JPH0118904B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides a formula that has an α-glucosidase inhibitory effect. A new aminocyclitol, which is an intermediate raw material for the compound represented by the general formula (In the formula, Y represents a hydrogen atom or a halogen atom.) The present invention relates to a compound represented by the following formula and a method for producing [] from valienamine using the compound. The present inventors have discovered that the N-substituted form of valienamine, that is, the general formula (wherein R represents an alkyl, aryl, or aralkyl group) unexpectedly reacts with a halogenating agent, and a halogen is added to one of the double bonds and an intramolecular cyclic carbamate bond (- Bicyclic compound formed by NH―CO―O―),
That is, the general formula A compound represented by (in the formula, X represents a halogen atom) is produced, and by dehalogenation and hydrolysis, the compound []
(hereinafter sometimes referred to as variolamine) was found to be obtainable, and as a result of further various studies, the present invention was completed. That is, the present invention involves (1) producing a compound represented by the general formula []; (2) producing a compound represented by the general formula [a] by reacting the compound represented by the general formula [] with a halogenating agent; Alternatively, the present invention relates to a method for producing the compound [], which comprises producing a compound represented by the formula [b] (described later) by subjecting the compound represented by the general formula [a] to a dehalogenation reaction. In the general formula [], [a], [], Y
is a hydrogen atom or a halogen such as fluorine, chlorine, bromine, or iodine;
sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl,
Decyl, vinyl, cyclohexenyl, cyclopropylmethyl, 1-cyclohexylethyl, cyclobutyl, 1-methylcyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl,
3,3,5-trimethylcyclohexyl, isobornyl, 2,2,2-trichloroethyl, 2,
Straight chain having 1 to 10 carbon atoms such as 2,2-tribroloethyl, 2,2,2-trichloro-tert-butyl,
Branched or cyclic saturated or unsaturated alkyl groups, e.g. aryl groups such as phenyl, naphthyl, etc.
Examples include aralkyl groups such as benzyl, phenethyl, α-naphthylmethyl, and 9-anthrylmethyl. These alkyl groups, aryl groups, and aralkyl groups include halogens such as fluorine, chlorine, bromine, and iodine, and 1-carbon atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. ~4 lower alkyl groups, such as methoxy, ethoxy, propoxy,
a lower alkoxy group having 1 to 4 carbon atoms such as butoxy,
1 to 3 substitutions may be made with nitro, p-methoxyphenylazo, p-phenylazo, phenyl, or the like. The raw material compound [ ] can be obtained by reacting valienamine with a carbonylating agent represented by the general formula RO--CO--Z, for example. In this carbonylating agent, Z is a halogen atom, such as chlorine,
Bromine, etc., or N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxy-5-norbornene-2,3-dicarboximide, 2-hydroxyimino-2-phenylacetonitrile, N-oxypiperidine, 3 ―
Oxypiperidine, p-nitrophenol, 2,
4-dinitrophenol, pentachlorophenol, 2,4,5-trichlorophenol, imidazole, 1-hydroxybenzotriazole,
4,6-dimethyl-2-mercaptopyrimidine,
It shows the residue of an active compound of 4,6-dimethylaminopyridine, 4,6-diethylaminopyridine, etc. and the carboxylic acid. Further, Z may be a residue of a carbonate ester, as in the case of -tert-butyl dicarbonate, diethyl carbonate, diphenyl carbonate, and the like. The reaction between the amino group of valienamine and the carbonylating agent described above can be carried out using water or other suitable solvents such as acetone, dioxane, tetrahydrofuran, etc.
