JPH0816116B2 - 1,6-Anhydrolactose derivative with selectively introduced protecting group and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Industrial Field of the Invention The present invention is a 1,6-anhydro with selectively introduced protecting group, which is useful for the synthesis of lactose derivatives such as N-acetyllactosamine. It relates to a lactose derivative. Incidentally, a lactose derivative plays a very important role as a constituent in vivo such as lactosamine, and lactose amine is known to have an intestinal regulating action. The above-mentioned compound according to the present invention, which provides such an intermediate for the synthesis of an important physiologically active substance, is a compound that is also attracting industrial attention.

(Prior Art) As a selective protected form of lactose, the following chemical structural formula
The compounds represented by 5, 6 and 7 are known. That is, Teshima et al. Reported Compound 5 in which four of eight hydroxyl groups of lactose were protected (Chemistry and Phar.
Maceutical Bulletin, Vol. 27, No. 3, 721 (1979). T
hiem et al. also reported compounds 6 and 7 in which eight hydroxyl groups were protected with a benzylidene group that can be deprotected under acidic conditions and an acetyl group that can be deprotected under basic conditions (J. Thi.
em et al. Journal of Chemical Research, 1980, 2729-27
50 (1980)).

However, compound 5 still has 4 hydroxyl groups, and compounds 6 and 7 are compounds 19, 20, 21, and 22 having 3 or more hydroxyl groups even if the protecting group is removed under basic conditions. Therefore, it is very difficult to selectively react with any one of the eight hydroxyl groups of lactose.

(Problems to be Solved by the Invention) Lactose has eight hydroxyl groups. Therefore, when synthesizing a target lactose derivative using lactose as a starting material, it is necessary to proceed with the synthesis while distinguishing these eight hydroxyl groups.

For example, Teshima et al. Synthesize a lactosamine derivative 9 according to FIG. 1 by using compound 5 as a starting material in order to synthesize a lactosamine derivative (Chem.Pharm.B, cited above).
ull.).

However, the yield in the step of obtaining compound 10 from compound 5 is 2
It is as low as 5.2%. This is because in compound 5, four of the eight hydroxyl groups of lactose are protected, but the remaining four hydroxyl groups have little difference in reactivity. In order to efficiently synthesize a desired lactose derivative from a lactose derivative having a large number of hydroxyl groups, it is necessary to selectively protect these hydroxyl groups and carry out the reaction only with the desired hydroxyl group.

Therefore, as a result of investigating a method of selectively protecting lactose, the present inventors have found that when deacetylated under basic conditions, only two hydroxyl groups are free and the remaining six hydroxyl groups are protected. Compounds that can easily lead to 1,4
To obtain compound 1 in which only 2,3 and 2 hydroxyl groups are free,
The present invention has been made.

(Means for Solving Problems) It is considered that 1,6-anhydrolactose is a compound in which the reducing terminal of lactose and the two hydroxyl groups at the 6-position of glucose are protected. Further, this ring structure can be restored to the original compound having a hydroxyl group by an acid such as trifluoroacetic acid.

On the other hand, ketals and acetals are known as protecting groups that can be deprotected under acidic conditions that selectively protect the 4- and 6-positions of sugar compounds.

Compound 5 is known as a compound in which 1,6-anhydrolactose and acetal are combined. But,
This compound has four hydroxyl groups as described above, and it is very difficult to proceed with the synthesis of lactosamine and the like by utilizing the reactivity of these four hydroxyl groups. Teshima et al. Obtained a compound 10 which is a synthetic raw material of lactosamine by reacting compound 5 with tosyl chloride.
It is reported to be very low at 5.2% (Chem.Pharm.
Bull.).

Therefore, the present inventors studied to selectively protect 4 out of 6 hydroxyl groups of 1,6-anhydrolactose with a ketal. That is, in the known compound 1,6-anhydrolactose represented by the structural formula 8, the two hydroxyl groups of the glucose moiety have the opposite conformation to the galactose moiety due to the formation of the 1,6-anhydro ring. Therefore, it is considered that acetalization or ketalization cannot be performed.

