JP6351107B2 - Method for producing thiolane skeleton type sugar compound and thiolane skeleton type sugar compound - Google Patents

Description

  The present invention relates to a method for producing a thiolane skeleton type sugar compound and a thiolane skeleton type sugar compound.

It is known that thionucleosides in which an oxygen atom is replaced by a sulfur atom exhibit antiviral activity or antitumor activity.
For example, 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine has excellent antitumor activity and is known to be useful as a tumor therapeutic agent. (See Patent Document 1).
Therefore, research on the route for synthesizing thionucleosides and synthetic intermediates has been actively conducted.
Of these, many reactions for forming a thiolane ring have been studied and proposed (see, for example, Patent Document 2 and Non-Patent Documents 1 to 3).
On the other hand, although it is not a sugar compound, the synthesis | combination of a benzotetrahydrothiophene ring (refer patent document 3) and the synthesis reaction (refer patent document 4 and nonpatent literature 4) of imino sugar are also known.

International Publication No. 1997/038001 Pamphlet Special table 2007-514463 gazette JP 2006-335737 A Chinese Patent Application No. 1010585855

J. et al. Org. Chem. 1996, 61, p. 822-823 Tetrahedron Letters, 1998, 39, p. 5201-5204 J. et al. Org. Chem. 1998, 63, p. 4821-4825 Synlett, 2010, No3, p. 488-492

Conventional methods for synthesizing a thiosugar by a reaction for forming a thiolane ring are mainly a dithioketal method and a pumeler method. The dithioketal method uses a relatively low-grade mercaptan such as dibenzyl mercaptan, so it has a strong malodor and is not preferable from an environmental and health viewpoint. On the other hand, the Pummerer method is not preferable in terms of yield and suitability for mass production because regioisomers are inevitably produced in the Pummerer rearrangement step.
Therefore, in the present invention, in a reaction for forming a thiolane ring, a method for producing a thionucleoside synthesis intermediate in a simple and high yield under mild conditions, a compound having a thiosugar skeleton in a small number of steps. It is an object to provide a production method that can be synthesized.
It is another object of the present invention to provide a thiolane skeleton type sugar compound or a synthetic intermediate compound useful as a synthetic intermediate of thionucleoside exhibiting antiviral activity or antitumor activity.

  As a result of various studies of reactions for forming a thiolane ring, the present inventors have found that the above-described problems can be solved by using a sulfur compound as a specific compound.

The above problem has been solved by the following means.
<1> A method for producing a compound represented by the following general formula (II) through a step of reacting a compound represented by the following general formula (I) with hydrogen sulfide or a salt thereof .

In the general formulas (I) and (II), R ¹ represents a hydrogen atom, an alkyl group or an acyl group, R ² represents —O—R ^2a or a fluorine atom, R ² ′ represents —O—R ^2a , A fluorine atom or = O is represented. Here, R ^2a represents a hydrogen atom, —CH ₂ —R ^2b or an acyl group. R ^2b , R ³ and R ⁵ each independently represents a hydrogen atom, an alkyl group, a vinyl group or an aryl group, and X represents a leaving group. Here, the bond from R ² ′ to the thiolane ring represents a single bond or a double bond.
The acyl group in R ¹ and R ^2a , the alkyl group in R ¹ , and the alkyl group and aryl group in R ^2b , R ³ and R ⁵ are a halogen atom, an alkyl group, an aryl group, a heterocyclic group, an alkoxy group , An aryloxy group, an alkylthio group or an arylthio group may be substituted.
However, when R ¹ is an unsubstituted alkyl group and R ² ′ is —O—R ^2a , R ^2a is a hydrogen atom, —CH ₂ —R ^2b or an acyl group, and R ^2b is an alkyl group. Group, a vinyl group or an aryl group, when R ¹ is a substituted alkyl group and R ² ′ is —O—R ^2a , R ^2a is a hydrogen atom, —CH ₂ —R ^2b or an acyl group. R ^2b is a hydrogen atom, an alkyl group or a vinyl group, and when R ¹ is a hydrogen atom or an acyl group, R ² ′ is ═O.
<2> The production method according to <1>, wherein the compound represented by the general formula (II) is a compound represented by any one of the following general formulas (II-1) to (II-10).

In formula (II-1) ~ (II -5), R 1, R 2b, R 3 and ^{R 5, R} 1, ^R 2b in the formula (II), the same meaning as ^{R 3} and ^{R 5} . R ^2c represents an alkyl group or an aryl group.
In General Formulas (II-6) to (II-10), R ¹¹ represents an alkyl group, and R ²¹ , R ³¹ and R ⁵¹ each independently represents an alkyl group.
Note that the alkyl group in R ¹¹ , R ^2c , R ²¹ , R ³¹ and R ⁵¹ and the aryl group in R ^2c are a halogen atom, an alkyl group, an aryl group, a heterocyclic group, an alkoxy group, an aryloxy group, an alkylthio group. Group or arylthio group may be substituted.
<3> R ² ′ in the general formula (II) is —O—CH ₂ —R ^2b or an arylcarbonyloxy group, and R ^2b is a hydrogen atom, an alkyl group, a vinyl group or an aryl group, Alternatively, the production method according to <1> or <2>, wherein the compound represented by the general formula (II) is represented by the general formula (II-1) or (II-2), and R ^2c is an aryl group. .
<4> R ¹¹ is a methyl group , R ²¹ is an alkyl group having 2 to 10 carbon atoms, and R ³¹ and R ⁵¹ are each independently an alkyl group having 1 to 10 carbon atoms <2 The manufacturing method of>.
<5> The production method according to <2> or <4>, wherein R ²¹ , R ^31, and R ⁵¹ are all the same substituent.
<6> In the step of reacting the compound represented by the general formula (I) with hydrogen sulfide or a salt thereof , the compound represented by the following general formula (IIA) is synthesized, and then represented by the general formula (IIA). The production method according to any one of <1> to <5>, wherein the compound represented by the general formula (II) is synthesized through a step of alkylating or acylating the compound.

In formula ^(IIA), R 2, ^{R 3} and ^{R 5} have the same meanings as ^R 2, ^{R 3} and ^{R 5} in the general formula (I).
<7> When R ² ′ in the general formula (II) is a hydroxy group, or when the compound represented by the general formula (II) is represented by the general formula (II-3), it is represented by the general formula (I). The step of dealkylating the compound represented by the following general formula (II-a) obtained through the step of reacting the compound obtained with hydrogen sulfide or a salt thereof , or the following general formula (II-b) The manufacturing method as described in <1> or <2> which manufactures the compound represented by the following general formula (II-c) at the process of deacylating the compound represented by these.

In formula (II-a) ~ (II -c), R 1, R 3 and ^{R 5} have the same meanings as ^R 1, ^{R 3} and ^{R 5} in the general formula (II). R ^2b has the same meaning as ^{R 2b} in the general formula (II-1). R ^2c have the same meanings as ^{R 2c} in the formula (II-2).
<8> When R ² ′ in the general formula (II) is ═O, or when the compound represented by the general formula (II) is represented by the general formula (II-5), it is represented by the general formula (I). The compound represented by the following general formula (II-c ′) obtained through the step of reacting the resulting compound with hydrogen sulfide or a salt thereof is oxidized through the step of oxidizing the compound represented by the following general formula (II-c ′). The production method according to <1> or <2>, wherein the compound represented by d) is produced.

一般式（ＩＩ’）において、Ｒ^１は水素原子、アルキル基またはアシル基を表し、Ｒ ^２ ”は−Ｏ−Ｒ ^２ａ ’または＝Ｏを表す。ここで、Ｒ ^２ａ ’は、水素原子、−ＣＨ_２−Ｒ ^２ｂ ’またはアシル基を表す。Ｒ ^２ｂ ’は、ビニル基を表す。Ｒ^３およびＲ^５は各々独立に、水素原子、アルキル基、ビニル基またはアリール基を表す。ここで、Ｒ ^２ ”からチオラン環への結合手は、単結合または二重結合を表す。
なお、Ｒ^１およびＲ^２ａ ’におけるアシル基、Ｒ^１におけるアルキル基、ならびに、Ｒ ^３およびＲ^５におけるアルキル基およびアリール基は、ハロゲン原子、アルキル基、アリール基、ヘテロ環基、アルコキシ基、アリールオキシ基、アルキルチオ基またはアリールチオ基が置換されていてもよい。
＜１３＞Ｒ ^２ ”が、＝Ｏである＜１２＞に記載の化合物。
＜１４＞下記一般式（ＩＩ−２’）〜（ＩＩ−５’）、（ＩＩ−７）または（ＩＩ−１０）のいずれかで表される化合物。
In formula (II-c ') and ^{(II-d), R 1} , R 3 and ^{R 5} have the same meanings as ^R 1, ^{R 3} and ^{R 5} in the general formula (II). R ¹ ′ represents an alkyl group or an acyl group.
The alkyl group and acyl group in R ¹ ′ may be substituted with a halogen atom, alkyl group, aryl group, heterocyclic group, alkoxy group, aryloxy group, alkylthio group or arylthio group.
<9> The production method according to any one of <1> to <3> or <6> to <8>, in which R ¹ is a hydrogen atom, an acetyl group, or a methyl group.
<10> The production method according to any one of <1> to <9>, wherein X is a halogen atom, an alkylsulfonyloxy group, or an arylsulfonyloxy group.
<11> The production method according to any one of <1> to <10>, wherein in the sulfur compound or a salt thereof, M is MSH or M ₂ S which is an alkali metal.
<12> A compound represented by the following general formula ( II ′ ).

'In, ^{R 1} represents a hydrogen atom, an alkyl group or an acyl ^{group, R} 2 "is ^{-O-R 2a} formula (II)' or other represents = O. In this ^{case, R 2a} 'represents a hydrogen atom , —CH ₂ —R ^2b ′ or an acyl group, R ^2b ′ represents a vinyl group, and R ³ and R ⁵ each independently represents a hydrogen atom, an alkyl group, a vinyl group or an aryl group. , R ² ″ to the thiolane ring represents a single bond or a double bond.
The acyl group in R ¹ and R ^2a ′ , the alkyl group in R ¹ , and the alkyl group and aryl group in R ³ and R ⁵ are halogen atoms, alkyl groups, aryl groups, heterocyclic groups, alkoxy groups, aryl groups oxy group, an alkylthio group or an arylthio group, but it may also be substituted.
<13> The compound according to <12>, wherein R ² ″ is ═O.
<14> under following general formula (II-2 ') ~ ( II-5'), (II-7) or other (II-10) or by represented Ru of compounds of.

In the general formulas ( II-2 ′ ) to (II-5 ′), R ¹ represents a hydrogen atom, an alkyl group or an acyl group , R ^1c represents an alkyl group, and R ³⁰ and R ⁵⁰ are each independently aryl. R ^2c represents an alkyl group or an aryl group.
In formula (II-7) Contact and ^{(II-10), R 11} represents an alkyl ^{group, R 21,} R ³¹ and ^{R 51} are to display the alkyl group each independently.
Incidentally, acyl group in ^{R 1, R 1, R 1c} , R 11, R 2c, an alkyl group definitive in R ^{21, R 31} and R ^{5 1,} as well ^as the aryl group in R ^{2c, R 30} and ^{R 50} is halogen atom, an alkyl group, an aryl group, a heterocyclic group, an alkoxy group, an aryloxy group, an alkylthio group or an arylthio group but it may also be substituted.
<15> The compound is a compound represented by the general formula (II-5 ′), wherein R ¹ is a hydrogen atom, a methyl group or an acetyl group, and R ³⁰ and R ⁵⁰ are a phenyl group <14 The compound as described in>.
<16> The compound is a compound represented by any one of formulas (II-7) and (II-10), wherein R ¹¹ is a methyl group, and R ²¹ , R ³¹ and R < ⁵¹ > The compound according to <14>, wherein ⁵¹ is each independently an alkyl group having 1 to 10 carbon atoms.
<17> The above compound is a compound represented by the general formula (II-7), wherein R ²¹ , R ³¹ and R ⁵¹ are each independently the same substituent, <14> or <16> The described compound.
<18> The compound according to <14>, wherein the alkyl group in R ^1c and R ¹¹ is an unsubstituted alkyl group.
<19> selected Ru of compounds from under Symbol.