The reaction can be carried out in an organic solvent such as methanol, dimethylformamide, chloroform, dichloromethane, etc. alone or in a mixed solvent, or in a mixed solution with water. This reaction can be carried out using inorganic bases such as sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, magnesium oxide, triethylamine such as triethylamine, tributylamine, N-methylmorpholine, pyridine, etc. It is desirable that the pH of the reaction solution be in the range of 7 to 12 in the presence of an organic base such as a class amine. The reaction temperature is usually about -10° to 60°C, and the reaction time is usually 30 minutes to 24 hours. The compound represented by the general formula [a] can be obtained by reacting the compound represented by the general formula [] with a halogenating agent. Such halogenating agents include chlorine, bromine,
Halogens such as iodine, hypohalous acids such as hypochlorous acid, hypobromous acid, hypoiodic acid, and hypohalous acids such as sodium, potassium, calcium, barium, and copper (primary and secondary). Metal salts, methyl ester, ethyl ester, tert-butyl ester of hypohalous acid, 2,4,
Hypohalous acid esters such as 6-tribromophenyl ester, N-chlorosuccinimide,
N-halogen succinimides such as N-bromosuccinimide and N-iodosuccinimide, metal halides such as titanium tetrachloride, cupric bromide, and potassium bromide, N,N-dibromobenzenesulfonamide, N-chloroacetamide , N-bromoacetamide, trichloroisocyanuric acid, N
-Chlorourea, methyl N,N-dichlorocarbamate, ethyl N-chlorocarbamate, iodobenzene dichloride, bromotrinitromethane, etc. are used. These reagents include oxygen, oxidizing agents such as hydrogen peroxide, acids such as p-toluenesulfonic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, boron trifluoride, silver acetate, silver n-butyrate, silver benzoate, and acetic acid. Heavy metal salts of organic carboxylic acids such as thallium, heavy metal oxides such as silver oxide and mercury oxide, silver carbonate,
It may be used simultaneously with metal carbonates such as calcium carbonate, alkali metal halides such as sodium iodide, potassium iodide, lithium bromide, and lithium chloride, and bases such as pyridine. The reaction is usually carried out using water, lower alcohols such as methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, N,N
-dimethylformamide, dimethylsulfoxide, sulfolane, dioxane, tetrahydrofuran, acetonitrile, acetone, chloroform,
dichloromethane, carbon tetrachloride, benzene, acetic acid,
It is carried out alone or in a mixed solvent such as. The reaction temperature is not particularly limited, but is usually 0 to 70°C.
The temperature is - depending on the type of halogenating agent.
The reaction may be carried out by cooling to about 80°C, or may be carried out by heating to the reflux temperature of the solvent. The compound represented by the general formula [a] can be prepared by a dehalogenation reaction, for example, a reductive dehalogenation reaction. This can lead to the compound represented by Reductive dehalogenating agents include various metal hydride complex reducing agents, especially borohydride complex reducing agents, such as sodium borohydride, potassium borohydride, lithium borohydride, sodium trimethoxyborohydride, Lithium triethylborohydride, sodium cyanoborohydride and the like are advantageously used. Examples of reaction solvents include water, methanol,
Alcohols such as ethanol, propanol, butanol, N,N-dimethylformamide, N
-Methylacetamide, dimethyl sulfoxide,
Glymes such as methyl cellosolve, dimethyl cellosolve, and diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, acetonitrile, or a mixed solvent thereof, or a mixture of these polar solvents and a nonpolar solvent such as ethyl acetate or benzene can be used. Although reaction conditions vary depending on the type of reducing agent, the reaction temperature is usually room temperature, sometimes under ice cooling, and sometimes heated to the reflux temperature of the solvent. The reaction time also depends on the reaction temperature.
Although it depends on the type of reducing agent, the purpose can usually be achieved by reacting for about several minutes to 24 hours. As the reductive dehalogenation method, a catalytic reduction method can also be used. That is, the reaction is carried out by shaking or stirring the compound represented by the general formula [a] in a suitable solvent in the presence of a catalyst for catalytic reduction in a hydrogen stream. As the catalyst for catalytic reduction, for example, palladium carbon, palladium black, Raney nickel, platinum black, platinum dioxide, etc. are used. As the reaction solvent, for example,
Water, alcohols such as methanol and ethanol,
Dioxane, tetrahydrofuran, dimethylformamide, or a mixed solvent thereof is used. The reaction is usually carried out at room temperature and pressure, but
It may be carried out under pressure or by heating.
