JPH02240093A - Production of glycoside-based compound of ketose - Google Patents

Abstract

PURPOSE:To industrially obtain the subject compound useful as a carcinostatic agent, sweetener, etc., in good yield by reacting a thiophosphinic acid ester derivative of a ketose at the anomeric position with a specific alcohol in the presence of a trityl salt. CONSTITUTION:A thiophosphinic acid ester derivative at the anomeric position of a ketose in which hydrogen of hydroxyl group in a saccharide having the anomeric position of the ketose is bound through ketal linkage is substituted with phosphinothioyl group expressed by the formula (R<1> and R<2> are alkyl or aryl) is reacted with an alcohol selected from aliphatic alcohols, aromatic alcohols, steroid alcohols, glycerol derivatives, saccharide derivatives and amino acid derivatives in a molar equiv. amount of 1 to several times, 3-200mol% trityl salt (e.g. trityl perchlorate) as an activator and a dehydrating agent (e.g. molecular sieves) in a solvent, such as ethanol, at -40 to -60 deg.C to afford the objective compound.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a glycoside compound by reacting an anomeric thiophosphinate derivative of ketose with an alcohol. Ketose glycoside compounds are attracting attention for use in medicines and agricultural chemicals as anticancer agents, toxin neutralizers, nerve cell growth agents, sweeteners, etc., but their synthesis requires unstable intermediates and industrial No good method is known yet. The conventionally known method is to use halogenoketose and alcohol.
However, it has many drawbacks such as poor stability of the raw material halogen oxide and the need for highly dehydrated reaction conditions, making it difficult to industrialize. As a result of extensive research in view of the above circumstances, the present inventors discovered that the objective could be achieved by using an anomeric thiophosphinic acid ester derivative of ketose and a trityl salt as an activator, and arrived at the present invention. The present invention will be explained in detail below. One of the raw materials of the present invention, an anomeric ophosphinic acid ester derivative of ketose, can be synthesized from a ketose with a free anomeric hydroxyl group and a halogenated phosphinothioyl in the presence of a base. Any known ketose can be used. Specifically, natural types such as toacetylneuraminic acid, 3-deoxy-2-octulosonic acid, and fructose, or synthetically substituted hydrogen at the C-1 position with an alkyl group, aryl group, carboxyl group, nitrile group, etc. Examples include non-natural ketoses substituted with Well-known halogenated phosphinothioyls can be used. Examples include dimethylphosphinothioyl chloride, dimethylphosphinothioyl bromide, diphenylphosphinothioyl chloride, and the like. As the base, well-known bases can be used. Examples include sodium hydroxide, triethylamine, 1,8-diazabicyclo[5.4.0 condec-7-ene, n-butyllithium, and the like. As the alcohol used as one of the raw materials for the pond of the present invention, well-known alcohols can be used, such as aliphatic alcohols, aromatic alcohols,
Examples include steroid alcohols, glycerol derivatives, sugar derivatives, and amino acid derivatives. Specifically, methanol, ethanol, octyl alcohol, phenol, benzyl alcohol, 1, 2, 3, 4-diisopropylidene galactose, 3β-cholestanol, isobropylidene glycerol, N-penzyloxycarponyl-serine An example is methyl ester. Next, we will explain the reaction between the anomeric thiophosphinic acid ester of ketose and the aforementioned alcohol.
In this method, there is no particular restriction on the molar ratio of these alcohols, and a large excess of alcohol may be used, but it is usually one to several times the molar equivalent. It is best to use a well-known organic solvent other than alcohol as the solvent.
Examples include ether, benzene, toluene, dichloromethane, etc. The reaction temperature is not particularly limited, but is between -40°C and 60°C, preferably between -20°C and 40°C. The reaction time varies depending on the reaction temperature, type of raw materials, etc., but ranges from several minutes to several tens of hours. The reaction is carried out on the anomeric thiophosphinic acid ester derivative of ketose in the presence of a well-known trityl salt. The trityl salt can be used in an amount of 3 to 200 mol%, but is preferably used in an amount of 5 to 50 mol%. Examples of well-known trityl salts include trityl perchlorate, p-methoxyphenyldiphenylmethyl perchlorate, trityl pentachlorostannate, trityl hexachloroantimonate, trityl tetrafluoroborate, and the like. These salts serving as activators need not be brought into an anhydrous state, and it is sufficient to simply coexist a dehydrating agent such as monocular sieves in the reaction system.

