JPH01156945A - Production of novel aminocyclitol - Google Patents

Abstract

PURPOSE:To readily obtain a valiolamine having inhibitory action on alpha- glucosidase, by using a novel aminocyclitol as a starting raw material, dehalogenating to give a compound, hydrolyzing the compound and optionally eliminating the protecting group. CONSTITUTION:A compound shown by formula I [R is alkyl, aryl or aralkyl which may be replaced with 1-3 of halogen, 1-4C alkyl and alkoxy; OR<1> is (protected) OH] is reacted with a halogenating agent to give an aminocyclitol shown by formula II (X is halogen) including a novel compound (novel compound when OR<1> is OH; X is H or halogen), which is then dehalogenated to give a compound shown by formula III. This compound as a raw material is hydrolyzed and optionally the protecting group is removed to give the aimed compound {=L(1S)-[1(OH),2,4,5/1,3]-5-amino-1-hydroxymethyl-1,2,3,4- cyclohexanetetrol} shown by formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel aminocyclitol, which is an intermediate raw material for a compound represented by the formula having an α-glucosidase inhibitory effect, that is, a novel aminocyclitol having the general formula (wherein Y represents a hydrogen atom or a halogen atom). The compound [I
]Relating to a method of manufacturing.

The present inventors have discovered that N-substituted forms of valienamine, namely those of the general formula (wherein R represents an alkyl, aryl or aralkyl group;
4 alkoxy, nitro, p-methoxyphenylazo, p
-7 Enylazo or phenyl may be substituted 1 to 3 times. ) unexpectedly reacts with a halogenating agent, adding a halogen to one double bond and forming an intramolecular cyclic carbamate bond (-NH-Co-0-) to the other.
A bicyclic compound formed by, that is, a compound represented by the general formula Hυ (in the formula, X represents a halogen atom) is produced, and by dehalogenating and hydrolyzing this, compound [I] can be obtained in good yield. (hereinafter sometimes referred to as pariolamine) was found to be obtainable, and as a result of further various studies, the present invention was completed.

That is, the present invention provides (1) a method for producing a compound CI), which comprises subjecting a compound represented by the general formula CI [b) below to a hydrolysis reaction and removing a protecting group if necessary; 2) - Formula [■3]
A method for producing a compound [■], characterized in that the compound represented by is subjected to a dehalogenation reaction and a hydrolysis reaction, and if necessary, a protecting group is removed, (3) - a compound represented by formula (III) is reacted with a halogenating agent to lead to a metal compound represented by the general formula [3], which is subjected to a dehalogenation reaction and a hydrolysis reaction, and if necessary, a protecting group is removed (CI)
Concerning the manufacturing method.

Said - Formula (n), (I[,], (Ill
), Y is a hydrogen atom or, for example, fluorine, chlorine,
bromine.

Halogen such as iodine, X is for example fluorine or chlorine.

Halogen such as bromine and iodine; R is, for example, methyl.

Ethyl, propyl, isopropyl, n-butyl.

5ec-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl.

Decyl, vinyl, cyclohexenyl, cyclopropylmethyl, 1-cyclohexylethyl, cyclobutyl, l-
Methylcyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl 1313.5-Trimethylcyclohexyl, isobornyl, 2.2.2-1-lichloroethyl, 2.2.2-tribromoethyl, 2.2.2-
Straight-chain 9-branched or cyclic saturated or unsaturated alkyl groups having 1 to 10 carbon atoms, such as trichloro-tert-butyl; aryl groups such as phenyl, 7-tyl, etc., such as benzyl, phenethyl, α-naphthyl; Indicates an aralkyl group such as methyl or 9-anthrylmethyl. These alkyl, aryl, and aralkyl groups include, for example, halogens such as fluorine, chlorine, bromine, and iodine, such as methyl, ethyl, propyl, and isopropyl.

n-butyl, 5ec-butyl, isobutyl, ter
Lower alkyl groups having 1 to 4 carbon atoms such as t-butyl, lower alkoxy groups having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, nitro, p-methoxyphenylazo, p-7 enylazo, phenyl, etc. 1 to 3 may be substituted.

