HU204505B - Process for producing pseudo-amino-sugars - Google Patents

Abstract

The present invention relates to a process for the preparation of pseudoamine sugars of the formula (III): wherein R 3 is hydrogen, A is hydrogen or C 1-7 -alkyl substituted with one or more hydroxyl groups and optionally phenyl is a bond of the R or S configuration. by providing a compound of formula (I) wherein R1 is a hydroxy protecting group for the preparation of compounds containing a hydrogen atom with hydroxylamine or the like; The compound of formula (R2) -NH2, wherein R2 is the same as for the above hydrogen atom, is prepared by reacting a compound other than hydrogen with one of the above groups, reducing the resulting compound, preferably H2 / Pt, or the like. sodium cyanoborohydride, and the remaining hydroxyl protecting groups are removed. EN 204 505 Description range: 16 pages (including 3 sheets)

Description

The present invention relates to a process for the preparation of pseudoamine sugars.

Valalamine and Valiololamine are known to inhibit alpha glucosidase function (J. Antibiot, 35, [1982], 1624-1626; J. Antibiot, 37, [1984] 1301-1307; Caibohydr, Sl. , 140, 180-200 (1985); J. Med. Chem., 29, 1038-1046 (1986)) and as such is useful in humans and mammals for the treatment of diseases associated with hyperglycemia, such as diabetes, obesity, hyperlemia and the like. treatment and prevention.

We have previously found that valien-amine and Valiol-amine are Streptomyces hygroscopicus subs. It can be isolated from a culture of Iimoneus (J. Antibiot. 37, [1984] 1301-1307) and valienamine can be produced by microbiological degradation of validamycin or validoxyamines (Japanese Patent Laid-Open Nos. 57-54593 and 58-1524961) and Valiolamine. it can also be prepared from vacuole amine (Carbohydr. Res., 140, 180-200-200 [1985]; European Patent Nos. 63,950 and 4,446,319 (1984)).

The following processes are also known for the preparation of DL-valienamine amine and DL-valiolamine amine: DL-1,2,3-yl-Oacetyl- (1,3 / 2,4,6) -4-bromo-6- bromomethyl-1,2,3-cyclohexane triol is used to prepare DL-valienamine [T. Toyokuni et al. Bull. Chem. Soc. Jpn., 56, 1161-1170. She. (1983) 1,1 DL-2,3-di-O-acetyl-1,7-O-benzylidene (1,3,4 / 2,5,6) -4-azido-6- (hydroxymethyl). -1,2,3,5-Cyclohexanetrol, DL-valenamine is prepared [S. Ogawa et al. J. Org. Chem., 48,1203-1207. She. (1983)] from DL-1,2,3-tri-O-acetyl- (1,3 / 2,4) -4-bromo-6-methylene-1,2,3-cyclohexane triol DL-penta-NO-. acetyl aliolamine [S. Ogawa et al. Chem. Lett, 1581-1582. She. [1985]]. However, one of the known methods did not resolve the DL blends.

The chemical preparation of an enantiomeric valienamine corresponding to a natural valence amine starting from L - (-) - quebrachytol has also been described (H. Paulsen, FR Heiker, Justus Liebigs Ann. Chem. 1981, 2180-2203). involves many steps and therefore the industrial applicability of the process is questionable.

It is also known to prepare N-substituted valen amine from D-glucose 1D- (1,2,3,6,2) -4-benzoyloxymethyl-6-bromo-1,2,3-tri-O-benzyl-4 cyclohexene-l, _2> 3-triol and its LD (l, 3 / 2,6) -izomeqeibőí [N. Sakairi, H. Kuzuhara, Tetrahedron Lett, 23,5327-5330. She. (1982)]. ^í

However, the disadvantage of the above chemical methods is that they are less stereoselective and difficult to access starting materials, and involve multiple reaction steps and are thus difficult to industrially implement. f

The simplest and most suitable method for the production of Valenamine and Valiolamine is the fermentation pathway in Streptomyces hygroscopicus subs. limoneus microorganism, but with little to no yield. 5

From an industrial point of view, the microbiological degradation of validamycin, in particular validamycin A, is the most preferred process for the production of valalamine, however, the disadvantage of the method being that only a few constituents of validamycin A are suitable (valen amine has a molecular weight of about 1 / 2.7 is part of validamycin), which makes the process quite expensive.

It is known that N-substituted Valenamine and Valiolamine can be prepared by reductive alkylation of the 5 amine groups of Valenamine and Valiolamine with aldehydes or ketones, or the amino group of Valenamine or Valiolamine with oxirane or halogen derivatives (J. Antibiotics, 35, 1624-1626 (1982); J. Med. Chem., 29, 1038-1046 (1986); 56194 (1982) and 8981210 (1983)). Until now, only valiolamine has been used for the preparation of N-substituted Valiolamine.

We have discovered that by using an inositol compound to view the N-substituted valiolamine moiety, it would be possible to use a primary amine having the appropriate structure to form the N-substituted moiety and thus, if the primary amine is more readily available than the corresponding aldehyde, ketone. or oxirane compound, the final product may be more preferably prepared in 0 than starting with a valiolamine.

SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of pseudoamino sugars of the formula

R ³ is hydrogen,

A is hydrogen or a C 1 -C 7 alkyl and wavy line substituted with one or more hydroxy and optionally phenyl, which represents a R- or S-configuration, such that a compound of formula (Τ ') wherein R ¹ is a hydroxy- protecting group - For the preparation of compounds containing a hydrogen atom with hydroxyamine, sit. For the preparation of compounds of the above group other than hydrogen by reaction with a compound of the general formula R ² -NH ² - wherein R ² has the same meaning other than the above hydrogen atom, the resulting compound is reduced, preferably H2 / Pt. using sodium cyanoborohydride and removing any remaining hydroxy protecting groups.

The compounds of formula (IH) prepared according to the invention are known.

