JP4160063B2 - Diabetes preventive or therapeutic agent containing oligosaccharide derivative - Google Patents

Description

  The present invention relates to a novel oligosaccharide derivative, a pharmacologically acceptable salt thereof, and a pharmacologically acceptable ester thereof.

  The present invention also relates to oligosaccharide derivatives having excellent α-amylase inhibitory action, blood glucose lowering action, lipid lowering action and the like, pharmacologically acceptable salts thereof and pharmacologically acceptable esters thereof.

  Furthermore, the present invention relates to hyperglycemia, hyperglycemia, glucose intolerance, diabetes, obesity, hyperlipidemia containing oligosaccharide derivatives and pharmacologically acceptable salts and pharmacologically acceptable esters thereof as active ingredients. Remedy and / or prophylactic agent (preferably postprandial hyperglycemia, diabetic remedy and / or It is a preventive drug.)

  Furthermore, the present invention provides a preventive or therapeutic agent for the above-mentioned diseases containing the above compound as an active ingredient, a composition for preventing or treating the above-mentioned diseases containing the above compound as an active ingredient, and for preventing or treating the above-mentioned diseases. The present invention relates to a method for preventing or treating the above-mentioned diseases, wherein the use of the above-mentioned compound for producing a pharmaceutical of the above, or a pharmacologically effective amount of the above-mentioned compound is administered to a warm-blooded animal (preferably human).

  Conventionally, as a promising therapeutic agent for hyperglycemia, digestive enzyme inhibitors such as `` basin '' containing voglibose (Takeda Pharmaceutical Co., Ltd.), `` glucobay '' containing acarbose (Bayer Yakuhin) Etc. are used in actual clinical practice. However, since both compounds inhibit α-glucosidase, they have drawbacks such as abdominal distension, flatulence, increased flatus, loose stool, diarrhea, and abdominal pain. It was also reported that liver dysfunction may occur.

  On the other hand, it has been known that the effect of suppressing the absorption of nutrients can be obtained by inhibiting α-amylase instead of α-glucosidase. Compounds have been known to reduce the. However, these compounds have weak α-amylase inhibitory activity, and no compound has sufficient α-amylase inhibitory activity.

  Some compounds having a partial structure (sugar derivative) in common with the oligosaccharide derivative of the present invention and exhibiting α-amylase inhibitory action are disclosed. However, in these compounds, the deoxynojirimycin skeleton is essential, or the hexahydro-3,5,6-trihydroxy-1H-azepine skeleton is essential. Different from the compounds of the invention.

Further, Japanese Patent Application No. 2004-21444 is cited as a prior application. On the other hand, this application is an application concerning the pharmaceutical use of the compound described in Japanese Patent Application No. 2004-21444, and the subject matter of this application is different from that of Japanese Patent Application No. 2004-21444.
International Publication No. 00/50434 International Publication No. 01/94367

  The α-amylase inhibitor is difficult to be decomposed in the digestive tract (particularly in the small intestine) and needs to act stably. However, since the α-amylase inhibitor already reported cannot be said to be sufficiently stable in the small intestine, there is a possibility that it cannot stably exhibit sufficient drug efficacy. In addition, instability in the gastrointestinal tract (particularly in the small intestine) may cause some influence on liver function due to absorption of the degradation products.

  Accordingly, the present inventors have conducted extensive research for the purpose of developing therapeutic and / or preventive drugs for hyperglycemia, diabetes and the like having excellent α-amylase inhibitory activity and high stability, and novel oligosaccharides. Derivatives have excellent α-amylase inhibitory action, blood glucose lowering action, lipid lowering action, hyperglycemia, hyperglycemia, glucose intolerance, diabetes, obesity, hyperlipidemia, fatty liver, liver hypertrophy, diabetes The present invention was completed by finding that it has improved complications, neuropathy, arteriosclerosis, cataract, diabetic nephropathy and the like and has high stability.

That is, the present invention relates to hyperglycemia, hyperglycemia, impaired glucose tolerance (IGT), diabetes, obesity, hyperlipidemia, fatty liver, liver hypertrophy, diabetic complications (eg, retinopathy, kidneys). , Neuropathies, etc.), oligosaccharide derivatives and pharmacologically acceptable salts thereof, and pharmacologically acceptable esters thereof, useful as therapeutic or prophylactic agents for neuropathy, arteriosclerosis, cataracts, diabetic nephropathy, etc. I will provide a.

  The present invention relates to the following general formula (I)

[Wherein A represents the following general formula (A1), (A2) or (A3)

R ¹ and R ² are the same or different and each represents a C 1-6 alkyl group, a hydroxymethyl group, a C 1-6 alkoxymethyl group or a C 1-6 haloalkyl group, and R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 hydroxyalkyl group, a C1-6 haloalkyl group, an amino group (the amino group is a C1-6 alkyl group or a C1-6 hydroxy group). 1 or 2 may be substituted with an alkyl group), a hydroxyl group, a hydrogen atom or a halogen atom, R ⁷ is a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 hydroxyalkyl group, C1-6 A haloalkyl group, a hydroxyl group or a hydrogen atom; n represents an integer of 1 or 2; ] Or a pharmacologically acceptable salt or ester thereof.

In the present invention, the “C1-3 alkyl group” is a linear or branched alkyl group having 1 to 3 carbon atoms, for example, a methyl, ethyl, n-propyl or isopropyl group. Can be mentioned. R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are preferably methyl groups.

In the present invention, the “C1-6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms. For example, as the “C1-3 alkyl group”, Listed groups or n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methyl Pentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3 Mention may be made of -dimethylbutyl or 2-ethylbutyl groups. R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ³ , R ⁴ , R ⁵ , R ⁶ are preferably substituted with 1 to 3 carbon atoms. And most preferably a methyl group.

In the present invention, the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and in R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ and R ¹¹ , preferably , A fluorine atom.

In the present invention, the “C1-3 haloalkyl group” or the “C1-6 haloalkyl group” is a group in which the “halogen atom” is substituted for the “C1-3 alkyl group” or the “C1-6 alkyl group”, respectively. is there. As the `` C1-3 haloalkyl group '', for example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 2,2-dibromoethyl groups can be mentioned, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ¹⁰ are preferably a fluoromethyl group. Examples of the “C1-6 haloalkyl group” include the groups listed as examples of the “C1-3 haloalkyl group”, or 4-iodobutyl, 4-fluorobutyl, 4-chlorobutyl, 5-iodopentyl, and 5-fluoropentyl. , 5-chloropentyl, 6-iodohexyl, 6-fluorohexyl, 6-chlorohexyl group, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^10. Is preferably a C1-3 haloalkyl group, more preferably a fluoromethyl group.

In the present invention, the “C1-3 hydroxyalkyl group” or “C1-6 hydroxyalkyl group” is a group in which a hydroxyl group is substituted on the “C1-3 alkyl group” or “C1-6 alkyl group”, respectively. Examples of the “C1-3 hydroxyalkyl group” include a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, and R ³ , R ⁴ , R ⁵ , R ⁶ and R ¹⁰ are preferably a hydroxymethyl group. It is. Examples of the “C1-6 hydroxyalkyl group” include the groups mentioned as examples of the “C1-3 hydroxyalkyl group”, and hydroxybutyl, hydroxypentyl, and hydroxyhexyl groups, and R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ and R ¹ are preferably a C 1-3 hydroxyalkyl group, and more preferably a hydroxymethyl group.

In the present invention, the “C1-3 alkoxy group” or “C1-6 alkoxy group” is a group in which the “C1-3 alkyl group” or “C1-6 alkyl group” is bonded to an oxygen atom, respectively. Examples of the “C1-3 alkoxy group” include methoxy, ethoxy, n-propoxy, and isopropoxy groups. Examples of the “C1-6 alkoxy group” include the groups listed as examples of the “C1-3 alkoxy group”, or n-butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2- Methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1 , 2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy group, and R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are preferably C1-3 alkoxy Group, more preferably a methoxy group.

In the present invention, the “C1-3 alkoxymethyl group” or “C1-6 alkoxymethyl group” is a group in which the “C1-3 alkoxy group” or “C1-6 alkoxy group” is bonded to a methyl group, respectively. . Examples of the “C1-3 alkoxymethyl group” include methoxymethyl, ethoxymethyl, n-propoxymethyl and isopropoxymethyl groups, and R ¹ and R ² are preferably methoxymethyl groups. As the “C1-6 alkoxymethyl group”, for example, the groups mentioned as examples of the above “C1-3 alkoxymethyl group”, or n-butoxymethyl, isobutoxymethyl, s-butoxymethyl, tert-butoxymethyl, n -Pentoxymethyl, isopentoxymethyl, 2-methylbutoxymethyl, neopentoxymethyl, n-hexyloxymethyl, 4-methylpentoxymethyl, 3-methylpentoxymethyl, 2-methylpentoxymethyl, 3, Examples include 3-dimethylbutoxymethyl, 2,2-dimethylbutoxymethyl, 1,1-dimethylbutoxymethyl, 1,2-dimethylbutoxymethyl, 1,3-dimethylbutoxymethyl, and 2,3-dimethylbutoxymethyl groups. R ¹ and R ² are preferably a “C1-3 alkoxymethyl group”, and more preferably a methoxymethyl group.

The oligosaccharide derivatives having the general formulas (I), (Ia) and (Ib) of the present invention can be converted to acid addition salts when they have a basic group according to a conventional method. Such salts include, for example, hydrohalic acid salts such as hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid; inorganics such as nitrates, perchlorates, sulfates and phosphates. Acid salts; salts of lower alkanesulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and ethanesulfonic acid; salts of arylsulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid; such as glutamic acid and aspartic acid Amino acid salts; examples include salts of carboxylic acids such as acetic acid, fumaric acid, tartaric acid, succinic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid, citric acid. . Preferred is a salt of hydrohalic acid, and most preferred is hydrochloride.

  Furthermore, since the oligosaccharide derivatives having the general formulas (I), (Ia) and (Ib) have a hydroxyl group, they can be converted into metal salts according to a conventional method. Examples of such salts include alkali metal salts such as lithium, sodium and potassium; alkaline earth metal salts such as calcium, barium and magnesium; and aluminum salts. Alkali metal salts are preferred.

  The oligosaccharide derivatives having the general formulas (I), (Ia) and (Ib) of the present invention can be converted into pharmacologically acceptable esters according to a conventional method. Such an ester is not particularly limited as long as it is medically used and pharmacologically acceptable as compared with the oligosaccharide derivatives having the general formulas (I), (Ia), and (Ib).

  The ester of the oligosaccharide derivative having the general formulas (I), (Ia) and (Ib) of the present invention is, for example, a C1-6 alkyl group (the alkyl group may be substituted with a trialkylsilyl group). , C7-16 aralkyl group, C1-5 alkanoyloxy substituted C1-5 alkyl group, C1-6 alkyloxycarbonyloxy substituted C1-5 alkyl group, C5-7 cycloalkyloxycarbonyloxy substituted C1- 5-alkyl group, C1-5 alkyl group substituted by C6-10 aryloxycarbonyloxy, 2-oxo-1,3-dioxolen-4-yl group having C1-6 alkyl as a substituent at the 5-position it can.

  Here, the C1-6 alkyl group is preferably a linear or branched alkyl group having 1 to 4 carbon atoms, more preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl. Group, optimally a methyl or ethyl group.

  The C1-5 alkyl group is a linear or branched alkyl group having 1 to 5 carbon atoms, preferably a methyl, ethyl, propyl, isopropyl, butyl or isobutyl group. Is a methyl group or an ethyl group.

  The C5-7 cycloalkyl group is a 5- to 7-membered saturated cyclic hydrocarbon group, and examples thereof include cyclopentyl, cyclohexyl, and cycloheptyl groups, and a cyclohexyl group is preferable.

  The C6-10 aryl group is an aromatic hydrocarbon group having 6 to 10 carbon atoms, and examples thereof include a phenyl, indenyl, and naphthyl group, and a phenyl group is preferable.

The C7-16 aralkyl group is a group in which the “C6-10 aryl group” is bonded to the “C1-6 alkyl group”, and examples thereof include benzyl, α-naphthylmethyl, β-naphthylmethyl, indenylmethyl, Phenanthrenylmethyl, anthracenylmethyl, diphenylmethyl, triphenylmethyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl 1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl 4-naphthylbutyl, 1-phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl, 5-phenylpentyl, 1-naphthylpe Til, 2-naphthylpentyl, 3-naphthylpentyl, 4-naphthylpentyl, 5-naphthylpentyl, 1-phenylhexyl, 2-phenylhexyl, 3-phenylhexyl, 4-phenylhexyl, 5-phenylhexyl, 6-phenyl Mention may be made of hexyl, 1-naphthylhexyl, 2-naphthylhexyl, 3-naphthylhexyl, 4-naphthylhexyl, 5-naphthylhexyl and 6-naphthylhexyl groups. In R ¹ and R ² , the “alkyl group” is preferably an “aralkyl group” having 1 to 4 carbon atoms, and more preferably a benzyl group.

Specific examples of suitable ester residues include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, benzyl, acetoxymethyl, 1- (acetoxy) ethyl, propionyloxymethyl, 1- (propionyloxy) Ethyl, butyryloxymethyl, 1- (butyryloxy) ethyl, isobutyryloxymethyl, 1- (isobutyryloxy) ethyl, valeryloxymethyl, 1- (valeryloxy) ethyl, isovaleryloxymethyl, 1- (Isovaleryloxy) ethyl, pivaloyloxymethyl, 1- (pivaloyloxy) ethyl, methoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyloxy) ethyl, propoxy Carbonyloxymethyl, 1- (pro Poxycarbonyloxy) ethyl, isopropoxycarbonyloxymethyl, 1- (isopropoxycarbonyloxy) ethyl, butoxycarbonyloxymethyl, 1- (butoxycarbonyloxy) ethyl, isobutoxycarbonyloxymethyl, 1- (isobutoxycarbonyloxy) Ethyl, t-butoxycarbonyloxymethyl, 1- (t-butoxycarbonyloxy) ethyl, cyclopentanecarbonyloxymethyl, 1- (cyclopentanecarbonyloxy) ethyl, cyclohexanecarbonyloxymethyl, 1- (cyclohexanecarbonyloxy) ethyl, Cyclopentyloxycarbonyloxymethyl, 1- (cyclopentyloxycarbonyloxy) ethyl, cyclohexyloxycarbonyloxymethyl, 1- (cyclohexyloxycarbonyl) Xyl) ethyl, benzoyloxymethyl, 1- (benzoyloxy) ethyl, phenoxycarbonyloxymethyl, 1- (phenoxycarbonyloxy) ethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl Or a 2-trimethylsilylethyl group.

The oligosaccharide derivatives having the general formulas (I), (Ia) and (Ib) have various isomers. For example, in the oligosaccharide derivatives having the general formulas (I), (Ia) and (Ib), optical isomers may exist in the A moiety and the sugar binding moiety. In the above general formulas (I), (Ia) and (Ib), stereoisomers based on these asymmetric carbon atoms and equivalent and unequal mixtures of these isomers are all represented by a single formula. . Accordingly, the present invention includes all of these isomers and mixtures of these isomers in various proportions.

  Furthermore, the present invention includes all of the above when the oligosaccharide derivatives having the general formulas (I), (Ia) and (Ib), salts or esters thereof form solvates (for example, hydrates). It is a waste.

More preferably, the following general formula (A1c)

It is.

  (A2) is preferably represented by the following general formula (A2a) or (A2b)

More preferably, the following general formula (A2c)

It is.

  (A3) is preferably the following general formula (A3a)

It is.

R ¹ is preferably a C 1-6 alkyl group or a hydroxymethyl group, more preferably a methyl group or a hydroxymethyl group, and particularly preferably a methyl group.

R ² is preferably a C 1-6 alkyl group or a hydroxymethyl group, more preferably a methyl group or a hydroxymethyl group, and particularly preferably a hydroxymethyl group.

R ³ in formulas (A1), (A1c) and (A1a) is preferably a C1-6 hydroxyalkyl group, a hydroxyl group, a halogen atom or a hydrogen atom, more preferably a C1-3 hydroxyalkyl group or hydrogen. An atom, particularly preferably a hydrogen atom. In general formulas (A2), (A2a), (A2b) and (A2c), preferably a C1-6 hydroxyalkyl group, a hydroxyl group, a hydrogen atom or a halogen atom, more preferably a C1-3 hydroxyalkyl group or hydrogen. An atom, particularly preferably a hydroxymethyl group. In general formulas (A3) and (A3a), preferably a C1-6 hydroxyalkyl group, an amino group, a hydroxyl group, a hydrogen atom or a halogen atom, more preferably a hydroxymethyl group, a hydroxyl group or an amino group, and particularly preferred Is a hydroxyl group.

R ⁴ is preferably a C1-6 hydroxyalkyl group, a hydrogen atom, a hydroxyl group or a halogen atom in the general formulas (A1), (A1c) and (A1a), more preferably a hydroxyl group or a halogen atom, particularly A hydroxyl group or a fluorine atom is preferred, and a hydroxyl group is most preferred. In general formulas (A2), (A2a), (A2b) and (A2c), a C1-6 hydroxyalkyl group, a hydrogen atom, a halogen atom or a hydroxyl group is preferred, and a hydroxyl group is more preferred. In general formulas (A3) and (A3a), preferably a C1-6 hydroxyalkyl group, an amino group, a hydroxyl group, a halogen atom or a hydrogen atom, more preferably a hydroxyl group, a halogen atom or a hydrogen atom, particularly preferably. Is a hydroxyl group.

R ⁵ in the general formulas (A1), (A1c) and (A1a) is preferably a hydroxyl group, a halogen atom, a C1-6 hydroxyalkyl group, a C1-6 haloalkyl group or a hydrogen atom, more preferably C1- A 6-hydroxyalkyl group, particularly preferably a C1-3 hydroxyalkyl group, and most preferably a hydroxymethyl group. In the general formulas (A3) and (A3a), preferably a C1-6 hydroxyalkyl group, a hydroxyl group, a hydrogen atom, a halogen atom or an amino group (the amino group is a C1-6 alkyl group or a C1-6 hydroxyalkyl group, 1 or 2 may be substituted), more preferably an amino group (the amino group may be substituted with 1 or 2 C1-6 alkyl group or C1-6 hydroxyalkyl group), Particularly preferred is an amino group.

R ⁶ is preferably a C1-6 hydroxyalkyl group, amino group, hydroxyl group, hydrogen atom or halogen atom in the general formulas (A3) and (A3a), more preferably a C1-6 hydroxyalkyl group, Particularly preferred is a C1-3 hydroxyalkyl group, and most preferred is a hydroxymethyl group.

R ⁷ is preferably a hydrogen atom, a C 1-6 hydroxyalkyl group or a C 1-6 alkyl group, more preferably a hydrogen atom or a methyl group, and particularly preferably a hydrogen atom.

R ⁸ and R ⁹ are preferably a C1-3 hydroxyalkyl group, a halogen atom, a hydrogen atom or a hydroxyl group, more preferably a hydrogen atom or a hydroxyl group.

R ¹⁰ is preferably a C 1-6 hydroxyalkyl group, more preferably a C 1-3 hydroxyalkyl group, and particularly preferably a hydroxymethyl group.

R ¹¹ is preferably a hydroxyl group.

  n is preferably 1.

  A is preferably the following general formula (A1) or (A2)

More preferably, (A1).

  The general formula (I) is preferably the following general formula (IA) or (IB)

More preferably, the following general formula (Ia) or (Ib)

Particularly preferred is (Ia).

Specific examples of the oligosaccharide derivatives having the above general formulas (I), (Ia) and (Ib) or pharmacologically acceptable salts or esters thereof according to the present invention include the compounds exemplified below. However, the present invention is not limited to the following exemplary compounds.

In Tables 1 to 45 below, “ ⁿ Pr” represents an n-propyl group, “ ⁱ Pr” represents an i-propyl group, “ ⁿ Bu” represents an n-butyl group, and “ ^t Bu” represents a t- “ ^I Bu” represents an i-butyl group, “ ⁿ Pn” represents an n-pentyl group, and “ ⁿ Hex” represents an n-hexyl group.

(Table 1)

(Table 2)

(Table 3)

(Table 4)

(Table 5)

(Table 6)

(Table 7)

(Table 8)

(Table 9)

(Table 10)

(Table 11)

(Table 12)

(Table 13)

(Table 14)

(Table 15)

(Table 16)

(Table 17)

(Table 18)

(Table 19)

(Table 20)

(Table 21)

(Table 22)

(Table 23)

(Table 24)

(Table 25)

(Table 26)

(Table 27)

(Table 28)

(Table 29)

(Table 30)

(Table 31)

(Table 32)

(Table 33)

(Table 34)

(Table 35)

(Table 36)

(Table 37)

(Table 38)

(Table 39)

(Table 40)

(Table 41)

(Table 42)

(Table 43)

(Table 44)

(Table 45)

  In the above table, preferred are 1-1, 1-115, 1-119, 1-155, 1-280, 1-354, 1-547, 1-556, 1-557, 3-1, 5-1, 5-3, 5-9, 5-22 or 5-28, and more preferred are (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidine-3 -Yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O-β-D-glucopyranosyl- α-D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-fluoro-6-deoxy-β-D-glucopyranosyl) -D- Glucopyranoside, (1R, 2S, 3R, 4R, 5R) -1-amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O- (6-deoxy-α-D-g (Copyranosyl) -α-D-glucopyranoside, (1R, 2S, 3R, 4R, 5R) -1-amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O- (6-deoxy- β-D-glucopyranosyl) -α-D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-methoxy-6-deoxy-β- D-glucopyranosyl) -D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-3,4-dihydro-2H-pyrrol-3-yl 4-O- (6-deoxy-α-D -Glucopyranosyl) -α-D-glucopyranoside or a pharmacologically acceptable salt or ester thereof.

The compound having the following general formula (I) according to the present invention can be produced, for example, by the following method using a known compound as a starting material.

In the above formula and the following description, A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and n are as described above. Is equivalent to However, when R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ represents a hydroxyl group or a group having a hydroxyl group, the hydroxyl group is protected. It may be.

  Process A

Process B
Ba method

    Bb method

    Bc method

  Process C

In the above process and the following description, X ¹ -X ¹⁹ , Y ^a1 -Y ^a5 and Y ^c1 -Y ^c3 are the same or different and are a hydrogen atom or a hydroxyl group (the hydroxyl group may be protected by a protecting group). Y ^b1 -Y ^b5 is the same or different and represents a halogen atom, a hydrogen atom or a hydroxyl group (the hydroxyl group may be protected by a protecting group), and P ¹ represents R ⁶ or a C 1-6 alkoxycarbonyl group (Preferably a t-butoxycarbonyl group), an amino-protecting group such as C7-16 aralkyloxycarbonyl group (preferably benzyloxycarbonyl group), and P ² and P ³ are the same or different. , R ⁷ , a C1-6 alkoxycarbonyl group (preferably a t-butoxycarbonyl group), a C7-16 aralkyloxycarbonyl group (preferably a benzyloxycarbonyl group) and a protecting group for an amino group, L ¹ , L ² , L ³ and L ⁴ are hydroxyl groups ( The hydroxyl group is protected by a protecting group, or a hydrogen atom may be replaced by a leaving group) or represents a leaving group.

The protecting group used for protecting the hydroxyl group is not particularly limited as long as it is generally used for protecting the hydroxyl group.For example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, Decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14 -Methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, icosanoyl and he Alkylcarbonyl groups such as icosanoyl, carboxylated alkylcarbonyl groups such as succinoyl, glutaroyl and adipoyl, halogeno lower alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl, lower alkoxy such as methoxyacetyl “Aliphatic acyl groups” such as lower alkylcarbonyl groups, unsaturated alkylcarbonyl groups such as (E) -2-methyl-2-butenoyl; arylcarbonyl groups such as benzoyl, α-naphthoyl, β-naphthoyl; -Halogenoarylcarbonyl groups such as bromobenzoyl, 4-chlorobenzoyl, lower alkylated arylcarbonyl groups such as 2,4,6-trimethylbenzoyl, 4-toluoyl, lower alkoxy such as 4-anisoyl Arylcarbonyl group, carboxylated arylcarbonyl group such as 2-carboxybenzoyl, 3-carboxybenzoyl, 4-carboxybenzoyl, nitrated arylcarbonyl group such as 4-nitrobenzoyl, 2-nitrobenzoyl, 2- (methoxycarbonyl) ) “Aromatic acyl groups” such as lower alkoxycarbonylated arylcarbonyl groups such as benzoyl, arylated arylcarbonyl groups such as 4-phenylbenzoyl; tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl A “tetrahydropyranyl or tetrahydrothiopyranyl group” such as 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; tetrahydrofuran-2-yl, Te “Tetrahydrofuranyl or tetrahydrothiofuranyl group” such as trahydrothiofuran-2-yl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl A “silyl group” such as a tri-lower alkylsilyl group substituted by 1 to 2 aryl groups such as a tri-lower alkylsilyl group such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropylsilyl; Lower alkoxymethyl groups such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and t-butoxymethyl; “Alkoxymethyl groups” such as lower alkoxylated lower alkoxymethyl groups such as til, halogeno lower alkoxymethyl such as 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl; 1-ethoxyethyl, “Substituted ethyl groups” such as lower alkoxylated ethyl groups such as 1- (isopropoxy) ethyl and halogenated ethyl groups such as 2,2,2-trichloroethyl; benzyl, α-naphthylmethyl, β-naphthylmethyl , Lower alkyl groups substituted with 1 to 3 aryl groups such as diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2- 1 to 3 aryl rings substituted with lower alkyl, lower alkoxy, halogen, cyano groups such as nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, methyl, piperonyl An “aralkyl group” such as a lower alkyl group substituted by an aryl group of; lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2 An “alkoxycarbonyl group” such as a lower alkoxycarbonyl group substituted with a halogen or tri-lower alkylsilyl group such as trimethylsilylethoxycarbonyl; an “alkenyloxycarbonyl group” such as vinyloxycarbonyl or allyloxycarbonyl; An aryl ring with 1 to 2 lower alkoxy or nitro groups, such as diloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl Can include an “aralkyloxycarbonyl group” which may be substituted. The reagent used for protecting the diol is not particularly limited as long as it is usually used for protecting the diol, but preferably an aldehyde derivative such as benzaldehyde or a ketone such as acetone. Derivatives, 2,2-dimethoxypropane, dimethoxy compounds such as dimethoxybenzyl can be mentioned.

The process for producing the compound (I) of the present invention comprises the following three processes.
That is,
(1) Step A is a step for producing intermediate (iii) which is the left side portion of compound (I).
(2) Step B is a step for producing intermediate (vii), which is the right part of compound (I), and method a, method b, and method c can be selected depending on the desired compound (I).
(3) Step C is a step for producing the compound (I) of the present invention by condensing the intermediate (iii) obtained in Step A and the intermediate (vii) obtained in Step B. .

  Hereinafter, each step will be described.

(Process A)
The starting compound (i) can be produced by protecting and deprotecting a hydroxyl group of a known compound by a known method. Moreover, the protection and deprotection of a hydroxyl group can be performed as necessary during this step.

  The protection and deprotection of hydroxyl groups is carried out by well-known methods. For example, according to Green Watts, "Protective groups in organic synthesis 3rd edition" (Wiley-Interscience, USA) It can also be done.

  Also, for example, the deprotection method can be carried out as follows.

  When a silyl group is used as a hydroxyl-protecting group, it is usually treated with a compound that generates a fluorine anion such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine, or potassium fluoride. Alternatively, it can be removed by treatment with acetic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid or an inorganic acid such as hydrochloric acid.

  In addition, when removing with a fluorine anion, reaction may be accelerated | stimulated by adding organic acids, such as formic acid, an acetic acid, and propionic acid.

  The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably it is diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether or the like. Ethers; nitriles such as acetonitrile and isobutyronitrile; water; organic acids such as acetic acid and mixed solvents thereof.

  The reaction temperature and reaction time are not particularly limited, but it is usually 0 to 100 ° C. (preferably 10 to 30 ° C.) for 1 to 24 hours.

  When the protective group for the hydroxyl group is an aralkyl group or an aralkyloxycarbonyl group, it is usually removed by contacting with a reducing agent in a solvent (preferably catalytic reduction at room temperature under a catalyst) or oxidation. A method of removing using an agent is preferred.

    The solvent used in the removal by catalytic reduction is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol, ethanol and isopropanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, Aromatic hydrocarbons such as toluene, benzene and xylene, aliphatic hydrocarbons such as hexane and cyclohexane, esters such as ethyl acetate and propyl acetate, formamide, dimethylformamide, dimethylacetamide, N-methyl-2 -Preferable are amides such as pyrrolidone and hexamethylphosphorotriamide, fatty acids such as formic acid and acetic acid, water, or a mixed solvent thereof, more preferably alcohols, fatty acids, alcohols and ethers. Solvent with alcohol, alcohol A mixed solvent of, or a mixed solvent of fatty acids and water.