The raw material compound (nI) is valienamine, for example, - formula R
It is obtained by reacting a carbonylating agent represented by O-C○-2. In this carbonylating agent, Z
represents a halogen atom, such as chlorine, bromine, etc., or N-hydroxysuccinimide, N-hydroxy7-thallimide, N-hydroxy-5-norbornene-2,3
-dicarboximide, 2-hydroxyimino-2-7
Enylacetonitrile, N-oxypiveridine, 3-oxypyridine, p-nitrophenol, 2,4-dinitrophenol, pentachlorophenol.

2.4.5-) Licrophenol, imidazole.

(2) Residues of active compounds of carboxylic acids such as -hydroxybenzotriazole, 4,6-dimethyl-2-mercaptopyrimidine, 4,6-dimethylaminopyridine, and 4,6-cystylaminopyridine are shown. Also 2 is G-t
It may also be the residue of a carbonic acid ester, as in the case of ert-butyl dicarponic acid, 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 appropriate solvents such as acetone, dioxane, and tetrahydrofuran.

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 formula [8] can be obtained by reacting the compound represented by the general formula (III) with a halogenating agent.

Such halogenating agents include chlorine and 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, hypohalous acid esters such as methyl ester, ethyl ester, tert-butyl ester, and 2.4.6-dribromophenyl ester of hypohalous acid, N-chlorosuccinimide, N-bromosuccinimide, N- N-halogen succinimides such as iodosuccinimide, metal halides such as titanium tetrachloride, cupric bromide, potassium bromide, N,N-dibromobenzenesulfonamide, N-chloroacetamide, N-bromoacetamide, trichloro Isocyanuric acid, N-chlorourea, methyl N,N-dichlorocarbamate.

Ethyl Ni lolocarbamate, iodobenzene dichloride, bromotrinitromethane, etc. are used. These reagents include oxygen, oxidizing agents such as hydrogen peroxide, p-toluenesulfonic acid, formic acid, and acetic acid.

Acids such as hydrochloric acid, sulfuric acid, boron trifluoride, silver acetate.

Heavy metal salts of organic carboxylic acids such as silver n-butyrate, silver benzoate, and thallium acetate, heavy metal oxides such as silver oxide and mercury oxide, metal carbonates such as silver carbonate and calcium carbonate, sodium iodide, and iodine. It may be used simultaneously with alkali metal halides such as potassium chloride, lithium bromide, and lithium chloride, and bases such as pyridine.

The reaction is usually carried out using water, methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol,
n-butyl alcohol, isobutyl alcohol, 5e
Lower alcohols such as c-butyl alcohol and tert-butyl alcohol, NlN-dimethylformamide, dimethyl sulfoxide, sulfolane, dioxane, tetrahydrofuran, acetonitrile, acetone, and 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 it is usually carried out at 0 to 70°C, and depending on the type of halogenating agent, it may be cooled to about -80°C or heated to the reflux temperature of the solvent. You may do so.

- The compound represented by the formula [18] can be led to the compound represented by the formula by a dehalogenation reaction, for example, a reductive dehalogenation reaction.

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 the reaction solvent include water and methanol.

Alcohols such as ethanol, propatool, butanol, N,N-dimethylformamide, N-methylacetamide, dimethylsulfoxide.

Glymes such as methyl cellosolve, dimethyl cellosolve, diethylene glycol dimethyl ether, dioxane, tetrahydrofuran, acetonitrile, or a mixed solvent thereof, or these polar solvents and ethyl acetate,
Mixtures with non-polar solvents such as benzene can be used.

