RU2126398C1 - Derivatives of aminoascorbic acid and methods of their synthesis and derivatives of haloidascorbic acid - Google Patents

Abstract

FIELD: organic chemistry, vitamin derivatives. SUBSTANCE: invention proposes derivatives of aminoascorbic acid of the formula (I)

where R' is H, C₁-C₈-alkyl, CH₂R₃; R'' is C₂-C₈-alkyl, CH₂R₃, or when R' means H then R'' means -C(O)H; R³ is 5- or 6-membered heterocycle containing oxygen, nitrogen or sulfur atom as a heteroatom, C₁-C₈-alkyl, C₆-C₁₂-aryl or cyclohexyl; R,R₁,R₂ are H, benzyl. These compounds show anticarcinogenic effect. Compounds of the formula (I) are synthesized by different methods, in part, by alkylation of a compound of the formula (II)

Description

в которой R'= H, C₁-C₁₈алкил, C₆ циклоалкил, C₆-C₁₂ арил, гетероил, который представляет собой гетероциклическое соединение, содержащее в кольце кислород, серу или азот в качестве гетероатома, R''= C₁-C₁₈ алкил. C₆циклоалкил, C₆-C₁₂арил, гетероил, который представляет собой гетероциклическое соединение, содержащее в кольце кислород, серу или азот в качестве гетероатома, R' и R''- CH₂R₃, где R₃=C₁-C₁₈ C₆циклоалкил, C₆-C₁₂-арил, гетероил, представляющий собой гетероциклическое соединение, содержащее в кольце кислород, серу или азот в качестве гетероатома, т.е. R'=H, R''= ацил, т.е. R'' = COR, где R'''=H, C₁- C₁₈алкил, C₆-циклоалкил, C₆-C₁₂арил, гетероил, представляющий собой гетероциклическое соединение, содержащее в кольце кислород, серу или азот в качестве гетероатома, R, R₁ и R₂=H или защищающая группа, которая легко удаляется в нейтральной среде, такая как бензил. Новые соединения, которые содержат (не)замещенную амино-группу, образуют соли с кислотами, причем, когда R=R₁=R₂=H, они образуют соли с основаниями. Незащищенные соединения формулы I в нейтральной среде существуют в виде цвиттер-иона. Новые производные аскорбиновой кислоты I, которые являются целью данного изобретения, можно получить несколькими путями из соединений общей формулы II

в которой X = галоид (Cl, Br, J) или амино (NH₂). Когда X= галоид, R=R₁= бензил, R₂= H, т.е. R=R₁=R₂=бензил, а когда X=амино, R=R₁=R₂=H. Новые соединения получают несколькими типами реакций, иллюстрируемыми следующими схемами:
I. Восстановительное алкилирование
Восстановительное алкилирование представляет собой обработку альдегида или кетона аммиаком или первичными, т.е. вторичными аминами в присутствии водорода и катализатора для гидрирования. Вместо водорода и катализатора, могут быть использованы другие восстановители, такие как боргидриды и муравьиная кислота. В данном изобретении восстановительное алкилирование амино-аскорбиновой кислоты (II, X= NH₂, R=R₁=R^1=R ₂=H) проводят различными альдегидами R₃CHO, что иллюстрируется схемой 1:
Схема 1. Восстановительное алкилирование амино-аскорбиновой кислоты

X=NH₂ R=R₁= R₂= H R^'= R"(CH₂R₃)₂ R = R₁= R₂= H
Восстановительное алкилирование проводят в воде, как растворителе, при температуре 20-25^oC. Используемым восстановителем является водород с катализатором 5% или 10% Pd/C, или боргидрид натрия, где R₄=H или CN. В случае каталитического восстановления время реакции составляет 1-2 часа, в то время как в случае восстановления боргидридами реакция протекает в течение 5-10 часов. Механизм восстановительного алкилирования иллюстрируемый схемой 1a.,
Схема 1a

