JPH024228B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel sugar compound and a novel method for producing the sugar compound. More specifically, the present invention includes:
General formula (′) (In the formula, R' represents an alkyl group having 2 to 5 carbon atoms or a saccharide.) and the general formula () (In the formula, R represents an alkyl group having 1 to 5 carbon atoms or a saccharide.) A general formula () characterized in that a metal salt is made to act on a compound represented by (In the formula, R has the same meaning as defined above.) The present invention relates to a novel method for producing a sugar compound represented by the following formula. The sugar compounds of the present invention are useful as physiologically active substances. R and in general formulas (), () and (')
In the definition of R', specific examples of the alkyl group having 1 to 5 carbon atoms and the alkyl group having 2 to 5 carbon atoms include methyl group, ethyl group, n-propyl group, i-
Propyl group, n-butyl group, i-butyl group, n-
Examples include pentyl group. Sugars include glucopyranose, mannopyranose,
A compound in which the hydrogen of the hydroxyl group at the 1st position of ribofuranose or arabinopyranose is substituted with an alkyl group, such as methyl, ethyl, propyl, butyl, etc., and the hydroxyl groups other than one of the other hydroxyl groups are protected with a hydroxyl protecting group, Specific examples include glucopyranosides such as methyl-2,3,4-tri-O-benzyl-α
-D-glucopyranoside, methyl-2,3,6-
mannopyranosides such as methyl-2,3,4-tri-O-
Benzyl-β-D-mannopyranoside, methyl-
2,3,6. Ribofuranosides such as tri-O-benzyl-β-D-mannopyranoside, such as methyl-
arapyranosides such as 2,3-di-D-benzyl-α-D-ribofuranoside, e.g. methyl-2,3
-di-O-benzyl-α-L-arabinopyranoside and the like. As the hydroxyl-protecting group, any hydroxyl-protecting group used in general synthetic chemistry may be used, such as benzyl group, benzyloxycarbonyl group, etc. Next, an example of the method for producing the sugar compound of the present invention will be explained. Using L-tartaric acid as a starting material, the formula The production of (2S,3S)-2,3-O-isopropylidene-4-hydroxybutanoic acid methyl ester (compound) represented by (for example, JAMusich and H.Rapoport; J.Amer.
Chem. Soc., 100, 4865 (1978)). For the compound, diphenyl disulfide 1-5
Equivalents, preferably 2-3 equivalents and the same molar amount of tributylphosphine as diphenyl disulfide are reacted with the compound in pyridine at 0-50°C, preferably 20-30°C for 5-15 hours. After the reaction, the reaction solution is concentrated and the residue is purified, for example, by column chromatography to obtain (2S,3S)-2,3-O
-Methyl isopropylidene-4-phenylthiobutyrate (compound) is obtained. 1-2 equivalents, preferably 1-1.2 equivalents of N-chlorosuccinimide are dissolved in a halogenated hydrocarbon solvent such as 1,2-dichloroethane, chloroform, methylene chloride, or carbon tetrachloride, and 0-50 °C, preferably 20−30
React for 5-15 hours at <0>C. After the reaction, insoluble matter is separated from the reaction solution, the solution is concentrated, and purified by column chromatography, etc. to obtain (2S, 3S)-
2.3-O-isopropylidene-4-chloro-4
-Phenylthiobutanoic acid methyl ester (compound V) is obtained. A compound and 1 to 10 equivalents, preferably 2 to 4 equivalents of an alcohol or saccharide represented by the general formula ROH (wherein R has the same meaning as above) relative to the compound, are added to tetrahydrofuran, diethyl ether, diisopropyl. Soluble in solvents such as ether, methylene chloride, benzene, and acetonitrile. A Lewis acid [e.g. silver oxide,
stannous chloride, ferric chloride, or a mixture of stannous chloride and silver perchlorate (1:1 mol/mol),
or a mixture of stannous chloride and tetra-n-butylammonium perchlorate (1:1 mol/mol)] at -20-50°C, preferably 0-30°C.