Examples of compounds of the formula R ² -NH ₂ are: ethanolamine, 3-amino-1-propanol, 2-amino-1-propanol, 2-amino-1,3-propanediol, 11-amino- 2-propanol, 2-amino-3-hydroxy-1-butanol, tris (hydroxymethyl) aminomethane, 2-amino-2-methyl-1,3-propanediol, 2-amino-2-methyl-1 -propanol, 2-amino-3-methyl-1-butanol, 3-amino-1,2-propanediol, 4-amino-1,2-butanediol, 2-amino-1-butanol, 2-amino-1,4 butane diol,

2-amino-1,5-pentanediol, 5-amino-1-pentanol, 6-amino-1-hexanol, methylamine, ethylamine, propylamine, butylamine, benzylamine, phenethylamine, amino- diphenylmethane, 2-amino-1-phenylethanol, 2-amino-2-phenylethanol, 2-amino-3-phenyl-1-propanol, 2-amino-3-hydroxy-3-phenyl-1-propanol, amino-3- (4-hydroxyphenyl) -1-propanol, β-aminoethylphenethyl alcohol. The hydroxyl groups of the above groups may be optionally protected. The mentioned formulas (II) and (III) wherein the group denoted by the same primers previously labeled R ² -NH ₂ amine compounds of formula R ² report.

HU 204 505 Β

For example, in the formulas I ', the hydroxyl protecting groups R ¹ are described in Protective Groups in Organic Chemistry, ed. J. F, W. McOnil, Plenium Publisher, London, 1973; Protective Groups in Organic Synthesis, TW Greene; John Whiley and Sons, New York.

Hydroxy protecting groups of ^R1 may be the same or different site.

It is known that sedoheptulose, the starting material of the compound of formula (Γ), accumulates in the culture medium of certain microorganisms (actimomycetes) [J. Biochem. (Tokyo), 54, 107-108. She. (1963); No. 5,240/1982] and can be isolated from this culture medium. Further, by heating the sedoheptulose in dilute mineral acid such as dilute sulfuric acid, sedoheptulose (2,7-anhydro-sedoheptulose) can be obtained as a crystalline material. Starting from D-idoheptulosan (2,7-anhydro-p-D-ido-2-heptulopyranose), sedoheptulosan can be prepared, for example, according to the following reaction steps (Scheme A):

i) protecting the hydroxyl group at the 4- and 5-positions of the sedoheptulosan, for example with the isopropyhdene group, ii) protecting the hydroxyl group at the 1- and 3-position with the benzoyl group (Bz), iii) removing the 4- and 5-hydroxy groups. (iv) protecting the hydroxy group at the 4-position, e.g. with a benzoyl group,

v) organosulfonylating the 5-hydroxy group, e.g. imidazolylsulfonyl, vi) inverting the configuration of the 5-hydroxy group by reacting with an acyloxy group such as benzoyloxy, and vii) removing the protecting groups if desired.

D-ido-heptulosan (2,7-anhydro-pD-ido-2-heptulopyranose) and 1,3,4,5-tetra-O-acetyl derivatives of 2,7-anhydro-pD-arabino-2 obtained from sedoheptulosan Starting from 5-heptothiolopyranose, K. Heyns et al., Chem. Bér., 108, 3611-3618. She. (1975)]. D-ido-heptulose and 2,7-anhydro-pD-ido-heptulopyranose by microbiological oxidation of D-gluco-D-ido-heptitol according to the procedure of JW Pratt [J. Am. Chem. Soc., 74, 2210-2214. She. (1952)]. Similar to these known procedures, D-ido-heptulosane (VH) is obtained, wherein R ¹ is hydrogen, and D-ido-heptulosane having a protected hydroxyl group is obtained.

The preparation of the compound of formula (Γ) starting from the D-ido-heptulosan compound of formula (VII) (R ¹ is a hydroxyl protecting group) is described in detail in Scheme B. The (Γ), to (Π) - (VII) wherein R ^1, R ^2, R ³ and A are as defined above R ⁴ represents hydrogen or a hydroxyl protecting group, X is a halogen atom such as iodine, bromine, chlorine or flouratom .

Step A-1

The compound of formula (VI) is obtained by cleaving the 2,7-anhydride bond of the compound of formula (VII). The preferred protecting group is hydroxyl R ¹ is benzoyl the cleavage reaction of the anhydro bond cleavage reaction was carried out with [ "1,6-anhydro derivatives of aldohexoses" by M. and J. Stanek Jr. Cemy "Adv. Carbohyd. Chem. Biochem. 34, 63-69. She. (1977)]. The cleavage reaction is preferably carried out in an acidic medium. Suitable acids include, for example, inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, perchloric acid, organic acids such as p-toluenesulfonic acid, acetic acid, acetic anhydride, trifluoroacetic acid, trifluoroacetic anhydride, Lewis acids, e.g. for example, boron trifluoride, boron trichloride, boron tribromide, zinc chloride, aluminum chloride, titanium tetrachloride, tin chloride, phosphorus pentachloride, phosphorus pentabromide, phosphorus pentoxide. The listed compounds may be used alone or in mixtures thereof.

The cleavage reaction is generally carried out in the presence of a scavenger. Suitable solvents are, for example, water, methanol, ethanol, propanol, trimethoxymethane, ethyl ether, chloroform, dichloromethane, acetone, acetic acid, trifluoroacetic acid, acetic anhydride, trifluoroacetic anhydride or any other solvent used in the reaction. does not affect its course. Preferably, the cleavage reaction is carried out in the presence of trimethoxymethane and zinc chloride in methanol, in the presence of trifluoroacetic acid and trifluoroacetic anhydride in trimethoxymethane, in which case compounds are obtained in which R ⁴ is methyl. The reaction temperature may vary as desired. The reaction can also be carried out under cooling to room temperature or under heating.

After completion of the reaction, the hydroxy group may be deprotected if desired, or the hydroxy group may be deprotected again.

Step A-2

In this step, the compound of formula (V) is prepared by halogenating the compound of formula (VI). While it is not always necessary to protect the 3-, 4- and 5-position hydroxyls, the 1-position primary hydroxyl group and the 2-position anomeric hydroxyl group must always be protected.

The halogenation reaction is carried out according to known halogenation procedures for hydroxyl groups. [Somé Approaches to the Synthesis of Halodeoxy Sugars: S. Hanessian, Advances in Chemistry Series 74; Deoxy Sugars, 159-201. She. (1968), edited by the American Chemical Society, and "Deoxyhalogeno Sugars" by W. A. Szaiek, Adv. Carbohydr. Chem. Biochem., 28, 225-306. She. (1973)].

Known halogenation reactions include, for example, reacting a phosphine compound such as triphenylphosphine with N-halosuccinimide such as N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide, preferably N-iodosuccinimide, or the hydroxyl group, e.g. sulfonyl groups such as p-lolylsulfonyl, methylsulfonyl, trifluoromethanesulfonyl, imidazole sulfonyl

HU 204505 Β, then metal halide (formula MX,

M is an alkali metal such as lithium, sodium or potassium; X is a halogen atom such as fluorine, chlorine, bromine or iodine.