позволяет получить моно- и дизамещенные производные амино-аскорбиновой кислоты. В нашем случае, однако, обнаружены и выделены только дизамещенные производные. Это подтверждает, что реакция алкилирования на второй фазе протекает очень быстро.This invention relates to new derivatives of ascorbic acid, namely, derivatives of amino-ascorbic acid of General formula I

in which R '= H, C ₁ -C ₁₈ alkyl, C ₆ cycloalkyl, C ₆ -C ₁₂ aryl, heteroil, which is a heterocyclic compound containing oxygen, sulfur or nitrogen in the ring as a heteroatom, R''= C ₁ -C ₁₈ alkyl. C ₆ cycloalkyl, C ₆ -C ₁₂ aryl, heteroyl, which is a heterocyclic compound containing oxygen, sulfur or nitrogen as a heteroatom in the ring, R 'and R''- CH ₂ R ₃ , where R ₃ = C ₁ - C ₁₈ C ₆ cycloalkyl, C ₆ -C ₁₂ aryl, heteroil, which is a heterocyclic compound containing oxygen, sulfur or nitrogen in the ring as a heteroatom, i.e. R '= H, R''= acyl, i.e. R`` = COR, where R '''= H, C ₁ - C ₁₈ alkyl, C ₆ -cycloalkyl, C ₆ -C ₁₂ aryl, heteroil, which is a heterocyclic compound containing oxygen, sulfur or nitrogen in the ring as heteroatoms, R, R ₁ and R ₂ = H or a protecting group that is easily removed in a neutral environment, such as benzyl. New compounds that contain a (un) substituted amino group form salts with acids, and when R = R ₁ = R ₂ = H, they form salts with bases. Unprotected compounds of formula I in a neutral environment exist as a zwitterion. The new derivatives of ascorbic acid I, which are the purpose of this invention, can be obtained in several ways from compounds of General formula II

in which X = halogen (Cl, Br, J) or amino (NH ₂ ). When X = halogen, R = R ₁ = benzyl, R ₂ = H, i.e. R = R ₁ = R ₂ = benzyl, and when X = amino, R = R ₁ = R ₂ = H. New compounds receive several types of reactions, illustrated by the following schemes:
I. Reductive alkylation
Reductive alkylation is the treatment of an aldehyde or ketone with ammonia or primary, i.e. secondary amines in the presence of hydrogen and a hydrogenation catalyst. Instead of hydrogen and a catalyst, other reducing agents such as borohydrides and formic acid can be used. In the present invention, reductive alkylation of amino-ascorbic acid (II, X = NH ₂ , R = R ₁ = R ^{1 = R} ₂ = H) is carried out with various R ₃ CHO aldehydes, as illustrated by Scheme 1:
Scheme 1. Reductive alkylation of amino-ascorbic acid

X = NH ₂ R = R ₁ = R ₂ = HR ^' = R "(CH ₂ R ₃ ) ₂ R = R ₁ = R ₂ = H
Reductive alkylation is carried out in water, as a solvent, at a temperature of 20-25 ^° C. The reducing agent used is hydrogen with a 5% or 10% Pd / C catalyst, or sodium borohydride, where R ₄ = H or CN. In the case of catalytic reduction, the reaction time is 1-2 hours, while in the case of reduction with borohydrides, the reaction proceeds within 5-10 hours. The reductive alkylation mechanism illustrated in Scheme 1a.,
Scheme 1a

allows you to get mono - and disubstituted derivatives of amino-ascorbic acid. In our case, however, only disubstituted derivatives are detected and isolated. This confirms that the alkylation reaction in the second phase proceeds very quickly.

2. The alkylation reaction
Mono- and disubstituted derivatives of amino-ascorbic acid are obtained by alkylation of the corresponding primary and secondary amines, according to reaction scheme 2.

X = галоид RH, R₁=R₂=бензил R=R₁=R₂=H
R=H, R₁=R₂=бензил или R=R₁=R₂=бензил
В реакциях алкилирования используют первичные и вторичные амины общей формулы NHR' R" в которой R' и R'' уже описаны для соединений общей формулы I. В этой реакции алкилирующим реагентом является галоид-аскорбиновая кислота общей формулы II. Так как галоид-аскорбиновая кислота имеет более трех гидроксильных групп, из которых гидроксильные группы ендиольной системы в положениях C₂, и C₃ являются очень реакционноспособными в щелочной среде, то молекулу необходимо соответственно защитить до реакции. Другими словами, необходимо подобрать защищающие группы, которые удаляются в нейтральных средах, такая как бензильная группа. Реакцию защиты проводят в соответствии со схемой 2a.Scheme 2. The alkylation reaction

X = halogen RH, R ₁ = R ₂ = benzyl R = R ₁ = R ₂ = H
R = H, R ₁ = R ₂ = benzyl or R = R ₁ = R ₂ = benzyl
In the alkylation reactions, primary and secondary amines of the general formula NHR R R ″ in which R ’and R ″ are already described for compounds of the general formula I are used. In this reaction, the alkylating agent is the halogen-ascorbic acid of the general formula II. Since the halogen is ascorbic acid has more than three hydroxyl groups, of which the hydroxyl groups of the endiol system in the C ₂ and C ₃ positions are very reactive in an alkaline medium, the molecule must be adequately protected before the reaction. and other groups which are removed in neutral environments, such as a benzyl group, The protection reaction is carried out in accordance with scheme 2a.