  The catalyst to be used is not particularly limited as long as it is usually used for the catalytic reduction reaction, but preferably palladium carbon, palladium black, Raney nickel, platinum oxide, platinum black, rhodium-aluminum oxide, Triphenylphosphine-rhodium chloride and palladium-barium sulfate are used.

  The pressure is not particularly limited, but is usually 1 to 10 atmospheres.

  The reaction temperature and reaction time vary depending on the starting material, the solvent, the type of catalyst, etc., but are generally 0 ° C. to 100 ° C. (preferably 20 ° C. to 70 ° C.), 5 minutes to 48 hours (preferably 1 Hours to 24 hours).

  The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in this reaction, but is preferably a hydrous organic solvent.

  Preferred examples of such an organic solvent include ketones such as acetone, methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride, nitriles such as acetonitrile, diethyl ether, tetrahydrofuran, and dioxane. Mention may be made of ethers, amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide and sulfoxides such as dimethyl sulfoxide.

  The oxidizing agent used is not particularly limited as long as it is a compound used for oxidation, but preferably potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), 2,3-dichloro-5. , 6-Dicyano-p-benzoquinone (DDQ) is used.

While the reaction temperature and reaction time vary depending on the starting materials, solvent and catalyst, etc., the reaction is usually carried out at 0 to 150 ° C. for 10 minutes to 24 hours.

  It can also be removed by reacting alkali metals such as metallic lithium and metallic sodium in liquid ammonia or alcohol such as methanol and ethanol at -78 to -20 ° C.

  Further, it can be removed by using an alkylsilyl halide such as aluminum chloride-sodium iodide or trimethylsilyl iodide in a solvent.

  The solvent to be used is not particularly limited as long as it does not participate in this reaction, but preferably a nitrile such as acetonitrile, a halogenated hydrocarbon such as methylene chloride, chloroform or a mixed solvent thereof. Is used.

  While the reaction temperature and reaction time vary depending on the starting materials, solvent and the like, the reaction is usually carried out at 0 to 50 ° C. for 5 minutes to 3 days.

  In addition, when the reaction substrate has a sulfur atom, aluminum chloride-sodium iodide is preferably used.

  When the hydroxyl protecting group is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it is removed by treatment with a base in a solvent.

  The base to be used is not particularly limited as long as it does not affect other parts of the compound, but preferably metal alkoxides such as sodium methoxide; sodium carbonate, potassium carbonate, lithium carbonate and the like. Alkali metal carbonates; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide; ammonia water; and ammonia such as concentrated ammonia-methanol.

  The solvent to be used is not particularly limited as long as it is used for a normal hydrolysis reaction. Water; alcohols such as methanol, ethanol and n-propanol; ethers such as tetrahydrofuran and dioxane; An organic solvent or a mixed solvent of water and the above organic solvent is preferable.

  The reaction temperature and reaction time vary depending on the starting materials, the solvent, the base used and the like, and are not particularly limited, but are usually 0 to 150 ° C. for 1 to 10 hours in order to suppress side reactions.

  When the hydroxyl protecting group is an alkoxymethyl group, a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a tetrahydrofuranyl group, a tetrahydrothiofuranyl group or a substituted ethyl group, it is usually treated with an acid in a solvent. To be removed.

  The acid to be used is not particularly limited as long as it is usually used as a Bronsted acid or Lewis acid, and is preferably hydrogen chloride; an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid; Bronsted acids such as organic acids such as fluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid: Lewis acids such as boron trifluoride, but also strongly acidic cation exchange resins such as Dowex 50W Can be used.

  The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; Aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate, butyl acetate, Esters such as diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobuta Alcohol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; water, or these The mixed solvent is preferably a halogenated hydrocarbon, an ester or an ether.

  The reaction temperature and reaction time vary depending on the starting material, the solvent and the type and concentration of the acid used, but are usually from -10 to 100 ° C (preferably from -5 to 50 ° C), and from 5 minutes to 48 hours. (Preferably 30 minutes to 10 hours).

  When the hydroxyl protecting group is an alkenyloxycarbonyl group, usually, in the same manner as the removal reaction conditions when the hydroxyl protecting group is the above-mentioned aliphatic acyl group, aromatic acyl group or alkoxycarbonyl group, Achieved by treatment with base.

  In the case of allyloxycarbonyl, it is particularly easy to remove by using palladium and triphenylphosphine or bis (methyldiphenylphosphine) (1,5-cyclooctadiene) iridium (I) .hexafluorophosphate. Therefore, it can be carried out with few side reactions.

  When the hydroxyl protecting group is a formyl group, it is removed by treatment with a base in a solvent.

  The base used is not particularly limited as long as it does not affect other parts of the compound, but an alkali metal hydrogen carbonate such as potassium hydrogen carbonate is preferably used.

  The solvent to be used is not particularly limited as long as it is used for a normal hydrolysis reaction. Water; alcohols such as methanol, ethanol and n-propanol; ethers such as tetrahydrofuran and dioxane; An organic solvent or a mixed solvent of water and the above organic solvent is preferable.

  The reaction temperature and reaction time vary depending on the starting materials, the solvent, the base used and the like, and are not particularly limited, but are usually 0 to 150 ° C. for 1 to 10 hours in order to suppress side reactions.

  When the hydroxyl protecting group is a halogen-substituted acetamide group such as a trifluoroacetamide group, it is removed by treatment with a base in a solvent.

The base to be used is not particularly limited as long as it does not affect other parts of the compound, but a basic resin such as Dowex 1 × 4 (OH ⁻ ) is preferably used.

  The solvent to be used is not particularly limited as long as it is used for a normal hydrolysis reaction. Water; alcohols such as methanol, ethanol and n-propanol are preferable, and water is more preferable. is there.

    A palladium catalyst such as palladium chloride or an iridium catalyst is suitable for deprotecting the anomeric allyl group.

    The solvent to be used is not particularly limited as long as it is used for a normal catalytic reaction, and an alcohol solvent such as methanol, an ether solvent such as tetrahydrofuran, or water is preferable, and more preferably, Methanol and tetrahydrofuran.

(Process A1)
This step is a step for producing compound (ii). After introducing a leaving group to the hydroxyl group at a desired site as necessary, a reagent corresponding to the R ¹ and R ² groups to be introduced and a nucleophilic substitution reaction Is achieved.

  When the leaving group is a halogen atom, the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material, but ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethylformamide, Amides such as dimethylacetamide and hexamethylphosphoric triamide, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, ethyl formate and ethyl acetate Esters, or mixed solvents thereof are preferred, halogenated hydrocarbons or ethers are more preferred, and dichloromethane or tetrahydrofuran is particularly preferred.

  The halogenating agent to be used is not particularly limited as long as it is used for a reaction in which a hydroxyl group is a halogen atom, but dialkylaminosulfur trihalides such as diethylaminosulfur trifluoride (DAST), thionyl chloride, thionyl bromide. Thionyl halides such as thionyl iodide, sulfuryl chloride, sulfuryl bromide, sulfuryl halides such as sulfuryl iodide, phosphorus trichloride, phosphorus tribromide, phosphorus trihalides such as phosphorus triiodide, five Examples thereof include phosphorus pentahalides such as phosphorus chloride, phosphorus pentabromide and phosphorus pentaiodide, and phosphorus oxyhalides such as phosphorus oxychloride, phosphorus oxybromide and phosphorus oxyiodide.

  The reaction temperature is from 0 ° C. to heating (boiling point of the solvent used), preferably from room temperature to heating (boiling point of the solvent used).

  The reaction time is 10 minutes to 24 hours, preferably 1 hour to 5 hours.

  When the leaving group is a sulfonyl group, the sulfonylating agent to be used is not particularly limited as long as it is usually used for a reaction for sulfonylating a hydroxyl group. For example, a halogenated alkanesulfonyl such as ethanesulfonyl chloride. And sulfonyl anhydrides such as p-toluenesulfonyl chloride, methanesulfonic anhydride, benzenesulfonic anhydride, and sulfonic anhydrides such as trifluoromethanesulfonic anhydride. Preferable is methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethanesulfonic anhydride.

  The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; benzene, Aromatic hydrocarbons such as toluene and xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate And esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether. Preferred are halogenated hydrocarbons, esters and ethers, and more preferred is tetrahydrofuran.

  The base used is not particularly limited as long as it is used as a base in a normal reaction, but preferably triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethyl Aniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4. 0] organic bases such as undec-7-ene (DBU), more preferably triethylamine or pyri It is down.

  The reaction temperature is 0 ° C. to under heating (boiling point of the solvent used), preferably 0 ° C. to room temperature.

  The reaction time is 10 minutes to 24 hours, preferably 10 minutes to 1 hour.

Reagents used as reagents corresponding to R ¹ and R ² groups are commercially available reducing agents, halogenating agents and the like.

  The reducing agent used is sodium borohydride, alkali metal borohydride such as lithium borohydride, lithium aluminum hydride, aluminum hydride compound such as lithium triethoxide aluminum hydride, sodium tellurium hydride A hydride reagent such as is preferred.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material. However, alcohols such as methanol and ethanol, ethers such as ether and tetrahydrofuran, or the above mixed solvents may be used. The halogenating agent to be used is not particularly limited as long as it is usually used in a halogenation reaction, but preferably dialkylaminosulfur trihalides such as diethylaminosulfur trifluoride (DAST), thionyl chloride. Thionyl halides such as thionyl bromide and thionyl iodide, sulfuryl chloride, sulfuryl bromide, sulfuryl halides such as sulfuryl iodide, phosphorus trihalides such as phosphorus trichloride, phosphorus tribromide and phosphorus triiodide , Pentahalogens such as phosphorus pentachloride, phosphorus pentabromide, phosphorus pentaiodide Phosphorous acids or phosphorus oxychloride, oxybromide phosphorus, there may be mentioned phosphorus oxyhalide, such as oxy iodide phosphorus, more preferably a diethylamino sulfur trifluoride.

  The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and examples thereof include ethers such as ether and tetrahydrofuran, preferably tetrahydrofuran.

  The reaction temperature is from 0 ° C. to heating (boiling point of the solvent used), preferably from room temperature to heating (boiling point of the solvent used).

  The reaction time is 10 minutes to 24 hours, preferably 1 hour to 5 hours.

(Process A2)
This step is a step for producing intermediate (iii), and is achieved by introducing a leaving group at the 1-position of compound (ii) according to the method of step A1.

(Process B)
(Ba method)
The starting compound (iv) can also be produced according to the method of Tetrahedron Vol. 26, 1985, p1469. Furthermore, the raw material compound (v) can be produced by protecting and deprotecting a hydroxyl group of a known compound by a known method. Further, as in Method A, the hydroxyl group can be protected and deprotected as necessary during this step. Further, when the substituent has a halogen atom, the halogen atom can be introduced according to the halogenation reaction in the step A1.

(Process Ba1)
This step is a step of producing the bicyclic compound (v), and is achieved by heating after reducing the azide group of the compound (iv).

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material, but examples thereof include water-soluble ethers such as tetrahydrofuran and dioxane, water, or a mixed solvent thereof. Is a mixed solvent of water and tetrahydrofuran.

  Examples of the azide group reducing agent include phosphines and aqueous ammonia. Examples include trialkylphosphine and ammonia water such as trimethylphosphine and triethylphosphine, and triarylphosphine and ammonia water such as triphenylphosphine, preferably triarylphosphine and ammonia water such as triphenylphosphine. .

  Moreover, a catalyst can also be used as a reducing agent. The catalyst to be used is not particularly limited as long as it is usually used for the catalytic reduction reaction. For example, palladium carbon, palladium black, palladium hydroxide carbon, Raney nickel, platinum oxide, platinum black, rhodium-aluminum oxide. , Triphenylphosphine-rhodium chloride, palladium-barium sulfate, and the like, preferably palladium carbon or palladium hydroxide carbon.

  When the catalyst is used as a reducing agent, the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material, but preferably alcohols such as methanol and ethanol, tetrahydrofuran, dioxane, and the like. And ethers such as acetic acid, fatty acids such as acetic acid, and esters such as ethyl acetate. More preferred is methanol.

  The reaction temperature is 0 ° C. to 50 ° C., preferably 0 ° C. to room temperature.

  The reaction time is 10 minutes to 24 hours, preferably 1 hour to 5 hours.

(Step Ba2)
This step is a step of producing a compound (vi) in which an amino group is protected, and is achieved by protecting the amino group of compound (v) with an appropriate protecting group.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material, but preferably ethers such as tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol, and alcohols such as methanol and ethanol. Ketones such as acetone, methyl ethyl ketone, amides such as N, N-dimethylformamide, N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide, and the like.

  The reagent to be used is not particularly limited as long as it is usually used for the reaction for introducing a protecting group into a free amino group, but is preferably di-t-butyl-dicarbonate, benzyloxycarbonyl chloride, Examples thereof include p-nitrobenzyloxycarbonyl chloride, and di-t-butyl-dicarbonate is more preferable.

  The base used is not particularly limited as long as it is used as a base in a normal reaction, but is preferably alkali metal carbonates, alkali metal hydrogencarbonates, and organic bases, and more preferably alkali metals. Metal bicarbonates.

  The reaction temperature is 0 ° C. to 50 ° C., preferably 0 ° C. to room temperature.

  The reaction time is 10 minutes to 24 hours, preferably 1 hour to 10 hours.

(Step Ba3)
This step is a step for producing a pyrrolidine compound (viia), in which one ring of the bicyclic compound (vi) is opened in the presence of a reducing agent, protecting the hydroxyl group as necessary, and an intermediate. This is achieved by deprotecting the hydroxyl group at the site of glycosylation with (iii).

  The reducing agent to be used is not particularly limited as long as it is usually used for the reduction reaction. For example, alkali metal borohydride such as sodium borohydride and lithium borohydride, lithium aluminum hydride, hydrogenation Examples thereof include an aluminum hydride compound such as lithium triethoxide aluminum and a hydride reagent such as sodium tellurium hydride, preferably sodium borohydride.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, alcohols such as methanol and ethanol, ethers such as dioxane, ether and tetrahydrofuran are used. , Water, or a mixed solvent as described above, preferably methanol or tetrahydrofuran.

  The reaction temperature is 0 ° C. to the boiling point of the solvent used, preferably 50 ° C. to the boiling point of the solvent used.

  The reaction time is 10 minutes to 24 hours, preferably 1 hour to 5 hours.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material. However, alcohols such as methanol and ethanol, ethers such as ether and tetrahydrofuran, or the above mixed solvents may be used. The reaction temperature which is suitable is from 0 ° C. to the boiling point of the solvent used, and preferably from 50 ° C. to the boiling point of the solvent used.

  The reaction time is 10 minutes to 24 hours, preferably 1 hour to 5 hours.

(Bb method)
The raw material compound (viii) can also be produced according to the method of Carbohydrate research Vol. 169, 1987, p23. Furthermore, the raw material compound (viii) can be produced by protecting and deprotecting a hydroxyl group of a known compound by a known method. Further, as in Method A, the hydroxyl group can be protected and deprotected as necessary during this step. Further, when the substituent has a halogen atom, the halogen atom can be introduced according to the halogenation reaction in the step A1.

(Step Bb1)
This step is a step for producing compound (ix), and is achieved by introducing a leaving group at the 6-position of raw material compound (viii) under the same conditions as in Step A1. Further, if necessary, the leaving group can be further converted into another leaving group.

(Step Bb2)
This step is a step of producing a compound (x) having an olefin end, and is achieved by heating the compound (ix) in a solvent in the presence of a catalyst.

  The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material, and preferably includes alcohols such as methanol, ethanol and isopropanol, water, or a mixed solvent thereof. Preferably, it is a mixed solvent of water and isopropanol.

  The catalyst used is not particularly limited as long as it is usually used for a reaction for reducing a double bond, but borohydride such as zinc, palladium carbon, platinum, Raney nickel, sodium borohydride, lithium borohydride, etc. Examples include alkali metal, lithium aluminum hydride, aluminum hydride compounds such as lithium triethoxide aluminum hydride, and hydride reagents such as sodium tellurium hydride, with zinc being preferred.

  The reaction temperature is 0 ° C. to the boiling point of the solvent used, preferably 50 ° C. to the boiling point of the solvent used.

  The reaction time is 10 minutes to 24 hours, preferably 1 hour to 5 hours.

(Step Bb3)
This step is a step of producing a compound (xi) having a hydroxylamino group, and is achieved by treating the compound (x) with hydroxylamine hydrochloride.

  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material, but is preferably a mixed solvent of alcohols such as methanol, ethanol and isopropanol and an organic base such as pyridine. Preferably, it is a mixed solvent of ethanol and pyridine.

  The reaction temperature is 0 ° C. to the boiling point of the solvent used, preferably 0 ° C. to 60 ° C.

  The reaction time is 10 minutes to 24 hours, preferably 1 hour to 5 hours.

(Step Bb4)
This step is a step for producing the bicyclic compound (xii), and is achieved by heating the compound (xi) in a solvent to cyclize.

  The solvent used is not particularly limited as long as it is inert, but for example, aromatic hydrocarbons such as benzene, toluene, and xylene are preferable, and toluene is more preferable.

  The reaction temperature is 0 ° C. to the boiling point of the solvent used, preferably 50 ° C. to the boiling point of the solvent used.

  The reaction time is 10 minutes to 24 hours, preferably 1 hour to 5 hours.

(Step Bb5)
This step is a step of producing an intermediate compound (viib), deprotecting the intermediate (iii) and the hydroxyl group at the site of glycosylation, and the secondary amine of the compound (xii) is the step A1 It can be achieved by protecting under the same conditions as above.

(Bc method)
The starting compound (xiii) can also be produced according to the method of Chemical Pharmaceutical Bulletin, Vol. 39, 1991, p2807. Furthermore, the raw material compound (xiii) can be produced by protecting and deprotecting a hydroxyl group of a known compound by a known method. Further, as in Method A, the hydroxyl group can be protected and deprotected as necessary during this step. Further, when the substituent has a halogen atom, the halogen atom can be introduced according to the halogenation reaction in the step A1.

(Step Bc1)
This step is a step for producing the intermediate compound (viic) and is achieved by deprotecting the hydroxyl-protecting group of the starting compound (xiii).

(Process C)
(Process C1)
This step is a step for producing the target compound (I), in which a glycosylation reaction is carried out with the intermediate compounds (iii) and (vii), and if necessary, the hydroxyl group and amino group are deprotected according to a conventional method. Achieved.

  As the leaving group at the anomeric position of compound (iii), fluorine, bromine, chlorine, trichloroimidate group, diphenyl phosphate group, diethyl phosphite group, thiomethyl group, phenylthio group and the like are preferable.

  The solvent used is not particularly limited as long as it is inert. For example, halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as ether and tetrahydrofuran, benzene, toluene, xylene and the like. Aromatic hydrocarbons are preferred, halogenated hydrocarbons or ethers are more preferred, and methylene chloride or ether is particularly preferred.

  The catalyst used is not particularly limited as long as it is a catalyst usually used for glycosyl reaction, but trimethylsilyl trifluoromethane sulfonic acid, trifluoromethane sulfonic acid, boron trifluoride ether complex, toluene sulfonic acid, silver trifluoromethane sulfonic acid, iodine Tetrabutylammonium chloride is preferred.

  The reaction temperature ranges from 0 ° C. to the boiling point of the solvent used, preferably room temperature.

  The reaction time is 10 minutes to 24 hours, preferably 1 hour to 5 hours.

  (I) can also be produced by subjecting intermediate compounds (iii) and (viic) to a glycosylation reaction followed by deprotection of the hydroxyl group and further under basic conditions.

When n = 2, compound (I) can be produced by the same method as method A and method C, using a trisaccharide derivative as a starting compound.

The target compound (I) can be converted to an acid addition salt, preferably a hydrochloride, when it has a basic group according to a conventional method.

  After completion of the reaction in each of the above steps, the target compound is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, washed with water, and the target compound is then contained. The organic layer is separated, dried over anhydrous magnesium sulfate and the like, and then the solvent is distilled off.

  If necessary, the obtained target product can be obtained by a conventional method such as recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, such as adsorption column chromatography, distribution column chromatography, etc. Separation and purification by eluting with an appropriate eluent by combining a method using a synthetic adsorbent, a method using ion exchange chromatography, or a normal phase / reverse phase column chromatography method using silica gel or alkylated silica gel. can do.

  The oligosaccharide derivatives having the general formulas (I), (Ia) and (Ib) of the present invention, pharmacologically acceptable salts and esters thereof are administered in various forms. The administration form is not particularly limited, and is determined according to various preparation forms, patient age, sex and other conditions, the degree of disease, and the like. For example, it is orally administered in the case of tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions, granules and capsules. In the case of a suppository, it is administered intrarectally. Oral administration is preferred.

  These various preparations are prepared by using known adjuvants that can be generally used in the field of known pharmaceutical preparations such as excipients, binders, disintegrants, lubricants, solubilizers, flavoring agents, and coating agents according to conventional methods. It can be formulated.

  In molding into tablets, conventionally known carriers can be widely used as carriers, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like. Form, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, binder such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder Sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and other disintegrants, sucrose, stearin, cacao butter, hydrogenated oil and other disintegration inhibitors, Class Ammonius Absorption accelerators such as bases, sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, purified talc, stearate, boric acid powder, polyethylene glycol, etc. A lubricant can be exemplified. Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets.

  In molding into the form of pills, those conventionally known in this field can be widely used as carriers, for example, glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc and other excipients, gum arabic powder, Examples thereof include binders such as tragacanth powder, gelatin and ethanol, and disintegrants such as lamina lankanten.

  In molding into the form of suppository, conventionally known carriers can be widely used as carriers, such as polyethylene glycol, cacao butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides and the like. it can.

  Furthermore, you may contain a coloring agent, a preservative, a fragrance | flavor, a flavoring agent, a sweetening agent, and other pharmaceuticals as needed.

  The amount of the active ingredient compound contained in the pharmaceutical preparation is not particularly limited and is appropriately selected within a wide range, but is usually 1 to 70% by weight, preferably 1 to 30% by weight in the total composition. Is appropriate.

  The dose varies depending on symptoms, age, body weight, administration method, dosage form, etc., but is usually 0.001 mg (preferably 0.01 mg, more preferably 0.1 mg) as the lower limit for adults a day, As an upper limit, 2,000 mg (preferably 200 mg, more preferably 100 mg) can be administered once to several times.

  The pharmaceutical composition containing the oligosaccharide derivative of the present invention and a pharmacologically acceptable salt thereof and a pharmacologically acceptable ester as an active ingredient has excellent α-amylase inhibitory action, blood glucose lowering action, lipid lowering action, etc. Has hyperglycemia, hyperglycemia, glucose intolerance, diabetes, obesity, hyperlipidemia, fatty liver, liver hypertrophy, diabetic complications, neuropathy, arteriosclerosis, cataract, diabetic nephropathy, etc. It is useful as a therapeutic agent and / or preventive agent (preferably a therapeutic agent and / or preventive agent for postprandial hyperglycemia and diabetes).

  EXAMPLES Next, although an Example, a test example, and a formulation example are given and this invention is demonstrated further in detail, this invention is not limited to these.

<Example 1>
(2R, 3R, 4R) -4-hydroxy-2- (hydroxymethyl) pyrrolidin-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranoside (Exemplary Compound No. 1- 1)