<20> selected Ru of compounds from under Symbol.

In formula (II-X-1) ~ (II-X-5), R x1 is a methyl ^{group, R x2} is to display the propyl group, butyl group or pentyl group.
<21> The compound according to any one of <12> to <20>, wherein the compound is a thionucleoside synthesis intermediate.

  In the present specification, each substituent may be further substituted with a substituent unless otherwise specified.

According to the present invention, in a reaction for forming a thiolane ring, a compound having a thiosugar skeleton can be synthesized by a production method for producing a synthesis intermediate of thionucleoside, in a simple and high yield, under mild conditions, with few steps. A manufacturing method can be provided.
Furthermore, it is possible to provide a thiolane skeleton type sugar compound useful as a synthetic intermediate of thionucleoside exhibiting antiviral activity or antitumor activity or a synthetic intermediate compound thereof.

<< Method for producing thiolane skeleton type sugar compound >>
The method for producing a thiolane skeleton type sugar compound of the present invention is a method for producing a stereocontrolled compound represented by the following general formula (II), and reacts the compound represented by the following general formula (I) with a sulfur compound. It goes through the process of making it.

In the general formulas (I) and (II), R ¹ represents a hydrogen atom, an alkyl group or an acyl group, R ² represents —O—R ^2a or a fluorine atom, R ² ′ represents —O—R ^2a , A fluorine atom or = O is represented. Here, R ^2a represents a hydrogen atom, —CH ₂ —R ^2b or an acyl group. R ^2b , R ³ and R ⁵ each independently represents a hydrogen atom, an alkyl group, a vinyl group or an aryl group, and X represents a leaving group. Here, the bond from R ^{2 ′} to the thiolane ring represents a single bond or a double bond.

In the case where R ² , R ² ′, O—CH ₂ —R ³ and CH ₂ —O—CH ₂ —R ⁵ in general formulas (I) and (II) are asymmetric carbon atoms, The configuration substituted by R ² , R ² ′, O—CH ₂ —R ³ and CH ₂ —O—CH ₂ —R ⁵ is substantially either R or S on each asymmetric carbon atom. In the general formula (II), R ² ′ is substantially located on either the α side or the β side, except for the case of ═O, and O—CH ₂ —R ³ is substantially It is located on either the α side or the β side, and CH ₂ —O—CH ₂ —R ⁵ is substantially located on either the α side or the β side.

Here, “passing” means that, even if it is only the step of reacting the compound represented by the general formula (I) with the sulfur compound, it is further represented by the general formula (I) after the step of reacting with the sulfur compound. This means that the compound synthesized in the step of reacting the compound with a sulfur compound may include a step of alkylating or acylating the compound .
In addition, it is preferable to perform the process of alkylating the OH body obtained by reaction with a sulfur compound, or the process of acylating after the process of making the compound represented with general formula (I) react with a sulfur compound. It is also preferable to perform a step of oxidizing —OH to ═O.

That is, when R ¹ in the general formula (II) is an acyl group, the compound represented by the following general formula (IIA) is synthesized in the step of reacting the compound represented by the general formula (I) with a sulfur compound. In the step of acylating the compound represented by the general formula (IIA), it is preferable to produce the compound represented by the following general formula (II).

In formula ^(IIA), R 2, ^{R 3} and ^{R 5} have the same meanings as ^R 2, ^{R 3} and ^{R 5} in the general formula (I).

Compounds represented by a general formula (II) as the carbon atoms constituting the thiolane ring is a basic skeleton, three asymmetric carbon atoms in the case of R 2 ^'is = O, otherwise asymmetric Has 4 carbon atoms.
In the present invention, the term “sterically controlled” means that a compound represented by the general formula (II) is produced by changing the configuration existing in the asymmetric carbon atom to a specific configuration.

  For example, in the case of a compound represented by the general formula (II-1) described later, it is as follows.

In the general formula (I-1) and ^{(II-1), R 1} , R 2b, R 3, R 5 and X, ^R 1 in the general formula (I) and ^{(II), R 2b, R} 3, R It is synonymous with ⁵ and X, and its preferable range is also the same. M represents an alkali metal.

Here, MSH performs a nucleophilic attack on the carbon atom substituted by X via the following reaction route. Since this nucleophilic substitution reaction is an S _N 2 reaction, only the arrangement of the thiolane ring on the 4-position carbon atom is inverted (valden inversion), and the arrangement of asymmetric carbon atoms other than the 4-position is fixed without change. ing. In addition, in the following reaction route, it is the arrangement | positioning in which the part shown with the round part of the continuous line is being fixed.

In general formula (II), the compound in which R ² ′ is a hydroxy group can be produced, for example, by the following steps. That is, the step of dealkylating the compound represented by the following general formula (II-a) obtained via the step of reacting the compound represented by the general formula (I) with a sulfur compound, or the following general formula The compound represented by the following general formula (II-c) can be produced by the step of deacylating the compound represented by (II-b).

In formula (II-a) ~ (II -c), R 1, R 3 and ^{R 5} have the same meanings as ^R 1, ^{R 3} and ^{R 5} in the general formula (II). R ^2b has the same meaning as ^{R 2b} in the general formula (II-1). R ^2c have the same meanings as ^{R 2c} in the formula described below (II-2).

  In addition, it is preferable to synthesize | combine the compound represented by the below-mentioned general formula (II-3) from the compound represented by general formula (II-a) or (II-b).

Moreover, in general formula (II), the compound whose R < ² >'is = O can be manufactured by the following process, for example. That is, following the step of oxidizing the compound represented by the following general formula (II-c ′) obtained through the step of reacting the compound represented by the general formula (I) with the sulfur compound, A compound represented by the general formula (II-d) can be produced.

In formula (II-c ') and ^{(II-d), R 1} , R 3 and ^{R 5} have the same meanings as ^R 1, ^{R 3} and ^{R 5} in the general formula (II). R ¹ ′ represents an alkyl group or an acyl group.

The solvent used for the reaction in the step of reacting the compound represented by the general formula (I) with the sulfur compound is not particularly limited as long as it does not affect the reaction. Examples include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones, nitriles, amides, sulfoxides, aromatic hydrocarbons, ureas and water. These solvents may be used as a mixture.
Preferred solvents are solvents having an amide moiety or a sulfonyl group in the partial structure, that is, amides, cyclic amides, ureas, cyclic ureas or sulfoxides.
Specific examples include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, N-ethylpyrrolidone, 1,3-dimethyl-2-imidazolidinone and dimethyl sulfoxide.

  The usage-amount of a solvent is not specifically limited, What is necessary is just 1-50 times amount (v / w) with respect to the compound represented by general formula (I), and 1-15 times amount (v / W) is preferred.

Sulfur compounds used in this reaction include hydrogen sulfide or a salt thereof, in the present invention that use hydrogen sulfide or a salt thereof.
Examples of the hydrogen sulfide salt include alkali metal salts and alkaline earth metal salts.
The sulfur compound is preferably MSH or M ₂ S in which M is an alkali metal. Here, M is an alkali metal.
Examples of the sulfur compound include hydrogen sulfide, sodium hydrogen sulfide, sodium sulfide, potassium hydrogen sulfide, calcium hydrogen sulfide, and magnesium sulfide, and sodium hydrogen sulfide is preferable.
The sulfur compound may be a hydrate or may be used by dissolving in an aqueous solution.

  The amount of the sulfur compound used is preferably 0.2 to 10-fold mol, more preferably 0.5 to 2.0-fold mol based on the compound represented by the general formula (I), and 0.7 to 1. A 5-fold mole is more preferred.

The reaction temperature is preferably -20 to 100 ° C, more preferably -10 to 80 ° C, and further preferably -5 to 60 ° C.
The reaction time is preferably 5 minutes to 50 hours, more preferably 5 minutes to 24 hours, and even more preferably 5 minutes to 6 hours.

Among the compounds represented by the general formula (II), the compound in which R ¹ is an alkyl group causes the compound represented by the general formula (IIA) to react with an alcohol represented by R ¹ OH in the presence of an acid. Can be obtained.
In addition, the alkyl part of alcohol and the alkyl group in R < ¹ > of general formula (II) are synonymous with the alkyl group in below-mentioned R < ¹ >, and its preferable range is also the same.

The acids used are Bronsted acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid and trifluoromethanesulfonic acid, as well as aluminum chloride, aluminum bromide, tetrachloride. Mention may be made of Lewis acids such as tin, titanium tetrachloride, titanium (IV) isopropoxide, zinc chloride and trimethylsilyl trifluoromethanesulfonate.
Preferred acids include hydrochloric acid, sulfuric acid, aluminum chloride, tin tetrachloride and trimethylsilyl trifluoromethanesulfonate. Hydrochloric acid may be supplied from a gas cylinder or may be generated by reacting R ¹ OH and acyl chloride (preferably acetyl chloride) in the system.

  The amount of these acids used is preferably 0.01 to 100 times mol, more preferably 0.1 to 10 times mol, and 0.5 to 5 times mol based on the compound represented by the general formula (IIA). Is more preferable.

As the reaction solvent, aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, amides, sulfoxides, aromatic hydrocarbons and ureas are preferable, and alcohols represented by R ¹ OH are more preferable. preferable.

The reaction temperature is preferably -20 to 100 ° C, more preferably -10 to 80 ° C, and further preferably -5 to 60 ° C.
The reaction time is preferably 5 minutes to 50 hours, more preferably 5 minutes to 24 hours, and even more preferably 5 minutes to 6 hours.

Examples of the acylating agent in the step of acylating the compound represented by the general formula (IIA) include acyl halides and acid anhydrides.
In addition, the acyl part of an acylating agent and the acyl group in R < ¹ > of general formula (II) are synonymous with the acyl group in R < ¹ > mentioned later, and its preferable range is also the same.

  These acylating agents are preferably 50 to 1000 mol%, more preferably 80 to 500 mol%, still more preferably 100 to 200 mol% with respect to the compound represented by the general formula (IIA).

  The reaction solvent is preferably aliphatic hydrocarbons, halogenated hydrocarbons, ethers, esters, ketones, nitriles, amides, sulfoxides, aromatic hydrocarbons or ureas, ethers, esters , Ketones, nitriles, amides, sulfoxides or aromatic hydrocarbons are more preferred.

In the acylating step, a base is preferably used. For example, pyridines, trialkylamines optionally having a ring structure, N, N-dialkylanilines, N-alkyl-N-arylanilines , Triarylamines, guanidines, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates and alkali metal hydrogen carbonates, pyridines or trialkylamines Are preferred.
Moreover, the usage-amount of a base has preferable 20-500 mol% with respect to the compound represented by general formula (IIA).

The reaction temperature is preferably -20 to 100 ° C, more preferably -10 to 80 ° C.
The reaction time is preferably 5 minutes to 50 hours, more preferably 10 minutes to 24 hours, and even more preferably 30 minutes to 6 hours.

  Further, the acylating step is the same without synthesizing the compound represented by the general formula (IIA) from the compound represented by the general formula (I), and then removing the compound represented by the general formula (IIA). It is preferable to synthesize in a container.

The compound represented by the general formula (II-c) can be synthesized by dealkylating the compound represented by the general formula (II-a) with a Lewis acid.
Examples of Lewis acids include triisobutylaluminum, trimethylaluminum, aluminum chloride, aluminum bromide, tin tetrachloride, titanium tetrachloride, titanium (IV) isopropoxide, zinc chloride, and trimethylsilyl trifluoromethanesulfonate. Triisobutylaluminum is more preferred.
These Lewis acids are preferably 0.01 to 100 times mol, more preferably 0.1 to 50 times mol, and 0.5 to 10 times mol based on the compound represented by the general formula (II-a). Further preferred.