X=Гал X=Гал
R=R₁=R₂=H R=R₁=R₂=бензил
Продукт реакции зависит от молярного соотношения реагентов. Если для одного моля галоид-аскорбиновой кислоты используют два моля защищающих реагентов, то получают соединение общей формулы II, где R₂=H, а если используют три моля или больший молярный избыток этого реагента, то получают полностью защищенное соединение. Удаление защищающих групп проводят в нейтральной среде с помощью каталитического восстановления, как это иллюстрируется схемой 2. Реакцию также можно проводить без изоляции интермедиата путем добавления катализатора к реакционной смеси после окончания алкилирования, и после этого путем снятия защиты (реакция в одном сосуде) в атмосфере водорода, где, как отмечается, в случае полностью защищенного соединения защищающую группу R₂ нелегко удалить, и поэтому в таких типах реакций чаще всего используют соединения общей формулы II, где R₂=H.Scheme 2a. Protection of the hydroxyl groups of halide ascorbic acid

X = Gal X = Gal
R = R ₁ = R ₂ = HR = R ₁ = R ₂ = benzyl
The reaction product depends on the molar ratio of the reactants. If two moles of protecting reagents are used for one mole of halogen-ascorbic acid, a compound of general formula II is obtained, where R ₂ = H, and if three moles or a larger molar excess of this reagent are used, a fully protected compound is obtained. The removal of the protecting groups is carried out in a neutral medium using catalytic reduction, as illustrated in Scheme 2. The reaction can also be carried out without isolation of the intermediate by adding a catalyst to the reaction mixture after alkylation is complete, and then by removing deprotection (reaction in one vessel) in a hydrogen atmosphere , where, as noted, in the case of a fully protected compound, the protecting group R _{2 is} not easy to remove, and therefore, in these types of reactions, compounds of general formula II are most often used, where R ₂ = H.

3. Acylation reaction
the amino group acylation reaction is carried out using reagents commonly known in the chemical literature, such as acid chlorides or anhydrides or active acid esters, those using reagents of the general formula:
R ₅ COR ₆
where R ₅ = H, alkyl, cycloalkyl, aryl or heteroil having the meaning indicated for formula I, and R ₆ = Cl, or OCOR ₇ , where R ₇ = alkyl, or OR ₈ where R ₈ represents a group known in chemistry as an active ester group such as succinyl or benzothiazolyl.

 The alkylation reaction is illustrated in scheme 3.

X=NH₂ R=R₁=R₂=H
R=R=R=H
Если реакцию ацилирования проводят с муравьиной кислотой (R₅=R₆=OH) или со смешанным ангидридом муравьиной и уксусной кислот (R₅=H, R₆=OCOR₇, R₇= CH₃), то получают N-формильное производное. Известно, что в восстановительных условиях N-формильные производные могут превращаться в соответствующие монометильные амино-производные. Однако, показано, что амино-аскорбиновая кислота образует амильные производные, которые очень стабильны в восстановительных условиях. Например, формил амино-аскорбиновая кислота не восстанавливается при давлении 80 бар и при 80^oC и ацильные производные амино-аскорбиновой кислоты значительно более стабильны при высоких температурах, чем аскорбиновая кислота. В упомянутых условиях, поддерживаемых на протяжении 8 часов, хроматографически не регистрируется какое-либо разрушение молекулы. Поскольку производные ациламино-аскорбиновой кислоты сохраняют свои восстанавливающие свойства, они могут быть использованы как антиоксиданты при температурах, превышающих температуру для аскорбиновой кислоты.Scheme 3. Acylation of the amino group