(1a) Allyl 4-O- (2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl) -2,3,6-tri-O-acetyl-D-glucopyranoside D-maltose monohydrate The Japanese product (36.0 g, 100 mmol) was dissolved in pyridine (200 mL), acetic anhydride (100 mL) and 4-dimethylaminopyridine (0.6 g, 4.90 mol) were added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was ice-cooled, ice (30 g) was added, and the mixture was stirred for 30 min and extracted with ethyl acetate (500 mL). The organic layer was diluted hydrochloric acid (1N, 200 mL), saturated aqueous sodium hydrogen carbonate (100 mL), saturated brine Washed with water (100 mL). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (700 mL), allyl alcohol (34 mL, 500 mol) and trimethylsilyl trifluoromethanesulfonate (18.1 mL, 100 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate (1 L), extracted with methylene chloride (500 mL), the organic layer was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. . The residue was purified by silica gel flash column chromatography (ethyl acetate: hexane, 2: 3, V / V) to obtain the title object compound (30.0 g, yield 31%) as a pale yellow amorphous.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.99 (3H, s), 2.00 (3H, s), 2,01 (6H, s), 2.03 (3H, s), 2.09 (3H, s), 2.14 (3H, s), 3.65-3.69 (1H, m), 3.93-4.14 (4H, m), 4.20-4.26 (2H, m), 4.30 (1H, dd, J = 13.2, 5.1 Hz), 4.47 (1H , dd, J = 12.4, 2.9 Hz), 4.57 (1H, d, J = 8.1 Hz), 4.83-4.87 (2H, m), 5.04 (1H, t, J = 9.5 Hz), 5.18-5.28 (3H, m), 5.35 (1H, t, J = 9.5 Hz), 5.41 (1H, d, J = 3.7 Hz), 5.79-5.88 (1H, m);
MS (FAB) m / z: 677 (M + H) ⁺ , 699 (M + Na) ⁺ .
(1b) Allyl 4-O- (4,6-O-benzylidene-α-D-glucopyranosyl) -D-glucopyranoside The compound (17.0 g, 25.1 mmol) synthesized in Example 1 (1a) was treated with methanol ( 250 mL), sodium methoxide (2 mL, 9.8 mol) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Dowex 50w × 8 was added until the reaction solution became neutral, and after filtration, the solvent was distilled off under reduced pressure. The residue was dissolved in N, N-dimethylformamide (200 mL), benzaldehyde dimethyl acetal (4.65 mL, 31.0 mmol) and p-toluenesulfonic acid monohydrate (226 mg, 1.19 mmol) were added, and 20 mmHg, 50 Stir at 5 ° C. for 5 hours. After adding triethylamine (1 mL) to the reaction solution, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (ethyl acetate: hexane: methanol, 5: 5: 1, V / V / V) to give the title object compound (10.0 g, yield 85%) as a pale yellow amorphous product. Got as.
¹ H NMR (400 MHz, CD ₃ OD): δ 3.16 (1H, t, J = 9.5 Hz), 3.28-3.32 (1H, m), 3.35 (1H, t, J = 9.5 Hz), 3.42 (1H, t, J = 9.5 Hz), 3.47 (1H, dd, J = 9.5, 3.6 Hz), 3.54 (1H, t, J = 9.5 Hz), 3.61-3.66 (2H, m), 3.71 (1H, t, J = 9.5 Hz), 3.74-3.81 (2H, m), 4.02-4.07 (1H, m), 4.12 (1H, dd, J = 10.3, 5.1 Hz), 4.22-4.29 (2H, m), 5.06 (1H, d, J = 10.2 Hz), 5.10 (1H, d, J = 4.4 Hz), 5.23 (1H, d, J = 17.5 Hz), 5.81-5.91 (1H, m), 7.22-7.24 (3H, m), 7.38-7.40 (2H, m);
MS (FAB) m / z: 471 (M + H) ⁺ , 493 (M + Na) ⁺ .
(1c) Allyl 4-O- (4,6-O-benzylidene-2,3-di-O-benzyl-α-D-glucopyranosyl) -2,3,6-tri-O-benzyl-D-glucopyranoside The compound (10.0 g, 21.3 mmol) synthesized in Example 1 (1b) was dissolved in N, N-dimethylformamide (300 mL), and sodium hydride (9.28 g, 213 mmol) was added under ice cooling. . After stirring for 30 minutes under ice-cooling, benzyl bromide (25 mL, 213 mmol) was added, and after stirring at room temperature for 3 hours, water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (500 mL). The extract was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 9: 1, V / V) to obtain the title object compound (18.5 g, yield 94%) as a pale yellow solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.49-3.68 (4H, m), 3.76-3.90 (3H, m), 3.93-4.03 (2H, m), 4.09-4.19 (3H, m), 4.42- 4.78 (10H, m), 4.84-5.07 (3H, m), 5.23 (1H, t, J = 9.8 Hz), 5.35 (1H, dd, J = 17.5, 8.8 Hz), 5.54 (1H, d, J = 3.9 Hz), 5.74 (1H, dd, J = 24.5, 3.9 Hz), 5.92-6.02 (1H, m), 7.17-7.51 (5H, m);
MS (FAB) m / z: 922 (M + H) ⁺ , 944 (M + Na) ⁺ .
(1d) Allyl 2,3,6-tri-O-benzyl-4-O- (2,3,4-tri-O-benzyl-α-D-glucopyranosyl) -D-glucopyranoside In Example 1 (1c) The synthesized compound (30.0 g, 32.5 mmol) was dissolved in diethyl ether (300 mL) and methylene chloride (150 mL), and lithium aluminum hydride (1.85 g, 48.8 mmol) and aluminum (III) chloride (6) .93 g, 52.0 mmol) was added, and the mixture was heated to reflux for 2 hours. The reaction mixture was diluted with diethyl ether (500 mL), 1N aqueous sodium hydroxide solution (5.6 mL) was added to the reaction mixture, and the mixture was stirred for 1 hr. After extraction with ethyl acetate, the organic layer was washed with 10% aqueous hydrochloric acid solution (100 mL), saturated aqueous sodium hydrogen carbonate solution (150 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. . The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 4: 1-3: 1 to 2: 1, V / V) to give the title object compound (21.1 g, yield 71%) Obtained as a yellow solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.40-3.71 (6H, m), 3.74-3.85 (2H, m), 3.90 (2H, m), 3.99-4.07 (1H, m), 4.10-4.20 ( 3H, m), 4.42-4.70 (7H, m), 4.76-5.08 (6H, m), 5.23 (1H, t, J = 10.7 Hz), 5.35 (1H, dd, J = 18.6, 8.8 Hz), 5.64 (1H, dd, J = 13.7, 3.9 Hz), 5.93-6.02 (1H, m), 7.18-7.34 (30H, m);
MS (FAB) m / z: 946 (M + Na) ⁺ , 924 (M + H) ⁺ .
(1e) Allyl 2,3,6-tri-O-benzyl-4-O- (2,3,4-tri-O-benzyl-6-deoxy-α-D-glucopyranosyl) -D-glucopyranoside Example 1 The compound synthesized in (1d) (15.2 g, 16.5 mmol) was dissolved in pyridine (300 mL), p-toluenesulfonyl chloride (12.5 g, 66.0 mmol) and 4-dimethylaminopyridine (2.01 g). 16.4 mmol) and stirred at room temperature for 13 hours. After evaporating the solvent under reduced pressure, the residue was poured into 10% aqueous hydrochloric acid (50 mL) and ethyl acetate (200 mL), and the organic layer was 10% aqueous hydrochloric acid (50 mL), saturated aqueous sodium bicarbonate (20 mL), and saturated brine. After washing with (20 mL) and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1-3: 1, V / V) to give the tosylate (13.5 g, yield 76%) as a yellow oil. This tosylate (13.5 g, 12.5 mol) was dissolved in diethyl ether (300 mL), lithium aluminum hydride (950 mg, 25 mol) was added, and the mixture was heated to reflux for 1 hour. 1N NaOH aqueous solution (1.0 mL) and water (1.0 mL) were added to the reaction solution, and the mixture was stirred for 30 minutes. After filtration through celite, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 6: 1, V / V) to obtain the title object compound (10.2 g, yield 90%) as a colorless solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.08 (3H, d, J = 5.8 Hz), 3.01 (1H, t, J = 9.5 Hz), 3.35 (1H, dd, J = 9.5, 3.7 Hz), 3.44-3.50 (2H, m), 3.66-3.72 (5H, m), 3.78 (1H, t, J = 9.5 Hz), 3.93 (1H, t, J = 9.5 Hz), 4.07 (1H, dd, J = 12.8, 5.9 Hz), 4.35 (1H, dd, J = 13.1, 5.1 Hz), 4.39-4.57 (7H, m), 4.69 (2H, d, J = 11.7 Hz), 4.77-4.88 (3H, m), 5.13 (1H, d, J = 10.0 Hz), 5.26 (1H, d, J = 16.9 Hz), 5.47 (1H, d, J = 3.7 Hz), 5.84-5.92 (1H, m), 7.09-7.26 (30H , m);
MS (FAB) m / z: 907 (M + H) ⁺ .
(1f) 4-O- (6-Deoxy-2,3,4-tri-O-benzyl-α-D-glucopyranosyl) -2,3,6-tri-O-benzyl-D-glucopyranoside Example 1 ( The compound synthesized in 1e) (10.2 g, 11.2 mmol) was dissolved in methanol (40 mL) and tetrahydrofuran (100 mL), palladium (II) chloride (400 mg, 2.24 mmol) was added, and the mixture was stirred at room temperature for 14 hours. . The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1 to 4: 1, V / V) to give the title object compound (8.17 g, yield 84%) as a pale yellow amorphous product. It was.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.14 (3H, d, J = 6.6 Hz), 3.09 (1H, t, J = 9.5 Hz), 3.41-3.47 (2H, m), 3.62-3.81 (4H , m), 3.96-4.05 (2H, m), 4.01-4.14 (1H, m), 4.49-4.68 (6H, m), 4.74-4.78 (2H, m), 4.84-4.96 (4H, m), 5.22 (1H, d, J = 3.6 Hz), 5.51 (1H, d, J = 3.7 Hz), 7.19-7.34 (30H, m);
MS (FAB) m / z: 889 (M + Na) ⁺ .
(1 g) Methyl 3-O-benzoyl-N-benzyloxycarbonyl-2,5-dideoxy-2,5-imino-α-D-lyxofuranoside methyl N-benzyloxycarbonyl-2,5-dideoxy-2,5- Imino-α-D-lyxofuranoside (Tetrahedron, 1986, vol 42, p. 5665-5692) (13.9 g, 49.8 mmol) was dissolved in methylene chloride (200 mL), pyridine (20 mL, 249.0 mmol), chloride. Benzoyl (11.6 mL, 99.6 mmol) was added and stirred at room temperature for 2 hours. 1N Hydrochloric acid (200 mL) was added to the reaction mixture at 0 ° C., and the mixture was extracted with methylene chloride (100 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (200 mL) and saturated brine (200 mL), and anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 5: 1-3: 1, V / V) to obtain the title object compound (15.82 g, yield 83%) as a colorless solid. .
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.42-3.46 (4H, 3s), 3.60 (1H, dd, J = 32.2, 10.8 Hz), 4.54 (1H, d, J = 34.2 Hz), 4.64 (1H , br, d, J = 7.9 Hz), 4.85 (1H, d, J = 36.2 Hz), 5.13-5.22 (2H, m), 5.47 (1H, s), 7.29-7.35 (5H, m), 7.41- 7.45 (2H, m), 7.59 (1H, t, J = 7.8 Hz), 7.95 (2H, t, J = 7.8 Hz);
MS (FAB) m / z: 406 (M + Na) ⁺ , 384 (M + H) ⁺ .
(1h) Benzyl (2R, 3R, 4R) -3-benzoyloxy-4-hydroxy-2- (hydroxymethyl) pyrrolidine-1-carboxylate The compound synthesized in Example 1 (1 g) (15.8 g, 41.41). 3 mmol) was dissolved in trifluoroacetic acid: water (4: 1, 160 mL) and stirred at room temperature for 15 minutes. Water (200 mL) was added to the reaction solution at 0 ° C., and the mixture was extracted with methylene chloride (300 mL). The organic layer was washed with saturated aqueous sodium hydrogencarbonate (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure. The residue was dissolved in ethanol (150 mL), sodium borohydride (0.78 g, 20.7 mmol) dissolved in water (15 mL) was added, and the mixture was stirred at 0 ° C. for 20 min. Saturated aqueous ammonium chloride (20 mL) was added to the reaction mixture at 0 ° C., and ethanol was evaporated under reduced pressure. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 1: 1, V / V) to give the title object compound (14.2 g, yield 89%) as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.68 (1H, d, J = 11.7 Hz), 3.86 (1H, dd, J = 11.7, 4.4 Hz), 3.93-4.04 (2H, m), 4.25-4.32 (2H, m), 5.09-5.32 (3H, m), 7.32-7.46 (7H, m), 7.59 (1H, t, J = 7.4 Hz), 7.99 (2H, d, J = 8.8 Hz);
MS (FAB) m / z: 372 (M + H) ⁺ .
(1i) benzyl (2R, 3R, 4R) -4-benzyloxy-2-benzyloxymethyl-3-hydroxypyrrolidine-1-carboxylate Compound (4.26 g, 11.5 mmol) synthesized in Example 1 (1h) ) Is dissolved in dichloromethane: cyclohexane (1: 2, 180 mL), benzyltrichloroacetimidate (10.6 mL, 57.5 mmol), trifluoromethanesulfonic acid (0.15 mL, 1.7 mmol) are added at room temperature. For 3 hours. Saturated aqueous sodium hydrogen carbonate (10 mL) was added to the reaction solution at 0 ° C., diluted with ethyl acetate (200 mL), washed with water (300 mL) and saturated brine (300 mL), dried over anhydrous sodium sulfate, The lower solvent was distilled off. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 10: 1 to 5: 1, V / V) to obtain 7.85 g of a pale yellow oil. The obtained pale yellow oily substance 7.85g was melt | dissolved in methanol (100 mL), 1M potassium carbonate aqueous solution (4 mL) was added, and it stirred at room temperature for 5 hours. Methanol was distilled off under reduced pressure, water (100 mL) was added, the mixture was extracted with ethyl acetate (100 mL), and the organic layer was washed with saturated brine (100 mL). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 2: 1, V / V) to give the title object compound (4.06 g, yield 64%) as a colorless solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.35 (1H, dd, J = 11.7, 3.7 Hz), 3.51-3.72 (1H, m), 3.66-3.89 (4H, m), 4.37-4.52 (5H, m), 4.98-5.07 (2H, m), 7.09-7.26 (15H, m);
MS (FAB) m / z: 448 (M + H) ⁺ .
(1j) Benzyl (2R, 3R, 4R) -4-benzyloxy-2-benzyloxymethyl-3-{[2,3,6-tri-O-benzyl-4-O- (2,3,4- Tri-O-benzyl-6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranosyl] oxy} pyrrolidine-1-carboxylate benzyl (2R, 3R, 4R) -4-benzyloxy-2-benzyloxymethyl -3-{[2,3,6-tri-O-benzyl-4-O- (2,3,4-tri-O-benzyl-6-deoxy-α-D-glucopyranosyl) -β-D-glucopyranosyl Oxy} pyrrolidine-1-carboxylate The compound synthesized in Example 1 (1f) (13.5 g, 15.57 mmol) was dissolved in methylene chloride (250 mL), and trichloroacetoni was dissolved. Tolyl (10 mL, 134.3 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (2 drops) were added and stirred at room temperature for 40 minutes. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1, 1% triethylamine, V / V) to obtain imidate (13.0 g, 82%) as a yellow oil. Obtained as a thing. The compound (5.48 g, 12.2 mmol) synthesized in Example 1 (1i) was dissolved in diethyl ether (400 mL), imidate (13.0 g, 13.0 mmol) was added, and trimethylsilyl trifluoromethanesulfonate (222 μL, 1.22 mmol) of diethyl ether (2 mL) was added dropwise and stirred at room temperature for 45 minutes. After adding triethylamine (1 mL) to the reaction solution, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane: diethyl ether, 4: 1, V / V) to give the title target compound α-isomer (11.6 g, 56%) as a pale yellow oil, The β isomer (3.7 g, 18%) was obtained as a pale yellow oil.
α form: ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.20 (3H, d, J = 5.9 Hz), 3.10-3.22 (2H, m), 3.30-3.38 (2H, m), 3.42 (1H, t , J = 8.8 Hz), 3.50-3.70 (5H, m), 3.76-3.87 (5H, m), 4.01-4.10 (1H, m), 4.26-4.51 (9H, m), 4.61 (1H, d, J = 11.0 Hz), 4.69-4.88 (8H, m), 4.96-5.16 (3H, m), 7.19-7.34 (43H, m), 7.43 (2H, d, J = 7.3 Hz);
MS (FAB) m / z: 1318 (M + Na) ⁺ .
β-form ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.17 (3H, d, J = 6.5 Hz), 3.10 (1H, t, J = 9.1 Hz), 3.41-3.48 (3H, m), 3.54-3.63 (3H, m), 3.69-3.78 (4H, m), 3.81-3.92 (2H, m), 4.02 (1H, s, J = 8.79 Hz), 4.25 (1H, d, J = 4.39 Hz), 4.40- 4.63 (13H, m), 4.73-4.79 (3H, m), 4.86-4.95 (4H, m), 5.09-5.19 (1H, m), 5.53 (1H, d, J = 3.67 Hz), 7.18-7.30 ( 45H, m);
MS (FAB) m / z: 1296 (M + H) ⁺ .
(1k) (2R, 3R, 4R) -4-Hydroxy-2- (hydroxymethyl) pyrrolidin-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranoside Example 1 The compound synthesized in (1j) (5.60 g, 4.32 mmol) was dissolved in methanol (350 mL), hydrochloric acid (4.8 mL) and 20% palladium hydroxide-carbon (2.8 g) were added, and hydrogen atmosphere was added. And stirred at room temperature for 4 hours. After filtration through Celite, 18% aqueous ammonia (6 mL) was added, the solvent was distilled off under reduced pressure, and the residue was purified with an ion exchange resin (Dowex 50w × 8) column (water to 5% aqueous ammonia). Further purification was performed using silica gel flash column chromatography (ethyl acetate: methanol: water, 2: 2: 1, V / V) to obtain the title object compound (1.20 g, 63%) as a colorless solid.
[α] _D ²⁰ +145.7 (c 0.36, H ₂ O);
¹ H NMR (400 MHz, D ₂ O): δ 1.28 (3H, d, J = 6.6 Hz), 2.93 (1H, dd, J = 12.4, 3.0 Hz), 3.12-3.20 (3H, m), 3.57- 3.65 (4H, m), 3.71-3.87 (6H, m), 3.92-3.98 (2H, m), 4.32-4.34 (1H, m), 5.13 (1H, d, J = 3.6 Hz), 5.34 (1H, d, J = 3.0 Hz);
¹³ C NMR (125.70 MHz, D ₂ O): δ 16.72, 51.62, 60.64, 61.62, 64.84, 68.79, 70.94, 71.07, 72.13, 72.83, 73.48, 74.96, 75.64, 77.13, 84.01, 97.44, 99,88;
MS (FAB) m / z: 442 (M + H) ⁺ , 464 (M + Na) ⁺ .
<Example 2>
(2R, 3R, 4R) -4-hydroxy-2- (hydroxymethyl) pyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside (Exemplary Compound No. 1- 1)

(2a) Allyl 4-O-β-D-glucopyranosyl-D-glucopyranoside α-D-cellobiose octaacetate (48.59 g, 71.6 mmol) was dissolved in methylene chloride (600 mL) and allyl alcohol was cooled with ice. (29 ml, 0.43 mol) and trimethylsilyl trifluoromethanesulfonate (16 mL, 86.0 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (200 mL). The extract was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (300 mL), sodium methoxide (28 mL, 0.14 mol) was added under ice cooling, and the mixture was stirred at room temperature for 2 hr. Dowex 50w × 8 was added until the reaction solution became neutral, and after filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (ethyl acetate: methanol: water, 8: 2 :: 1, V / V) to give the title object compound (24.8 g, yield 91%) as a pale yellow amorphous product. Obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.20-3.40 (9H, m), 3.40-3.65 (4H, m), 4.00-4.40 (3H, m), 5.18 (1H, d, J = 11.7 Hz) , 5.35 (1H, d, J = 17.6 Hz), 5.95 (1H, ddd, J = 17.6, 11.7, 5.9 Hz);
MS (FAB) m / z: 383 (M + H) ⁺ .
(2b) Allyl 2,3,6-tri-O-benzyl-4-O- (2,3-di-O-benzyl-4,6-O-benzylidene-β-D-glucopyranosyl) -D-glucopyranoside The compound synthesized in Example 2 (2a) (24.8 g, 64.9 mmol) was dissolved in N, N-dimethylformamide (300 mL), benzaldehyde dimethyl acetal (13 mL, 84.4 mmol) and p-toluenesulfonic acid monoester. Hydrate (617 mg, 3.24 mmol) was added, and the mixture was stirred at 20 mmHg and 50 ° C. for 5 hours. After adding triethylamine (900 μL) to the reaction solution, the solvent was distilled off under reduced pressure. Water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (200 mL × 5). The extract was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (400 mL), sodium hydride (20 g, 0.45 mmol) was added under ice-cooling, the mixture was stirred at the same temperature for 10 min, and then benzyl bromide (54 mL, 0.45 mmol). ) And stirred at room temperature for 2.5 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (500 mL). The extract was washed with water (100 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 10: 1 to 7: 1, V / V) to obtain the title object compound (46.6 g, yield 78%) as a pale yellow solid. It was.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.10-5.00 (26H, m), 5.18 (1H, d, J = 11.7 Hz), 5.35 (1H, d, J = 17.6 Hz), 5.60 (1H, s ), 5.95 (1H, ddd, J = 17.6, 11.7, 5.9 Hz), 7.20-7.60 (30H, m);
MS (FAB) m / z: 922 (M + H) ⁺ .
(2c) Allyl 2,3,6-tri-O-benzyl-4-O- (2,3,4-tri-O-benzyl-β-D-glucopyranosyl) -D-glucopyranoside In Example 2 (2b) The synthesized compound (63.0 g, 68.4 mmol) was dissolved in diethyl ether (800 mL) and methylene chloride (400 mL), and lithium aluminum hydride (10.4 g, 0.27 mol) and aluminum chloride (III) (36 0.4 g, 0.27 mol) was added and the mixture was heated to reflux for 1 hour. The reaction mixture was diluted with diethyl ether (500 mL), 1N aqueous sodium hydroxide solution (21.0 mL) was added to the reaction mixture, and the mixture was stirred for 1 hr. After extraction with ethyl acetate, the organic layer was washed with 10% aqueous hydrochloric acid solution (500 mL), saturated aqueous sodium hydrogen carbonate solution (500 mL) and saturated brine (300 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. . The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 4: 1-3: 1 to 2: 1, V / V) to give the title object compound (37.8 g, yield 60%) Obtained as a yellow solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.10-5.00 (29H, m), 5.18 (1H, d, J = 10.8 Hz), 5.35 (1H, d, J = 22.5 Hz), 5.95 (1H, ddd , J = 22.5, 10.8, 5.9 Hz), 7.20-7.60 (30H, m);
MS (FAB) m / z: 924 (M + H) ⁺ .
(2d) Allyl 2,3,6-tri-O-benzyl-4-O- (2,3,4-tri-O-benzyl-6-toluenesulfonyl-β-D-glucopyranosyl) -D-glucopyranoside 2 (2c) (37.8 g, 41.0 mmol) was dissolved in pyridine (300 mL), p-toluenesulfonyl chloride (15.6 g, 82.0 mmol) and 4-dimethylaminopyridine (1. 0 g, 0.82 mmol) was added and stirred at room temperature for 13 hours. After evaporating the solvent under reduced pressure, the residue was poured into 10% aqueous hydrochloric acid (50 mL) and ethyl acetate (200 mL), and the organic layer was 10% aqueous hydrochloric acid (50 mL), saturated aqueous sodium bicarbonate (20 mL), and saturated brine. After washing with (20 mL) and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 5: 1-3: 1, V / V) to obtain the title object compound (32.6 g, yield 74%) as a yellow oil. It was.
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.35 (3H, s), 3.10-5.00 (28H, m), 5.18 (1H, d, J = 10.8 Hz), 5.35 (1H, d, J = 22.5 Hz ), 5.95 (1H, ddd, J = 22.5, 10.8, 5.9 Hz), 7.10-7.65 (34H, m);
MS (FAB) m / z: 1078 (M + H) ⁺ .
(2e) Allyl 2,3,6-tri-O-benzyl-4-O- (2,3,4-tri-O-benzyl-6-deoxy-β-D-glucopyranosyl) -D-glucopyranoside Example 2 The compound synthesized in (2d) (32.6 g, 30.3 mol) was dissolved in diethyl ether (600 mL), lithium aluminum hydride (1.72 g, 45.4 mol) was added, and the mixture was heated to reflux for 1 hour. The reaction mixture was diluted with diethyl ether (200 mL), 1N NaOH aqueous solution (2.0 mL) and water (2.0 mL) were added, and the mixture was stirred for 30 min. After filtration through celite, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 7: 1-6: 1, V / V) to give the title object compound (15.0 g, yield 55%) as a colorless solid. .
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.20 (3H, d, J = 6.0 Hz), 3.10-5.00 (26H, m), 5.20 (1H, d, J = 10.8 Hz), 5.35 (1H, d , J = 22.5 Hz), 5.95 (1H, ddd, J = 22.5, 10.8, 5.9 Hz), 7.10-7.65 (30H, m);
MS (FAB) m / z: 908 (M + H) ⁺ .
(2f) 2,3,6-tri-O-benzyl-4-O- (2,3,4-tri-O-benzyl-6-deoxy-β-D-glucopyranosyl) -D-glucopyranoside Example 2 ( The compound synthesized in 2e) (15.0 g, 16.5 mmol) was dissolved in methanol (150 mL) and tetrahydrofuran (30 mL), palladium (II) chloride (586 mg, 3.31 mmol) was added, and the mixture was stirred at room temperature for 14 hours. . The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 5: 1-4: 1-3: 1, V / V) to give the title object compound (12.0 g, yield 84%) Obtained as a yellow amorphous.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.19-1.22 (3H, m), 2.96-3.66 (8H, m), 3.77-4.02 (3H, m), 4.34-4.37 (2H, m), 4.54- 4.89 (10H, m), 5.00-5.19 (2H, m), 7.23-7.45 (30H, m);
MS (FAB) m / z: 868 (M + H) ⁺ .
(2g) benzyl (2R, 3R, 4R) -4-benzyloxy-2-benzyloxymethyl-3-{[2,3,6-tri-O-benzyl-4-O- (2,3,4- Tri-O-benzyl-6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranosyl] oxy} pyrrolidine-1-carboxylate Compound synthesized in Example 2 (2f) (18.8 g, 21.8 mmol) Is dissolved in methylene chloride (400 mL), trichloroacetonitrile (10.9 mL, 109 mmol), 1,8-diazabicyclo [5.4.0] -7-undecene (0.33 mL, 2.18 mmol) is added, and room temperature is added. For 15 minutes. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1, 1% triethylamine, V / V) to give a colorless oily imidate (19.8 g, 90%). Got. The compound (9.5 g, 21.2 mmol) synthesized in Example 1 (1i) was dissolved in diethyl ether (480 mL), and trimethylsilyl trifluoromethanesulfonate (0.38 mL, 2.12 mmol) was dissolved in diethyl ether (0.38 mL) under a nitrogen atmosphere. 20 mL) and added. A solution of imidate in diethyl ether (100 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. Triethylamine (0.35 mL, 2.54 mmol) was added to the reaction mixture, the solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate (200 mL), and saturated aqueous sodium hydrogen carbonate (200 mL) and saturated brine (200 mL). Washed. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified using silica gel flash column chromatography (hexane: diethyl ether, 3: 1, V / V) to give the title object compound (13 .3 g, 47%) and its β isomer (4.5 g, 16%) were obtained as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.20 (3H, d, J = 5.9 Hz), 3.10-3.22 (2H, m), 3.30-3.38 (2H, m), 3.42 (1H, t, J = 8.8 Hz), 3.50-3.70 (5H, m), 3.76-3.87 (5H, m), 4.01-4.10 (1H, m), 4.26-4.51 (9H, m), 4.61 (1H, d, J = 11.0 Hz ), 4.69-4.88 (8H, m), 4.96-5.16 (3H, m), 7.19-7.34 (43H, m), 7.43 (2H, d, J = 7.3 Hz);
MS (FAB) m / z: 1318 (M + Na) ⁺ .
(2h) (2R, 3R, 4R) -4-hydroxy-2- (hydroxymethyl) pyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside Example 2 The compound (13.3 g, 10.3 mmol) synthesized in (2 g) was dissolved in a 1% hydrochloric acid methanol solution (250 mL), 20% palladium hydroxide-carbon (4 g) was added, and the mixture was stirred under a hydrogen atmosphere for 2 hours. After removing the catalyst by Celite filtration, 28% aqueous ammonia (5 mL) was added and stirred for 10 minutes. The solvent was distilled off under reduced pressure, and after passing through an ion exchange resin (Dowex 50w × 8) column with water (200 mL), 1% aqueous ammonia (200 mL) was allowed to flow. The aqueous ammonia containing the target compound is concentrated under reduced pressure and purified using silica gel flash column chromatography (ethyl acetate: methanol: water, 5: 2: 1 to 1: 1: 1, V / V) to give the title target compound (1.6 g, 35%) was obtained as a colorless solid.
[Α] _D ²⁰ +88.8 (c 0.52, H ₂ O);
¹ H NMR (500 MHz, D ₂ O): δ 1.22 (3H, d, J = 6.8 Hz), 2.88 (1H, m), 3.07-3.16 (3H, m), 3.21 (1H, dd, J = 7.8 , 7.8 Hz), 3.36 (1H, dd, J = 9.8, 9.8 Hz), 3.42 (1H, m), 3.49-3.55 (2H, m), 3.61-3.72 (5H, m), 3.75-3.83 (2H, m), 3.89 (1H, m), 4.24 (1H, m), 4.38 (1H, d, J = 7.9 Hz), 5.02 (1H, d, J = 3.9 Hz);
¹³ C NMR (D ₂ O): δ 16.9, 51.7, 60.0, 61.8, 64.7, 71.0, 71.1, 71.6, 72.2, 73.6, 75.0, 75.5, 75.9, 79.2, 84.3, 97.4, 102.7;
MS (FAB) m / z: 442 (M + H) ⁺ .
<Example 3>
(2R, 3R, 4R) -4-hydroxy-2- (hydroxymethyl) pyrrolidin-3-yl 4-O-β-D-glucopyranosyl-α-D-glucopyranoside (Exemplary Compound No. 1-155)

(3a) Allyl 2,3,6-tri-O-benzyl-4-O- (2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl) -D-glucopyranoside α-D-cellobiose Octaacetate (4.15 g, 6.12 mmol) is dissolved in methylene chloride (50 mL) and allyl alcohol (2.09 mL, 30.6 mmol) and trimethylsilyl trifluoromethanesulfonate (1.11 mL, 6.12 mmol) are cooled with ice. 12 mmol) was added and stirred at room temperature for 4 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (50 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (40 mL), sodium methoxide (2.36 mL, 12.2 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 1 hr. Dowex 50w × 8 was added until the reaction solution became neutral, and after filtration, the solvent was distilled off under reduced pressure. The residue was dissolved in N, N-dimethylformamide (60 mL), sodium hydride (2.67 g, 61.2 mmol) was added under ice-cooling, the mixture was stirred at the same temperature for 10 min, and then benzyl bromide (8.01 mL). 67.3 mmol) and stirred at room temperature for 2 hours. Water (40 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water (40 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. did. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 20: 1 to 10: 1 to 8: 1, V / V) to give the title object compound (4.85 g, yield 78%) Obtained as a yellow solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.29-3.71 (10H, m), 3.80-4.15 (3H, m), 4.36-4.61 (8H, m), 4.67-4.89 (8H, m), 5.04- 5.11 (1H, m), 5.17-5.22 (1H, m), 5.29-5.34 (1H, m), 5.91-5.98 (1H, m), 7.07-7.41 (35H, m);
MS (FAB) m / z: 1014 (M + H) ⁺ .
(3b) 2,3,6-tri-O-benzyl-4-O- (2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl) -D-glucopyranoside Example 3 (3a) The compound synthesized in step (4.85 g, 4.79 mmol) was dissolved in dimethyl sulfoxide (40 mL), potassium t-butoxide (2.15 g, 19.2 mmol) was added, and the mixture was stirred at 110 ° C. for 1 hour. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in 1,4-dioxane (36 mL), 16% aqueous sulfuric acid solution (3 mL) was added, and the mixture was stirred at 100 ° C. for 1 hr. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 4: 1 to 3: 1, V / V) to obtain the title object compound (3.15 g, yield 68%) as a brown oil. It was.
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.96-3.95 (9H, m), 4.30-4.38 (3H, m), 4.45-4.81 (7H, m), 4.98-5.10 (1H, m), 7.09- 7.32 (35H, m);
MS (FAB) m / z: 974 (M + H) ⁺ .
(3c) (2R, 3R, 4R) -4-benzyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-pyrrolidin-3-yl 2,3,6-tri-O-benzyl-4-O- ( 2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl) -α-D-glucopyranoside The compound synthesized in Example 3 (3b) (537 mg, 0.55 mmol) was converted into methylene chloride (15 mL). And trichloroacetonitrile (277 μL, 2.76 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (2 drops) were added, and the mixture was stirred at room temperature for 40 minutes. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1, 1% triethylamine, V / V) to obtain imidate (611 mg, 99%) as a yellow oil. Obtained. The compound synthesized in Example 1 (1i) (223 mg, 0.50 mmol) was dissolved in diethyl ether (10 mL), trimethylsilyl trifluoromethanesulfonate (9 μL, 0.05 mmol) was added, and imidate (611 mg, 0.55 mmol) was added. Of diethyl ether (4 mL) was added dropwise and stirred at room temperature for 45 minutes. After adding triethylamine (4 drops) to the reaction solution, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: diethyl ether, 2: 1, V / V) to obtain the title object compound (395 mg, 57%) as a pale yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.24-3.86 (17H, m), 4.00-4.10 (2H, m), 4.25-4.54 (11H, m), 4.66-4.87 (8H, m), 4.95- 5.12 (3H, m), 7.12-7.39 (50H, m);
MS (FAB) m / z: 1402 (M + H) ⁺ .
(3d) (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O-β-D-glucopyranosyl-α-D-glucopyranoside Compound synthesized in Example 3 (3c) (611 mg, 0.55 mmol) was dissolved in methanol (8 mL) and ethyl acetate (2 mL), and a hydrochloric acid-methanol solution (2 mL) and 20% palladium hydroxide-carbon (400 mg) were added. Stir for hours. After filtration through celite, the solvent was distilled off under reduced pressure, methanol (2 mL) and 28% aqueous ammonia (300 μL) were added, and the mixture was stirred at room temperature for 10 min. After evaporating the solvent under reduced pressure, the residue was purified with an ion exchange resin (Dowex 50w × 8) column (water to 1.4% aqueous ammonia). The product was further purified by silica gel flash column chromatography (ethyl acetate: methanol: water, 1: 1: 1, V / V) to obtain the title object compound (54 mg, 42%) as a colorless amorphous.
[Α] _D ²⁰ +91.9 (c 0.38, D ₂ O);
¹ H NMR (400 MHz, D ₂ O): δ 2.90 (1H, dd, J = 12.5, 2.2 Hz), 3.11 (1H, dd, J = 12.5, 5.1 Hz), 3.16-3.22 (2H, m), 3.28-3.43 (3H, m), 3.49-3.82 (10H, m), 3.88-3.91 (1H, m), 4.23-4.27 (1H, m), 4.40 (1H, d, J = 8.1 Hz), 5.01 ( 1H, d, J = 4.4 Hz);
MS (FAB) m / z: 458 (M + H) ⁺ .
<Example 4>
(2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-fluoro-6-deoxy-β-D-glucopyranosyl) -D-glucopyranoside (Exemplary Compound No. 1 -278)