The reaction time is usually about 2 to 18 hours. Further, a reductive dehalogenation reaction may be carried out using an organic tin hydride. That is, by dissolving or suspending (n-
C ₄ H ₉ ) ₃ SnH, (n-C ₄ H ₉ ) ₂ SnH ₂ , (n-
C ₃ H ₇ ) ₃ SnH, (C ₂ H ₅ ) ₃ SnH, (C ₆ H ₅ ) ₃ SnH,
Organotin hydrides such as (C ₆ H ₅ ) ₂ SnH ₂ and initiators of radical reactions (e.g. α, α′-
Azo compounds such as azobisisobutyronitrile,
The purpose can be achieved by adding and reacting a peroxide such as benzoyl peroxide, triphenylboric acid, etc., preferably α,α'-azobisisobutyronitrile. In addition, reductive desorption can be performed using aluminum hydride metal complexes such as lithium aluminum hydride, sodium aluminum hydride, sodium triethoxyaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, and sodium diethylaluminum hydride. A method of carrying out a halogenation reaction. By reaction with sodium or lithium in liquid ammonia. A method of reductive dehalogenation using zinc and hydrochloric acid or acetic acid, a method of dehalogenation by electrolytic reduction reaction, etc. can also be used. By hydrolyzing the compound represented by formula [b] thus obtained, the target compound [], that is, variolamine can be obtained. The hydrolysis reaction of the cyclic carbamate bond (-O-CO-NH-) of the compound represented by the general formula [b] is carried out in the presence of an alkali such as sodium hydroxide, potassium hydroxide, barium hydroxide, or sodium methoxide. Alternatively, it is carried out in the presence of an acid such as hydrochloric acid or sulfuric acid, usually in an aqueous solution, or in a suitable solvent such as an organic solvent such as methanol, ethanol, propanol, acetone, dioxane, tetrahydrofuran, or a mixture with water. . The reaction temperature is usually room temperature to the reflux temperature of the solvent, and the reaction time is usually about 5 to 24 hours, although it varies depending on the reaction temperature. In addition, in the step of leading the compound represented by general formula [a] to variolamine, the cyclic carbamate bond (-O-CO-NH-) of the compound represented by general formula [a]
After being hydrolyzed, the halogen atom may be subjected to a reductive dehalogenation reaction, or the hydrolysis reaction and the reductive dehalogenation reaction may be performed simultaneously. Alternatively, valienamine can be converted into a compound represented by formula [a] by reacting valienamine with a halogenating agent and then reacting with a carbonylating reagent, or by reacting a carbonylating reagent simultaneously with the halogenating reaction. You can lead to In addition, in a series of steps leading to variolamine from a compound represented by formula [], formula [a],
It is not always necessary to once isolate each synthetic intermediate compound represented by formula [b] in a pure state, and the reaction solution may be used as it is or after being partially purified for use in the next step reaction. . The hydroxyl group of the compounds represented by the general formulas [a], [b], and [] is a protecting group that is generally used as a protecting group for hydroxyl groups in sugar chemistry, such as formyl,
Acetyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, propionyl, isopropionyl, pivaloyl, benzoyl, p-nitrobenzoyl, p-phenylazobenzoyl, p-phenylbenzoyl, ethoxycarbonyl, isobutyloxycarbonyl ,
Benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, p-nitrophenoxycarbonyl, 3-benzoylpropionyl, benzoylformyl, benzylthiocarbonyl, phenylcarbamoyl, etc. acyl type protecting group, methanesulfonyl, p-toluenesulfonyl, benzenesulfonyl, benzylsulfonyl, sulfonyl type protecting group such as 2,4-dinitrobenzenesulfonyl, 2,4-dinitrobenzenesulfenyl group,
Methyl, ethyl, tert-butyl, ethoxyethyl, allyl, trityl, monomethoxytrityl,
Dimethoxytrityl, trimethoxytrityl, trimethylsilyl, dimethylethylsilyl, 2,3
-diphenyl-2-cyclopropen-1-yl,
Ether type protecting groups such as phenyl, benzyl, p-methoxybenzyl, methylene, ethylidene, isopropylidene, methoxymethylene, ethoxymethylene, methoxyethylidene, dimethoxymethylene, cyclopropylidene, cyclopentylidene,
It may be protected with an acetal or ketal type protecting group such as cyclohexylidene, cycloheptylidene, benzylidene, tetrahydropyranyl, methoxytetrahydropyranyl. Introduction of such a protecting group may be advantageous for the purpose of increasing solubility in a reaction solvent, for example. After the reaction, these protecting groups may be removed by a known method suitable for removing each protecting group. Compounds represented by the formula [] obtained in this way, that is, variolamine, and the general formula []