X = NH ₂ R = R ₁ = R ₂ = H
R = R = R = H
If the acylation reaction is carried out with formic acid (R ₅ = R ₆ = OH) or with mixed formic anhydride and acetic acid (R ₅ = H, R ₆ = OCOR ₇ , R ₇ = CH ₃ ), an N-formyl derivative is obtained. It is known that under reducing conditions, N-formyl derivatives can be converted into the corresponding monomethyl amino derivatives. However, it has been shown that amino ascorbic acid forms amyl derivatives that are very stable under reducing conditions. For example, formyl amino-ascorbic acid does not recover at a pressure of 80 bar and at 80 ^° C and the acyl derivatives of amino-ascorbic acid are significantly more stable at high temperatures than ascorbic acid. Under the conditions mentioned, maintained for 8 hours, no molecular degradation is detected chromatographically. Since derivatives of acylamino-ascorbic acid retain their reducing properties, they can be used as antioxidants at temperatures higher than the temperature for ascorbic acid.

 New derivatives of amino-ascorbic acid demonstrate anticarcinogenic properties that have been tested on the following tumor cell lines: Hela (carcinoma portio vaginalis cervicis); Hep 2 (laryngeal carcinoma); MiaPaCa 2 (pancreatic carcinoma) and K562 (erythroleukemia), all human cell lines and W138 (normal human fibroblasts), which are used as a control.

Human tumor cell lines and human fibroblasts are grown in liquid DMEM media (Eagle medium modified with Dulbecco) supplemented with 10% fetal calf serum (FCS), 2 mM in glutamine, 100 U / ml penicillin and 100 μg / ml streptomycin in a humid atmosphere with 5% CO ₂ at 37 ^° C. Cells are inoculated at a concentration of 10 ⁴ cells / ml.

Samples were dissolved in DMEM without serum, and 0.1 N NaOH was added to pH 7.4. The concentrations used were 10 ^-3 M, 2 • 10 ^-3 M and 3 • 10 ^-3 M. The results illustrated in the drawing represent the average of four parallel samples ± standard deviation (CO). The results are illustrated in the drawing.

 As can be seen from the drawing, the tested derivatives do not affect the growth of normal fibroblast W138 cells, but they, however, inhibit the growth of tumor cells, especially Hep 2.

 The preparation of new derivatives of amino-ascorbic acid is illustrated by the following examples, which, however, are in no way limiting.

Examples of reductive alkylation
Example 1 N, N-dimethylamino-ascorbic acid
(I, R '= R''= CH ₃ , R = R ₁ = R ₂ = H)
Method a): reduction by addition of a Pd / C catalyst.

To a solution of amino ascorbic acid (II, X = NH ₂ , R = R ₁ = R ₂ = H) (1.2 g) in water (100 ml) was added a 35% aqueous solution of formaldehyde (2.4 ml) and a 10% catalyst Pd / C (0.48 g), after which it was stirred under a hydrogen pressure of 0.8 bar in a vessel according to Parr for 1 hour. The catalyst was removed by filtration, and the aqueous solution was evaporated to a volume of approximately 2-3 ml. The concentrate was purified by silica gel column chromatography (kieselguhr 60 0.063-0.2 mm art. 7734), eluting with methanol-water = 7: 3 solvent. The fractions that contain the product (tlc, silica gel 60 F ₂₅₄ Merck by sputtering with phosphorolebdenic acid) are combined and then evaporated to dryness to give 0.3 g of product, mp. 207-210 ^o C; = [α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = + 46.5 ^o (c = 0.1 H ₂ O).

IR (KBr) (cm ^-1 ): 3400, 2900, 2800, 2350, 1750, 1650, 1620, 1480, 1430, 1100, 1050.

¹ H NMR ppm (d) (DO), 2.83 (6H, s), 3.22-3.37 (2H, m), 4.2-4.25 (1H, m), 4.28- 4.29 (1H, d, J = 2.17 Hz).

¹ H NMR ppm (d) (CF ₃ COOD): 3.2-3.23 (6H, d, J = 8.79 Hz), 3.58-3.83 (2H, m), 4.79- 4.83 (1H, m), 5.02 (1H, s).

¹³ C NMR ppm (d) (CF ₃ COOD + D ₂ O): 40.97, 44.19, 58.47, 62.98, 75.43, 152.43, 161.23.

EI-MS m / z: 203 (M ⁺ ), 58, 82, 88, 112, 130.