Then, the compound 8 was reacted with 1,1-dimethoxycyclohexane under reduced pressure in the presence of a catalytic amount of camphorsulfonic acid in dimethylformamide, and the obtained reaction mixture was acetylated with pyridine and acetic anhydride. Compound 2 was obtained. It was also found that compound 3 was obtained by increasing the reaction temperature and decreasing the degree of vacuum. The amount of 1,1-dimethoxycyclohexane to be further reacted,
Reaction conditions such as reaction temperature, reaction time and degree of vacuum were examined. As a result, in order to obtain compound 2, the molar amount of 1,1-dimethoxycyclohexane is preferably 2 to 9 times,
3.3 to 7.5 times the molar amount, the degree of vacuum is 10 to 100 mmHg, preferably 25 to 50 mmHg, and the reaction temperature is 40 to 70 ° C, desirably 45 to
The reaction time at 55 ° C. was 0.5 to 10 hours, preferably 3 to 6 hours. To obtain compound 3, 1,1
-The amount of dimethoxycyclohexane is 2 to 12 times, preferably 4 to 7 times, and the degree of reduced pressure is 10 to 250 mmHg.
Desirably, the reaction temperature was 70 to 120 ° C., preferably 80 to 110 ° C., the reaction time was 1 to 10 hours, preferably 6 to 9 hours. Moreover, camphorsulfonic acid, paratoluenesulfonic acid, and methanesulfonic acid were suitable as the acid used as the catalyst.

Compounds 2 and 3 are 1,6-anhydro ring deprotected by a strong acid such as trifluoroacetic acid, two ketal groups deprotected by a weak acid such as acetic acid, and an acetyl group deprotected by a basic acid. It is a selective protected form of lactose in which all or almost all of the eight hydroxyl groups are selectively protected by various kinds of protecting groups, and the compound 1 has only two hydroxyl groups free and the other six groups. Since all the hydroxyl groups are protected,
It is useful as a synthetic intermediate for various lactose derivatives.

 Hereinafter, the present invention will be further described with reference to examples.

Example 1 (Synthesis of Compound 2) Compound 8 (1100 mg), 1,1-dimethoxycyclohexane (1.61 g), dimethylformamide (20 ml) and camphorsulfonic acid (30 mg) were reduced under a reduced pressure of 50 mmHg for 3.5 hours 5
Heated at 0 ° C. The resulting solution was cooled to room temperature, anhydrous sodium bicarbonate was added, and the mixture was stirred for 30 minutes and the crystals were filtered. The filtrate was concentrated under reduced pressure, pyridine (10 ml) and acetic anhydride (10 ml) were added, and the mixture was stirred at room temperature for 24 hours. The resulting solution was added to ice water and extracted with dichloromethane. The organic layer was washed with 2N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and then water.

The solvent was evaporated under reduced pressure and the residue was separated by silica gel column chromatography (eluent toluene: ethyl acetate = 5:
1), Compound 2 was obtained.

Yield 650 mg, yield 34%, [[alpha]] _D = -36 [deg.] (C = 0.50, chloroform).

Elemental analysis: Calculated value C: 59.15, H: 7.09 Actual value C: 59.20, H: 7.09 NMR (CDCL3) δ (ppm); 1.17-1.80 (m, 20H, H-cyclohexy
l), 2.11 (s, 3H, OAc), 2.22 (s, 3H, OAc), 3.36 (s, 3
H, OAc), 3.48 (dd, 1H, H-3 '), 3.52 (s, 1H, H-4), 3.
79-4 / 06 (m, 4H, H-6ab, H-6′ab), 4.12 (t, 1H, H-
2 '), 4.40 (broad s, 1H, H-4'), 4.53 (s, 1H, H-
3), 4.81 (broad d, 1H, H-5), 4.87 (d, 1H, H-1 '),
5.50 (s, 1H, H-2), 5.64 (s, 1H, H-1).

Example 2 (Synthesis of Compound 3) Compound 8 (550 mg), 1,1-dimethoxycyclohexane (1.46 g), dimethylformamide (15 ml) and camphor sulfonic acid (10 mg) under reduced pressure of 160 mmHg for 2 hours 110.
The mixture was further heated at 90 ° C. under reduced pressure of 70 mmHg for 6 hours. Cool the resulting solution to room temperature and add anhydrous sodium bicarbonate 30
The mixture was stirred for minutes and the crystals were filtered. The filtrate was concentrated under reduced pressure, pyridine (10 ml) and acetic anhydride (10 ml) were added, and the mixture was stirred at room temperature for 24 hours. The resulting solution was added to ice water and extracted with dichloromethane. The organic layer was washed with 2N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and then water.

The solvent was evaporated under reduced pressure and the residue was separated by silica gel column chromatography to obtain compound 3.