Compounds represented by the above can be prepared by methods known per se, such as filtration, centrifugation, concentration, vacuum concentration, drying, freeze-drying, adsorption, desorption, and methods that utilize differences in solubility in various solvents (for example, solvent extraction, tumbling, (precipitation, crystallization, recrystallization, etc.), chromatography (e.g., chromatography using ion exchange resins, activated carbon, high porous polymers, Cephadex, Cephadex ion exchangers, cellulose, ion exchange cellulose, silica gel, alumina, etc.) It can be isolated and purified by e. Valiolamine suppresses the metabolism of carbohydrates in humans and non-human animals, so it has the effect of suppressing the rise in blood sugar, and it can be used to treat hyperglycemic symptoms and various diseases caused by hyperglycemia, such as obesity and fat. hyperlipidemia, hyperlipidemia (arteriosclerosis), diabetes,
It is a useful compound for the prevention of prediabetes and diseases caused by sugar metabolism by oral microorganisms, such as dental caries. In addition, foods manufactured with the addition of variolamine are
It is suitable as a food for patients with metabolic disorders, and also for healthy people as a food for preventing metabolic disorders. It is also useful as a feed additive for livestock to obtain low-fat, high-quality edible meat. Therefore, variolamine is useful as a pharmaceutical, food additive, and animal feed additive. Variolamine is administered orally or parenterally, preferably orally. Variolamine also has little toxicity (Lat LD ₅₀ >500 mg/Kg) and can be used as the free base or hydrate and can be converted into any non-toxic acid addition salt with a pharmaceutically acceptable acid by conventional methods. It can also be used as Such acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,
Inorganic acids such as nitric acid, organic acids such as acetic acid, propionic acid, malic acid, citric acid, fumaric acid, maleic acid, ascorbic acid, mandelic acid, and methanesulfonic acid are used. Variolamine is used alone or in combination with a non-toxic carrier. For example, coffee, soft drinks, fruit juice, beer, milk, jam,
It may be used with liquid or solid foods such as fresh bean paste, seasonings, or various staple foods and side dishes.
It can be used directly or in the form of a food additive, or taken before or after meals. Furthermore, it can also be used as a feed additive for livestock to obtain low-fat, high-quality edible meat. Variolamine can be diluted with a non-toxic carrier such as a liquid carrier such as water, ethanol, ethylene glycol, or polyethylene glycol, or a solid carrier such as starch, cellulose, or polyamide powder, and then prepared into ampoules, granules, tablets, etc. Pills, capsules, syrups, etc. can be prepared according to conventional methods and used for the various uses mentioned above. In addition, sweeteners, preservatives, dispersants, and coloring agents can also be used. Specifically, for example, variolamine about 20~
By taking a preparation containing 500 mg after each meal, it is possible to suppress the increase in blood glucose concentration caused by eating. The present invention will be explained in more detail below with reference to test examples, reference examples, and examples, but the scope of the present invention is not limited thereto. Test example Glucosidase inhibitory activity α-glucosidase (yeast, type, manufactured by Sigma, USA) using maltose and sucrose as substrates and maltase and satucalase prepared from pig small intestine mucosa [B. ) and Dahlquist (A.
Acta Chemica Scandinavica (12 volumes) by Dahlqvist,
1997-2006, prepared according to the method described in 1958], the inhibitory activity to be tested is determined by adding the inhibitor to be tested to 0.25 ml of an enzyme solution appropriately diluted with 0.02 M phosphate buffer solution (PH 6.8) in the same buffer. of solution 0.5ml and substrate
Add 0.25 ml of the same buffer solution of 0.05 M maltose or 0.05 M sucrose, react this mixture at 37°C for 10 minutes, and add glucose B-test reagent (glucose oxidase reagent for glucose measurement, manufactured by Wako Pure Chemical Industries, Ltd.).