Although reaction conditions vary depending on the type of reducing agent, the reaction temperature is usually room temperature, in some cases under ice cooling, and in some cases heated to the reflux temperature of the solvent. Although the reaction time also varies depending on the reaction temperature and the type of reducing agent, the purpose can usually be achieved by allowing the reaction to occur 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 formula [8] 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 may be used. The reaction is usually
It is carried out at room temperature and pressure, but it can also be carried out under pressure.
It may also be heated.

The reaction time is usually about 2 to 18 hours.

Further, the reductive dehalogenation reaction may be carried out using an organic tin hydride. Namely, benzene.

Toluene, xylene, ethyl ether, dioxa.

(nC4H9)3Sn by dissolving or suspending it in an organic solvent such as diethylene glycol monoethyl ether, diethylene glycol monoethyl ether, etc.
H, (n-C4Hs)2snH2, (n-CxHy)3
SnH.

(C=Hs)nsnH, (CsH6)3SnH, (Ca
H6) Organotin hydrides such as 2SnH2 and radical reaction initiators (e.g. azo compounds such as a,α-azobisisobutyronitrile, peroxides such as benzoyl peroxide, other triphenylboronic acid, etc.) are preferred. The objective can be achieved by adding and reacting 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 (nb) thus obtained, the target compound [I], that is, pariolamine can be obtained. - Mathematical formula [■b
] of the compound represented by the cyclic carbamate bond (-0-
The hydrolysis reaction of Co-NH-) is sodium hydroxide and potassium hydroxide.

In the presence of an alkali such as barium hydroxide or sodium methoxide, or in the presence of an acid such as hydrochloric acid or sulfuric acid,
Usually, the reaction is carried out in an aqueous solution, a suitable solvent such as an organic solvent such as methanol, ethanol, propatool, 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 to pariolamine from the compound represented by the formula [■8], the cyclic carbamate (cyc I icc) of the compound represented by the formula (na) is
After the arbamate) bond (-0-Co-NH-) is 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. You can.

In addition, by reacting valienamine with a halogenating agent and then reacting with a carbonylating reagent, or by reacting a carbonylating reagent at the same time as the halogenation reaction, valienamine can be converted into a compound represented by the formula [■Y]. Good too.

Further, in a series of steps leading to pariolamine from the compound represented by formula (nI), formula (nI3).

It is not necessarily necessary to once isolate each synthetic intermediate compound represented by the formula [lrb:] into a pure state, and the reaction solution may be used as it is or after being partially purified for the reaction in the next step. good.

- The hydroxyl group of the compounds represented by formulas CI[8), (nb), and (m) 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,
Impropionyl, pivaloyl, benzoyl, p-nitrobenzoyl, p-phenylazobenzoyl, p-7enylbenzoyl, ethoxycarbonyl, isobutyloxycarbonyl, benzyloxycarbonyl, 2,2.2
-Trichloroethoxycarbonyl, 2.2.2-1-ribromoethoxycarbonyl, p-nitrophenoxycarbonyl, 3-benzoylpropionyl, benzoylformyl, benzylthiocarbonyl, phenyl 5 Acyl-type protecting groups such as rubamoyl, methanesulfonyl ,p-
Sulfonyl type bed NL such as toluenesulfonyl, benzenesulfonyl, benzylsulfonyl, 2,4-dinitrobenzenesulfonyl 2°4-dinitrobenzenesulfenyl group, methyl.

Ethyl, tert-butyl, ethoxyethyl, allyl.

Ether type protection of trityl, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl, trimethylsilyl, dimethylethylsilyl, 2,3-diphenyl-2-cyclopropen-1-yl, phenyl, benzyl, p-methoxybenzyl, etc. groups, methylene, ethylidene, isopropylidene, methoxymethylene, ethoxymethylene, methoxyethylidene, dimethoxymethylene, cyclopropylidene, cyclopentylidene, cyclohexylidene, cyclohebutylidene, benzylidene, tetrahydropyranyl, methoxytetodehydropylidene, etc. It may be protected with an acetal or ketal type protecting group. 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.