Reaction solvents are preferably aliphatic hydrocarbons, halogenated hydrocarbons, ethers, amides, sulfoxides, aromatic hydrocarbons and ureas, more preferably aliphatic hydrocarbons, halogenated carbons. Hydrogens, ethers or aromatic hydrocarbons.
The reaction temperature is preferably -20 to 100 ° C, more preferably -10 to 80 ° C, and further preferably -5 to 60 ° C.
The reaction time is preferably 5 minutes to 50 hours, more preferably 5 minutes to 24 hours, and even more preferably 5 minutes to 6 hours.

The compound represented by the general formula (II-c) can also be synthesized by deacylating the compound represented by the general formula (II-b) by acting a nucleophile.
Preferred nucleophiles are alcohols (eg methanol, ethanol, propanol and butanol), water, ammonia, primary amines (eg methylamine, ethylamine, propylamine and butylamine) and secondary amines (eg dimethyl). Amine and diethylamine). In the case of alcohols or water, it is more preferable to use an alkali or alkaline earth metal salt thereof.
More preferred nucleophiles are methanol, water or their alkali metal salts, ammonia or methylamine.

The reaction solvent is preferably aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones, nitriles, amides, sulfoxides, aromatic hydrocarbons, ureas or water, More preferred are alcohols, ethers, amides, sulfoxides or water, and still more preferred are alcohols (particularly preferably methanol) or water.
The nucleophile is preferably 0.1 to 100 times mol, more preferably 0.8 to 50 times mol, and further 1 to 30 times mol based on the compound represented by the general formula (II-b). preferable.
However, the alkali metal alkoxide in the case of using an alkali metal alkoxide (preferably sodium methoxide) as a nucleophile in an alcohol solvent (preferably methanol) is preferably 0.001 to 0.5 times mol, more preferably 0. 0.01-0.3 times mole, more preferably 0.05-0.2 times mole may be used.

The reaction temperature is preferably -20 to 100 ° C, more preferably -10 to 80 ° C, and further preferably -5 to 60 ° C.
The reaction time is preferably 5 minutes to 50 hours, more preferably 5 minutes to 24 hours, and even more preferably 5 minutes to 6 hours.

The oxidizing agent in the step of oxidizing the compound represented by the general formula (II-c ′) to the compound represented by the general formula (II-d) is 1,1,1-triacetoxy-1,1-dihydro- 1,2-benziodoxol-3 (1H) -one, o-iodoxybenzoic acid, dimethyl sulfoxide / acetic anhydride, etc., among which 1,1,1-triacetoxy-1,1-dihydro -1,2-benziodoxol-3 (1H) -one or o-iodoxybenzoic acid is preferred, and 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one is more preferred.
For example, when 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one is used as the oxidizing agent, the oxidizing agent is represented by the general formula (II-c ′ ) To 50 to 500 mol% is preferable, 75 to 300 mol% is more preferable, and 90 to 200 mol% is more preferable.

As the reaction solvent, dichloromethane is usually used.
The reaction temperature is preferably 0 to 80 ° C, more preferably 10 to 30 ° C.
The reaction time is preferably 10 minutes to 48 hours, more preferably 30 minutes to 12 hours, and even more preferably 60 minutes to 6 hours.

R ¹ in the compound represented by the general formula (II-d) is the same as R ¹ ′ in the general formula (II-c ′). The alkyl group or acyl group in R ¹ ′ may be led to a hydrogen atom.

<< thiolane skeleton type sugar compound >>
Chi Oran skeleton type sugar compound is a compound represented by the above general formula (II).
In the general formula (II), R ¹ represents a hydrogen atom, an alkyl group, or an acyl group, and R ² ′ represents —O—R ^2a , a fluorine atom, or ═O. Here, R ^2a represents a hydrogen atom, —CH ₂ —R ^2b or an acyl group. R ^2b , R ³ and R ⁵ each independently represents a hydrogen atom, an alkyl group, a vinyl group or an aryl group, and X represents a leaving group.
When the carbon atom substituted by R ² ′, O—CH ₂ —R ³ and CH ₂ —O—CH ₂ —R ⁵ in the general formula (II) is an asymmetric carbon atom, R ² ′ is ═O Except for the case where O-CH ₂ -R ³ is substantially located on either the α side or the β side, and CH ₂ —O—CH ₂ —R ⁵ is substantially located on either the α side or the β side.

  Here, “substantially” means, for example, the asymmetric purity of each asymmetric carbon (other than the anomeric position) [when the S form is excessive, (S form / (S form + R form) × 100) ] Is 95% or more, preferably 97% or more, more preferably 99% or more.

R ¹ is preferably an alkyl group among a hydrogen atom, an alkyl group, and an acyl group.
R number of carbon atoms in the alkyl group in ¹ is preferably 1 to 20, more preferably 1 to 10, more preferably 1 to 4, 1 is particularly preferred.
Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, octyl and dodecyl, and methyl or ethyl is preferable, and methyl is more preferable.
The alkyl group in R ¹ is preferably an unsubstituted alkyl group.

1-20 are preferable, as for carbon number of an acyl group, 2-20 are more preferable, and 2-12 are more preferable. The acyl group is preferably an alkylcarbonyl group or an arylcarbonyl group.
Examples of the alkylcarbonyl group include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, lauroyl, myristoyl, palmitoyl and stearoyl. The acyl group in R ¹ includes formyl.
Examples of the arylcarbonyl group include benzoyl, 4-methylbenzoyl, 4-chlorobenzoyl, 4-phenylbenzoyl and 2-naphthoyl.
The acyl group for R ¹ is more preferably an alkylcarbonyl group, and even more preferably an acetyl group.
Among these, R ¹ is preferably a hydrogen atom, an acetyl group or a methyl group, and more preferably an acetyl group or a methyl group.

  These acyl groups may be substituted with a substituent, and examples of the substituent include a halogen atom, an alkyl group, an aryl group, a heterocyclic group, an alkoxy group, an aryloxy group, an alkylthio group, and an arylthio group.

R ^2b and R ³ and R ⁵ in R ² ′ each independently represent a hydrogen atom, an alkyl group, a vinyl group or an aryl group.
1-10 are preferable and, as for carbon number of an alkyl group, 1-3 are more preferable, for example, methyl, ethyl, isopropyl, n-propyl, and 2-ethylhexyl are mentioned.
6-20 are preferable, as for carbon number of an aryl group, 6-16 are more preferable, 6-12 are more preferable, for example, phenyl and naphthyl are mentioned.
The alkyl group and the aryl group may have a substituent, and examples thereof include a halogen atom, an alkyl group, an aryl group, a heterocyclic group, an alkoxy group, an aryloxy group, an alkylthio group, and an arylthio group.

When R ^2a in R ² ′ is an acyl group, examples of the acyl group include an alkylcarbonyl group and an arylcarbonyl group, and an arylcarbonyl group is preferable. Moreover, the specific acyl groups include acyl groups mentioned in R ^1, other than an aryl group is preferred, the same as the preferable range of the acyl groups in R ^1.

R ² ′ is preferably —O—CH ₂ —R ^2b or an arylcarbonyloxy group among the above groups.
R ^2b , R ³ and R ⁵ are preferably aryl groups.

  The compound represented by general formula (II) is preferably a compound represented by any one of the following general formulas (II-1) to (II-10).

In formula (II-1) ~ (II -5), R 1, R 2b, R 3 and ^{R 5} are ^{R 1,} R 2b in the formula (II), and ^{R 3} and ^{R 5} synonymous. R ^2c represents an alkyl group or an aryl group.

^{-O-C (= O) -R} 2c is in formula (II-2), when ^{R 2a} in the ^{-O-R 2a} in ^{R 2} 'in formula (II) is an acyl group, i.e. alkylcarbonyloxy Group and arylcarbonyloxy group, respectively.
Therefore, the preferred range of —O—C (═O) —R ^2c is the same as the preferred ranges of the alkylcarbonyloxy group and arylcarbonyl group in R ² ′, and an aryloxycarbonyl group is preferred.
The aryl group of R ^2c may be substituted with a substituent, and examples of the substituent include a halogen atom, an alkyl group, an aryl group, a heterocyclic group, an alkoxy group, an aryloxy group, an alkylthio group, and an arylthio group. R ^2c is preferably an aryl group, more preferably phenyl, 4-halogen-substituted phenyl, 4-methylphenyl, 4-phenylphenyl, 4-alkoxyphenyl or 2-naphthyl.

The compound represented by the general formula (II) is more preferably a compound represented by the above general formula (II-1) or (II-2), wherein R ^2c is an aryl group.

  The compound represented by any one of the general formulas (II-1) to (II-5) is preferably a compound represented by any one of the following general formulas (II-1 ′) to (II-5 ′).

In the general formulas (II-1 ′) to (II-5 ′), R ¹ represents a hydrogen atom, an alkyl group, or an acyl group, R ^1b represents an unsubstituted alkyl group or an arylcarbonyl group, R ^20b , R ³⁰ and R ⁵⁰ each independently represents an aryl group, and R ^2c represents an alkyl group or an aryl group.

The alkyl group or arylcarbonyl group in R ^1b is synonymous with the alkyl group or arylcarbonyl group in R ¹ of the general formula (II), and the preferred range is also the same.
^Further, the aryl group in R ^{20b, R 30} and ^{R 50} is formula (II-1) ^R 2b of ~ (II-5), has the same meaning as the aryl group in ^{R 3} and ^{R 5,} the preferred range is also the same is there.

R ¹ is a hydrogen atom, a methyl group or an acetyl group, R ^1b is a methyl group, R ^20b , R ³⁰ and R ⁵⁰ are phenyl groups, and R ^2c has a chlorine atom, an alkyl group or an alkoxy group. It is preferably a phenyl group.
In addition, it does not have O—CH ₂ —R ^20b or O—C (═O) R ^2c at the 2-position, and is represented by General Formulas (II-3 ′) to (II-5 ′) having a specific substituent. The preferred ranges of R ¹ , R ³⁰ and R ⁵⁰ also apply to the compounds that are made.

In General Formulas (II-6) to (II-10), R ¹¹ represents an alkyl group or an acyl group, and R ²¹ , R ³¹ and R ⁵¹ each independently represents an alkyl group.

The number of carbon atoms in the alkyl group in R ¹¹ is preferably 1 to 20, more preferably 1 to 10, more preferably 1 to 4, 1 is particularly preferred.
Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, octyl and dodecyl, and methyl or ethyl is preferable, and methyl is more preferable.
Further, the alkyl group in R ¹¹ is preferably an unsubstituted alkyl group.

1-20 are preferable, as for carbon number of an acyl group, 2-20 are more preferable, and 2-12 are more preferable. The acyl group is preferably an alkylcarbonyl group or an arylcarbonyl group.
Examples of the alkylcarbonyl group include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, lauroyl, myristoyl, palmitoyl and stearoyl. The acyl group in R ¹ includes formyl.
Examples of the arylcarbonyl group include benzoyl, 4-methylbenzoyl, 4-chlorobenzoyl, 4-phenylbenzoyl and 2-naphthoyl.
The acyl group in R ¹¹ is more preferably an alkylcarbonyl group, and even more preferably an acetyl group.
R ¹¹ is particularly preferably a methyl group or an acetyl group.

R ^21, the carbon number of the alkyl group in ^{R 31} and ^{R 51} are, 1 to 10, more preferably 2 to 10, 3 to 7 are more preferred.
Examples of the alkyl group include methyl, ethyl, isopropyl, n-propyl and 2-ethylhexyl.
The alkyl group may have a substituent, and examples thereof include a halogen atom, an alkyl group, an aryl group, a heterocyclic group, an alkoxy group, an aryloxy group, an alkylthio group, and an arylthio group. Examples of the aryl group include phenyl and naphthyl.