Calculate by adding 3 ml (Japan), further heating at 37°C for 20 minutes, and measuring the absorbance of the reaction solution at 505 nm. When p-nitrophenyl-α-D-glucopyranoside was used as a substrate, the inhibitory activity against α-glucosidase (yeast, type, Sigma, USA) and glucoamylase (Sparrow mold, Sigma, USA) was
0.02M phosphate buffer containing 0.005mg/ml (PH6.8)
Add 0.5 ml of the same buffer solution of the inhibitor to 0.25 ml and
Add 0.25 ml of the same buffer solution of 0.01 Mp-nitrophenyl-α-D-glucopyranoside and react at 37°C for 15 minutes, then add 3 ml of 0.1 M sodium carbonate aqueous solution.
is added to stop the reaction, and the absorbance of the reaction solution at 400 nm is measured and calculated. The 50% inhibitory concentration is
The inhibition rate (%) is determined and calculated for samples containing 3 to 5 different inhibitory substance concentrations. Table 1 shows the 50% inhibitory concentration (IC ₅₀ ) of variolamine against various α-glucosidases.

【table】

[Table] Reference example 1 Benzyloxycarbonyl valienamine Dissolve 15 g of valienamine in 300 ml of water, add 100 ml of ethyl acetate, and then add 25 ml of benzyloxycarbonyl chloride and 12 ml of sodium bicarbonate under ice cooling.
Add g at once and stir at room temperature for 3 hours. After adjusting the pH of the reaction solution to 6, the aqueous layer is separated and washed with ethyl acetate. After concentrating the aqueous layer under reduced pressure to approximately 150ml,
When the concentrate is left in the refrigerator overnight, benzyloxycarbonylvalienamine crystals are obtained. Yield: 16.4 g The crystal mother liquor was subjected to column chromatography using MCI gel CHP-20P (manufactured by Mitsubishi Chemical Industries, Ltd. (Japan), 350 ml), and after washing the column with water, it was eluted with a water-80% methanol/water gradient. The eluted fraction is concentrated under reduced pressure and then freeze-dried to obtain a white powder of benzyloxycarbonylvalienamine. Yield: 3.5 g Elemental analysis: Calculated C ₁₅ H ₁₉ NO ₆ (%): C, 58.24; H, 6.19; N, 4.53. Experimental values (%): C, 58.38; H, 6.24; N, 4.54. [α] ²⁶ _D +125.4゜ (C=1, H ₂ O) Reference example 2 Ethoxycarbonyl valienamine 25 g of valienamine, 360 ml of water and 180 ml of dioxane
Dissolve in a mixture of and cool to 0° to 5°C. Add 25 g of ethyl chlorocarbonate, and add dropwise a saturated aqueous sodium bicarbonate solution to adjust the pH to 7 while stirring at the same temperature for 1 hour. Add 2N hydrochloric acid to the reaction solution to adjust the pH to 5.5, and then concentrate under reduced pressure. The residue was subjected to column chromatography using Amberlite CG-50 (H ⁺ type, manufactured by Rohm and Haas (USA), 1.5) and eluted with water. The eluted fraction is concentrated under reduced pressure and then freeze-dried to obtain a white powder of ethoxycarbonylvalienamine. Yield: 26.2 g Elemental analysis _{: C10H17NO6} calculation (%): C, 48.58; _H , 6.93; N, 5.67. Experimental values (%): C, 48.30; H, 6.87; N, 5.37. [α] ²⁶ _D +123.9° (C=1, H ₂ O) Example 1 9-bromo-6,7,8-trihydroxy-hydroxymethyl-3-oxo-2-oxa-4
-Azabicyclo [3.3.1] Nonane Add 200 ml of an aqueous solution of 9.3 g of benzyloxycarbonyl valienamine and 250 ml of an aqueous solution of 5.3 g of bromine to 100 ml of water cooled to 5° to 10°C, and bring the temperature of the reaction solution to 5°.
While maintaining the temperature at 10°C, drop the solution over a period of approximately 1 hour. The reaction solution was further stirred at the same temperature for 1.5 hours, adjusted to pH 6 with saturated aqueous sodium hydrogen carbonate solution, and washed with ethyl acetate. Concentrate the aqueous layer under reduced pressure and remove the residue.
Apply to MCI gel CHP-20P column chromatography (Mitsubishi Chemical Industries, Japan, 600ml) and elute with water.
