JPH0460120B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a glycoside compound by reacting a thiophosphinate derivative at the anomeric position of a sugar with an alcohol.

Glycoside compounds are widely distributed in nature, and are attracting attention as they are used as physiologically active substances, such as antibiotics and anticancer agents, in pharmaceuticals and agricultural chemicals, but their synthesis requires unstable intermediates. The only known methods are methods that use the human body or methods that use harsh reaction conditions, and no method that can be used industrially is known yet.

Among the conventionally known methods, the method of W. Koenig and E. Knorr [see Chem. Ber. vol. 34, p. 957 (1901, Germany)] is known as a commonly used method.

In this method, halogenosaccharide and alcohol are reacted, but the stability of the raw material halogenosaccharide is poor.
It has many drawbacks, such as the need to carry out the reaction under highly dehydrated conditions, making industrialization difficult.

As a result of intensive research in view of the above circumstances, the present inventor found that the purpose could be achieved by using a specific sugar derivative, and arrived at the present invention.

That is, the gist of the present invention is a method for producing a glycoside compound using a thiophosphinic acid ester at the anomeric position of a sugar and an alcohol.

The present invention will be explained in detail below.

Known sugars can be used as the raw material for the anomeric thiophosphinate derivative of sugar, which is one of the raw materials of the present invention.

It is necessary that the anomeric position of these sugars is hemiacetal bonded. The cyclic hemiacetal may be a 5-membered ring or a 6-membered ring. Usually aldoses are used, but ketoses can also be used. Specifically, these sugars include tetraoses such as erythrose and threoses, pentoses such as ribose, arabinose, and xylose;
Hexoses such as glucose, galactose, mannose, allose, and talose, or partially deoxylated sugars such as deoxyribose, amino sugars such as N-acetylglucosamine, and oligosaccharides in which these sugars are ether-linked to each other. can also be used. These sugars are D
Any of the L-isomer, L-isomer, and mixtures thereof can be used.

It is desirable to protect all hydroxyl groups other than the anomeric positions of these sugars.

As the protecting group for the hydroxyl group, conventionally known ones can be used. Specifically, methods of protecting with acyl groups such as acetyl, trifluoroacetyl, trichloroacetyl, benzoyl, P-nitrobenzoyl, etc., methods of acetalization with acetaldehyde, acetone, etc., and hydrocarbon groups such as methyl, benzyl, triphenylmethyl, etc. For example, the method of etherification can be mentioned.

The anomeric thiophosphinic acid ester of a sugar can be easily synthesized by reacting the above-mentioned sugar derivative with a strong base and then reacting it with a halogenated phosphinothioyl.

As the halogenated phosphinothioyl that can be used in this method, well-known ones can be used. That is, various halides such as dimethylphosphinothioyl, diethylphosphinothioyl, methylphenylphosphinothioyl, and diphenylphosphinothioyl can be used.

The halogen may be any of fluorine, chlorine, bromine, and iodine, but chloride and bromide are usually used.

As the strong base, well-known ones can be used. That is, alkali metals such as metallic sodium, metallic lithium, metallic potassium, sodium methoxide,
Metal alcoholates such as thallium ethoxide, alkali metal hydrides such as sodium hydride, n-
These include alkyl or aryl metals such as butyllithium and phenyllithium, and strong basic amines such as 1,8-diazabicyclo-[5,4,0]-undecene-7.

Although it is possible to use the halogenated phosphinothioyl and the strong base in large excess relative to the sugar, the amount is usually 1 to 2 molar equivalents.

There are no particular restrictions on the solvent. That is, benzene, toluene, chloroform, dichloromethane, ethyl acetate, tetrahydrofuran, dimethylformamide, acetonitrile, nitromethane and the like can be mentioned.

The reaction temperature is not particularly limited from -60°C to the boiling point of the solvent.

Anomeric thiophosphinates of sugars exist in α and β forms, which can be separated from a mixture, but they can also be produced with good selectivity by changing the solvent, base, reaction temperature, etc. It is. On the other hand, as a raw material for the glycosylation reaction, either the α-form, the β-form, or a mixture thereof can be used.

As the alcohol used as another raw material in the method of the present invention, well-known alcohols can be used. That is, compounds having hydroxyl groups such as aliphatic alcohols, aromatic alcohols, steroid alcohols, glycerol derivatives, sugar derivatives, and amino acid derivatives can be used.