Example 2
Method b): reduction with borohydride
To a solution of amino-ascorbic acid (0.5 g) in water (50 ml) was added a 35% aqueous solution of formaldehyde (1 ml), sodium cyanoborohydride (NaBH ₃ CN, 0.537 g) and cold acetic acid (0.3 g), then stirred in nitrogen atmosphere for 5 hours at 20-25 ^o C. Then the reaction mixture was concentrated to a volume of approximately 1-2 ml, purified by column chromatography on silica gel, and then eluted with methanol-water = 7: 3 solvent. Fractions, containing the product (tlc) is collected and then evaporated to dryness, yielding 0.28 g of a product identical to the product of Example 1.

Example 3
N, N-di-n-propylamino-ascorbic acid
(I, R 'R''= C ₃ H ₇ , R = R ₁ = R ₂ = H)
To a solution of amino ascorbic acid (0.32 g) in water (15 ml) was added n-propanol (C ₃ H ₆ O, 0.11 g), sodium cyanoborohydride (NaBH ₃ CN, 0.32 g), and then added cold acetic acid (0.2 ml), after which the reaction mixture was stirred under nitrogen for 3 hours at 20-25 ^° C. The reaction mixture was concentrated to a volume of approximately 1 ml, and purified by silica gel column chromatography by elution with an ethanol-water solvent = 1: 1. Fractions that contain the product (tlc, silica gel 60 F ₂₄₅ EtOH: H ₂ O = 9: 1) are evaporated to dryness to give 0.2 g of the product.

¹ H NMR ppm (d) (D ₂ O): 0.9-0.94 (6H, t), 1.69-1.7 (4H, m), 3.11-3.2 (4H, t ), 3.37-3.38 (2H, m), 3.4-3.45 (1H, m), 4.37-4.38 (1H, d).

Example 4
N, N-dibenzylamino-ascorbic acid (I, R '= R''= CH ₂ C ₆ H ₅ , R = R ₁ = R ₂ = H)
Benzaldehyde (0.228 g), sodium cyanoborohydride (0.382 g) and cold acetic acid (0.2 ml) are added to a solution of amino-ascorbic acid (0.36 g) in water (20 ml), and then stirred under nitrogen atmosphere for 3 hours at 20-25 ^o C. the Reaction mixture was concentrated to a volume of approximately 1 ml and purified by silica gel column chromatography (Kieselguhr 60 0.062-0.2 mm art. 7734), eluting with ethanol-water = 8: 2 solvent. Fractions that contain the product (tlc) are collected and then evaporated to dryness to give 0.25 g of the product.

¹ H NMR ppm (d) (D ₂ O): 3.92 (2H, s), 4.31-4.35 (1H, m), 4.59-4.61 (1H, d, J = 2 15 Hz), 4.83 (4H, s), 7.59-7.69 (10H, m).

Example 5
N, N'-difurfurylamino-ascorbic acid
(I, R '= R''= CH ₂ C ₄ H ₃ O, R = R ₁ = R ₂ = H)
To a solution of amino ascorbic acid (0.52 g) in water (26 ml), furfural (1.45 g), sodium cyanoborohydride (0.565 g) and cold acetic acid (0.5 ml) are added, after which the reaction mixture is stirred under nitrogen atmosphere for 5 hours at 20-25 ^° C. The mixture was concentrated under reduced pressure to a volume of 2 ml and purified by column chromatography on silica gel, eluting with an ethanol-water = 8: 2 solvent. The fractions that contain the product (tlc) are collected and then evaporated to dryness to give 0.7 g of product
mp = 220 ^o C (decomposition): [α] $\genfrac{}{}{0ex}{}{\text{20}}{\text{D}}$ = +22 ^o (s = 0.58, H ₂ O) IR (KBr) (cm ^-1 ): 3550, 3500, 3450, 2350, 2200, 1630, 1380, 1100, 750,
Examples of alkylation reactions
Example 6
N-methylamino-ascorbic acid
(I, R '= H, R''= CH, R = R ₁ = R ₂ = H).

To a solution of 2,3-dibenzyl-6-bromo-6-deoxy-ascorbic acid (II, X = Br, R = R ₁ = Bn, R ₂ = H (0.5) methanol (10 ml) was added 20% methanol methylamine solution (10 ml) and stirred for 1 hour, after which the mixture was kept overnight at 20 ^° C. The reaction mixture was concentrated under reduced pressure to dryness, methanol (15 ml) and a 10% Pd / C catalyst (0.015) were added to the residue. g) and stirred under a hydrogen pressure of 2 bar in a vessel according to Parr for 3 hours.The catalyst is separated by filtration, after which the solution is concentrated under reduced pressure to a volume of 2 ml and then purified by silica gel column chromatography, eluting with a 8: 2 methanol-water solvent. The fractions that contain the product (tlc) are collected and then evaporated to dryness to obtain 0.05 g of the product.