Yield 326 mg, yield 33.8%, [α] _D = + 54 ° (c = 0.76, chloroform), melting point 210-211 ° C. (chloroform).

Elemental analysis: Calculated value C: 59.15, H: 7.09 Actual value C: 59.19, H: 7.13 NMR (CDCl3) δ (ppm); 1.25-1.86 (m, 10H, HH-cyclohe
xyl), 2.10 (s, 6H, OAc), 3.73-3.78 (m, 3H, H-2 ′, H-
4, H-6), 3.76 (duplicate with dd, H-4, H-6), 3.84 (broad s, 1
H, H-6), 3.91 (dd, J 3,4, 6.4Hz, t, 1H, H-3), 4.03 (m, 1
H, H-5 '), 4.08 (dd, 1H, H-3'), 4.14 (dd, 1H, H-
4 '), 4.28 (dd, 1H, H-6'), 4.40 (dd, 1H, H-6 '),
4.43 (d, 1H, H- 1 '), 4.54 (d, J 2,3, 7.6Hz, 1H, H-2),
4.52 (broad d, 1H, H-5), 5.25 (s, 1H, H-1).

Example 3 (Synthesis of Compound 2) Compound 8 (550 mg), 1,1-dimethoxycyclohexane (1.83 g), DMF (10 ml) and camphor sulfonic acid (30 mg) were prepared at 50 ° C. and 25 mmHg in the same manner as in Example 1. After reacting for 6 hours and separating in the same manner as in Example 1, Compound 2 was obtained.

 Yield 469 mg, yield 48.6%.

Example 4 (Synthesis of Compound 1) A methanol solution of sodium methylate (5 M / l, 0.02 ml) was added to a methanol solution (10 ml) of compound 2 (568 mg), and the mixture was stirred at room temperature for 5 hours. Add H ⁺ type ion exchange resin (Dowex 50W-X8) to the solution to neutralize it, then pass the resin through,
The solvent was distilled off under reduced pressure. The residue was recrystallized with a mixed solvent of ethanol-chloroform to obtain compound 1.

Yield 387 mg, yield 80%, [α] _D = -58 ° (C = 0.83, methanol), melting point 218-220 ° C.

Elemental analysis: Calculated value C: 59.49, H: 7.49 Actual value C: 59.48, H: 7.38 Reference Example 1 5 mol / l sodium methylate in methanol solution (0.05m) in methanol solution (10ml) of compound 3 (484mg)
l) was added and the mixture was stirred for 5 hours at room temperature. H ⁺ in the resulting solution
Type strong acid resin 50W-X8 was added to neutralize. The resin was passed through and the solvent was distilled off under reduced pressure.

Anhydrous pyridine (10 ml) and trityl chloride (28
(0 mg) was added and the mixture was stirred for 2 hours, p-toluenesulfonic acid chloride (194 mg) was added, and the mixture was further stirred for 4 hours. The resulting solution was added to ice water (20 g) and extracted with chloroform (100 ml). The chloroform layer was washed with 2N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and water in this order, and dried over anhydrous sodium sulfate.

Methanol (20 ml) and camphorsulfonic acid (10 mg) were added to the residue, and the mixture was stirred at room temperature for 10 hours.

Pyridine (10 ml) and a sodium methylate methanol solution (5 M / l, 0.210 ml) were added to the obtained solution, and the mixture was stirred overnight.

The resulting solution was neutralized with glacial acetic acid, the solvent was evaporated under reduced pressure, and the residue was extracted with water (50 ml) and methylene chloride (50 ml). The methylene chloride layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, water, and dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure, and sodium azide (300 m
g) and dimethylformamide (30 ml) were added, and the mixture was heated at 110 ° C for 48 hours. The solvent was evaporated under reduced pressure, chloroform (200 ml) and water (200 ml) were added to the residue, the extracted chloroform layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Sulfuric acid: acetic anhydride: acetic acid = (1:
The mixture (10 ml) of 70:30 by volume) was added, and the mixture was stirred at room temperature for 15 hours. The obtained solution was treated in the same manner as in Reference Example 2 to obtain 232 mg of compound 13. Yield 35%.

Further, by treating the compound 13 in the same manner as in Reference Example 2 described later, the compound 9 is obtained.

 A flowchart of the above reaction is shown in FIG.