More preferably, R ¹¹ is a methyl group or an acetyl group, and R ²¹ , R ³¹ and R ⁵¹ are each independently an alkyl group having 1 to 10 carbon atoms.
It is particularly preferable that R ²¹ , R ³¹ and R ⁵¹ are all the same substituent.

  The compound represented by any one of the general formulas (II-6) to (II-10) is represented by the following general formula (II-6 ′) or (II-8 ′) or the above general formula (II-7), A compound represented by either (II-9) or (II-10) is preferred.

In General Formula (II-6 ′), R ^11a represents an alkyl group or an acyl group, and R ^21a , R ^31a, and R ^51a each independently represents an alkyl group. However, when R ^11a is an acyl group, at least one of R ^21a , R ^31a and R ^51a is an unsubstituted alkyl group.
In General Formula (II-8 ′), R ^11b represents an alkyl group or an acyl group, and R ^21b , R ^31b, and R ^51b each independently represents an alkyl group. However, when R ^11b , R ^21b , R ^31b, and R ^51b are all alkyl groups, the total number of these carbon atoms is 5 or more.

The alkyl group or acyl group in R ^11a and R ^11b has the same meaning as the alkyl group or acyl group in R ¹¹ , and the preferred range is also the same.
^The alkyl group in ^{R 21a, R 31a, R 51a} , R 21b, R 31b and ^{R 51b are} the same meaning as the alkyl group in R ^{21, R 31} and ^{R 51,} the preferred range is also the same.

R ¹¹ , R ^11a and R ^11b are methyl groups or acetyl groups, and R ²¹ , R ^21a , R ^21b , R ³¹ , R ^31a , R ^31b , R ⁵¹ , R ^51a and R ^51b are each independently It is preferable that it is a C1-C10 alkyl group.
Among them, R ²¹ , R ³¹ and R ⁵¹ are the same substituent, R ^21a , R ^31a and R ^51a are the same substituent, and R ^21b , R ^31b and R ^51b are the same substituent. It is more preferable.

Hereinafter, specific examples of the compounds represented by a general formula (II). In addition, the compound represented by general formula (II) to illustrate is not limited to these.

Compound represented by general formula (II-1)

Compound represented by general formula (II-2)

Compound represented by general formula (II-3)

Compound represented by general formula (II-4)

Compound represented by general formula (II-5)

Compound represented by general formula (II-6)

Compound represented by general formula (II-7)

Compound represented by general formula (II-8)

Compound represented by general formula (II-9)

Compound represented by general formula (II-10)

  Of the compounds exemplified as the compounds represented by any one of the general formulas (II-1) to (II-5), the following compounds are particularly preferable.

  Of the compounds exemplified as the compounds represented by any one of the general formulas (II-6) to (II-10), the following compounds are particularly preferable.

In the general formulas (II-X-1) to (II-X-5), R ^x1 represents an acetyl group or a methyl group, and R ^x2 represents a methyl group, a propyl group, a butyl group, or a pentyl group.

R ^x2 is preferably a propyl group, a butyl group or a pentyl group, more preferably a butyl group or a pentyl group, and even more preferably a butyl group.

Compounds represented by a general formula (II) is synthesized compound represented by the formula (I) via the step of reacting a sulfur compound.
In the present invention, compounds represented by a general formula (II) is a ^{R 1} is an unsubstituted alkyl group, if ^{R 2} 'is ^{-O-R 2a, R 2a} is a hydrogen atom, When —CH ₂ —R ^2b or an acyl group, R ^2b is an alkyl group, a vinyl group or an aryl group, R ¹ is a substituted alkyl group, and R ² ′ is —O—R ^2a , R ^2a is a hydrogen atom, —CH ₂ —R ^2b or an acyl group, R ^2b is a hydrogen atom, an alkyl group or a vinyl group, and when R ¹ is a hydrogen atom or an acyl group, R ² ′ is O.
In the present invention, in general formulas (I) and (II), the acyl group in R ¹ and R ^2a , the alkyl group in R ¹ , and the alkyl group and aryl group in R ^2b , R ³ and R ⁵ are A halogen atom, an alkyl group, an aryl group, a heterocyclic group, an alkoxy group, an aryloxy group, an alkylthio group or an arylthio group may be substituted.

<< Compound Represented by Formula (I) >>
In the general formula (I), ^{R 3} and ^{R 5} has the same meaning as ^{R 3} and ^{R 5} in the general formula (II), and preferred ranges are also the same. R ² represents —O—R ^2a or a fluorine atom, and R ^2a has the same meaning as R ^2a in formula (II), and the preferred range is also the same.
X represents a leaving group.

X is preferably a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
1-10 are preferable, as for carbon number in an alkylsulfonyloxy group, 1-6 are more preferable, 1-3 are more preferable, and 1 is especially preferable.
Examples of the alkylsulfonyloxy group include methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, n-butylsulfonyloxy, t-butylsulfonyloxy, octylsulfonyloxy and dodecylsulfonyloxy.
6-16 are preferable, as for carbon number in an arylsulfonyloxy group, 6-12 are more preferable, and 6-10 are more preferable.
Examples of the arylsulfonyloxy group include benzenesulfonyloxy, toluenesulfonyloxy, naphthylsulfonyloxy, 4-chlorobenzenesulfonyloxy and 2,4,5-trichlorobenzenesulfonyloxy.

  Among the compounds represented by the general formula (I), the compounds for synthesizing the compounds represented by the general formulas (II-1) to (II-5) are represented by the following general formulas (I-1) to (I -5).

In the general formula (I-1) ~ (I -5), R 2b, R 2c, R 3 and ^{R 5} have the general formula (II-1) ~ (II -5) in ^{R 2b, R 2c, R 3} and has the same meaning as R ^5, the preferred range is also the same. X is synonymous with X in general formula (I), and its preferable range is also the same.

  Among the compounds represented by the general formula (I), the compounds for synthesizing the compounds represented by the general formulas (II-6) to (II-10) are represented by the following general formulas (I-6) to (I-6) It is represented by (I-10).

In the general formula (I-6) ~ (I -10), R 21, R 31 and ^{R 51} are the general formula (II-6) ~ (II -10) has the same meaning as ^{R 21, R 31} and ^{R 51} in The preferred range is also the same. X is synonymous with X in general formula (I), and its preferable range is also the same.

Here, a specific example is shown below on behalf of the compound in general formula (I-1) and (I-6). However, do not inventions is limited by to this.
In addition, in the general formulas (I-2) to (I-5) and (I-7) to (I-10), the compounds to which the leaving groups shown below are applied are also exemplified.

  The compound represented by the general formula (I) is disclosed in Chinese Patent Application No. 1010585855, Synlett, 2010, No3, p. 488-492, Journal of Organic Chemistry, 1992, 57, p. 5899-5907, Biomacromolecules, 2010, 11, p. 2415-2421 and Tetrahedron, 1994, 50, p. It can be synthesized according to the method described in 5361-5368.

  Here, the compound represented by the following general formula (h) or (h ′) is included in the compound represented by the general formula (I-1) or (I-2), and is synthesized by the following synthesis scheme, for example. can do.

In formula (h) and ^{(h '), R 2b,} R 2c, R 3, R 5 and X have the general formula (I-1) and (I-2) in ^{R 2b, R 2c, R 3} , It has the same meanings as R ⁵ and X, and the preferred range is also the same.

  Compound (a) [L-xylose] is alkylated to synthesize compound (b), and this is, for example, alkylated to obtain a compound represented by general formula (d), which is then hydrolyzed to give a general compound. A compound represented by the formula (e) was synthesized and reacted with O-methylhydroxylamine to obtain a compound represented by the general formula (f), and then a leaving group X was introduced to protect the protected carbonyl. A compound represented by the general formula (h) can be synthesized by deprotecting the methoxyimino group which is a protecting group.

  The compound represented by the general formula (h ′) can also be synthesized from the compound represented by the general formula (d ′) in the same manner as the compound represented by the general formula (h).

<< Use of Compound Represented by General Formula (II) >>
The compound represented by the general formula (II) is 1- (2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine, 1- (2-deoxy, which is useful as an antitumor agent. -2-methylene-4-thio-β-D-arabinofuranosyl) cytosine, 1- (2-deoxy-2,2-difluoro-4-thio-β-D-arabinofuranosyl) cytosine and / or It is a useful compound for the production of these peripheral compounds.

Examples of the use of the compound represented by the general formula (II) include a compound represented by the general formula (V).
The compound represented by the general formula (V) can be synthesized, for example, by reacting the compound represented by the general formula (II) with a silylated nucleobase and further deprotecting the compound.

In formula (IV), ^{R 2} ', ^{R 3} and ^{R 5} has the general formula (II) ^{R 2} in the' have the same meanings as ^{R 3} and ^{R 5,} the preferred range is also the same. B ′ represents a nucleobase or a group obtained by protecting an amino group in a nucleobase with an acyl group. The bond from R ^{2 ′} to the thiolane ring represents a single bond or a double bond.
In the general formula (V), R ²² represents a hydroxy group when R ² ′ represents —O—R ^2a in the general formula (II), and R ² ′ in the general formula (II) otherwise. It is synonymous with. B represents a nucleobase. The bond from R ²² to the thiolane ring represents a single bond or a double bond.
B′-SiR ₃ represents a silylated nucleobase or a group obtained by acylating and protecting an amino group in a nucleobase, and R represents an alkyl group (preferably methyl).
Here, the nucleobase in the general formulas (IV) and (V) has the same meaning as the nucleobase in the general formulas (IV-4) and (V-4) described later.

  Below, the manufacturing method of the compound represented by the compound represented by general formula (IV) and the compound represented by general formula (V) from the compound represented by general formula (II) is demonstrated in detail.

<< Thionucleoside synthesis route from compound represented by formula (II-4) >>
The thionucleoside represented by the general formula (V-4) is obtained from the compound represented by the general formula (II-4) directly or via the compound represented by the general formula (III-4). It can be synthesized by synthesizing and deprotecting the compound represented by IV-4).

In formula (III-4) and (IV-4), has the same meaning as ^{R 3} and ^{R 5 R 3} and ^{R 5} in formula (II), and their preferable ranges are also the same.
In the general formula (III-4), X ¹ represents a halogen atom (preferably a bromine atom).
In the general formula (IV-4), B ′ represents a nucleobase or a group obtained by protecting an amino group in a nucleobase with an acyl group.
In general formula (V-4), B represents a nucleobase.
B′-SiR ₃ represents a silylated nucleobase or a group obtained by acylating and protecting an amino group in a nucleobase, and R represents an alkyl group (preferably methyl).
B (X ² ) ₃ is boron trihalide, and X ² represents a halogen atom, preferably a chlorine atom or a bromine atom.

Here, the nucleobases in the general formulas (IV-4) and (V-4) are adenine which may be substituted, guanine which may be substituted, cytosine which may be substituted, thymine which may be substituted or It means uracil which may be substituted, and represents, for example, the following groups.
In addition, * shows the part couple | bonded with 1 position of a thiolane ring.

The compound represented by the general formula (III-4) can be synthesized by halogenating the compound represented by the general formula (II-4) with a halogenating agent. The compound represented by the general formula (IV-4) is obtained by reacting a nucleobase or a silylated compound which is a protected amino group thereof with a compound represented by the general formula (II-4) or (III-4). Can be synthesized by introducing a nucleobase or a protected amino group thereof.
Here, after synthesizing the compound represented by the general formula (IV-4), the amino group may be acylated to improve the crystallinity for purification.

<< Thionucleoside synthesis route from compound represented by formula (II-3) >>
The thionucleosides represented by the general formulas (V-11) to (V-14) are described in Journal of Organic Chemistry, 1996, 61, p. By a method similar to or similar to the method described in 822-823, from the compound represented by the general formula (II-3) to the compound represented by the general formula (II-5), 11) to (II-14) are synthesized. Subsequently, a compound corresponding to general formula (IV-4) into which a nucleobase or a protected amino group thereof was introduced was synthesized by the same method as that for the compound represented by general formula (II-4) described above. It can be synthesized by deprotection.