Aliphatic alcohols include methanol, ethanol, propanol, isopropanol, cetyl alcohol, butanol, ethylene glycol,
Examples include propylene glycol.
Needless to say, cycloaliphatic alcohols such as cyclohexanol, methylcyclohexanol, and menthol can also be used.

Aromatic alcohols include phenol, p-chlorophenol, o-chlorophenol, phenetol, p-nitrophenol, o-nitrophenol, 2,4-dinitrophenol, p-cresol, o-cresol, α-naphthol, β-
Naphthol, catechol, resorcinol, hydroquinone, etc. can be mentioned.

Examples of steroid alcohols include cholesterol, cholestanol, stigmasterol, campesterol, sitosterol, ergosterol, fucosterol, estrone, estradiol, testosterone, androsterone, and the like.

Examples of glycerol derivatives include glycerin and its monoacyl derivatives protected with the above-mentioned protecting groups, and glycerin diacyl derivatives. Here, examples of the acyl group include acetyl, benzoyl, palmityl, stearyl, oleyl, etc., and diacyl groups may be the same or different acyl groups.

Well-known sugar derivatives can be used. That is, the sugars mentioned above can be used, but they do not necessarily have to be hemiacetal linked.

It goes without saying that oligosaccharides can also be used.

Sugars have many hydroxyl groups, and it is desirable to protect them as much as possible. As the protecting group, those mentioned above can be used.

Examples of amino acid derivatives include serine, threonine, hydroxyproline, hydroxylysine, and tyrosine. These amino acids exist in L-form and D-form, and either one or a mixture may be used. It goes without saying that amino alcohols obtained by reducing the carboxyl groups of amino acids and peptides in which amino acids are condensed can also be used. Furthermore, amino acids whose amino groups, carboxyl groups, etc. are protected by well-known methods can also be used.

Next, the reaction of the anomeric thiophosphinic acid ester of sugar and alcohol, which is the method of the present invention, will be explained. In this method, the molar ratio of the two is not particularly limited, and the alcohol may be used in large excess, and is usually one to several times the molar equivalent.

Needless to say, alcohol-based solvents cannot be used as the solvent. Other solvents such as benzene, toluene, dichloromethane, chloroform,
Tetrahydrofuran, dimethylformamide, etc. can be used, but preferably a solvent such as tetrahydrofuran, benzene, etc. is used.

There is no particular restriction on the reaction temperature, but it is usually -20℃~
40°C, preferably -10°C to 25°C.

The reaction time varies depending on the reaction temperature, the type of raw materials, etc., but is in the range of several minutes to several hours.

The reaction is carried out in the presence of a known silver salt, copper salt or mercury salt in an equimolar or excess molar amount to the alcohol component. Well-known silver salts, copper salts or hydroxides include silver perchlorate, silver acetate, silver trifluoromethanesulfonate, silver p-toluenesulfonate, silver nitrate, copper perchlorate, mercury perchlorate, mercury acetate, etc. Silver perchlorate and copper perchlorate are preferably used. It is sufficient to use these metal salts in the presence of a dehydrating agent such as a molecular sieve in the reaction system without making them particularly anhydrous.

As described above, the method of the present invention can produce useful compounds in good yields under mild neutral conditions, produces few by-products, and has great industrial value.

The present invention will be described in more detail below with reference to Examples, but the present invention is not limited in any way by the Examples unless it exceeds the gist thereof.

Example 1 2,3,4,6-tetrabenzyl-D-glucopyranose dimethylthiophosphinic acid ester
126.5g (0.2mmol) of tetrahydrofuran (1
ml), 16 μm (0.4 mmol) of methanol and 0.207 mg (1 mmol) of silver perchlorate were added, and the mixture was stirred at room temperature for 30 minutes. After the solvent was distilled off under reduced pressure, purification using preparative silica gel thin layer chromatography (developing agent: n-hexane: ethyl acetate = 3:1) yielded methyl 2,3,
91.5 mg (83 mol%) of 4,6-tetrabenzyl-D-glucopyranoside was obtained as an oily substance.
NMR ((CDCl ₃ , ppm); 3.39 (S, 3H, 7.23 (S, 7.33 (S, 20H, Ph)) Example 2 Silver nitrate 0.170 g instead of silver perchlorate in Example 1
(1 mmol) and reacted in exactly the same way,
23.0 mg (20 mol %) of methyl 2,3,4,6-tetrabenzyl-D-glucopyranoside was obtained as an oily substance. NMR was consistent with Example 1.

