FR2580644A1 - Derivatives of ascorbic acid - Google Patents

Abstract

New derivative of ascorbic acid, of general formula I: in which R<1> represents a linear or branched alkyl group containing from 1 to 17 carbon atoms, a cycloalkyl group or an aryl group, R<2>CO represents an aliphatic acid residue containing from 4 to 18 carbon atoms which is branched at the alpha position or a cycloalkanoic acid residue, and R<3> represents a hydrogen atom, a linear or branched alkanoic acid residue containing from 2 to 18 carbon atoms, a cycloalkanoic acid residue or an arylcarboxylic acid residue.

Description

ASCORBIC ACID DERIVATIVES
The present invention relates to new derivatives of ascorbic acid and, more particularly, to derivatives of ascorbic acid, the hydroxyl group of which in position 3 is acylated by a branched aliphatic acid in position O, or a cycloalkanoic acid. , and in which the hydroxyl groups in position 2 and 6 are acylated simultaneously by a linear or branched aliphatic acid, a cycloalkanoic acid or an aromatic carboxylic acid.

In its use as an ingredient of fortifying nutrients or cosmetic substances, ascorbic acid has been found to be disadvantageous because the enediol moiety is liable to oxidize, resulting in poor storage power over time. Due to the very low fat solubility, the stability in creams becomes poor, which is associated with the other disadvantage of low percutaneous absorbability.

To overcome the above disadvantages, a variety of ester derivatives of linear aliphatic acids or having a methyl branch in the> J position (iso-branching) have been proposed. For example, esters of 2,6-di-aliphatic acids have been described in the Publication of
Japanese Patent No. 43-5885, 2,6-diisooctanoates in the
Japanese Patent Publication No. 45-15391, 2,5,6-trialiphatic acid esters in Patent Publication
Japanese No. 43-9216, and 2-monoaliphatic acid esters in Japanese Patent Publication No. 45-41577.

However, those ascorbic acid derivatives, in which only one hydroxyl group of the enediol moiety is acylated, undergo staining during storage and do not always exhibit improved preservability.

On the other hand, the only known derivatives, in which the two hydroxyl groups. of the enediol fragment are acylated,
are the tetraacylated products in which the hydroxyl groups at positions 5 and 6 are simultaneously acylated. Tetraacylated products have been found to be disadvantageous by their low content of ascorbic acid per unit weight of the product and by their low vitamin C activity.

The present inventors have carried out intensive research to overcome the disadvantages of the known derivatives of ascorbic acid and have found that among the derivatives of 2,3-di-0-acyl- or 2,3,6- tri-O-acylascorbic, those in which the 3- position is acylated by an aliphatic acid branched at O, or cycloalkanoic acid are improved over the known esters of ascorbic and aliphatic acids. The present invention is accomplished on the basis of the above finding.

formule dans laquelle
R1 représente un groupe alkyle, linéaire ou ramifié, ren
fermant de 1 à 17 atomes de carbone, un groupe cycloalkyle
ou un groupe aryle,
R2CO représente un reste, renfermant de 4 à 18 atomes de
carbone, d'acide aliphatique ramifié en o( ou un reste
d'acide cycloalcanoique, et
R3 représente un atome d'hydrogène, un reste, renfermant
de 2 à 18 atomes de carbone, d'acide alcanoique, linéaire
ou ramifié, un reste d'acide cycloalcanoique ou un reste
d'acide arylcarboxylique. In accordance with the present invention, there is provided an ascorbic acid derivative, which is represented by the following general formula

formula in which
R1 represents an alkyl group, linear or branched, ren
closing from 1 to 17 carbon atoms, a cycloalkyl group
or an aryl group,
R2CO represents a residue, containing from 4 to 18 atoms of
carbon, of aliphatic acid branched into o (or a residue
cycloalkanoic acid, and
R3 represents a hydrogen atom, a residue containing
from 2 to 18 carbon atoms, alkanoic acid, linear
or branched, a residue of cycloalkanoic acid or a residue
arylcarboxylic acid.

The radical R1 of the ascorbic acid derivative represented by the formula (I) is a linear alkyl group, such as methyl, ethyl, n-propyl, n-butyl or the like; a branched alkyl group, such as isopropyl, sec-butyl, t-butyl, 1-ethylpropyl, 1-ethylpentyl, 1-heptyldecyl, 4,6,6-trimethyl-1- (1,3,3-trimethylbutyl) heptyl or the like; a cycloalkyl group, such as cyclohexyl, cyclopentyl or the like; and an aryl group, such as phenyl. The R2CO group is, for example, 2-isobutanoyl, pivaloyl, 2-ethylbutanoyl, 2-ethylhexanoyl, 2-heptylundecanoyl, 5,7,7-trimethyl-2- (1,3,3-trimethylbutyl) octanoyl, cyclohexanoyl or the like. .

The R3 radical represents, for example, a hydrogen atom; a residue of linear alkanoic acid, such as acetyl, propanoyl, n-butanoyl, n-pentanoyl or the like; a branched alkanoic acid residue, such as isobutanoyl, 2-methylbutanoyl, pivaloyl, 2-ethylbutanoyl, 2-ethylhexanoyl, 2-heptylundecanoyl, 5,7,7-trimethyl-2 (1,3,3-trimethylbutyl) octanoyl or the like; or an aryl carboxylic acid residue, such as benzoyl.

schéma dans lequel - X représente un atome d'halogène, - R4CO représente un reste d'acide aliphatique ramifié eno(
et présentant un encombrement stérique important ou un res
te d'acide cycloalcanoique, et - R présente la même signification que celle définie au
préalable.

Ascorbic acid derivatives represented by general formula (I) are prepared, for example, according to one of the following reaction schemes

scheme in which - X represents a halogen atom, - R4CO represents a branched aliphatic acid residue eno (
and exhibiting a significant steric hindrance or a res
te of cycloalkanoic acid, and - R has the same meaning as defined in
prior.

diagram in which - R5CO represents a residue of aliphatic acid which is not
branched in position or a residue of rami aliphatic acid
trusted in &alpha; and exhibiting low steric hindrance, and - R2 and X respectively have the same meanings
than those defined in advance.

In reaction schemes (iii) to (vi), each R6CO group represents a residue, containing from 2 to 18 carbon atoms, of linear or branched elkanoic acid, a residue of cycloalkanoic acid or a residue of acid. carboxylic aryl, and R, R,
R3 and X have, respectively, the same meanings as those defined beforehand.

According to the reactions of the reaction schemes
(i) and (ii), an acyl halide is reacted with 5,6-isopropylideneascorbic acid, in order to acylate the hydroxyl groups in positions 2 and 3 of the ascorbic acid, thus making it possible to obtain l 2,3-diacyl-5,6-isopropylidene ascorbic acid, after which an acid catalyst is reacted to remove the isopropylidene group, in order to obtain the 2,3-di-O-acylascorbic acid derivatives (Ia) Yes B)
Note that the process of the acylation reaction of 5,6-isopropylideneascorbic acid, at positions 2 and 3, varies depending on the type of acylating agent. If the acylating agent is a halide of an acid aliphatic branched in i and having a large steric hindrance or a cycloalkanoic acid halide, the hydroxyl group in position 3 is first acylated and, then, the hydroxyl group in position 2 is acylated (reaction scheme (i)).

On the other hand, if the acylating agent used is a halide of an aliphatic acid unbranched in position or of an aliphatic acid branched in and having a small steric hindrance, the hydroxyl group in position 3 is first acylated and this group acyl is transposed to the hydroxyl group in position 2. Then, position 3 where
the hydroxyl group was formed as a result of the transposition being acylated (reaction scheme (ii)).

In cases where 2,3-di-0-acylascorbic acid derivatives are prepared in which the acyl groups in positions 2 and 3 are identical, it suffices to react an acylating agent with 5,6-isopropylideneascorbic acid, in an amount of two or more moles per mole of the acid, according to reaction scheme (ii).

On the other hand, when preparing compounds in which the acyl groups in positions 2 and 3 are different, two different types of acylating agents are used which are reacted successively, in accordance with reaction scheme (i) or (ii) ).