The compound represented by the formula CI) obtained in this way, i.e. pariolamine, the compound represented by the formula (n), etc., can be prepared by means known per se, such as filtration, centrifugation, concentration, vacuum concentration, drying. , freeze-drying, adsorption, desorption, methods that utilize differences in solubility in various solvents (e.g., solvent extraction, dissolution transfer, precipitation, crystallization, recrystallization, etc.), chromatography (e.g., ion exchange resins, activated carbon, high It can be isolated and purified by chromatography using porous polymers, Sephadex, Sephadex ion exchangers, cellulose, ion exchange cellulose, silica gel, alumina, etc.

Paryolamine suppresses the metabolism of carbohydrates in humans and non-human animals, so it has an effect of suppressing the rise in blood sugar levels, and it can be used to treat hyperglycemic symptoms and various diseases caused by hyperglycemia, such as obesity and obesity. It is an advantageous compound for preventing hyperlipidemia (arteriosclerosis), diabetes, prediabetes, and diseases caused by sugar metabolism by oral microorganisms, such as dental caries. In addition, foods manufactured by adding pariolamine,
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, pariolamine is useful as a pharmaceutical and food additive, and as an animal feed additive. Paryolamine is administered orally or parenterally, preferably orally.

Paryolamine has almost no toxicity (ra)LDS
I+ 500 mg/kg or more), can be used as the free base Mataha hydrate, and can also be used as any non-toxic acid addition salt with a pharmaceutically acceptable acid by conventional methods. Such acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid.

Inorganic acids such as nitric acid, acetic acid, propionic acid, malic acid,
Organic acids such as tonic acid, fumaric acid, maleic acid, ascorbic acid, mandelic acid, and methanesulfonic acid are used. Paryolamine 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 raw bean paste, seasonings, or various staple foods and side dishes, and it can be used directly or in the form of a food additive, or it can be 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.

Paryolamine can be used, for example, in a liquid carrier such as water, ethanol, ethylene glycol, polyethylene glycol, etc.
It is diluted with a non-toxic carrier such as a solid carrier such as starch, cellulose, or polyamide powder, and prepared into ampoules, granules, tablets, pills, capsules, syrups, etc. according to a conventional method, and used for the various uses mentioned above. It can be provided to In addition, sweeteners, preservatives, dispersants, and coloring agents can also be used.

Specifically, for example, about 20 to 500 paryolamine
By taking a preparation containing mg after each meal, it is possible to suppress the increase in blood glucose concentration caused by the #7 meal.

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 α- when using maltose and sucrose as glucosidase inhibitory activity substrates
Glucosidase (yeast, type I, manufactured by Sigma, USA)
and maltase and saccharase prepared from pig small intestine mucosa [Porgestrem (B, Borgstr5
m) and Dahlquist (A.

Acta Chemica 5cand by Dahlqvist
inavica) Volume 12.

1997-2006, prepared according to the method described in 1958], the inhibitory activity of the inhibitor to be tested was determined by adding 0.25% of the enzyme solution appropriately diluted with 0.02M phosphate buffer (pH 6-8). Add 0.5 ml of the buffer solution and 0.25+n12 of the same buffer solution containing 0.05 M maltose or 0.05 M sucrose as a substrate, and stir the mixture at 37 °C.
C for 10 minutes, add glucose B-test reagent (glucose oxidase reagent for glucose measurement, manufactured by Wako Pure Chemical Industries, Ltd. 1 Japan) 3-, further heat at 37°C for 20 minutes, and measure the absorbance of the reaction solution at 505 nm. Calculate by

The inhibitory activity against σ-glucosidase (yeast, type I, manufactured by Sigma, USA) and glucoamylase (Arachnoid fungus, manufactured by Sigma, USA) when p-nitrophenyl-α-D-glucopyranoside was used as the substrate was α−
glucosidase at 0.005 mg/m (2 containing 0,
Add 0.25 mL of the same buffer solution of the inhibitor and 0.25+++12 of the same buffer solution of 0.01 M p-nitrophenyl-σ-D-glucopyranoside to 0.25 mL of 0.2M phosphate buffer solution (pH 6,8) and mix at 37 degrees. After reacting at C for 15 minutes, the reaction is stopped by adding three 0.1 M aqueous sodium carbonate solution, and the absorbance of the reaction solution at 400 nm is measured and calculated. The 50% inhibitory concentration is calculated by determining the inhibition rate (%) for samples of 3 to 5 different concentrations of the inhibitor.