Reference Example 2 Compound 1 (485 mg) in dichloromethane solution (10 ml)
To the above, trifluoromethanesulfonic anhydride (290 mg) was added, and the mixture was stirred at room temperature for 4 hours.

The resulting solution was evaporated under reduced pressure, sodium azide (300 mg) and dimethylformamide (20 ml) were added to the residue, and the temperature was 110 ° C.
The mixture was heated and stirred for 48 hours. Water (50 ml) was added to the obtained solution, extraction was performed with chloroform (100 ml), and the chloroform layer was dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure, and the residue was sulfuric acid: acetic anhydride: acetic acid =
A mixture (10 ml) of (1:70:30 volume ratio) was added, and the mixture was stirred at room temperature for 4 hours. Add the residue to 200 g of ice water and 100 ml of chloroform.
It was extracted with. The chloroform layer was washed with saturated aqueous sodium bicarbonate solution and water, and dried over anhydrous sodium sulfate. Chloroform was distilled off under reduced pressure and the residue was separated by silica gel column chromatography to obtain compound 13 (397 mg). Yield 6
0%.

Compound 13 was prepared by the method of Teshima et al. (Chemistry and Pharma
Ceutical Bulletin, Vol. 27, No. 3, p. 721 (1979), reduction with Raney nickel and acetylation with acetic anhydride were carried out to obtain Compound 9, that is, the acetyl derivative of N-acetyllactosamine, in a yield of 94%.

 A flowchart of the above reaction is shown in FIG.

In Reference Example 1 and Reference Example 2, compound 1 and compound 3
When the compound 9 was synthesized starting from, the total yield was 0.60 × 0.94 × 100 = 56.4% and 0.35 × 0.94 × 100 =
In contrast to 32.9%, according to the method of Teshima et al., The total yield when starting from compound 5 and similarly synthesizing compound 9, is only 7.3%. Although the starting materials differ for both, the yield of the step of synthesizing compound 5 from compound 5 by the method of Teshima et al.
Considering that it is extremely low at 5.2%, the method of this reference example is remarkably excellent.

Ketalization using a ketal exchange reaction with 1,1-dimethoxycyclohexane as in Examples 1 to 3,
It is considered that various compounds are produced when dimethoxycyclohexane is used in excess, and it has not been put to practical use. However, the present inventors have found that compounds 2 and 3 are selectively obtained by controlling the temperature and the degree of reduced pressure during the reaction. On the other hand, Compounds 2 and 3 can be easily led to Compounds 1 and 4 in which only two hydroxyl groups are released by treating them under basic conditions (for example, a catalytic amount of sodium methylate in methanol). it can. Compounds 1 and 4 have only two reactable hydroxyl groups and all other hydroxyl groups are protected, so that when the reaction is performed only on the 2-position hydroxyl group of lactose as in Reference Examples 1 and 2, a high yield is obtained. Only the 2nd position can be modified with. From this, it is understood that the compounds 1, 2 and 3 of the present invention are very useful as synthetic intermediates for lactose derivatives.

(Effects of the Invention) For example, 1,6-anhydrolactose, which is an excellent intermediate of lactosamine to which a protective group is selectively introduced, can easily give lactosamine, which is a substance having important physiological activity, in high yield. Derivatives are provided.

[Brief description of drawings]

FIG. 1 is a flowchart of a synthetic reaction of a known lactosamine derivative, and FIGS. 2 and 3 are flowcharts of reactions of Reference Examples 1 and 2, respectively.

Claims (3)

[Claims] 1. A 1,6-anhydrolactose derivative represented by any one of the following chemical structural formulas 1, 2 and 3. 2. A 1 to 9-fold molar amount of 1,6-anhydrolactose in dimethylformamide in the presence of an acid catalyst.
40 with dimethoxycyclohexane and a reduced pressure of 10 to 100 mmHg
The method for synthesizing the compound represented by the chemical formula 2 according to claim 1, wherein the compound is heated to ˜70 ° C. for 0.5 to 10 hours and then acetylated with pyridine and acetic anhydride. 3. A 2- to 12-fold molar amount of 1,1-anhydrolactose in dimethylformamide in the presence of an acid catalyst.
Dimethoxycyclohexane and 70 under reduced pressure of 10-250 mmHg
The method for synthesizing the compound represented by the chemical formula 3 according to claim 1, wherein the compound is heated to ˜120 ° C. for 1 to 10 hours and then acetylated with pyridine and acetic anhydride.