The halogenation reaction is generally carried out in the presence of a solvent. Suitable solvents are, for example, Ν, Ν-dimethylformamide, dimethylsulfoxide, pyridine, acetone, 2,4-pentanedione, 2-byananone, ethylene glycol, methanol, ethanol, glycerol, dioxane, tetrahydrofuran, chloroform. , tetrachloroethane, carbon tetrachloride, benzene. In addition to these compounds, of course, other solvents which do not adversely affect the reaction may be employed. The reaction temperature is not critical and may be carried out under cooling, at room temperature or under heating. 15

Step A-3

In this step, the 6,7-unsaturated compound of formula (IV) is prepared by dehydrohalogenating the 7-halogen compound of formula (V). Removal of the hydrogen halide is carried out according to known procedures (Synthesis and Reactions of Unsaturated Sugara, L. Hongh, Advances in Chemistry Series 74: Deoxy Sugara, 120-140). She. (1968), ed. American Chemical Society]. Preferred of these reactions is the reaction of a compound of formula (V) with anhydrous silver fluoride in the presence of pyridine.

Step A-4

In this step, the compound of formula (például) is prepared, for example, by reacting a compound of formula (IV) with a mercury salt (S) such as mercury (S) chloride, mercury (S) acetate, bigany (S) trifluoroacetate or with mercury (H) sulfate in an aqueous organic solvent medium such as aqueous acetone. The reaction temperature is usually 10 ° C to the reflux temperature and the reaction time is generally 2 to 10 hours, although the latter is dependent on the reaction temperature employed.

Step A-5

In this step, the pseudoamino sugar of formula (HI) (A and - are as defined above) by reacting a compound of formula (I) with a primary amine of formula (Π) (R ² is as defined above) and then the resulting Schiff base is reduced and, if desired, the hydroxyl protecting groups removed.

The above Schiff base formation reaction and reduction of the resulting Schiff base can be carried out in a continuous reaction vessel in a continuous operation. 50

The compound of Formula © and the ©):

The condensation reaction of the primary amine of formula I and reduction of the resulting Schiff base is generally carried out in the presence of a solvent. Suitable solvents are, for example, water, alcohols such as methanol, ethanol, propanol, butanol; dimethyl <

sulfoxide, N, N-dimethylformamide; N-methyl-acetamide; (Glim compounds such as methylcellosolve, dimethylcellosolve, diethylene glycol, dimethyl ether and a mixture of these compounds. Suitable solvents include the aforementioned compounds and mixtures of aromatic hydrocarbons such as benzene, toluene and esters). such as ethyl acetate.

The temperature of the Schiff base formation reaction is not critical and the reaction is usually carried out at room temperature to 100 ° C. The reaction time is generally dependent on the reaction temperature employed and may vary from a few minutes to 24 hours. Various metal complex hydrides such as alkali metal borohydride, potassium borohydride, lithium may be used to reduce the Schiff base. boron hydride, sodium trimethoxyborohydride; alkali metal cyanoborohydrides such as sodium cyanoborohydride, alkali metal aluminum hydrides, dialkylamine boranes such as dimethylaminoborane If the reaction is carried out with an alkali metal cyanoborohydride such as sodium cyanoborohydride The reaction temperature may be varied within wide limits. Generally, room temperature and depending on the reagents employed, ice-cooling may be employed, but in other cases temperatures of about 100 ° C may be employed. Generally, the reaction temperature depends on the Schiff base to be reduced and the reducing agent used. Generally, the reaction time is a few minutes to 24 hours and is dependent on the reaction temperature.

Reduction of the Schiff base can also be accomplished by catalytic reduction. The catalytic reduction is generally accomplished by shaking or stirring the Schiff base in the appropriate solvent under a stream of hydrogen in the presence of a catalyst. Examples of the catalyst include platinum black, platinum dioxide, palladium black, palladium carbon, Raney nickel. Suitable solvents are, in general, the solvents mentioned above, for example, water, alcohols such as methanol, ethanol; ethers such as dioxane, tetrahydrofuran; NX-dimethylphoimamide or a mixture of these solvents. The reaction is usually carried out at room temperature under atmospheric pressure, but may also be carried out at elevated pressure and elevated temperature.

For example, a compound of formula (III) wherein A is hydrogen can be prepared by reacting a compound of formula (I ') with a compound of formula (H) wherein R ² is a hydroxy group, i.e. a hydroxylamine, and the resulting oxime compound reduced. Alternatively, instead of hydroxylamine, an O-substituted hydroxylamine such as O-methylhydroxylamine or O-benzylhydroxylamine is reacted with a compound of formula (I ') and the resulting O-alkyloxime or The O-aralkyloxime is reduced. The reduction of the hydroxyimino group may be carried out either before or after the deprotection of the hydroxyl group.

Examples of suitable catalysts for the catalytic reaction include palladium, platinum catalysts such as platinum oxide,

Palladium catalysts such as palladium on carbon, nickel catalysts such as Raney nickel, rhodium catalysts such as rhodium carbon, and aluminum hydride compounds such as lithium aluminum hydride. The reduction is most preferably carried out under an inert gas atmosphere such as nitrogen or argon.

The hydroxyl protecting groups of formula (IH) are removed in a known manner. For example, acetal protecting groups such as cyclohexylidene, isopropylidene, benzylidene or trityl are removed by hydrolysis, for example by hydrolysis with acids such as hydrochloric acid, acetic acid, sulfuric acid. Acyl-type protecting groups (e.g., acetyl or benzoyl) are removed by alkaline hydrolysis such as ammonia, sodium hydroxide, barium hydroxide or sodium methoxide. Benzyl ether-protecting groups (benzyl, p-methoxybenzyl) are removed. catalytic reduction or reductive cleavage, the latter using metal sodium in the presence of liquid ammonia.

The compounds of formula (I ') and (IH) obtained above and the starting materials for their preparation are separated from the reaction medium in a known manner and purified according to known methods, such as concentration, centrifugation, concentration, concentration. under reduced pressure, drying, freeze-drying, absorption, desorption, methods based on various solubilities such as extraction, phase conversion, precipitation, crystallization or recrystallization, chromatography such as ion exchange chromatography, activated carbon, high porosity polymer, , chromatography on silica gel or alumina.