Reaction schemes (iii) to (vi) relate to the preparation of a 2,3,6-tri-0-acylascorbic acid.

More particularly, (iii) a branched acyl in O (, halogenated) is reacted with ascorbic acid or a 6-0-acylascorbic acid, in order to obtain a 2,3-di (acyl branched in d) - 6-O-acylascorbic (Ic). Note that the expression "branched acyl in O (" is intended to encompass the meaning cycloalkanoyl and this whenever it appears below. (Iv) A branched acyl is reacted in , halogenated, with 6-O-acylascorbic acid, to subject the hydroxyl group in position 3 alone to selective acylation to introduce a branched acyl group in, and followed by reaction with halogenated acyl, which allows thus obtaining a 2,3,6-tri-0-acylascorbic acid (Id), in which at least the hydroxyl group in position 3 is converted into the branched acyl group in. (v) A branched acyl is reacted in , halogenated, with 2,6-di-O-acylacor bic acid, in order to obtain a 2,3,6-tri-0-acyl-ascorbic acid (Ie), which has, in position 3, the acyl group e branched into o (. (vi) A halogenated acyl is reacted with a 2,3-di-O-acylascorbic acid, in order to obtain a 2,3,6-O-acylascorbic acid (Id).

It is preferred that the acyl halides serving as acylating agents in Reaction Schemes (i) to (vi) are acid chlorides and acid bromides.

The solvents for the acylation reaction should preferably be halogenated alkanes, such as dichloromethane, chloroform, dichloroethane and the like. The use of organic bases, such as pyridine, as catalysts is preferred from the viewpoint of yield. The reaction temperature is 0 to 40 C, and the reaction time may depend on the types of acylating agents and solvents used in the reaction and is preferably in the range of 30 minutes to 5 hours.

To remove the isopropylidene group from 2,3-di-0-acyl-5,6-isopropylideneascorbic acid, in reaction schemes (i) and (ii), it is preferred to react an inorganic acid, such as acid. hydrochloric or sulfuric acid; with the acid, in an alcoholic solvent, such as methanol, ethanol or the like, at a temperature of 0 to 300C.

The branched aliphatic acids, which are used as starting materials, can be prepared by a process which consists in subjecting a linear or branched aldehyde, containing 7 to 10 carbon atoms, to aldol condensation, in order to obtain an aldehyde. unsaturated branched in, followed by hydrogenation and oxidation, to obtain a branched saturated aliphatic acid. The branched saturated aliphatic acid prepared by the above process, which is most readily available, is a branched aliphatic acid containing 18 carbon atoms and, more particularly, 5,7,7-trimethyl-2 (1,3,3-trimethylbutyl) -octanoic acid, which is obtained by subjecting the dimer of isobutylene to an oxo reaction , resulting in a branched aldehyde containing 9 carbon atoms, then subjecting the branched aldehyde to aldol condensation, resulting in a branched unsaturated aldehyde containing 18 carbon atoms, followed by hydrogenation and oxidation. This octanoic acid is marketed by "Nissan Chem. Co., Ltd." and is referred to simply as NK-isostearic acid.

Alternatively, one can prepare the branched aliphatic acids enO (by subjecting a primary alcohol, linear or branched, containing 7 to 10 carbon atoms, to the Guerbet reaction, which gives a branched alcohol by and oxidizing the alcohol The branched saturated aliphatic acid obtained by the above process, which is most readily available, is 2-heptylundecanoic acid, which is obtained by subjecting nonyl alcohol to the reaction of
Guerbet, followed by an oxidation reaction [and it is marketed by "Mitsubishi Chemical Industries
Limited "and is referred to simply as ritual MK-isostea acid
5,6-Isopropylideneascorbic acid, which is another starting substance, is prepared by reaction between ascorbic acid and acetone, in acetyl chloride [ME Jung and TJ Shaw, J. An. Chem. Soc., 102, 6304 (1980) and K. Jackson and J. Jones, Can. J. Chem., 47, 2498 (1969)].

Ascorbic acid, the hydroxyl group of which at positions 2 and / or 6 is acylated and which is useful as a starting material in reaction schemes (iii) to (v) is prepared according to known methods. Further, 2,3-di-0-acylascorbic acid, which is a starting substance in reaction scheme (vi), is prepared according to reaction scheme (i) or (ii).

The resulting ascorbic acid derivatives according to the present invention do not undergo staining with time and are stable in an oxidizing atmosphere with high vitamin C activity. Consequently, cosmetic products comprising these derivatives are very stable in aqueous systems without causing discoloration, unpleasant odor and decreased activity, and they exhibit good vitamin C activity.

The present invention is described by way of examples.

Example 1
5,6-Isopropylideneascorbic acid (5.40 g, 25.0 mmol) is dissolved in a mixed solvent of dry pyridine (20.2 ml) and methyl chloride (250 ml), in which a solution, in methylene chloride (40 ml), NK-isostearic acid chloride (15.1 g, 50.0 mmol) is added dropwise over 35 minutes. After completion of the dropwise addition, the mixture was stirred for 2 hours, followed by washing with dilute hydrochloric acid and water, in that order, and drying over sulfate. of anhydrous sodium. The solvent is removed by distillation under reduced pressure and the resulting oily substance is subjected to chromatography on a column of silica gel, whereby 2,3-di (NK-isostearoyl) -5.6 acid is obtained. -isopropylideneascorbic (17.7 g, yield: 94%).

Elemental analysis:
Calculated for C45H8008: C72.15%, H 10.76%
Found: C 72.2%, H 10.8%
Mass spectrum (20 eV)
733 ($ 2.0, M ± CH), 155 (17.9),
127 (22.7), 121 (18.1), 113 (22.3), 99 (19.3),
85 (18.6), 71 (17.9), 57 (100)
EtOH UV # (log #) 223.1 mm (4.04)
max
Undiluted IR)
2960, 2920, 2875, 1790, 1780, 1705, 1470,
1365, 1205, 1110, 1070 cm-1 13C-NMR 25MHz # ppm (CDCl3)
170.8 (s), 170.3 (s), 165.2 (s, Cl), 152.2 (s,
C3), 122.6 (s, C2), 110.8 (s), 75.4 (d, C4),
72.9 (d, C5), 65.4 (t, C6), alkyl moieties omitted 1H-60MN NMR # #ppm (CDCl3)
5.33 (m, 1H, C4- H), 4.0 - 4.4 (m, 3H), 0.8
2.7 (m, 76H)
In the same manner as described above, 2,3-di- (MK-isostearoyl) -5,6-isopropylideneascorbic acid (yield: 97%), 2,3- acid was prepared. di (2-ethylhexanoyl) -5,6-isopropylideneascorbic (yield: 91%), 2,3-di (2-ethylbutanoyl) -5,6-isopropylideneascorbic acid (yield: 92%), acid 2, 3-di (isobutanoyl) -5,6-isopropylideneascorbic (yield: 77%), 2,3-di (cyclohexanoyl) -5,6-isopropylideneascorbic acid (yield: 96%), and 2,3 -di (pivaloyl) -5,6-isopropylideneascorbic
(yield: 79%). Of these, 2,3-di (2-ethylbutanoyl) -5,6-isopropylideneascorbic acid and 2,3-di (pivaloyl) -5,6-isopropylideneascorbic acid have were isolated and purified by recrystallization. The physical properties of the products are shown in Tables 1, 2 and 3.

Example 2
2-Acetyl-3-pivaloyl-5,6-isopropylideneascor bic acid
(i) 5,6-Isopropylideneascorbic acid (10.8 g, 50.0 mmol) was suspended in a mixed solvent of dry pyridine (40.4 ml) and methylene chloride (750 ml) , wherein a solution of pivalic acid chloride (6.02g, 49.9mmol) in methylene chloride (50ml) was added dropwise over 41 minutes. During the dropwise addition, the reaction temperature was 22-260C. After the completion of the dropwise addition, the mixture was stirred for 2 hours, after which a solution of acetyl chloride ( 3.97g, 50.6mmol) in methylene chloride (50ml) was added dropwise over 3 minutes, followed by stirring for a further 1 hour. Then, the reaction solution was washed with dilute hydrochloric acid, water and brine, in that order, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain crystals. The crystals were recrystallized from a mixed benzene-hexane solvent, in order to obtain 6.58 g of the compound designated in the title of this example. The mother liquor was subjected to chromatography on silica gel, in order to obtain 2.85 g of the compound named in the title of this example (9.43 g in total, yield: 55%) and 2,3-dipivaloyl-5,6-isopropylideneascorbic acid (1.59 g, yield: : 8%).