The eluted fraction was concentrated under reduced pressure to about 50 ml, and when the concentrated solution was left in the refrigerator, 9-bromo-6,7,8-trihydroxy-1-hydroxymethyl-3-oxo-
Crystals of 2-oxa-4-azabicyclo[3.3.1]nonane are obtained. Yield: 6.5 g Elemental analysis: C ₈ H ₁₂ NO ₆ Br.H ₂ O Calculated values (%): C, 30.39; H, 4.46; N, 4.43; Br, 25.28. Experimental values (%): C, 30.30; H, 4.54; N, 4.40; Br, 25.41. [α] ²⁴ _D +41.5° (C=1, H ₂ O) IR ν ^KBr _nax cm ^-1 :1700 (-CO-) Example 2 9-chloro-6,7,8-trihydroxy-1
-Hydroxymethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane Dissolve 2.6 g of chlorine in 300 ml of water and cool to 0° to 5°C. 250 ml of an aqueous solution of 9.3 g of benzyloxycarbonylvalienamine was added dropwise to this, and the mixture was further heated at the same temperature.
Stir for 1.5 hours. After adjusting the pH to 6 by adding a saturated aqueous sodium hydrogen carbonate solution to the reaction mixture, the mixture was washed with ethyl acetate. After concentrating the aqueous layer under reduced pressure, the residue was applied to MCI gel CHP-20P column chromatography (Mitsubishi Chemical Industries, Ltd. (Japan), 400 ml) and eluted with water. When the eluted fraction was concentrated under reduced pressure and lyophilized, 9-chloro-6,
A white powder of 7,8-trihydroxy-1-hydroxymethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane is obtained. Elemental analysis: _{C8H12NO6Cl.1 / 2H2O} Calculated value (%): C, 36.58; H, 4.99; _N , 5.33; Cl, 13.50. Experimental values (%): C, 36.52; H, 5.14; N, 5.25; Cl, 13.87. [α] ²⁶ _D +43.1° (C=1, H ₂ O) IR ν ^KBr _nax cm ^-1 :1700 (-CO-) Example 3 9-bromo-6,7,8-trihydroxy-1
-Hydroxymethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane a 20 ml of an aqueous solution of 4.54 g of ethoxycarbonylvalienamine and 50 ml of an aqueous solution of 1.76 g of bromine
Drop simultaneously into 30ml of water cooled to 10°C while keeping the same temperature. After stirring the reaction solution for an additional 1.5 hours at the same temperature, the pH was adjusted to 5.4 by adding saturated aqueous sodium hydrogen carbonate solution, and the mixture was concentrated under reduced pressure. residue
Apply to MCI gel CHP-20P column chromatography (Mitsubishi Kasei Corporation (Japan), 250ml) and elute with water. When the eluted fraction was concentrated under reduced pressure and lyophilized, 9-
Bromo-6,7,8-trihydroxy-1-hydroxymethyl-3-oxo-2-oxa-4
- Azabicyclo [3.3.1] White powder of nonane is obtained. b. Cool 50ml of methanol to 5° to 10°C. This includes benzyloxycarbonyl valienamine 9.3
A solution of 5.3 g of bromine in 50 ml of methanol and a solution of 5.3 g of bromine in 20 ml of methanol are simultaneously added dropwise. The reaction solution was further stirred at the same temperature for 1 hour, and then concentrated under reduced pressure. Ethanol/ethyl acetate (1:5) to the residue
If you add 400ml and leave it in the refrigerator overnight, it will be 9-
Bromo-6,7,8-trihydroxy-1-hydroxymethyl-3-oxo-2-oxa-4
- Azabicyclo [3.3.1] Crude crystals of nonane (8.6
g) is obtained, which is recrystallized from water to obtain 8.1 g of columnar crystals. Example 4 6,7,8-trihydroxy-1-hydroxymethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane a 9-bromo-6,7,8-trihydroxy-
Add 0.5 g of sodium borohydride to 50 ml of an aqueous solution of 1.0 g of 1-hydroxymethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane.