Example 3 A reaction was carried out in the same manner as in Example 1 using 72.7 mg (0.2 mmol) of β-cholestanol instead of methanol.
Purification using silica gel thin layer chromatography (developing agent: n-hexane:ether = 4:1) resulted in β
- 62.7 mg of cholestanil 2,3,4,6-tetrabenzyl-D-glucopyranoside as an oily substance
(34 mol%) was obtained. NMR (CDCl ₃ , ppm);
0.40−2.43(m, 47H, cholestanil CH ₃ , CH ₂ ,
CH) 7.24 (S, 7.33 (S, 20H, Ph) Example 4 Using 20 mg (0.2 mmol) of cyclohexanol in place of β-cholestanol in Example 1 and treating in the same manner, cyclohexyl 2,3,4, 59.7 mg (49 mol %) of 6-tetrabenzyl-D-glucopyranoside was obtained as an oily substance.

Example 5 In the same manner as in Example 1, 75.7 mg (0.2 mmol) of 2,3,4,6-tetrabenzyl-α-D-glucopyranose diphenylthiophosphinic acid ester was used. , 82.3 mg (75 mol %) of 4,6-tetrabenzyl-D-glucopyranoside was obtained as an oily substance.

Example 6 2,3,4,6-tetrabenzyl-α-D-glucopyranose dimethylthiophosphinic acid ester 63.3 mg (0.1 mmol), β-cholestanol 38.9 mg
(0.1 mmol), about 100 mg of molecular sieves 4A,
20.7 mg (0.1 mmol) of silver perchlorate was added to a mixture of 0.5 ml of benzene with stirring using 1 ml of benzene. After reacting overnight, a 5% aqueous sodium sulfide solution was added to remove insoluble materials. The liquid was extracted twice with ether, and the ether layer was washed with water and dried. The solvent was distilled off under reduced pressure, and the resulting oily substance was separated and purified using preparative silica gel thin layer chromatography.
- Glucopyranoside as white crystals 65.0 mg (71
% by mole) was obtained. Melting point 117.5-119.0℃.

In addition, 15.9 mg (17 mol%) of the corresponding β-glycoside was obtained as white crystals. Melting point: 93.5℃.

Example 7 92.9 mg (0.2 mmol) of methyl 2,3,4-tribenzyl-α-D-glucopyranoside was used in place of β-cholestanol in Example 6, and 126.5 mg of dimethylthiophosphinate derivative was used.
(0.2 mmol), silver perchlorate 41.5 mg (0.2 mmol), and benzene 2 ml, methyl 2,3,4-tribenzyl-6-(2,3,
120.6 mg (61 mol%) of 4,6-tetrabenzyl-α-D-glucopyranosyl-α-D-glucopyranoside was obtained as white crystals. Melting point: 101℃.
In addition, 15.5 mg (8 mol%) of the corresponding β-anomer was obtained.

Example 8 Same as Example 7, 92.9 mg of methyl 2,3,6-tribenzyl-α-D-glucopyranoside
(0.2 mmol), dimethylthiophosphinate derivative 253.0 mg (0.4 mmol), silver perchlorate 83.0 mg
(0.4 mmol), methyl 2,
3,6-tribenzyl-4-(2,3,4,6-
Tetrabenzyl-α-D-glucopyranosyl)-
α-D-glucopyranoside as an oily substance
145.9 mg (74 mol%) was obtained. NMR; 3.34ppm
(S, 3H, OCH ₃ ), 6.93-7.50ppm (m, 35H,
Ph). In addition, 15.8 mg (8 mol %) of the corresponding β-anomer was obtained as an oily substance.

