JPH09249683A - N-actyl-d-neuraminic acid derivaitive and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel N-acetyl-D-neuraminic acid derivative which is prepared efficiently by reaction of a specific N-acetyl-D-neuraminate salt with an alkyl halide and is useful as a synthetic intermediate for medicines, agrochemicals, cosmetics, reagents and the like. SOLUTION: This compound is a novel N-acetyl-D-neuraminic ester derivative of formula I (R<1> is a 2-10C alkyl, an alkenyl, an aralkyl; R<2> is an acyl), typically methyl 5-acetamido-4,7,8,9-tetra-0-acetyl-3,5-dideoxy-D-glycero-D-galacto-2- nonulopyranose, and is useful as a synthetic intermediate for medicines, agrochemicals, cosmetics, reagents and the like. The objective compound is prepared by reaction of an N-acetyl-D-neuraminate salt bearing free hydroxyl groups of formula II (X is a metal ion) with an alkyl halide, then, when necessary, acylation of free hydroxyl groups.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD N-Acetyl-D-neuraminic acid is widely found at the end of sugar chains showing natural physiological activity.
These compounds have attracted attention as pharmaceuticals, agricultural chemicals, cosmetics, reagents and the like. The N-acetyl-D-neuraminic acid ester derivative of the present invention can be used as an important synthetic intermediate in the production of these compounds.

[0002]

2. Description of the Related Art As a conventionally known method for esterifying unprotected N-acetyl-D-neuraminic acid, there is a method of introducing a methyl ester group using an acidic resin in methyl alcohol.

[0003]

DISCLOSURE OF THE INVENTION In conventional alcohol,
In the esterification method of unprotected N-acetyl-D-neuraminic acid using an acidic resin, it is difficult to introduce an ester group other than a methyl group using an alcohol other than methanol.

[0004]

Means for Solving the Problems The present inventors have prepared a carboxyl group at the 1-position from unprotected N-acetyl-D-neuraminic acid by reacting N-acetyl-D-neuraminate with an alkyl halide. The present invention has been achieved by knowing that various N-acetyl-D-neuraminic acid ester derivatives in which various ester groups are introduced into the group can be efficiently obtained. Hereinafter, the present invention will be described in detail.

First, N-acetyl-D-neuraminic acid salt can be obtained by reacting N-acetyl-D-neuraminic acid with an equivalent amount of an inorganic base in an aqueous solution, concentrating and drying. Well-known inorganic bases can be used. For example, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, lithium carbonate,
Barium carbonate, magnesium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, potassium hydroxide, lithium hydroxide, sodium hydroxide, rubidium hydroxide, barium hydroxide, lithium iodide, sodium iodide, potassium iodide, rubidium iodide , Lithium fluoride, sodium fluoride, potassium fluoride and basic resins. A reaction temperature of room temperature and a reaction time of several minutes are sufficient.

When N-acetyl-D-neuraminate is reacted with an alkyl halide in a solvent such as dimethylformamide, the desired compound, N-acetyl-, is obtained in good yield.
D-neuraminic acid ester can be easily obtained.

Well-known alkyl halides can be used as the alkyl halide used as one of the starting materials of the present invention. For example, methyl bromide, ethyl bromide,
Propyl bromide, octyl bromide, allyl bromide, benzyl bromide, and p-methoxybenzyl bromide, methyl iodide, ethyl iodide, propyl iodide, octyl iodide, allyl iodide, benzyl iodide, and iodo P-methoxybenzyl chloride, benzyl chloride, p-methoxybenzyl chloride, octyl chloride, allyl chloride and the like. The number of equivalents of the halogenated alkyl group ranges from the equivalent to a large excess.

As the organic solvent, known ones other than dimethylformamide can be used. For example, methylene chloride, chloroform, benzene, toluene, ethyl acetate, hexamethylenephosphoric triamide, acetonitrile and the like can be mentioned.

The reaction temperature is not particularly limited and is usually from 0 ° C to 1 ° C.
It is in the range of 50 ° C, preferably 50 ° C to 120 ° C.
The reaction time is also in the range of several tens of minutes to several tens of hours, preferably 1 to 5 hours, and there is no particular limitation. Also, N-acetyl-D
Needless to say, when the neuraminate and the alkyl halide are reacted, a crown ether such as 18-crown-6 can be added to the system to carry out the reaction.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

[0011]

Example 1 N-acetyl-D-neuraminic acid 0.50
0 g (1.6 mmol) of water 5 ml and methanol 3 ml
Dissolved in 0.260 g (0.80 mm) of cesium carbonate
ol) was added and the mixture was reacted at room temperature for several minutes, and then the solvent was distilled off under reduced pressure to obtain a solid substance. Add 8 ml of dimethylformamide and 0.10 ml of methyl bromide (1.7 mmo
1) was added and reacted at 40 ° C. for 2 hours and 30 minutes, then acidic resin IRA-120 was added and the mixture was stirred for 30 minutes. After filtration, the organic solvent was distilled off under reduced pressure to obtain an oily substance.
To confirm the structure of this compound, 1.6 ml of a mixed solution prepared with 15.8 ml of acetic anhydride and 0.12 ml of 60% perchloric acid was added to the obtained oily substance, and after reacting at room temperature for 2 hours and 30 minutes, The mixture was poured into ice water, extracted with chloroform, and the organic layer was washed with saturated aqueous ammonium chloride and sodium chloride solutions. The organic solvent is dried over anhydrous sodium sulfate, the inorganic matter is filtered off, the organic solvent is distilled off under reduced pressure, and the oily substance obtained is purified by silica gel column chromatography to obtain methyl 5-acetamide-4,7,8,9. 0.460 g (yield 58%) of -tetra-O-acetyl-3,5-dideoxy-D-glycero-D-galacto-2-nonuropyranose was obtained. ¹ H
_{-NMR = 3.85 (3H, OCH 3} )