Pharmaceutically acceptable addition salts may also be prepared from the compounds of formula (ΙΠ) according to the invention. These salts include, for example, salts with organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, organic acids such as acetic acid, malic acid, citric acid, ascorbic acid, mandelic acid, methanesulfonic acid.

The compounds of formula (III) obtained by the process of the present invention, wherein R ³ is hydrogen and represents the -S-configuration, are represented by formula (IIIa), wherein A is as defined above. These compounds, i.e. valiolamine and its N-substituted derivatives, and salts thereof is practically non-toxic (LD is not greater than _{50 in} rats, 500 mg / kg) and alpha-glucosidase-inhibitory action and suppress the carbohydrate metabolism of humans and in animals. Thus, these compounds inhibit the rise of blood glucose levels and are useful in the treatment and prevention of hyperglycemic symptoms. They are also useful in the treatment of diseases caused by hyperglycemia, such as diabetes, pre-diabetes, obesity, pathological obesity, hyperlipaemia (altered sclerosis), and diseases related to diabetes mellitus in the oral cavity (for example, tooth decay).

It is further known that sedate heptulose, which is the preferred starting material for the compound of formula (Γ), is produced in large amounts in the culture medium of certain bacterial species, so that these compounds can very advantageously be prepared inexpensively. Sedo-heptulosane or 2,7-anhydrobeta-ido-heptulopyranose (D-ido-heptulosane) can be prepared very cheaply from sedo-heptulose and thus the process according to the invention is very useful for the valiolamines and their For the preparation of N-substituted valiolamine derivatives.

The following Reference Examples and Examples illustrate the process of the invention in more detail without limiting it. The proportions of the solvent mixtures used in the examples are always by volume unless otherwise indicated.

Reference Example 1

4,5-O-Isopropylidene-sedo-heptulosar g sed-heptulosan (2,7-anhydro-β-D-altro-2-heptulopyranose) was powdered and suspended in 320 ml of acetone, followed by 2.5 ml of conc. sulfuric acid was added and the resulting mixture was stirred at room temperature for 18 hours. The resulting crystalline material is then filtered off and washed with acetone to give 28 g of the title compound.

Compound Elemental Analysis for C _{10 H] O} O _6:

C H Calculated (%) 51.72 6.94 Found (%) 51.58 6.97

Reference Example 2

1.3-Di-O-Benzoyl-4H-O-isopropylidene-sedephthalosane g 4,5-O-isopropylidene-sedephthalosane was suspended in a mixture of 85 ml of Ν, Ν-dimethylformamide (DMF) and 5 ml of pyridine and then added dropwise while cooling, at about -30 ° C, to 9 ml of benzoyl chloride. The resulting mixture was stirred at -5 to -10 ° C for 2.5 hours, then added to ice water (200 mL) and the resulting oily product was extracted with ethyl acetate. The ethyl acetate extract was washed with 2N hydrochloric acid followed by saturated sodium bicarbonate, dried over anhydrous sodium sulfate, evaporated under reduced pressure and chromatographed on silica gel (toluene / ethyl acetate = 10: 1). The eluates were combined, evaporated to dryness under reduced pressure and the residue dried under reduced pressure overnight. 8.8 g of the title compound are obtained.

Reference Example 3

1.3-Di-O-Benzoyl-sedo-heplulosan In a mixture of 80% acetic acid (8.8 g) was dissolved 1,3-di-O-benzoyl-4,5-O-isopropylidene-sedeheptulosan.

Stir at 70-75 ° C for 2 hours. Water (170 mL) was added and the reaction mixture was reduced 5

HU 204505 Β leave 9.5 g of the title product as a white powder.

Elemental analysis for the compound of formula (^ H ^ NiOnS):

concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was evaporated. Ethyl ether / petroleum ether (3: 1) was added to the residue, and the resulting mixture was allowed to stand overnight in the refrigerator to give 7.3 g of crude 1,3-di-O-benzoyl sedoheptulosan.

Reference Example 4

1,3,4-Tri-O-Benzoyl-Sedeheptulosan 14.1 g of 1,3-di-O-benzoyl-Sedeheptulosan are dissolved in 140 ml of dichloromethane, 4.7 ml of pyridine are added and the resulting solution is added dropwise 5.64 g of benzoyl chloride dissolved in 50 ml of dichloromethane are added at -40 ° C. The reaction mixture was stirred for 2.5 hours at -40 to -30 ° C and then poured into ice water. and stir for 30 minutes. The dichloromethane layer was separated, the aqueous layer was extracted with dichloromethane, and the dichloromethane extract was washed with 2N hydrochloric acid followed by saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. To the residue was added 1 liter of a 1:10 ethyl petroleum ether mixture and the mixture was left overnight in the refrigerator to give 17.5 g of the title compound.

Elemental analysis for C ^ ^H ^Og:

C H Calculated (%) 66.66 4.80 Found (%) 67.04 - 4.74

NMR (CDCl ₃ ) δ: 2.51 (1H, d, J = 6Hz, -OH), 3.9-4.25 (2H, m, 7-CH 3, 4.25-4.5 (1H, m, 5CH;

exchange: δ 4.38 (dd, J = 3Hz, 5Hz) with D ₂ O addition: 4.58 (2H, s, 1-CH 3, 4.7-4.9 (1H, m, 6-CH )

5.46 (1H, dd, J = 3Hz, 9Hz, 4-CH), 5.94 (1H, d, J = 9Hz, 3-CH), 7.1-7.7 (9H, m ) and 7.8-8.2 (6H, m) (C ₆ H ₅ x 3)

PREPARATION 5 ₂ l 3,4-tri-0-benzoyl-5-0- (imidazolylsulfonyl) -szedobeptulozdn

Dissolve 9.48 g of 1,3,4-tri-O-benzoyledo-heptulosan in 100 ml of DMF, add 3.2 ml of sulfuryl chloride at -40 ° C, and add After stirring for 20 minutes at -40 ° C, re-cool to -40 ° C and add 13.6 g of imidazole. The cooling bath is then removed, the mixture is stirred at room temperature for 50 hours and then poured into 300 ml of ice water and the resulting oily substance is extracted with ethyl acetate. The ethyl acetate extract was washed with 2N hydrochloric acid followed by saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel (600 mL, toluene / ethyl acetate)

3: 2), the eluates are concentrated under reduced pressure and 100 ml of petroleum ether are added. The resulting mixture is left to stand in a refrigerator overnight.