(4a) Allyl 2,3,6-tri-O-benzyl-4-O- (2,3,4-tri-O-benzyl-6-fluoro-6-deoxy-β-D-glucopyranosyl) -α- D-glucopyranoside The compound synthesized in Example 2 (2c) (6.43 g, 6.97 mmol) was dissolved in 1,2-dimethoxyethane (130 mL), and diethylaminosulfur trifluoride (2 mL, 20.50 mmol) was added. And stirred at 60 ° C. for 1 hour. Methanol (10 mL) was added to the reaction solution under ice cooling, and the mixture was stirred for 30 minutes. Ethyl acetate (50 mL) was added, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 6: 1, V / V) to obtain the title object compound (5.06 g, yield 78%) as a yellow solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.00-5.20 (28H, m), 5.25 (1H, d, J = 8.0 Hz), 5.40 (1H, d, J = 16.0 Hz), 6.00 (1H, m ), 7.20-7.60 (30H, m);
MS (FAB) m / z: 926 (M + H) ⁺ .
(4b) Allyl 2,3,6-tri-O-benzyl-4-O- (2,3,4-tri-O-benzyl-6-fluoro-6-deoxy-β-D-glucopyranosyl) -D- Glucopyranoside The compound synthesized in Example 4 (4a) (5.06 g, 5.47 mmol) was dissolved in methanol (75 mL) and tetrahydrofuran (15 mL), palladium (II) chloride (190 mg, 1.09 mmol) was added, and room temperature was added. For 14 hours. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 4: 1-3: 1 to 2: 1, V / V) to give the title object compound (3.07 g, yield 63%) Obtained as a yellow amorphous.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.10-5.20 (27H, m), 7.20-7.60 (30H, m);
MS (FAB) m / z: 886 (M + H) ⁺ .
(4c) (2R, 3R, 4R) -4-Benzyloxy-N-benzyloxycarbonyl-2- (benzyloxymethyl) pyrrolidin-3-yl 2,3,6-tri-O-benzyl-4-O- (2,3,4-Tri-O-benzyl-6-fluoro-6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside The compound synthesized in Example 4 (4b) (646.0 mg, 0. 73 mmol) was dissolved in methylene chloride (12 mL), trichloroacetonitrile (0.38 mL, 3.66 mmol), 1,8-diazabicyclo [5.4.0] unde-7-cene (1 drop) was added, and room temperature was added. For 30 minutes. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 4: 1, 1% triethylamine, V / V) to give a yellow oily imidate (740.2 mg, 98.5). %). The compound (326.7 mg, 0.73 mmol) synthesized in Example 1 (1i) was dissolved in diethyl ether (13 mL), and trimethylsilyl trifluoromethanesulfonate (6.6 μL, 0.037 mmol) was dissolved in diethyl ether (nitrogen atmosphere). 2 mL) and added. A solution of imidate (740.2 mg) in diethyl ether (5 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. Triethylamine (5.0 μL, 0.036 mmol) was added to the reaction mixture, the solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate (20 mL), and saturated sodium bicarbonate (20 mL) and saturated brine (20 mL) Washed. The organic layer is dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, and the residue containing the α, β mixture is purified using silica gel flash column chromatography (hexane: ethyl acetate, 6: 1, V / V). Of these, the title compound α-form (126.0 mg, 13%) was isolated as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ3.00-5.20 (39H, m), 7.00-7.60 (45H, m);
MS (FAB) m / z: 1315 (M + H) ⁺ .
(4d) (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-fluoro-6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside
The compound synthesized in Example 4 (4c) (126.0 mg, 0.096 mmol) was dissolved in methanol (10 mL) containing 1% aqueous hydrochloric acid solution, 20% palladium hydroxide-carbon (100 mg) was added, and hydrogen atmosphere was added. Stir for 2 hours. After removing the catalyst by Celite filtration, 28% aqueous ammonia (0.5 mL) was added and stirred for 10 minutes. The solvent was distilled off under reduced pressure, and the aqueous solution (100 mL) was applied to an ion exchange resin (Dowex 50w × 8) column, and then flushed with 1% aqueous ammonia (100 mL). The aqueous ammonia containing the target compound is concentrated under reduced pressure and purified using silica gel flash column chromatography (ethyl acetate: methanol: water, 5: 2: 1 to 1: 1: 1, V / V) to give the title target compound (23.1 mg, 52%) was obtained as a colorless amorphous.
[Α] _D ²⁰ +49.6 (c 0.30, H ₂ O);
¹ H NMR (400 MHz, D ₂ O): δ 3.00-3.07 (1H, m), 3.20-3.27 (2H, m), 3.30-3.80 (21H, m), 3.95 (1H, s), 4.29 (1H , brs), 4.43 (1H, d, J = 8.0 Hz), 4.50-4.80 (2H, m), 5.00 (1H, d, J = 4.0 Hz);
MS (FAB) m / z: 460 (M + H) ⁺ .
<Example 5>
(2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-fluoro-6-deoxy-β-D-glucopyranosyl) -6-fluoro-6-deoxy- α-D-glucopyranoside (Exemplary Compound No. 1-280)

(5a) Allyl 6-Ot-butyldimethylsilyl-2,3-di-O-benzyl-4-O- (6-Ot-butyldimethylsilyl-2,3,4-tri-O-benzyl -Β-D-glucopyranosyl) -D-glucopyranoside The compound synthesized in Example 2 (2a) (7.76 g, 20.30 mmol) was dissolved in N, N-dimethylformamide (160 mL) and t-butyldimethylsilyl. Chloride (7.65 mL, 50.75 mmol) and imidazole (4.15 g, 60.90 mmol) were added and stirred at room temperature for 1 hour. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (120 mL), sodium hydride (4.0 g, 91.67 mmol) was added under ice-cooling, the mixture was stirred at the same temperature for 10 min, and then benzyl bromide (11 mL, 92 mL). .48 mmol) was added and stirred at room temperature for 3 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL). The organic layer was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. did. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 12: 1, V / V) to give the title object compound (8.67 g, yield 89%) as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 0.00-0.20 (12H, m), 0.90-1.00 (18H, m), 3.00-5.20 (26H, m), 5.20 (1H, d, J = 8.0 Hz) , 5.35 (1H, d, J = 16.0 Hz), 6.00 (1H, m), 7.20-7.60 (25H, m);
MS (FAB) m / z: 1062 (M + H) ⁺ .
(5b) Allyl 2,3-di-O-benzyl-4-O- (2,3,4-tri-O-benzyl-β-D-glucopyranosyl) -D-glucopyranoside Synthesized in Example 5 (5a) The compound (8.67 g, 8.17 mmol) was dissolved in tetrahydrofuran (150 mL), 1.0 M tetrabutylammonium fluoride in THF (20 mL, 20 mmol) was added, and the mixture was stirred at room temperature for 5 hours. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (methylene chloride: methanol, 50: 1, V / V) to give the title object compound (4.19 g, yield 62%). Obtained as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ3.00-5.20 (28H, m), 5.20 (1H, d, J = 12.0 Hz), 5.30 (1H, d, J = 18.0 Hz), 5.98 (1H, m), 7.20-7.40 (25H, m);
MS (FAB) m / z: 833 (M + H) ⁺ .
(5c) Allyl 2,3-di-O-benzyl-6-fluoro-6-deoxy-4-O- (2,3,4-tri-O-benzyl-6-fluoro-6-deoxy-β-D -Glucopyranosyl) -D-glucopyranoside The compound synthesized in Example 5 (5b) (4.19 g, 5.03 mmol) was dissolved in 1,2-dimethoxyethane (85 mL), and diethylaminosulfur trifluoride (2.5 mL, 25.61 mmol) was added and the mixture was stirred at 60 ° C. for 1 hour. Methanol (10 mL) was added to the reaction solution under ice cooling, and the mixture was stirred for 30 minutes. Ethyl acetate (50 mL) was added, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 5: 1 to 4: 1, V / V) to obtain the title object compound (2.23 g, yield 53%) as a yellow solid. .
¹ H NMR (400 MHz, CDCl ₃ ): δ3.00-5.10 (26H, m), 5.23 (1H, m), 5.33 (1H, m), 5.95 (1H, m), 7.20-7.40 (25H, m );
MS (FAB) m / z: 837 (M + H) ⁺ .
(5d) Allyl 2,3-di-O-benzyl-6-fluoro-6-deoxy-4-O- (2,3,4-tri-O-benzyl-6-fluoro-6-deoxy-β-D -Glucopyranosyl) -D-glucopyranoside The compound (2.23 g, 2.66 mmol) synthesized in Example 5 (5c) was dissolved in acetic acid (20 mL) and water (1 mL), and palladium (II) chloride (0.47 g, 2.65 mmol) and sodium acetate (0.87 g, 10.61 mmol) were added and stirred at room temperature for 14 hours. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate 3: 1, V / V) to obtain the title object compound (0.73 g, yield 34%) as a pale yellow amorphous.
¹ H NMR (400 MHz, CDCl ₃ ): δ3.00-5.10 (25H, m), 7.20-7.60 (25H, m);
MS (FAB) m / z: 797 (M + H) ⁺ .
(5e) (2R, 3R, 4R) -4-Benzyloxy-N-benzyloxycarbonyl-2- (benzyloxymethyl) pyrrolidin-3-yl 2,3-di-O-benzyl-6-fluoro-6- Deoxy-4-O- (2,3,4-tri-O-benzyl-6-fluoro-6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside Compound synthesized in Example 5 (5d) ( 730.0 mg, 0.92 mmol) was dissolved in methylene chloride (13.5 mL) and trichloroacetonitrile (0.46 mL, 4.60 mmol), 1,8-diazabicyclo [5.4.0] -7-undecene ( 1 drop) was added and stirred at room temperature for 30 minutes. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 4: 1, 1% triethylamine, V / V) to give a yellow oily imidate (675.3 mg, 78%). Got. The compound (412.3 mg, 0.92 mmol) synthesized in Example 1 (1i) was dissolved in diethyl ether (13 mL), and trimethylsilyl trifluoromethanesulfonate (8.3 μL, 0.046 mmol) was dissolved in diethyl ether (13 mL) under a nitrogen atmosphere. 2 mL) and added. Subsequently, a solution of imidate (675.3 mg) in diethyl ether (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Triethylamine (7.0 μL, 0.050 mmol) was added to the reaction mixture, the solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate (20 mL), and saturated sodium bicarbonate (20 mL) and saturated brine (20 mL). Washed. The organic layer is dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, and the residue containing the α, β mixture is purified using silica gel flash column chromatography (hexane: ethyl acetate, 6: 1, V / V). Of these, the title compound α-form (122.6 mg, 11%) was isolated as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ3.00-5.20 (37H, m), 7.00-7.60 (40H, m);
MS (FAB) m / z: 1227 (M + H) ⁺ .
(5f) (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-fluoro-6-deoxy-β-D-glucopyranosyl) -6-fluoro-6 -Deoxy-α-D-glucopyranoside
The compound synthesized in Example 5 (5e) (122.6 mg, 0.10 mmol) was dissolved in methanol (10 mL) containing a 1% aqueous hydrochloric acid solution, 20% palladium hydroxide-carbon (100 mg) was added, and hydrogen atmosphere was added. Stir for 2 hours. After removing the catalyst by Celite filtration, 28% aqueous ammonia (0.5 mL) was added and stirred for 10 minutes. The solvent was distilled off under reduced pressure, and the aqueous solution (100 mL) was applied to an ion exchange resin (Dowex 50w × 8) column, and then flushed with 1% aqueous ammonia (100 mL). The aqueous ammonia containing the target compound was concentrated under reduced pressure and purified using silica gel flash column chromatography (ethyl acetate: methanol: water, 5: 2: 1 to 1: 1: 1, V / V) to give the title target compound (25.9 mg, 56%) was obtained as a colorless solid.
¹ H NMR (400 MHz, D ₂ O): δ 3.20-3.90 (22H, m), 4.10 (1H, s), 4.41 (1H, d, J = 8.1 Hz), 4.50-4.80 (4H, m), 5.05 (1H, d, J = 6.3 Hz);
MS (FAB) m / z: 462 (M + H) ⁺ .
<Example 6>
(1S, 3R, 4R, 5S) -1-Amino-3-hydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside ( Exemplified compound number 5-28)

(6a) Methyl 4,6-O-benzylidene-3-O-benzyl-2-deoxy-D-glucopyranoside 2-deoxy-D-glucose (10.1 g, 61.5 mmol) dissolved in methanol (100 mL) Then, hydrochloric acid-methanol solution (50 mL) was added, and the mixture was heated to reflux for 3 hours. After cooling to room temperature, triethylamine was added until the reaction solution became basic, and the solvent was distilled off under reduced pressure. The residue was dissolved in N, N-dimethylformamide (100 mL), benzaldehyde dimethyl acetal (12.9 mL, 86.1 mmol) and p-toluenesulfonic acid monohydrate (585 mg, 3.08 mmol) were added, and 20 mmHg, 50 Stir at 0 ° C. for 3 hours. After cooling to room temperature, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water (50 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and then decompressed. The lower solvent was distilled off. The residue was dissolved in N, N-dimethylformamide (100 mL), 55% sodium hydride (3.99 g, 92.3 mmol) was added under ice-cooling, the mixture was stirred at the same temperature for 10 min, and benzyl bromide (11. 0 mL, 92.3 mmol) was added, and the mixture was stirred at room temperature for 19 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water (50 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. did. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 20: 1 to 10: 1, V / V) to obtain the title object compound (16.0 g, yield 73%) as a yellow solid. .
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.66-1.83 (1H, m), 2.24-2.34 (1H, m), 3.33 (3H, s), 3.65-3.85 (3H, m), 3.98-4.04 ( 1H, m), 4.22-4.35 (1H, m), 4.66-4.84 (3H, m), 5.60-5.62 (1H, m), 7.23-7.40 (8H, m), 7.49-7.52 (2H, m);
MS (FAB) m / z: 357 (M + H) ⁺ .
(6b) Methyl 3-O-benzyl-2-deoxy-D-glucopyranoside The compound (2.00 g, 5.62 mmol) synthesized in Example 6 (6a) was dissolved in acetic acid (15 mL) and water (5 mL). The mixture was stirred at 60 ° C. for 2 hours and 30 minutes. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 2: 1 to 1: 2, V / V) to give the title object compound (1. 33 g, 88% yield) was obtained as a pale yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.49-1.64 (1H, m), 2.11 (1H, brs), 2.25-2.36 (1H, m), 2.62 (1H, brs), 3.33 (3H, s) , 3.44-3.65 (2H, m), 3.76-3.87 (3H, m), 4.41-4.52 (1H, m), 4.65-4.71 (1H, m), 4.81-4.82 (1H, m), 7.26-7.37 ( 5H, m);
MS (FAB) m / z: 267 (MH) ⁺ .
(6c) Methyl 3-O-benzyl-2-deoxy-6-Op-toluenesulfonyl-D-glucopyranoside The compound synthesized in Example 6 (6b) (12.2 g, 45.3 mmol) was converted into pyridine (100 mL). And p-toluenesulfonyl chloride (13 g, 68.0 mmol) and 4-dimethylaminopyridine (553 mg, 4.53 mmol) were added and stirred at room temperature for 12 hours. Under ice-cooling, the reaction mixture was poured into 10% aqueous hydrochloric acid (80 mL) and ethyl acetate (200 mL), and the organic layer was washed with 10% aqueous hydrochloric acid (80 mL), saturated aqueous sodium bicarbonate (80 mL), and saturated brine (50 mL). After washing and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1-3: 1, V / V) to obtain the title object compound (16.9 g, yield 88%) as a pale yellow amorphous product. It was.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.54-1.61 (1H, m), 2.20-2.28 (1H, m), 2.44 (3H, s), 3.27 (3H, s), 3.41-3.48 (2H, m), 3.70-3.76 (2H, m), 4.22-4.41 (2H, m), 4.47-4.57 (1H, m), 4.63-4.68 (1H, m), 4.75-4.76 (1H, m), 7.26- 7.36 (7H, m), 7.79-7.84 (2H, m);
MS (FAB) m / z: 421 (MH) ⁺ .
(6d) Methyl 4-O-benzoyl-3-O-benzyl-2-deoxy-6-Op-toluenesulfonyl-D-glucopyranoside Compound (16.9 g, 40.0 mmol) synthesized in Example 6 (6c) ) Was dissolved in methylene chloride (150 mL), triethylamine (22 mL, 0.16 mol), benzoyl chloride (14 mL, 0.12 mol) and 4-dimethylaminopyridine (489 mg, 4.00 mmol) were added, and the mixture was stirred at room temperature for 18 hours. did. Water (80 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (100 mL). The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 4: 1 to 3: 1, V / V) to give the title object compound (20.8 g, yield 99%) as a yellow oil. It was.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.71-1.78 (1H, m), 2.26-2.31 (1H, m), 2.33 (3H, s), 3.32 (3H, s), 3.94-4.14 (4H, m), 4.40-4.44 (1H, m), 4.52-4.59 (1H, m), 4.80-4.81 (1H, m), 5.03-5.08 (1H, m), 7.09-7.20 (6H, m), 7.40- 7.49 (3H, m), 7.57-7.62 (1H, m), 7.66-7.71 (2H, m), 7.87-7.96 (2H, m);
MS (FAB) m / z: 527 (M + H) ⁺ .
(6e) Methyl 4-O-benzoyl-3-O-benzyl-2,6-dideoxy-6-iodo-D-glucopyranoside The compound (2.53 g, 4.81 mmol) synthesized in Example 6 (6d) was dissolved in toluene. (30 mL), sodium iodide (3.6 g, 24.0 mmol) and 18-crown-6-ether (254 mg, 0.96 mmol) were added, and the mixture was stirred at 100 ° C. for 3 hours under a nitrogen atmosphere. After cooling to room temperature, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. did. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 15: 1-10: 1, V / V) to give the title object compound (2.11 g, yield 91%) as a pale yellow oil. Obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.72-1.86 (1H, m), 2.31-2.41 (1H, m), 3.17-3.26 (1H, m), 3.33-3.40 (1H, m), 3.45 ( 3H, s), 3.69-3.86 (1H, m), 3.99-4.31 (1H, m), 4.44-4.48 (1H, m), 4.57-4.62 (1H, m), 4.90-4.91 (1H, m), 5.03-5.18 (1H, m), 7.13-7.26 (5H, m), 7.43-7.49 (2H, m), 7.58-7.62 (1H, m), 8.02-8.04 (2H, m);
MS (FAB) m / z: 483 (M + H) ⁺ .
(6f) 4-O-benzoyl-3-O-benzyl-2,5,6-trideoxy-D-xylo-hexa-5-enose oxime The compound synthesized in Example 6 (6e) (2.11 g, 4. 38 mmol) was dissolved in isopropanol (50 mL) and water (2 mL), zinc dust (2 g) washed with 5% aqueous hydrochloric acid was added, and the mixture was heated to reflux for 25 minutes. After cooling to room temperature, the mixture was filtered through Celite, and the solvent was removed under reduced pressure. The residue was dissolved in ethanol (50 mL), hydroxylamine hydrochloride (913 mg, 13.1 mmol) and pyridine (1.06 mL, 13.1 mmol) were added, and the mixture was stirred at 60 ° C. for 50 min. After cooling to room temperature, the solvent was distilled off under reduced pressure, water (20 mL) was added, the mixture was extracted with ethyl acetate (100 mL), the organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and then reduced in pressure. The lower solvent was distilled off. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 6: 1-5: 1-4: 1-3: 1, V / V) to give the title object compound (1.14 g, yield 77). %) As a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.47-2.55 (1H, m), 2.61-2.79 (1H, m), 3.88 (0.5H, dt, J = 8.1, 5.1 Hz), 3.94 (0.5H, dt, J = 8.1, 4.4 Hz), 4.65 (0.5H, d, J = 11.7 Hz), 4.67 (0.5H, d, J = 11.7 Hz), 4.74 (0.5H, d, J = 11.7 Hz), 4.75 (0.5H, d, J = 11.7 Hz), 5.33-5.36 (1H, m), 5.41-5.47 (1H, m), 5.74-5.77 (1H, m), 6.01 (1H, ddd, J = 16.8, 5.9 , 5.1 Hz), 6.84 (0.5H, t, J = 5.1 Hz), 7.26-7.33 (5H, m), 7.43-7.48 (2.5H, m), 7.56-7.60 (1H, m), 8.06-8.08 ( 2H, m);
MS (FAB) m / z: 340 (M + H) ⁺ .
(6g) (3aR, 4R, 5R, 6aS) -4-benzoyloxy-5-benzyloxy-hexahydro-cyclopenta [c] isoxazole (3aS, 4R, 5R, 6aR) -4-benzoyloxy-5-benzyloxy- Hexahydro-cyclopenta [c] isoxazole The compound synthesized in Example 6 (6f) (5.0 g, 14.7 mmol) was dissolved in toluene (100 mL) and heated to reflux for 40 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 2: 1 to 1: 1, V / V) to give the title object compound (mixture) (4.08 g, 82% yield) was obtained as an orange oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.92 (0.3H, ddd, J = 10.2, 5.1, 5.1 Hz), 2.00-2.13 (1.4H, m), 2.28-2.35 (0.3H, m), 2.99 -3.01 (0.3H, m), 3.37 (0.7H, dd, J = 8.8, 7.3 Hz), 3.43-3.49 (0.7H, m), 3.99-4.22 (4.3H, m), 4.63 (0.3H, d , J = 11.7 Hz), 4.63 (1.4H, s), 4.67 (0.3H, d, J = 9.5 Hz), 5.21 (0.3H, t, J = 3.7 Hz), 5.28 (0.7H, d, J = 3.7Hz), 7.25-7.35 (5H, m), 7.43-7.47 (2H, m), 7.54-7.60 (1H, m), 7.99-8.08 (2H, m);
MS (FAB) m / z: 340 (M + H) ⁺ .
(6h) (3aR, 4R, 5R, 6aS) -5-benzyloxy-1-benzyloxycarbonyl-4-hydroxy-hexahydro-cyclopenta [c] isoxazole Compound (4.08 g) synthesized in Example 6 (6 g) 12.0 mmol) was dissolved in methanol (40 mL), sodium methoxide (696 μL, 3.61 mmol) was added and stirred at room temperature for 2 hours, Dowex 50W × 8 was added until the reaction solution became neutral, and the mixture was filtered. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate (40 mL), and a saturated aqueous sodium hydrogencarbonate solution (20 mL) and benzyloxychloroformate (2.4 mL, 16.8 mmol) were added under ice cooling, The organic layer was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 2: 1 to 1: 1, V / V) to give the title object compound (789 mg, 18% yield). Gave a pale yellow solid and its diastereomer (1.62 g, 36% yield) as a pale yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.57-1.63 (1H, m), 2.47 (1H, brs), 2.50-2.56 (1H, m), 2.73-2.77 (1H, m), 3.61-3.69 ( 2H, m), 3.88-3.92 (1H, m), 4.01 (1H, d, J = 8.8 Hz), 4.49 (1H, d, J = 11.7 Hz), 4.48-4.55 (1H, m), 4.60 (1H , d, J = 11.7 Hz), 5.18 (2H, s);
MS (FAB) m / z: 370 (M + H) ⁺ .
(6i) (3aR, 4R, 5R, 6aS) -5-Benzyloxy-1-benzyloxycarbonyl-hexahydro-cyclopenta [c] isoxazol-4-yl 2,3,6-tri-O-benzyl-4-O -(2,3,4-Tri-O-benzyl-6-deoxy-β-D-glucopyranosyl) -D-glucopyranoside Compound (751 mg, 0.87 mmol) synthesized in Example 2 (2f) was converted into methylene chloride (15 mL). ), Trichloroacetonitrile (435 μL, 4.33 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (2 drops) were added, and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 6: 1 to 5: 1, 1% triethylamine, V / V) to obtain imidate (734 mg, 84%). Obtained as a yellow oil. The compound synthesized in Example 6 (6h) (244 mg, 0.66 mmol) was dissolved in diethyl ether (12 mL), trimethylsilyl trifluoromethanesulfonate (12 μL, 0.07 mmol) was added, and imidate (734 mg, 0.73 mmol) was added. Of diethyl ether (3 mL) was added dropwise and stirred at room temperature for 1 hour. After adding triethylamine (4 drops) to the reaction solution, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: diethyl ether, 2: 1 to 1: 1, V / V), and the title object compound (α, β mixture) (516 mg, yield 64%) was colorless. Obtained as amorphous.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.19 (1.5H, d, J = 2.9Hz), 1.20 (1.5H, d, J = 2.9 Hz), 1.62-1.68 (0.5H, m), 1.79- 1.84 (0.5H, m), 2.39-2.45 (0.5H, m), 2.48-2.53 (0.5H, m), 2.73-2.77 (0.5H, m), 2.85-2.86 (0.5H, m), 3.10- 3.60 (8H, m), 3.69-4.02 (6H, m), 4.10-4.14 (1H, m), 4.32-4.64 (8H, m), 4.69-4.87 (7H, m), 5.00 (0.5H, d, J = 10.7 Hz), 5.12 (0.5H, d, J = 3.9 Hz), 5.18 (1H, d, J = 10.7 Hz), 7.18-7.43 (50H, m);
MS (FAB) m / z: 1217 (M) ⁺ .
(6j) (3aR, 4R, 5R, 6aS) -5-Benzyloxy-1-methyloxycarbonyl-hexahydro-cyclopenta [c] isoxazol-4-yl 2,3,6-tri-O-benzyl-4-O -(2,3,4-Tri-O-benzyl-6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside The compound (516 mg, 0.42 mmol) synthesized in Example 6 (6i) was dissolved in methanol ( 6 mL) and toluene (6 mL), sodium methoxide (221 μL, 1.15 mmol) was added, and the mixture was stirred at 50 ° C. for 40 minutes. After cooling to room temperature, Dowex 50W × 8 was added until the reaction solution became neutral, and after filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: diethyl ether, 1.5: 1 to 1: 1, V / V) to obtain the title object compound (173 mg, yield 47%) as a colorless amorphous. .
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.61-1.69 (1H, m), 2.48-2.55 (1H, m), 2.72-2.78 (1H, m), 3.13 (1H, dd, J = 9.5, 8.8 Hz), 3.21 (1H, dd, J = 9.5, 5.9 Hz), 3.31 (1H, dd, J = 8.1, 7.3 Hz), 3.36-3.54 (5H, m), 3.59-3.62 (1H, m), 3.79 (3H, s), 3.74-3.94 (5H, m), 3.99 (1H, d, J = 8.8 Hz), 4.32-4.38 (2H, m), 4.50-4.67 (7H, m), 4.76-5.00 (5H , m), 5.01 (1H, d, J = 11.0 Hz), 5.12 (1H, d, J = 3.7 Hz), 7.14-7.44 (35H, m);
MS (FAB) m / z: 1141 (M) ⁺ .
(6k) (3aR, 4R, 5R, 6aS) -5-Benzyloxy-hexahydro-cyclopenta [c] isoxazol-4-yl 2,3,6-tri-O-benzyl-4-O- (2,3 4-tri-O-benzyl-6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside The compound synthesized in Example 6 (6j) (363 mg, 0.32 mmol) was dissolved in methanol (8 mL). 1N aqueous potassium hydroxide solution (4 mL) was added, and the mixture was stirred at 80 ° C. for 8 hr. After cooling to room temperature, a saturated aqueous ammonium chloride solution (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and then the solvent under reduced pressure. Was distilled off. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 1.5: 1 to 1: 1, V / V) to give the title object compound (313 mg, yield 91%) as a pale yellow amorphous product. It was.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.20 (3H, d, J = 5.9 Hz), 1.56-1.64 (1H, m), 2.26-2.36 (1H, m), 2.76-2.86 (1H, m) , 3.13 (1H, dd, J = 9.5, 8.8 Hz), 3.19-3.25 (2H, m), 3.32 (1H, dd, J = 8.8, 8.1 Hz), 3.43-3.53 (3H, m), 3.67-3.69 (2H, m), 3.81-3.95 (6H, m), 4.35-4.40 (2H, m), 4.51-4.67 (7H, m), 4.74-4.87 (6H, m), 5.01 (1H, d, J = 10.3 Hz), 7.15-7.44 (35H, m);
MS (FAB) m / z: 1084 (M + H) ⁺ .
(61) (1S, 3R, 4R, 5S) -1-Amino-3-hydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D -Glucopyranoside Compound (313 mg, 0.29 mmol) synthesized in Example 6 (6k) was dissolved in methanol (8 mL) and ethyl acetate (4 mL), hydrochloric acid (5 drops) and 20% palladium hydroxide-carbon (300 mg) And stirred at room temperature for 6 hours under hydrogen atmosphere. After filtration through Celite, the solvent was distilled off under reduced pressure, methanol (3 mL) and 28% aqueous ammonia (300 μL) were added, and the mixture was stirred at room temperature for 10 min. After the solvent was distilled off under reduced pressure, the residue was purified with an ion exchange resin column (Dowex 50W × 8) (water to 2.8% aqueous ammonia). The product was further purified using silica gel flash column chromatography (ethyl acetate: methanol: water, 1: 1: 1, V / V) to obtain the title object compound (107 mg, yield 81%) as a pale yellow solid.
¹ H NMR (500 MHz, D _2O ): δ 1.19 (1H, d, J = 5.9 Hz), 1.53 (1H, dt, J = 13.7, 6.8 Hz), 2.18-2.23 (1H, m), 2.27-2.33 (1H, m), 3.07 (1H, dd, J = 9.8, 8.8 Hz), 3.19 (1H, dd, J = 9.8, 7.8 Hz), 3.34 (1H, dd, J = 9.8, 8.8 Hz), 3.37- 3.41 (1H, m), 3.47-3.51 (2H, m), 3.58 (1H, dd, J = 14.7, 6.8 Hz), 3.66-3.80 (6H, m), 3.86 (1H, dd, J = 6.8, 4.9 Hz), 4.11-4.14 (1H, m), 4.36 (1H, d, J = 7.8 Hz), 5.06 (1H, d, J = 3.9 Hz);
¹³ C NMR (125 MHz, D _2O ): δ 16.89, 38.27, 47.74, 49.85, 59.41, 60.05, 70.97, 71.19, 71.56, 72.22, 73.64, 74.96, 75.45, 75.51, 79.24, 84.26, 97.34, 102.68;
MS (FAB) m / z: 456 (M + H) ⁺ .
<Example 7>
(2R, 3R, 4R, 5R) -2,5-dihydroxymethyl-4-hydroxypyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside (Exemplary Compound No. 1-557)

