ), 31.2 (C ₍₂₎ H ₂ ), 28.8 (C ₍₃₎ H ₂ ), 28.7 (C ₍₄₎ H ₂ ), 26.2 (C ₍₅₎ H ₂ ), 22.1 (C ₍₆₎ H ₂ ), 22.0 (C ₍₇₎ H ₂ ), 13.9 (CH ₃ ).

IR spectrum (vaseline oil), ν, cm ^-1 : 3472 (s), 3322 (s), 3210 (s), 1648 (s br.), 1615 (s br.), 1568 (s br.), 1107 (c), 1072 (cf.), 948 (w. sr), 722 (wed), 494 (w. sr).

Example 6. 2-benzylsemicarbazide hydrochloride (II, R = CH ₂ C ₆ H ₅ ).

To a suspension of NaH (0.380 g, 15.84 mmol) in dry MeCN (15 ml) add (1.740 g, 15.11 mmol) of semicarbazone acetone (III). The resulting suspension is stirred for 1 hour, a solution of benzyl bromide (2.730 g, 15.96 mmol) in MeCN (10 ml) is added and boiled with stirring for 6.5 hours. Next, the precipitate is filtered off, the mother liquor is evaporated, 14.5 ml of 36% hydrochloric acid solution is added to the residue, the resulting solution is evaporated in vacuum at 60 ° C. The solid residue is triturated with isopropyl alcohol to form a suspension, cooled to 0 ° C, the precipitate is filtered off, washed with cold isopropyl alcohol, cold diethyl ether, petroleum ether, and dried. 1.816 g (60%) of 2-benzylsemicarbazide hydrochloride are obtained. An analytically pure sample is obtained by recrystallization from EtOH. T. pl. 139-139.5 ° С (with decomposition).

Calculated,%: C 47.63, H 6.00, N 20.84. C ₈ H ₁₂ ClN ₃ O. Found,%: C 47.41, H 6.18, N 20.87.

Spectrum ¹ H NMR (300.13 MHz, DMSO-d ₆ ) δ, ppm: 9.88 (3H, s br, NH ₃ ⁺ ), 7.29-7.43 (5H, m, CH _(arom) ), 7.05 (2H , bs, NH ₂ ), 4.84 (2H, s, CH ₂ ).

Spectrum ¹³ C NMR (75.48 MHz, DMSO-d ₆ ) δ, ppm: 157.6 (C = O), 135.4 (C _(arom) ), 128.6 (2 C _(arom) ), 128.1 (2 C _{(arom )} ), 127.9 (C _(arom) ), 51.7 (CH ₂ ).

IR spectrum (liquid paraffin), ν, cm ^-1 : 3330 (br. S), 3302 (br. S), 3161 (br. S), 2765 (br. S), 2683 (br. S), 2573 ( Bw), 1674 (s), 1616 (Bhp), 1587 (Bhc), 1551 (Bhc), 1234 (Bhc), 1201 (Bhc), 1153 (Bhc ), 1085 (s), 1038 (s), 930 (cf.), 770 (cf.), 747 (s), 700 (s), 633 (s), 593 (broad s.), 528 (s), 470 (with).

Claims (7)

The method of obtaining 2-alkyl-substituted semicarbazides of the formula (I) or their hydrochlorides of the formula (II)

where R = alkyl or substituted alkyl, which consists in indirect alkylation of unsubstituted semicarbazide at the nitrogen atom N2, characterized in that it includes the following stages: a) carry out the reaction of semicarbazide hydrochloride with acetone in the presence of sodium acetate in water to obtain acetone semicarbazone, which precipitates during the reaction and is isolated by a filtration operation; b) the obtained semicarbazone acetone is deprotonated by the action of an equivalent amount of sodium hydride with stirring in dry acetonitrile for 1 h at room temperature; c) the obtained sodium salt of semicarbazone acetone without isolation and in the same solvent — acetonitrile — is alkylated at the nitrogen atom N2 under the action of suitable alkylating reagents, and (i) an equivalent amount of dimethyl sulfate is used to introduce the methyl group and the reaction is carried out for 17 h at room temperature; (ii) for the introduction of other alkyl groups, besides methyl, use a 5-10 fold molar excess of the corresponding alkyl bromide and the reaction is carried out by boiling in acetonitrile for 9 hours; (iii) an equivalent amount of the corresponding bromide is used to introduce the substituted alkyl group and the reaction is carried out by boiling in acetonitrile for 9 hours; d) the obtained 2-alkyl-substituted semicarbazones are subjected to acidic hydrolysis without intermediate isolation and purification, for which the reaction masses are filtered from precipitates of salts after the end of alkylation, the solvent is removed in vacuum at a bath temperature up to 40 ° C, 17-36% hydrochloric is added to the residues acid in an amount of 5-10 equivalents of HCl per 1 equivalent of semicarbazone and the resulting solutions are immediately evaporated in vacuo at a bath temperature of up to 60 ° C, while the solid residues, which are 2-alkyl substituted hydrochlorides of semicarbazide in formula (II), triturated with isopropyl alcohol precipitation was filtered off and dried; d) to obtain 2-alkyl-substituted semicarbazides of formula (I), hydrochlorides of 2-alkyl-substituted semicarbazides of formula (II), obtained at the previous stage, are treated with a small excess of sodium carbonate in water, followed by extraction of the product with ethyl acetate, distilling the solvent from the combined extract, rubbing the residue with petroleum ether before crystallization.