^R 1, ^{R 3} and ^{R 5} in the general formula (II-11) ~ (II -14) has the same meaning as ^R 1, ^{R 3} and ^{R 5} in the general formula (II), and preferred ranges are also the same.
Here, B of the thionucleoside represented by the general formulas (V-11) to (V-14) is a nucleobase group, and is synonymous with B in the general formula (V-4), and the preferred range is also the same. It is.

The compound represented by the general formula (II-5) can be synthesized by oxidizing the compound represented by the general formula (II-3).
The compound represented by the general formula (II-11) can be synthesized from the compound represented by the general formula (II-5) by a Wittig reaction, and the compound represented by the general formula (II-12) is deoxygenated. It can be synthesized from the compound represented by formula (II-5) by fluorination reaction.
The compounds represented by general formulas (II-13) and (II-14) can be synthesized by reacting the compound represented by general formula (II-5) with a Grignard reagent.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not construed as being limited thereto.

  Unless otherwise specified, the measurement was performed using the following measuring equipment.

(Measurement equipment used)
¹ H-NMR spectrum Measuring instrument: AVANCE 300 manufactured by Bruker
All δ values are given in ppm.

Example 1
[A] Synthesis of (3S, 4S, 5R) -3,4-bis (benzyloxy) -5-((benzyloxy) methyl) thiolan-2-ol and its alkoxy form

  Synthesis by reacting (2S, 3S, 4S) -1,3,4-tris (benzyloxy) -5-oxopentan-2-yl methanesulfonate with 15% aqueous sodium hydrogen sulfide solution as follows. did.

(2S, 3S, 4S) -1,3,4-tris (benzyloxy) -5-oxopentan-2-yl methanesulfonate 0.4 g in N, N-dimethylformamide 16 mL solution at 10 ° C. or lower, 0.4 mL of 15% aqueous sodium hydrogen sulfide solution was added dropwise, and the mixture was stirred at 25 ° C. for 1 hour. To the reaction mixture, 30 mL of ethyl acetate and 30 mL of a saturated aqueous sodium chloride solution were added, and the aqueous layer was removed. The organic layer was washed three times with an aqueous sodium hydrogen carbonate solution and once with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/3, final ratio 1/2) to give (3S, 4S, 5R) -3, 0.2 g of 4-bis (benzyloxy) -5-((benzyloxy) methyl) thiolan-2-ol was obtained.
As a result of measuring ¹ H-NMR, it was an anomeric mixture of about 50:50.

¹ H-NMR (CDCl ₃ ) δ value:
3.28 (0.5 H, dd, J = 12 Hz), 3.29 (0.5 H, dd, J = 7.7 Hz), 3.41 (0.5 H, dd, J = 5.1, 10. 0 Hz), 3.45 (0.5 H, dd, J = 6.0, 9.5 Hz), 3.51-3.60 (1 H, m), 3.65 (0.5 H, t, J = 9) .6 Hz), 3.93-3.98 (0.5 H, m), 4.06 to 4.16 (0.5 H, m), 4.21 (0.5 H, dd, J = 4.9, 7.2 Hz), 4.21 (0.5 H, brs), 4.29 (0.5 H, d, J = 1.4 Hz), 4.41-4.73 (6 H, m), 5.18 ( 0.5H, dd, J = 4.0, 7.7 Hz), 5.39 (0.5 H, td, J = 1.1, 6.5 Hz), 7.20-7.37 (15H, m)

  To a solution of 1.43 g of (3S, 4S, 5R) -3,4-bis (benzyloxy) -5-((benzyloxy) methyl) thiolan-2-ol in 50 mL of methanol at 0-10 ° C. under nitrogen atmosphere. 0.92 mL of acetyl chloride was added and stirred at room temperature for 23 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give (2R, 3S, 4S) -3,4-bis (benzyloxy) -2-((benzyloxy) as a colorless oil. 0.87 g of methyl) -5-methoxythiolane was obtained.

¹ H-NMR (CDCl ₃ ) δ value:
3.31 (3H, s), 3.33-3.40 (1H, m), 4.10-4.20 (2H, m), 4.45 (1H, dd, J = 7.2, 9 .2 Hz), 4.52 (2 H, s), 4.63 (1 H, dd, J = 6.6, 9.2 Hz), 4.61-4.69 (4 H, m), 4.79 (1 H) , D, J = 11.6 Hz), 7.40-7.22 (15H, m)

[B] Synthesis of (3S, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -2-methoxythiolan-3-ol

  (3S, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -2-methoxythiolan-3-ol was synthesized as follows.

  To 0.85 g of (2R, 3S, 4S) -3,4-bis (benzyloxy) -2-((benzyloxy) methyl) -5-methoxythiolane, 1.0 mol / L 19 mL of a toluene solution of isobutylaluminum was added and stirred at 60 ° C. for 18 hours. Ice, an aqueous potassium sodium tartrate solution (Rochelle salt) and ethyl acetate were added to the reaction mixture at 0 to 10 ° C., and the organic layer was separated. The extract was washed successively with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give (3S, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl)- 0.65 g of 2-methoxythiolan-3-ol was obtained.

¹ H-NMR (CDCl ₃ ) δ value:
2.64 (1H, d, J = 9.6 Hz), 3.37 (3H, s), 3.41-3.49 (2H, m), 3.61-3.69 (1H, m), 3.86-3.93 (1H, m), 4.31 (1H, ddd, J = 4.4, 8.2, 9.6 Hz), 4.53 (2H, s), 4.68 (1H) , D, J = 11.6 Hz), 4.71 (1H, d, J = 4.4 Hz), 4.80 (1H, d, J = 11.6 Hz), 7.22-7.38 (10H, m)

[C] Synthesis of (4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -2-methoxythiolan-3-one

  It was synthesized by Dess-Martin oxidation of (3S, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -2-methoxythiolan-3-ol as follows. .

  (3S, 4S, 5R) -4- (Benzyloxy) -5-((benzyloxy) methyl) -2-methoxythiolan-3-ol 108 mg in dichloromethane 3 mL solution at room temperature under nitrogen atmosphere at 1,1 , 1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one (Des Martin periodinane) 190 mg was added and stirred at room temperature for 80 minutes. Ethyl acetate, aqueous sodium thiosulfate solution and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was stirred at room temperature for 100 minutes. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give (4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -2- 94 mg of methoxythiolan-3-one was obtained.

¹ H-NMR (CDCl ₃ ) δ value:
2.64 (1H, d, J = 9.6 Hz), 3.38 (3H, s), 3.42-3.48 (1H, m), 3.53-3.67 (2H, m), 4.30 (1H, d, J = 5.4 Hz), 4.53 (2H, s), 4.61 (1H, d, J = 11.7 Hz), 4.83 (1H, s), 4. 87 (1H, d, J = 11.7 Hz), 7.22-7.40 (10H, m)

[D] 4-Amino-1-((3S, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -3-hydroxy-3-methylthiolan-2-yl) -1 , 2-Dihydropyrimidin-2-one and 4-amino-1-((3R, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -3-hydroxy-3-methylthiolane Synthesis of 2-yl) -1,2-dihydropyrimidin-2-one

  4-Amino-1-((3S, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -3-hydroxy-3-methylthiolan-2-yl as follows ) -1,2-dihydropyrimidin-2-one and 4-amino-1-((3R, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -3-hydroxy-3 -Methylthiolan-2-yl) -1,2-dihydropyrimidin-2-one was synthesized.

  To a solution of 1.29 g of (4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -2-methoxythiolan-3-one in 30 mL of tetrahydrofuran was added 3% at −40 ° C. under a nitrogen atmosphere. A 3.0 mol / 0.0 mol / L methylmagnesium bromide tetrahydrofuran solution was added, and the mixture was stirred at −40 ° C. for 1 hour and then at room temperature for 1 hour. An aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give (2R, 3S, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) as a colorless oil. ) -2-Methoxy-3-methylthiolan-3-ol 0.29 g, (2S, 3R, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -2-methoxy-3 -0.07 g of methylthiolan-3-ol, and 0.47 g of a 0.65: 0.35 mixture of (2R, 3S, 4S, 5R) and (2S, 3R, 4S, 5R) isomers were obtained.

(2R, 3S, 4S, 5R) -4- (Benzyloxy) -5-((benzyloxy) methyl) -2-methoxy-3-methylthiolan-3-ol
¹ H-NMR (CDCl ₃ ) δ value:
1.44 (3H, s), 3.18 (1H, br), 3.33 (1H, dt, J = 4.4, 8.1 Hz), 3.38 (3H, s), 3.46 ( 1H, dd, J = 8.1, 9.4 Hz), 3.74 (1H, dd, J = 4.3, 9.4 Hz), 3.82 (1H, d, J = 8.1 Hz), 4 .41 (1H, s), 4.53 (2H, s), 4.59 (1H, d, J = 11.7 Hz), 4.92 (1H, d, J = 11.7 Hz), 7.38 -7.25 (10H, m)

(2S, 3R, 4S, 5R) -4- (Benzyloxy) -5-((benzyloxy) methyl) -2-methoxy-3-methylthiolan-3-ol
¹ H-NMR (CDCl ₃ ) δ value:
1.33 (3H, s), 3.40 (3H, s), 3.44-3.55 (4H, m), 3.81 (1H, dt, J = 4.6, 6.5 Hz), 4.45-4.55 (2H, m), 4.57 (1H, s), 4.60-4.71 (2H, m), 7.23-7.39 (10H, m)

  (2R, 3S, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -2-methoxy-3-methylthiolan-3-ol and (2S, 3R, 4S, 5R)- A mixture of 4- (benzyloxy) -5-((benzyloxy) methyl) -2-methoxy-3-methylthiolan-3-ol (0.65: 0.35) in 112 mg of acetonitrile in 1.5 mL of nitrogen Under an atmosphere, 67 mg of cytosine and 0.30 mL of trimethylsilyl N- (trimethylsilyl) ethanecarboxyimidate were added at room temperature, followed by stirring at 80 ° C. for 1 hour. At room temperature, 0.22 mL of trimethylsilyl trifluoromethanesulfonate was added and stirred at 80 ° C. for 5 hours. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and colorless oily 4-amino-1-((4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -3-methyl-3-((trimethylsilyl) was obtained. ) Oxy) thiolan-2-yl) -1,2-dihydropyrimidin-2-one was obtained.

  To a 3 mL solution of the obtained colorless oil in tetrahydrofuran was added 0.3 mL of a 1.0 mol / L tetrabutylammonium fluoride tetrahydrofuran solution at 0 ° C. in a nitrogen atmosphere, and the mixture was stirred at room temperature for 80 minutes. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The organic layer was washed successively with water, aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography. White solid 4-amino-1-((2S, 3S, 4S, 5R) -4- (benzyloxy) -5- ((Benzyloxy) methyl) -3-hydroxy-3-methylthiolan-2-yl) -1,2-dihydropyrimidin-2-one and 4-amino-1-((2R, 3S, 4S, 5R)- 0.41: 0.59 mixture of 4- (benzyloxy) -5-((benzyloxy) methyl) -3-hydroxy-3-methylthiolan-2-yl) -1,2-dihydropyrimidin-2-one 7 mg, and white solid 4-amino-1-((2R, 3R, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -3-hydroxy-3-methylthiolane-2 -Ile) It was obtained 1,2-dihydro-pyrimidin-2-one 5 mg.