2-acetyl-3-pivaloyl-5,6-isopropylidèneas acid
goat.

Colorless needle crystals with a melting point of 96 to 97 "C.

Elemental analysis: Calculated for C16H2208: C56.13%, H 6.48%
Found: C 56.13%, H 6.50%
Mass spectrum (20eV)
327 (16.5%, M ± CH3), 243 (6.7), 216 (12.7),
200 (21.6), 101 (31.0), 85 (17.9), 59 (8.2),
57 (100)
EtOH
UV # (log #) 221 nm (4.02)
max
IR # (KBr)
3000, 2950, 1765, 1695, 1370, 1200, 1150,
1115, 1075cm-1
13C-NMR 25MHz #ppm (CDCl3)
172.6 (s), 165.9 (s), 165.5 (s, Cl), 151.3 (s,
C3), 122.1 (s, C2), 110.8 (s), 75.4 (d, C4),
73.3 (t, C5), 65.4 (t, C6), 39.5 (s), 26.9
(q), 25.8 (q), 25.5 (q), 20.0 (q)
1H-NMR 60MHz # ppm (CDCl3)
5.11 (m, 1H, C4-H), 4.0 - 45 (m, 3H), 2.22
(s, 3H), 1.36 (s, 3H), 1.33 (s, 3H), 1.30 (s,
9H)
(ii) 5,6-Isopropylideneascorbic acid (5.409, 25.0 mmol) was suspended in a mixed solvent of dry pyridine (20.2 ml) and methylene chloride (250 ml). While the reaction temperature was maintained at 6 to 9 OC, a solution of acetyl chloride (1.94 g, 24.8 mmol) in methylene chloride
(25 mL) was added dropwise over 15 minutes. After the addition made dropwise, the reaction mixture was stirred at room temperature for 1 hour and 10 minutes. The reaction solution was cooled and maintained at 90 ° C. in which a solution of pivalic acid chloride (3, 8 g, 25.6 mmol) in methylene chloride
(25 mL) was added dropwise over 10 minutes. Then, the reaction solution was stirred, at room temperature, for 3.5 hours, followed by washing with dilute hydrochloric acid, water and brine, in that order. , and drying over anhydrous sodium sulfate. The solvent was removed by distillation, to obtain an oil, which was then subjected to column chromatography on silica gel, in order to isolate the compound named in the title of this example (3.38 g, yield: 39%) together with a by-product consisting of 2,3-dipivaloyl-5,6-isopropylideneascorbic acid (0.81 g, yield: 8%) .

Example 3
2-isobutanoyl-3-pivaloyl-5,6-isopropylidene acid
ascorbic
5,6-Isopropylideneascorbic acid (5.40 g, 250.0 mmolen was suspended in a mixed solvent of dry pyridine (20.2 ml) and methylene chloride (200 ml, in which a solution of pivalic acid chloride (3.08g, 25.6mmol) in methylene chloride (25ml) was added dropwise over 10 minutes.During the dropwise addition, the reaction temperature was in the range of 21 to 240 C. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours, followed by a dropwise addition of a solution of isobutyric acid chloride (2.80 g, 26.2 mmol9 in methylene chloride (25 ml) over 13 minutes, during which time the reaction temperature was in the range of 23 to 250C.

After the dropwise addition, the reaction mixture was stirred, at room temperature, for 2.5 hours and washed first with dilute hydrochloric acid and then with water, and the mixture was washed. followed by drying over anhydrous sodium sulfate. The solvent was removed by distillation, in order to obtain an oil, and the oil was subjected to separation chromatography on a silica gel column, in order to obtain the compound designated in the title of this example ( 5.30 g, yield: 57%) and 2,3-diisobutanoyl-5,6-isopropylideneascorbic acid (0.45 g, yield: 5%) as a by-product.

2-Isobutanoyl-3-pivaloyl-5,6-isopropylideneascorbic acid.

Elemental analysis:
Calculated for C18H2608: C 58.37%, H 7.08%
Found: C 58.36%, H 7.14%
Mass spectrum (20eV)
341 (10.5%, M ± 15), 298 (6.5), 229 (5.5), 228
(42.9), 101 (17.4), 72 (5.8), 71 (100), 43
(35.6)
EtOH
UV # (log #) 222.1 nm (4.02)
max
IR # (undiluted)
2990, 2950-, 2900, 1780, 1700, 1465, 1370,
1270, 1200, 1130, 1120, 1080, 1060, 1020cm-1
13C- 25MHz NMR # ppm (CDCl3)
172.5 (s), 172.2 (s), 165.6 (s, C1), 151.1 (s,
C3), 122.2 (s, C2), 110.8 (s), 75.4 (d, C4),
73.3 (d, C5), 65.4 (t, C6), 39.4 (s), 33.7
(d), 26 9 (q), 25.8 (q), 25.5 (q), 18.8 (q)
1H-NMR 60MHz 3 ppm (CDCl3)
5.09 (d, J = 2.0Hz, 1H, C4 - H), 4.0 - 4.5 (m,
3H), 2.77 (sep, J = 6.9Hz, 1H), 1.38 (s, 3H),
1.32 (s, 3H), 1.28 (s, 9H), 1.24 (d, J = 6.9Hz,
6H)
Example 4
2-0-Benzoyl-3-0-pivaloyl-5,6-0,0-isopropyli acid
dene-L-ascorbic:
5.6-0.0-Isopropylidene-L-ascorbic acid (2.16 g, 10.0 mmol) was dissolved in a mixture of methylene chloride (150 mL) and dry pyridine (8.07 ml) in which a solution of pivalic acid chloride (1.329, 11.0 mmolX in methylene chloride (15 ml) was added dropwise over 14 minutes. Benzoic acid (1.55g, 11.0mmol in methylene chloride (15ml) was added dropwise to the reaction mixture, over 16 minutes. After stirring for a further 2 hours, the mixture was washed with cold dilute hydrochloric acid and water, in that order, and dried over sodium sulfate. The solvent was removed by distillation and the resulting residue was subjected to silica gel column chromatography, in order to obtain 2-0-benzoyl-3-0-pivaloyl-5,6-0,0-isopropylidene-L-ascorbic acid (3.04 g, yield: 75%).

Melting point: 117-1180C
Elemental analysis
Calculated for C21H2408: C 62.37%, H 5.98%
Found: C 62.34%, H 5.96%
EtOH
Uv 2L 232.8 nm (log # 4.34)
max IR # (KBr)
2986, 1779, 1743, 1716, 1602, 1353, 1254,
1140, 1116, 1074, 1050, 1020, 1005, 714cm-1
13C- 25MHz NMR # ppm (CDCl3)
172.7 (s), 165.6 (s, C1), 161.9 (s), 151.7 (s,
C3), 134.3 (d), 130.6 (d), 128.8 (d), 127.5
(s), 122.4 (s, C2), 110.8 (s), 75.6 (d, C4),
73.2 (d, C5), 65.5 (t, C6), 39.5 (s), 26.9
(q), 25r8 (q), 25.5 (q) 1H- RMM 60MHz #ppm (CDCl3)
8.0 - 8.3 (m, 2H), 7.2 - 7.8 (m, 3H), 5.20 (d,
J = 1.5Hz, 1H, C4-H), 4.0 - 4.5 (m, 3H), 1.42
(s, 3H), 1.36 (s, 3H), 1.27 (s, 9H) Table 1
Elemental Analysis, Melting Point and UV Absorption