Table 1 shows the 50% inhibitory concentration (ICso) of variolamine against various α-glucosidases.

(Left below) Table 1 Reference example 1 for σ-glucosidase of pariolamine Benzyloxycarbonyl valienamine valienamine 1
Dissolve 5g in 300 precepts of water, add ethyl acetate 100+111
After adding 2, 25 g of benzyloxycarbonyl chloride and 12 g of sodium bicarbonate were added at once under water cooling, and the mixture was stirred 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 about 150 ml, the concentrated solution is left in a refrigerator overnight to obtain crystals of benzyloxycarbonylvalienamine. Yield: 16.4 g The crystal mother liquor was subjected to column chromatography using MCI gel CHP-20P (Mitsubishi Kasei Corporation (Japan), 350 mC), 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 3.5g Elemental analysis: Cr s HIs N Oa calculated value (
%): C, 58,24; H, 6,19; N, 4
．． 53° Experimental value (%): C, 58, 38; H, 6
, 24; N, 4.54° Reference Example 2 Ethoxycarbonyl valienamine 25 g of valienamine was mixed with water 360- and dioxane 180+
Dissolve in n+2 mixture and cool to 06-5°C. 2.5 g of ethyl chlorocarbonate was added thereto, and a saturated aqueous sodium bicarbonate solution was added dropwise to adjust the pH to 7 while stirring at the same temperature for 1 hour. The reaction solution was adjusted to pH 5.5 by adding 2N hydrochloric acid, and then concentrated under reduced pressure. The residue was washed with Amberlite CG-50 (manufactured by HL Rohm and Haas).
The product was subjected to column chromatography (USA), 1°512) and eluted with water. The eluted fraction is concentrated under reduced pressure and then freeze-dried to obtain a white powder of ethoxycarbonylvalienamine.

Yield 26.2g Elemental analysis 201°H,? No.

Calculated value (%): C, 48,58; H, 6,93;
N, 5.67° Experimental value (%): C, 48,30;
H, 6,87, N, 5.37° Example 1 9-bromo-6,7,8-trihydroxy-1-hydroxymethyl-3-oxo-2-oxa-4-azabicyclo(3,3,1 ) Nonane was cooled to 5° to 10°C; an aqueous solution of 9.3 g of benzyloxycarbonyl valienamine in 100 g of water.
and 5.3 g of bromine in an aqueous solution, and the temperature of the reaction solution was set to 5.
It is simultaneously added dropwise over a period of about 1 hour while maintaining the temperature between 10 °C and 10 °C. 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. The aqueous layer was concentrated under reduced pressure, and the residue was purified using MCI gel CHP.
-20P column chromatography (Mitsubishi Chemical Industries Department (Japan),
600 g) and eluted with water. The elution fraction is approximately 50m
When concentrated under reduced pressure to 12 and left the concentrated solution in the refrigerator, 9-
Bromo-6,7,8-trihydroxy-1-hydroxymethyl-3-oxo-2-oxa-4-azabicyclo(
3,3,1) Nonane crystals are obtained.

Yield 6.5g.