4-amino-1-((2S, 3S, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -3-hydroxy-3-methylthiolan-2-yl) -1, 2-dihydropyrimidin-2-one and 4-amino-1-((2R, 3S, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -3-hydroxy-3-methylthio Lan-2-yl) -1,2-dihydropyrimidin-2-one 0.41: 0.59 mixture
¹ H-NMR (CD ₃ OD) δ value:
1.19 (1.23H, s), 1.40 (1.77H, s), 3.40-4.02 (4H, m), 4.42-4.71 (4H, m), 5. 61 (0.59H, d, J = 7.2 Hz), 5.70 (0.41H, d, J = 7.2 Hz), 6.15 (0.59H, s), 6.27 (0.41H) , S), 7.24-7.41 (10H, m), 8.15 (0.41H, d, J = 7.2 Hz), 8.31 (0.59H, d, J = 7.8 Hz)

4-amino-1-((2R, 3R, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -3-hydroxy-3-methylthiolan-2-yl) -1, 2-Dihydropyrimidin-2-one
¹ H-NMR (CD ₃ OD) δ value:
1.19 (3H, s), 2.63 (1H, s), 3.64-3.84 (3H, m), 3.94 (1H, d, J = 8.7 Hz), 4.45 ( 1H, d, J = 11.1 Hz), 4.54 (1H, d, J = 11.1 Hz), 4.59 (1H, d, J = 11.6 Hz), 4.68 (1H, d, J = 11.6 Hz), 5.21 (1H, d, J = 7.5 Hz), 6.23 (1 H, s), 7.23-7.45 (10 H, m), 8.38 (1 H, d) , J = 7.5Hz)

[E] 4-Amino-1-[(3S, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) -3-methylthiolan-2-yl] -1,2-dihydropyrimidine-2- ON and 4-amino-1-[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) -3-methylthiolan-2-yl] -1,2-dihydropyrimidine-2 -On synthesis

  4-Amino-1-[(3S, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) -3-methylthiolan-2-yl] -1,2-dihydropyrimidine as follows 2-one and 4-amino-1-[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) -3-methylthiolan-2-yl] -1,2-dihydro Pyrimidin-2-one was synthesized.

  4-Amino-1-((3S, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -3-hydroxy-3-methylthiolan-2-yl) -1,2- Dihydropyrimidin-2-one ((2R, 3S, 4S, 5R) isomer: (2S, 3S, 4S, 5R) isomer = 41: 59) 7.0 mg of dichloromethane in 0.4 mL solution was added to titanium tetrachloride (1M dichloromethane). Solution) 0.060 mL was added, and the mixture was stirred at 0 ° C. for 1.5 hours under a nitrogen atmosphere. After stirring at room temperature for 3.5 hours, 0.030 mL of titanium tetrachloride (1M dichloromethane solution) was further added and stirred at room temperature for 1.5 hours. Methanol was added to the reaction mixture, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: methanol / ethyl acetate), and 4-amino-1-[(3S, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl). -3-Methylthiolan-2-yl] -1,2-dihydropyrimidin-2-one ((2S, 3S, 4S, 5R) isomer: (2R, 3S, 4S, 5R) isomer = 28: 72) 8 mg was obtained.

4-Amino-1-[(2S, 3S, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) -3-methylthiolan-2-yl] -1,2-dihydropyrimidin-2-one
¹ H-NMR (CD ₃ OD) δ value:
1.17 (3H, s), 3.61-3.65 (1H, m), 3.73 (1H, dd, J = 11.0, 6.6 Hz), 3.88 (2H, dd, J = 10.9, 5.6 Hz), 3.95 (1 H, d, J = 2.0 Hz), 5.85 (1 H, d, J = 7.9 Hz), 6.26 (1 H, s), 8 .31 (1H, d, J = 7.9 Hz)

4-Amino-1-[(2R, 3S, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) -3-methylthiolan-2-yl] -1,2-dihydropyrimidin-2-one
¹ H-NMR (CD ₃ OD) δ value:
1.34 (3H, s), 3.24 (1H, q, J = 5.1 Hz), 3.88-3.91 (3H, m), 5.87 (1H, D, J = 7.3 Hz) ), 6.23 (1H, S), 8.34 (1H, d, J = 7.3 Hz)

  4-amino-1-[(2R, 3R, 4S, 5R) -4- (benzyloxy) -5-[(benzyloxy) methyl] -3-hydroxy-3-methylthiolan-2-yl] -1, To a solution of 2-dihydropyrimidin-2-one 7.0 mg in dichloromethane 0.4 mL was added titanium tetrachloride (1M dichloromethane solution) 0.060 mL, and the mixture was stirred at 0 ° C. for 1.5 hours under a nitrogen atmosphere. After stirring at room temperature for 3.5 hours, 0.030 mL of titanium tetrachloride (1M dichloromethane solution) was further added and stirred at room temperature for 1.5 hours. Methanol was added to the reaction mixture, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: methanol / ethyl acetate), and 4-amino-1-[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxy 0.9 mg of (methyl) -3-methylthiolan-2-yl] -1,2-dihydropyrimidin-2-one was obtained.

4-Amino-1-[(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) -3-methylthiolan-2-yl] -1,2-dihydropyrimidin-2-one
¹ H-NMR (CD ₃ OD) δ value:
1.12 (3H, s), 3.48 (1H, dt, J = 9.9, 4.0 Hz), 3.75 (1H, d, J = 9.2 Hz), 3.95 (2H, Dt , J = 4.0, 0.7 Hz), 5.98 (1H, D, J = 7.9 Hz), 6.12 (1H, s), 8.38 (1H, d, J = 7.3 Hz)

[F] Synthesis of Raw Material The raw material (2S, 3S, 4S) -1,3,4-tris (benzyloxy) -5-oxopentan-2-yl methanesulfonate has a plurality of The process was synthesized.

  Concentrated sulfuric acid (0.81 mL) was added dropwise to a mixed solution of (3S, 4S, 5S) -5- (hydroxymethyl) oxolane-2,3,4-triol (20 g) and methanol (285 mL) and stirred at 25 ° C. for 6 hours ( After the reaction solution became a homogeneous solution), it was allowed to stand overnight. After neutralizing the reaction solution by adding 5.5 mL of 28% sodium methoxide / methanol solution, 100 mL of toluene was added to the reaction solution, and the solvent was distilled off under reduced pressure (2S, 3S, 4S) -2- ( 25.1 g of a crude product of hydroxymethyl) -5-methoxyoxolane-3,4-diol was obtained.

  3.2 g of sodium hydride (60%, dispersed in liquid paraffin) was slowly added over 30 minutes to a N, N-dimethylformamide solution of 2.1 g of the obtained crude product under a nitrogen stream at 10 ° C. or lower. After stirring at 25 ° C. for 45 minutes, 9.3 mL of benzyl bromide was added dropwise and further stirred at that temperature for 24 hours. After adding 100 mL of ethyl acetate and 200 mL of 1N aqueous hydrochloric acid to the reaction solution, the aqueous layer was removed. The organic layer was washed successively with 100 mL of aqueous sodium hydrogen carbonate solution and 100 mL of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/5, final ratio 1/4) to give (2S, 3R, 4S, 5R)- 2.5 g of 3,4-bis (benzyloxy) -2-((benzyloxy) methyl) -5-methoxyoxolane and (2S, 3R, 4S, 5S) -3,4-bis (benzyloxy) -2 1.7 g of-((benzyloxy) methyl) -5-methoxyoxolane was obtained.

(2S, 3R, 4S, 5R) -3,4-bis (benzyloxy) -2-((benzyloxy) methyl) -5-methoxyoxolane
¹ H-NMR (CDCl ₃ ) δ value:
3.40 (3H, s), 3.71 (1H, dd, J = 7.2, 10.2 Hz), 3.79 (1H, dd, J = 5.0, 10.2 Hz), 3.96 −3.98 (1H, m), 4.05 (1H, dd, J = 2.6, 5.9 Hz), 4.40−4.63 (7H, m), 4.91 (1H, d, J = 1.1 Hz), 7.24-7.37 (15 H, m)

(2S, 3R, 4S, 5S) -3,4-bis (benzyloxy) -2-((benzyloxy) methyl) -5-methoxyoxolane
¹ H-NMR (CDCl ₃ ) δ value:
3.40 (3H, s), 3.59 (1H, dd, J = 6.6, 10.6 Hz), 3.71 (1H, dd, J = 4.0, 10.6 Hz), 4.02 (1H, dd, J = 4.3, 5.9 Hz), 4.31 (1H, dd, J = 6.0, 7.1 Hz), 4.39 (1H, dt, J = 3.89, 6) .9 Hz), 4.48-4.66 (6H, m), 4.81 (1 H, d, J = 4.3 Hz), 7.22-7.36 (15 H, m)

(2S, 3R, 4S, 5R) -3,4-bis (benzyloxy) -2-((benzyloxy) methyl) -5-methoxyoxolane and (2S, 3R, 4S, 5S) -3 , 4-Bis (benzyloxy) -2-((benzyloxy) methyl) -5-methoxyoxolane 1.1 g of trifluoroacetic acid solution was cooled to 10 ° C. or lower, and 2.1 mL of water was added dropwise. Stir at 4 ° C. for 4 hours. The reaction solution was slowly added to a mixed solution of 100 mL of ethyl acetate / 100 mL of water / 30 g of sodium bicarbonate while stirring, and the aqueous layer was removed. The organic layer was washed successively with 50 mL of aqueous sodium hydrogen carbonate solution, 50 mL of water and 50 mL of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/3, final ratio 1/2) to give (3S, 4R, 5S) -3, 2.8 g of 4-bis- (benzyloxy) -5-((benzyloxy) methyl) oxolan-2-ol was obtained.
As a result of measuring ¹ H-NMR, it was an anomeric mixture of about 65:35.

¹ H-NMR (CDCl ₃ ) δ value:
3.63-4.13 (5H, m), 4.36-4.64 (7H, m), 5.24 (0.65H, d, J = 11.9 Hz), 5.47 (0.35H) , Dd, J = 4.2, 9.7 Hz), 7.23-7.39 (15H, m)

(3S, 4R, 5S) -3,4-bis- (benzyloxy) -5-((benzyloxy) methyl) oxolan-2-ol in a solution of methanol (27.5 mL) in 27.5 mL of methanol, 3.4 mL of pyridine, p- Toluenesulfonic acid monohydrate (1.7 g) and O-methylhydroxylamine hydrochloride (1.0 g) were added at 25 ° C., stirred at the same temperature for 3 hours, and allowed to stand overnight. About 15 mL of methanol was distilled off under reduced pressure, 100 mL of ethyl acetate and 100 mL of water were added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed successively with 0.5N aqueous hydrochloric acid, aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give colorless oily methoxy ((2R, 3R, 4S) 2.94 g of -2,3,5-tris (benzyloxy) -4-pentylidene) amine was obtained.
As a result of measuring ¹ H-NMR, it was an about 82:18 oxime isomer mixture.

¹ H-NMR (CDCl ₃ ) δ value:
2.43 (0.82H, d, J = 6.9 Hz), 2.65 (0.18H, d, J = 5.4 Hz), 3.37-3.47 (2H, m), 3.74 (0.82H, dd, J = 2.7, 6.1 Hz), 3.79 (0.18H, dd, J = 3.5, 5.2 Hz), 3.88 (3H, s), 3. 94-4.02 (1H, m), 4.25 (0.82H, dd, J = 6.1, 8.0 Hz), 4.37-4.67 (5H, m), 4.76 (0 .18H, d, J = 11.3 Hz), 4.78 (0.82 H, d, J = 11.3 Hz), 4.89 (0.18 H, dd, J = 5.2, 6.8 Hz), 6.86 (0.18H, d, J = 6.8 Hz), 7.24-7.36 (15H, m), 7.42 (0.82H, d, J = 8.0 Hz)

Methyl ((2R, 3R, 4S) -2,3,5-tris (benzyloxy) -4-pentylidene) amine in a solution of 2.9 g of ethyl acetate in 30 mL of ethyl acetate at 10 ° C. or less and 1.5 mL of triethylamine and methanesulfonyl chloride in an amount of 0. 75 mL was added and stirred at 25 ° C. for 7 hours. 50 mL of ethyl acetate and 100 mL of 1N hydrochloric acid water were added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed with 100 mL of sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution 100
After sequentially washing with mL and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give (2S, 3S, 4R) -1,3,4-tris (benzyloxy) -5- (methoxy) as a colorless oil. 3.4 g of imino) pentan-2-yl methanesulfonate was obtained.
As a result of measuring ¹ H-NMR, it was an about 82:18 oxime isomer mixture.