React for 0.5-24 hours. After the reaction, the reaction solution has a PH
After adding 7.0 phosphate buffer and separating insoluble materials, the solution is extracted with ethyl acetate. The oil obtained by concentrating the ethyl acetate layer is purified by thin layer chromatography, column chromatography, etc. to obtain the general formula (In the formula, R has the same meaning as above.) A compound represented by the following is obtained. (In the formula, R has the same meaning as above.) Lithium aluminum hydride in an amount of 1 to 3 moles based on the compound and the compound is dissolved in a solvent such as tetrahydrofuran, diethyl ether, diisopropyl ether, etc., and the mixture is heated at -10 to 30°C. , preferably at -5-50°C for 0.5-5 hours. After the reaction,
After decomposing excess lithium aluminum hydride with a saturated aqueous sodium sulfate solution, insoluble matter is separated and the liquid is concentrated, the resulting oily substance is purified by thin layer chromatography, color chromatography, etc. to obtain the general formula (In the formula, R has the same meaning as above.) A compound represented by the following is obtained. Then, the compound is heated in a mixed solvent of hydrochloric acid and methanol (1:1 V/V) at 0-50°C, preferably at 20°C.
5-15 hours at 30°C, or incubate the compound in 40-90% aqueous acetic acid at 30-80°C, preferably 55-65°C.
for 1-3 hours or 0.5 hours of compound
- 0-50 in methanol containing 3 equivalents, preferably 1-1.5 equivalents of para-toluenesulfonic acid.
℃, preferably 20-30℃ for 10-24 hours. After the reaction, the reaction solution is concentrated and purified by thin layer chromatography, column chromatography, etc. to obtain the general formula () (In the formula, R has the same meaning as above.) A compound represented by the following is obtained. The compound is reacted with a metal salt in a solvent to stereoselectively form the general formula () (In the formula, R has the same meaning as defined above.) A target compound represented by the following formula is obtained. As the solvent, ether solvents such as 1,2-dimethoxyethane, tetrahydrofuran, and dioxane, or mixed solvents of these and water are used. Examples of metal salts include divalent palladium salts such as palladium chloride, palladium cyanide, and palladium acetate, or divalent mercury salts such as mixtures of mercuric chloride and mercury oxide, and mixtures of mercuric iodide and mercury oxide. and mercury oxide are used. The amount of the metal salt to be used relative to the compound represented by the general formula () is preferably 0.5 to 1 equivalent when the metal salt is a divalent palladium salt, and 1 to 2 equivalents when the metal salt is a mercury compound. The reaction is carried out at a temperature of 0 to 50°C, preferably 20 to 30°C, for a time of 15 minutes to 4 hours, preferably 30 minutes to 2 hours. The target product represented by the general formula () is isolated from the reaction solution as follows. After the reaction, insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting oily substance was subjected to conventional treatment methods such as column chromatography,
Obtain the target product by thin layer chromatography or the like. Examples and reference examples are shown below. Example 1 108.7 mg (0.445 mmol) of 4-methoxy-4-phenylthio-(2S,3S)-butane-1,2,3-triol obtained in Reference Example 1 described later was mixed with 4 ml of water.
was dissolved in a mixed solvent with 1,2-dimethoxyethane. 50.0 mg (0.223 mmol) of palladium acetate was added to this solution, and the mixture was stirred at room temperature for 1 hour. The solvent was removed from the liquid from which insoluble materials were filtered off by concentration under reduced pressure to obtain an oily substance. This oily substance was applied to a flash column (silica gel: Art9385, manufactured by Merck & Co., Ltd., developing solvent, ethyl acetate:methanol = 20:1 V/V).
56 mg (yield 94%) of 1-O-methyl-α-L-threofuranoside was obtained. Physical properties ^1H NMR (CDCl ₃ ) ppm3.35 (S)3H3.40−4.50
(m) 6H4.85 (S) 1H ¹³ C.NMR (CDCl ₃ ) ppm54.9, 55.6, 71.2,
74.6, 76.4, 76.6, 78.9, 79.9, 102.6, 108.5 This 1-O-methyl-α-L-threofuranoside has an anometallic carbon of 102.6 in the above ¹³ C NMR.
and 108.5ppm (integral ratio: 1:6)
According to the literature [RGSRitchie, N.Cry, K, koush, HJkoch
and ASPerlin; Can.J.Chem, 53, 1424 (1975)]
It is known that the ratio of α-form and β-form is
Raw material 4-methoxy-phenylthio-
It is the same as that of the isomer of (2S,3S)-butane-1,2,3-triol. Example 2 In Example 1, the results shown in Table 1 were obtained in the same manner as in Example 1 except that the raw materials shown in Table 1 were used.

