WO2007013592A1

WO2007013592A1 - Novel method for synthesis of intermediate in synthesis of carbapenem using sugar template

Info

Publication number: WO2007013592A1
Application number: PCT/JP2006/314992
Authority: WO
Inventors: Kinichi Tadano; Kenichi Takao; Masayuki Okue; Shinjiro Sumi; Keiichi Ajito
Original assignee: Meiji Seika Kaisha, Ltd.
Priority date: 2005-07-29
Filing date: 2006-07-28
Publication date: 2007-02-01
Also published as: JPWO2007013592A1; JP5143556B2

Abstract

Disclosed is a method for producing an intermediate in the synthesis of a useful carbapenem anti-bacterial agent with good efficiency, more specifically the method described above which enables the introduction of a methyl group into position 1 of the carbapenem skeleton in a highly stereoselective manner and does not need the use of any expensive asymmetric auxiliary group, any catalyst that may cause an ultra-low temperature reaction or have any toxicity to a human body or the like and can recover the auxiliary group. In this method, a sugar template containing a propionate unit represented by the formula (II) is reacted with an acetoxyazetidinone represented by the formula (III) to form a carbon-carbon bond between them, thereby introducing a methyl group into position 1 of the carbapenem skeleton in the desired β-stereoselective manner.

Description

Specification

A novel method for synthesizing power rubapenem synthesis intermediates using sugar templates

[0001] Technical field

The present invention relates to a novel synthesis method of an intermediate j8-methylcarboxylic acid for synthesizing a powerful rubapenem antibacterial agent and a novel synthetic intermediate. More specifically, starting with acetoxazetidinone, the propionic acid unit introduced into the sugar template is reacted with this, and the propionic acid unit bound to the sugar template is stereoselectively bound. The present invention relates to a method for synthesizing β-methylcarboxylic acid via a compound and a synthesis intermediate via this method.

[0002] Putujutsu

Strong rubapenem antibacterial agents have strong antibacterial activity and high safety, and are classified as clinically useful injection antibacterial agents. However, the strength of rubapenem antibacterial agents has been approved for use in children with fewer side effects compared to quinolone antibacterial agents, which are mainly used orally in Japan. Furthermore, in Japan, as the first attempt in the world, clinical development of oral force rubapenem that is highly effective against Streptococcus pneumoniae and Haemophilus influenzae including resistant bacteria is being promoted.

[0003] However, unlike other 13-ratata antibiotics, rurubenem antibacterial agents depend on chemical synthesis for major manufacturing processes. In addition, the production cost is slightly higher than antibiotics produced by chemical modification. Therefore, various methods for efficiently producing useful carbapenem antibacterial agents themselves or important synthetic intermediates for producing them have been studied.

[0004] 1976 Carbapenem antibiotic chemamycin, the first natural force discovered in the world by Merck, Imipenem, Panipe, a powerful rubapenem antibacterial agent introduced early in the factory The structure of the nem is the force in which the first position of the force rubapenem skeleton is unsubstituted. Subsequently, the injection force rubapenem antibacterial agent, meropenem, biapenem, and The first position of ertapenem has a j8-methyl structure in which the methyl group is substituted on the front side of the page. If they have the same 2-side chain structure, the 1-position is generally not substituted. In vitro antibacterial activity is stronger in compounds that have a structure, and compounds that have a β-methyl structure have better chemical and biological stability. There are many. Therefore, in general, the evaluation of a powerful rubapenem antibacterial agent having a 1 β-methyl structure is gradually becoming established today.

[0005] One of the important keys to constructing a 1β-methylcarbapenem skeleton by synthetic chemistry is to control the stereochemistry of the 1-position methyl group. One of the known forces in controlling the stereochemistry of the 1-position methyl group is j8-methylcarboxylic acid represented by the following formula (IV).

[Chemical 1]

[0006] In this compound of formula (IV), the stereochemistry of the methyl group corresponding to the 1-position substituent of rububapenem has already been determined, and more useful synthetic intermediates from this compound It can be chemically induced. Specifically, by chemical induction from the compound of formula (IV) to the following enol phosphatate ZMAP (V), a biene penem in which a substituent is introduced via a sulfur atom at the 2-position of force rubapenem. It is possible to produce various useful compounds represented.

[Chemical 2]

(V)

[0007] In addition, as described in WO2004 / 055027, it is also possible to produce a useful force rubapenem antibacterial agent from the compound of formula (IV) via another intermediate.

[0008] In the synthesis of β-methylcarboxylic acid represented by the formula (IV), a number of methods using acetoxazetidinone represented by the formula (III) have been reported.

[0009] First, as described in Heterocycles, 21, 29, 1984, BG Christensen et al. Used a method of introducing a reverse methyl group into an acetate unit previously introduced into azetidinone in the synthesis of β-methyl carboxylic acid. I got it. The force of introducing methyl group in 75% yield by reacting 2 equivalents of LDA in THF at -78 ° C in the presence of 1 equivalent of soot at -78 ° C and then reacting with excess methyl iodide. 1: 4 oc body was dominant.

[0010] In addition, CU Kim et al., As described in Tetrahedron Lett., 28, 507, 1987, started from acetoxazetidinone to -70 ° C in the presence of a catalytic amount of trimethylsilyltrifluoromethanesulfonate in methylene chloride. LDA-Zr (Cp) C1 acts to generate enolate

twenty two

Then, they found an aldol condensation type reaction in which a propionic acid allylthioester or aralkylthioester was reacted. By this method, when a phenolthio group was used as the thioester, 13-methylcarboxylic acid thioester was obtained in a yield of 52%, and a selectivity of | 8 of 97: 3 was achieved. However, problems such as low-temperature reaction and expensive reagents for enolate generation remained.

[0011] Nagao et al., As described in J. Org. Chem., 57, 4243, 1992, used the chelated transition state of a 6-membered ring to make a stereoselective introduction of a methyl group. Successful. That is, in the presence of tin ¹¹ -trifluoromethanesulfonate, N-ethylpiberidine and asymmetric thiazolidinethione were added at -40 to -50 ° C in THF, and acetoxazetidinone was calorie added to the obtained tin enolate. As a result, the target product was obtained in a yield of 74%, and a / 3 selectivity of 91: 9 was achieved. This method has problems such as the use of a tin reagent, and the use of thiazolidinethione, which is an expensive asymmetric auxiliary group (in this case, a diastereoauxiliary group), and high stereoselectivity cannot be obtained. US Pat. No. 6,858,727 also reports a method for introducing a propionic acid unit into acetoxazetidinone by a Reformatsky-type reaction.

[0012] As a completely new concept, there is a report of an approach that is asymmetrical in advance, constructs a methyl group !, and then determines the stereochemistry of the methyl group. That is, WO2004 / 055027 As described in Tetrahedron Lett., 35, 2271, 1994, after first introducing the diallyl ester of methylmalonic acid into acetoxazetidinone, the nitrogen atom is further protected with a silyl group and a palladium catalyst is used. As a result, the construction of the j8-methyl group was achieved using stereoselective dearyl decarboxylation as a key reaction. Although this method is industrially superior and scaled-up production was carried out, a protective group on the nitrogen atom is essential to induce high diastereoselectivity, and power that cannot be economically satisfied. (Journal of Synthetic Organic Chemistry, 57, 3 87, 1999) o As described in Tetrahedron Lett., 3 5, 2275, 1994 An example of V reaction in response to acetoxyzetidinone was reported in 1994!

[0013] In order to construct a β-methyl group, a number of methods for stereoselective hydrogenation reduction after first introducing exomethylene have been reported, but acetoxazetidinone force is short and efficient. There are almost no examples of producing j8-methylcarboxylic acid.

[0014] Regarding the reaction of enolate reported by J. Org. Chem., 57, 4243, 1992, detailed examination of conditions including the structure of the oxazolidinone skeleton, the type of Lewis acid, the reaction temperature, and the order of addition The industrial production method of β-methylcarboxylic acid has been established. One example thereof is the technique described in Japanese Patent Publication No. 3220985. In this method, we focused on the oxazolidinone skeletal structure because stereoselectivity could not be obtained with a straight-chain amide even if various substituents were studied. Fix Lewis acid to tetrasalt 匕 titanium, limit to isopropylazolidinone skeleton by reacting acetolazetidinone with enolate of various propionic acid amides limited to diisopropylethylamine or triethylamine as organic base The stereoselectivity of the reaction and the isolated yield were compared. As a result, when using the ability to introduce two alkyl substituents at the 4-position of the oxazolidinone skeleton, or at the same time using propiolamide in which the 2-position carbo group is converted to a thiocarbol group, high stereoselectivity and tolerance are obtained. It has been found that possible yields are obtained. However, in this case as well, the cost of synthesizing oxazolidinone is not necessarily low, and in order to achieve an acceptable isolation yield, it is necessary to use more than an equal amount of propionylamide. There wasn't.

[0015] Recently, by an enolate using an ethyl ketone that is not an amide of propionic acid, An example of the synthesis of β-methylcarboxylic acid from acetoxazetidinone is reported in Tetrahedron, 60, 867, 2004. This method was excellent in stereoselectivity and achieved a medium yield. However, since it is a ketone rather than an amide, after synthesis of a binding product with acetoxyzetidinone, for example, ozone or the like. It was necessary for the carbon-carbon bond to be cleaved by using a ton-scale industrial production method.

On the other hand, some of the present inventors found methyl 6-deoxy-α-D-darcoviranoside chemically derived from D-glucose as a starting material, and Org. Lett., 1, 1447, 1999, Synlett, 200 0, 979, J. Org. Chem., 66, 5965, 2001, and Synlett, 2001, 1772, for 1,4-addition and α-alkylation reactions, and Synlett, 2001, 481, Carbohydr. Chem., 20, 519, 2001, and Synlett, 2003, 1865 have reported application to useful chemical synthesis reactions including various asymmetric reactions and stereoselective reactions such as cycloaddition reactions. Synlett, 2004, 2066 reports on the application of sugar templates as a tool for asymmetric synthesis. However, there have been no reports on the application of the sugar template to the preparation of synthetic rubapenem synthesis intermediates so far as the present inventors know.