<SEP> Group <SEP> Acyle <SEP> Calculated <SEP> (%) <SEP> Found <SEP> (%) <SEP> Point <SEP> of <SEP>#EtOH (log #)
<tb><SEP> C <SEP> H <SEP> C <SEP> H <SEP> Merge (C)
<tb> 2,3-di <SEP> (NK-isostearoyl) <SEP> 72.15 <SEP> 10.76 <SEP> 72.2 <SEP> 10.8 <SEP> oil <SEP> 113.1 (4.04)
<tb> 2,3-di <SEP> (MK-isostearoyl) <SEP> 72.15 <SEP> 10.76 <SEP> 71.87 <SEP> 10.87 <SEP> oil <SEP> 222.9 (4.03)
<tb> 2,3-di <SEP> (2-ethylhexanoyl) <SEP> 64.03 <SEP> 8.60 <SEP> 63.97 <SEP> 8.64 <SEP> oil <SEP> 221.3 (4.06)
<tb> 2,3-di <SEP> (2-ethylbutanoyl) <SEP> 61.15 <SEP> 7.82 <SEP> 61.14 <SEP> 7.79 <SEP> 83-85.5 <SEP > 221.3 (4.05)
<tb> 2,3-diisobutanoyl <SEP> 57.30 <SEP> 6.79 <SEP> 57.10 <SEP> 6.81 <SEP> oil <SEP> 222.1 (4.02)
<tb> 2,3-dicyclohexanoyl <SEP> 63.29 <SEP> 7.39 <SEP> 63.53 <SEP> 7.69 <SEP> oil <SEP> 222.3 (4.01)
<tb> 2,3-dipivaloyl <SEP> 59.36 <SEP> 7.34 <SEP> 59.22 <SEP> 7.39 <SEP> 111.5-112.5 <SEP> 221 <SEP> ( 4.01)
<tb> 2-acetyl-3-pivalyl <SEP> 56.13 <SEP> 6.48 <SEP> 56.13 <SEP> 6.50 <SEP> 96 <SEP> - <SEP> 97 <SEP> 221 <SEP> (4.02)
<tb> 2-isobutanoyl-3-pivaloyl <SEP> 58.37 <SEP> 7.08 <SEP> 58.36 <SEP> 7.14 <SEP> oil <SEP> 22.1 <SEP> (4, 02)
<tb>
Table 2
Spectrum of
Mass (20 eV)
Acyl group m / e (%)
2,3-di (NK- 733 (2.0, M + - 15), 155 (17.9), 127 (22.7),
isostearoyl) 121 (18.1), 113 (22.3), 112 (15.8), 101
(136), 99 (19.3) 85 (18.6), 71 (17.9),
57 (100)
2,3-di (MK- 733 (10.2, M + - 15), 425 (17.1), 424 (64.6),
isostearoyl) 268 (12.0), 266 (60.6), 240 (19.1), 239
(100), 101 (27.0), 85 (12.6), 71 (13.4),
57 (10.3)
2,3-di (2-ethyl- 453 (15.1, M + - 15), 327 (5.9), 285 (7.8),
hexanoyl) 284 (49.4), 128 (8.3), 127 (94.6), 101
(19.8), 100 (7.5), 99 (100), 57 (81.4)
2,3-di (2-ethyl- 397 (3.4, M + - 15), 101 (11.3), 99 (60.1), butanoyl) 98 (100), 88 (30.9), 84 (38.1), 71 (72.8),
58 (21.8), 55 (39.8), 43 (20.1) 2,3-diiso- 341 (10.5, M + - 15), 298 (6.5), 229 (5.5) , butanoyl 228 (42.9), 101 (17.4), 72 (58), 71 (100),
43 (35.6) 2,3-dicycl- 421 (10.4, M + - 15), 311 (6.0), 269 (8.7), hexanoyl 268 (56.9), 112 (3.9 ), 111 (50.1), 109
(3.5), 101 (14.3), 84 (7.1), 83 (100) 2,3-dipivaloyl 369 (19.0, M + - 15), 326 (12.9), 242 (15 , 4),
216 (22.5), 101 (24.2), 85 (52.3), 57 (100) 2-acetyl- 327 (13.1, M + -15), 242 (4.0), 216 (6 , 2), 3-pivaloyl 200 (11.7), 101 (11.8), 85 (8.6), 59 (5.1),
58 (5.2), 57 (100) 2-isobutanoyl- 355 (18.4, M + - 150, 312 (15.8), 242 (9.2), 3-pivaloyl 228 (30.4), 216 (6.6), 101 (31.9), 85
(33.6), 71 (57.3), 57 (100), 43 (14.3) Table 3 13C-NMR 25MHz #ppm (CDCl3) alkyl moieties omitted

<SEP> Group <SEP> Acyle <SEP> C1 <SEP> C2 <SEP> C3 <SEP> C4 <SEP> C5 <SEP> C6 <SEP> Cisopropylidene
<tb> 2,3-di <SEP> (NK-isostearoyl) <SEP> 165.2 <SEP> 122.6 <SEP> 152.2 <SEP> 75.4 <SEP> 72.9 <SEP> 65 , 4 <SEP> 110.8 <SEP> 25.7 <SEP> 25.5
<tb> 2,3-di <SEP> (MK-isostearoyl) <SEP> 165.4 <SEP> 122.6 <SEP> 152.0 <SEP> 75.4 <SEP> 73.0 <SEP> 65 , 4 <SEP> 110.8 <SEP> 25.7 <SEP> 25.5
<tb> 2,3-di <SEP> (2-ethylhexanoyl) <SEP> 165.3 <SEP> 122.7 <SEP> 152.0 <SEP> 75.4 <SEP> 73.0 <SEP> 65 , 4 <SEP> 110.8 <SEP> 25.7 <SEP> 25.5
<tb> 2,3-di <SEP> (2-ethylbutanoyl) <SEP> 165.3 <SEP> 122.9 <SEP> 152.0 <SEP> 75.4 <SEP> 73.0 <SEP> 65 , 4 <SEP> 110.8 <SEP> 25.7 <SEP> 25.5
<tb> 2,3-diisobutanoyl <SEP> 165.7 <SEP> 122.3 <SEP> 151.0 <SEP> 75.5 <SEP> 73.1 <SEP> 65.4 <SEP> 110.7 <SEP> 25.7 <SEP> 25.4
<tb> 2,3-dicyclohexanoyl <SEP> 165.6 <SEP> 122.4 <SEP> 151.0 <SEP> 75.5 <SEP> 73.3 <SEP> 65.4 <SEP> 110.9 <SEP> 25.5 <SEP> 25.2
<tb> 2,3-dipivaloyl <SEP> 165.4 <SEP> 122.5 <SEP> 151.2 <SEP> 75.4 <SEP> 73.3 <SEP> 65.4 <SEP> 110.8 <SEP> 25.8 <SEP> 25.5
<tb> 2-acetyl-3-pivaloyl <SEP> 165.5 <SEP> 122.1 <SEP> 151.2 <SEP> 75.4 <SEP> 73.4 <SEP> 65.4 <SEP> 110 , 8 <SEP> 25.8 <SEP> 25.5
<tb> 2-isobutanoyl-3-pivaloyl <SEP> 165.6 <SEP> 122.2 <SEP> 151.1 <SEP> 75.4 <SEP> 73.3 <SEP> 65.4 <SEP> 100 , 8 <SEP> 25.8 <SEP> 25.5
<tb>
Example 5
2,3-Di (NK-isostearoyl) -5,6-isopropylideneascorbic acid (19.7 g, 26.3 mmol) was dissolved in ethanol (200 mL), to which acid Concentrated hydrochloric acid (10 mL) was added, followed by stirring at room temperature for 11 hours. Water (400ml) was added to the reaction mixture, which was extracted with methylene chloride (200ml x 2), followed by washing with water (300ml x 1) and then with saline solution (300 ml x 2) and drying over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, to obtain an oil, which was subjected to column chromatography on silica gel treated with silane, to obtain 2,3-di ( NK-isostearoyl) ascorbic (14.9 g, yield: 81%).