(7a) (1R, 3S, 4S, 6R, 7R) -7-Benzyloxy-6-hydroxymethyl-3-methoxy-2-oxa-5-aza-bicyclo [2,2,1] heptane azide epoxide (Tetrahedron) , 26, 1985, 1469) (2.03 g, 6.97 mmol) was dissolved in ethanol (40 mL), Lindlar catalyst (0.4 g) was added, and the mixture was stirred under a hydrogen atmosphere for 2 hours. After removing the catalyst by Celite filtration, it was dissolved in ethanol (40 mL) and heated to reflux for 1 hour. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (methylene chloride: ethanol, 20: 1 to 10: 1, V / V) to give the title object compound (1.21 g, yield). 65%) was obtained as a brown solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.15-2.35 (2H, br), 3.19 (1H, dd, J = 5.8, 5.9 Hz), 3.35 (3H, s), 3.41 (1H, s), 3.65 (1H, dd, J = 5.8, 11.7 Hz), 3.73 (1H, dd, J = 5.8, 11.7 Hz), 4.11 (1H, s), 4.18 (1H s), 4.54 (1H, d, J = 11.7 Hz) ), 4.61 (1H, d, J = 11.7 Hz), 4.64 (1H, s), 7.29-7.38 (5H, m);
MS (FAB) m / z: 266 (M + H) ⁺ .
(7b) (1R, 3R, 4S, 6R, 7R) -7-hydroxy-6-hydroxymethyl-3-methoxy-2-oxa-5-aza-bicyclo [2,2,1] heptane-5-carboxylic acid Benzyl ester The compound (930 mg, 3.51 mmol) synthesized in Example 7 (7a) was dissolved in methanol (20 mL), 20% palladium hydroxide-carbon (280 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 6 hours. After removing the catalyst by Celite filtration, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate: saturated aqueous sodium hydrogen carbonate solution (2: 1, 20 mL), benzyl chloroformate (0.75 mL, 5.27 mmol) was added, and the mixture was stirred at 0 ° C. for 2 hr. Water (20 mL) was added at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine (20 mL). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 1: 1-3: 1, V / V) to give the title object compound (759 mg, yield 70%) as a colorless solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.33 (3H, s), 3.50-4.00 (3H, m), 4.10-4.25 (3H, m), 4.61 (1H, brs), 4.60-4.74 (2H, m), 5.10-5.25 (2H, m), 7.25-7.45 (5H, m);
MS (FAB) m / z: 310 (M + H) ⁺ .
(7c) (1R, 3S, 4S, 6R, 7R) -7-benzyloxy-6-tert-butyldimethylsilyloxymethyl-3-methoxy-2-oxa-5-aza-bicyclo [2,2,1] Heptane-5-carboxylic acid benzyl ester The compound synthesized in Example 7 (7b) (152 mg, 0.49 mmol) was dissolved in pyridine (4 mL), t-butyldimethylsilyl chloride (82 mg, 0.54 mmol) was added, Stir at 0 ° C. for 3 hours. After confirming the absence of the raw material by TLC, benzoyl chloride (86 μL, 0.74 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour. Water (20 ml) was added at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine (20 mL). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 10: 1, V / V) to give the title object compound (218 mg, yield 84%) as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ -0.24--0.04 (6H, m), 0.72 (4.5H, s), 0.77 (4.5H, s), 3.34 (1.5H, s), 3.38 (1.5 H, s), 3.67-3.80 (2H, m), 3.91 (0.5H m), 4.10 (0.5H, m), 4.40 (0.5H, s), 4.46 (0.5H, m), 4.66 (0.5H, s), 4.69 (1H, m), 4.78 (0.5H, m), 5.15 (2H, m), 5.44 (1H, m), 7.39-7.36 (5H, m), 7.41 (2H, m), 7.55 ( 1H, m), 7.95 (2H, m);
MS (FAB) m / z: 528 (M + H) ⁺ .
(7d) (2R, 3R, 4R, 5R) -N-benzyloxycarbonyl-3-benzoyl-2,5-dihydroxymethyl-4-hydroxypyrrolidine Compound synthesized in Example 7 (7c) (997 mg, 1.89 mmol) ) Was dissolved in trifluoroacetic acid: water (4: 1, 12 mL) and stirred at room temperature for 15 minutes. Water (20 mL) was added to the reaction solution at 0 ° C., and the mixture was extracted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (20 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was dissolved in ethanol (15 mL), sodium borohydride (35.7 mg, 0.10 mmol) dissolved in water (5 mL) was added, and the mixture was stirred at 0 ° C. for 20 min. Saturated aqueous ammonium chloride (2 mL) was added to the reaction mixture at 0 ° C., and ethanol was evaporated under reduced pressure. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL). The organic layer was washed with saturated brine (15 mL) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 2: 1, V / V) to give the title object compound (643 mg, yield 85%) as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.60-3.38 (9H, m), 4.98-5.19 (4H, m), 7.20-7.30 (5H, m), 7.36. (2H, m), 7.50 (1H , m), 7.89 (2H, d, J = 7.3 Hz);
MS (FAB) m / z: 402 (M + H) ⁺ .
(7e) (2R, 3R, 4R, 5R) -N-benzyloxycarbonyl-3-hydroxy-2,5-dibenzyloxymethyl-4-benzyloxypyrrolidine The compound synthesized in Example 7 (7d) (643 mg, 1.60 mmol) is dissolved in dichloromethane: cyclohexane (1: 2, 18 mL), benzyltrichloroacetimidate (2.7 mL, 14.4 mmol), trifluoromethanesulfonic acid (29 μL, 0.32 mmol) are added, and room temperature is added. For 2 hours. Saturated aqueous sodium hydrogen carbonate (5 mL) was added to the reaction mixture at 0 ° C., diluted with ethyl acetate (200 mL), washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and then reduced in pressure. The lower solvent was distilled off. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 20: 1 to 10: 1, V / V) to obtain 1080 mg of colorless oil. 1080 mg of the obtained colorless oil was dissolved in methanol: tetrahydrofuran (4: 1, 25 mL), potassium carbonate (44 mg, 0.32 mmol) was added, and the mixture was stirred at room temperature for 2.5 hr. Methanol was distilled off under reduced pressure, water (15 mL) was added, the mixture was extracted with ethyl acetate (15 mL), and the organic layer was washed with saturated brine (15 mL). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 4: 1, V / V) to give the title object compound (715 mg, yield 78%) as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.40-3.49 (2H, m), 3.62 (1H, dd, J = 4.4, 8.8 Hz), 3.79-4.12 (4H, m), 4.19 (1H, dd, J = 3.7, 10.3 Hz), 4.26-4.61 (6H, m), 5.01 (1H, d, J = 16.8 Hz), 5.03 (1H, d, J = 16.8 Hz), 5.51 (1H, m), 7.15- 7.38 (20H, m);
MS (FAB) m / z: 568 (M + H) ⁺ .
(7f) (2R, 3R, 4R, 5R) -N-benzyloxycarbonyl-2,5-dibenzyloxymethyl-4-benzyloxypyrrolidin-3-yl 2,3,6-tri-O-benzyl-4 -O- (2,3,4-tri-O-benzyl-6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside The compound (426 mg, 0.49 mmol) synthesized in Example 2 (2f) , Methylene chloride (8 mL), trichloroacetonitrile (0.25 mL, 2.45 mmol), 1,8-diazabicyclo [5.4.0] -7-undecene (7 μL, 0.05 mmol) was added, and at room temperature. Stir for 15 minutes. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1, 1% triethylamine, V / V) to obtain a colorless oily imidate (398 mg, 80%). It was. The compound synthesized in Example 7 (7e) (248 mg, 0.44 mmol) was dissolved in diethyl ether (8 mL), and trimethylsilyl trifluoromethanesulfonate (7 μL, 44 μmol) was added under a nitrogen atmosphere. A solution of imidate in diethyl ether (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hours. Triethylamine (12 μL, 88 μmol) was added to the reaction solution, the solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate (20 mL), and washed with saturated aqueous sodium hydrogen carbonate (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel flash column chromatography (hexane: diethyl ether, 4: 1, V / V) to give the title object compound (218 mg 31%) as a colorless oil.
¹ H NMR (500 MHz, CDCl ₃ ): δ 1.23 (3H, d, J = 5.9 Hz), 2.92-3.19 (4H, m), 3.26-3.73 (13H, m), 3.85 (1H, dd, J = 5.1, 5.1 Hz), 3.93 (1H, dd, J = 5.1, 5.1 Hz), 4.31 (1H, d, J = 8.0 Hz), 5.03 (1H, d, J = 3.6 Hz);
MS (FAB) m / z: 472 (M + H) ⁺ .
(7g) (2R, 3R, 4R, 5R) -2,5-dihydroxymethyl-4-hydroxypyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside The compound synthesized in Example 7 (7f) (218 mg, 0.15 mmol) was dissolved in 1% hydrochloric acid methanol solution (5 mL), 20% palladium hydroxide-carbon (110 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 2 hr. After removing the catalyst by Celite filtration, 28% aqueous ammonia (0.8 mL) was added and stirred for 10 minutes. The solvent was distilled off under reduced pressure, and after passing through an ion exchange resin column with water (30 mL), 1% aqueous ammonia (30 mL) was passed. The aqueous ammonia containing the target compound is concentrated under reduced pressure and purified using silica gel flash column chromatography (ethyl acetate: methanol: water, 5: 2: 1 to 1: 1: 1, V / V) to give the title target compound (47 mg, 64%) was obtained as a colorless solid.
¹ H NMR (400 MHz, D ₂ O): δ 1.15 (3H, d, J = 5.9 Hz), 2.92-3.19 (4H, m), 3.26-3.73 (13H, m), 3.85 (1H, dd, J = 5.1, 5.1 Hz), 3.93 (1H, dd, J = 5.1, 5.1 Hz), 4.31 (1H, d, J = 8.0 Hz), 5.03 (1H, d, J = 3.6 Hz);
MS (FAB) m / z: 472 (M + H) ⁺ .
<Example 8>
(2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-methoxy-6-deoxy-β-D-glucopyranosyl) -D-glucopyranoside (Exemplary Compound No. 1 -354)

(8a) Allyl 2,3,6-tri-O-benzyl-4-O- (2,3,4-tri-O-benzyl-6-fluoro-6-deoxy-β-D-glucopyranosyl) -α- D-glucopyranoside The compound (2.19 g, 2.37 mmol) synthesized in Example 2 (2c) was dissolved in N, N-dimethylformamide (45 mL), and sodium hydride (0.12 g, 2 .75 mmol) was added, and after stirring for 10 minutes, methyl iodide (0.3 mL, 4.82 mmol) was added and stirred at room temperature for 5 hours. Methanol (5 mL) was added to the reaction solution under ice cooling, and the mixture was stirred for 30 minutes. Ethyl acetate (20 mL) was added, and the organic layer was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 6: 1 to 5: 1, V / V) to give the title object compound (1.80 g, yield 81%) as a colorless oil. It was.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.21 (3H, s), 3.30-5.00 (28H, m), 5.10 (1H, m), 5.20 (1H, m), 5.95 (1H, m), 7.20 -7.40 (30H, m);
MS (FAB) m / z: 938 (M + H) ⁺ .
(8b) Allyl 2,3,6-tri-O-benzyl-4-O- (2,3,4-tri-O-benzyl-6-methoxy-6-deoxy-β-D-glucopyranosyl) -D- Glucopyranoside Compound (1.80 g, 1.92 mmol) synthesized in Example 8 (8a) was dissolved in methanol (30 mL) and tetrahydrofuran (6 mL), and palladium (II) chloride (67.4 mg, 0.38 mmol) was added. And stirred at room temperature for 14 hours. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 5: 1-4: 1-3: 1, V / V) to give the title object compound (1.43 g, yield 83%) colorless. Obtained as amorphous.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.20 (3H, s), 3.25-5.00 (27H, m), 5.10 (1H, m), 7.20-7.40 (30H, m);
MS (FAB) m / z: 898 (M + H) ⁺ .
(8c) (2R, 3R, 4R) -4-benzyloxy-N-benzyloxycarbonyl-2- (benzyloxymethyl) pyrrolidin-3-yl 2,3,6-tri-O-benzyl-4-O- (2,3,4-Tri-O-benzyl-6-methoxy-6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside Compound synthesized in Example 8 (8b) (762.6 mg, 0. 85 mmol) is dissolved in methylene chloride (14 mL), trichloroacetonitrile (0.43 mL, 4.29 mmol), 1,8-diazabicyclo [5.4.0] unde-7-cene (1 drop) is added, and room temperature is added. For 30 minutes. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 4: 1, 1% triethylamine, V / V) to give a colorless oily imidate (567.8 mg, 64%). Got. The compound (380.8 mg, 0.85 mmol) synthesized in Example 1 (1i) was dissolved in diethyl ether (13 mL), and trimethylsilyl trifluoromethanesulfonate (8.0 μL, 0.044 mmol) was dissolved in diethyl ether (8.0 mL) under a nitrogen atmosphere. 2 mL) and added. A solution of imidate (567.8 mg) in diethyl ether (5 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. Triethylamine (8.0 μL, 0.057 mmol) was added to the reaction mixture, the solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate (20 mL), and saturated sodium bicarbonate (20 mL) and saturated brine (20 mL). Washed. The organic layer is dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, and the residue containing the α, β mixture is purified using silica gel flash column chromatography (hexane: diethyl ether, 3: 1, V / V). Of these, the title compound α-form (150.1 mg, 13%) was isolated as a colorless amorphous substance.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.20 (3H, s), 3.25-5.20 (39H, m), 7.20-7.40 (45H, m);
MS (FAB) m / z: 1327 (M + H) ⁺ .
(8d) (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-methoxy-6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside
The compound (150.1 mg, 0.11 mmol) synthesized in Example 8 (8c) was dissolved in methanol (10 mL) containing 1% aqueous hydrochloric acid solution, 20% palladium hydroxide-carbon (100 mg) was added, and hydrogen atmosphere was added. Stir for 2 hours. After removing the catalyst by Celite filtration, 28% aqueous ammonia (0.5 mL) was added and stirred for 10 minutes. The solvent was distilled off under reduced pressure, and the aqueous solution (100 mL) was applied to an ion exchange resin (Dowex 50w × 8) column, and then flushed with 1% aqueous ammonia (100 mL). The aqueous ammonia containing the target compound is concentrated under reduced pressure and purified using silica gel flash column chromatography (ethyl acetate: methanol: water, 5: 2: 1 to 1: 1: 1, V / V) to give the title target compound (49.1 mg, 95%) was obtained as a colorless solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.00-4.20 (19H, m), 3.27 (3H, s), 4.37 (1H, d, J = 8.0 Hz), 4.98 (1H, d, J = 3.7 Hz );
MS (FAB) m / z: 472 (M + H) ⁺ .
<Example 9>
(2R, 3R, 4R) -4-fluoro-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranoside (Exemplary Compound No. 1-115 )

(9a) (2R, 3R, 4R) -3-Benzoyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-4-hydroxy-pyrrolidine Compound synthesized in Example 1 (1h) (3.37 g, 9 0.07 mmol) is dissolved in methylene chloride: cyclohexane (1: 2, 180 mL) and benzyltrichloroacetimidate (2.0 mL, 10.88 mmol), trifluoromethanesulfonic acid (2.57 ml, 15.3 mmol) are added. And stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction solution at 0 ° C., diluted with ethyl acetate (200 mL), washed with water (300 mL) and saturated aqueous sodium hydrogen carbonate solution (300 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 5: 1 to 2: 1, V / V) to obtain 4.71 g of a pale yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.50-4.20 (4H, m), 4.45-4.80 (3H, m), 5.00-5.60 (5H, m), 7.32-7.46 (12H, m), 7.59 ( 1H, m), 7.99 (2H, m);
MS (FAB) m / z: 462 (M + H) ⁺ .
(9b) (2R, 3R, 4S) -3-Benzoyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-4-hydroxy-pyrrolidine Compound synthesized in Example 9 (9a) (183 mg, 0.40 mmol ) Was dissolved in methylene chloride (4 mL), pyridine (96 μL, 1.20 mmol) and trifluoromethanesulfonic anhydride (0.10 mL, 0.60 mmol) were added, and the mixture was stirred at 0 ° C. for 20 minutes. Water (10 mL) was added at 0 ° C., and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine (10 mL). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 2: 1, V / V) to give the title object compound (92 mg, yield 50%) as a pale-yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.25-4.20 (4H, m), 4.25-4.75 (3H, m), 5.10-5.60 (5H, m), 7.32-7.46 (12H, m), 7.59 ( 1H, t, J = 7.4 Hz), 7.99 (2H, d, J = 8.8 Hz);
MS (FAB) m / z: 462 (M + H) ⁺ .
(9c) (2R, 3R, 4R) -N-Benzyloxycarbonyl-2-benzyloxymethyl-4-fluoro-pyrrolidine The compound synthesized in Example 9 (9b) (980 mg, 2.12 mmol) was converted to 1,2 -Dissolved in dimethoxyethane (20 mL) and diethylaminosulfur trifluoride (0.84 mL, 6.36 mmol) was added at -20 ° C. The temperature was gradually raised, and the mixture was stirred at 60 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added at 0 ° C. until no foaming occurred, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine (20 mL). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 4: 1, V / V) to obtain a pale yellow oil (545 mg). The obtained pale yellow oil (545 mg) was dissolved in methanol (10 mL), potassium carbonate (50 mg) was added, and the mixture was stirred at room temperature for 20 min. After evaporating the solvent under reduced pressure, water (20 mL) was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine (20 mL). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 2: 1, V / V) to give the title object compound (263 mg, yield 34%) as a colorless oil. Got as.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.10-4.20 (4H, m), 4.25-4.75 (3H, m), 4.80-5.20 (5H, m), 7.30-7.45 (10H, m);
MS (FAB) m / z: 360 (M + H) ⁺ .
(9d) (2R, 3R, 4R) -N-Benzyloxycarbonyl-2-benzyloxymethyl-4-fluoro-pyrrolidin-3-yl 2,3,6-tri-O-benzyl-4-O- ( 2,3,4-Tri-O-benzyl-6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranoside The compound synthesized in Example 1 (1f) (657 mg, 0.76 mmol) was converted into methylene chloride ( 12 mL), trichloroacetonitrile (0.38 mL, 3.8 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (11 μL, 76 μmol) were added, and the mixture was stirred at room temperature for 15 minutes. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1, 1% triethylamine, V / V) to obtain a colorless oily imidate (767 mg, 100%). It was. The compound synthesized in Example 9 (9c) (263 mg, 0.73 mmol) was dissolved in diethyl ether (12 mL), and trimethylsilyl trifluoromethanesulfonate (13 μL, 73 μmol) was added under a nitrogen atmosphere. A solution of imidate in diethyl ether (8 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hours. Triethylamine (20 μL, 146 μmol) was added to the reaction solution, the solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate (20 mL), and washed with saturated aqueous sodium hydrogen carbonate (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified using silica gel flash column chromatography (hexane: diethyl ether, 4: 1, V / V) to give the title compound α form (109 mg, 12%), β-form (52 mg, 6%) was obtained as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.09 (3H, d, J = 4.2 Hz), 3.00-5.60 (35H, m), 7.10-7.40 (40H, m);
MS (FAB) m / z: 1209 (M + H) ⁺ .
(9e) (2R, 3R, 4R) -4-fluoro-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranoside Example 9 ( The compound synthesized in 9d) (109 mg, 90.2 μmol) was dissolved in a 1% hydrochloric acid methanol solution (5 mL), 20% palladium hydroxide-carbon (55 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 1 hour. After removing the catalyst by Celite filtration, 28% aqueous ammonia (0.2 mL) was added and stirred for 10 minutes. The solvent was distilled off under reduced pressure, and after passing through an ion exchange resin (Dowex 50w × 8) column with water (30 mL), 1% aqueous ammonia (30 mL) was allowed to flow. The aqueous ammonia containing the target compound is concentrated under reduced pressure and purified using silica gel flash column chromatography (ethyl acetate: methanol: water, 5: 2: 1 to 1: 1: 1, V / V) to give the title target compound (26 mg, 65%) was obtained as a colorless solid.
¹ H NMR (500 MHz, CDCl ₃ ): δ 1.18 (3H, d, J = 5.9 Hz), 2.98-3.16 (4H, m), 3.47-3.77 (12H, m), 4.11 (1H, dd, J = 4.9, 20.5 Hz), 5.02 (1H, m), 5.23 (1H, m);
MS (FAB) m / z: 444 (M + H) ⁺ .
<Example 10>
(2R, 3R, 4R) -4-hydroxy-2-fluoromethyl-pyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside (Exemplary Compound No. 1-119) )

(10a) (2R, 3R, 4R) -3-Benzoyloxy-N-benzyloxycarbonyl-2-fluoromethyl-4-hydroxy-pyrrolidine Compound synthesized in Example 1 (1h) (257 mg, 0.69 mmol) Was dissolved in 1,2-dimethoxyethane (5 mL), and diethylaminosulfur trifluoride (0.11 mL, 0.83 mmol) was added at -20 ° C. The temperature was gradually raised, and the mixture was stirred at 60 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added at 0 ° C. until no foaming occurred, followed by extraction with ethyl acetate (15 mL), and the organic layer was washed with saturated brine (15 mL). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 3: 1, V / V) to give a colorless oil (113 mg, 44%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.50-4.25 (4H, m), 4.50-5.55 (3H, m), 5.40-5.60 (2H, m), 7.20-7.50 (7H, m), 7.60 ( 1H, m), 8.00-8.10 (2H, m);
MS (FAB) m / z: 374 (M + H) ⁺ .
(10b) (2R, 3R, 4S) -3-Benzoyloxy-N-benzyloxycarbonyl-4-benzyloxy-2-fluoromethyl-pyrrolidine Compound synthesized in Example 10 (10a) (344 mg, 0.92 mmol) ) Is dissolved in methylene chloride: cyclohexane (1: 2, 10 mL), benzyltrichloroacetimidate (0.68 mL, 3.68 mmol), trifluoromethanesulfonic acid (16 μL, 0.18 mmol) are added, and 4 at room temperature. Stir for hours. Saturated aqueous sodium hydrogen carbonate (1 mL) was added to the reaction mixture at 0 ° C., diluted with ethyl acetate (20 mL), washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and then reduced in pressure. The lower solvent was distilled off. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 8: 1 to 5: 1, V / V) to give a colorless oil (307 mg, 68%).
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.50-5.25 (7H, m), 5.50-5.75 (4H, m), 7.20-7.50 (12H, m), 7.60 (1H, m), 8.00-8.10 ( 2H, m);
MS (FAB) m / z: 464 (M + H) ⁺ .
(10c) (2R, 3R, 4S) -N-Benzyloxycarbonyl-4-benzyloxy-2-fluoromethyl-pyrrolidine The compound (307 mg, 0.66 mmol) synthesized in Example 10 (10b) was dissolved in methanol (6 mL). ), Potassium carbonate (27 mg, 0.20 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. Methanol was distilled off under reduced pressure, water (15 mL) was added, the mixture was extracted with ethyl acetate (15 mL), and the organic layer was washed with saturated brine (15 mL). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 3: 1, V / V) to give the title object compound (176 mg, yield 74%) as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.35-4.80 (7H, m), 5.50-5.75 (4H, m), 7.20-7.50 (10H, m);
MS (FAB) m / z: 360 (M + H) ⁺ .
(10d) (2R, 3R, 4R) -N-Benzyloxycarbonyl-4-benzyloxy-2-fluoromethyl-pyrrolidin-3-yl 2,3,6-tri-O-benzyl-4-O- ( 2,3,4-Tri-O-benzyl-6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside The compound synthesized in Example 2 (2f) (398 mg, 0.46 mmol) was converted into methylene chloride ( 8 mL), trichloroacetonitrile (0.23 mL, 2.30 mmol), 1,8-diazabicyclo [5.4.0] -7-undecene (7 μL, 0.05 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. . After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1, 1% triethylamine, V / V) to obtain a colorless oily imidate. The compound (165 mg, 0.46 mmol) synthesized in Example 10 (10c) was dissolved in diethyl ether (8 mL), and trimethylsilyl trifluoromethanesulfonate (8 μL, 46 μmol) was added under a nitrogen atmosphere. A solution of imidate in diethyl ether (4 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2.5 hours. Triethylamine (13 μL, 92 μmol) was added to the reaction mixture, the solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate (15 mL), and washed with saturated aqueous sodium hydrogen carbonate (15 mL) and saturated brine (15 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified using silica gel flash column chromatography (hexane: diethyl ether, 4: 1, V / V) to give the title object compound (53 mg 10%) as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.10 (3H, d, J = 4.2 Hz), 3.00-5.60 (35H, m), 7.10-7.40 (40H, m);
MS (FAB) m / z: 1209 (M + H) ⁺ .
(10e) (2R, 3R, 4R) -4-Hydroxy-2-fluoromethyl-pyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside Example 10 ( The compound synthesized in 10d) (53 mg, 43.9 μmol) was dissolved in a 1% hydrochloric acid methanol solution (5 mL), 20% palladium hydroxide-carbon (30 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 3 hours. After removing the catalyst by Celite filtration, 28% aqueous ammonia (0.2 mL) was added and stirred for 10 minutes. The solvent was distilled off under reduced pressure, and after passing through an ion exchange resin column with water (30 mL), 1% aqueous ammonia (30 mL) was passed. The aqueous ammonia containing the target compound was concentrated under reduced pressure and purified using silica gel flash column chromatography (ethyl acetate: methanol: water, 5: 2: 1 to 1: 1: 1, V / V) to give the title target compound (1.6 mg, 8%) was obtained as a colorless solid.
¹ H NMR (500 MHz, CDCl ₃ ): δ 1.18 (3H, d, J = 4.0 Hz), 2.98-4.25 (16H, m), 4.50 (2H, m), 5.83 (1H, m);
MS (FAB) m / z: 444 (M + H) ⁺ .