C H N 5 calculated (%) 58.67 4.13 4.41 because(%) 58.71 4.10 4.43

NMR (CDCl 3) δ: 4.04 (1H, dd, J = 5Hz, J = 8Hz, 7-CH), 4.08 (1H, d, J = 8Hz, 7-CH), 4.59 (2H, s, 1-CH3, 4.75-4.90 (1H, m, 6-CH; 5.27 (1H, 10 dd, J = 2.5 Hz, 4 Hz, 5-CH)), δ , 49 (1H, dd, J = 4 Hz, 9.5 Hz, 4-CH), 5.92 (1H, d, J = 9.5 Hz, 3-Ch), 6.78, 7.15 and 7.18 (1H each, s, imidazole), 7.2-7.7 (9H, m) and 7.8-8.2 (6H, m) (C ₅ H ₅ x 3)

Reference Example 6

2,7-anhydro-l, 3,4,5-tetra-O-benzoyl - $ - D-ido-2-pyranose heptulopyranoside

9.5 g of 1,3,4-thio-O-benzoyl-5-O-imidazolylsulfonyl) -edo-hepululose are dissolved in 140 ml of toluene and 11 g of tetra-n-butylammonium benzoate are added, and the resulting mixture was stirred at 100 ° C for 3 hours and finally the solvent was distilled off under reduced pressure. The residue was partitioned between ethyl acetate and water, the aqueous phase was extracted again with ethyl acetate, the ethyl acetate layers were combined and washed with 2N hydrochloric acid followed by saturated sodium bicarbonate, dried over anhydrous sodium sulfate and the solvent was evaporated. . The residue is chromatographed (1 L silica gel, 19: 1 toluene / ethyl acetate) and the eluate is evaporated to dryness. This gave 6.8 g of the compound of Cön as a white powder.

Elemental analysis for C ₃₅ H ₂₈ O ₁₀ :

C H calcd (%) 69.07 4.64 found (%) 69.34 4.67

NMR (CDCl 3) δ: 4.02 (1H, dd, J = 4.5 Hz, 8 Hz, 7-CH), 4.50 (1H, d J = 8 Hz, 7-CH), 4.60 ( 2H, s, 1-CH3, 5.10 (1H, t, J = 4.5 Hz, 6-CH), 5.54 (1H, dd, J = 4.5 Hz, 8.5 Hz, 5- Ch), 4.80 (1H, d,

J = 8.5 Hz, 3-CH), 6.80 (1H, J = 8.5 Hz, 4-CH), 7.2-7.7 (12H, m) and 7.8-8, 2 (8H, m) (C6H3X4)

Reference Example 7

Dissolve 3 g of 2,7-anhydro-2,3,4,5 in methyl-1,3,4-trans-O-benzoyl-D-ido-2-heptulopyranoside in methanol and 15 ml in methyl formic acid ester. Tetra-O-benzoyl-1-D-ido-2-heptulopyranose was added followed by 3 g of zinc chloride and the mixture was stirred at room temperature for 40 hours. The reaction mixture was concentrated under reduced pressure, the residue was partitioned between ethyl acetate and water, the ethyl acetate layer was washed with 2N hydrochloric acid, saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was chromatographed (100 mL silica gel, 5: 1 toluene / ethyl acetate) to elute the eluate to dryness.

This gave 1.05 g of the title compound as a white powder.

Elemental analysis for CsJ ^ On:

C H Calculated (%) 67.49 5.03 Found (%) 66.98 4.74

NMR (CDCl ₃ ) δ: 2.36 (1H, broad s, -OH), 3.69 (3H, s,

OCH ₃ ), 3.97 (1H, dd, J = 6.5 Hz, 9.5 Hz, 7-CH), 4.21 (1H, dd, J = 7 Hz, 9.5 Hz, 7-CH ), 4.56 (2H, s, 1-CH3), 4.60-4.75 (1H, m, 6-CH), 5.31 (1H, dd, J = 5 Hz, 8.5 Hz, 5 -CH), 5.82 (1H, d, J = 8.5 Hz, 3-CH), 5.96 (1H, t, J = 8.5 Hz, 4-CH), 7.15-7, 7 (12H, m) and 7.8-8.2 (8H, m) (C ₆ H ₅ x 4)

δ. PREPARATION

Melyl-1,3,4-bis-O-benzoyl-7-deoxy-7-iodo-D-ido-2-heptulopyranoside In DMF, 950 g of 1,3,4,5-tetra-Obenzoyl-D- Ido-2-heptulopyranoside, 1.65 g triphenylphosphine and 1.2 g iodosuccinimide were added and the resulting mixture was stirred at room temperature overnight. Ice water (100 mL) was added, the resulting oily solution was extracted with ethyl acetate, and the extract was washed with saturated sodium thiosulfate solution, 2N hydrochloric acid, then sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. evaporated. The residue was chromatographed (200 mL silica gel, toluene / ethyl acetate 10: 1) and the eluate was concentrated to give the title product as a white powder (780 mg).

Reference Example 9

Methyl-1,3,46-tetra-O-benzoyl-7-deoxy-L-xylo-2hept-6-enulopyranoside [i.e., Melyl-1,3,4,5-letra-Obenzoyl-7-deoxy-D -ido-2-hept-6-enulopyrazide] Dissolve 500 mg of methyl 1,3,4,5-tetra-O-benzoyl-7-deoxy-7-iodo-D-ido-2-heptulo- in pyridine (ml). pyranoside, silver fluoride (1 g) was added, the mixture was stirred at room temperature for 18 hours, and ethyl ether (100 mL) was added. The insoluble material was collected by filtration, washed with ethyl ether, and the filtrates were combined with the washings and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 2N hydrochloric acid and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was chromatographed (100 mL silica gel, 9: 1 toluene / ethyl acetate) and the eluates were evaporated to dryness under reduced pressure to give 249 mg of the title compound as a white powder.