Elemental analysis: C@H+2NO,Br”H,0 Calculated value (%): C, 30,39; H, 4,46; N,
4.43; Br, 25.28° Experimental value (%”): C, 30,30; H, 4,54
; N, 4.40°Br, 25.41a Example 2 9-chloro-6,7,8-)dihydroxy-1-hydroxymethyl-3-oxo-2-oxa-4-azabicyclo(3,3,1 ) Dissolve 2.6 g of nonane chlorine in 300 g of water and cool to 0°-5°C. 250 g of an aqueous solution of 9.3 g of benzyloxycarbonyl valienamine was added dropwise to this, and 1.
Stir for 5 hours. The reaction mixture was adjusted to pH 6 by adding a saturated aqueous sodium bicarbonate solution, and then washed with ethyl acetate. After concentrating the aqueous layer under reduced pressure, the residue was subjected to MCI gel CHP-20P column chromatography (Mitsubishi Chemical Industries (Japan), 400d).
and eluted with water. When the eluted fraction was concentrated under reduced pressure and lyophilized, 9-chloro-6,7,8-1-dihydroxy-1
A white powder of -hydroxymethyl-3-oxo-2-oxa-4-azabicyclo(3,3,1)nonane is obtained.

Elemental analysis: CaH1xN Oac12-1 /
2 H20 calculated value (%): C, 36, 58; H,
4,99; N, 5.33; CI2.13.50° Experimental value (%): C, 36,52; H, 5,14;
N, 5.25; ca, 13.87° Example 3 9-bromo-6,7,8-trihydroxy-1-hydroxymethyl-3-oxo-2-oxa-4-azabicyclo(3,3, 1) Nonane a) 20 mQ of an aqueous solution of 45.4 g of ethoxycarbonylvalienamine and 50 mQ of an aqueous solution of 1.76 g of bromine
are simultaneously dropped into 30 mα of water cooled to 5° to 10° C. while maintaining the same temperature. After stirring the reaction solution for another 1.5 hours at the same temperature, a saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH.
Adjust to 5.4 and concentrate under reduced pressure. MCI gel C
It was subjected to HP-20P column chromatography (Mitsubishi Chemical Industries, Japan, 250 mf2) and eluted with water. When the eluted fraction was concentrated under reduced pressure and lyophilized, 9-bromo-6,7,8-1
-dihydroxy-1-hydroxymethyl-3-oxo-
A white powder of 2-oxa-4-azabicyclo(3,3,I)nonane is obtained.

b) Cool 50 mQ of methanol to 5°-10°C.

Add to this 9.3 g of benzyloxycarbonyl valienamine.
A solution of 50 ml of methanol and a solution of 5.3 g of bromine in 20 methanol were simultaneously added dropwise. The reaction solution was further heated at the same temperature for 1
After stirring for an hour, concentrate under reduced pressure.

Add 400 mQ of ethanol/ethyl acetate (1:5) to the residue.
When added and left in the refrigerator overnight, 9-bromo6.7
．． Crude crystals (8.6 g) of 8-trihydroxy-1-hydroxymethyl-3-oxo-2-oxal 4-azabicyclo(3,3,1) nonane were obtained, and when recrystallized from water, columnar crystals 8 were obtained. .1 g was obtained.

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-1
-Hydroxymethyl-3-oxo-2-oxa-4-azabicyclo[3,3,1)nonane1. Aqueous solution of Og 50
mQ, an aqueous solution of 0.5 g of sodium borohydride 20
Add the solution dropwise at room temperature and stir for an additional 2 hours. The reaction solution was adjusted to pH 5 by adding acetic acid, and then concentrated under reduced pressure. The residue was subjected to activated carbon column chromatography (180 m<2), and after washing the column with water, it was eluted with 50% aqueous methanol. After concentrating the eluted fraction under reduced pressure, methanol-ethanol (1:10) was added to the residue.
is added and left in the refrigerator to obtain crystals of 6.7.8-)lihydroxy=1-hydroxymethyl-3-oxo-2-oxa-4-azabicyclo(3,3,1)nonane. Yield 560mg0 Elemental analysis: c 8H13N Oa calculation value (%):
C, 43,83; H, 5,98; N, 6.39
゜Experimental value (%): C, 43,81; H, 5,95i
N, 6.55°NMR (D20) TMS (external standard)
δ value: 2.07 (IH.