<Example 11>
(2R, 3R, 4S) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranoside (Exemplary Compound No. 1-1 )

(11a) (2R, 3R, 4S) -N-Benzyloxycarbonyl-4-benzyloxy-2-benzyloxymethyl-3-hydroxy-pyrrolidine Compound synthesized in Example 9 (9b) (815 mg, 1.77 mmol) ) In dichloromethane: cyclohexane (1: 2, 45 mL), benzyltrichloroacetimidate (0.66 mL, 3.54 mmol), trifluoromethanesulfonic acid (24 μL, 0.27 mmol) are added, and 1 at room temperature. Stir for 5 hours. Saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction solution at 0 ° C., diluted with ethyl acetate (200 mL), washed with water (50 mL) and saturated aqueous sodium hydrogen carbonate solution (50 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 4: 1, V / V) to obtain a pale yellow oil (866 mg). The obtained pale yellow oil (866 mg) was dissolved in methanol (15 mL), potassium carbonate (65 mg) was added, and the mixture was stirred at room temperature for 1 hr. After evaporating the solvent under reduced pressure, water (20 mL) was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine (20 mL). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 5: 1 to 2: 1, V / V) to give the title object compound (233 mg, yield 30%). Was obtained as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.35-4.25 (6H, m), 4.25-4.70 (4H, m), 5.00-5.30 (4H, m), 7.09-7.26 (15H, m);
MS (FAB) m / z: 448 (M + H) ⁺ .
(11b) (2R, 3R, 4S) -N-Benzyloxycarbonyl-2-benzyloxymethyl-4-benzyloxy-pyrrolidin-3-yl 2,3,6-tri-O-benzyl-4-O- (2,3,4-Tri-O-benzyl-6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranoside The compound (513 mg, 0.59 mmol) synthesized in Example 1 (1f) was converted into methylene chloride. (10 mL), trichloroacetonitrile (0.3 mL, 2.95 mmol), 1,8-diazabicyclo [5.4.0] -7-undecene (9 μL, 0.06 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. did. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1, 1% triethylamine, V / V) to obtain a colorless oily imidate (447 mg, 75%). It was. The compound synthesized in Example 11 (11a) (233 mg, 0.52 mmol) was dissolved in diethyl ether (10 mL), and trimethylsilyl trifluoromethanesulfonate (9 μl, 59 μmol) was added under a nitrogen atmosphere. A solution of imidate in diethyl ether (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hours. Triethylamine (16 μL, 118 μmol) was added to the reaction solution, the solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate (20 mL), and washed with saturated aqueous sodium hydrogen carbonate (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified using silica gel flash column chromatography (hexane: diethyl ether, 5: 1-4: 1, V / V). The target compound α-form (58 mg, 8%) and β-form (51 mg, 7%) were obtained as colorless oils.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.15 (3H, d, J = 5.6 Hz), 3.10-5.20 (36H, m), 1.15 (1H, d, J = 6.3 Hz), 7.20-7.39 (45H , m);
MS (FAB) m / z: 1297 (M + H) ⁺ .
(11c) (2R, 3R, 4S) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranoside Example 11 ( The compound synthesized in 11b) (58 mg, 44.7 μmol) was dissolved in 1% hydrochloric acid methanol solution (5 mL), 20% palladium hydroxide-carbon (30 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 1.5 hours. After removing the catalyst by Celite filtration, 28% aqueous ammonia (0.2 mL) was added and stirred for 10 minutes. The solvent was distilled off under reduced pressure, and after passing through an ion exchange resin (Dowex 50w × 8) column with water (30 mL), 1% aqueous ammonia (30 mL) was allowed to flow. The aqueous ammonia containing the target compound is concentrated under reduced pressure and purified using silica gel flash column chromatography (ethyl acetate: methanol: water, 5: 2: 1 to 1: 1: 1, V / V) to give the title target compound (13 mg, 68%) was obtained as a colorless solid.
¹ H NMR (400 MHz, D ₂ O): δ 1.19 (3H, d, J = 4.1 Hz), 2.80-4.60 (17H, m), 5.00 (1H, d, J = 3.6 Hz), 5.24 (1H, d, J = 3.0 Hz);
MS (FAB) m / z: 442 (M + H) ⁺ .
<Example 12>
(2R, 3R, 4R) -2-hydroxymethyl-3-hydroxy-pyrrolidin-4-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside) (Exemplary Compound No. 1- 556)

(12a) (2R, 3R, 4R) -N-benzyloxycarbonyl-2-benzyloxymethyl-3-hydroxy-pyrrolidin-4-yl 2,3,6-tri-O-benzyl-4-O- (2 , 3,4-Tri-O-benzyl-6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside The compound synthesized in Example 2 (2f) (607 mg, 0.70 mmol) was added to methylene chloride (10 mL). ), Trichloroacetonitrile (500 μL, 4.98 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (2 drops) were added, and the mixture was stirred at room temperature for 40 minutes. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1, 1% triethylamine, V / V) to obtain imidate (630 mg, 89%) as a yellow oil. Obtained. The compound synthesized in Example 9 (9a) (323 mg, 0.700 mmol) was dissolved in diethyl ether (10 mL), imidate (630 mg, 0.623 mmol) was added, and trimethylsilyl trifluoromethanesulfonate (6.3 μL, 34.L). 8 μmol) was added dropwise and stirred at room temperature for 45 minutes. After adding triethylamine (4 drops) to the reaction solution, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: diethyl ether, 6: 1, V / V) to obtain the title object compound (610 mg, 75%) as a pale yellow oil. Subsequently, this pale yellow oil (610 mg, 0.465 mmol) was dissolved in methanol (10 mL), potassium carbonate water (1 M, 1 mL, 1 mmol) was added, and the mixture was stirred at room temperature for 3 hr. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (hexane: diethyl ether, 2: 1, V / V) to give the title object compound (280 mg, yield 50%) as a colorless solid. Obtained.
¹ H NMR (400 MHz, D ₂ O): δ 1.19 (3H, d, J = 5.8 Hz), 2.83 (1H, brs), 3.12 (1H, t, J = 9.3 Hz), 3.17-3.23 (1H, m), 3.29-3.37 (2H, m), 3.39-3.45 (2H, m), 3.51 (1H, dd, J = 9.76, 2.93 Hz), 3.60 (1H, brt, J = 7.8 Hz), 3.72-4.01 (7H, m), 4.27-4.56 (6H, m), 4.60-4.63 (2H, m), 4.73-4.75 (4H, brm), 4.78 (1H, d, J = 10.75 Hz), 4.85 (1H, d , J = 10.74 Hz), 4.87 (1H, d, J = 9.77 Hz), 4.92 (1H, d, J = 2.93 Hz), 5.01-5.12 (3H, m), 7.21-7.34 (38H, m), 7.43 (2H, d, J = 6.83 Hz);
MS (FAB) m / z: 1207 (M + H) ⁺ .
(12b) (2R, 3R, 4R) -2-Hydroxymethyl-3-hydroxy-pyrrolidin-4-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside Example 12 ( The compound synthesized in 12a) (90 mg, 74.6 μmol) was dissolved in methanol (10 mL), hydrochloric acid (140 μL) and 20% palladium hydroxide-carbon (90 mg) were added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. . After Celite filtration, aqueous ammonia (5%) was added until the pH became neutral, the solvent was distilled off under reduced pressure, and purification was performed with an ion exchange resin (Dowex 50w × 8) column (water to 5% aqueous ammonia). did. The product was further purified by silica gel flash column chromatography (ethyl acetate: methanol: water, 1: 1: 1, V / V) to obtain the title object compound (26 mg, 79%) as a colorless solid.
¹ H NMR (400 MHz, D ₂ O): δ 1.32 (3H, d, J = 5.8 Hz), 3.17-3.22 (2H, m), 3.30-3.38 (2H, m), 3.44-3.55 (2H, m ), 3.60-3.64 (2H, m), 3.74-3.86 (6H, m), 3.92 (1H, brd, J = 11,72 Hz), 4.13 (1H, brs), 4.24 (1H, brs), 4.48 ( 1H, d, J = 7.81 Hz), 5.11 (1H, d, J = 2.93 Hz);
MS (FAB) m / z: 442 (M + H) ⁺ .
<Example 13>
(2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -β-D-glucopyranoside (Exemplary Compound No. 1-1 )

Compound β-form (60 mg, 46.3 μmol) synthesized in Example 1 (1j) was dissolved in methanol (4 mL), hydrochloric acid (56 μL) and 20% palladium hydroxide-carbon (60 mg) were added, and hydrogen atmosphere was added. Stir at room temperature for 4 hours. After filtration through Celite, 18% aqueous ammonia (3 drops) was added, the solvent was distilled off under reduced pressure, and the residue was purified with an ion exchange resin (Dowex 50w × 8) column (water to 5% aqueous ammonia). The product was further purified by silica gel flash column chromatography (ethyl acetate: methanol: water, 3: 2: 1, V / V) to obtain the title object compound (10 mg, 49%) as a colorless solid.
¹ H NMR (400 MHz, D ₂ O): δ 1.29 (3H, d, J = 5.8 Hz), 2.93 (1H, dd, J = 11.7, 3.6 Hz), 3.15-3.35 (4H, m), 3.51- 3.65 (5H, m), 3.74-3.80 (5H, m), 3.93-4.00 (2H, m), 4.40 (1H, br, s), 4.56 (1H, d, J = 7.3 Hz), 5.34 (1H, br, s);
MS (FAB) m / z: 464 (M + Na) ⁺ , 442 (M + H) ⁺ .
<Example 14>
(1R, 2S, 3R, 4R, 5R) -1-amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α- D-glucopyranoside (Exemplified Compound No. 5-1)

(14a) Methyl 4-O-benzoyl-2,3-di-O-benzyl-6-Op-toluenesulfonyl-α-D-glucopyranoside methyl 2,3-di-O-benzyl-6-Op -Toluenesulfonyl-α-D-glucopyranoside (J. Org. Chem., 2001, 66, 5965-5975) (163.9 g, 310 mmol) was dissolved in methylene chloride (1.5 L) and 4-dimethylaminopyridine ( 43.5 g, 352 mmol) and triethylamine (49.0 mL, 352 mmol) were added, and benzoyl chloride (43.2 mL, 372 mmol) was added dropwise with ice cooling, followed by stirring at 0 ° C. for 1 hour. Dilute hydrochloric acid (2N, 500 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (1 L). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (1 L) and saturated brine (1 L), dried over anhydrous sodium sulfate, The solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 1: 1, V / V) to obtain the title object compound (196 g, yield 99%) as a colorless solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.34 (3H, s), 3.40 (3H, s), 3.58 (1H, dd, J = 9.3, 3.4 Hz), 3.98-4.10 (4H, m), 4.57 -4.65 (3H, m), 4.79 (1H, d, J = 10.8 Hz), 5.06 (1H, dd, J = 9.8, 9.8 Hz), 7.08-7.10 (5H, m), 7.18 (2H, d, J = 7.8 Hz), 7.29-7.35 (5H, m), 7.41-7.45 (2H, m), 7.57-7.61 (1H, m), 7.67 (2H, d, J = 7.8 Hz), 7.89 (2H, d, J = 8.8 Hz);
MS (FAB) m / z: 633 (M + H) ⁺ .
(14b) Methyl 4-O-benzoyl-2,3-di-O-benzyl-6-deoxy-6-iodo-α-D-glucopyranoside The compound (196 g, 310 mmol) synthesized in Example 14 (14a) was dissolved in toluene. In (2 L), sodium iodide (235 g, 1.57 mol) and 18-crown-6-ether (16.6 g, 62.8 mmol) were added under a nitrogen atmosphere, and the mixture was stirred at 100 ° C. for 2 hours. The reaction solution was cooled to room temperature, filtered, and the residue was washed with toluene. The filtrate and washings were washed with saturated aqueous sodium hydrogen carbonate (1 L) and saturated brine (1 L), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title object compound (181 g, yield 99%). Was obtained as a colorless solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.12 (1H, dd, J = 11.0, 8.8 Hz), 3.29 (1H, dd, J = 11.0, 2.2 Hz), 3.51 (3H, s), 3.64 (1H , dd, J = 9.6, 3.7 Hz), 3.82-3.89 (1H, m), 4.06 (1H, dd, J = 9.6, 8.8 Hz), 4.60-4.68 (3H, m), 4.82 (1H, d, J = 11.0 Hz), 4.82 (1H, d, J = 12.8 Hz), 5.06 (1H, dd, J = 9.5, 9.5 Hz), 7.08-7.10 (5H, m), 7.29-7.38 (5H, m), 7.42 -7.47 (2H, m), 7.57-7.61 (1H, m), 7.98 (2H, d, J = 8.0 Hz);
MS (FAB) m / z: 589 (M + H) ⁺ .
(14c) 4-O-benzoyl-2,3-di-O-benzyl-5,6-dideoxy-D-xylo-hexa-5-enose oxime
The compound synthesized in Example 14 (14b) (181 g, 307 mmol) was dissolved in isopropanol (1.5 L) and distilled water (50 mL), zinc powder (180 g) washed with dilute hydrochloric acid was added, and the mixture was heated at 100 ° C. for 1 hour. Stir. The reaction solution was filtered through Celite, the filtrate was washed with ethanol, and the filtrate and the washing solution were distilled off under reduced pressure. The residue was dissolved in ethanol (500 mL), hydroxylamine hydrochloride (42.7 g, 615 mmol) and pyridine (49.7 mL, 615 mmol) were added, and the mixture was stirred at 80 ° C. for 40 min. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1, V / V) to give the title object compound (126 g, yield 92%) as a colorless solid. Obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.83 (0.7H, dd, J = 5.8, 4.9 Hz), 3.99 (0.3H, dd, J = 6.2, 3.9 Hz), 4.23 (0.7H, dd, J = 7.8, 4.9 Hz), 4.42 (1H, dd, J = 11.8, 3.9 Hz), 4.65 (1H, d, J = 11.7 Hz), 4.68-4.76 (3H, m), 4.97 (0.3H, dd, J = 5.8, 3.9 Hz), 5.23 (1H, dd, J = 10.7, 5.9 Hz), 5.31-5.37 (1H, m), 5.78-5.94 (2H, m), 7.20-7.38 (9H, m), 7.40- 7.48 (3H, m), 7.53-7.59 (1H, m), 8.00-8.07 (2H, m);
MS (FAB) m / z: 446 (M + H) ⁺ .
(14d) (3aR, 4R, 5R, 6S, 6aR) -4-benzoyloxy-5,6-dibenzyloxy-hexahydro-cyclopenta [c] isoxazole Compound synthesized in Example 14 (14c) (126 g, 282 mmol) Was dissolved in toluene (800 mL) and stirred at 120 ° C. for 8 hours. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 3: 1, V / V) to give the title object compound (59.7 g, yield 48%) as colorless. Obtained as a solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.83-2.91 (1H, m), 3.45-3.60 (1H, m), 3.89-3.95 (2H, m), 4.11-4.18 (1H, m), 4.55 ( 1H, m), 4.75-4.87 (4H, m), 5.01 (1H, dd, J = 7.8, 6.8 Hz), 5.09-5.13 (1H, m), 7.22-7.40 (10H, m), 7.43-7.47 ( 2H, m), 7.57-7.61 (1H, m), 7.97-8.00 (2H, m);
MS (FAB) m / z: 446 (M + H) ⁺ .
(14e) (3aR, 4R, 5S, 6S, 6aR) -1-benzyloxycarbonyl-5,6-dibenzyloxy-4-hydroxy-hexahydro-cyclopenta [c] isoxazole Compound synthesized in Example 14 (14d) (59.7 g, 134 mmol) was dissolved in methanol (1 L), sodium methoxide (10 mL, 49 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. Saturated aqueous ammonium chloride (500 mL) was added to the reaction mixture at 0 ° C., and the mixture was extracted with ethyl acetate (1.5 L), and the organic layer was washed with saturated brine (50 mL). To this organic layer were added saturated aqueous sodium hydrogencarbonate (500 mL) and benzyloxychloroformate (22.9 mL, 160 mmol) at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hr. The organic layer was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 1: 1, V / V) to obtain the title object compound (61.3 g, yield 96%) as a colorless solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.30 (1H, brd, J = 3.7 Hz, OH), 2.91 (1H, ddd, J = 8.9, 8.9, 5.7 Hz, H-3a), 3.58 (1H, dd, J = 9.0, 5.7 Hz, H-3), 3.73 (1H, dd, J = 8.6, 8.4 Hz, H-5), 3.82 (1H, ddd, J = 8.9, 8.6, 3.7 Hz, H-4 ), 3.84 (1H, dd, J = 8.4, 5.6 Hz, H-6), 3.98 (1H, d, J = 9.0 Hz, H-3), 4.54 (1H, d, J = 11.3 Hz), 4.54 ( 1H, dd, J = 8.9, 5.6 Hz, H-6a), 4.63 (1H, d, J = 11.7 Hz), 4.84 (1H, d, J = 11.3 Hz), 4.87 (1H, d, J = 11.7 Hz) ), 5.20 (1H, d, J = 12.1 Hz), 5.27 (1H, d, J = 12.1 Hz), 7.23-7.40 (15H, m).
MS (FAB) m / z: 476 (M + H) ⁺ .
(14f) (3aR, 4R, 5R, 6S, 6aR) -1-benzyloxycarbonyl-5,6-dibenzyloxy-hexahydro-cyclopenta [c] isoxazol-4-yl 2,3,6-tri-O- Benzyl-4-O- (6-deoxy-2,3,4-tri-O-benzyl-α-D-glucopyranosyl) -α-D-glucopyranoside Compound synthesized in Example 1 (1f) (215 mg, 0. 248 mmol) is dissolved in methylene chloride (5 mL), trichloroacetonitrile (460 μL, 4.61 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (2 drops) are added and 40 minutes at room temperature. Stir. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1, 1% triethylamine, V / V) to obtain imidate (250 mg, 99%) as a yellow oil. Obtained. The compound synthesized in Example 14 (14e) (100 mg, 0.21 mmol) was dissolved in diethyl ether (10 mL), imidate (250 mg, 0.248 mmol) was added, and trimethylsilyl trifluoromethanesulfonate (3.8 μL, 0.8 mL). 021 mmol) was added dropwise and stirred at room temperature for 45 minutes. After adding triethylamine (4 drops) to the reaction solution, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: diethyl ether, 2: 1, V / V) to obtain the title object compound (55 mg, 17%) as a pale yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.15 (3H, d, J = 6.8 Hz), 3.01-3.12 (2H, m), 3.14 (1H, dd, J = 9.8, 3.9 Hz), 3.50-3.62 (3H, m), 3.64-3.80 (2H, m), 3.80-3.96 (5H, m), 3.99-4.10 (2H, m), 4.43 (1H, d, J = 11.7 Hz), 4.47 (1H, d , J = 11.7 Hz), 4.50-4.62 (7H, m), 4.68-4.93 (8H, m), 5.06 (1H, d, J = 11.7 Hz), 5.18-5.29 (3H, m), 5.61 (1H, d, J = 3.9 Hz), 7.05-7.41 (45H, m);
MS (FAB) m / z: 1324 (M + H) ⁺ .
(14 g) (1R, 2S, 3R, 4R, 5R) -1-amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -Α-D-glucopyranoside The compound synthesized in Example 14 (14f) (53 mg, 40.4 μmol) was dissolved in methanol (10 mL), hydrochloric acid (10 μL) and 20% palladium hydroxide-carbon (53 mg) were added, The mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. After filtration through Celite, the solvent was distilled off under reduced pressure, and the residue was purified with an ion exchange resin (Dowex 50w × 8) column (water to 5% aqueous ammonia). The product was further purified by silica gel flash column chromatography (ethyl acetate: methanol: water, 1: 1: 1, V / V) to obtain the title object compound (5 mg, 26%) as a colorless solid.
¹ H NMR (400 MHz, D ₂ O): δ 1.18 (3H, d, J = 6.8 Hz), 2.00-2.08 (1H, m), 2.15-2.22 (1H, m), 3.03-3.09 (1H, m ), 3.16-3.22 (1H, m), 3.45-3.57 (5H, m), 3.58-3.78 (8H, m), 3.81-3.89 (3H, m), 5.10 (1H, d, J = 2.9 Hz), 5.23 (1H, d, J = 2.9 Hz);
MS (FAB) m / z: 472 (M + H) ⁺ .
<Example 15>
(1R, 2S, 3R, 4R, 5R) -1-amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α- D-glucopyranoside (Exemplified Compound No. 5-1)

(15a) (3aR, 4R, 5R, 6S, 6aR) -1-benzyloxycarbonyl-5,6-dibenzyloxy-hexahydro-cyclopenta [c] isoxazol-4-yl 2,3,6-tri-O- Benzyl-4-O- (6-deoxy-2,3,4-tri-O-benzyl-β-D-glucopyranosyl) -α-D-glucopyranoside Compound (1.0 g, synthesized in Example 2 (2f)) 1.15 mmol) is dissolved in methylene chloride (30 mL) and trichloroacetonitrile (460 μL, 4.61 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (2 drops) are added at room temperature. Stir for 40 minutes. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1, 1% triethylamine, V / V) to obtain imidate (970 mg, 84%) as a yellow oil. Obtained. The compound synthesized in Example 14 (14e) (508 mg, 1.06 mmol) was dissolved in diethyl ether (20 mL), imidate (970 mg, 0.97 mmol) was added, and trimethylsilyl trifluoromethanesulfonate (17 μL, 0.097 mmol). Was added dropwise and stirred at room temperature for 45 minutes. After adding triethylamine (4 drops) to the reaction solution, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: diethyl ether, 1: 1, V / V) to obtain the title object compound (125 mg, 9%) as a pale yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.22 (3H, d, J = 6.8 Hz), 2.81-2.87 (1H, m), 3.15 (1H, dd, J = 9.8, 8.7 Hz), 3.19-3.24 (1H, m), 3.28-3.36 (2H, m), 3.40-3.45 (1H, m), 3.52 (1H, dd, J = 8.8, 3.9 Hz), 3.55-3.59 (1H, m), 3.75 (1H , dd, J = 10.7, 3.9 Hz), 3.79-3.84 (2H, m), 3.86-3.91 (1H, m), 3.93-4.01 (2H, m), 4.31 (1H, d, J = 11.7 Hz), 4.35 (1H, d, J = 7.8 Hz), 4.50 (1H, d, J = 11.7 Hz), 4.52-4.59 (2H, m), 4.60-4.64 (3H, m), 4.70-4.87 (10H, m) , 4.89 (1H, d, J = 12.7 Hz), 5.00 (1H, d, J = 10.7 Hz), 5.07 (1H, d, J = 3.9 Hz), 5.21 (1H, d, J = 11.7 Hz), 5.28 (1H, d, J = 12.7 Hz), 7.10-7.43 (45H, m);
MS (FAB) m / z: 1324 (M + H) ⁺ .
(15b) (1R, 2S, 3R, 4R, 5R) -1-amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -Α-D-glucopyranoside The compound synthesized in Example 15 (15a) (115 mg, 86.8 μmol) was dissolved in methanol (20 mL) and ethyl acetate (1 mL), and hydrochloric acid (10 μL) and 20% palladium hydroxide-carbon were dissolved. (115 mg) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. After filtration through Celite, the solvent was distilled off under reduced pressure, and the residue was purified with an ion exchange resin (Dowex 50w × 8) column (water to 5% aqueous ammonia). The product was further purified by silica gel flash column chromatography (ethyl acetate: methanol: water, 1: 1: 1, V / V) to obtain the title object compound (30 mg, 73%) as a colorless amorphous.
[Α] _D ²⁰ +60.9 (c 0.11, H ₂ O);
¹ H NMR (400 MHz, D ₂ O): δ 1.21 (3H, d, J = 6.8 Hz), 2.17-2.25 (1H, m), 3.05-3.10 (1H, m), 3.18-3.27 (2H, m), 3.30-3.92 (14H, m), 4.38 ( 1H, d, J = 7.8 Hz), 5.08-5.10 (1H, m);
MS (FAB) m / z: 472 (M + H) ⁺ .
<Example 16>
(1R, 2S, 3R, 4R, 5R) -1- (2-hydroxy-1-hydroxymethyl-ethylamino) -2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O- (6 -Deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside (Exemplified Compound No. 5-22)

(16a) (3aR, 4R, 5R, 6S, 6aR) -4-benzoyloxy-5,6-dibenzyloxy-1- (1,3-dihydroxyprop-2-yl) -hexahydro-cyclopenta [c] isoxazole The compound synthesized in Example 14 (14d) (3.07 g, 6.89 mmol) was dissolved in methanol (10 mL) and tetrahydrofuran (10 mL), and 1,3-dihydroxyacetone (1.86 g, 20.7 mmol) and acetic acid were dissolved. (1 mL) was added and after stirring at 70 ° C. for 30 minutes, sodium cyanoborohydride (1.30 g, 20.67 mmol) was added and stirred at 70 ° C. for 10 hours. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel flash column chromatography (methylene chloride: methanol, 20: 1, V / V) to give the title object compound (1.20 g, yield 33%) colorless. Obtained as a solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.35 (1H, dd, J = 6.8, 4.9 Hz), 2.39 (1H, t, J = 5.9 Hz), 2.77-2.82 (1H, m), 2.93-3.00 (1H, m), 3.74-3.84 (3H, m), 3.88-3.94 (1H, m), 3.96-4.08 (3H, m), 4.21-4.26 (2H, m), 4.74-4.86 (4H, m) , 5.05 (1H, d, J = 7.8, 5.9 Hz), 7.26-7.38 (10H, m), 7.45-7.50 (2H, m), 7.59-7.64 (1H, m), 7.98-8.02 (2H, m) ;
MS (FAB) m / z: 520 (M + H) ⁺ .
(16b) (3aR, 4R, 5S, 6S, 6aR) -5,6-Dibenzyloxy-1- (2,2-dimethyl- [1,3] dioxan-5-yl) -4-hydroxy-hexahydro- Cyclopenta [c] isoxazole The compound synthesized in Example 16 (16a) (1.20 g, 2.31 mmol) was dissolved in acetone (30 mL), and 2,2-dimethoxypropane (2.27 mL, 18.5 mmol), p -Toluenesulfonic acid monohydrate (660 mg, 3.47 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. Saturated aqueous sodium hydrogen carbonate (50 mL) was added to the reaction mixture at 0 ° C., and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (50 mL). The solvent was distilled off under reduced pressure, the residue was dissolved in methanol, sodium methoxide (0.4 mL, 1.96 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. Saturated aqueous ammonium chloride (50 mL) was added to the reaction solution at 0 ° C., and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Distilled off. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 1: 1, V / V) to give the title object compound (840 mg, yield 80%) as a colorless solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.39 (3H, s), 1.47 (3H, s), 2.06 (1H, d, J = 3.9 Hz), 2.85-2.96 (2H, m), 3.49 (1H , dd, J = 9.8, 6.8 Hz), 3.67-3.72 (1H, m), 3.75-3.85 (6H, m), 3.89-3.97 (2H, m), 4.67 (1H, d, J = 11.7 Hz), 4.68 (1H, d, J = 11.7 Hz), 4.76 (1H, d, J = 11.7 Hz), 4.85 (1H, d, J = 11.7 Hz), 7.26-7.38 (10H, m);
MS (FAB) m / z 456: (M + H) ⁺ .
(16c) (3aR, 4R, 5S, 6S, 6aR) -5,6-dibenzyloxy-1- (2,2-dimethyl- [1,3] dioxan-5-yl) -hexahydro-cyclopenta [c] Isoxazol-4-yl 2,3,6-tri-O-benzyl-4-O- (6-deoxy-2,3,4-tri-O-benzyl-β-D-glucopyranosyl) -α-D-glucopyranoside The compound synthesized in Example 2 (2f) (600 mg, 0.692 mmol) was dissolved in methylene chloride (20 mL), trichloroacetonitrile (277 μL, 2.76 mmol) and 1,8-diazabicyclo [5.4.0]. -7-Undecene (2 drops) was added and stirred at room temperature for 40 minutes. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1, 1% triethylamine, V / V) to obtain imidate (550 mg, 80%) as a yellow oil. Obtained. The compound synthesized in Example 16 (16b) (230 mg, 0.501 mmol) was dissolved in diethyl ether (10 mL), imidate (550 mg, 0.551 mmol) was added, and trimethylsilyl trifluoromethanesulfonate (45 μL, 0.250 mmol). Was added dropwise and stirred at room temperature for 45 minutes. After adding triethylamine (4 drops) to the reaction solution, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 3: 1, V / V) to obtain the title object compound (140 mg, 20%) as a pale yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.22 (3H, d, J = 5.8 Hz), 1.43 (3H, s), 1.49 (3H, s), 2.70-2.80 (2H, m), 3.11-3.17 (1H, m), 3.19-3.27 (1H, m), 3.30-3.54 (6H, m), 3.61-3.95 (12H, m), 4.34 (1H, d, J = 11.7 Hz), 4.38 (1H, d , J = 7.3 Hz), 4.52 (1H, d, J = 12.5 Hz), 4.58-4.73 (5H, m), 4.73-4.90 (8H, m), 5.00 (1H, d, J = 3.7 Hz), 5.03 (1H, d, J = 11.0 Hz), 7.17-7.38 (38H, m), 7.43-7.47 (2H, m).
MS (FAB) m / z: 1304 (M + H) ⁺ .
(16d) (1R, 2S, 3R, 4R, 5R) -1- (2-hydroxy-1-hydroxymethyl-ethylamino) -2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O -(6-Deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside The compound synthesized in Example 16 (16c) (146 mg, 113 μmol) was dissolved in acetic acid (10 mL) and distilled water (2.5 mL). Stir at 50 ° C. for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 1: 1, V / V) to obtain diol (128 mg, 101 μmol) as colorless crystals. Diol (118 mg, 93.3 μmol) was dissolved in methanol (20 mL) and ethyl acetate (1 mL), hydrochloric acid (30 μL) and 20% palladium hydroxide-carbon (118 mg) were added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. did. After filtration through Celite, the solvent was distilled off under reduced pressure, and the residue was purified with an ion exchange resin (Dowex 50w × 8) column (water to 5% aqueous ammonia). The product was further purified by silica gel flash column chromatography (ethyl acetate: methanol: water, 1: 1: 1, V / V) to obtain the title object compound (43 mg, 84%) as a colorless solid.
¹ H NMR (400 MHz, D ₂ O): δ 1.32 (3H, d, J = 6.8 Hz), 2.34-2.41 (1H, m), 2.88-2.94 (1H, m), 3.16-3.22 (1H, m ), 3.29-3.38 (2H, m), 3.42-3.50 (1H, m), 3.49-3.97 (16H, m), 4.48 (1H, d, J = 7.8 Hz), 5.18 (1H, d, J = 7.8 Hz);
¹³ C NMR (100 MHz, D ₂ O): δ16.9, 44.0, 58.5, 58.7, 60.0, 60.1, 60.6, 61.3, 70.9, 71.3, 71.6, 72.2, 73.6, 75.0, 75.5, 79.1, 79.2, 80.5, 81.9, 97.8, 102.7;
MS (FAB) m / z: 546 (M + H) ⁺ .
<Example 17>
(1R, 2S, 3S, 4R, 5R) -1-Amino-2-fluoro-3-hydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O- (6-deoxy-β-D-glucopyranosyl)- α-D-glucopyranoside (Exemplified Compound No. 5-9)