¹ H-NMR (CDCl ₃ ) δ value:
2.88 (0.54H, s), 2.93 (2.46H, s), 3.39 (0.18H, dd, J = 5.0, 11.6 Hz), 3.50 (0.82H) , Dd, J = 5.8, 11.2 Hz), 3.62-3.72 (1.18 H, m), 3.87 (0.54 H, s), 3.88 (2.46 H, s) 3.90 (0.82H, dd, J = 4.4, 6.0 Hz), 4.08-4.16 (1.64H, m), 4.19-4.48 (3H, m), 4.55-4.66 (2.18H, m), 4.73 (0.18H, dd, J = 2.8, 5.7 Hz), 4.85-4.92 (1H, m), 5 .79 (0.18H, d, J = 5.8 Hz), 7.26-7.34, (15H, m), 6.05 (0.82H, d, J = 7.7 Hz)

  (2S, 3S, 4R) -1,3,4-Tris (benzyloxy) -5- (methoxyimino) pentan-2-yl methanesulfonate 3.4 g in acetone 60 ml solution in 30% formalin aqueous solution 40 ml and 2N hydrochloric acid 1.55 mL of water was added and stirred at 25 ° C. for 20 hours. About 50 mL of acetone was distilled off under reduced pressure, 100 mL of ethyl acetate and 50 mL of aqueous sodium hydrogen carbonate solution were added, and the aqueous layer was removed. The organic layer was washed successively with 100 mL of aqueous sodium hydrogen carbonate solution, 100 mL of water and 100 mL of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/2, final ratio 1/1) to give (2S, 3S, 4S) -1, 2.9 g of 3,4-tris (benzyloxy) -5-oxopentan-2-yl methanesulfonate was obtained.

¹ H-NMR (CDCl ₃ ) δ value:
2.93 (3H, s), 3.56 (1H, dd, J = 6.3, 12.5 Hz), 3.74 (1H, dd, J = 4.4, 11.8 Hz), 3.90 (1H, dd, J = 0.50, 5.0 Hz), 4.18 (1H, dd, J = 4.4, 6.3 Hz), 4.36-4.73 (6H, m), 4. 88-4.94 (1H, m), 7.23-7.37 (15H, m), 7.62 (1H, s)

Example 2
[A] Synthesis of (3S, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -2-hydroxythiolan-3-yl 4-methylbenzoate and its alkoxy form

  (2S, 3S, 4S) -3,5-bis (benzyloxy) -4- (methanesulfonyloxy) -1-oxopentan-2-yl 4-methylbenzoate was converted to 15% hydrogen sulfide as follows: It was synthesized by reacting with an aqueous sodium solution.

(2S, 3S, 4S) -3,5-bis (benzyloxy) -4- (methanesulfonyloxy) -1-oxopentan-2-yl 4-methylbenzoate 0.85 g N, N-dimethylformamide 16 mL To the solution, 0.9 mL of a 15% aqueous sodium hydrogen sulfide solution was added dropwise at 10 ° C. or lower, and the mixture was stirred at 25 ° C. for 1 hour. To the reaction mixture, 80 mL of ethyl acetate and 80 mL of saturated aqueous sodium chloride solution were added, and the aqueous layer was removed. The organic layer was washed successively with an aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/2) to give colorless oily (3S, 4S, 5R) -4- (benzyloxy 0.47 g of) -5-((benzyloxy) methyl) -2-hydroxythiolan-3-yl 4-methylbenzoate was obtained.
As a result of measuring ¹ H-NMR, it was an anomeric mixture of about 80:20.

¹ H-NMR (CDCl ₃ ) δ value:
2.42 (3H, m), 3.37 (0.8 H, d, J = 8.5 Hz), 3.40 (0.2 H, d, J = 11.6 Hz), 3.49-3.61 (2H, m), 4.05 (0.2H, dd, J = 6.5, 9.0 Hz), 4.35-4.72 (5.8H, m), 5.35-5.46 ( 1.8H, m), 5.68 (0.2H, brs), 7.19-7.36 (12H, m), 7.79 (0.4H, d, J = 8.2 Hz), 7. 94 (1.6H, d, J = 8.2Hz)

  (3S, 4S, 5R) -4- (Benzyloxy) -5-((benzyloxy) methyl) -2-hydroxythiolan-3-yl 4-methylbenzoate in 10 mL of methanol in 10 mL or less Then, 0.14 mL of acetyl chloride was added dropwise, stirred at 25 ° C. for 1 hour, and allowed to stand at room temperature for 3 days. To the reaction solution, 100 mL of ethyl acetate and 50 mL of an aqueous sodium hydrogen carbonate solution were added, and the aqueous layer was removed. The organic layer was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/5) to give (2R, 3S, 4S, 5R) -4- (benzyl Oxy) -5-((benzyloxy) methyl) -2-methoxythiolan-3-yl 4-methylbenzoate 0.04 g and (2S, 3S, 4S, 5R) -4- (benzyloxy) -5 0.05 g of ((benzyloxy) methyl) -2-methoxythiolan-3-yl 4-methylbenzoate was obtained.

(2R, 3S, 4S, 5R) -4- (Benzyloxy) -5-((benzyloxy) methyl) -2-methoxythiolan-3-yl 4-methylbenzoate
¹ H-NMR (CDCl ₃ ) δ value:
2.42 (3H, s), 3.26 (3H, s), 3.42-3.56 (2H, m), 3.65 (1H, dd, J = 7.3, 9.1 Hz), 4.42 (1H, dd, J = 5.5, 8.7 Hz), 4.56 (2H, s), 4.71 (2H, d, J = 2.6 Hz), 5.11 (1H, d , J = 4.1 Hz), 5.37 (1H, dd, J = 4.1, 8.7 Hz), 7.23-7.36 (12H, m), 7.93 (2H, d, J = 8.2Hz)

(2S, 3S, 4S, 5R) -4- (Benzyloxy) -5-((benzyloxy) methyl) -2-methoxythiolan-3-yl 4-methylbenzoate
¹ H-NMR (CDCl ₃ ) δ value:
2.41 (3H, s), 3.39 (3H, s), 3.51 (1H, dd, J = 6.7, 9.7 Hz), 3.66 (1H, dd, J = 6.1) , 9.7 Hz), 3.87 (1H, dd, J = 6.1, 12.1 Hz), 4.14-4.17 (1H, m), 4.49 (2H, s), 4.64. (2H, dd, J = 12.1, 30.3 Hz), 5.02 (1H, brs), 5.72-5.74 (1H, m), 7.21-7.30 (12H, m) 7.68 (2H, d, J = 7.7 Hz)

[B1] Synthesis of (2R, 3S, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -2-methoxythiolan-3-ol

  (2R, 3S, 4S, 5R) -4- (Benzyloxy) -5-((benzyloxy) methyl) -2-methoxythiolan-3-yl 4-methylbenzoate was converted to sodium methoxy as follows: It was synthesized by reacting with sulfoxide.

  (2R, 3S, 4S, 5R) -4- (Benzyloxy) -5-((benzyloxy) methyl) -2-methoxythiolan-3-yl 4-methylbenzoate 0.03 g in 10 mL methanol A drop of methoxide (28% methanol solution) was added, and the mixture was stirred at 25 ° C. for 1 hour and allowed to stand overnight. One drop of acetic acid was added to the reaction solution, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/3 → 1/1) to give a colorless oil (2R , 3S, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -2-methoxythiolan-3-ol 0.03 g was obtained.

¹ H-NMR (CDCl ₃ ) δ value:
2.64 (1H, d, J = 9.6 Hz), 3.37 (3H, s), 3.41-3.49 (2H, m), 3.61-3.69 (1H, m), 3.91 (1H, dd, J = 6.0, 8.2 Hz), 4.31 (1H, ddd, J = 4.4, 8.2, 9.6 Hz), 4.53 (2H, s) 4.68 (1H, d, J = 11.6 Hz), 4.71 (1 H, d, J = 4.4 Hz), 4.80 (1H, d, J = 11.6 Hz), 7.22- 7.38 (10H, m)

[B2] Synthesis of (2S, 3S, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -2-methoxythiolan-3-ol

  (2S, 3S, 4S, 5R) -4- (Benzyloxy) -5-((benzyloxy) methyl) -2-methoxythiolan-3-yl 4-methylbenzoate was converted to sodium methoxy as follows: It was synthesized by reacting with sulfoxide.

  (2S, 3S, 4S, 5R) -4- (Benzyloxy) -5-((benzyloxy) methyl) -2-methoxythiolan-3-yl 4-methylbenzoate 0.03 g in 10 mL of methanol in sodium A drop of methoxide (28% methanol solution) was added, and the mixture was stirred at 25 ° C. for 1 hour and allowed to stand overnight. One drop of acetic acid was added to the reaction solution, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/3 → 1/1) to give a pale yellow oily ( 2S, 3S, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -2-methoxythiolan-3-ol 0.04 g was obtained.

¹ H-NMR (CDCl ₃ ) δ value:
3.36-3.83 (4H, m), 3.52 (2H, d, J = 4.1 Hz), 3.75 (1H, dd, J = 4.8, 9.1 Hz), 3.88 (1H, t, J = 3.9 Hz), 4.34-4.40 (1H, m), 4.50 (1H, d, J = 12.2 Hz), 4.57 (2H, d, J = 11.2 Hz), 4.68 (1 H, d, J = 12.2 Hz), 4.94 (1 H, dd, J = 2.5 Hz), 7.27-7.35 (10 H, m)

[C] Synthesis of raw material In addition, (2S, 3S, 4S) -3,5-bis (benzyloxy) -4- (methanesulfonyloxy) -1-oxopentan-2-yl 4-methylbenzoate which is a raw material Was synthesized in multiple steps as follows.

  (3S, 4S, 5S) -5- (Hydroxymethyl) oxolane-2,3,4-triol (49.6 g) and acetone (1500 mL) were added dropwise with 33 mL of sulfuric acid at 30 ° C. or lower, and at 25 ° C. for 2.5 hours. Stir and cool to below 15 ° C. After slowly adding 83 mL of 28% aqueous ammonia to the reaction solution to adjust the pH to 7-8, the insoluble material was filtered off, the filtrate was concentrated under reduced pressure to 180 g, concentrated hydrochloric acid 2.6 mL / water 160 mL was added, and acetone was added. 40 mL was added and stirred at 60 ° C. for 20 minutes. After adding 18 g of sodium bicarbonate to the reaction solution, acetone was distilled off under reduced pressure, and 60 g of sodium chloride and 350 mL of ethyl acetate were added to separate the layers. The aqueous layer was extracted with 300 mL of ethyl acetate, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to give (3aS, 5S, 6R, 6aS) -5- (hydroxymethyl) -2 , 2-dimethyl-tetrahydro-2H-furo [2,3-d] [1,3] dioxol-6-ol 58 g was obtained.