As described above, the present invention enables the production of useful compounds in good yields under mild conditions, produces few by-products, and has great industrial value. EXAMPLES The present invention will be specifically explained below with reference to examples, but the present invention is not limited in any way by the following examples unless the gist of the invention is exceeded.

Reference example 1 34 2 ~ 3.1 (m+ 15H), 7. 0 ~ 7.

4 (s.20 strokes) 1, 3, 4. 5-Tetra O-benzyru-D-arabino 2-hekituroviranose 220 mmg (
0.41 mmol) was dissolved in 2 ml of THF, and cooled with water for 1 hour.
．． 0.3m of butyl lithium in 15M hexane solution
1 (0.45 mmo!) and stirred for 15 minutes.
mmol) in THF 1m+ and add. Stir at 0°C for 2 hours, add water and extract with dichloromethane.
After drying the organic layer with anhydrous sodium lyltate, the solvent was distilled off under reduced pressure to prepare a silica gel thin layer chromatography reagent;
Purify with hexane: ethyl sulfate = 4:1) to 1,
3, 4. 204 mg (79%) of 5-tetra 0-benzy-D-arabino 2-hekituroviranosyldimethylphosphinothioate was obtained. H-NMR; 1.6-2. 0 (d, 6
}! ). Reference example 2 Reference example 1 1. 3, 4. 5-Tetler 0
3, 4, 3. Hydrogen at the C-1 position of glucose is substituted with a methyl group instead of -benzyl-D-arabino-2-hekilovyranose. A similar reaction was carried out using 2 mg (0.74 mmol) of 7-tetra 0-benzy-1-deoxy-D-glucose 2-hebroviranose 3, 4. 5. 7-tetra O-benzyl-1-deoxy-D-glucose 2-hebuturoviranosyldimethylphosphinothioate} 200 mg (4
2%). IH-NMR; 1.7
~2. 1 (t, 9H). 3. 5 ~5.
1 (m, 14H), 7. 0 to 7.
5 (m, 20H) Reference Example 3 1 of Reference Example 1. 3, 4. 5-Tetler 0-
4, 5, 6. Hydrogen at the C-1 position of glucose is substituted with an ethyl group instead of benzy-D-arabino-2-hekituropyranose. 8-tetler 0-benzyru 1. 2-Dideoxy-D-Elisco D-Gluco 3-Octuroviranose 295mg (0.52mm
4,5,6.8-Tetra O-benzyl-1,2-dideoxy-D-erythro D-glucose 3-octulobyranosyldimethylphosphinothioate 93 mg (27%) obtain. 'H-NMR; 0.7-1. 1 (t,
3H), 1. 6-2. 1 (m, 6H)
, 2. 2 ~2. 7 (m, 2H),
3. Spit. 2(m, 14H),? ．．
s~7. 5 (m. 20H)'#204 mg of dimethylphosphinothioate compound synthesized in Example 1
(0.32 mmol), 3C-cholestanol 1
Suspend 26 mg (0.32 mmol), 1 mg (0.032 mmol) of trityl perchlorate, and 1 ml of molecular sieves powder in 1 ml of benzene, stir at room temperature for 30 minutes until saturated, and add 5 ml of an aqueous sodium bicarbonate solution. The reaction was stopped. The reaction mixture was filtered and extracted with dichloromethane, the organic layer was dried over anhydrous Fare! I sodium, the solvent was distilled off under reduced pressure, and preparative silica gel thin layer chromatography (Jilm agent; hexane: acetic acid) ethyl = 4:1)
When purified with 167mg of the target glycosyl compound
(57%) obtained. 'H-NMR; 0. 2 ~2. 2 (
m, 46H), 3. CL~5. 1 (m.
16H), 7. 0 ~ 7, 6 (m, 20H
) Example 2 97 mg (0.115 mmol) of the dimethylphosphinothioate compound synthesized in Reference Example 2, 58 mg (0.15 mmol) of 3Q-nirestanol, 5 mg (0.01!5 mmol) of trityl perchlorate,
Molecular sieves powder was suspended in 1 ml of benzene, stirred at room temperature for 30 minutes, and dissolved in saturated hydrogen carbonate.Example 3 Dimethylphosphinothioate compound synthesized in Reference Example 2*78 mg (0.12 mmol). 3fi'-prestanol 47mg (0.12mmol)+
Trityl perchlorate 2.3 mg (0.006 mmol),
Molecular sieves powder is suspended in 1 ml of benzene, stirred at room temperature for 30 minutes, and 5 ml of saturated aqueous sodium bicarbonate solution is added to stop the reaction. Thereafter, the same treatment as in Example 1 was carried out to obtain 79 mg (71%) of a glycosyl compound. 'H-NMR is the same as in Example 2.

The layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the mixture was purified with igI silica gel layer chromatography (glabella; hexane: ethyl acetate = 481), yielding 111 mg (80%) of the desired glycosyl compound. Obtained. 'H-NMR; 0. 2 ~2. 2 (
m. 49H). 3. 1-5. 2 (m,
158). 7. 0 ~ 7.5 (m, 20H
) Example 4 78 mg (0.12 mmol.) of the dimethylphosphinothioate compound synthesized in Reference Example 2, 38 mg (0.1 mmol.) of monocholestanol, 15 mg (0.01 mmol.
ol), suspend the molecular sieves powder in 1 ml of benzene, stir for 30 minutes in a mixing chamber, and then add 5 ml of a saturated aqueous sodium bicarbonate solution to stop the reaction. The reaction mixture was filtered and extracted with dichloromethane, the organic layer was dried over aqueous sodium sulfate, the solvent was distilled off under reduced pressure, and preparative silica gel thin layer chromatography (71 mixture: hexane: ethyl acetate = 4: 1) was carried out. When purified, 46 mg (43%) of the desired glycosyl compound was obtained. 'H-NMR is the same as in Example 2.

Example 6 67 mg (0. lmmo 1) of the dimethylphosphinothioate compound synthesized in Reference Example 1, 38 mg (o. lmmo +) of 319-cholestanol + 3 mg (0.01 mmol) of trityl tetrafluoroborate
+ Suspend the molecular sieves powder in 1 ml of benzene, stir at room temperature for 30 minutes, and add 5 ml of saturated aqueous sodium bicarbonate solution to stop the reaction. The reaction mixture was filtered and extracted with methylene chloride, the skin layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the mixture was subjected to thin layer chromatography on silica gel for preparation (hexane: ethyl acetate = 4:1).
), the target glycoside compound was 33 mg.
(34%) was obtained. 'H-NMR was the same as in Example 2. Example 6 Dimethylphosphinothioate compound synthesized in Reference Example 1 $67 mg (0.1 mmol), 3p-cholestanol 3Bmg (0.1 mmol), tin trityl pentachloride 5 mg (0.0 mmol), molecular sieves powder Suspend it in 1 ml of benzene and leave it for 30 minutes ff! Stir at room temperature (5 ml of saturated aqueous sodium bicarbonate solution is added to stop the reaction. The reaction mixture is filtered, extracted with dichloromethane, the first layer is dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. Purification using silica gel thin layer chromatography (developing agent: hexane: ethyl acetate = 4+1) yielded 41 mg (43%) of the desired glycosyl compound.
) obtained.

'H-NMR is the same as in Example 2.