Elemental analysis
Calculated for C42H7608: C 71.14%, H 10.80%
Found: C 70.8%, H 10.8%
Mass spectrum (19eV)
708 (1.8%, M +), 268 (20.1), 267 (100), 183
(34.3), 155 (38.0), 141 (21.6), 127 (34.0), @
113 (29.4), 99 (22.2), 57 (63.6)
EtOH
UV # (log #) 221.7 nm (4.03)
max
IR) (undiluted)
3430, 2940, 2910, 2860, 1770, 1700, 1465,
1360, 1195, 1100, 1065cm-1
13C-NMR 25MHz #ppm (CDCl3)
171.1 (s), 170.0 (s), 166.0 (s, C1), 153.1 (s,
C3), 122.8 (s, C2), 77.1 (d, C4), 69.6 (d,
C5), 63.0 (t, C6) fraqments alkyl omitted
1H-NMR 60MHz g ppm (CDCl3)
5.35 (m, 1H, C4-H), 3.6 - 4.2 (m, 3H), 2 9
(1H, OH), 2.6 (1H, OH), 0.7 - 2.1 (m, 70H)
In the same manner as described above, crude products were isolated and purified by chromatography or recrystallization, in order to obtain 2,3-di (NK-isostearoyl) ascorbic acid (yield: 53 %), 2,3-di (2-ethylhexanoyl) ascorbic acid (yield: 94%), 2,3-di (2-ethylbutanoyl) ascorbic acid (yield 100%), acid 2,3-di (isobutanoyl) ascorbic (yield 45%), 2,3-di- (cyclohexanoyl) ascorbic acid (yield: 59%), and 2,3-di (pivaloyl) ascorbic acid (yield: 89%). The physical properties of the products are shown in Tables 4, 5 and 6.

Example 6
2-Acetyl-3-pivaloylascorbic acid:
2-Acetyl-3-pivaloyl-5,6-isopropylideneascorbic acid (8.96 g, 26.2 mmolX was dissolved in methanol (120 ml), to which concentrated hydrochloric acid (10 ml) was dissolved. was added, followed by stirring at room temperature for 2 hours. Water (200ml) was added to the reaction mixture, which was extracted with methylene chloride (100ml x 3). The organic phase was washed with water (200ml x 2) and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the resulting residue (2.88g) was recrystallized from hexaneacetate. ethyl, to obtain 2-acetyl-3-pivaloylascorbic acid (1.79 g, yield: 23%).

Colorless needle crystals, melting point 119-120.50C.

Elemental analysis
Calculated for C 13H1808: C 51.65%, H 6.00%
Found: C 51.63%, H 6.02%
Mass spectrum (70eV)
397 (3.3%), 256 (918), 101 (8.0), 100 (2.8),
99 (40.8), 72 (6.3), 71 (100), 55 (3.8), 43
(29.7)
EtOH
UV # (log #) 222.6 nm (4.02)
max
IR # (KBr)
3400, 2990, 2970, 2900, 1770, 1695, 1210,
1190, 1140, 1100, 1070, 1040cm-1
13C- 25MHz NMR # ppm (CDCl3)
166.7 (s, C1), 152.2 (s, C #), 122.0 (s, C2),
76.9 (d, C4), 69.8 (d, C5), 63.0 (t, C6)
1H- NMR 60MHz # ppm (CDCl3)
5.18 (d, J = 2Hz, 1H, C4 -H), 2.6 - 4.2 (m, 3H),
3.20 (d, J = 6Hz, 1H, OH), 2.79 (broad s, 1H, OH)
2.23 (s, 3H), 1.30 (s, 9H)
Example 7
2-isobutanoyl-3-pivaloylascorbic acid
Isopropylideneascorbic acid (5.40 g, 25.0 mmol was suspended in a mixed solvent of dry pyridine (20.2 ml) and methylene chloride (250 ml), to which a solution, in chloride of methylene (28 mL), isobutyric acid chloride (3.05 g, 28.6 mmol) was added dropwise over 15 minutes. After stirring at room temperature for 1 hour, a solution in chloride of methylene (28 ml), pivalic acid chloride (3.18 g, 26.4 mmol) was added dropwise over 7 minutes The reaction mixture was stirred at room temperature, for 1 hour, washed with chlorine acid
dilute water (1.2N, 250ml x 1) and water (300ml x 2) in that order, and dried over anhydrous sodium sulfate.

The solvent was removed by distillation under reduced pressure, to obtain an oily substance (10.2 g).

This material was dissolved in methanol (75 ml), and concentrated hydrochloric acid (7 ml) was added, followed by stirring at room temperature for 1 hour. After addition of water, the reaction system was extracted with methylene chloride (100 ml x 5). The resulting organic phase was washed with brine and water, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the resulting residue (9.56 g) was recrystallized from hexane-ethyl acetate mixture, in order to obtain 2-isobutanoyl-3-pivaloylascorbic acid (6 , 71 g, yield: 81%).

Colorless needle crystals, melting point 94.5-96.50C.

Elemental analysis
Calculated for C15H2208: C 54.54%, H 6.71%.

Found: C 54.62%, H 6.71%
Mass spectrum (20eV)
246 (6.9%), 228 (11.2), 116 (6.7), 85 (35.0)
71 (100), 57 (92.2), 43 (16.7)
UR EtOH (log e) 2 2 5 min (410 2)
IR # (KBr)
3400, 2980, 2950, 2910, 1760,
1690, 1350, 1200, 1150, 1090,
1065, 1050, 1030, 1010, 970,
755cm-1 13C- NMR 25MHz # ppm (CDCl3)
172.6 (s), 172.5 (s), 166.7 (s, C1),
152.2 (s, C3), 122.0 (s, C2), 76.9
(d, C4), 69.8 (d, C5), 63.0 (t, C6),
39.5 (s), 33.7 (d), 26.9 (q), 18.8
(q) 1H- NMR 270MHz # ppm (CDCl3, in
presence of D2O)
5.20 (d, J = 2.6Hz, 1H, C4 - H), 3.97
(ddd, J = 5.5. 2.6 Hz, 1H, C5
H), 3.85 (ddd, J = 11.7.5.5.5.5Hz,
1H, C6 - H), 3.79 (ddd, J = 11.7,
5.5, 5.5 Hz, C6 - H), 2.80 (hept,
J = 7.0Hz, 1H), 1.30 (s, 9H), 1.20
(d, J = 7.0Hz, 6H)
Example 8
2-0-Benzoyl-3-0-pivaloyl-L-ascorbic acid
2-0-Benzoyl-3-0-pivaloyl-5,6-0,0-isopro-pylidene-L ascorbic acid (2.00 g, 4.95 mmol) was dissolved in a mixed solvent of methanol. (40ml) and ethanol (40ml), to which concentrated hydrochloric acid (1.5ml) was added, followed by stirring at room temperature, for 1.5 hours. Water was added to the reaction mixture, which was extracted with methylene chloride. The resulting organic phase was washed with brine and dried over sodium sulfate. The solvent was removed by distillation and the resulting residue was recrystallized from hexane-ethyl acetate, to obtain 2- acid. 0-Benzoyl-3-0-pivaloyl-L-ascorbic (1.44 g, yield: 72%>.

Melting point: 108.5-109.5 C.

Elemental analysis
Calculated for C18H2008: C 59.34%, H 5.53%
Found: C 59.09%, H 5.57%.