Elemental analysis for C3 ₆ H ₃₀ O ₁₀ :

C H Calculated (%) 69.56 4.86 Found (%) 70.03 5.09

NMR (CDCl 3) δ: 3.68 (3H, s, OCH ₃ ), 4.45 (2H, broad s, 1-CH ₃ ), 5.32 (1H, d, J = 9Hz, 5-CH or CH), 5.64 (1H, d, J = 9Hz, 3-CH or

5-CH), 5.81 (1H, t, J = 9Hz, 4-CH), 5.91 and 6.03 (each 1H, s, 7-CH3, 7.2-7.7 (12H, m) and 7.8-8.2 (8H, m) (C ₅ H ₅ x 4)

Reference Example 10

4L-4,6 / 5-Ti-Benzyloxy-3-benzyloxymethyl-2-cyclohexenone oxime Dissolve 2 g of 4L-4,6 / 5-tri (benzyloxy) in dimethylsulfoxide (ml). -3-benzyloxymethyl-2-cyclohexenone and 2 g of hydroxylamine hydrochloride were added and the resulting mixture was stirred for 24 hours at room temperature. The reaction mixture was partitioned between ethyl acetate (250 mL) and water (150 mL), the organic layer was separated, washed with 2N hydrochloric acid, aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (250 mL, 10: 1 toluene / ethyl acetate). The eluates (450-800 ml) were concentrated and dried. 1.27 g of the title compound are obtained in the form of a colorless syrup.

Elemental analysis for C ₃₅ H ₃₅ NO ₅ :

C H N calculated (%) 76.48 6.42 2.55 measured (%) 76.66 6.32 2.35

Example 1

2D-2,3,4-tri-0-benzoyl- (2,46- (OH) / 36) -5- (benzoyloxy-methyl) -2,3,4f, -lelrahidroxi-cik.lohexanon

620 mg of methyl 1,3,4,5-tetra-O-benzoyl-7-deoxy] -Lxilo-2-hept-6-enulopyranoside is dissolved in 40 ml of 80% acetone-water, 275 mg of mercury chloride are added, and the resulting mixture was stirred at room temperature for 8 hours and then concentrated under reduced pressure to about 20 ml, to which was added 100 ml of ethyl acetate and 100 ml of water, the mixture was stirred and the ethyl acetate layer was separated with 2N hydrochloric acid. and washed with a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (60 mL, toluene / ethyl acetate = 5: 1), and the eluate was concentrated under reduced pressure to give 248 mg of the title compound as a white powder.

Analysis for C 5 H ₃ O _{2 g} of Compound _10:

CH calculated (%) 69.07 4.64 found (%) 68.74 5.03 1 H-NMR (CDCl ₃ ) δ: 2.38 (1H, broad s, -OH), 2.88 and

3.04 (each IH, ABq, J = 14.5 Hz, 6CH _2), 4.81 (2H, s, _-CH2 0-), 5.43 (lH, d, J = 10Hz, 4- CH), 5.81 (1H, t, J = 10 Hz, 2-CH), 6.11 (1H, d, J = 10 Hz, 2-CH), 7.2-7.7 (2H, m ) and 7.8-8.3 (8H, m) (C ₆ H ₅ X 4) [α] D = -28.2 ° (c = 1, CHCl 3) TLC (silica gel)

60F-254 (Merck): toluene / ethyl acetate (2: 1):

R f = 0.52; toluene-acetone (9: 1): _Rf = 0.31; n-hexane / ethyl acetate (3: 2): _Rf = 0.38.

Solubility: in methanol, ethyl acetate, toluene,

EN 204505 kl Soluble in acetone and chloroform, insoluble in water and petroleum ether.

Example 2 (1S) - [1 (OH) (2,45H, 3] -5 - {[2-Hydroxy-1- (hydroxymethyl) ethyl] amino} -1C- (hydroxymethyl) -1, 2,3,4-cyclohexane teirol

Dissolve 410 mg of 2D-2,3,4'-tri-O-benzoyl- (2,4,5 (OH) / 3,5) 5- (benzoyloxymethyl) in 150 ml of a 1: 9 acetic acid / ethanol mixture. -2,3,4,5-Tetrahydroxycyclohexanone and 280 mg of 2-amino-1,3-propanedrole were stirred at room temperature for 30 minutes and then stirred. 300 mg of sodium cyanide-skin bridge are added. The mixture is then stirred at room temperature overnight, then concentrated under reduced pressure and the residue is dissolved in 100 ml of methanol / acetone / 1 N sodium hydroxide (1: 1). The solution was stirred at room temperature for 5.5 hours, the organic solvent was distilled off under reduced pressure, and the concentrated solution was adjusted to pH 1 with 2N hydrochloric acid and washed with ethyl acetate. The resulting material was stirred with 100 ml of Dowex 50W x 8 resin (H ⁺ ) for 30 minutes at room temperature, and the solution was poured onto a column filled with the same resin, and the column was washed with water and 0.5N aqueous ammonia. The eluate was concentrated under reduced pressure, the residue was applied to Amberlite CG 50 resin filled (ΝΗ ⁺ _4, 250 ml) column and washing with water. The eluate was concentrated under reduced pressure and ethanol was added. The resulting mixture was heated at reflux for 15 minutes and then concentrated under reduced pressure. The residue was 2 ml, which was left overnight to give the product as a white powder. [α] D ₂₅ + 26.9 ° (c = 1, H ₂ O)

NMR (D ₂ O): 1.54 (1H, dd, J = 3Hz, 15Hz, 6-CHax), 2.10 (1H, dd, J = 3Hz, 15Hz, 6-CHeq), 2 , 90 (1H, quint, J = 5 Hz, -N-CH), 3.35-4.0 (10H, the residue was dissolved in 130 mL of methanol, 70 mL of 1 N sodium hydroxide was added and the mixture was stirred overnight at room temperature). The reaction solution was adjusted to pH 4 with 2N hydrochloric acid and concentrated under reduced pressure, the residue was partitioned between water (50 mL) and ethyl acetate (50 mL), the aqueous layer was separated, washed with ethyl acetate and then Dowex 50Wx8 (H ⁺ , 400 ml) was applied to a column filled with resin, the column was washed with water and the eluate was triturated with 0.5 N aqueous ammonia solution, and the eluate was concentrated under reduced pressure, and the residue was washed with Amberlite CG-50 (NH ₄ ⁺ , 250 ml). is applied to a packed column, the column is washed with water, the eluate is mixed with 0.1 N aqueous ammonia and evaporated under reduced pressure. Flash chromatography on a column packed with Dowex 1x2 (OH; 400 mL) eluting with water. The first fractions (360-480 mL) were concentrated and freeze-dried to give 59 mL of (1S) - [1 (OH), 2,4 / 1, 3,5] -5 - [(2-hydroxyethyl) - amino] -1C- (hydroxymethyl) -1,2,3,4-cyclo-hexane is added. Subsequent fractions (520,680 mL) were also concentrated under reduced pressure and freeze-dried to give 228 mg of (1S) (1 (OH), -2,4,5 / 1,3) -5 - [(2-hydroxyethyl). ) -amino] -1C- (hydroxymethyl) -1,2,3,4-cyclohexane-tetrole is obtained.