20 ml of an aqueous solution was added dropwise at room temperature, and the mixture was further stirred for 2 hours. After adjusting the pH to 5 by adding acetic acid to the reaction solution, it was concentrated under reduced pressure. The residue was subjected to activated carbon column chromatography (180 ml), and after washing the column with water, it was eluted with 50% methanol water. After concentrating the eluted fraction under reduced pressure, methanol-ethanol (1:10) was added to the residue and left in the refrigerator to form 6,7,8-trihydroxy-1-hydroxymethyl-3-oxo-2-oxa- Crystals of 4-azabicyclo[3.3.1]nonane are obtained. Yield 560mg. Elemental analysis: _C8H13NO6 calculated value ₍ %): C, 43.83; _H , 5.98; N, 6.39. Experimental values (%): C, 43.81; H, 5.95; N, 6.55. [α] ²⁴ _D +36.4° (C=1, H ₂ O) IR ν ^KBr _nax cm ^-1 :1670 (C=O). NMR ( _D2O ) TMS (external reference) δ value: 2.07
(1H, dd, J=2 and 15Hz), 2.34 (1H,
dd, J=5 and 15Hz), 3.45-4.1 (6H). mp254-255℃ (decomposition) b 9-bromo-6,7,8-trihydroxy-
Dissolve 2.0 g of 1-hydroxymethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane in 100 ml of water, add 400 mg of palladium black, and stir for 8 hours in a hydrogen stream. After removing the catalyst by filtration and washing with water, the filtrate and washing liquid are combined, the pH is adjusted to 6 by adding a saturated aqueous sodium bicarbonate solution, and the mixture is concentrated under reduced pressure. The residue was subjected to MCI gel CHP-20P column chromatography (Mitsubishi Chemical Industries, Japan, 250 ml) and eluted with water. The eluted fraction was subjected to activated carbon column chromatography (250 ml), and after washing the column with water,
Elute with a water-methanol gradient. The eluted fraction was concentrated under reduced pressure, methanol was added to the residue, and the mixture was left in the refrigerator overnight to obtain 6,7,8-
trihydroxy-1-hydroxymethyl-3-
Crystals of oxo-2-oxa-4-azabicyclo[3.3.1]nonane are obtained. Yield 780mg. Reference example 3 1L (1S) - (1 - (OH), 2, 4, 5/1,
3)-5-amino-1-hydroxymethyl-
1,2,3,4-cyclohexanetetrol Dissolve 4.0 g of 6,7,8-trihydroxy-1-hydroxymethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane in 200 ml of water. After adding 16 g of barium hydroxide, the mixture was heated and stirred at 70° to 80°C for 4 hours. After cooling the reaction solution to room temperature, carbon dioxide gas was passed through it for 30 minutes, and the resulting barium carbonate precipitate was filtered off. The filtrate is concentrated under reduced pressure, and the concentrated solution is subjected to column chromatography using Amberlite CG-50 (NH ⁺ ₄ type, manufactured by Rohm and Haas (USA), 250 ml). After washing the column with water, elute with 0.1N ammonia water and concentrate the eluted fraction under reduced pressure. Dowex 1×2 (OH type, manufactured by Dow Chemical Company (USA))
Apply to column chromatography as described in 1.1) and elute with water.
After concentrating the elution fraction under reduced pressure, lyophilize it to 1L (1S)
-(1(OH),2,4,5,/1,3)-5-amino-1-hydroxymethyl-1,2,3,4-
A white powder of cyclohexanetetrol is obtained. Yield: 3.3 g Elemental analysis: _{C7H15NO5.H2O Calculated} value (%): C, 39.80; _H , 8.11; _N , 6.63. Experimental values (%): C, 39.94; H, 8.08; N, 6.67. [α] ²⁵ _D +19.6° (C=1, H ₂ O) NMR (D ₂ O) TMS (external group difference) δ value: 1.80
(1H, dd, J = 3.8 and 15.5), 2.07 (1H,
dd, J=3 and 15.5), 3.4-3.6 (1H),
3.55 (1H, d, J=10), 3.63 (2H), 3.72
(1H, dd, J = 4.2 and 10), 3.99 (1H,
t, J=10).

Claims (1)

[Claims] 1. General formula (wherein, Y represents a hydrogen atom or a halogen atom). 2 General formula (In the formula, R represents an alkyl, aryl or aralkyl group) by reacting the compound represented by the general formula (wherein, X represents a halogen atom), or to produce a compound represented by the general formula (wherein, X has the same meaning as above) is subjected to a dehalogenation reaction to obtain the formula A general formula characterized by producing a compound represented by A method for producing a compound represented by the formula (wherein, Y represents a hydrogen atom or a halogen atom).