UV #EtOH 23 3.5 nm (log # 4.34) IR # (KBr)
3364, 2986, 1782, 1752, 1695,
1269, 1248, 1158, 1119, 1092,
1026, 708cm-1 13C- NMR 25MHz # ppm (CDCl3)
172.8 (s), 166.4 (s, C1), 162.3 (s), 152.6
(s, C3), 134.3 (d), 130.6 (d), 128.8 (d),
127.4 (s), 122.3 (s, C2), 77.0 (d, C4),
69.7 (d, C5), 62.9 (t, C6), 39.5 (s), 26.8 (q) 1H- NMR 60MHz # ppm (CDCl3)
8.0 ~ 8.2 (m, 2H), 7.2 ~ 7.7 (m, 3H), 5.27
(d, J = 1.8Hz, 1H, C4 - H), 3.7 ~ 4.2 (m, 3H),
3.44 (lerge s, 2H, OH), 1.23 (s, 9H) Table 4
Elemental Analysis - Melting Point and UV Spectrum

<SEP> Calculated <SEP> (%) <SEP> Found <SEP> (%) <SEP> Point <SEP> of <SEP>#EtOH (logE)
<tb><SEP> Group <SEP> Acyle <SEP> C <SEP> H <SEP> C <SEP> H <SEP> merge (C)
<tb> 2,3-di <SEP> (NK-isostearoyl) <SEP> 71.14 <SEP> 10.80 <SEP> 70.8 <SEP> 10.8 <SEP> oil <SEP> 221.7 (4.03)
<tb> 2,3-di <SEP> (MK-isostearoyl) <SEP> 71.14 <SEP> 10.80 <SEP> 71.17 <SEP> 10.64 <SEP> oil <SEP> 222.0 (4.02)
<tb> 2,3-di <SEP> (2-ethylhexanoyl) <SEP> 61.66 <SEP> 8.47 <SEP> 61.58 <SEP> 8.51 <SEP> oil <SEP> 221.6 (4.04)
<tb> 2,3-di <SEP> (2-ethylbutanoyl) <SEP> 58.05 <SEP> 7.58 <SEP> 57.99 <SEP> 7.71 <SEP> oil <SEP> 221.8 (4.03)
<tb> 2,3-diisobutanoyl <SEP> 53.16 <SEP> 6.37 <SEP> 53.14 <SEP> 6.36 <SEP> 89-90.5 <SEP> 223.3 (4.02 )
<tb> 2,3-dicyclohexanoyl <SEP> 60.59 <SEP> 7.12 <SEP> 60.28 <SEP> 7.15 <SEP> 80.5-82 <SEP> 222.6 (4.04 )
<tb> 2,3-dipivaloyl <SEP> 55.81 <SEP> 7.02 <SEP> 56.58 <SEP> 7.11 <SEP> 116-117 <SEP> 222.2 (3.99)
<tb> 2-acetyl-3-pivaloyl <SEP> 51.65 <SEP> 6.00 <SEP> 51.63 <SEP> 6.02 <SEP> 119-120.5 <SEP> 222.6 (4 , 02)
<tb> 2-isobutanoyl-3-pivaloyl <SEP> 54.54 <SEP> 6.71 <SEP> 54.62 <SEP> 6.71 <SEP> 94.5-96.5 <SEP> 222.5 (4.02)
<tb>
Table 5
Mass spectrum (20 eV) * 19 eV ** 70 eV
Acyl group m / e (%)
2,3-di (NK- 693 (8.0), 268 (20.1), 267 (1.00), 183
isostearoyl) * (34.3), 169 (18.9), 155 (38.0), 141 (21.6),
127 (34.0), 113 (29.4), 99 (22.2), 85 (17.1),
57 (63.6)
2,3-di (MK- 709 (0.3, M +), 267 (64.9), 239 (100),
isostearoyl) 186 (53.7), 171 (38.2), 158 (95.8), 129
(42.8), 98 (37.9), 85 (40.3), 73 (36.8),
71 (51.6), 57 (49.3)
2,3-di (2-ethyl- 284 (3.0), 187 (5.7), 128 (8.1), 127 (100),
hexanoyl) 116 (3.2), 101 (4.3), 100 (4.9), 99 (71.8),
73 (7.8), 57 (67.1), 55 (3.7)
2,3-di (2-ethyl-256 (6.9), 171 (1.6), 159 (8.2), 154 (15.4), butanoyl) 101 (2.6), 100 (6 , 7), 99 (100), 98 (1.3),
72 (5.9), 71 (96.0), 70 (1.2), 43 (4.5) 2,3-diiso- 298 (1.2, M + - 18), 229 (1.6) , 228 (10.0), butanoyl 131 (8.1), 116 (1.3), 72 (4.7), 71 (100),
70 (1.3), 44 (1.5), 43 (26.8) 2,3-dicyclo- 128 (34.1), 111 (23.6), 110 (18.7), 99 hexanoyl ( 18.9), 83 (100), 73 (58.6), 69 (19.8),
68 (37.6), 56 (32.2), 55 (62.8), 41 (18.1), 2,3-dipivaloyl 242 (3.1), 86 (22.0), 68 (5 , 3), 58 (4.9),
57 (100), 56 (26.6), 55 (2.0), 42 (1.8), 41 (11.6) 2-acetyl- 397 (3.3), 299 (2.3), 256 (9.8), 101 (8.0), 3-pivaloyl ** 100 (2.8), 99 (40.8), 72 (6.3), 71 (100),
55 (3.8), 43 (29.7), 41 (4.7) 2-isobutanoyl- 246 (6.9), 228 (11.2), 158 (5.2), 116 3-pivaloyl ( 6.7), 85 (35.0), 72 (4.7), 71 (100), 58
(4.3), 57 (92.2), 43 (15.7) Table 6 13C- 25MHz NMR # ppm (CDCl3) *: 67.5 MHz Alkyl fragments omitted

<SEP> Group <SEP> Acyle <SEP> C1 <SEP> C2 <SEP> C3 <SEP> C4 <SEP> C5 <SEP> C6
<tb> 2,3-di <SEP> (NK-isostearoyl) <SEP> 166.0 <SEP> 122.3 <SEP> 153.1 <SEP> 77.1 <SEP> 69.6 <SEP> 63 , 0
<tb> 2,3-di <SEP> (MK-isostearoyl) <SEP> 166.0 <SEP> 122.9 <SEP> 152.8 <SEP> 77.1 <SEP> 69.7 <SEP> 63 , 0
<tb> 2,3-di <SEP> (2-ethylhexanoyl) <SEP> 166.4 <SEP> 122.8 <SEP> 153.0 <SEP> 77.1 <SEP> 69.6 <SEP> 63 , 0
<tb> 2,3-di <SEP> (2-ethylbutanoyl) * <SEP> 166.2 <SEP> 122.9 <SEP> 153.0 <SEP> 77.0 <SEP> 69.5 <SEP> 63.0
<tb> 2,3-diisobutanoyl <SEP> 166.3 <SEP> 122.1 <SEP> 151.9 <SEP> 76.8 <SEP> 69.7 <SEP> 62.9
<tb> 2,3-dicyclohexanoyl <SEP> * <SEP> 166.6 <SEP> 122.9 <SEP> 151.8 <SEP> 76.7 <SEP> 69.6 <SEP> 62.9
<tb> 2,3-dipivaloyl <SEP> * <SEP> 166.2 <SEP> 122.6 <SEP> 152.4 <SEP> 76.8 <SEP> 69.9 <SEP> 62.8
<tb> 2-acetyl-3-pivaloyl <SEP> 166.7 <SEP> 122.0 <SEP> 152.2 <SEP> 76.9 <SEP> 69.8 <SEP> 63.0
<tb> 2-isobutanoyl-3-pivaloyl <SEP> 166.4 <SEP> 122.1 <SEP> 152.1 <SEP> 76.8 <SEP> 69.8 <SEP> 62.9
<tb>
Example 9
253,6-Tri-O- (NK-isostearoyl) -L-ascorbic acid
L-Ascorbic acid (1.76g, 10mmol) was suspended in a mixed solvent of methylene chloride (200ml) and dry pyridine (16.2ml) and cooled on a bath of. frozen water. An acid chloride solution
NK-isostearic (12.1 g, 40 minol) in methylene chloride (50 ml) was added dropwise to the mixture over 25 minutes during which time the reaction temperature was maintained at a value of 3 at 50C. After completion of the dropwise addition, the reaction system was stirred again, at room temperature, over a period of 3 days. The reaction solution was washed with water (100ml x 1), 1.2N hydrochloric acid (100ml x 2), water (100ml x 1) and brine (200 ml x 2) in that order, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the resulting residue was subjected to silica gel column chromatography, to obtain 2,3,6-tri-0- (NK-isostearoyl) acid. -L-Ascorbic (8.08 g, yield: 83%).