dd, J=2 and 15Hz), 2.34(IH, d
d, J=5 and 15Hz), 3.45-4.1 (6
H).

mp254-255°C (decomposition) b) 9-bromo-6,7,8-trihydroxy-1
-Hydroxymethyl-3-oxo-2-oxa-4-azabicyclo(3,3,1)nonane2. Og to 100m of water
400 mg of palladium black was added to the solution, and the mixture was stirred in a hydrogen stream for 8 hours. After removing the catalyst by filtration and washing with water, the filtrate and washing liquid were combined, and a saturated aqueous sodium bicarbonate solution was added to adjust the pH to 6.
and concentrate under reduced pressure.

The residue was purified by MCI gel CHP-20P column chromatography (
manufactured by Mitsubishi Chemical Industries (Japan), 250 m12), and eluted with water. The eluate fraction was subjected to activated carbon column chromatography (250
After washing the column with water, it is eluted 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.
．． 8-1-lihydroxy-1-hydroxymethyl-3-
Oxo-2-oxa-4-azabicyclo[:3.3.1
) Nonane crystals are obtained. Yield 780mg.

Example 5 1L(I5)-(1(OH), 2.4.5/1.3)
-5-amino-1-hydroxymethyl-1,2,3゜4
-Cyclohexanetetrol 6.7.8-trihydroxy-1-hydroxymethyl-
3-oxo-2-oxa-4-azabicycloC3,3,
1) Nonane 4. After dissolving Og in 200ml of water and adding 16g 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, add carbon dioxide gas for 30 minutes.
The barium carbonate precipitate formed was filtered off. The filtrate was concentrated under reduced pressure, and the concentrated solution was transferred to Amberlite CG-50 (N
Ha type.

Manufactured by Rohm and Haas (USA), 250m12)
column chromatography. After washing the column with water, elute with 0°IN aqueous ammonia, and concentrate the eluted fraction under reduced pressure. The residue is subjected to column chromatography using DOWEX 1
I 5)-(1(OH), 2.4°5/1.3)-5-
A white powder of amino-1-hydroxymethyl-1,2,3,4-cyclohexanetetrol is obtained. Yield 3.
3g Elemental analysis: C7HrsN Os・H,0 Calculated value (%): C, 39,80; H, 8,11; N
, 6.63° Experimental value (%): C, 39,94; H
, 8, 08; N, 6.67°NMR (D20) TMS
(External standard) δ value: 1.80 (IH.

dd, J=3.8 and 15.5Hz), 2.07(
IH, dd, J = 3 and 15.5 Hz), 3.4
~3.6 (LH), 3.55 (IH, d, J=lOH
z), 3.63 (2H), 3.72 (IH, dd,
J=4.2 and 1OHz), 3.99(LH,t,
J=lOHz).

Agent Patent Attorney Iwa 1) Hiroshi

Claims (3)

[Claims] (1) A compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. A method for producing a compound represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼, which is characterized by removing (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, OR^1 represents the optionally protected hydroxyl group,
represents a halogen atom) is subjected to a dehalogenation reaction and a hydrolysis reaction, and if necessary, protective groups are removed. A method for producing a compound that is (3) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R represents an alkyl, aryl, or aralkyl group, and these groups are halogen, C_1_4 alkyl, C
A compound represented by _1_4 (which may be substituted with 1 to 3 alkoxy, nitro, p-methoxyphenylazo, p-phenylazo or phenyl, and OR^1 represents a hydroxyl group which may be protected) is used as a halogenating agent. This leads to a compound represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, OR^1 has the same meaning as above, and X represents a halogen atom), and a dehalogenation reaction and A method for producing a compound represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼, which is characterized by subjecting it to a hydrolysis reaction and removing a protective group if necessary.