【table】

[Table] Reference example 1 Step 1: Put a mixture of 75.0 g (0.50 mol) of L-tartaric acid, 162 ml of methanol, and 25 ml of concentrated sulfuric acid into a Soxhlet extractor containing 100 g of 3A molecular sieve, and add 160 ml of methanol. The mixture was heated under reflux for 18 hours. After cooling, the reaction solution was neutralized with anhydrous sodium carbonate, the insoluble materials were removed, and then distilled under reduced pressure to obtain 64.5 g (69%) of dimethyl-L-tartrate diester. Obtained dimethyl-L-tartrate diester 35.6
g (0.20mol) and 2,2-dimethoxypropane
31.4g (0.302mol) and p-toluenesulfonic acid 1
A solution of 121 mg (0.64 mmol) of the hydrate in benzene (80 ml) was placed in a Soxhlet extractor containing 20 g of 4A molecular sieves, and heated under reflux for 2.25 hours.
After cooling, add 210 mg of anhydrous potassium carbonate and stir at room temperature.
Stir for hours. Thereafter, it was filtered and the solvent of the liquid was removed under reduced pressure. 400 ml of ether was added to the resulting residue, and the ether solution was washed with a saturated sodium tetraborate (Na ₂ B ₄ O ₇ ) aqueous solution, water, and brine, respectively, and after drying, dimethyl-2,3-
O-isopropylidene-L-tartrate diester
38.5g (88%) was obtained. Obtained dimethyl-2,3-O-isopropylidene-L-tartrate diester 2.18 g (10 mmol)
657 mg of potassium hydroxide in 3 ml of methanol solution of
(10 mmol) was added dropwise at room temperature over 1 hour. After the addition, the mixture was further stirred for 1 hour, the solvent was concentrated, 10 ml of water was added, and the mixture was extracted three times with 20 ml of ether to separate the aqueous layer. The aqueous layer was treated with 2N hydrochloric acid.
After adjusting the pH to 3.5, the mixture was saturated with common salt and then extracted six times with 20 ml of ether. After drying the ether layer, it was distilled under reduced pressure to obtain 1.18 g (53%) of methyl-2,3-O-isopropylidene-L-tartrate monoester. Methyl-2,3-O-isopropylidene-L
- 4.5g (22mmol) of tartaric acid in 65ml THF solution
℃33ml of a 1 molar solution of borohydride (BH ₃ ) in THF was added over 10 minutes. After that, the mixture was stirred at room temperature for 24 hours, the solvent was removed under reduced pressure, 40 ml of water was added, the mixture was further saturated with sodium chloride, and the mixture was diluted with 150 ml of ether.
Extracted twice. The ether layer was washed with 30 ml of 0.5N sodium hydrogen chloride water and 30 ml of saturated saline, dried, and distilled under reduced pressure to give (2S,3S)-2,3-O-isopropylidene-4.
-1.85g of hydroxybutanoic acid methyl ester
(44%) obtained. Step 2: Compound obtained in Step 1 in an argon stream
In a solution of 662 mg (3.48 mmol) in pyridine (4 ml),
2.28 g (10.4 mmol) of diphenyl disulfide was added, followed by 2.5 ml (10.4 mmol) of tributylphosphine, and the mixture was stirred overnight (about 15 hours) at room temperature. After the reaction,
After evaporating the solvent under reduced pressure, the residue was purified by flash column chromatography (developing solvent: hexane: ethyl acetate = 10: |V/V) to obtain ((2S,
3S)-2,3-O-isopropylidene-4-phenylthiobutanoic acid methyl ester 908 mg (yield 92
%) was obtained. Step 3: Compound obtained in step 2 in an argon stream
467 mg of N-chlorosuccinimide was added to a solution of 902 mg (3.20 mmol) dissolved in 5 ml of carbon tetrachloride.