Elemental analysis
Calculated for C60H11009: C 73.87%, H 11.37%
Found: C 74.2%, H 11.5% UV #EtOH (log #) 221.5 nm (4.05) IR # (undiluted)
3460, 2955, 2900, 2860, 1790,
1770, 1735, 1705, 1460, 1360,
1105, 1065 cm-1 13C- NMR 25MHz # ppm (CDCl3)
175.6 (s), 170.9 (s), 170.3 (s), 165.3 (s, C1),
152.5 (s, C3), 123.1 (s, C2), 77.1
(d, C4), 67.6 (d, C3), 64.3 (t, C6),
Alkyl fragments omitted 1H- NMR 60MHz # ppm (CDCl3)
5.34 (m, 1H, C4-H), 3.9 ~ 4.5 (m, 3H),
0.8 ~ 2.6 (m, 106H)
Example 10
2,3,6-Tri-0- (MK-isostearoyl) -L-ascorbic acid
L-ascorbic acid (1.76 g, 10 mmo) es) was suspended in a mixed solvent of methylene chloride (280 ml) and dry pyridine (25.8 ml) and cooled on a bath. ice water A solution of acid chloride
MK-isostearic (9.69 g, 31.9 mmol) in methylene chloride (50 ml) was added dropwise to the mixture over 30 minutes, during which time the reaction temperature was maintained at a value of 3.5 to 4.50C. After completion of the dropwise addition, the mixture was stirred at room temperature, for 6 hours, followed by washing with 1.8N hydrochloric acid (200ml x 1). , water (200 ml x 2) and saline solution (200 ml x 1), in that order, and by drying over anhydrous sodium sulfate. The solvent is removed by distillation under reduced pressure and the resulting oil was subjected to column chromatography on silica gel treated with silicone, to obtain 2,3,6-tri0- (MK-isostearoyl) -L-ascorbic acid (5.26 g, yield: 54 %).

Elemental analysis
Calculated for C60H11009: C 73.87%, H 11.37%
Find ; C 73.2, H 11.2%.

UV #EtOH (log #) 221.4 nm (3.98) IR # (undiluted)
3450, 2960, 2930, 2860,
1790, 1770, 1740, 1710, 1460,
1110 cm-1
13C- 25MHz NMR # ppm (CDCl3)
176.5 (s), 171.7 (s), 170.7 (s), 165.5 (s, C1),
152.1 (s, C3), 123.0 (s, C2), 76.4 (d,
C4), 67.6 (d, C5), 64.3 (t, C6)
Alkyl fragments omitted 1H- @ NMR 60MHz # ppm (CDCl3)
5.26 (m, 1H, C4-H), 3.9 ~ 4.5 (m, 3H),
0.6 ~ 2.8 (m, 106H)
Example 11
2,3,6-Tri-0- (2-ethylhexanoyl) -L-ascorbic acid
L-ascorbic acid (3.57g, 20.3mmol) was suspended in a mixture of methylene chloride (200ml) dry pyridine (10ml) and cooled on an ice water bath. Then, a solution of 2-ethylhexanoic acid chloride (10.2 g, 62.9 mmol) in methylene chloride (50 mL) was added dropwise to the mixture over 35 minutes. After completion of the dropwise addition, the mixture was stirred for 30 minutes and the cooling bath was removed, followed by further stirring, at room temperature, for 70 hours. The reaction mixture was then washed with 0.6N hydrochloric acid (100ml x 3), water (200ml x 1) and brine (200ml x 1 and 400ml x 1), in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting oil was subjected to silica gel column chromatography, to obtain acid 2, 3,6-tri-0- (2-ethylhexanoyl) -L-ascorbic (3.369, yield: 30%).

Elemental analysis
Calculated for C30H5009: C 64.96%, H 9.09%
Found: C 64.31%, H 9.36%.

UV #EtoH (log #) 221.1 nm (3.96)
IR # (undiluted)
3450, 2960, 2940, 2870, 1770,
1740, 1705, 1460, 1380, 1330,
1200, 1170, 1110, 1090, 1070,
940 cm-1 13C- NMR 25MHz #ppm (CDCl3)
176.4 (s), 171.7 (s), 170.7 (s), 165.8 (s, C1),
152.3 (s, C3), 123.1 (s, C2), 76.5
(d, C4), 67.5 (d, C5), 64.2 (t, C6),
Alkyl fragments omitted 1H- NMR 60MHz # ppm (CDCl3
5.30 (m, 1H, C4-H), 4.6 ~ 3.9 (m, 3H),
2.7 ~ 2.0 (m, 2H), 2.0 ~ 0.7 (m, 44H)
Example 12
2,3-Di-0- (2-ethylbutanoyl) -6-0-stearoyl-L-as acid
corbic
6-0-Stearoyl-L-ascorbic acid (4.43 g, 10.0 mmol) was dissolved in a mixed solvent of methylene chloride (150 ml) and dry pyridine (8.07 ml), wherein a solution of 2-ethylbutanoic acid chloride (2.75g, 20.4mmol) in methylene chloride (60ml) was added dropwise over 18 minutes at reaction solution temperature from 22 to 250C. After stirring at room temperature for 2 hours, the reaction solution was charged into 0.4N hydrochloric acid (300 ml). The resulting organic phase was separated and the aqueous phase was extracted with methylene chloride (50ml x 1). The organic phases were combined, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the resulting oil was subjected to column chromatography. silica gel, in order to obtain 2,3-di-û- (2-ethylbutanoyl) -6-Q-stearoyl-L-ascorbic acid (2.89 g, yield: 45).

Elemental analysis
Calculated for C36H62ûg: C 67.68%, H 9.78%
Found: C 67.59%, H 9.76% UV #EtOH (log #) 220.7 (4.03)
IR # (KBr)
3420, 2924, 2852, 1798, 1780, 1740,
1702, 1466, 1170, 1122, 1062, 882 cm-1 13C- NMR 25MHz # ppm (CDCl3)
173.8 (s), 171.5 (s), 170.4 (s), 165.6 (s, C1),
152.3 (s, C3), 123.0 (s, C2), 76.5 (d, C4),
67.4 (d, C5), 64.3 (t, C6)
Alkyl omitted fragments 1H-NMR 60MHz # ppm (CDCl3)
5.31 (m, 1H, C4-H), 4.5 ~ 3.9 (m, 3H),
2.67 (broad s, 1H, OH), 2.6 ~ 2.2 (m, 4H),
2.0 ~ 0.7 (m, 53H)
Example 13
2-0-Benzoyl-3-0-pivaloyl-6-0-stearoyl-L-as- acid
corbic
6-0-Stearoyl-L-ascorbic acid (4.43 g, 10.0 mmolX was dissolved in a mixed solvent of methylene chloride (150 ml) and dry pyridine (10 ml), in which a solution of pivalic acid chloride (1.27 g, 10.6 mmol) in methylene chloride (20 ml) was added dropwise over 25 minutes. After stirring at room temperature for 1 hour a solution of d chloride Benzoic acid (1.49 g, 10.6 mmol in methylene chloride (20 ml) was added over 15 min. The reaction mixture was further stirred at room temperature, for 2 hours, and washed with 1 min. 'chloric acid
Cold dilute oxyhydrogen. The dilute hydrochloric acid phase was extracted with methylene chloride (50 ml x 1), and the extract was combined with the organic phase. After washing with water and brine, the organic phase was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain a solid. The solid substance thus obtained was subjected to column chromatography on silica gel, in order to obtain 2-0-benzoyl-3-0 pivaloyl-6-0-stearoylascorbic acid (1.85 g, yield: 29%), 2,3-di-0-benzoyl-6-0-stearoylascorbic acid (0.37 g, yield: 6%) and 2,3-di-0-pivaloyl-6 acid -0-Stearoylascorbic (0.179, yield: 3%).