(17a) Methyl 2-deoxy-2-fluoro-D-glucopyranoside 1,3,4,6-tetra-O-acetyl-2-deoxy-2-fluoro-β-D-glucopyranose (Carbohydr. Res., 153) , 1986, 168-170) (13.4 g, 38.3 mmol) was dissolved in methanol (150 mL), Dowex 50w × 8 (19 g) was added, and the mixture was stirred at 80 ° C. for 12 hours. The reaction solution was filtered through Celite, and the filtrate was washed with methanol. The filtrate and the washing solution were combined and distilled under reduced pressure. The residue was purified by silica gel flash column chromatography (methylene chloride: methanol, 10: 1 to 5: 1, V / V) to obtain the title object compound (3.37 g, yield 45%) as a colorless solid. .
¹ H NMR (400 MHz, CD ₃ OD): δ 3.32-3.36 (1H, m), 3.43 (1.5H, s), 3.52-3.64 (2H, m), 3.54 (1.5H, s), 3.65-3.70 (1H, m), 3.80-3.92 (2.5H, m), 4.16-4.29 (0.5H, m), 4.43 (0.5H, dd, J = 7.8, 2.9 Hz), 4.88 (0.5H, d, J = 3.9 Hz).
MS (FAB) m / z: 197 (M + H) ⁺ .
(17b) Methyl 4,6-O-benzylidene-2-deoxy-2-fluoro-D-glucopyranoside The compound synthesized in Example 17 (17a) (3.5 g, 17.9 mmol) was dissolved in dimethylformamide (70 mL). Benzaldehyde dimethyl acetal (3.75 mL, 25.0 mmol) and p-toluenesulfonic acid monohydrate (170 mg, 0.892 mmol) were added, and the mixture was stirred at 50 ° C. under reduced pressure for 2 hours. Triethylamine (2 mL) was added to the reaction solution, and the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 3: 1, V / V) to give (3.36 g, 66% yield) as a colorless solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.42-3.58 (1H, m), 3.48 (2H, s), 3.60 (1H, s), 3.70-3.90 (1.33H, m), 3.98-4.08 (0.66 H, m), 4.16-4.40 (2H, m), 4.48-4.54 (1H, m), 4.94 (0.66H, d, J = 4.4 Hz), 5.02-5.06 (0.33H, m), 5.52-5.54 ( 1H, m), 7.36-7.41 (3H, m), 7.46-7.51 (2H, m);
MS (FAB) m / z: 285 (M + H) ⁺ .
(17c) Methyl 4-O-benzoyl-3-O-benzyl-2-deoxy-2-fluoro-6-Op-toluenesulfonyl-D-glucopyranoside Compound (3.36 g) synthesized in Example 17 (17b) 11.8 mmol) was dissolved in dimethylformamide (50 mL), sodium hydride (741 mg, 17.7 mmol) was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was ice-cooled, benzyl bromide (1.68 mL, 14.1 mmol) was added, and the mixture was stirred at room temperature for 2 hr. Saturated aqueous ammonium chloride (50 mL) was added to the reaction mixture at 0 ° C., and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Distilled off. Acetic acid (16 mL) and distilled water (4 mL) were added to the residue, and the mixture was stirred at 60 ° C. for 3 hours. The reaction mixture was evaporated under reduced pressure and azeotroped with toluene. The residue was dissolved in pyridine (10 mL), p-toluenesulfonic acid chloride (1.75 g, 9.20 mmol) and 4-dimethylaminopyridine (101 mg, 0.83 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 6 hours. did. The reaction mixture was ice-cooled, diluted hydrochloric acid (2N, 80 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate (200 mL) and saturated brine (200 mL), and anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (40 mL), and 4-dimethylaminopyridine (1.28 g, 10.5 mmol), benzoyl chloride (1.30 mL, 11.2 mmol), triethylamine (1.46 mL, 10.5 mmol) under ice-cooling. ) And stirred at 0 ° C. for 3 hours. The reaction mixture is ice-cooled, diluted hydrochloric acid (2N, 80 mL) is added, and the mixture is extracted with methylene chloride (100 mL). The organic layer is washed with saturated aqueous sodium bicarbonate (200 mL) and saturated brine (100 mL), and anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 3: 1, V / V) to obtain the title object compound (4.16 g, yield 65%) as a colorless solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.35 (3 / 2H, s), 2.36 (3 / 2H, s), 3.47 (3 / 2H, s), 3.55 (3 / 2H, s), 3.79- 3.88 (1H, m), 4.01-4.15 (3H, m), 4.28-4.62 (3.5H, m), 4.77 (1H, dd, J = 11.7, 5.1 Hz), 4.91 (0.5H, d, J = 4.4 Hz), 5.05-5.12 (1H, m), 7.06-7.10 (5H, m), 7.18-7.22 (2H, m), 7.42-7.48 (2H, m), 7.58-7.65 (1H, m), 7.66- 7.71 (2H, m), 7.89-7.93 (2H, m);
MS (FAB) m / z: 545 (M + H) ⁺ .
(17d) Methyl 4-O-benzoyl-3-O-benzyl-2,6-dideoxy-2-fluoro-6-iodo-D-glucopyranoside The compound synthesized in Example 17 (17c) (3.83 g, 7. 03 mmol) was dissolved in toluene (120 mL), and sodium iodide (5.27 g, 39.2 mmol) and 18-crown-6-ether (370 mg, 1.40 mmol) were added under a nitrogen atmosphere. Stir for hours. The reaction solution was cooled to room temperature, filtered, and the residue was washed with toluene. The filtrate and washings were washed with saturated aqueous sodium hydrogen carbonate (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 5: 1, V / V) to obtain the title object compound (3.38 g, yield 96%) as a colorless solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.12-3.21 (1H, m), 3.27-3.32 (1H, m), 3.57-3.62 (1H, m), 3.58 (3 / 2H, s), 3.65 ( 3 / 2H, s), 3.82-3.91 (1H, m), 4.38-4.68 (5 / 2H, m), 4.79 (1H, dd, J = 11.7, 6.8 Hz), 4.99 (1 / 2H, dd, J = 3.9 Hz), 5.06-5.13 (1H, m), 7.07-7.18 (5H, m), 7.43-7.48 (2H, m), 7.59-7.64 (1H, m), 7.95-8.00 (2H, m);
MS (FAB) m / z: 501 (M + H) ⁺ .
(17e) 4-O-benzoyl-3-O-benzyl-2-fluoro-2,5,6-trideoxy-D-xylo-hexa-5-enose oxime Compound synthesized in Example 17 (17d) (3. 37 g, 6.74 mmol) was dissolved in isopropanol (40 mL) and distilled water (1.3 mL), zinc dust (4 g) washed with dilute hydrochloric acid was added, and the mixture was stirred at 100 ° C. for 1 hour. The reaction solution was filtered through Celite, the filtrate was washed with ethanol, and the filtrate and the washing solution were distilled off under reduced pressure. The residue was dissolved in ethanol (80 mL), hydroxylamine hydrochloride (1.18 g, 17.1 mmol) and pyridine (1.38 mL, 17.1 mmol) were added, and the mixture was stirred at 60 ° C. for 40 min. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 5: 1, V / V) to give the title object compound (1.31 g, yield 54%) as colorless. Obtained as a solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.87-3.94 (0.7H, m), 4.13-4.22 (0.3H, m), 4.64-4.82 (2H, m), 5.22 (0.7H, ddd, J = 46.9, 6.8, 4.9 Hz), 5.34-5.55 (2H, m), 5.75-5.88 (1.3H, m), 5.98-6.07 (1H, m), 7.24-7.62 (8H, m), 8.03-8.08 (2H , m);
MS (FAB) m / z: 358 (M + H) ⁺ .
(17f) (3aR, 4R, 5S, 6S, 6aR) -4-benzoyloxy-5-benzyloxy-6-fluoro-hexahydro-cyclopenta [c] isoxazole Compound synthesized in Example 17 (17e) (1.31 g 3.66 mmol) was dissolved in toluene (30 mL) and stirred at 120 ° C. for 8 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 3: 1, V / V) to give the title object compound (965 mg, yield 74%) as a colorless solid. Obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.91-2.98 (1H, m), 3.50-3.58 (1H, m), 4.00-4.10 (1H, m), 4.21-4.28 (1H, m), 4.54 ( 1H, brd, J = 7.8 Hz), 4.72 (1H, d, J = 12.7 Hz), 4.83 (1H, d, J = 12.7 Hz), 4.84 (1H, ddd, J = 52.7, 7.8, 5.8 Hz), 4.98-5.02 (1H, m), 5.11-5.15 (1H, m), 7.28-7.36 (5H, m), 7.45-7.49 (2H, m), 7.59-7.63 (1H, m), 7.97-8.00 (2H , m);
MS (FAB) m / z 358: (M + H) ⁺ .
(17g) (3aR, 4R, 5S, 6S, 6aR) -5-Benzyloxy-1-benzyloxycarbonyl-6-fluoro-4-hydroxy-hexahydro-cyclopenta [c] isoxazole Synthesized in Example 17 (17f) The compound (950 mg, 2.66 mmol) was dissolved in methanol (10 mL), sodium methoxide (270 μL, 1.30 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. Saturated aqueous ammonium chloride (50 mL) was added to the reaction mixture at 0 ° C., and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Distilled off. The residue was dissolved in ethyl acetate (100 mL), saturated aqueous sodium hydrogen carbonate (50 mL) and benzyloxychloroformate (570 μL, 4.00 mmol) were added at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hr. The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 1: 1, V / V) to obtain the title object compound (1.00 g, yield 97%) as a colorless solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.29 (1H, brd, J = 3.3 Hz, OH), 2.92-2.99 (1H, m, H-3a), 3.60 (1H, dd, J = 9.0, 5.8 Hz, H-3), 3.82-3.91 (2H, m, H-5, H-4), 3.98 (1H, d, J = 8.8 Hz, H-3), 4.61 (1H, d, J = 12.7 Hz , CH ₂ Ph), 4.62-4.70 (1H, m, H-6a), 4.72-4.76 (1 / 2H, m, H-6), 4.84 (1H, d, J = 12.7 Hz, CH ₂ Ph), 4.82-4.86 (1 / 2H, m, H-6), 5.21 (2H, s), 7.23-7.40 (10H, m);
MS (FAB) m / z: 388 (M + H) ⁺ .
(17h) (3aR, 4R, 5S, 6S, 6aR) -5-benzyloxy-1-benzyloxycarbonyl-6-fluoro-hexahydro-cyclopenta [c] isoxazol-4-yl 2,3,6-tri-O -Benzyl-4-O- (6-deoxy-2,3,4-tri-O-benzyl-β-D-glucopyranosyl) -α-D-glucopyranoside Compound synthesized in Example 2 (2f) (840 mg, 0 .969 mmol) is dissolved in methylene chloride (10 mL), trichloroacetonitrile (460 μL, 4.61 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (2 drops) are added, and 40 ml at room temperature. Stir for minutes. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1, 1% triethylamine, V / V) to obtain imidate (830 mg, 85%) as a yellow oil. Obtained. The compound (300 mg, 0.756 mmol) synthesized in Example 17 (17 g) was dissolved in diethyl ether (15 mL), imidate (830 mg, 0.832 mmol) was added, and trimethylsilyl trifluoromethanesulfonate (13 μL, 0.0756 mmol). Was added dropwise and stirred at room temperature for 45 minutes. After adding triethylamine (4 drops) to the reaction solution, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: diethyl ether, 2: 1, V / V) to obtain the title object compound (86 mg, 9%) as a pale yellow oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 1.20 (3H, d, J = 5.9 Hz), 2.87-2.94 (1H, m), 3.10-3.16 (1H, m), 3.19-3.24 (1H, m) , 3.28-3.38 (3H, m), 3.42-3.46 (1H, m), 3.51 (1H, dd, J = 9.8, 3.9 Hz), 3.55-3.59 (1H, m), 3.74 (1H, dd, J = 10.7, 3.9 Hz), 3.79-3.84 (2H, m), 3.84-3.89 (1H, m), 3.94 (1H, d, J = 9.8 Hz), 4.00-4.06 (1H, m), 4.31 (1H, d , J = 12.7 Hz), 4.35 (1H, d, J = 7.8 Hz), 4.49 (1H, d, J = 12.7 Hz), 4.58-4.88 (13H, m), 5.01 (1H, d, J = 10.8 Hz) ), 5.05 (1H, d, J = 3.9 Hz), 5.18-5.26 (2H, m), 7.15-7.43 (40H, m);
MS (FAB) m / z: 1236 (M + H) ⁺ .
(17i) (1R, 2S, 3S, 4R, 5R) -1-Amino-2-fluoro-3-hydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O- (6-deoxy-β-D- Glucopyranosyl) -α-D-glucopyranoside The compound synthesized in Example 17 (17h) (85 mg, 68.8 μmol) was dissolved in methanol (20 mL) and ethyl acetate (1 mL), hydrochloric acid (30 μL) and 20% palladium hydroxide. -Carbon (85 mg) was added, and it stirred at room temperature under hydrogen atmosphere for 4 hours. After filtration through Celite, the solvent was distilled off under reduced pressure, and the residue was purified with an ion exchange resin (Dowex 50w × 8) column (water to 5% aqueous ammonia). The product was further purified by silica gel flash column chromatography (ethyl acetate: methanol: water, 1: 1: 1, V / V) to obtain the title object compound (28 mg, 86%) as a colorless amorphous.
¹ H NMR (400 MHz, D ₂ O): δ 1.21 (3H, d, J = 5.9 Hz), 2.23-2.30 (1H, m), 3.04-3.10 (1H, m), 3.18-3.25 (2H, m ), 3.28-3.61 (6H, m), 3.64-3.80 (5H, m), 3.86-3.91 (1H, m), 4.11-4.18 (1H, m), 4.37 (1H, d, J = 8.8 Hz), 4.41-4.46 (1 / 2H, m), 4.52-4.57 (1 / 2H, m), 5.06-5.08 (1H, m);
¹³ C NMR (100 MHz, D ₂ O): δ16.9, 44.0, 58.5, 58.7, 60.0, 60.1, 60.6, 61.3, 70.9, 71.3, 71.6, 72.2, 73.6, 75.0, 75.5, 79.1, 79.2, 80.5, 81.9, 97.8, 102.7;
MS (FAB) m / z: 474 (M + H) ⁺ .
<Example 18>
(2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-3,4-dihydro-2H-pyrrol-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D- Glucopyranoside (Exemplary Compound No. 3-1)

(18a) 1,2-O-benzyl-4-deoxy-3-O-formyl-4-trifluoroacetamide-α-D-arabinoside 2-O-benzyl-4-deoxy-3-O-formyl-4- Trifluoroacetamido-D-arabinoside (Chem. Pharm. Bull., 1991, 39, 2807-2812) (0.80 g, 2.20 mmol) was dissolved in methylene chloride (50 mL) and benzyltrichloroacetimidate ( 0.82 mL, 4.40 mmol) and trifluoromethanesulfonic acid (40 μL, 0.22 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate (30 mL) was added to the reaction mixture at 0 ° C., diluted with ethyl acetate (100 mL), washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and then reduced in pressure. The lower solvent was distilled off. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 6: 1, V / V) to give the title object compound (0.73 g, yield 74%) as a pale yellow amorphous product.
¹ HNMR (CDCl ₃ ) δ: 3.55 (1H, dd, J = 12.5, 2.2 Hz), 3.63 (1H, dd, J = 10.3, 3.7 Hz), 4.13 (1H, d, J = 13.9 Hz), 4.50 ( 1H, d, J = 11.0 Hz), 4.53 (1H, d, J = 12.5 Hz), 4.61 (1H, d, J = 11.7 Hz), 4.62 (1H, br, s), 4.75 (1H, d, J = 12.5 Hz), 4.90 (1H, d, J = 2.9 Hz), 5.44 (1H, dd, J = 10.3, 4.4 Hz), 6.69 (1H, d, J = 7.33 Hz), 7.13-7.38 (10H, m ), 8.00 (1H, s);
MS (FAB) m / z: 476 (M + Na) ⁺ .
(18b) 1,2-di-O-benzyl-4-deoxy-4-trifluoroacetamide-α-D-arabinoside The compound (0.73 g, 1.61 mmol) synthesized in Example 18 (18a) was dissolved in methanol ( (30 mL) and water (5 mL), potassium hydrogen carbonate (1.00 g, 10.0 mmol) was added, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate (50 mL) was added, and the organic layer was washed with saturated brine (20 mL). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 6: 1, V / V) to obtain the title object compound (205 mg, yield 41%) as a colorless amorphous.
¹ H NMR (CDCl ₃ ) δ: 2.84 (1H, d, J = 2.2Hz), 3.44 (1H, dd, J = 9.5, 2.9 Hz), 3.76 (1H, dd, J = 12.5, 1.5 Hz), 3.92 (1H, dd, J = 12.5, 1.5 Hz), 4.20-4.28 (2H, m), 4.47 (1H, d, J = 11.7 Hz), 5.53 (2H, s), 4.72 (1H, d, J = 12.5 Hz), 4.91 (1H, d, J = 3.7 Hz), 6.67 (1H, br, d, J = 5.86 Hz), 7.12-7.38 (10H, m);
MS (FAB) m / z: 426 (M + H) ⁺ , 448 (M + Na) ⁺ .
(18c) 1,2-di-O-benzyl-4-deoxy-4-trifluoroacetamide-3-O- {2,3,6-tri-O-benzyl-4-O- (2,3,4) -Tri-O-benzyl-6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranosyl} -α-D-arabinoside The compound synthesized in Example 2 (2f) (0.70 g, 0.81 mmol) was obtained. , Methylene chloride (20 mL), trichloroacetonitrile (1.00 mL, 10.0 mmol) and 2 drops of 1,8-diazabicyclo [5.4.0] -7-undecene were added and stirred at room temperature for 30 minutes. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1, 1% triethylamine, V / V) to give a colorless oily imidate (0.75 g, 92%). Got. The compound synthesized in Example 18 (18b) (205 mg, 0.48 mmol) and imidate (0.75 g, 0.74 mmol) were dissolved in diethyl ether (30 mL), and trimethylsilyl trifluoromethanesulfonate (8.7 μL) under a nitrogen atmosphere. 0.074 mmol) was added and stirred at room temperature for 3 hours. Triethylamine (0.1 mL) was added to the reaction mixture, the solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate (30 mL), and washed with saturated aqueous sodium hydrogencarbonate (20 mL) and saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified using silica gel flash column chromatography (hexane: diethyl ether, 3: 1, V / V) to give the title object compound (185 mg 31%) and its β isomer (250 mg, 41%) as colorless amorphous.
¹ H NMR (CDCl ₃ ) δ: 1.17 (3H, d, J = 5.9 Hz), 3.12 (1H, t, J = 9.5 Hz), 3.19-3.25 (1H, m), 3.36 (1H, t, J = 9.5 Hz), 3.44-3.50 (2H, m), 3.54-3.64 (3H, m), 3.75 (1H, t, J = 9.5 Hz), 3.81-3.98 (4H, m), 4.19 (1H, dd, J = 8.8, 4.4 Hz), 4.35-4.39 (3H, m), 4.45 (1H, d, J = 11.7 Hz), 4.49-4.54 (3H, m), 4.59-4.61 (2H, m), 4.67-4.80 ( 6H, m), 4.84 (1H, d, J = 11.0 Hz), 4.90 (1H, d, J = 1.0 Hz), 4.94 (1H, d, J = 11.7 Hz), 5.02 (1H, d, J = 11.0 Hz), 5.18 (1H, d, J = 3.7 Hz), 6.88 (1H, br, d, J = 7.3 Hz), 7.10-7.40 (40H, m);
MS (FAB) m / z: 1296 (M + Na) ⁺ .
(18d) 4-Deoxy-4-trifluoroacetamide-3-O- {4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranosyl} -D-arabinoside Example 18 (18c) The compound synthesized in (1) (180 mg, 0.14 mmol) was dissolved in methanol (10 mL), 20% palladium hydroxide-carbon (120 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 3 hr. After removing the catalyst by Celite filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (ethyl acetate: methanol, 4: 1, V / V) to obtain the title object compound (69 mg, 88.5%) as a colorless solid.
¹ H NMR (D ₂ O) δ: 1.32 (3H, d, J = 5.9 Hz), 3.19 (1H, t, J = 9.5 Hz), 3.30-3.34 (2H, m), 3.46 (1H, t, J = 9.5 Hz), 3.52 (1H, br, t, J = 7.4 HZ), 3.59-3.67 (3H, m), 3.72-3.88 (3H, m), 3.97-4.07 (2H, m), 4.19-4.29 ( 1H, m), 4.48 (1H, d, J = 8.0 Hz), 4.58-4.66 (2H, m), 5.24 (1H, br, s);
MS (FAB) m / z: 576 (M + Na) ⁺ .
(18e) (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-3,4-dihydro-2H-pyrrol-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α -D-Glucopyranoside The compound synthesized in Example 18 (18d) (47 mg, 0.085 mmol) was dissolved in water (10 mL), ion exchange resin Dowex-1x4 (OH ⁻ ) (3.0 g) was added, and at room temperature. Stir for 1.5 hours. The ion exchange resin was removed and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (chloroform: methanol: water, 6: 4: 1, V / V) to obtain the title object compound (8.0 mg, yield 21.4%) as a colorless amorphous. It was.
¹ H NMR (D ₂ O) δ: 1.32 (3H, d, J = 5.9 Hz), 3.16-3.21 (1H, m), 3.31-3.33 (1H, m), 3.45-3.52 (2H, m), 3.63 -3.69 (2H, m), 3.80-3.96 (5H, m), 4.08 (1H, br, s), 4.25 (1H, d, J = 4.9 Hz), 4.49 (1H, d, J = 6.8 Hz), 4.94 (1H, d, J = 4.9 Hz), 5.17 (1H, d, J = 4.0 Hz), 7.68 (1H, br, s);
MS (FAB) m / z: 462 (M + Na) ⁺ .
<Example 19>
(2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- {4-O- (β-D-glucopyranosyl) -β-D-glucopyranosyl} -α-D- Glucopyranoside (Exemplified compound number 1-547)