T. pl. = 155-160 ^o C; IR (KBr) (cm ^-1 ): 3400, 2900, 2810, 2380, 1740, 1600, 1480, 1380, 1150, 1110, 1050.

¹ H NMR ppm (d) (D ₂ O): 2.72 (3H, s), 3.21-3.29 (2H, m), 3.73-4.29 (1H, m), 4.37-4, 40 (1H, d, J = 2.2 Hz).

Example 7
N, N-dimethylamino-ascorbic acid
(I, R '= R''= CH ₃ , R = R ₁ = R ₂ = H).

To a solution of 2,3-dibenzyl-6-bromo-6-deoxy-ascorbic acid (II, 1 = Br, R = R ₁ = Bn, R ₂ = H) (0.27 g) in methanol (5 ml) was added A 20% methanol solution of dimethylamine (5 ml) was stirred for 1 hour, and then the mixture was kept for 24 hours at 20-25 ^° C. The reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in methanol (10 ml), to which 10% Pd / C catalyst (0.01 g) was added and stirred under a 2 bar hydrogen pressure in a vessel according to Parr for 3 hours. The catalyst was separated by filtration, and methanol was concentrated under reduced pressure to a volume of 2 ml. The product is then purified by silica gel column chromatography, eluting with 8: 2 methanol-water solvent. Fractions that contain the product (tlc) are collected and then evaporated to dryness to give 0.03 g of a product that is identical to the product of Example 1.

Protection of the hydroxyl groups of halide ascorbic acid
Example 8
2,3,5-tribenzyl-6-bromo-6-deoxy-ascorbic acid (II, X = Br, R = R ₁ = R ₂ = Bn).

Potassium carbonate (0.91 g) and benzyl chloride are added to a solution of 6-bromo-6-deoxy-ascorbic acid (II, X = Br, R = R ₁ = R ₂ = H) (1 g) in dimethylformamide (15 ml) (1.64 g) and then stirred under nitrogen for 2 hours at 60 ^° C. The reaction mixture was concentrated under reduced pressure to dryness, after which chloroform (15 ml) and water (5 ml) were added to the residue. The organic layer was separated and washed twice with water (5 ml) and then dried over sic sodium sulfate. The chloroform solution was concentrated under reduced pressure to a volume of 2 m, then purified by column chromatography on silica gel, eluting with a solvent of chloroform-ethanol 32: 1. The fractions that contain the product are collected and then evaporated to dryness to give 0.2 g of the product.

IR CHCl ₃ (cm ^-1 ): 3400, 3090, 3060, 3040, 2950, 1760, 1670, 1500, 1460, 1320, 1210, 1150, 1050.

¹ H NMR ppm (d) (CDCl ₃ ): 3.51-3.54 (2H, m), 4.03-4.07 (1H, m), 4.91-4.92 (1H, d, J = 2.14 Hz), 5.08 (2H, s), 5.09 (2H, s), 5.16-5.19 (2H, d), 7.20-7.37 (15H, m )

Example 9
The method of obtaining 2,3-dibenzyl-6-bromo-6-deoxy-ascorbic acid (II, X = Br, R = R ₁ = Bn, R ₂ = H)
To a solution of 6-bromo-6-deoxy-ascorbic acid (II, X = Br, R = R '= R ₂ = H) (2 g) in dimethylformamide (30 ml), potassium carbonate (1.2 g) and benzyl chloride are added (2.2 g), then stirred under nitrogen for 2 hours at 60 ^° C. The reaction mixture was concentrated under reduced pressure to an oily residue. Chloroform (30 ml) and water (10 ml) are added to the residue. The organic layer was separated and washed with water (2 x 10 ml) and then dried over sic sodium sulfate. The chloroform solution was concentrated to a volume of 2 ml, then purified by silica gel column chromatography, eluting with a solvent of methylene chloride-ethanol (80: 1). Fractions that contain the product (tlc) are collected and then evaporated to an oily residue that has all the physicochemical properties described in the literature.

Acylation reaction
Example 10
Formylamino Ascorbic Acid
(I, R '= H, R''= CHO, R = R ₁ = R ₂ = H)
Acetic and formic acid anhydride (3.7 ml) is obtained by stirring acetic anhydride (2.5 ml) and formic acid (1.2 ml) for 2 hours at 50-60 ^o C, after which it was cooled to 0 ^o C. Amino ascorbic acid (I, R '= R''= H, R = R ₁ = R ₂ = H, 0.5 g is dissolved and stirred for 4.5 hours at 20-24 ^° C. The reaction mixture is concentrated at reduced pressure, evaporated after adding water (5 ml), and then dissolved in 2 ml of water, after which it was purified by silica gel column chromatography, then the solvent was eluted with 8: 2 methanol-acetonitrile. ktsii which contain the product (tlc), collected and evaporated to dryness under reduced pressure to give 0.26 g of product.

T. pl. = 200 ^o C (decomposition) IR (KBr) (cm ^-1 ): 3450, 2900, 2350, 1740, 1670, 1600, 1390, 1250, 1150, 1110, 1050.

¹ H NMR ppm (d) (D ₂ O): 3.31-3.54 (2H, m), 3.97-4.02 (1H, m), 4.42 (1H, d, J = 2 3 Hz), 8.03 (1H, s).

¹³ C NMR ppm (d) (CF ₃ COOD + D ₂ O): 43.2. 66.0, 73.2, 119.3, 153.8, 166.9, 174.0
EI-MS m / z: 55, 566 57, 59, 62, 69, 79, 73, 84, 85, 86, 87, 103, 113.

 Example 11

N-octylamino-ascorbic acid
(1, R '= H, R''= (CH ₂ ) ₇ CH ₃ , R = R ₁ = R ₂ = H)
Octanal (octaldehyde, 1.8 g), sodium cyanoborohydride (0.35 g) and glacial acetic acid (0.2 ml) are added to a solution of amino-ascorbic acid (0.49 g) in water (500 ml). The reaction mixture was stirred for 4 hours in a nitrogen atmosphere at a temperature of 20-25 ^o C, evaporated to a volume of about 2 ml and chromatographic using a column packed with silica gel. It is eluted with a mixture of acetonitrile - water (5: 1). The fractions containing the product (tic) are combined and evaporated to dryness. Yield 0.25 g.

¹ H NMR ppm CD ₃ OD: 0.98 (3H, t), 1.40 (10H, s); 1.63 (2H, s); 1.81 (2H, s); 3.24- 3.40 (2H, m); 4.20-4.22 (1H, m); 4.45 (1H, d).

IR (KBr) (cm ^-1 ): 3397; 2958; 2926; 2855; 1738; 1675; 1627.

 Example 12

N-cyclohexylmethylamino-ascorbic acid
(1, R '= H, R''= CH ₂ ; C ₆ H ₁₁ , R = R ₁ = R ₂ = H)
To a solution of amino ascorbic acid (0.49 g) in water (500 g) are added cyclohexanecarboxaldehyde (1.6 g), sodium cyanoborohydride (0.35 g) and glacial acetic acid (0.2 ml). The reaction mixture was stirred for 7 hours under nitrogen at a temperature of 20-25 ^o C and washed with toluene (2 x 20 ml). The aqueous layer was evaporated under reduced pressure to a volume of about 2 ml and chromatographed on a silica gel column. Elute with acetonitrile-water (3: 1). Product containing fractions (tlc) were combined and evaporated to dryness. Yield 0.33 g.

¹ H NMR ppm (D ₂ O): 4.43 (1H, d); 4.11-4.14 (1H, m); 3.02-3.30) (4H, m); 1.87-1.98 (1H, m); 1.70-1.73 (2H, m); 1.52-1.57 (2H, m); 1.14-1.29 (4H, m); 1.03-1.07 (2H, m).

IR (KBr) (cm ^-1 ): 3424; 2935; 2858; 1722; 1601.

Example 13. N-4 '- (2'-phenylimidazoyl) methylamino ascorbic acid
(1, R '= H, R' = CH ₂ C ₉ H ₇ N ₂ ; R = R ₁ = R ₂ = H)
To a solution of amino ascorbic acid (0.5 g) in water (1500 ml) was added 2-phenylimidazole-4-carboaldehyde (0.59 g) sodium cyanoborohydride (0.36 g) and glacial acid. The reaction mixture is stirred for 8 hours in a nitrogen atmosphere at a temperature of 50-55 ^o C, then evaporated to a volume of about 2 ml and chromatographed on a silica gel column (Kiesel gel 60, 0.063-0.2 mm) using an acetonitrile mixture as eluant water (3: 1). The fractions containing the product (tlc, silica gel 60 F ₂₅₄ ) are combined and evaporated to dryness. Yield: 0.16 g of product.

¹ H NMR ppm (D ₂ O): 3.18 (2H, m); 4.10 (1H, m); 4.15 (2H, s); 4.26 (1H, d); 7.24 (1H, s); 7.35 (3H, m); 7.62 (2H, m).

IR (KBr) (cm ^-1 ): 3432; 1728; 1591; 1410; 1121.

 Example 14

N, N-di- (2-thiophenylmethyl) amino-ascorbic acid
(1, R '= R''= CH ₂ C ₄ H ₃ S, R = R ₁ = R ₂ = H)
Thiophene-2-carboxaldehyde (1.66 g), sodium cyanoborohydride (0.36 g) and glacial acetic acid (0.3 ml) are added to a solution of amino-ascorbic acid (0.52 g) in water (50 ml). The reaction mixture was stirred for 24 hours in a nitrogen atmosphere at a temperature of 20-25 ^o C, evaporated under reduced pressure to a volume of about 2 ml and purified on a column of silica gel with a mixture of n-propanol-1N NH ₄ OH-acetone (3: 2: 0.2 ) Product containing fractions (tlc) were combined and evaporated to dryness. Yield 0.38 g.

¹ H NMR ppm (D ₂ O): 4.05-4.20 (3H, m); 4.55 (1H, d); 4.65-4.75 (4H, m); 6.95-6.99 (4H, m); 7.30-7.32 (2H, m).

IR (KBr) (cm ^-1 ): 3400; 1730; 1670; 1570.

Claims (11)

1. Derivatives of amino ascorbic acid of General formula I

where R 'is H, C ₁ is C ₈ alkyl or CH ₂ R ₃ ;
R "means C ₂ - C ₈ -alkyl, CH ₂ R ³ or, when R'-H,
R ″ means —C (O) H;
R ₃ is a 5- or 6-membered heterocycle containing oxygen, nitrogen or sulfur, C ₁ -C ₈ -alkyl, C ₆ -C ₁₂ -aryl or cyclohexyl as a heteroatom;
R, R ₁ and R _{2 are} hydrogen or benzyl. 2. The compound according to claim 1, where R 'and R "is propyl, R, R ₁ and R _{2 are} hydrogen. 3. The compound according to claim 1, where R 'and R "mean furfuryl, R, R ₁ and R ₂ mean hydrogen. 4. The compound according to claim 1, where R'-hydrogen, R "is formyl and R, R ₁ and R _{2 are} hydrogen.  5. The compounds according to claim 1, having antioxidant activity.  6. The compounds according to claim 1, having anticarcinogenic activity. 7. A method of obtaining derivatives of amino ascorbic acid of the formula I according to claim 1, characterized in that the compound of general formula

subjected to reductive alkylation with a compound of the general formula
R ₃ CHO,
where R ₃ - as indicated in claim 1,
in a hydrogen atmosphere in the presence of a metal catalyst or borohydride of the general formula
NaBH ₃ R ₄ ,
where R ₄ means hydrogen or CN,
as a reducing agent. 8. The method of obtaining derivatives of amino ascorbic acid of the general formula I according to claim 1, characterized in that the compound of the general formula
R'R''NH,
where R 'and R''- as indicated in claim 1,
alkylate with a compound of the general formula

where X is a halogen;
R and R 'are benzyl;
R _{2 is} H or R, R ₁ and R _{2 are} benzyl. 9. The method of obtaining derivatives of amino ascorbic acid of the general formula I according to claim 1, where RH, R ″ - C (O) H, R, R ₁ and R ₂ - H or benzyl or R and R ₁ - benzyl, R ₂ - H, characterized in that the compound of General formula

where R, R ₁ and R ₂ - H or benzyl or R and R ₁ - benzyl, R ₂ -H,
acylated with a compound of the general formula
HCOR ₆ ,
where R ₆ means OCOR ₇ , R ₇ is lower alkyl. 10. Derivatives of halogen ascorbic acid of General formula II

in which X is chlorine, bromine or iodine;
R, R ₁ and R ₂ are benzyl. 11. The derivative of claim 10, wherein X is bromine, R, R ₁ and R ₂ are benzyl.

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