JPS6130661B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel gluconolactam derivative represented by the following general formula (). R = benzyl or benzoyl group X = hydrogen or hydroxyl group The present inventors previously discovered and isolated a substance represented by the formula shown below from nature for the first time, named it moranoline, and reported it. (Yagi et al.: Journal of the Japanese Society of Agricultural Chemistry, Vol. 50, p. 571 (1976)). Subsequently, the present inventors discovered that moranolin is an extremely useful substance as a medicine, invented a medicine whose main ingredient is moranolin, and filed a patent application. The present inventors subsequently engaged in research on the synthesis of moranolin, and succeeded in synthesizing moranolin using industrially inexpensive glucose or gluconic acid derivatives as starting materials. The substances included in the present invention are important intermediates in this synthesis and are useful substances. For example, a substance according to the invention in which R is a benzyl group is reduced with a hydride reducing agent such as lithium aluminum hydride, aluminum hydride or diporane to give a piperidine derivative, followed by catalytic reduction or a hydrohalic acid such as hydrogen bromide. Moranoline can be obtained by debenzylation by treatment with acid. When R is a benzoyl group, moranoline can be obtained by reducing with lithium aluminum hydride or by reducing with diborane and then hydrolyzing the benzoyl group. Examples of substances included in the present invention are listed below, and their physical constants are shown.

【table】

[Table] The compounds included in the present invention can be synthesized by various methods using glucose or 5-ketogluconic acid as a raw material. For example, the compound ()() is obtained by oxidizing 2,3,4,6-tetra-O-benzylglucose with DMSO-acetic anhydride.
-Tetra-O-benzylgluconic acid-γ-lactone, then treated with methanol containing a catalytic amount of hydrogen chloride to open the lactone ring to form a hydroxy-methyl ester, and then oxidized the hydroxyl group with DMSO-acetic anhydride. 2, 3, 4, 6-tetra-
O-benzyl-5-ketogluconate methyl ester (). Compound () () can be obtained by reducing () via oxime or imine. In this case, an important feature of this method is to reduce the hydroxyl group in a form protected by benzyl ether or benzoyl ester; if the hydroxyl group is reduced in the free state, it has an idose-type configuration which is less useful. () Substances are preferentially produced. Also, the substances of compounds () to () are 2.
3,4,6-tetra-O-benzylgluconic acid-
γ-lactone or 2,3,4,6-tetra-O-
2,3,4,6-tetra-O-benzyl (or benzoyl)- obtained by treating benzoylgluconate-γ-lactone with ammonia to obtain a hydroxy-amide compound, and then oxidizing the hydroxyl group with DMSO-acetic anhydride. It can be synthesized by ring-closing 5-ketogluconamide () with an acid catalyst.

【formula】

[Formula] The method for synthesizing the substances included in the present invention will be explained in more detail with reference to Examples. Example 1 Synthesis of compounds (), () 2,3,4,6-tetra-O-benzyl-5-
17 g of an oxime (oil) obtained by heating and refluxing methyl ketogluconate with hydroxylamine hydrochloride in the presence of sodium acetate in methanol for 2 hours is dissolved in 200 ml of ethanol containing 5.0 g of caustic potassium, and about 25 ml of Raney-nickel catalyst is dissolved. and catalytic reduction at room temperature and pressure for 96 hours. After the reaction is completed, the catalyst is separated, the liquid is dried under reduced pressure, the residue is dissolved in benzene, washed with dilute alkali and dilute acid, and benzene is distilled off to obtain a crude reaction product (oil). This reaction product was separated and purified using high performance liquid chromatography (preparative use, column: Poracil, solvent: chloroform: n-hexane: isopropanol = 100:50:1),
Recrystallized from methanol (11.4g)
3.5 g of () substance (difficult to crystallize, oily substance) was obtained. Example 2 Synthesis of compounds (), () 2,3,4,6-tetra obtained by treating 2,3,4,6-tetra-O-benzylglucono-γ-lactone with ammonia gas in ether -O-
Benzyl gluconamide (melting point 86.5-87.5℃,
[α] ²⁴ _D = +26.4゜(methanol)) 72g
Dissolve in a mixture of 600 ml of DMSO and 120 ml of acetic anhydride,
React at ℃ for 8 hours. After the reaction, it was diluted with water, extracted with benzene, and the extract was recrystallized from a mixture of isopropanol and hexane. Yield: 45g. Melting point 113-114.5℃.
[α] ²⁴ _D = +2.8° (chloroform). 20 g of 2,3,4,6-tetra-O-benzyl-5-ketogluconamide obtained above was dissolved in 200 ml of chloroform, 10 ml of acetic acid was added, and the mixture was reacted at room temperature for 72 hours. After the reaction, the reaction solution was washed with dilute alkali and then distilled off, and the residue was separated and purified by silica gel column chromatography and recrystallized from isopropanol to obtain 8.1 g of () substance and 7.7 g of () substance. Example 3 Synthesis of compounds () and () 2.2 obtained by benzoylating glucono-γ-lactone with benzoyl chloride-pyridine
2,3,4,6-tetra-O- obtained by treating 3,4,6-tetra-O-benzoyl-γ-gluconolactone with ammonia gas in chloroform
Benzoyl gluconamide (melting point 151-153℃,
[α] ²⁴ _D = +41.8゜(chloroform)) 70g
Dissolve in a mixture of 280 ml of DMSO and 140 ml of acetic anhydride, and react at 4°C overnight and then at 22°C for 8 hours. After the reaction, the reaction solution was diluted with water, extracted with ethyl acetate, the extract was directly dissolved in 300 ml of chloroform, 10 ml of acetic acid was added, and the mixture was reacted at room temperature for 3 hours. After the reaction, the reaction product was washed with dilute alkali, the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography.
Recrystallized from isopropanol () substance 42.5
g, () 11.5 g of material was obtained.

Claims (1)

[Claims] A gluconolactam derivative represented by the following general formula (). However, in the formula, R represents a benzyl group or a benzoyl group, and X represents hydrogen or a hydroxyl group.