(19a) (2R, 3R, 4R) -4-Benzyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-pyrrolidin-3-yl 4-O-acetyl-2,3,6-tri-O-benzyl -Α-D-glucopyranoside
4-O-acetyl-2,3,6-tri-O-benzyl-glucopyranoside (Agric. Biol. Chem, 1986, 50, 2261-2272) (2.21 g, 4.49 mmol) was added to methylene chloride (45 mL). And trichloroacetonitrile (2.3 mL, 22.44 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (65 μL, 0.44 mmol) were added, and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 2: 1, 1% triethylamine, V / V) to obtain imidate (2.06 g, 72.0%). Obtained as a yellow oil. The compound (2.00 g, 4.47 mmol) synthesized in Example 1 (1i) was dissolved in diethyl ether (100 mL), imidate (2.06 g, 3.23 mmol) was added, and trimethylsilyl trifluoromethanesulfonate (40 μL, 0.22 mmol) of diethyl ether (2 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. Triethylamine (50 μL) was added to the reaction mixture, the solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate (20 mL), and washed with saturated aqueous sodium hydrogen carbonate (20 mL) and saturated brine (10 mL). The organic layer is dried over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, and the residue containing the α, β mixture is purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1, V / V). Of these, the title compound α-form (1.93 g, 46.6%) was isolated as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ) δ 1.82 (3H, s), 3.20-5.20 (26H, m), 7.10-7.40 (30H, m);
MS (FAB) m / z: 922 (M + H) ⁺ .
(19b) (2R, 3R, 4R) -4-Benzyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-pyrrolidin-3-yl 2,3,6-tri-O-benzyl-α-D-glucopyranoside The compound (1.57 g, 1.70 mmol) synthesized in Example 19 (19a) was dissolved in methanol (30 mL), potassium carbonate (235 mg, 1.70 mmol) was added, and the mixture was stirred at room temperature for 14 hours. The mixture was diluted with ethyl acetate (10 mL), and washed with saturated aqueous sodium hydrogen carbonate (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 3: 1, V / V) to obtain the title object compound (1.41 g, 94.0%) as a colorless oily substance.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.40-5.20 (26H, m), 7.10-7.40 (30H, m);
MS (FAB) m / z: 880 (M + H) ⁺ .
(19c) Allyl 2,3,6-O-tri-benzoyl-4-O- (2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl) -D-glucopyranoside Example 2 (2a ) (4.0 g, 10.46 mmol) was dissolved in pyridine (30 mL), benzoyl chloride (12.1 mL, 104.24 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into 10% aqueous hydrochloric acid (20 mL) and methyl chloride (20 mL), and the organic layer was washed with 10% aqueous hydrochloric acid (20 mL), saturated aqueous sodium bicarbonate (20 mL) and saturated brine (20 mL). After drying with sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 5: 1-5: 2, V / V) to give the title object compound (8.10 g, yield 70%) as a colorless oil. It was.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.71-4.27 (6H, m), 4.44-4.51 (1H, m), 4.58-4.63 (1H, m), 4.72 (1H, d, J = 6.4Hz) , 4.93-5.81 (10H, m), 7.17-8.11 (35H, m);
MS (FAB) m / z: 1111 (M + H) ⁺ .
(19d) 2,3,6-O-tri-benzoyl-4-O- (2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl) -D-glucopyranoside Example 19 (19c) The compound synthesized in (8.10 g, 7.29 mmol) was dissolved in methanol (75 mL) and tetrahydrofuran (15 mL), palladium (II) chloride (258 mg, 1.45 mmol) was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 3: 1 to 2: 1, V / V) to give the title object compound (5.10 g, yield 66%) as a pale yellow solid. It was.
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.96-3.13 (1H, m), 3.79-3.92 (2H, m), 4.05-4.25 (2H, m), 4.33-4.40 (1H, m), 4.47- 4.50 (1H, m), 4.60-4.63 (1H, m), 4.89-6.15 (7H, m), 7.21-8.01 (35H, m);
MS (FAB) m / z: 1071 (M + H) ⁺ .
(19e) (2R, 3R, 4R) -4-Benzyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-pyrrolidin-3-yl 2,3,6-tri-O-benzyl-4-O- { 2,3,6-tri-O-benzoyl-4-O- (2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl) -β-D-glucopyranosyl} -α-D-glucopyranoside The compound synthesized in Example 19 (19d) (414.4 mg, 0.39 mmol) was dissolved in methylene chloride (8 mL), trichloroacetonitrile (200 μL, 1.99 mmol) and 1,8-diazabicyclo [5.4.0]. ] -7-undecene (6 μL, 0.04 mmol) was added and stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 2: 1, 1% triethylamine, V / V) to obtain imidate (255.1 mg, 53.8%). Obtained as a colorless amorphous. The compound synthesized in Example 19 (19b) (185.3 mg, 0.21 mmol) was dissolved in diethyl ether (8 mL), imidate (225.1 mg, 0.21 mmol) was added, and trimethylsilyl trifluoromethanesulfonate (38 μL, 0.21 mmol) in diethyl ether (2 mL) was added dropwise and stirred at room temperature for 2 hours. Triethylamine (35 μL) was added to the reaction solution, the solvent was distilled off under reduced pressure, diluted with ethyl acetate (10 mL), and washed with saturated aqueous sodium hydrogen carbonate (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 4: 1 to 3: 1, V / V) to isolate the title object compound (295.8 mg, 72.9%) as a colorless amorphous substance. did.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.20-5.60 (40H, m), 7.10-7.40 (65H, m);
MS (FAB) m / z: 1932 (M + H) ⁺ .
(19f) (2R, 3R, 4R) -4-benzyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-pyrrolidin-3-yl 2,3,6-tri-O-benzyl-4-O- { 4-O- (β-D-glucopyranosyl) -β-D-glucopyranosyl} -α-D-glucopyranoside The compound synthesized in Example 19 (19e) (295.8 mg, 0.15 mmol) was dissolved in methanol (6 mL). Potassium carbonate (20 mg, 0.14 mmol) was added and stirred at room temperature for 6 hours. The mixture was diluted with ethyl acetate (10 mL), and washed with saturated aqueous sodium hydrogen carbonate (10 mL) and saturated brine (10 mL). The mixture was neutralized with methanol-hydrochloric acid, and the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (methylene chloride: methanol, 30: 1 to 20: 1 to 10: 1, V / V) to give the title object compound (100.7 mg, 55.8%) colorless. Obtained as a solid.
¹ H NMR (400 MHz, CD ₃ OD): δ 3.20-5.60 (40H, m), 7.10-7.40 (30H, m);
MS (FAB) m / z: 1204 (M + H) ⁺ .
(19 g) (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- {4-O- (β-D-glycopyranosyl) -β-D-glucopyranosyl} -α -D-Glucopyranoside The compound synthesized in Example 19 (19f) (100.7 mg, 0.084 mmol) was dissolved in methanol (10 mL), 36% hydrochloric acid (280 μL) and palladium hydroxide (100 mg) were added, and hydrogen atmosphere was added. Under stirring at room temperature for 4 hours. After filtration through Celite, 18% aqueous ammonia (1 mL) was added, the solvent was distilled off under reduced pressure, and the residue was purified with an ion exchange resin (Dowex 50w × 8) column (water to 1% aqueous ammonia). Further, the product was purified using silica gel flash column chromatography (ethyl acetate: methanol: water, 5: 2: 1 to 1: 1: 1, V / V) to give the title object compound (10.0 mg, 19.2%). Was obtained as a colorless solid.
¹ H NMR (400 MHz, D ₂ O): δ 3.00-3.95 (25H, m), 4.38 (1H, d, J = 8.1 Hz), 4.42 (1H, d, J = 8.0 Hz), 5.00 (1H, d, J = 2.6 Hz);
MS (FAB) m / z: 620 (M + H) ⁺ .

<Example 20>
(2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- {4-O- (β-D-glucopyranosyl) -β-D-glucopyranosyl} -α-D- Galactopyranoside (Exemplified Compound No. 1-547)

(20a) (2R, 3R, 4R) -4-benzyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-pyrrolidin-3-yl 4-O-acetyl-2,3,6-tri-O-benzyl -Α-D-galactopyranoside 4-O-acetyl-2,3,6-O-tri-benzyl-D-galactopyranoside (BCSJ, 1989, 62, 3549-3666) (1.60 g, 3 .25 mmol) in methylene chloride (30 mL) and trichloroacetonitrile (1.6 mL, 15.96 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (50 μL, 0.33 mmol). The mixture was further stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 6: 1, 1% triethylamine, V / V) to obtain imidate (1.37 g, 66%) as a yellow oil. Obtained as a thing. The compound synthesized in Example 1 (1i) (0.96 g, 2.01 mmol) was dissolved in diethyl ether (50 mL), imidate (1.37 g, 2.15 mmol) was added, and trimethylsilyl trifluoromethanesulfonate (20 μL, 0.11 mmol) in diethyl ether (2 mL) was added dropwise and stirred at room temperature for 2 hours. Triethylamine (10 μL) was added to the reaction solution, the solvent was distilled off under reduced pressure, diluted with ethyl acetate (20 mL), and washed with saturated aqueous sodium hydrogen carbonate (20 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue containing the α, β mixture was subjected to silica gel flash column chromatography (hexane: ethyl acetate, 6: 1-4: 1, V / V). The title compound α-form (0.98 g, 50%) was isolated as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ2.02 (3H, s), 5.15-3.38 (25H, m), 5.61 (1H, m), 7.16-7.35 (30H, m);
MS (FAB) m / z: 922 (M + H) ⁺ .
(20b) (2R, 3R, 4R) -4-Benzyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-pyrrolidin-3-yl 2,3,6-tri-O-benzyl-α-D-galacto Pyranoside The compound synthesized in Example 20 (20a) (0.98 g, 1.06 mmol) was dissolved in methanol (20 mL), potassium carbonate (147 mg, 1.06 mmol) was added, and the mixture was stirred at room temperature for 14 hours. The mixture was diluted with ethyl acetate (10 mL), and washed with saturated aqueous sodium hydrogen carbonate (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 4: 1, V / V) to give the title object compound (772.4 mg, 83%) as a colorless oil.
¹ H NMR (400 MHz, CDCl ₃ ): δ 2.70-2.81 (1H, m), 3.46-5.15 (26H, m), 7.15-7.37 (30H, m);
MS (FAB) m / z: 880 (M + H) ⁺ .
(20c) (2R, 3R, 4R) -4-benzyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-pyrrolidin-3-yl 2,3,6-tri-O-benzyl-4-O- { 2,3,6-tri-O-benzoyl-4-O- (2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl) -β-D-glucopyranosyl} -α-D-galacto Pyranoside The compound synthesized in Example 19 (19d) (516.8 mg, 0.48 mmol) was dissolved in methylene chloride (10 mL), and trichloroacetonitrile (240 μL, 2.39 mmol) and 1,8-diazabicyclo [5. 4.0] -7-undecene (7.5 μL, 0.05 mmol) was added and stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 4: 1, 1% triethylamine, V / V) to obtain imidate (376.9 mg, 65%) as a colorless amorphous product. Got as. The compound synthesized in Example 20 (20b) (270.0 mg, 0.31 mmol) was dissolved in diethyl ether (15 mL), imidate (376.9 mg, 0.31 mmol) was added, and trimethylsilyl trifluoromethanesulfonate (56 μL, 0.31 mmol) in diethyl ether (2 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. Triethylamine (50 μL) was added to the reaction mixture, the solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate (20 mL), and washed with saturated aqueous sodium hydrogen carbonate (20 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 4: 1 to 3: 1, V / V) to isolate the title object compound (390.8 mg, 65%) as a colorless amorphous.
¹ H NMR (400 MHz, CDCl ₃ ): δ 3.20-5.70 (40H, m), 7.10-7.40 (65H, m);
MS (FAB) m / z: 1932 (M + H) ⁺ .
(20d) (2R, 3R, 4R) -4-benzyloxy-N-benzyloxycarbonyl-2-benzyloxymethyl-pyrrolidin-3-yl 2,3,6-tri-O-benzyl-4-O- { 4-O- (β-D-glucopyranosyl) -β-D-glucopyranosyl} -α-D-galactopyranoside Compound (390.8 mg, 0.20 mmol) synthesized in Example 20 (20c) was dissolved in methanol (8 mL). ), Potassium carbonate (27.6 mg, 0.20 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The mixture was diluted with ethyl acetate (10 mL), and washed with saturated aqueous sodium hydrogen carbonate (10 mL) and saturated brine (10 mL). The mixture was neutralized with methanol-hydrochloric acid, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (methylene chloride: methanol, 30: 1 to 20: 1 to 10: 1, V / V) to give the title object compound (146.5 mg, 61%) as a colorless solid Obtained.
¹ H NMR (400 MHz, CD ₃ OD): δ1.13 3.20-4.70 (37H, m), 4.97 (1H, d, J = 3.6 Hz), 5.07 (2H, s), 7.23-7.39 (30H, m );
MS (FAB) m / z: 1226 (M + Na) ⁺ .
(20e) (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- {4-O- (β-D-glycopyranosyl) -β-D-glucopyranosyl} -α -D-galactopyranoside The compound (146.5 mg, 0.12 mmol) synthesized in Example 20 (20d) was dissolved in methanol (15 mL), and 36% hydrochloric acid (420 μL) and palladium hydroxide (150 mg) were added. The mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. After filtration through Celite, 18% aqueous ammonia (1 mL) was added, the solvent was distilled off under reduced pressure, and the residue was purified with an ion exchange resin (Dowex 50w × 8) column (water to 1% aqueous ammonia). Further purification was performed using silica gel flash column chromatography (ethyl acetate: methanol: water, 5: 2: 1 to 1: 1: 1, V / V) to give the title target compound acetate (23.6 mg, 32%). ) Was obtained as a colorless solid.
¹ H NMR (400 MHz, D ₂ O): δ 3.17-3.87 (22H, m), 4.01 (1H, s), 4.11 (1H, s), 4.36 (1H, m), 4.38 (1H, d, J = 8.0 Hz), 4.56 (1H, d, J = 8.0 Hz), 5.04 (1H, s);
MS (FAB) m / z: 620 (M + H) ⁺ .
<Test Example 1>
α-Amylase Inhibitory Action (1) Preparation of Human α-Amylase Solution “Caribzyme AMY” (manufactured by Kokusai Reagent Co., Ltd.) was used as a human pancreatic α-amylase (HPA). Distilled water was added to commercially available HPA and dissolved to a concentration of 200 IU / l to obtain an α-amylase solution. The activity of α-amylase was measured using a commercially available α-amylase measuring reagent “Neo-amylase test first” (Daiichi Chemical Co., Ltd.).
(2) Preparation of inhibitor solution Each test compound was prepared with distilled water so that the final concentration was 0.1 to 30 μg / ml.
(3) Measurement of human α-amylase inhibitory activity of the inhibitor
Distilled water 3.78 to 3.9 ml and inhibitor solution 0 to 120 μl were added to 100 μl of HPA solution to adjust the total volume to 4 ml. After incubating at 37 ° C. for 10 minutes, 1 tablet of Blue Starch (Neo-Amylase Test Id, manufactured by Daiichi Chemicals Co., Ltd.) was added, stirred for about 10 seconds with a mixer, and then heated at 37 ° C. for 30 minutes. Thereafter, 1.0 ml of 0.5N aqueous sodium hydroxide solution was added and stirred to stop the reaction, centrifugation (1,500 G, 5 minutes) was performed, and the absorbance of the supernatant was measured at 620 nm. The control was added with no inhibitor. In addition, distilled water was added to the blank instead of the α-amylase solution. The inhibition rate was calculated by the following formula, and the final concentration (μg / ml) of the test compound required to inhibit the activity of the HPA solution by 50% is shown in Table 46 as IC ₅₀ value.

(Table 46)
From Table 46, it was found that the compound of the present invention has an excellent α-amylase inhibitory action.

<Test Example 2>
Postprandial hyperglycemia inhibitory action (1) Animals used Commercially available normal mice (ddY mice, male, 8 weeks old when used, sold by Japan SLC Co., Ltd.)
(2) Experimental method / results In the administration group, 5 mice fasted for 20 hours in advance were mixed well with 0.5% carboxymethyl cellulose and the test compound and commercially available corn starch were mixed to give 0.3 mg (the amount of test compound) ) / 2 g (corn starch amount) / 1 kg (body weight). The control group was the same as described above except that the test compound was not mixed.

  Blood glucose was collected from the tail vein of mice before and at 0.5, 1, 2, and 3 hours after administration, and blood glucose level was measured. AUC of blood glucose elevation (area under the curve of blood glucose elevation value transition, mg / dl × hr) Thus, the inhibition rate (%) was calculated from the following formula. The blood glucose level was measured using a simple blood glucose meter (Glucoloader GXT, manufactured by A & T Corp.).

(Table 47)
From Table 47, it was found that the compound of the present invention has an excellent inhibitory effect on blood sugar elevation. Therefore, it is considered that the compound of the present invention is useful as a therapeutic agent for postprandial hyperglycemia.

<Test Example 3>
Hypoglycemic action (1) Animal used Commercially inherited obese diabetic mouse (C57BL / KsJ-db / db mouse, male, 16 weeks old when used, sold by CLEA Japan)
(2) Experimental methods / results Using a mouse with diabetes, purified feed (carbohydrate content: 65.95% w / w, Oriental Yeast Co., Ltd.) so that the test compound has a concentration of 0.005% (w / w) Each group was allowed to freely ingest a group of 5 mice for 1 week. The control group was the same as described above except that the test compound was not mixed.

  The blood glucose level was measured before the start of administration and one week after the start of administration. Blood was collected from the tail vein of the mouse, and the blood glucose level was measured using a simple blood glucose meter (Glucoloader GXT, manufactured by A & T Corp.), and the blood glucose lowering rate (%) was calculated from the following formula.

(Table 48)
From Table 48, it was found that the compound of the present invention has an excellent hypoglycemic effect. Therefore, it is considered that the compound of the present invention is useful as a therapeutic agent for diabetes.

<Formulation example>
(1) Capsule Compound of Example 1 10 mg
Lactose 110 mg
Corn starch 58 mg
Magnesium stearate 2 mg
180 mg total
Mix the powder of each component shown above well and pass through a 60 mesh sieve (mesh standard is Tyler standard). 180 mg of the resulting powder is weighed out and filled into gelatin capsules (No. 3) to prepare capsules.
(2) Tablet 10 mg of the compound of Example 1
Lactose 85 mg
Corn starch 34 mg
Microcrystalline cellulose 20 mg
Magnesium stearate 1 mg
150 mg total
The powder of each component shown above is mixed well and compressed into tablets each weighing 150 mg. If necessary, these tablets may be coated with sugar or film.
(3) Granules Compound of Example 1 10 mg
Lactose 839 mg
Corn starch 150 mg
Hydroxypropylcellulose 1 mg
1000 mg total
The powder of each component shown above is mixed well, moistened with pure water, granulated with a basket type granulator, and dried to obtain granules.

Claims (16)

The following general formula (I)

[Wherein A represents the following general formula (A1), (A2) or (A3)

R ¹ and R ² are the same or different and each represents a C 1-6 alkyl group, a hydroxymethyl group, a C 1-6 alkoxymethyl group or a C 1-6 haloalkyl group, and R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 hydroxyalkyl group, a C1-6 haloalkyl group, an amino group (the amino group is a C1-6 alkyl group or a C1-6 hydroxy group). 1 or 2 may be substituted with an alkyl group), a hydroxyl group, a hydrogen atom or a halogen atom, R ⁷ is a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 hydroxyalkyl group, C1-6 A haloalkyl group, a hydroxyl group or a hydrogen atom; n represents an integer of 1 or 2; Or a pharmacologically acceptable salt or ester thereof.
However, the compound represented by the general formula (I) is (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O-β-D-glucopyranosyl-α-D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy -2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-fluoro-6-deoxy-β-D-glucopyranosyl) -D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy-2-hydroxy Methyl-pyrrolidin-3-yl 4-O- (6-methoxy-6-deoxy-β-D-glucopyranosyl) -D-glucopyranoside,
(2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranoside, (2R, 3R, 4R ) -4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside
(1R, 2S, 3R, 4R, 5R) -1-Amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α- D-glucopyranoside, (1R, 2S, 3R, 4R, 5R) -1-amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O- (6-deoxy-β-D-glucopyranosyl ) -α-D-glucopyranoside and (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-3,4-dihydro-2H-pyrrol-3-yl 4-O- (6-deoxy-α-D A compound selected from -glucopyranosyl) -α-D-glucopyranoside,
The ester includes a C1-6 alkyl group (the alkyl group may be substituted with a trialkylsilyl group), a C7-16 aralkyl group, a C1-5 alkyl group substituted with C1-6 alkanoyloxy, C1- C1-5 alkyl group substituted by 6 alkyloxycarbonyloxy, C1-5 alkyl group substituted by C5-7 cycloalkyloxycarbonyloxy, C1-5 alkyl group substituted by C6-10 aryloxycarbonyloxy, and 5-position Represents an ester selected from 2-oxo-1,3-dioxolen-4-yl groups having C1-6 alkyl as a substituent. (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranoside, (2R, 3R, 4R ) -4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy- 2-Hydroxymethyl-pyrrolidin-3-yl 4-O-β-D-glucopyranosyl-α-D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4- O- (6-Fluoro-6-deoxy-β-D-glucopyranosyl) -D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6 -Methoxy-6-deoxy-β-D-glucopyranosyl) -D-glucopyranoside or a pharmacologically acceptable salt or ester thereof.
However, the ester is a C1-6 alkyl group (the alkyl group may be substituted with a trialkylsilyl group), a C7-16 aralkyl group, a C1-5 alkyl group substituted with C1-6 alkanoyloxy, C1-5 alkyl group substituted by C1-6 alkyloxycarbonyloxy, C1-5 alkyl group substituted by C5-7 cycloalkyloxycarbonyloxy, C1-5 alkyl group substituted by C6-10 aryloxycarbonyloxy, and An ester selected from 2-oxo-1,3-dioxolen-4-yl groups having C1-6 alkyl as a substituent at the 5-position is shown. (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranoside, (2R, 3R, 4R ) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside or a pharmacologically acceptable salt or ester thereof Pharmaceutical composition.
However, the ester is a C1-6 alkyl group (the alkyl group may be substituted with a trialkylsilyl group), a C7-16 aralkyl group, a C1-5 alkyl group substituted with C1-6 alkanoyloxy, C1-5 alkyl group substituted by C1-6 alkyloxycarbonyloxy, C1-5 alkyl group substituted by C5-7 cycloalkyloxycarbonyloxy, C1-5 alkyl group substituted by C6-10 aryloxycarbonyloxy, and An ester selected from 2-oxo-1,3-dioxolen-4-yl groups having C1-6 alkyl as a substituent at the 5-position is shown.   A pharmaceutical composition comprising (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranoside.   A pharmaceutical composition comprising (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside. (1R, 2S, 3R, 4R, 5R) -1-Amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α- D-glucopyranoside, (1R, 2S, 3R, 4R, 5R) -1-amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O- (6-deoxy-β-D-glucopyranosyl ) -α-D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-3,4-dihydro-2H-pyrrol-3-yl 4-O- (6-deoxy-α-D -Glucopyranosyl) -α-D-glucopyranoside or a pharmacologically acceptable salt or ester thereof.
However, the ester is a C1-6 alkyl group (the alkyl group may be substituted with a trialkylsilyl group), a C7-16 aralkyl group, a C1-5 alkyl group substituted with C1-6 alkanoyloxy, C1-5 alkyl group substituted by C1-6 alkyloxycarbonyloxy, C1-5 alkyl group substituted by C5-7 cycloalkyloxycarbonyloxy, C1-5 alkyl group substituted by C6-10 aryloxycarbonyloxy, and An ester selected from 2-oxo-1,3-dioxolen-4-yl groups having C1-6 alkyl as a substituent at the 5-position is shown. Prevention or treatment of postprandial hyperglycemia, hyperglycemia, glucose intolerance, diabetes, obesity, diabetic complications, hyperlipidemia, fatty liver, liver hypertrophy, neuropathy, arteriosclerosis, cataract or diabetic nephropathy 7. A pharmaceutical composition according to any one of claims 1 to 6 for use. ,
However, the above hyperlipidemia, fatty liver, liver hypertrophy, neuropathy, arteriosclerosis and cataract are hyperlipidemia, fatty liver, liver hypertrophy, neuropathy, arteriosclerosis caused by postprandial hyperglycemia or diabetes And show cataract. The pharmaceutical composition according to any one of claims 1 to 6 , for the prevention or treatment of postprandial hyperglycemia, diabetic complications or obesity.
However, the diabetic complications indicate diabetic complications resulting from postprandial hyperglycemia or diabetes. It is a postprandial hyperglycemia prophylactic or therapeutic agents, pharmaceutical composition according to any one of claims 1 to 6. The pharmaceutical composition according to any one of claims 1 to 6 , for the prevention or treatment of diabetes. The following general formula (I)

[Wherein A represents the following general formula (A1), (A2) or (A3)

R ¹ and R ² are the same or different and each represents a C 1-6 alkyl group, a hydroxymethyl group, a C 1-6 alkoxymethyl group or a C 1-6 haloalkyl group, and R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 hydroxyalkyl group, a C1-6 haloalkyl group, an amino group (the amino group is a C1-6 alkyl group or a C1-6 hydroxy group). 1 or 2 may be substituted with an alkyl group), a hydroxyl group, a hydrogen atom or a halogen atom, R ⁷ is a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 hydroxyalkyl group, C1-6 A haloalkyl group, a hydroxyl group or a hydrogen atom; n represents an integer of 1 or 2; ] The alpha-amylase inhibitor containing the compound represented by these, or its pharmacologically acceptable salt or ester.
However, the compound represented by the general formula (I) is (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O-β-D-glucopyranosyl-α-D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy -2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-fluoro-6-deoxy-β-D-glucopyranosyl) -D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy-2-hydroxy Methyl-pyrrolidin-3-yl 4-O- (6-methoxy-6-deoxy-β-D-glucopyranosyl) -D-glucopyranoside,
(2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranoside, (2R, 3R, 4R ) -4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside
(1R, 2S, 3R, 4R, 5R) -1-Amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α- D-glucopyranoside, (1R, 2S, 3R, 4R, 5R) -1-amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O- (6-deoxy-β-D-glucopyranosyl ) -α-D-glucopyranoside and (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-3,4-dihydro-2H-pyrrol-3-yl 4-O- (6-deoxy-α-D A compound selected from -glucopyranosyl) -α-D-glucopyranoside,
The ester includes a C1-6 alkyl group (the alkyl group may be substituted with a trialkylsilyl group), a C7-16 aralkyl group, a C1-5 alkyl group substituted with C1-6 alkanoyloxy, C1- C1-5 alkyl group substituted by 6 alkyloxycarbonyloxy, C1-5 alkyl group substituted by C5-7 cycloalkyloxycarbonyloxy, C1-5 alkyl group substituted by C6-10 aryloxycarbonyloxy, and 5-position Represents an ester selected from 2-oxo-1,3-dioxolen-4-yl groups having C1-6 alkyl as a substituent. The following general formula (I)

[Wherein A represents the following general formula (A1), (A2) or (A3)

R ¹ and R ² are the same or different and each represents a C 1-6 alkyl group, a hydroxymethyl group, a C 1-6 alkoxymethyl group or a C 1-6 haloalkyl group, and R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 hydroxyalkyl group, a C1-6 haloalkyl group, an amino group (the amino group is a C1-6 alkyl group or a C1-6 hydroxy group). 1 or 2 may be substituted with an alkyl group), a hydroxyl group, a hydrogen atom or a halogen atom, R ⁷ is a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 hydroxyalkyl group, C1-6 A haloalkyl group, a hydroxyl group or a hydrogen atom; n represents an integer of 1 or 2; ] Or a pharmacologically acceptable salt or ester thereof.
However, the compound represented by the general formula (I) is (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O-β-D-glucopyranosyl-α-D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy -2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-fluoro-6-deoxy-β-D-glucopyranosyl) -D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy-2-hydroxy Methyl-pyrrolidin-3-yl 4-O- (6-methoxy-6-deoxy-β-D-glucopyranosyl) -D-glucopyranoside,
(2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranoside, (2R, 3R, 4R ) -4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside
(1R, 2S, 3R, 4R, 5R) -1-Amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α- D-glucopyranoside, (1R, 2S, 3R, 4R, 5R) -1-amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O- (6-deoxy-β-D-glucopyranosyl ) -α-D-glucopyranoside and (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-3,4-dihydro-2H-pyrrol-3-yl 4-O- (6-deoxy-α-D A compound selected from -glucopyranosyl) -α-D-glucopyranoside,
The ester includes a C1-6 alkyl group (the alkyl group may be substituted with a trialkylsilyl group), a C7-16 aralkyl group, a C1-5 alkyl group substituted with C1-6 alkanoyloxy, C1- C1-5 alkyl group substituted by 6 alkyloxycarbonyloxy, C1-5 alkyl group substituted by C5-7 cycloalkyloxycarbonyloxy, C1-5 alkyl group substituted by C6-10 aryloxycarbonyloxy, and 5-position Represents an ester selected from 2-oxo-1,3-dioxolen-4-yl groups having C1-6 alkyl as a substituent. The following general formula (I) for producing the pharmaceutical composition according to claim 1

[Wherein A represents the following general formula (A1), (A2) or (A3)

R ¹ and R ² are the same or different and each represents a C 1-6 alkyl group, a hydroxymethyl group, a C 1-6 alkoxymethyl group or a C 1-6 haloalkyl group, and R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 hydroxyalkyl group, a C1-6 haloalkyl group, an amino group (the amino group is a C1-6 alkyl group or a C1-6 hydroxy group). 1 or 2 may be substituted with an alkyl group), a hydroxyl group, a hydrogen atom or a halogen atom, R ⁷ is a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 hydroxyalkyl group, C1-6 A haloalkyl group, a hydroxyl group or a hydrogen atom; n represents an integer of 1 or 2; Or a pharmacologically acceptable salt or ester thereof.
However, the compound represented by the general formula (I) is (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O-β-D-glucopyranosyl-α-D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy -2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-fluoro-6-deoxy-β-D-glucopyranosyl) -D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy-2-hydroxy Methyl-pyrrolidin-3-yl 4-O- (6-methoxy-6-deoxy-β-D-glucopyranosyl) -D-glucopyranoside,
(2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranoside, (2R, 3R, 4R ) -4-Hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside
(1R, 2S, 3R, 4R, 5R) -1-Amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α- D-glucopyranoside, (1R, 2S, 3R, 4R, 5R) -1-amino-2,3-dihydroxy-5-hydroxymethyl-cyclopent-4-yl 4-O- (6-deoxy-β-D-glucopyranosyl ) -α-D-glucopyranoside and (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-3,4-dihydro-2H-pyrrol-3-yl 4-O- (6-deoxy-α-D A compound selected from -glucopyranosyl) -α-D-glucopyranoside,
The ester includes a C1-6 alkyl group (the alkyl group may be substituted with a trialkylsilyl group), a C7-16 aralkyl group, a C1-5 alkyl group substituted with C1-6 alkanoyloxy, C1- C1-5 alkyl group substituted by 6 alkyloxycarbonyloxy, C1-5 alkyl group substituted by C5-7 cycloalkyloxycarbonyloxy, C1-5 alkyl group substituted by C6-10 aryloxycarbonyloxy, and 5-position Represents an ester selected from 2-oxo-1,3-dioxolen-4-yl groups having C1-6 alkyl as a substituent. (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-α-D-) for the manufacture of a pharmaceutical composition according to claim 4. Use of glucopyranosyl) -α-D-glucopyranoside. (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-β-D-) for the manufacture of a pharmaceutical composition according to claim 5. Use of glucopyranosyl) -α-D-glucopyranoside. Use according to claims 13 to 15 , wherein the pharmaceutical composition is a pharmaceutical composition for the prevention or treatment of diabetes.