[0012]

Example 2 N-acetyl-D-neuraminic acid 1.55
g (5.0 mmol) was dissolved in 15 ml of water, 0.816 g (2.5 mmol) of cesium carbonate was added, and after reacting at room temperature for several minutes, the solvent was distilled off under reduced pressure to obtain a solid substance. To this, 20 ml of dimethylformamide and 0.520 ml (6.0 mmol) of allyl bromide were added, and the mixture was heated at 60 ° C.
After reacting for 2 hours and 30 minutes, the acidic resin IRA-12
0 was added and the mixture was stirred for 30 minutes. After filtration, the organic solvent was distilled off under reduced pressure to obtain an oily substance. To confirm the structure of this compound, 5.0 ml of a mixed solution prepared by acetic anhydride 49.5 ml and 60% perchloric acid aqueous solution 0.37 ml was added to the obtained oily substance, and the mixture was reacted at room temperature for 2 hours and 30 minutes. The mixture was poured into ice water, extracted with chloroform, and the organic layer was washed with saturated ammonium chloride and sodium chloride aqueous solution. The organic solvent is dried over anhydrous sodium sulfate, the inorganic matter is filtered off, the organic solvent is evaporated under reduced pressure, and the oily substance obtained is purified by silica gel column chromatography to obtain allyl 5-acetamido-4,
1,475 g (yield 57%) of 7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-D-galacto-2-nonuropyranose was obtained. ¹ H-NM
R = 2.021, 2.025, 2.098, 2.142
(CH ₃ COα), 2.032, 2.039, 2.08
1,2.093 (CH ₃ COβ), 5.886-5.9
84 ( ¹ H, m), 5.855 (NHα), 6.262
(NHβ), ¹³ C-NMR = 35.94 (C-3β),
36.06 (C-3α), 62.69 (C-9α), 6
3.63 (C-9β), 94.68 (C-2β), 9
4.93 (C-2β)

[0013]

Example 3 N-Acetyl-D-neuraminic acid 1.54
g (5.0 mmol) was dissolved in 15 ml of water, 0.819 g (2.5 mmol) of cesium carbonate was added, and after reacting at room temperature for several minutes, the solvent was distilled off under reduced pressure to obtain a solid substance. To this, 20 ml of dimethylformamide and 0.720 ml (6.0 mol) of benzyl bromide were added, and the temperature was adjusted to 80 ° C.
After reacting for 2 hours and 30 minutes, the acidic resin IRA-12
0 was added and the mixture was stirred for 30 minutes. After filtration, the organic solvent was distilled off under reduced pressure to obtain an oily substance. To confirm the structure of this compound, to the obtained oily substance was added 53.2 ml of acetic anhydride and 5.4 ml of a mixed solution of 0.37 ml of 60% aqueous perchloric acid, and the mixture was reacted at room temperature for 2 hours and 30 minutes. The mixture was poured into ice water, extracted with chloroform, and the organic layer was washed with saturated ammonium chloride and sodium chloride aqueous solution. The organic solvent is dried over anhydrous sodium sulfate, the inorganic matter is filtered off, the organic solvent is evaporated under reduced pressure, and the resulting oily substance is purified by silica gel column chromatography to obtain benzyl 5-acetamide-
1.362 g (yield 48%) of 4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-D-galacto-2-nonulopyranose was obtained. ¹ H-
NMR = 1.890, 1.971, 2.002, 2.0
14, 2.021, 2.045, 2.063, 2.06
7, 2.069, 2.135 (CH ₃ CO α and β),
6.100, 6.376 (NH α and β), ₁₃ C-NM
R = 35.90 (C-3β), 36.06 (C-3
α), 62.60 (C-9α), 63.55 (C-9
β), 94.77 (C-2β), 95.02 (C-2
α)

[0014]

As described above, according to the present invention, an N-acetyl-D-neuraminic acid ester derivative can be easily produced from unprotected N-acetyl-D-neuraminic acid. These ester derivatives are important synthetic intermediates in pharmaceuticals, agricultural chemicals, cosmetics and reagents.

Claims (7)

[Claims] [Claim 1] Formula 1 (wherein R ¹ is an alkyl group having 2 to 10 carbon atoms,
An alkenyl group, an aralkyl group and R ² represent hydrogen and an acyl group. ) N-acetyl-D-neuraminic acid ester derivative represented by ## STR2 ## The N-acetyl-D-neuraminic acid ester derivative according to claim 1, which is represented by Formula 2 (wherein All represents an allyl group and R represents hydrogen or an acetyl group). (3) The N-acetyl-D-neuraminic acid ester derivative according to claim 1, which is represented by Formula 3 (wherein Bn represents a benzyl group, R represents hydrogen or an acetyl group). (4) Formula 4 in which a hydroxyl group is free (wherein X represents a metal ion)
Wherein N-acetyl-D-neuraminate represented by the formula and an alkyl halide are reacted, wherein R ¹ is an alkyl group having 2 to 10 carbon atoms, an alkenyl group or an aralkyl group. , R ² represents hydrogen or an acyl group), and a method for producing an N-acetyl-D-neuraminic acid ester derivative. 5. The method according to claim 4, wherein the reaction is carried out in dimethylformamide. 6. The method according to claim 4, wherein the reaction is performed by heating. 7. The method according to claim 4, wherein a cesium salt is used as the N-acetyl-D-neuraminate.