(3.50 mmol) was added and stirred overnight at room temperature. After filtering the insoluble matter from the reaction solution, the solvent was distilled off under reduced pressure to obtain (2S,3S)-2,3-O-isopropylidene-4-chloro-4-phenylthiobutanoic acid methyl ester. was obtained quantitatively. Step 4: 342 mg of stannous chloride in an argon stream
(1.80 mmol), silver perchlorate 373 mg (1.80 mmol) and 3A molecular sieve, 1.80 g ether
The 18 ml suspension was cooled to 0°C, where 473 mg (1.50 mmol) of the compound obtained in step 3 and 192 mg of methanol were added.
Gradually add a solution of (6.00 mmol) in 18 ml of ether,
Stirred at 0°C for 1 hour. After the reaction, the reaction solution was transferred to 20 ml of phosphate buffer of pH 7, extracted with ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, it was purified by flash column chromatography (developing solvent: hexane: ethyl acetate = 5:1 V/V) (2S, 3S).
-O-isopropylidene-4-methoxy-4-phenylthiobutanoic acid methyl ester 320 mg (yield
69%). Step 5: In an argon stream, add 1.51 g (4.86 mmol) of the compound obtained in Step 4 to a solution of 185 mg (4.86 mmol) of lithium aluminum hydride suspended in 8 ml of tetrahydrofuran (THF).
An aqueous solution prepared by dissolving . After adding 0.35 ml of a saturated aqueous sodium sulfate solution to the reaction solution and filtering out insoluble materials, the residue after evaporating the solvent was subjected to flash column chromatography (developing solvent: hexane: ethyl acetate 1:1V/
V) to produce 1-hydroxy. 2S, 3S) -O-
1.14 g (yield: 83%) of isopropylidene-4-methoxy-44-phenylthiobutane was obtained. A solution of this compound in 4 ml of methanol was cooled to 0°, 4 ml of a 2N aqueous hydrochloric acid solution was added thereto, and the mixture was reacted at room temperature for 6 hours. After adding 546 mg (6.5 mmol) of sodium hydrogen carbonate to the reaction solution,
The residue obtained by distilling off the solvent under reduced pressure was purified by flash column chromatography (developing solvent: ethyl acetate:methanol = 10:1 V/V) to obtain 4-methoxy-4-phenylthio-(2S,3S)-butane. -1,
616 mg (yield 63%) of 2,3-triol was obtained. Diastereomer ratio is approximately 6:1 from ¹³ CNMR
It is. Reference Example 2-4 In Reference Example 1, methanol in step 4 was
The desired products shown in Table 2 were obtained in the same manner as in Reference Example 1 except that the raw materials shown in the table were used.

[Table] Reference Example 5 The α form of the target product (1-O-methyl-α-L-threofuranoside) obtained in Example 1 was isolated by thin layer chromatography, and its optical rotation was measured. Furthermore, the hydroxyl group of the target product was converted to paranitrobenzoylation and elemental analysis was performed. 1-O-methyl-α-L-threofuranoside [α] ²⁰ _D = −92.8° (C = 1.6, H ₂ O) Literature value ^* +97° (c = 1.6, H ₂ O) (1-O-methyl- α-D-Threofuranoside) *JNBoxter and ASPerline; Can.J.Chem.,
38, 2217 (1960) PNB: Paranitrobenzoyl elemental analysis value C H N Actual value (%) 52.62 3.66 6.49 Calculated value (%) 52.78 3.73 6.48 Melting point 120.5℃

Claims (1)

[Claims] 1 General formula () (In the formula, R represents an alkyl group having 1 to 5 carbon atoms or a compound in which the hydrogen of the hydroxyl group at the 1st position of glucopyranose is substituted with an alkyl group, and the hydroxyl groups other than one of the other hydroxyl groups are protected with a benzyl group. A general formula () characterized by the action of a metal salt on a compound represented by (). (In the formula, R has the same meaning as defined above.) A novel method for producing a sugar compound represented by: