JPH0633302B2 - Process for producing glycoside compound of amino sugar - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a glycoside compound by reacting a C-1 position thiophosphinic acid ester derivative of an amino sugar with an alcohol or an ether derivative in which a hydroxyl group of the alcohol is protected.

Glycoside compounds of amino sugars are attracting attention for use as medicines and agricultural chemicals as antibiotics and carcinostatic agents, but unstable intermediates are used in their synthesis, and only those that can be used as a protecting group for amino groups are very rare. Limited and industrially superior methods have not been known.

The conventionally known method involves reacting a halogenoamino sugar with an alcohol, but the halogenoamino sugar as a raw material is poor in stability, requires highly dehydrated reaction conditions, and has a benzyloxycarbonyl group as a protecting group for an amino group. Is known to give no glycosides [Che
m. Ber. Vol. 100, p. 271 (1967, Germany)], there are many drawbacks such as limitation of what can be used as a protecting group for amino group, and industrialization is difficult. Even when the above C-1 thiophosphinic acid ester derivative of amino sugar was used, the yield of glycoside compound of amino sugar was not satisfactory by the method described in JP-A-60-136591.

As a result of earnest studies in view of the above circumstances, the present inventor has reached the present invention by knowing that the use of a specific activator can achieve the purpose even if the above-mentioned amino sugar derivative is used.

Hereinafter, the present invention will be described in detail.

The C-1 position thiophosphinic acid ester derivative of amino sugar, which is one of the starting materials of the present invention, can be synthesized in the presence of an amino sugar having a free hydroxyl group at the C-1 position, phosphinothioyl chloride and a base. Known amino sugars can be used. Specific examples thereof include glucosamine, mannosamine, galactosamine, etc. As the amino-protecting group, those protected by a known method can be used. For example, formyl, acetyl, benzoyl, phthaloyl, p-methoxybenzylidene, dinitrophenyl, benzyloxycarbonyl, t-
Examples include butoxycarbonyl and 9-fluorenylmethyloxycarbonyl. It goes without saying that azides that are equivalent to amino groups can be used. Well-known phosphinothioyl chloride can be used. Examples thereof include dimethylphosphinothioyl chloride chloride and didephenylphosphinothioyl chloride chloride.

Alcohol used as one of the other raw materials of the present invention may be known one. For example, aliphatic alcohol, steroid alcohol, glycerol derivative, sugar derivative,
Amino acid derivatives are mentioned.

Further, ether derivatives in which the hydroxyl groups of these alcohols are protected can also be used. Specific examples thereof include ether derivatives having a protective group such as trimethylsilyl, trityl and tributylstannyl.

Next, the reaction between the C-1 position thiophosphinic acid ester of an amino sugar and the above-mentioned alcohol or ether will be described. In this method, the molar ratio of these is not particularly limited, and alcohol or ether may be used in a large excess,
Usually, it is 1 to several times the molar equivalent.

Well-known organic solvents other than alcohol can be used as the solvent.
For example, ether, benzene, toluene, dichloromethane and the like can be mentioned.

The reaction temperature is not particularly limited, but is -40 ° C to 60 ° C, preferably -20 ° C to 40 ° C. The reaction time varies depending on the reaction temperature, the type of raw material, etc., but is in the range of several hours to several tens hours.

The reaction is carried out in the coexistence of a well-known trityl salt, lithium salt, ammonium salt or tin salt with the C-1 position thiophosphinic acid ester derivative of amino sugar. Alternatively, excess iodine is added to an amino sugar derivative in the presence of a trityl salt, a lithium salt, an ammonium salt, or a tin salt. Alternatively, an iodine compound is added to an amino sugar derivative in the presence of a trityl salt, a lithium salt, an ammonium salt, or a tin salt. When iodine or an iodine compound is added, the trityl salt, the lithium salt, the ammonium salt or the tin salt may be added in an amount of 3 to 90% by mole, preferably 5 to 50% by mole.
Well-known trityl salt, lithium salt, ammonium salt, and tin salt include trityl perchlorate, p-methoxyphenylmethyldiphenyl perchlorate, trityl tetrafluoroborate,
Trityl hexamonate antimonate, Trityl hexafluorophosphate Lithium perchlorate, Tetrabutylammonium perchlorate, Tetrabutylammonium hexafluorophosphate, Tetrabutylammonium tetrafluoroborate, Tin trifluoromethanesulfonate, Nitric acid Examples thereof include tin chloride and tin trifluoromethanesulfonate. Tin salts are tin dichloride and trityl chloride, tin dichloride and trimethylsilyl chloride,
A combination of tin trifluoromethanesulfonate and trimethylsilyl chloride can also be used. It is sufficient to allow a dehydrating agent such as molecular sieves to coexist in the reaction system without making the salt serving as the activator particularly anhydrous. Examples of the iodine compound include N-iodosuccinimide. Iodine or an iodine compound can be used in an amount of 20% to several times, preferably 50% to 2 times. Iodine or an iodine compound can be used as a solid or liquid as it is, but it is used by dissolving it in a commonly used solvent and diluting it.

According to the method of the present invention, the useful compound can be produced in a good yield under mild conditions as described above, the amount of by-products is small, and its industrial value is great.

Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to the following examples as long as the gist thereof is not exceeded.

Example 1 3,4,6-Tri-0-benzyl-2-deoxy-2-
Benzyloxycarbonylamino-α-D-glucopyranose dimethylthiophosphinic acid ester 67.1 mg
(0.1 mmol), β-cholestanol 40.5 mg
(0.1 mmol) and trityl perchlorate 3.2 mmg
Molecular sieves 4A coexisted in (0.01 mmol) and dissolved in benzene (1 ml), iodine was dissolved in benzene to make 0.094 M, and 1.09 ml (0.0
1 mmol) and stirred at room temperature for 15 hours, then added water and extracted with methylene chloride. The organic layer was washed with 5% aqueous sodium thiosulfate solution, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After removal and purification by silica gel thin-layer chromatography for adjustment (developing agent: benzene: methanol = 3-: 1), β-cholestanyl 3,4,6-tri-0 was obtained.
-Benzyl-2-deoxy-2-benzyloxycarbonylamino-β-D-glucopyranoside 68.8 mg (7
2%) was obtained. C ¹³ -NMR is 98.98 ppm
(C-1 carbon) Example 2 45.8 mg (0.1 mm) of β-cholestanyl trimethylsilyl ether instead of β-cholestanol of Example 1
was reacted in exactly the same manner as described above, β-cholestanyl 3,4,6-tri-0-benzyl-2-deoxy-2-benzyloxycarbonylamino-β-D-glucopyranoside 68.8 mg (72%) was obtained. Was obtained. NMR
Was in agreement with Example 1.

Example 3 In place of the trityl perchlorate of Example 2, 5.4 mg (0.01 mmol) of trityl hexamonate antimonate was used and reacted in exactly the same manner. Β-cholestanyl 3,4,6
-Tri-0-benzyl-2-deoxy-2-benzyloxycarbonylamino-β-D-glucopyranoside 8
5.5 mg (90%) was obtained. NMR was consistent with Example 1.

Example 4 In place of the trityl perchlorate of Example 2, 3 mg (0.01 mmol) of trityl tetrafluoroborate was used and reacted in exactly the same manner. Β-cholestanyl 3,4,6-tri-0-benzyl- 2-deoxy-2-benzyloxycarbonylamino-β-D-glucopyranoside 58.7 mg
(62%) was obtained. NMR was consistent with Example 1.

Example 5 In place of the trityl perchlorate of Example 2, 1.4 mg (0.009 mmol) of lithium perchlorate was used and the reaction was carried out in exactly the same manner. Β-cholestanyl 3,4,6-tri-
0-benzyl-2-deoxy-2-benzyloxycarbonylamino-β-D-glucopyranoside 72.3 mg
(77%) was obtained. NMR was consistent with Example 1.

Example 6 In place of the trityl perchlorate of Example 2, 4 mg (0.01 mmol) of tetrabutylammonium perchlorate was used and the reaction was carried out in exactly the same manner. Β-cholestanyl 3,4,4
6-tri-0-benzyl-2-deoxy-2-benzyloxycarbonylamino-β-D-glucopyranoside 6
0.7 mg (64%) was obtained. NMR was consistent with Example 1.

Example 7 Toluene was used instead of benzene in Example 2, and the reaction was carried out in exactly the same manner. Β-cholestanyl 3,4,6
-Tri-0-benzyl-2-deoxy-2-benzyloxycarbonylamino-β-D-glucopyranoside 6
8.1 mg (73%) was obtained. NMR was consistent with Example 1.

Example 8 When methylene chloride was used instead of benzene as the solvent in Example 2, and the reaction was conducted in exactly the same manner, β-cholestanyl 3,
63.8 mg (68%) of 4,6-tri-0-benzyl-2-deoxy-2-benzyloxycarbonylamino-β-D-glucopyranoside were obtained. NMR is from Example 1
Matched with.

Example 9 0.74 ml of a solution prepared by dissolving methanol in benzene instead of β-cholestanol of Example 1 to make 0.131M.
(0.1 mmol) was added, and molecular sieves 3A were allowed to coexist, and the reaction was performed in exactly the same manner.
25.7 mg (45%) of 4,6-tri-0-benzyl-2-deoxy-2-benzyloxycarbonylamino-β-D-glucopyranoside was obtained. C ¹³ -NMR is 1
01.58 ppm (C-1 carbon) Example 10 1 ml (0.1 mmol) of 0.103 M prepared by dissolving methyl trimethylsilyl ether in benzene instead of methanol in Example 9 was added, and the same reaction was performed. Methyl 3,4,6-tri-0-benzyl-2
-Deoxy-2-benzyloxycarbonylamino-β
19.1 mg (31%) of -D-glucopyranoside was obtained. NMR was consistent with Example 9.