Summary of the Invention

[0017] The present inventors consider that the efficient synthesis of β-methylcarboxylic acid (IV) is one key in order to produce useful power rubapenem with high versatility. A new synthesis method of 13-methylcarboxylic acid (IV) was studied, starting from acetoxazetidinone, a common intermediate in the world. As a result, it is possible to construct a j8-methyl group with high stereoselectivity by enolating a propionic acid unit introduced into a sugar template that can be synthesized using inexpensive D-glucose as a starting material and linking it with acetoxyzetidinone. I found it. The compound thus obtained is subjected to a deesterification reaction, and is an important versatile synthetic intermediate for producing useful rubapenem antibacterial agent. Easily converted to carboxylic acid. In addition, the compound to which the saccharide template thus obtained is bound is a novel compound. The present invention is based on these findings.

[0018] Therefore, the present invention provides a synthetic intermediate acetoxazetidinone as a starting material, and 1 β -methyl The purpose is to provide a novel method for efficiently synthesizing β-methylcarboxylic acid, an intermediate useful for constructing a strong rubapenem skeleton!

Another object of the present invention is to provide a novel synthetic intermediate useful for the construction of a 1 j8 -methylcarbapenem skeleton.

The method according to the present invention is a method for producing a compound represented by the following formula (Γ):

[Chemical 4]

[Where

R ¹ represents a hydrogen atom or a silyl protecting group,

R ² represents an optionally substituted lower alkyl group, an optionally substituted lower alkyl group, or a substituted aralkyl group,

R ³ and R ⁴ may be the same or different and each represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, or an optionally substituted! /, Aralkyl A group, or a silyl protecting group,

Or R ³ and R ⁴ may be joined together to form (CH 2) n—, where n represents 1 to 3,

2

R ⁵ represents a hydrogen atom, a halogen atom, an R¾0 group, or an OR ⁷ group, where R ⁶ is a substituted

Three

Represents an optionally substituted lower alkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, and R ⁷ represents a hydrogen atom, an optionally substituted lower alkyl group, a substituted A lower alkenyl group which may be substituted, an aralkyl group which may be substituted, or a silyl protecting group]

The method comprises the following formula (II):

[Chemical 5]

[Wherein R ² , R ³ , R ⁴ , and R ⁵ are synonymous with the formula (Γ)], and the following formula (III):

[Chemical 6]

(III)

[Wherein R ¹ is synonymous with the formula (Γ)]

And reacting with each other.

The novel synthetic intermediate according to the present invention is a compound represented by the following formula (I) or a salt thereof:

[Chemical 7]

In particular, it is a compound represented by the following formula (Γ) or a salt thereof:

[Chemical 8]

σ)

During,

R ¹ represents a hydrogen atom or a silyl protecting group,

R ² represents an optionally substituted lower alkyl group, an optionally substituted lower alkyl group, or a substituted or unsubstituted aralkyl group,

R ³ and R ⁴ may be the same or different and each may be a hydrogen atom or substituted A lower alkyl group which may be substituted, a lower alkyl group which may be substituted, or an optionally substituted! /, An aralkyl group or a silyl protecting group;

Or, R ³ and R ⁴ are a connexion together - represent Yogu n is 1 to 3 be formed n- a (CH),

2

R ⁵ represents a hydrogen atom, a halogen atom, a group R 0, or a group OR ⁷ where R ⁶ is a substituted

Three

Represents an optionally substituted lower alkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, and R ⁷ represents a hydrogen atom, an optionally substituted lower alkyl group, a substituted A lower alkenyl group which may be substituted, an aralkyl group which may be substituted, or a silyl protecting group].

[0021] According to the method of the present invention, the production cost is low because it is not necessary to protect the nitrogen atom of the acetoxazetidinone ring having high stereoselectivity. The compound represented by the formula (I) can be quantitatively converted to methyl carboxylic acid (IV) without using harmful chemicals, and the advantage is that the sugar template can be recovered. It is done.

Detailed description of the invention

[0022] 魏

The meanings of the terms used in the present specification are as follows.

“Halogen atom” means a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom.

Specific examples of the “silyl protecting group” include a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, and the like.

“Alkyl group” means a linear, branched or cyclic lower alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl. And hexyl.

The “alkyl group” means a chain or branched alkenyl group having 2 to 6 carbon atoms. For example, bur, 1-probe, aryl, iso-probe, butenyl, iso-butyr And so on.

The “aralkyl group” means an aryl group having a lower alkyl having 1 to 6 carbon atoms. For example, benzyl, phenethyl, β-naphthylmethyl, α-naphthylmethyl, triphenyl- Rumethyl, p-chloromethyl benzyl, p-methoxyphenylmethyl and the like.

Specific examples of “aryl group” include phenol and naphthyl. “Substituted, may be an alkyl group”, “Substituted, may be an alkyl group”, “Substituted, may be an aralkyl group”, “Substituted, may be, As the “substituent” in the “aryl group”, a halogen atom, amino group, nitro group, cyano group, hydroxyl group, lower alkyl group, lower alkoxy group (for example, methoxy, ethoxy, propoxy group, isopropoxy group, butoxy, And an alkoxy group having 1 to 6 carbon atoms such as an isobutoxy group).

[0023] Compound of formula (I) or formula (Γ)

The compound synthesized by the method according to the present invention is a azetidinone derivative represented by the above formula (I) and formula ().

In these formulas (I) and (Γ), R ¹ represents a hydrogen atom or a silyl-type protecting group. The group that may be described in the above definition is preferred, and more preferably A hydrogen atom, a trimethylsilyl group, and a tert-butyldimethylsilyl group.

In addition, R ² represents a substituted !, may represent a lower alkyl group, be substituted !, a lower alkenyl group, or an optionally substituted aralkyl group. The group which may be described in (1) is mentioned as a preferable thing, More preferably, they are a methyl group and a benzyl group.

[0026] R ³ and R ⁴ may be the same or different and each represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkyl group, or a substituted Represents an aralkyl group or a silyl protecting group which may be substituted. Preferable examples include groups that may be described in the above definition, and more preferable examples include a hydrogen atom, a methyl group, a benzyl group, a p-methoxyphenylmethyl group, a p-chlorobenzoyl group, and tert-butyl. Examples thereof include a dimethylsilyl group and a β-naphthylmethyl group.

[0027] R ³ and R ⁴ may be joined together to form (CH 2) η—. Η represents 1 to 3, preferably

2

Is 1.

[0028] R ⁵ represents a hydrogen atom, a halogen atom, an R ⁶ SO group, or an OR ⁷ group. Where R ⁶ is a substitution

Three

Represents an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, preferably a group which may be described in the above definition. R 0 group is more preferably methanesulfol group, benzenesulfol group, p-

Three

A toluenesulfol group and a benzylsulfol group. R ⁷ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aralkyl group, or a silyl protecting group, preferably the above The group which may be described in the definition is mentioned, More preferably, they are a hydrogen atom, a trimethylsilyl group, a trifluoromethyl group, a t_butyldimethylsilyl group, and a tert-butyldiphenylsilyl group.

[0029] Manufacturing method according to the present invention

The production method according to the present invention will be described using the following scheme.

[Chemical 9]

[0030] (1) Preparation of compound of formula (II)

(a) a compound of formula (II) (wherein R ² = as defined for formula (I), R ⁵ = R¾0 group or

Three

OR ⁷ groups)

First, various substituents as R 3 and R ⁴ are introduced into the 2-position and 3-position hydroxyl groups of 1-substituted-4,6- 0-protected-a-D-darcobilanoside. Here, the 4- and 6-position hydroxyl-protecting groups are not limited as long as they protect the hydroxyl groups in the following reactions. Examples thereof include benzylidene group, isopropylidene group, cyclohexylidene group, ethylidene group, and the like. And the like.

[0031] Examples of the substituent introduced into the hydroxyl groups at the 2-position and the 3-position include an alkyl group, an alkenyl group, and Alternatively, when an aralkyl group is introduced, a halogenated alkyl, a halogenated alkyl or a halogenated aralkyl is reacted at room temperature or under heating conditions in the presence of a base in an organic solvent. The halide may be chloride, bromide, or iodide, and preferably salt. From the viewpoint of improving the yield, a phase transfer catalyst may be used as necessary. Examples of the phase transfer catalyst include halogenated tetrabutyl ammonium, halogenated tetrabenzyl ammonium, and halogenated tetraethyl ammonium, preferably tetranormal butyl ammonium iodide. It is.

[0032] Examples of the reaction solvent include dimethylformamide, dimethylacetamide, or dimethyl sulfoxide, and preferably dimethylformamide. Examples of the base include organic bases such as diisopropylethylamine and triethylamine, and inorganic bases such as sodium carbonate and sodium hydride, preferably sodium hydride.

[0033] When a silyl group (silyl protecting group) is introduced as a substituent to be introduced into the hydroxyl groups at the 2-position and the 3-position, the silylation reagent is used in an organic solvent in the presence of a base. Is allowed to react under room temperature or heating conditions.

[0034] Examples of the reaction solvent include dimethylformamide, dimethylacetamide, and tetrahydrofuran. Tetrahydrofuran is preferable. Examples of the base include organic bases such as diisopropylethylamine, triethylamine and imidazole, and inorganic bases such as sodium carbonate and sodium hydride, preferably sodium hydride.

[0035] Examples of the silyl reagent include salt, trimethylsilyl, salt, triethylsilyl, tertiary butyldimethylsilyl chloride, and salt, tertiary butyldiphenylsilyl. It is tertiary butyl dimethyl silyl.

[0036] When tetrahydrofuran is used as a reaction solvent which is preferably carried out under heating, it is preferably heated to reflux.

Here, the substituent introduced into the hydroxyl group at the 2-position and the substituent introduced into the hydroxyl group at the 3-position may be the same or different, that is, the reactivity difference between the 2-position and 3-position hydroxyl groups. It is possible to introduce different substituents into the hydroxyl group at the 2-position and the hydroxyl group at the 3-position by utilizing a primary hydroxyl-protecting group or the like.

[0038] R ³ and R ⁴ are joined together to form one (CH 2) n — (where n represents 1 to 3). For the first compound, a cyclic ether such as a cyclic acetal or cyclic ketal having a corresponding structure is selected as the first 4,6-0-protected-a-D-darcoviranoside and subjected to the following steps.

[0039] Thereafter, the protecting group of 4,6- 0-protected-a-D-darcobilanoside having a substituent introduced at the 2-position and 3-position, respectively, is removed. When the protecting group is a benzylidene group, the benzylidene group can be removed quantitatively and easily under acidic conditions or by hydrogenation reduction. When the substituents at the 2- and 3-position hydroxyl groups are alkyl groups, alkenyl groups, or aralkyl groups, it is preferable to remove the benzylidene group under acidic conditions. The substituents at the 2-position and 3-position hydroxyl groups are preferred. In the case of a silyl protecting group, it is preferable to remove the benzylidene group by hydrogenation reduction. Acidic conditions include diluted formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, hydrochloric acid, or sulfuric acid, respectively, and preferably heated to reflux in 80% acetic acid. As hydrogenation reduction, hydrogen is reacted in the presence of a metal catalyst in an organic solvent that may be mixed with water. Examples of the reaction solvent include tetrahydrofuran, 1,4-dioxane, methanol, ethanol and the like, preferably ethanol. Examples of the metal catalyst include noradium black, palladium carbon, palladium hydroxide carbon, platinum, Raney nickel, and the like, and preferably hydrogen is reacted in the presence of palladium hydroxide carbon.

Next, substituents are introduced at the 2-position and 3-position, respectively, and the target functional group is introduced as an R¾0 group or an OR ⁷ group at the 6-position of the a-D-darcobilanoside. The protecting group is removed

Three

These compounds have free hydroxyl groups at the 4- and 6-positions, but the 6-position, which is the primary hydroxyl group, is more reactive than the 4-position, which is the secondary hydroxyl group. Using this, it is possible to introduce the desired functional group into the hydroxyl group at the 6-position regioselectively.

[0041] First, a compound of formula (II) in which R ⁵ is a group R 0 is prepared in an organic solvent in the presence of a base.

Three

A sulfonylating reagent having a structure (that is, substituted as R ⁶ , may be a lower alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group). Thus, the sulfonyl group can be obtained by regioselectively introducing the 6-position hydroxyl group. According to a preferred embodiment of the present invention, examples of the sulfo group introduced into the hydroxyl group at the 6-position include a methane sulfo group, a benzene sulfo group, a p-toluene sulfonyl group, and a benzyl sulfo group. , More preferably p-tru This is a sulfonyl group. Examples of the reaction solvent include methylene chloride, tetrahydrofuran, dimethylformamide, 1,4-dioxane and the like, preferably methylene chloride. Examples of the base include organic bases such as diisopropylethylamine triethylamine, and inorganic bases such as sodium carbonate and sodium hydride. When methylene chloride is used as a reaction solvent, it is preferable to add a small amount of dimethylaminopyridine using triethylamine as a base. For example, selective 6-position P-toluenesulfolation often proceeds quantitatively, depending on the structure of the atomic group introduced into the hydroxyl group at the 3-position.

[0042] The compound of the formula (II) in which R ⁵ is a group R ⁷⁰ is an alkylating reagent, alkenylating reagent, aralkylating reagent having a corresponding structure in the presence of a base in an organic solvent, It can be obtained by reacting a silylation reagent to introduce an alkyl group, an alkenyl group, an aralkyl group, or a silyl protecting group into the hydroxyl group at the 6-position regioselectively. According to a preferred embodiment of the present invention, examples of the substituent introduced into the hydroxyl group at the 6-position include a methyl group, a benzyl group, a trifluoromethyl group, a trimethylsilyl group, and a tertiary butyldimethylsilyl group. Preferred are a trimethyl group and a tertiary butyldimethylsilyl group. Examples of the reaction solvent include methylene chloride, tetrahydrofuran, dimethylformamide, 1,4-dioxane, pyridine and the like. Preferred are dimethylformamide and pyridine. Examples of the base include organic bases such as diisopropylethylamine, triethylamine and dimethylaminopyridine, and inorganic bases such as sodium carbonate and sodium hydride, with organic bases being preferred.

[0043] Finally, a propionyl group is introduced into the free hydroxyl group at the 4-position. The reaction can be carried out in an organic solvent in the presence of a base group at room temperature or under heating conditions. Examples of the propionylation reagent used include propionic acid anhydrides and various propionic acid halides, and propionic acid anhydrides are preferred. Examples of the reaction solvent include methylene chloride, tetrahydrofuran, pyridine, dimethylformamide, and the like, and preferably pyridine. Examples of the base include diisopropylethylamine, triethylamine, organic bases such as dimethylaminopyridine, and inorganic bases such as sodium carbonate and sodium hydride. When the reaction solvent is pyridine, dimethylamine is used as the base. Preference is given to using minopyridine. [0044] Through the above steps, a compound of the formula (Π) in which substituents are introduced into the hydroxyl groups at the 2nd, 3rd and 6th positions of a-D-darcobilanoside can be obtained.

[0045] In the above steps, the production steps are described in the order of the construction of the 6-position hydroxyl group after the introduction of substituents at the 2-position and 3-position, but the order is not limited to this. That is, the 6-position hydroxyl group with the functional group introduced first may be constructed, and then the 2- and 3-positions may be constructed.

[0046] (b) Compound of formula (II) (where R ² = as defined for formula (I), R ⁵ = hydrogen atom, halogen atom)

The compound in which R ⁵ is a halogen atom is a compound in which a substituent is introduced into the 2- and 3-position hydroxyl groups obtained by the above-described process, and a P-toluenesulfonyl group is introduced into the 6-position hydroxyl group. Convert the 6th position of a-D-Dalcobilanoside in (VI). That is, the compound of the formula (VI) in which the hydroxyl group at the 6-position is sulfo-reduced can be obtained by reacting with a salt containing a halogen element in an organic solvent at room temperature or under heating conditions. Examples of the salt containing a halogen element include sodium iodide, lithium bromide, and potassium salt, and sodium iodide is preferable. Examples of the reaction solvent include acetone, 2-butanone, or dimethylformamide, and 2-butanone is preferable. The reaction is carried out at room temperature or under heating conditions. When 2-butanone is used as the reaction solvent, it should be heated to reflux.

[0047] Next, in the compound in which R ⁵ is a hydrogen atom, the 6-position obtained as described above was iodinated (X-D-darcobilanoside was hydrogenated in an organic solvent in the presence of a metal catalyst. Examples of the organic solvent used in the reaction include tetrahydrofuran, 1,4-dioxane, methanol, ethanol, etc., preferably ethanol, and the metal catalyst is palladium black, Examples thereof include palladium carbon, palladium hydroxide carbon, platinum, and Raney nickel, and Raney nickel is preferably used.

[0048] In addition, the compound in which R ⁵ is a hydrogen atom is obtained by the above-described method of obtaining hydroxyl group 6-position sulphonyl-sulfurized a-D-darcobilanoside, lithium aluminum hydride, etc. in tetrahydrofuran. It can also be obtained by directly reducing the P-toluenesulfol form. In addition, the 6th position can be deoxylated by a known established method, for example, the method described in “Organic Reactions” can also be used. [0049] Finally, as in the case of (a) above, a propionyl group is introduced into the 4-position free hydroxyl group. The reaction can be carried out in an organic solvent in the presence of a base at room temperature or under heating conditions with a propionylation reagent. Examples of the propionyl reagent used include propionic acid anhydrides and various propionic acid halides, with propionic acid anhydrous being preferred. Examples of the reaction solvent include methylene chloride, tetrahydrofuran, pyridine, or dimethylformamide, and pyridine is preferred. Examples of the base include diisopropylpyrutylamine triethylamine, organic bases such as dimethylaminopyridine, and inorganic bases such as sodium carbonate and sodium hydride. When the reaction solvent is pyridine, dimethylamino as the base. Preference is given to using pyridine.

[0050] (2) Reaction of compound of formula (II) with compound of formula (III)

After dissolving the compound of formula (II) in the reaction solvent, it is cooled, a base and an additive are added if necessary, and the compound of formula (III) is gradually added and reacted.

[0051] Examples of the reaction solvent include tetrahydrofuran, jetyl ether, toluene, and the like. These solvents can be used alone, or two or more kinds can be used in an appropriate ratio. In the case of using a mixture of two or more, for example, a mixture of tetrahydrofuran and dimethyl ether, a mixture of tetrahydrofuran and toluene, a mixture of tetrahydrofuran and dimethylformamide, and the like are preferably used.

[0052] Examples of the base include lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide, and lithium hexamethyldisilazide is preferable. The amount added is preferably about 1.2 to 5 equivalents.

[0053] Additives that can be prepared as necessary include lithium chloride, tin tetrachloride, tetrasalt titanium, tetrasalt zirconium, salt sodium, zinc chloride, lithium bromide, fluoride. Lithium chloride, calcium chloride and the like, and lithium chloride is preferable. Add 5 to 10 equivalents of these. The reaction temperature is such that a binding reaction is possible in the range from −78 ° C. to room temperature, preferably the power to maintain −78 ° C. The temperature is raised moderately from −78 ° C.

[0054] The molar ratio of the compound of formula (II) to the compound of formula (III) in the above reaction is not particularly limited, but it will generally be used in an equal amount.

[0055] Through the above steps, a compound represented by the formula (I) is obtained, and in particular, the configuration of the formula (Γ) The compound is obtained in high yield. The compound of the formula (Γ) may be purified and isolated as necessary. Examples of the method include silica gel column chromatography, cephadex column chromatography, resin chromatography, and recrystallization. Is a purification method by recrystallization, more preferably a recrystallization method using hexane and isopropyl ether. In this stage, it is possible to purify at the j8-methylcarboxylic acid stage after proceeding to the next step without completely isolating the β-form.

[0056] (3) Conversion of compound of formula (Γ) to compound of formula (IV)

The compound of formula (IV) can be obtained by reacting the compound of formula (Γ) with an inorganic base in a reaction solvent. At this time, the compound of the formula (VI) can be recovered quantitatively. According to a preferred embodiment of the present invention, a small amount of peracid is added to the reaction system during this reaction.

In the conversion of the compound of the formula (IV), the inversion of the steric chemistry underlying the “methyl group” can be completely suppressed.

[0057] Examples of the reaction solvent include hydrous methanol, hydrous ethanol, hydrous tetrahydrofuran, and hydrous 1,4-dioxane, preferably hydrous methanol, and more preferably 50% methanol.

[0058] Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like. Preferably, 0.2 M lithium hydroxide aqueous solution is mixed with the same amount of methanol and used.

[0059] The peroxide added in a small amount for the purpose of preventing the reversal of stereochemistry is preferably a small amount of hydrogen peroxide.

Example

[0060] The present invention will be described in more detail based on the following examples, but the present invention is not limited to the following examples.

[0061] The general formulas in the following examples are based on the following (Y) and (Z). The production ratio of (Y) and (Z) was calculated by ¹ H-NMR.

[Chemical 10]

Kiryu § τ00

Tildisilazide (1M tetrahydrofuran solution) was added. After stirring at -78 ° C for 30 minutes, 30.4 mg of 4-acetoxyzetidinone dissolved in 1 ml of tetrahydrofuran was added over 15 minutes. After stirring at -78 ° C for 30 minutes, 1 ml of saturated aqueous solution of ammonium chloride was added and the temperature was gradually raised to room temperature. The mixture was diluted with 10 ml of ethyl acetate and washed 3 times with 5 ml of saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 3: 1) to obtain 31.5 mg (yield 61%) of the title compound as a white powder (Y: Z = 4.3: 1). Furthermore, 10.3 mg of methyl 6-deoxy-2,3-di-0-methyl-4-0-propiol-α-D-gnolecopyranoside was recovered.

Decoration 13

Compound Y, wherein R ¹ is t-butyldimethylsilyl group, R ² acetyl group, R ³ force S methyl group, R ⁴ is methyl group, R ⁵ force toluenesulfo-loxy group And compound 化 synthesis

41.3 mg of methyl 2,3-di-0-methyl-4-0-propiool-6-Op-toluenesulfol-a-D-darcobilanoside is dissolved in 1 ml of tetrahydrofuran and brought to -78 ° C. Then, 0.11 ml of lithium hexamethyldisilazide (1M hexane solution) was added. After stirring at -78 ° C for 30 minutes, 27.4 mg of 4-acetoxyzetidinone dissolved in 1 ml of tetrahydrofuran was added over 15 minutes. After stirring at -78 ° C for 2 hours, 1 ml of saturated aqueous ammonium chloride solution was added, and the temperature was gradually raised to room temperature. The mixture was diluted with 20 ml of ethyl acetate and washed 3 times with 10 ml of saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 2: 1) to give 3.1 mg (yield 5%) of the title compound as a colorless syrup (Y: Z => 25: 1). Further, 25.1 mg of methyl 2,3-di-0-methyl-4-0-propiool-6-0-ρ-toluenesulfol-a-D-darcopyranoside was recovered.

Compound Y

^J H NMR (300 MHz, CDC1) δ 0.08 (s, 6Η), 0.87 (s, 9H), 1.21 (d, J = 7.1 Hz, 3H),

Three

1.22 (d, J = 6.0 Hz, 3H), 2.45 (s, 3H), 2.75 (m, IH), 2.94 (dd, J = 2.4, 5.0 Hz, IH), 3.25 (dd, J = 3.6, 9.5 Hz , IH), 3.41 (s, 3H), 3.49 (s, 3H), 3.50 (s, 3H), 3.57 (t, J =

8Z-. : Ϊ́, · Π # ½ οε. 8Z- 9ΐ · ο e. 8z-

9

^ 0) Ζί¾? ^ \ ¾QT¾ :、人 ^^ / ^^ / (H ^ _S

S battle [9900]. Tied ¾ί times ³¹¹¹

»-/ Beyer / d— 0- 9-/-0- ^-0--S'S ^ ^ ¾ $ ° (ΐ: 0 · 8 = Ζ: On)

(% 9 * ¾i) ^sra ^ z ^ ^^ w ^^ mn, consolation ^ (vz = ^^ m

: ·

,

. Two times ε, 缀氺 ma-¾]

o) w ΟΪ, tsu ^ 譽 ^ 邈 oz ^ m- ^. > ηπϋ¾ 次 ^

Ye

si¾Be ^ E ¾ ~ — ^ ^§ ω ΖΊΖ ^ ^^^ ^ ^ ^ ΐ, Tsu

½ οε d. 8Ζ- ° ^ t ^ (m ^^ a> m) A ^^^^^ ^

8Γ0 d. SL- »-/ Beyer-d— 0- 9-/ 0- ^-0--S'S ^ 0) Sui 6" TS

^ \ ¾ατ¾ :、人呦 ^: / ^^ / Behe β- (¾ ^ ^ ^^

, 6) ¾ ^^, 6) ¾ ^^, 6) ¾ (,:-Difficult [S900]

• (H

Z ' ^Z HZ'S = f' P) SL'L HZ ' ^Z HZ'S = f' P) SS "Z '(HI' s) T6" S '(HI' ^ H S'6 = f 18

-f '(HI' ZH 9 · ε = f 'P) 08,' (HI '^ H Γ9' 9'S = f 'PP) OZ'f' (HI '^ H Γ9' 8'S = f 'PP

) SVf '(HI' ZH -f 'ζ-Ζ = f' PP) ZO'f '(Ηΐ' ω) ΐΖ ・ ε '(Η2' ω) 86T-88T '(Ηΐ' ^ Η S'6

Z66MC / 900Zdf / X3d 61Z6SCT0 / .00Z OAV The temperature was raised to room temperature. The mixture was diluted with 10 ml of ethyl acetate and washed 3 times with 5 ml of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 5: 1) to obtain 2.2 mg (yield 4%) of the title compound as a white powder (Y: Z = 2.0 : 1). Furthermore, 82.2 mg of methyl 2,3-di-0-methyl-4-0-propionyl-6-0-trityl-α-D-darcobilanoside was recovered.

Compound Y

Mass (ESI) 765 (M + NH) +, C H NO Si

4 42 57 9

Example 6

R ¹ is a t-butyldimethylsilyl group, R ² acetyl group, R ³ force S methyl group, R ⁴ is methyl group, R ⁵ is t-butyldimethylsilyloxy group Synthesis of Compound Y and Compound Ζ

Dissolve 18.3 mg of methyl 6-Ot-butyldimethylsilyl-2,3-di-0-methyl-4-0-propionyl-a-D-darcobilanoside in 1 ml of tetrahydrofuran and add 9.8 mg of lithium chloride. After calorific reduction, 0.23 ml of lithium hexamethyldisilazide (1M hexane solution) was added at -78 ° C. After stirring at -78 ° C for 30 minutes, 13.5 mg of 4-acetoxyzetidinone dissolved in 1 ml of tetrahydrofuran was added over 15 minutes. After stirring at -78 ° C for 2 hours, 1 ml of a saturated aqueous solution of ammonium chloride was added and gradually warmed to room temperature. The mixture was diluted with 20 ml of ethyl acetate and washed 3 times with 10 ml of saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 4: 1) to obtain 7.4 mg (yield 25%) of the title compound as a colorless syrup (Y: Z = 4.2: 1) ). Further, 8.4 mg of methyl 6-0-1-butyldimethylsilyl-2,3-di-0-methyl-4-0-propionyl-at-D-darcobilanoside was recovered.

Compound Y

^J H NMR (300 MHz, CDC1) δ 0.04 (s, 6Η), 0.07 (s, 6H), 0.87 (s, 9H), 0.89 (s, 9H

Three

), 1.22 (d, J = 7.0 Hz, 3H), 1.27 (d, J = 6.0 Hz, 3H), 2.75 (dq, J = 4.5, 7.0 Hz, 1H), 2.81 (dd, J = 2.3, 4.9 Hz , 1H), 3.30 (dd, J = 3.3, 9.6 Hz, 1H), 3.45 (s, 3H), 3.51 (s, 3H), 3.52 (s, 3H), 3.59 (t, J = 9.6 Hz, IH), 3.60—3.65 (m, 2H), 3.71 (m, IH), 4.00 (dd, J = 2.3, 4.5 Hz, IH ), 4.19 (m, IH), 4.85 (t, J = 9.6 Hz, IH), 4.89 (d, J = 3.3 Hz, IH), 5.85 (s, IH).

Mass (ESI) 620 (M + H) ⁺ , CH NO Si

29 57 9 2

[0068] Example 7

Dissolve 37.0 mg of methyl 6-Ot-butyldimethylsilyl-2,3-di-0-methyl-4-0-propionyl-a-D-darcobilanoside in 1 ml of tetrahydrofuran at -78 ° C. 0.24 ml of lithium hexamethyldisilazide (1M hexane solution) was added. After stirring at -78 ° C for 30 minutes, 27.0 mg of 4-acetoxyzetidinone dissolved in 1 ml of tetrahydrofuran was added over 15 minutes. After stirring at -78 ° C for 2 hours, 1 ml of a saturated aqueous solution of ammonium chloride was added and the temperature was gradually raised to room temperature. The mixture was diluted with 20 ml of ethyl acetate and washed 3 times with 10 ml of saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 4: 1) to give 16.8 mg (yield 29%) of the title compound as a colorless syrup (Y: Z = 2.7 : 1). Furthermore, 18.0 mg of methyl 6-O-t-butyldimethylsilyl-2,3-di-0-methyl-4-0-propiol-a-D-darcobilanoside was recovered.

[0069] Example 8

Compound Y wherein R ¹ is a t-butyldimethylsilyl group, R ² butyl group, R ^{3 is a} benzyl group, R ^{4 is a} benzyl group, and R ⁵ is a hydrogen atom, and Compound Ζ Synthesis

33.0 mg of methyl 2,3-di-0-benzyl-6-deoxy-4-0-propiol-α-D-glucopyranoside was dissolved in 1 ml of tetrahydrofuran, and 33.7 mg of lithium chloride was removed. Then, 0.40 ml of lithium hexamethyldisilazide (1M hexane solution) was added at -78 ° C. After stirring at -78 ° C for 30 minutes, 19.2 mg of 4-acetoxyzetidinone dissolved in 1 ml of tetrahydrofuran was added over 15 minutes. After stirring at -78 ° C for 2 hours, 1 ml of saturated aqueous ammonium chloride solution was added, and the temperature was gradually raised to room temperature. Mix the mixture with 20 ml of ethyl acetate. Diluted with water and washed 3 times with 10 ml of saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 5: 1) to give the title compound as a colorless syrup.

15.3 mg (yield 37%) was obtained (Y: Z = 2.8: 1). In addition, 15.3 mg of methyl 2,3-di-0-benzyl-6-deoxy-4-0-propiol-at-D-darcobilanoside was recovered.

Compound Y

^J H NMR (300 MHz, CDC1) δ 0.03 (s, 3H), 0.05 (s, 3H), 0.86 (s, 9H), 1.14 (d, J

Three

= 6.6 Hz, 3H), 1.22 (d, J = 7.0 Hz, 3H), 1.25 (d, J = 6.0 Hz, 3H), 2.61 (dq, J = 4.2, 7.0 Hz, IH), 2.81 (dd, J = 2.2, 4.2 Hz, IH), 3.40 (s, 3H), 3.59 (dd, J = 3.4, 9.4 Hz, IH), 3.78 (dq, J = 9.4, 6.6 Hz, IH), 3.89 (t, J = 9.4 Hz, IH), 3.91 (dd, J = 2.2, 4.2 Hz, IH), 4.07 (m, IH), 4.55 (d, J = 3.4 Hz, 1 H), 4.59 (d, J = 10.8 Hz, 1 H), 4.63 (d, J = 11.4 Hz, 1 H), 4.75 (d, J = 10.8 Hz, 1 H), 4.77 (t, J = 9.4 Hz, IH), 4.95 (d, J =

11.4 Hz, IH), 5.60 (s, IH), 7.30-7.32 (m, 10H).

Mass (ESI) 642 (M + H) ⁺ , CH NO Si

35 51 8

Decorative 19

Dissolve 24.9 mg of methyl 2,3-di-0-benzyl-6-deoxy-4-0-propiol-α-D-glucopyranoside in 1 ml of tetrahydrofuran, and add 0.30 ml of it at -78 ° C. Lithium hexyl disilazide (1M hexane solution) was prepared. After stirring at −78 ° C. for 30 minutes, 14.3 mg of 4-acetoxyzetidinone dissolved in 1 ml of tetrahydrofuran was added over 15 minutes. After stirring at -78 ° C for 2 hours, 1 ml of saturated aqueous ammonium chloride solution was added, and the temperature was gradually raised to room temperature. The mixture was diluted with 20 ml of ethyl acetate and washed 3 times with 10 ml of saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 5: 1) to obtain 16.6 mg (yield 52%) of the title compound as a colorless syrup (Y: Z = 1.7 : Do In addition, 11.3 mg of methyl 2,3-di-0-benzyl-6-deoxy-4-0-propiol-α-D-glucopyranoside was recovered.

iimm [oo]

• (H 'ω) ΐτΐ- ^ ΥΙ' {98 · 9— S8'9 '(HI 99'S' (Ηΐ 'ZH z • ΐΐ = f' Ρ) 8 · '(HI' ZH V6 = f ') Z' (Η ΐ '^ Η S'll = f' Ρ) 69 ·, '(Η ΐ' ^ Η Ζ'Π

= f 'ρ) ee ^' (Η ΐ 'ZH s'n = f' ρ) m '(H I' ^ Hε = f 'ρ)' '(HI o ^' (HI

< ^Z H ε · 'ε = f' ΡΡ) ΐ6 · ε '(HI' ΖΗ νβ = ί ') esx' (ΗΘ ^<S ) β∑τ '(ΗΪ τ' (ΗΙ

' ^Ζ Η νβ' νζ = ί 'ΡΡ) ε' (Ηε ζε · ε '(ΗΪ' ΖΗ Ο · 'ε = f' ΡΡ) WZ '(HI' ΖΗ ε-

'= f' bp) iQ-z '(HS' ZH ε- = f 'Ρ) 8ΐ ・ ΐ' (HS 'ΖΗ ε · 9 = f' Ρ) ZVl '(HS' ZH V9 = f 'Ρ) ΟΓΐ '(Η6 ^<s ) 8 ・ 0' (HS 's) WTO' (HS 's) CO 9 (\ DQD ^<Z H OOS) HNH _T

入呦 ^ ¾T 回³¹¹¹ Z-Ll ^ A ^ ^^^-Q- »— /-ci l— O— Be: ^^^ H — d—〇

.教教 S, 《粼 ¾ エ ^ マ (H 邈 ^ 氺雜 ¾ 簠斜萆回继缀氺マ-¾ ベ] ^^^ ^ Οΐ 、っ譽邈 l ^ra ΐ, · Π # ½ Φ £ ^ E ^ tsu. 8Ζ-. ^ É W SI ^ be / — 0)

9 ·: _η 缀 ΰ, ΐ,: · η # ½ οε. SL-. ^ Shun

\ ¾ατ¾ :、人呦 ^ 士 n 峯氺 "^ ^ o- ^ w-^^ ^ m ^

Z66MC / 900Zdf / X3d Z6SCT0 / .00Z OAV Composition of object z

Dissolve 18.0 mg of methyl 2,3-di-0-p-chloro-benzyl-6-deoxy-4-0-propiol-α-D-darcobilanoside in 1 ml of tetrahydrofuran, and add 9.1 mg of lithium chloride. After calorific content, 0.22 ml of lithium hexamethyldisilazide (1M hexane solution) was calorified at -78 ° C. After stirring at -78 ° C for 30 minutes, 12.2 mg of 4-acetoxyzetidinone dissolved in 1 ml of tetrahydrofuran was added over 15 minutes. After stirring at -78 ° C for 2 hours, 1 ml of saturated aqueous solution of ammonium chloride was added and the temperature was gradually raised to room temperature. The mixture was diluted with 20 ml of ethyl acetate and washed 3 times with 10 ml of saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 4: 1) to obtain 11.0 mg (yield 37%) of the title compound as a colorless syrup (Y : Z = 2.2: 1). In addition, 3.8 mg of methyl 2,3-di-Ο-ρ-black benzyl-6-deoxy-4-0-propio-at-D-darcobilanoside was recovered.

Compound Y

^J H NMR (300 MHz, CDC1) δ 0.02 (s, 3Η), 0.05 (s, 3H), 0.88 (s, 9H), 1.12 (d, J

Three

= 6.3 Hz, 3H), 1.13 (d, J = 6.3 Hz, 3H), 1.20 (d, J = 7.2 Hz, 3H), 2.65 (dq, J = 4.1, 7.2 Hz, IH), 2.85 (dd, J = 2.2, 4.6 Hz, IH), 3.41 (s, 3H), 3.55 (dd, J = 3.7, 9.5 Hz, IH), 3.78 (m, IH), 3.86 (t, J = 9.5 Hz, IH), 3.93 (dd, J = 2.2, 4.1 Hz, IH), 4.11 (m, IH), 4.56 (d, J = 12.1 Hz, 1 H), 4.58 (d, J = 10.2 Hz, 1 H), 4.60 (d, J = 3.7 Hz, 1 H), 4.64 (d, J = 12.1 Hz, 1 H), 4.77 (t, J = 9.5 Hz, IH), 4.83 (d, J = 10.2 Hz, IH), 5.73 ( s, IH), 7.12-7.31 (m, 8H).

Mass (ESI) 710 (M + H) ⁺ , CH CI NO Si

35 49 2 8

Example 12

R ¹ is a t-butyldimethylsilyl group, R ² is a methyl group, R ³ is a P-chlorobenzyl group, R ⁴ is a P-chlorobenzyl group, and R ⁵ is a hydrogen atom. Compound Y and Compound Ζ

Dissolve 17.9 mg of methyl 2,3-di-0-p-chloro-benzyl-6-deoxy-4-0-propiol-α-D-darcobilanoside in 1 ml of tetrahydrofuran at -78 ° C. 0.21 ml of lithium hexamethyldisilazide (1M hexane solution) was added. Stir at -78 ° C for 30 minutes uso

¾ / ¾. ^ Times ΐΛ ヽ Iίa 丄.; N ヽヽ u, ϋ l-. .

1) () () () () 9p 1 wn6 osoε 200ε 9003800εHΗΗH YU HsssZ11--------...

) () () (ppp 3εΓΐε ε9 πΐε ε9 fΗH s 卜 f 3ΗH fΗH f = = = = ZZZ--------....

) () () (ρρpp ε6εε 69εε one inch εΐ s esΐΗ fΗΗΗ frΗH = = ΖSΖZ---------* ....

) () (Ρ ε6∞6εΐ 6εΐ fΗ fΓΗ =--* .. Hz, 1H), 4.10 (dq, J = 4.6, 6.3 Hz, 1H), 4.57 (d, J = 3.3 Hz, 1 H), 4.79 (d, J = 12.0 Hz, 1 H), 4.81 (d, J = 12.0 Hz, 1 H), 4.83 (t, J = 9.3 Hz, 1H), 4.92 (d, J = 12.0 Hz, 1 H), 5.14 (d, J = 12.0 Hz, 1H), 5.64 (s, 1H ), 7.45-7.49 (m, 6H), 7.72-7.83 (m, 8H).

Mass (ESI) 742 (M + H) ⁺ , CH NO Si

43 55 8

Example 14

R ¹ is a t-butyldimethylsilyl group, R ² cation group, R ³ is a t-butyldimethylsilyl group, R ⁴ is a t-butyldimethylsilyl group, and R ⁵ is a hydrogen atom. Synthesis of certain compound Y and compound Z

224 mg of methyl 2,3-di-Ot-butyldimethylsilyl-6-deoxy-4-0-propiol-α-D-darcoviranoside is dissolved in 4 ml of tetrahydrofuran and 2.42 ml at -78 ° C Lithium hexamethyldisilazide (1M hexane solution) was added. After stirring at -78 ° C for 30 minutes, 116 mg of 4-acetoxyzetidinone dissolved in 2 ml of tetrahydrofuran was added over 15 minutes. After stirring at -78 ° C for 2 hours, 1 ml of saturated aqueous ammonium chloride solution was added, and the temperature was gradually raised to room temperature. The mixture was diluted with 20 ml of ethyl acetate and washed 3 times with 10 ml of saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 4: 1) to obtain 17.7 mg (yield 6%) of the title compound as a white powder (Υ: Ζ = 1:> 25) ). Furthermore, 176 mg of methyl 2,3-di-O-t-butyldimethylsilyl-6-deoxy-4-0-propiol-a-D-darcobilanoside was recovered.

Compound Z

^J H NMR (300 MHz, CDC1) δ 0.03 (s, 3Η), 0.07 (s, 3H), 0.08 (s, 3H), 0.10 (s, 3H

Three

), 0.11 (s, 3H), 0.11 (s, 3H), 0.83 (s, 9H), 0.87 (s, 9H), 0.93 (s, 9H), 1.09 (d, J = 6.0 Hz, 3H) , 1.23 (d, J = 6.0 Hz, 3H), 1.23 (d, J = 7.2 Hz, 3H), 2.57 (dq, J = 9.0, 7.2 Hz, 1H), 2.89 (dd, J = 1.5, 3.0 Hz, 1H), 3.38 (s, 3H), 3.66 (dd, J = 3.6, 8.7 Hz, 1H), 3.69 (m, 1H), 3.69 (m, 1H), 3.92 (t, J = 8.7 Hz, 1H), 4.20 (dq, J = 1.5, 6.0 Hz, 1H), 4.61 (d, J = 3.6 Hz, 1H), 4.73 (dd, J = 8.7, 9.2 Hz, 1H), 6.01 (s, 1H).

Mass (ESI) 690 (M + H) +, CH NO Si ¾_η # ½ οε

^ Ma (Η ™

^ a) z ^, human ^^ H H ^^ _S , (A

9 Zhang [ZOO] IS ON HD ' ₊ (Η +) (IS3) ^ss

• (HI 's) Z8 "S' (HI 's) 9Γ3' (HI 's) SI'S' (HI '^ H · ε = f' Ρ) ITS '(Ηΐ' ^ Η 9 · 6 = f ΐ6 · '(Ηΐ' ω) 6ΐ · '(Ηΐ' ΖΗ S '' Ζ-Ζ = ί 'ΡΡ) εθ ·' (Ηΐ '^ Η 9 · 6 = f') ΐ6 · ε '(Ηΐ

'ω)' (HS 's) OS'S' (Ηΐ 'ΖΗ 9 ・ 6' VZ = ί 'ΡΡ) WZ' (Ηΐ '^ Η ε ·' ε = ['ΡΡ) Ζ6 "Ζ' (Ηΐ 'ΖΗ 8 · 9 'ε · = [' & Ρ) SL'Z '(HS' ^ Η 8'S = f 'Ρ) 92 "ΐ' (HS '^ Η 8 · 9 = f' Ρ) ΖΊ

'(HS' ΖΗ 2 "9 = f 'Ρ)' (Η6 ' ^S ) Ζ8' (Η9 ' ^S ) ΖΟ 9 (\ DQD' ^Ζ Η 00S) Η Ν Η _Τ

入呦 ^

. ¾τ times ^Sui

-a- »--^ ΰ _ο ^ -ο-^-^^-έ ^ -ο- -ε'2- ^: ^-9 ^ ^ ¾ $ ° (ΐ: ο =

ZA) -M (% Z ^) ^Sm S ^^ ^ w ^^ WM, consolation ^ (1- = /-^

ω 翁 ¾ エ ^ マ (Λ ^ Β ^ »斜单. 回 ε 、缀氺マ-¾Be ^

ox, tsu 譽 / 邈 z ^. · Ηπϋ¾¾ ^

¾_η # ½ οε SL- ^ Ma (H ™ 6ΐ

^ a) z ^, people呦^ in the H-Mine氺_{^ S, (A imm [9} oo]

Z66MC / 900Zdf / X3d LZ Z6SCT0 / .00Z OAV Added. After stirring at -78 ° C for 2 hours, 1 ml of saturated aqueous solution of ammonium chloride was added and the temperature was gradually raised to room temperature. The mixture was diluted with 20 ml of ethyl acetate and washed 3 times with 10 ml of saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 4: 1) to obtain 14.0 mg (yield 33%) of the title compound as a colorless syrup (Y: Z = 1.7: 1). Furthermore, 8.7 mg of methyl 6-deoxy-2,3-di-0-methylene-4-0-propiol-a-D-darcobilanoside was recovered.

[0078] Example 17

Synthesis of compounds represented by R ¹ force t-butyldimethylsilyl group among compounds represented by formula (IV)

In a mixed solution of 1 ml of methanol, 1 ml of 0.2 M lithium hydroxide aqueous solution, and 0.108 ml of 35% aqueous hydrogen peroxide, 98.7 mg of the compound obtained in Example 1 was placed at room temperature. For 20 hours. The reaction was diluted with 10 ml of water and extracted 8 times with 10 ml of methylene chloride. All the extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 42.2 mg (quantitative) of methyl 6-deoxy-2,3-di-0-methyl-α-D-darcobilanoside. It was. Subsequently, 1M hydrochloric acid was added dropwise to the aqueous layer until the pH reached 2, and then extracted with 10 ml of methylene chloride three times. All the extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 49.7 mg (yield 86%) of the title compound as a white powder.

[0079] Participant Example 1

Synthesis of methyl 6-deoxy-2,3-di-0-methyl-4-0-propiol-at-D-darcobilanoside

415 mg of methyl 6-deoxy-2,3-di-0-methyl-a-D-darcoviranoside (J.Org.Chem., 48, 5126, 1983) was dissolved in 10 ml of pyridine and cooled with ice. 0.774 ml of propionic acid anhydrous and 24.6 mg of dimethylaminopyridine. After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 8: 1) to obtain 517 mg (yield 98%) of the title compound as a colorless syrup.

^J H NMR (300 MHz, CDC1) δ 1.13 (d, J = 6.3 Hz, 3H), 1.17 (t, J = 7.5 Hz, 3H), = f 'ΡΡ) ΐ · ε' (HI 'ΖΗ ε · οι' οτ = f 'ΡΡ) εο · ε' (ΗΪ 'ΖΗ Ζ · Ζ' ΓΘΪ = f ^{, ¾} ρ) βοτ '(HI'

ΖΗ VI 'Γ9ΐ = f' ^b P) 66 · ΐ '(HS' ^ Η VI = f S6 9 (OQD ' ^Ζ Η 0Ζ2) Η Ν Η _τ (% ε6 * ¾ί) §ω

m '■ Be ^^ ·

. Suzaku S 瀚 m

雜邈

Ϋ́ ΐ υι 890, Stop ^^ ΐ¾ (ΐ66 ΐ 'ZZLZ' Lf

S 8

»--Έίί4-0-9--^ _ο ¾ΰ _ο ^ -0-^--έ ^ -0- -ε'2

[1800]

\ ΗΖ ' ^Ζ Η Z'S = f' Ρ) LVL ΗΖ ' ^Ζ Η Z'S = f' Ρ) SS "'(Ηΐ' ^ Η ST = f 'Ρ) IV' (Ηΐ 'ΖΗ 9 ・ 6' · 6 = f 'ΡΡ)' (Ηΐ '^ Η 6 ΐ' 2 "9 = f 'ΡΡ) S0''(Ηΐ' ^ Η 6 • Οΐ 'Z = ί' ΡΡ) 86 · ε '(Ηΐ' ΖΗ V6 'Ζ' 9 Ί'Ζ = ί 'ΡΡΡ) 8Τ' (Ηΐ '^ Η 9 ・ 6 = f') SST

'(Ηε' s) 6 · ε '(Ηε svz' (HS βζτ '(HI' ΖΗ 9 ・ 6 'ex = f' ρρ) · ε '(HS wz

ΗΖ ' ^Ζ Η 9 "Z = f IS' (HS 'ΖΗ 9" Z = f £ Vl 9 (OQD ^<Z H 00S) HNH _T

. ¾ (% 8? Ill

) 88ΐet; ^;] 遨, 攝攝エ v (vz = ^^ m 4-^-^ Translation) "^ Di Be ίί ^ ^ o> ^Sui ε ΐ, 呦氺雜邈呦氺雜邈

Q) 080, ^^^

(ε86ΐ '92 ΐ3 'Sf 〇),

, 匚 /-α- "-/ Beyer I- d- 0- 9-^-0--S'S ^ 0) Sui 681-α-»

ZW [0800] "(Ηΐ 'ZH 9 · ε = f' Ρ) ZS'f '(Ηΐ' ZH 9 • 6 = f 89 ·, '(Ηΐ' ZH ε · 9 '9 · 6 = f' ¾Ρ) Ζ · ε '(Ηΐ' ^ Η 9 ・ 6 = f '(HS' s) TST

'(HS' s) '(HS' s) ZYZ '(Ηΐ' ΖΗ 9 ・ 6 '9 · ε = f' ΡΡ) '(Η2' ^ Η S'Z = f 9S

Z66MC / 900Zdf / X3d 63 Z6SCT0 / .00Z OAV 6.6, 10.3 Hz, IH), 3.34 (dd, J = 3.7, 9.5 Hz, IH), 3.47 (s, 3H), 3.54 (s, 3H), 3.55 (s, 3H), 3.55 (t, J = 9.5 Hz, IH), 3.74 (ddd, J = 2.0, 6.6, 9.5 Hz, IH), 4.84 (t, J = 9.5 Hz, IH), 4.93 (d, J = 3.6 Hz, IH), 7.18—7.31 (m, 9H), 7.42-7.46 (m, 6H).

[0082] Reference Example 4

Synthesis of methyl 6-O-t-butyldimethylsilyl-2,3-di-O-methyl-4-0-propionyl-α-D-darcobilanoside

61.6 mg of methyl 6-Ot-butyldimethylsilyl-2,3-di-0-methyl-α-D-darcoviranoside (Bull.So Chim.Fr., 134, 1057, 1997) dissolved in 1.5 ml of pyridine Under ice-cooling, 0.031 ml of propionic anhydride and 2.3 mg of dimethylaminopyridine were prepared. After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 8: 1) to obtain 70.1 mg (yield 92%) of the title compound as a colorless syrup.

^J H NMR (300 MHz, CDC1) δ 0.01 (s, 6Η), 0.86 (s, 9H), 1.15 (t, J = 7.6 Hz, 3H),

Three

2.33 (q, J = 7.6 Hz, 2H), 3.26 (dd, J = 3.6, 9.7 Hz, IH), 3.42 (s, 3H), 3.48 (s, 3H), 3.50 (s, 3H), 3.55 (t , J = 9.7 Hz, IH), 3.58-3.62 (m, 2H), 3.66 (m, IH), 4.79 (t, J = 9.7 Hz, IH), 4.82 (d, J = 3.6 Hz, IH).

[0083] Participant Example 5

Synthesis of methyl 2,3-di-O-benzyl-6-deoxy-4-0-propiol-at-D-darcobilanoside

1.14 g of methyl 2,3-di-0-benzyl-6-deoxy-a-D-darcoviranoside (J.Org.Chem., 66, 5965, 2001) was dissolved in 22 ml of pyridine and cooled with ice. 0.53 ml of propionic acid anhydrous and 38.9 mg of dimethylaminopyridine were prepared. After stirring at room temperature for 20 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 20: 1) to obtain 1.30 g (yield 98%) of the title compound as a colorless syrup.

^J H NMR (300 MHz, CDC1) δ 1.08 (t, J = 7.6 Hz, 3H), 1.11 (d, J = 6.2 Hz, 3H),

Three

2.17 (dq, J = 10.6, 7.6 Hz, IH), 2.21 (dq, J = 10.6, 7.6 Hz, IH), 3.38 (s, 3H), 3.57 (dd, J = 3.6, 9.4 Hz, IH), 3.75 (m, IH), 3.87 (t, J = 9.4 Hz, IH), 4.53 (d, J = 3.6 Hz, 1H), 4.64 (d, J = 11.4 Hz, 1H), 4.65 (d, J = 12.1 Hz, 1H), 4.78 (t, J = 9.4 Hz, 1H), 4.79 (d, J = 12.1 Hz, 1H) , 4.89 (d, J = 11.4 Hz, 1H), 7.26-7.34 (m, 10H).

[0084] Reference Example 6

Synthesis of methyl 2,3-di-O-p-methoxybenzyl-6-O-p-toluenesulfol-α-D-darcopyranoside

564 mg of methyl 2,3-di-0-p-methoxybenzyl-a-D-darcoviranoside (Tetrahedro n, 55, 2205, 1999) was dissolved in 11 ml of methylene chloride and 0.714 ml of triethyla under ice-cooling. Min, 31.8 mg dimethylaminopyridine, and 490 mg tosyl chloride were added. After stirring at room temperature for 23 hours, the reaction solution was diluted with 50 ml of a saturated aqueous solution of ammonium chloride and extracted three times with 25 ml of methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 4: 1) to obtain 672 mg (yield 88%) of the title compound as a yellow syrup.

^J H NMR (300 MHz, CDC1) δ 2.15 (d, J = 3.6 Hz, 1H), 2.43 (s, 3H), 3.31 (s, 3H),

Three

3.35 (m, 1H), 3.42 (dd, J = 3.6, 9.4 Hz, 1H), 3.65—3.71 (m, 2H), 3.80 (s, 3H), 3.81 (s, 3H), 4.20 (d, J = 3.6 Hz, 2H), 4.57 (d, J = 12.0 Hz, 1H), 4.59 (d, J = 11.1 Hz, 1 H), 4.60 (d, J = 3.6 Hz, 1H), 4.70 (d, J = 12.0 Hz, 1H), 4.90 (d, J = 11.1 Hz, 1H), 6.86-6.89 (m, 4H), 7.24-7.32 (m, 6H), 7.77 (d, J = 8.3 Hz, 2H).

[0085] Participant Example 7

Synthesis of methyl 6-deoxy-2,3-di-op-methoxybenzyl-a-D-darcoviranoside 653 mg methyl 2,3-di-0-p-methoxybenzyl-6-0-p-toluenesulfol -a -D- Darcobilanoside was dissolved in 13 ml of tetrahydrofuran, and 84.2 mg of aluminum lithium hydride was added under ice cooling. The mixture was stirred for 3.5 hours under reflux with heating and then returned to room temperature. The reaction mixture was ice-cooled, 2 ml of water was added, and the precipitated solid was filtered through celite and washed with ethanol. The filtrate and washings were combined and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 3: 1) to give 440 mg of the title compound as a colorless syrup ( Yield 95%).

^J H NMR (300 MHz, CDC1) δ 1.22 (d, J = 6.3 Hz, 3H), 2.09 (d, J = 2.1 Hz, 1H),

Three

3.11 (dt, J = 2.1, 9.3 Hz, 1H), 3.37 (s, 3H), 3.47 (dd, J = 3.4, 9.3 Hz, 1H), 3.59 (m, . ¾ (% u * ¾i) ^SUI

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'{' ω) 98 · 9— S8'9 '(Ηΐ' ΖΗ ε · ΐΐ = ['Ρ) SL'f' (Ηΐ '^ Η 6 · ΐΐ = f' Ρ) '(Ηΐ' ^ Η S

• 6 = f ΪΓ '(ΗΪ' ΖΗ 6 · π = f 'ρ) e ^' (ΗΪ 'ΖΗ ε · ΐΐ = f' ρ) ee ^ '(HI' ^ Η ex = f

'Ρ) S' (Ηΐ 'ΖΗ S'6 = f' (Η9 ' ^s ) 6ΖΤ' (Ηΐ 'ω) ZL' £ '(Ηΐ' ^ Η S'6 'ST = f' pp) sex '(Ηε 's) 9ε · ε' (HI 'ZH VL' Ζ8 = f '& ρ) zz'z' (HI 'ZH VL' Ζ · 8 = f '& ρ)% vz

'(HS' ZH Z'9 = f 'Ρ) 60 · ΐ' (HS '^ Η Z "Z = f 60 · ΐ 9 ODOD ^ HVi 00S) HNH _T e ^ (ΐ: 8 = 4S: Be ^ Nabe-san) One 4mu ci ^ ma / f, ¾¾¾

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8 ¥ [9800] • (Η 'ω) ΖΖ'1- <τΐ' {'^) 06 · 9- 98 · 9' (Ηΐ 'ζ

Η 0 · ΐΐ = ['Ρ) W' (Ηΐ 'ΖΗ = ί' Ρ) \ 1 '(Ηΐ' ^ Η S ΐ = f 'Ρ) 09 ・,' (Ηΐ '^ Η 0 · π = Γρ) 09 · '(ΗΪ' ΖΗ νζ = f 'ρ) oe ^' (Η9 ^<S ) 08 · ε '(ΗΪ' ΖΗ ε · 6 = f 9 · ε '(HI

Z66MC / 900Zdf / X3d Z6SCT0 / .00Z OAV (Ηΐ 'ω) ZVZ' (Ηΐ 'ΖΗ V6 = ί') 1∑τ '(Ηΐ' ω) 6VZ '(Ηΐ' ^ Η V6 'Ζ = ί' ΡΡ) ΖΥΖ

'(Ηε' s) εε · ε '(Ηε ζνζ' (ΗΪ 'ΖΗ ε · ε = f' ρ) 6ε 9 θοαο 'ΖΗ οοε) Η Ν Η _Τ

. (% 88 ¾ί) §ω S9S

fi ^ ^ 0> ^Sui VLI, Be ^ ^ D (Ho ¹¹¹ 6W0, Stop ^^, ¾ 缀 ^ Be ^

α 匚-α- »-/ Beyer Αί- d- Ο- 9-Be: ^ crn ^-d- o-,-S'S

TW [6800]

• (H8 ZZ'L-ZZ'L '(Ηΐ' ^ Η 8 · ΐΐ = f 'Ρ) Z6'f' (Ηΐ '^ Η 8 · ΐΐ = f' Ρ) 89 · '(Ηΐ' ζ

Η VZl = ί 'Ρ) 99 ·,' (Ηΐ 'ΖΗ VZ = ί' Ρ) W '(Ηΐ' ^ Η Γ2ΐ = f 'Ρ) 09 ·,' (Η2 'ω) ΐ8 · ε- Τ' ( Ηΐ 'ΖΗ S'6 = f 9ΖΤ ΗΖ' ω) S9 "S-TS" S '(Ηΐ' ^ Η S'6 'V £ = f' ΡΡ) V £ '

(Ηε 's) 6ε · ε' (ΗΪ '^) 8ε' (ΗΪ 'ΖΗ 9'S = f S6'i 9 (OQD' ^Ζ ο οοε) Η Ν Η _Τ

. ¾ (%

OT W [8800]

• (Ηεΐ 'ω) ινι-ζτι' (HI 'S

) SS'S '(Ηΐ' ZH 8 · ΐΐ = f 'Ρ) 98 ·,' (Ηΐ '^ Η 8 · ΐΐ = f' Ρ) IV '(Ηΐ' ^ Η 0 ΐ = f 'Ρ) 9Ζ

· '(Ηΐ' ΖΗ 0 ΐ = f 'Ρ) 99 ·,' (Ηΐ 'ΖΗ 9 · ε = f' Ρ) S9 '' (Ηΐ '^ Η Ζ · 6 = ί' ΡΡ) 82 "f '( Ηΐ 'ΖΗ 9 · 6 = f ΐ0 ·' (Ηΐ 'ω) S8T' (Ηΐ '^ Η Ζ · 6 = f' (Ηΐ '^ Η 9 · 6 = f'

¾ 6ST '(Ηΐ' ΖΗ 9 ・ 6 '9 · ε = f' ΡΡ) SST '(HS ZVZ 9 (OQD' ^Ζ Η 00S) Η Ν Η _τ

Z66MC / 900Zdf / X3d εε Z6SCT0 / .00Z OAV , 4.19 (d, J = 11.0 Hz, IH), 4.27 (dd, J = 4.7, 11.0 Hz, IH), 4.57 (d, J = 12.6 Hz, 1 H), 4.60 (d, J = 3.3 Hz, IH ), 4.63 (d, J = 12.6 Hz, IH), 4.67 (d, J = 11.7 Hz, IH), 4.87 (d, J = 11.7 Hz, IH), 7.23-7.33 (m, 10H), 7.77 (d, J = 8.1 Hz, 2H).

[0090] Reference Example 12

Synthesis of methyl 2,3-di-Op-chloro-benzyl-6-deoxy-at-D-darcoviranoside 317 mg of methyl 2,3-di-0-p-chloro-benzyl-6-0-p-toluenesulfo -Lu-α-D-glucoviranoside was dissolved in 7 ml of tetrahydrofuran, and 40.3 mg of aluminum lithium hydride was added under ice cooling. The mixture was stirred for 2 hours under reflux with heating and then returned to room temperature. The reaction mixture was ice-cooled, 1 ml of water was added, and the precipitated solid was filtered through celite and washed with ethanol. The filtrate and washings were combined and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 3: 1) to give 191 mg of the title compound as a colorless syrup (yield). 84%).

^J H NMR (300 MHz, CDC1) δ 1.25 (d, J = 6.2 Hz, 3H), 2.12 (d, J = 2.6 Hz, IH),

Three

3.16 (dt, J = 2.6, 9.5 Hz, IH), 3.38 (s, 3H), 3.48 (dd, J = 3.6, 9.5 Hz, IH), 3.64 (m, IH), 3.70 (t, J = 9.5 Hz , IH), 4.60 (d, J = 3.6 Hz, IH), 4.61 (d, J = 9.8 Hz, IH), 4.63 (d, J = 9.8 Hz, IH), 4.66 (d, J = 11.8 Hz , IH), 4.92 (d, J = 11.8 Hz, IH), 7.23-7.33 (m, 8H).

[0091] Participant Example 13

Synthesis of methyl 2,3-di-O-p-chloro-benzyl-6-deoxy-4-0-propionyl-α-D-darcobilanoside

191 mg of methyl 2,3-di-0-p-chloro-benzyl-6-deoxy-α-D-darcopyranoside is dissolved in 4 ml of pyridine, 0.074 ml of propionic anhydride and 5.5 mg under ice cooling Of dimethylaminopyridine was added. After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 8: 1) to obtain 191 mg (yield 88%) of the title compound as a colorless syrup.

^J H NMR (300 MHz, CDC1) δ 1.09 (t, J = 7.7 Hz, 3H), 1.12 (d, J = 6.2 Hz, 3H),

Three

2.20 (dq, J = 8.5, 7.7 Hz, IH), 2.24 (dq, J = 8.5, 7.7 Hz, IH), 3.36 (s, 3H), 3.52 (dd, J = 3.5, 9.5 Hz, IH), 3.72 (m, IH), 3.82 (t, J = 9.5 Hz, IH), 4.58 (d, J = 11.3 Hz, 1H), 4.59 (d, J = 3.5 Hz, 1H), 4.60 (d, J = 11.9 Hz, 1H), 4.68 (d, J = 11.9 Hz, 1H), 4.76 (t, J = 9.5 Hz, 1H) , 4.78 (d, J = 11.3 Hz, 1H), 7.18-7.28 (m, 8H).

[0092] Reference Example 14

Synthesis of methyl 2,3-di-O-β-naphthylmethyl-oc-D-darcobilanoside

344 mg of methyl 4,6-di-0-benzylidene-2,3-di-0-13-naphthylmethyl-α-D-glucoviranoside (Tetrahedron Lett., 42, 4033, 2001) 7 ml 80% The mixture was dissolved in an acetic acid aqueous solution and stirred for 10 hours under heating to reflux. After returning to room temperature, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent; hexane: ethyl acetate = 1: 1) to obtain 265 mg (yield 91%) of the title compound as a white powder.

JH NMR (270 MHz, CDC1) δ 1.87 (br, 1Η), 2.32 (br, 1H), 3.40 (s, 3H), 3.55—3.6

Three

3 (m, 2H), 3.59 (dd, J = 3.6, 9.5 Hz, 1H), 3.73—3.80 (m, 2H), 3.88 (t, J = 9.5 Hz, 1 H), 4.64 (d, J = 3.6 Hz, 1H), 4.85 (d, J = 11.9 Hz, 1H), 4.91 (d, J = 8.8 Hz, 1H), 4.95 (d, J = 8.8 Hz, 1H), 5.22 (d, J = 11.9 Hz, 1H), 7.46-7.53 (m, 6H), 7.76-7.85 (m, 8H).

[0093] Participant Example 15

Synthesis of methyl 2,3-di-Ο-β-naphthylmethyl-6-Ο-ρ-toluenesulfol-α-D-darcopyranoside

265 mg of methyl 2,3-di-0- | 8-naphthylmethyl-0; -0-glucopyranoside is dissolved in 5 ml of methylene chloride, 0.156 ml of triethylamine, 6.8 mg of dimethyl under ice cooling Aminopyridine and 213 mg of tosyl chloride were added. After stirring at room temperature for 26 hours, 1 ml of a saturated aqueous solution of ammonium chloride was prepared. The mixture was diluted with 10 ml of ethyl acetate and washed 3 times with 5 ml of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 3: 1) to obtain 326 mg of the title compound as a white powder (yield 93%).

^J H NMR (270 MHz, CDC1) δ 2.26 (d, J = 2.9 Hz, 1H), 2.39 (s, 3H), 3.33 (s, 3H),

Three

3.47 (dt, J = 2.9, 9.2 Hz, 1H), 3.56 (dd, J = 3.7, 9.2 Hz, 1H), 3.71 (m, 1H), 3.82 (t, J = 9.2 Hz, 1H), 4.20-4.22 (m, 2H), 4.58 (d, J = 3.7 Hz, 1H), 4.82 (d, J = 11.9 Hz, 1H), 4.89 (d, J = 8.6 Hz, 1H), 4.93 (d, J = 8.6 Hz , 1H), 5.18 (d, J = 11.9 Hz, 1H), ) WL-WL '(Ηΐ' ZH Q-Zl = f 'P) 80'S' (HI '^ H 0 ΐ = f' Ρ) 96, '(Ηΐ' ^ Η 0 ΐ = f 'Ρ) S8'' (Ηΐ 'ΖΗ 0 ΐ = f' Ρ) ε8 · '(Ηΐ' ZH V6 = ί ') Wf' (Ηΐ '^ Η VZ = ί' Ρ) 93

-f '(Ηΐ' ZH V6 = ί ') 96 · ε' (Ηΐ '^ Η 0 · 9' V6 = ί <b P) 9ΖΤ '(Ηΐ' ^ Η V6 'VZ = ί' ΡΡ

) 9 · ε '(Ηε' s) ο · ε '(ΗΪ' ΖΗ ε- Vex = f '¾ρ) 6rs' (HI 'ΖΗ ε-' 'si = f' ¾ρ) π

'(HS' ΖΗ 0 · 9 = f 'Ρ) ΟΓΐ' (HS 'ZH Z'L = f 0 · ΐ 9 ODOD' ^ Η 00S) WM Η _τ

;] 遨、灞

H é ^ (ΐ: = / 邈 4S: be ^ nabe 缀) one 4 mu ci ^ ma / f, ¾¾) ^§ ω 8 · ε, 呦氺雜邈 ΰ ΰ υι ε¾

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^

TW [S600] • (Η8 'ω) ^ 8 "-S"' (Η9 'ω) es

-9 ^ "'(Ηΐ' ZH 6 · ΐΐ = f 'Ρ)' (Ηΐ '^ Η 6 · 6 = f' Ρ) S6 '' (Ηΐ '^ Η 6 · 6 = f' Ρ) 68 f '(Ηΐ' ΖΗ 6 · ΐΐ = f 'Ρ) 28 ^' (Ηΐ '^ Η Ζ · ε = f' Ρ) 09 ·, '(Ηΐ' ^ Η ε · 6 = f Τ8Τ '(Ηΐ

'ω) wz' (ΗΪ 'ΖΗ ε · 6' τ = ('ρρ) ΐ9 · ε' (Ηε βζτ '(ΗΪ' ΖΗ ε · 6 '9 = f' ρ) osx

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"(HOT 'ω) S8" Z-9Z "Z' (Η9 'ω) Ζ ^' L-W L ΗΖ 'ω) £' L ~ 9Z'L

Z66MC / 900Zdf / X3d 9ε Z6SCT0 / .00Z OAV m, 6H), 7.73-7.82 (m, 8H).

[0096] Reference Example 18

Synthesis of methyl 6-deoxy-2,3-di-O-methylene-4-0-propiol-at-D-darcobilanoside

80.6 mg of methyl 6-deoxy-2,3-di-0-methylene-a-D-darcoviranoside (Bull. Chem. Soc. Jpn., 54, 2169, 1981) was dissolved in 1.6 ml of pyridine and iced. Under cooling, 0.055 ml of propionic anhydride and 4.0 mg of dimethylaminopyridine were added. After stirring at room temperature for 1.5 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 4: 1) to obtain 97.8 mg (yield 94%) of the title compound as a colorless syrup.

^J H NMR (300 MHz, CDC1) δ 1.18 (t, J = 7.7 Hz, 3H), 1.24 (d, J = 6.4 Hz, 3H),

Three

2.40 (q, J = 7.7 Hz, 2H), 3.48 (dd, J = 3.2, 9.6 Hz, 1H), 3.49 (s, 3H), 3.71 (m, 1H), 3.92 (t, J = 9.6 Hz, 1H ), 4.93 (t, J = 9.6 Hz, 1H), 5.09 (d, J = 3.2 Hz, 1H), 5.12 (s, 1H), 5.16 (s, 1H).

[0097] The compounds obtained in the above Examples and Reference Examples and the reactions carried out are summarized as follows.

In the following, the following abbreviations are used.

Me: methyl group, Bn: benzyl group, MPM: p-methoxyphenyl methyl, PCB: p-chlorophenyl, NAP: β-naphthylmethyl, Tr: triphenylmethyl, Ts: p-toluenesulfur, TBS : T-Butyldimethylsilyl

[Chemical 11]

Example I

[Chemical 13]

Reference example 1

Reference example 2

Reference example 3

Reference example 4

[Chemical Formula 14] Reference Example 5

Reference Example 6

Reference example

Reference Example 8

Reference Example 9

[Chemical 15] Reference example 1 o

Reference example

Reference Example _{1 2}

Reference Example 1 3

Reference Example 7

Reference Example 1 8

Claims

The scope of the claims

A method for producing a compound represented by the following formula (I ′),

[Where

R ¹ represents a hydrogen atom or a silyl protecting group,

2

Three

The method comprises the following formula (II):

[Chemical 2]

[Chemical 3]

R ¹ is synonymous with the formula (Γ)]

And reacting.

A method for producing a compound represented by the following formula (IV), which comprises hydrolyzing a compound represented by the formula (I ′) obtained by the method according to claim 1:

[Chemical 4]

(IV)

[Wherein R ¹ represents a hydrogen atom or a silyl protecting group].

A method for producing a compound represented by the following formula (IV), comprising hydrolyzing a compound represented by the formula (Γ) according to claim 1:

[Chemical 5]

(IV)

[In the formula, R ¹ represents a hydrogen atom or a silyl protecting group.

A compound represented by the following formula (I) or a salt thereof:

[Chemical 6]

[Where

R ¹ represents a hydrogen atom or a silyl protecting group, R ² represents an optionally substituted lower alkyl group, an optionally substituted lower alkyl group, or a substituted aralkyl group,

2

Three

A compound represented by the following formula (Γ) or a salt thereof:

[Chemical 7]

[Where

R ¹ represents a hydrogen atom or a silyl protecting group,

2

Three

Which may be a lower alkyl group, an optionally substituted Ariru group or substituted also represents an Ararukiru group, R ⁷ is a hydrogen atom, a lower alk substituted, Represents a kill group, an optionally substituted lower alkenyl group, an optionally substituted aralkyl group, or a silyl protecting group].

[6] R ⁵ is a hydrogen atom A compound according to claim 4 or 5.

[7] R ⁵ is a group OR ^7, The compound according to claim 4 or 5.