Example 7 Example 8 Dimethylphosphinothioate compound synthesized in Reference Example 3! 88 mg (0.13 mmol), 3C-cholestanol 51 mg (0.13 mmol)
l), trityl perchlorate 4mg (0.01mm
o l), add molecular sieves powder to lml of benzene
The mixture was suspended in water, stirred at room temperature for 30 minutes, and 5 ml of a saturated aqueous sodium carbonate solution was added to stop the reaction. The reaction mixture was filtered and extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the mixture was subjected to preparative silica gel thin layer chromatography (developing agent: hexane: ethyl acetate = 4).
:1) After thorough training, the target glycosyl compound was 49
mg (39%) was obtained. H-NMR; 0. 2 ~2. 2
(m, 5 1 1{). 3. 3-5.
1 (m, 115H), . 7. 0 ~?
．． i5 (m, 20H) 84 mg (0.13 mmol) of the dimethylphosphinothioate compound synthesized in Reference Example 2, (1) 20 mg (0.13 mmol) of mono-menthol, 4. 5mg (0.013m
mo +), molecular sieves powder with benzene lm
To l! The mixture was stirred at room temperature for 30 minutes, and 5 ml of a saturated aqueous sodium bicarbonate solution was added to stop the reaction. The reaction mixture was filtered and extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the mixture was purified using preparative silica gel thin layer chromatography (indoor solution; hexane: ethyl acetate = 4:1). After purification, 48 mg (53%) of the desired glycosyl compound was obtained. 'H-NMR; 0. 6 ~1. 8 (m
, 18H). 2. 0-2. 6 (m,
3H), 3. 1 to 5. 1 (m, 1
5H), 8. 9-7. 4 (m. 20
H) Tiger Example 9 H-NMR; 1. 2 ~ 1. 6
(m, 15H). 3. 1 to 5.
1 (m, 20H), 5. 4 ~
15. 6(d, 11{), 7.
0 to 7. 5 (m, 20H) Example 10 Dimethylphosphinothioate compound synthesized in Reference Example 2 84 mg (0.13 mmol), 1.2
-3.4-di-0-isobropylidene-D-galactose 34 mg (0.13 mmol +), trityl perchlorate 4 mg (0.013 mmol), molecular sieves powder in benzene Iml! ! Make it muddy,
Stir at room temperature for 30 minutes, then add 5 ml of saturated aqueous sodium hydrogen carbonate solution to stop the reaction. The reaction mixture was filtered and extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the mixture was subjected to V4IA silica gel thin layer chromatography (developing agent: hexane: ethyl sulfate = 4:1).
The target glycosyl compound was 84 mg (
81%) was obtained. Dimethylphosphinothioate compound IJ synthesized in Reference Example 2 78 mg (0.12 mmol), n-octanol 16 mg (0.12 mmol)
, trityl perchlorate 4 mg (0,0 1 3 mmo
l) Suspend the molecular sieves powder in 1 ml of benzene, stir for 30 minutes at leap room temperature, and add 5 ml of saturated aqueous sodium bicarbonate solution to stop the reaction. The reaction mixture was filtered and extracted with dichloromethane, the aqueous layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the mixture was subjected to preparative silica gel thin layer chromatography (hexanes: ethyl sulfate = 4:1).
), the target glycosyl compound was 66 mg.
(82%) obtained. '}l-NMR; O. 1. (ml 8 H). 3. 2 to 6. ([n, 6 H), 7. ~7. (ml20H)

Claims (1)

[Scope of Claims] 1. The hydrogen of the hydroxyl group of the sugar in which the anomeric position of the ketose is ketal bonded has the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 and R^2 are unsubstituted or An anomeric thiophosphinic acid ester derivative of a ketose substituted with a phosphinothioyl group represented by (representing a substituted alkyl group or aryl group), an aliphatic alcohol,
A method for producing a ketose glycoside compound, which comprises reacting an alcohol selected from aromatic alcohols, steroid alcohols, glycerol derivatives, sugar derivatives, and amino acid derivatives in the presence of a trityl salt. 2. The production method according to claim 1, characterized in that a dimethylthiophosphinic acid ester derivative is used as the anomeric thiophosphinic acid ester of ketose. 3. The manufacturing method according to claim 1, characterized in that a catalytic amount of trityl perchlorate is used as the trityl salt.