Example 11 When 16.5 mg (0.1 mmol) of menthol was used in place of β-cholestanol of Example 1, the reaction was carried out in exactly the same manner. Menthyl 3,4,6-tri-0-benzyl-2-deoxy 2-benzyloxycarbonylamino-β-D-glucopyranoside 48.6 mg (67
%)was gotten. C ¹³ -NMR is 97.95 ppm (C
-1 carbon) Example 12 Methyl 2, instead of β-cholestanol of Example 1
5,4-tri-0-benzyl-6-0-trimethylsilyl-α-D-glucopyranoside 52.8 mg (0.1 mm
ol) and reacted in exactly the same manner, methyl 2,
3,4-Tri-0-benzyl-6- (3,4,6-tri-0-benzyl-2-deoxy-2-benzyloxycarbonylamino-β-D-glucopyranosyl) -α-D
-29.9 mg (30%) of glucopyranoside was obtained.
C ¹³ -NMR is 98.06 ppm (amino sugar C-1 carbon) Example 13 Instead of β-cholestanol of Example 1, methyl 2,
When 3,4-tri-0-benzyl-α-D-glucopyranoside 46.6 mg (0.1 mmol) was reacted in exactly the same manner, methyl 2,3,4-tri-0-benzyl-
6- (3,4,6-tri-0-benzyl-2-deoxy-2-benzyloxycarbonylamino-β-D-glucopyranosyl) -α-D-glucopyranoside 38.7 mg
(38%) was obtained. NMR was consistent with Example 12.

Example 14 90 mg of 3,4,6-tri-0-benzyl-2-deoxy-2-benzyloxycarbonylamino-D-glucopyranose dimethylphosphinic acid ester of Example 13
(0.13 mmol), trityl perchlorate 18.9 mm
g (0.55 mmol), methyl 2,3,4-tri-0
-Benzyl-α-D-glucopyranoside 46.8 mg
(0.1 mmol) was used and the molar ratio of Example 13 was changed and the reaction was carried out in exactly the same manner. Methyl 2,3,4-tri-0-benzyl-6- (3,4,6-tri-0- 70.8 mg (68%) of benzyl-2-deoxy-2-benzyloxycarbonylamino-β-D-glucopyranosyl) -α-D-glucopyranoside was obtained. NMR was consistent with Example 12.

Example 15 Methyl 2,3,4-tri-0-benzyl-of Example 14
α-D-glucopyranoside is methyl 2,3,6-tri-
When 0-benzyl-α-D-glucopyranoside was substituted and reacted in exactly the same manner, methyl 2,3,6-tri-0 was obtained.
-Benzyl-4- (3,4,6-tri-0-benzyl-
2-deoxy-2-benzyloxycarbonylamino-
33.8 mg (33%) of β-D-glucopyranoside) -α-D-glucopyranoside was obtained. C ¹³ -NMR is 9
8.1 ppm (amino sugar C-1 carbon) Example 16 3,4,6-tri-0-benzyl-2-deoxy-2-
Acetamide-D-glucopyranose dimethylthiophosphinic acid ester 58.4 mg (0.1 mmol), β-
Molecular sieves 4A was coexisted with 38.9 mmg (0.1 mmol) of cholestanol and 3.4 mmg (0.01 mmol) of trityl perchlorate and dissolved in benzene (1 ml), and iodine was dissolved in benzene to 0.126M. 0.4 ml (0.05 mmol) of the compound was added, and the same operation as in Example 1 was performed below to obtain β-cholestanyl 3,4,6-
Obtained with 63.2 mg (73%) of tri-0-benzyl-2-deoxy-2-acetamido-β-D-glucopyranoside. NMR (CDCl.ppm) 0.5-2.2
(M.47H. Cholestanil CH ₃ , CH ₂ , CH) Example 17 The amount of trityl perchlorate of Example 16 was 34.3 mg (0.
1 mmol) and without adding iodine, the same operation as described below was carried out, and β-cholestanyl 3,4,6-tri-0-benzyl-2-deoxy-2-acetamido-β-D-glucopyranoside 63.2 mg (73 %). NM
R was consistent with Example 16.

Claims (3)

[Claims] 1. A hydrogen of the hydroxyl group at the C-1 position of a sugar having a hemiacetal bond at the C-1 position of an amino sugar is represented by the general formula [I]. (In the formula, R ¹ and R ² represent an unsubstituted or substituted alkyl group or aryl group.) C- of the amino sugar represented by
When reacting a 1-position thiophosphinic acid ester derivative with an alcohol selected from an aliphatic alcohol, a steroid alcohol, a glycerol derivative, a sugar derivative, an amino acid derivative or an ether derivative in which a hydroxyl group of the alcohol is protected, a trityl salt, a lithium salt, or an ammonium salt salt,
A method for producing a glycoside compound of an amino sugar, which is characterized by allowing a tin salt to coexist. 2. The production method according to claim 1, wherein the trityl salt, lithium salt, ammonium salt, tin salt and iodine coexist. 3. The method according to claim 1, wherein a trityl salt, a lithium salt, an ammonium salt, a tin salt and an iodine compound are allowed to coexist.