(S) - [l (OH), 2,4 / l, 3,5] -5 - [(2-hydroxyethyl) amino] C- (hydroxymethyl) -l, 2,3,4 -cyclohexane-tetrol (previously eluted isomer):

NMR (D ₂ 0): 1.16 (IH, ζ J = 12 Hz, 6-CHax), 2.50 (IH, dd, J = 4Hz, 12Hz, 6-CHeq), 2.50 to 3 , 05 (3H, m, 6-CH, N-CH3, 3.25-3.95 (7H, m) (1S) -8 (OH), - 2.4,5 / 1,3] -5 - [(2-Hydroxyethyl) amino] -1C- (hydroxymethyl) -1,2,3,4-cyclohexane tetrol (the last eluted isomer):

NMR (D ₂ O): 1.52 (IH, dd, Jt = 3 Hz, 15 Hz, 6-CHax), 2.14 (IH, dd, J = 3.5 Hz, 15 Hz, 6-CHeq) , 2.25 to 3.15 (2H, m, _N-CH2), 3.25 (IH, q, J = 3 Hz, 5-CH), 3.35 to 4.0 (7H, m)

Elemental analysis for QH ₁₉ NO ₆ :

m) calculated (%) C 45.56 H 8.07 N 5.90 Example 3 measured (%) 45.59 8.03 5.99

(S) - [l (OH), 2,45Íl, 3] -5 - [(2-H-hydroxy} ethyl) amino] IC (hydroxymethyl) -l (2,3,4-cyclohexane tetrol and 45 (1S) - [1 (O) - (2,4ll, 3,5] -5 - {[(2-hydroxyethyl) amino] -1-C- (hydroxyethyl) amino} -IC- ( hydroxymethyl) cyclohexane-1,2,3,4-lelrol

880 mg of 2D-2,3,4-tri-O-benzoyl- (2,3,5 (OH) / 3,5] -5- (benzoyloxymethyl) -2,3,4,5-tetrahydroxy- Cyclohexanone 50 is dissolved in 50 ml of methanol and 1 ml of ethanolamine is added, followed by 1 g of cyanohydride hydride, and the resulting mixture is stirred overnight at room temperature, then the mixture is concentrated under reduced pressure, the residue is taken up in 50 ml The ethyl acetate layer was separated, the aqueous layer was separated, the aqueous layer was extracted again with ethyl acetate, the ethyl acetate layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

Example 4 (1S) - [1 (0H) -, 2,4,5, 3J-5 - {[(R) -CL- (Hydroxyenyl) benzyl] amino} -1C- (hydroxy) me (II) -l, 2,3,4-cyclohexane lelrol

860 mg of 2D- [2,4,5 (OH) / 3,5] -2,3,4-fri-O-benzoyl-550 (benzoyloxymethyl) -2,3,4,5-tetrahydroxy- cyclohexanone was dissolved in 45 mL of DMF, 950 mg of D-phenylglycinol acetate and 650 mg of sodium cyanoborohydride were added and the mixture was stirred at 55 ° C for 12 hours. The reaction solution was then concentrated under reduced pressure 55, the residue was partitioned between ethyl acetate (100 mL) and water (50 mL), the ethyl acetate layer was washed with 2% acetic acid, saturated sodium bicarbonate solution, and dried over anhydrous sodium sulfate. concentrated under reduced pressure. The residue 30 was dissolved in 80 ml of 5: 3 methanol / acetone

Dissolve in 204,505 5, add 20 ml of 1N sodium hydroxide and stir at room temperature for 3.5 hours. The solution was adjusted to pH 3 with 2N hydrochloric acid and concentrated under reduced pressure, the residue partitioned between water (100 mL) and ethyl acetate (50 mL), and the aqueous layer washed with ethyl acetate followed by Dowex 50Wx8 (H ⁺ , 150). ml) is chromatographed on a column packed with resin, eluted with water and the eluate is mixed with 0.5 N aqueous ammonia. The resulting material was concentrated under reduced pressure, and the residue was chromatographed on a column packed with Amberlite CG-50 (NH ₄ ⁺ , 180 mL) and eluted with water. The eluate was concentrated under reduced pressure and allowed to stand overnight in a refrigerator to give 150 mg of the title compound as white crystals.

157-158 ° C.

[α] D = -10.6 ° (c = 1, H ₂ O)

-6.5 (c = 0.1 in NHCl)

NMR (D ₂ O): 1.43 (IH, dd, J = 3.5 Hz, 15 Hz, 5CHax), 1.73 (IH, dd, J = 3.5 Hz, 15 Hz, 6CHeq) 3, 25-3.7 (4H, m) 3.7-4.0 (5H, m) 7.58 (5H, s, Ph)

Example 5 (1S) - [1 (OH), 2,4,5ll, 3] -5-Amino-1-C- (hydroxymethyl) -1,2,3,4-cyclohexane-telrol (VALI-amine)

a) Dissolve 1 g of 2D- [2,4,5 (OH) / 3,5] -2,3,4-tri-O-benzoyl-5- (benzoyloxymethyl) -2,3 in 200 ml of methanol. 4,5-tetrahydroxycyclohexanone, 400 mg of hydroxylamine hydrochloride and 2 ml of pyridine are added, the mixture is stirred overnight at room temperature, concentrated under reduced pressure, and the residue is partitioned between 100 ml of ethyl acetate and 20 ml of water. The acetate layer was separated, washed with 2N hydrochloric acid, saturated sodium bicarbonate solution, water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (100 mL) eluting first with 10: 1 toluene / ethyl acetate, then 5: 1 toluene / ethyl acetate, and then concentrating the eluates under reduced pressure. There were thus obtained 410 mg of 2D- [2,4,5- (OH) / 3,5] -2,3,4-tri-benzoyl-5- (benzoyloxymethyl) -2,3,4,5-. tetrahydroxycyclohexanone oxime was obtained.

b) Dissolve in 20 ml methanol obtained as above

410 mg of the oxime compound are added, 4 ml of concentrated ammonium solution are added and the mixture is stirred at room temperature overnight. Water was added to the reaction mixture, evaporated to dryness under reduced pressure, water was added again, and the reaction was repeated. This gives about 50 ml of concentrate to which 2 ml of acetic acid is added and washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure, the organic solvent was distilled off and water (50 mL) was added again to the residue. To this aqueous solution was then added 200 mg of platinum dioxide and stirred at room temperature under a stream of hydrogen for 4 hours. The catalyst was filtered off, washed with water and the filtrate and washings combined and evaporated to dryness under reduced pressure, the residue was chromatographed on a column of Amberlite CG-50 _(NH4 ^+, 180 ml) of resin, 300 ml of water and 0.05 ml wash with aqueous ammonia. The fractions (1330-1880 ml) were combined, concentrated under reduced pressure and freeze-dried to give 69 mg of valiolamine as a white powder.