Reference Example 1 2.70 mg (5 mmol) of 2,3,4,6-tetrabenzyl-D-glucopyranose is dissolved in tetrahydrofuran (20 ml) and cooled to -30°C under a nitrogen atmosphere. To this, 1.6Mn-butyllithium/n-
Add 3.4ml (5.4mmol) of hexane solution and after 10 minutes 0.69g of dimethylphosphinothioyl chloride
(5.4 mmol). The reaction solution was stirred at -30°C for 3 hours and then returned to room temperature. Ether and water are added to this to separate the layers, and the ether layer is washed with water, dried, and concentrated under reduced pressure to obtain 3.71 g of an oily substance. When this was purified by silica gel column chromatography (2.5 x 42 cm) using dichloromethane as the eluent, 2,3,4,6-
Tetrabenzyl-D-glucopyranose dimethylthiophosphinate as white crystals at 2.41
g (76 mol%) was obtained. The ratio of α and β forms is 98:
It was 2. Decantation with n-hexane yields 2,3,4,6-tetrabenzyl-α-D-
Glucopyranose dimethylthiophosphinate was obtained. Melting point 62-64℃ NMR (CDCl ₃ , ppm) 1.86 (d, 6H, p-CH ₃ , J=13Hz) 6.18
(d, d, 1H, H-1, J = 13Hz, 3Hz) 7.23 (S, 7.30 (S, 20H, Ph) Reference example 2 2,3,4,6-tetrabenzyl-D-glucopyranose 2.38g ( Dissolve 4.4 mmol) in 20 ml of tetrahydrofuran, and add 2.75 ml (4.8 mmol) of 1.6M n-butyllithium/n-hexane solution at 0°C.
and 0.62 g of dimethylphosphinothioyl chloride.
(4.8 mmol) was used. The same procedure as in Reference Example 1 was carried out.
When purified by silica gel column chromatography (2.5 x 30 cm) using dichloromethane as eluent, 2, 3, 4,
6-tetrabenzyl-D-glucopyranose dimethylthiophosphinic acid ester as an oily substance
2.78 g (99 mol%) was obtained. The ratio of α-form and β-form determined by NMR was 50:50.

Reference Example 3 1.08 g (2 mmol) of 2,3,4,6-tetrabenzyl-D-glucopyranose was dissolved in a mixed solution of 10 ml of benzene and 10 ml of tetrahydrofuran.
Add 0.15 thallium ethoxide while passing nitrogen through this.
ml (2.1 mmol) was added and stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure, and after drying, it was dissolved again in 10 ml of benzene, followed by dimethylphosphinothioyl chloride (0.28 g).
g (2.2 mmol) was added and reacted for 4 hours. Thereafter, when purified in the same manner as in Reference Example 1, 0.38 g of 2,3,4,6-tetrabenzyl-D-glucopyranose dimethylthiophosphinic acid ester was obtained as white crystals.
(30 mol%) was obtained. The ratio of α and β forms determined by NMR was 9:91, and by decanting with n-hexane, 2,3,4,6-tetrabenzyl-β-D-glucopyranose dimethylthiophosphinic acid was obtained. An ester was obtained. Melting point 76-77℃ NMR (CDCl ₃ , ppm) 1.85 (d, d, 6H, p-CH ₃ , J=13Hz,
8Hz) 5.37 (dd, 1H, H-1, J=13Hz,
7Hz) 7.26 (S, 7.28 (S, 7.30 (S, 20H, Ph)) Reference example 4 2,3,4,6-tetrabenzyl-D-glucopyranose 108.1 mg (0.2 mmol), 20% n-butyllithium/ n-hexane solution 103.1μ
(0.22mmol), diphenylphosphinothioyl chloride 55.6mg (0.22mmol), tetrahydrofuran 1ml
The same procedure as in Reference Example 1 was carried out using . When purified using silica gel thin layer chromatography (20 x 20 cm), 2,3,4,6-tetrabenzyl-α-D-
81.3 mg (55 mol%) of glucopyranose diphenylthiophosphinic acid ester was obtained as an oily substance.

NMR (CDCl ₃ , ppm) 6.38 (dd, 1H, H-1, J = 13Hz, 3Hz)
6.98−8.26 (m, 30H, Ph)

Claims (1)

[Scope of Claims] 1 The hydrogen of the hydroxyl group at the anomeric position of a sugar whose anomeric position is hemiacetal bonded has the general formula [] (In the formula, R ¹ and R ² represent either a methyl group, ethyl group, propyl group, isopropyl group, butyl group, s-butyl group, t-butyl group, phenyl group, or p-methoxyphenyl group.) An anomeric thiophosphinic acid ester derivative of a sugar represented by the formula and an alcohol selected from aliphatic alcohols, aromatic alcohols, steroid alcohols, glycerol derivatives, sugar derivatives, and amino acid derivatives are coexisted with silver salts, copper salts, or mercury salts. 1. A method for producing a glycoside compound, which comprises causing a reaction. 2. The production method according to claim 1, wherein the thiophosphinate derivative at the anomeric position of a sugar is a dimethylthiophosphinate derivative at the anomeric position of a sugar. 3. The production method according to claim 1, wherein the thiophosphinate derivative at the anomeric position of a sugar is a diphenylthiophosphinate derivative at the anomeric position of a sugar. 4. The manufacturing method according to claim 1, characterized in that silver perchlorate is used as the silver salt.