Elemental analysis
Calculated: C 66.85%, H 9.57%
Found: C 66.87%, H 9.58%
EtOH
UV # (log #) 221.8 (4.00)
max
IR # (undiluted)
3490, 2926, 2854, 1788, 1743, 1710, 1473,
1353, 1257, 1143, 1119, 1083, 1068, 1020,
702 cm-1
13C- 25MHz NMR # ppm (CDCl3)
173.8 (s), 172.5 (s), 165.9 (s, C1), 151.5 (s, C3)
122.5 (s, C2), 76.3 (d, C4), 67.6 (d, C5),
64.3 (t, C6), Alkyl fragments omitted
1H-flMN 60MHz g ppm (CDCl3)
5.18 (m, 1H, C4-H), 4.5 - 3} 9 (m, 3H),
2.36 (t, J = 7Hz, 2H), 1.7 - 0.8 (m, 51H)
Example 14
2,6-Di-0-palmitoyl-3-0-pivaloyl-L-ascorbic acid
2,6-Di-0-palmitoyl-L-ascorbic acid (3.26 g, 4.99 mmol) was dissolved in a mixed solvent of dry pyridine (4.06 ml) and methylene chloride ( 150 ml), in which a solution of pivalic acid chloride (0.656 g, 5.44 mmol) in methylene chloride (20 ml) was added dropwise over 26 minutes. After dropwise addition, the reaction system was stirred, at room temperature, for a further 80 minutes, and washed with cold dilute hydrochloric acid. The resulting aqueous phase was extracted with methylene chloride (50ml x 1) and the extract was combined with the organic phase. The organic phase was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography, in order to 'obtain 2,6-di-0-palmitoyl- 3-0-pivaloylascorbic acid (1.01 g, yield: 27%) and 3,5-di-0-pivaloyl-2,6 acid -di-0-palmitoylascorbic (0.41 g, yield: 10%).

2,6-Di-0-palmitoyl-3-0-pivaloylascorbic acid
Elemental analysis
Calculated for C43H7609: C 70.07%, H 10.39%
Found: C 70.04%, H 10.40%.

EtOH
UV # (log #) 221.8 (4.02)
max
IR 9 (undiluted)
3520, 2924, 2856, 1786, 1744, 1706, 1470,
1174, 1134, 1070, 1018 cm-1
13C NMR 25MHz s ppm (CDCl3)
173.9 (s), 172.7 (s), 169.1 (s), 165.9 (s, C1)
151.3 (s, C3), 122.3 (s, C2), 76.3 (d, C4)
67.7 (d, C5), 64.3 (t, C6)
1H- NMR 60MHz # ppm (CDCl3)
5.17 (m, 1H, C4-H), 4) 5 - 3.9 (m, 3H),
2.7 - 2.1 (m, 4H), 1.8 - 0.7 (m, 75H)
Example 15
6-0- (NK-isostearoyl) -2,3-di-0-pivaloyl-1-ascor acid
goat
2,3-Di-0-pîvaloyl-L-ascorbic acid (3.45 g, 10.0 mmol), prepared in Examples 1 and 4 and dry pyridine (8.07 ml) were dissolved. in methylene chloride (150 mL), and a solution of NK-isostearic acid chloride (3.12 g, 10.3 mmol) in methylene chloride (30 mL) was added dropwise over 16 minutes . After the dropwise addition, the reaction system was stirred at room temperature for 4.5 hours and washed with cold dilute hydrochloric acid. The resulting aqueous phase was extracted with methylene chloride (50ml x 1) and the extract was combined with the organic phase. After washing with water, the organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography, in order to Obtain 6-0- (NK-isostearoyl) -2,3-di-0-p-valoylascorbic acid (2.81 g, yield: 46%).

Elemental analysis
Calculated for: C34H5809: C 66.85%, H 9.57%
Found: C 66.63%, H 9.70% UV #EtOH (log #) 221.6 (4.07) IR # (undiluted) ~
3480, 2960, 2912, 2876, 1792,
1776, 1738, 1482, 1142, 1122,
1070 cm-1 13C- NMR 25MHz # ppm (CDCl3)
178.4 (s), 173.9 (s), 169.8 (s), 165.6 (s, C1),
151.6 (s, C3), 123.0 (s, C2), 76.4 (d, C4),
67.4 (d, C5), 64.4 (t, C6)
Example 16
2-0-Benzoyl-6-0- (2-ethylbutanoyl) -3-0-piva- loyl-L-ascorbic acid
2-0-Benzoyl-3-0-pivaloyl-L-ascorbic acid (61.2 g, 16.8 mmol), prepared in Examples 4 and 8, and dry pyridine (6.78 ml) were dissolved in methylene chloride (300ml), mixture to which a solution of 2-ethylbutanoic acid chloride (2.31g, 17.2mmolX in methylene chloride (30ml) was added dropwise After the dropwise addition, the reaction system was stirred at room temperature for 1.5 hours and washed with cold dilute hydrochloric acid The resulting aqueous phase was extracted with water. methylene chloride (50ml x 1) and the extract was combined with the organic phase. After washing with water, the organic phase was dried over anhydrous sodium sulfate and the solvent was distilled off under The resulting residue was subjected to column chromatography on silica gel, in order to obtain 2-0-benzoyl-6-0- (2-ethylbutanoyl) -3-û-pivaloylascorbic acid (1 , 78 g, yield: 23%) and 2-0-benzoyl-5,6-di 0- (2-ethylbutanoyl) -3-0-pivaloylascorbic acid (0.26 g, yield = 3%).

2-0-Benzoyl-6-0- (2-ethylbutanoyl) -3-0-pivaloyl-ascorbic acid.

Elemental analysis
Calculated for C24H3009: C 62.33%, H 6.54%
Found: C 62.45%, H 6.52%
UV #EtOH 23 2.1 nm 13C- NMR 67.5MHz # ppm (CDCl3)
178.7 (s), 170.5 (s), 165.7 (s, C1), 162.2
(s), 152.1 (s, 3), 134.4 (d), 130.7 (d),
128.8 (d), 127.5 (s), 123.1 (s, C2), 76.4
(d, C4), 67.6 (d, C5), 64.5 (t, C6),
48.4 (d), 39.0 (s), 27.2 (q), 24.6 (t), 11.6 (q) 1H- 60MHz NMR # ppm (CDCl3)
8.2 ~ 8.0 (m, 2H), 7.7 ~ 7.3 (m, 3H), 5.28
(d, J = 1.4Hz, 1H, C4 - H), 4.6-4.0 (m,
3H), 2.44 (tt, J = 6.7Hz, 6.7Hz, 1H),
1.56 (tq, J = 6.7Hz, 6.9Hz, 4H), 1.23 (s,
9H), 0.87 (t, J = 6.9Hz, 6H)
Example 17
The stability of the compounds in accordance with the present invention was estimated according to the following method.

The ascorbic acid derivatives to be tested were each dissolved in acetonitrile. Samples of each solution were, respectively, stored at 500C for 7 days, and exposed to sunlight for 7 days. Both types of samples were subjected to UV analysis and the residues of the derivative in these samples were determined by UV spectral absorbance of the respective samples. The results are shown in Table 7.

Table 7
ABCDEF sample
Concentration 1.48 x 10-4 1.55 x 10-4 1.40 x 10-4 1.46 x 10-4 1.44 x 10-4 1.39 x 10-4
(NOT)
Residue (%)
50 C, 7 days 5.5 86.2 93.2 89.6 94.4 96.5
Exposure to 8.9 47.1 86.5 77.8 80.3 94.3 light (3.66J / cm) (3.66J / cm) (3.65J / cm) (3.65J / cm) (3.65J / cm) (3.66J / cm) solar
A: 6-0-monopalmitoylascorbic acid
B: 2,6-di-0-palmitoylascorbic acid
C: 2,3-di-0- (2-ethylbutanoyl) -6-0-stearoyl acid
ascorbic
D: 2,3-di-0-pivaloyl-6-0-stearoylascorbic acid
E: 2,3-di-0-pivaloyl-6-0- (NK-isostearoyl) acid
ascorbic
F: 2,3-di- (NK-isostearoyl) ascorbic acid.

Claims (1)

CLAIM Ascorbic acid derivative represented by the general formula (I)

formula in which R1 represents an alkyl group, linear or branched, ren closing from 1 to 17 carbon atoms, a cycloalkyl group or an aryl group, R2CO represents a residue, containing from 4 to 18 atoms of carbon, branched aliphatic acid eni or a residue cycloalkanoic acid, and R3 represents a hydrogen atom, a residue containing from 2 to 18 carbon atoms, linear alkanoic acid or branched, a residue of cycloalkanoic acid or a residue aryl carboxylic acid.