[a] jf = + 19.6 ° (c = 1, H ₂ O) 'H NMR (D ₂ O, 300 MHz) β: 1.68 (IH, dd, J = 3.8, 15.5 Hz , 5-Hax), 1.88 (1H, dd, J = 2.9, 15.5 Hz, 6-Heq), 3.33 (1H, q *. J 2.9, 3.8, 4, 2 Hz, 5-H), 3.41 (1H, d, J = 9.5 Hz, 2-H), 3.44 and 3.52 (each 1H, ABq, J = 11.3 Hz, -CH ₂ O-),

3.57 (aH, dd, J = 4.2, 9.9 Hz, 4-H), 3.83 (1H, t *, J = 9.5,9.9 Hz, 3-H) (* apparent cleavage)

Example 6 (1S) - [1 (OH), 2,4,511,3J-2,3,4-Trio-O-benzyl-5 - {(2-hydroxy-1- (hydroxymethyl) ethyl) - amino} -1C- (benzyloxymethyl) -1,2,3,4-cyclohexane tetrol 600 mg (1S) - [1 (OH), 2,4 / 1,3] -2,3,4-tri -O-Benzyl-1 C- (benzyloxymethyl) -5-oxo-1,2,3,4-cyclohexane-tetrole and 230 mg of 2-amino-1,3-propanediol were dissolved in 40 ml of methanol and After stirring at room temperature for 1 hour, 1 g of sodium borohydride is added, the mixture is cooled in an ice-water bath and stirred for 16 hours under cooling, the mixture is concentrated in vacuo and the residue is partitioned between 140 ml ethyl acetate and 50 ml The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue which was chromatographed on silica gel (60 mL), eluting with ethyl acetate to give the title compound as a white powder (380 mg).

[α] D = + 30.0 ° (c = 1, CHCl ₃ )

Elemental analysis for C ₃₈ H ₄₅ NO ₇ :

C Η N

C H N calculated (%) 72.70 7.23 2.23 measured (%) 72.43 7.27 2.31

Example 7 (1S) -fl (OH), 2,4,5 / 1,3] -5 - {[2-Hydroxy-1- (hydroxymethyl) ethyl] amino} -1C- (hydroxymethyl) ) -1,2,3,4-cyclohexane-1

200 mg (1S) - [1 (OH), 2,4,5 / 1,3] -2,3,4-tri-O-benzyl-5 - [[2-hydroxy-1-hydroxymethyl] ethyl ) -amino} -1-C-hydroxymethyl-1,2,3,4-cyclohexane-tetrole is dissolved in 20 ml of a 1:19 mixture of 90% formic acid in methanol, 100 mg of palladium on carbon is added and the mixture is added overnight. and stirred at room temperature under a nitrogen atmosphere. The catalyst is then filtered off, washed with a 1: 1 mixture of methanol / water, the filtrate and the washings are combined and concentrated in vacuo. The residue was chromatographed on a Dowex 50Wx8 (OH ', 70ml) column, washed with water, eluted with 0.5N ammonium hydroxide and the eluate concentrated in vacuo. The residue was chromatographed on a column packed with Amberlite CG-50 (NH ⁺ 4, 180 mL), eluted with water, and the eluate evaporated to dryness in vacuo9.

HU 204505 uk after all. The residue was dissolved in ethanol (10 mL) and heated to reflux for 10 minutes. The mixture was then allowed to stand in the refrigerator overnight to give 80 mg of the title compound as a colorless crystalline solid.

162-163 ° C;

[alpha] H = + 26.2 ° (c = HJO) * H NMR (D ₂ 0, 400 MHz) δ: 1.50 (IH, dd, J = 2.9, 15.3 Hz, 6-CHax ), 2.05 (IH, dd, J = 3,3,15,3 Hz, 6-CHeq), 2.86 (IH, m, CH (CH ₂ OH 2) ^, 3.38 (IH, dt *, J = 2,9,3,3,4,2 Hz, 1-CH), 3.41 (1H, d, J = 9.5 Hz, 4-H), 3.49 and 3.52 (each 1H, ABq, J = 11.4 Hz, 7-CH), 3.59 (dd, J = 6.5, 11.5 Hz) and 3.66 (dd, J = 4.9.11, 5Hz) (each IH, -CH ₂ 0-), 3.69 (IH, dd, J = 4.2, 9.8 Hz, 2-CH), 3.64 (dd, J = 3.8, 11.7 Hz) and 3.71 (dd, J = 5,1,11,7 Hz) (each IH, -CH ₂ 0-), 3.83 (IH, t *, J = 9.5, 9.8 Hz, 3-CH) (* apparent splitting); ^I3 C NMR (d ₂ O, 25.2 MHz) δ 30.3 (t), 55.2 (d), 57.4 (d); 59.4 (t), 65.9 (t), 72.8 (d), 73.8 (d), 74.7 (d), 76.8 (s)

Claims (1)

Patent Claim Point A process for the preparation of pseudoamino sugars of the formula: wherein R ³ is hydrogen, A is hydrogen or (C 1 -C 7) alkyl substituted with one or more hydroxy groups and optionally phenyl, and the wavy line is a R or S-bond, characterized in that a compound of formula (Γ) wherein R ¹ is a hydroxyl group for the preparation of compounds containing a hydrogen atom, with hydroxylamine or with a hydroxylamine; For the preparation of compounds of the above group other than hydrogen by reaction with a compound of the formula R ² -NH ² - wherein R ² has the same meaning other than the above hydrogen atom, the resulting compound is reduced, preferably H2ZPt, iU. using sodium cyano-dermal hydride and removing any remaining hydroxyl protecting groups.