¹ H-NMR (CDCl ₃ ) δ value:
1.33 (3H, s), 1.49 (3H, s), 2.72 (1H, brs), 4.02-4.19 (4H, m), 4.10 (1H, d, J = 1.5 Hz), 4.53 (1H, d, J = 3.7 Hz), 5.99 (1H, d, J = 3.7 Hz)

  (3aS, 5S, 6R, 6aS) -5- (hydroxymethyl) -2,2-dimethyl-tetrahydro-2H-furo [2,3-d] [1,3] dioxol-6-ol 53 g N, N -To a 320 mL solution of dimethylformamide, 33.5 g of 60% sodium hydride and 1.0 g of tetrabutylammonium iodide were slowly added at 10 ° C or lower under a nitrogen atmosphere, and stirred at that temperature for 45 minutes. To this solution, 89 mL of benzyl bromide was added dropwise over 30 minutes and stirred at 25 ° C. for 3.5 hours. Ethyl acetate (500 mL) and water (500 mL) were added to the reaction solution, and the organic layer was washed successively with 0.5 N aqueous hydrochloric acid (500 mL) twice, sodium hydrogen carbonate aqueous solution (500 mL) once, and saturated sodium chloride aqueous solution (once). The organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/10 → 1/4) to give a pale yellow color. Oily (3aS, 5S, 6R, 6aS) -6- (benzyloxy) -5-((benzyloxy) dimethyl) -2,2-dimethyl-tetrahydro-2H-furo [2,3-d] [1,3 102 g of dioxole was obtained.

¹ H-NMR (CDCl ₃ ) δ value:
1.31 (3H, s), 1.49 (3H, s), 3.76 (2H, dd, J = 3.4, 6.1 Hz), 3.97 (1H, d, J = 3.2 Hz) ), 3.88 (1H, dt, J = 3.2, 6.1 Hz), 4.51 (2H, dd, J = 2.3, 12.0 Hz), 4.59-4.68 (3H, m), 5.93 (1H, d, J = 3.8 Hz), 7.25-7.35 (10H, m)

(3aS, 5S, 6R, 6aS) -6- (Benzyloxy) -5-((benzyloxy) dimethyl) -2,2-dimethyl-tetrahydro-2H-furo [2,3-d] [1,3] dioxole 39 mL of acetyl chloride was added dropwise to 102 g of a 500 mL solution of methanol at 10 ° C. or lower, stirred at 25 ° C. for 30 minutes, and then allowed to stand overnight. To the reaction solution, 100 g of sodium bicarbonate was slowly added, insoluble matters were filtered off, the filtrate was concentrated to 150 g, and 300 mL of ethyl acetate and 300 mL of an aqueous sodium bicarbonate solution were added. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over sodium sulfate, and the solvent was distilled off under reduced pressure to give (3S, 4S, 5S) -4- (benzyloxy) -5-((benzyl 92 g of oxy) methyl) -2-methoxyoxolan-3-ol were obtained.
As a result of measuring ¹ H-NMR, it was an anomeric mixture of about 50:50. The NMR results of each spot obtained by column purification are shown below.

Component of Rf (ethyl acetate / hexane = 1/2) = 0.38
¹ H-NMR (CDCl ₃ ) δ value:
2.71 (1H, d, J = 7.4 Hz), 3.49 (3H, s), 3.65 (1H, dd, J = 6.7, 10.5 Hz), 3.73 (1H, dd) , J = 4.2, 10.5 Hz), 4.00 (1H, dd, J = 4.1, 5.9 Hz), 4.23-4.28 (1H, m), 4.37-4. 41 (1H, m), 4.55 (2H, dd, J = 6.7, 12.0 Hz), 4.73 (2H, dd, J = 12.0, 31.4 Hz), 4.99 (1H , D, J = 4.7 Hz), 7.27-7.34 (10H, m)

Component of Rf (ethyl acetate / hexane = 1/2) = 0.17
¹ H-NMR (CDCl ₃ ) δ value:
1.91 (1H, d, J = 4.8 Hz), 3.40 (3H, s), 3.70 (1 H, dd, J = 7.2, 10.4 Hz), 3.78 (1 H, dd) , J = 4.7, 10.3 Hz), 4.00 (1H, dd, J = 2.9, 6.1 Hz), 4.20-4.22 (1H, m), 4.46-4. 48 (1H, m), 4.52-4.66 (4H, m), 4.80 (1H, d, J = 1.7 Hz), 7.27-7.34 (10H, m)

(3S, 4S, 5S) -4- (Benzyloxy) -5-((benzyloxy) methyl) -2-methoxyoxolan-3-ol in a solution of 14.6 g of acetonitrile in 70 mL of acetonitrile at 10 ° C. or less. 8 mL and 6.6 mL of toluoyl chloride were added dropwise, stirred at 25 ° C. for 1 hour, and allowed to stand overnight. To the reaction solution, 250 mL of ethyl acetate and 70 mL of an aqueous sodium hydrogen carbonate solution were added and separated. The organic layer was washed twice with 200 mL of 0.5N aqueous hydrochloric acid and saturated aqueous sodium chloride solution and dried over sodium sulfate to give (3S, 4R, 5S) -4- (benzyloxy) -5- 21 g of ((benzyloxy) methyl) -2-methoxyoxolan-3-yl 4-methylbenzoate was obtained.
As a result of measuring ¹ H-NMR, it was an anomeric mixture of about 50:50.

¹ H-NMR (CDCl ₃ ) δ value:
2.41 (1.5H, s), 2.42 (1.5H, s), 3.36 (1.5H, s), 3.45 (1.5H, s), 3.69-3. 81 (2H, m), 4.06 (0.5 H, d, J = 5.5 Hz), 4.45-4.69 (5 H, m), 4.85 (0.5 H, d, J = 12) .4 Hz), 5.08 (0.5 H, s), 5.20 (0.5 H, t, J = 4.7 Hz), 5.28 (0.5 H, d, J = 4.5 Hz), 5 .39 (0.5H, s), 7.22-7.38 (12H, m), 7.89 (1H, d, J = 8.2 Hz), 8.22 (1H, d, J = 8. 2Hz)

(3S, 4R, 5S) -4- (Benzyloxy) -5-((benzyloxy) methyl) -2-methoxyoxolan-3-yl 4-methylbenzoate was added to a solution of 19.2 g of trifluoroacetic acid in 75 mL of trifluoroacetic acid. 11.5 mL of water was added at ° C, and the mixture was stirred at 25 ° C for 3 hours. About 65 mL of trifluoroacetic acid was distilled off under reduced pressure, and the residue was slowly poured into a mixed solution of 300 mL of ethyl acetate and 300 mL of 10% aqueous sodium hydrogen carbonate solution with stirring. After removing the aqueous layer, the organic layer was washed successively with 10% aqueous sodium hydrogen carbonate solution (300 mL), water (300 mL) and saturated aqueous sodium chloride solution (300 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/3 → 1/2) to give colorless oily (3S, 4R, 5S) -4- (benzyloxy) 10.8 g of -5-((benzyloxy) methyl) -2-hydroxyoxolan-3-yl 4-methylbenzoate was obtained.
As a result of measuring ¹ H-NMR, it was an anomeric mixture of about 60:40.

¹ H-NMR (CDCl ₃ ) δ value:
2.42 (1.8H, s), 2.42 (1.2H, s), 2.97 (0.4H, d, J = 7.4 Hz), 3.72 to 3.82 (2.6H) M), 4.19 (0.6 H, dd, J = 1.0, 4.7 Hz), 4.34 (0.4 H, dd, J = 3.5, 5.4 Hz), 4.45 ( 0.6H, dd, J = 5.3, 10.3 Hz), 4.53-4.65 (3.2 H, m), 4.74 (0.6 H, d, J = 12.1 Hz), 4 .83 (0.6 H, d, J = 11.7 Hz), 5.32-5.38 (1 H, m), 5.41 (0.6 H, d, J = 1.6 Hz), 5.77 ( 0.4H, dd, J = 4.2, 7.4 Hz), 7.22-7.34 (12H, m), 7.88-7.93 (2H, m)

(3S, 4R, 5S) -4- (Benzyloxy) -5-((benzyloxy) methyl) -2-hydroxyoxolan-3-yl 4-methylbenzoate in a solution of 10.8 g of methanol in 60 mL of pyridine 12. 4 mL, 6.2 g of p-toluenesulfonic acid monohydrate and 3.6 g of O-methylhydroxylamine hydrochloride were added at 25 ° C., stirred at 25 ° C. for 2 hours, and allowed to stand overnight. To the reaction mixture, 300 mL of ethyl acetate and 300 mL of 1N hydrochloric acid were added, and the aqueous layer was removed. The organic layer was washed with an aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution one after another, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give colorless oily (2R, 3R, 4S) -3,5-bis. 11.6 g of (benzyloxy) -4-hydroxy-1- (methoxyimino) pentan-2-yl 4-methylbenzoate was obtained.
As a result of measuring ¹ H-NMR, it was about 77:23 oxime isomer mixture.

¹ H-NMR (CDCl ₃ ) δ value:
2.39-2.41 (3.77 H, m), 2.55 (0.23 H, d, J = 6.1 Hz), 3.42-3.55 (2 H, m), 3.87 (2 .31H, s), 3.93 (0.69H, s), 3.98-4.16 (2H, m), 4.40-4.64 (3H, m), 4.80 (0.23H) , D, J = 11.2 Hz), 4.81 (0.77H, d, J = 11.1 Hz), 5.91 (0.77H, t, J = 6.5 Hz), 6.29 (0. 23H, dd, J = 4.5, 5.9 Hz), 6.88 (0.23 H, d, J = 5.9 Hz), 7.22-7.32 (12 H, m), 7.58 (0 .77H, d, J = 6.7 Hz), 7.93 (2H, d, J = 8.2 Hz)

To a solution of 11.2 g of (2R, 3R, 4S) -3,5-bis (benzyloxy) -4-hydroxy-1- (methoxyimino) pentan-2-yl 4-methylbenzoate in 100 mL of ethyl acetate at 10 ° C. Below, 5.4 mL of triethylamine and 2.7 mL of methanesulfonyl chloride were added dropwise, and the mixture was stirred at 25 ° C. for 2 hours. To the reaction mixture was added 200 mL of 1N aqueous hydrochloric acid, and the aqueous layer was removed. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give colorless oily (2R, 3S, 4S) -3,5-bis ( 13.0 g of benzyloxy) -4- (methanesulfonyloxy) -1- (methoxyimino) pentan-2-yl 4-methylbenzoate was obtained.
As a result of measuring ¹ H-NMR, it was about 77:23 oxime isomer mixture.

¹ H-NMR (CDCl ₃ ) δ value:
2.41 (2.31H, s), 2.43 (0.23H, s), 2.94 (0.39H, s), 3.01 (2.31H, s), 3.75-3. 82 (2H, m), 3.86 (2.31 H, s), 3.90 (0.69 H, s), 4.41 (0.77 H, t, J = 5.2 Hz), 4.42 ( 0.23H, dd, J = 2.7, 7.1 Hz), 4.48-4.49 (2H, m), 4.71 (2H, dd, J = 11.2, 23.2 Hz), 4 .96-5.03 (1H, m), 5.83 (0.77H, dd, J = 5.5, 6.2 Hz), 6.15 (0.23H, dd, J = 2.7, 5) 0.0 Hz), 6.78 (0.23 H, d, J = 5.0 Hz), 7.23-7.34 (12 H, m), 7.49 (0.77 H, d, J = 6.2 Hz) 7.93 (2H, d, J 8.2Hz)

  To a solution of 13.5 g of (2R, 3S, 4S) -3,5-bis (benzyloxy) -4- (methanesulfonyloxy) -1- (methoxyimino) pentan-2-yl 4-methylbenzoate in 240 mL of acetone Formalin 160 mL and 2 N hydrochloric acid 6.0 mL were added, stirred at 25 ° C. for 1 hour, allowed to stand overnight, and further stirred at 40 ° C. for 5 hours. About 200 mL of acetone was distilled off under reduced pressure, 200 mL of ethyl acetate and 200 mL of an aqueous sodium hydrogen carbonate solution were added, and the aqueous layer was removed. The organic layer was washed with 200 mL of water and saturated aqueous sodium chloride solution and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/2 → 1/1) to give a colorless oily (2S, 3S, 4S) -3,5- 10.0 g of bis (benzyloxy) -4- (methanesulfonyloxy) -1-oxopentan-2-yl 4-methylbenzoate was obtained.

¹ H-NMR (CDCl ₃ ) δ value:
2.44 (3H, s), 2.96 (3H, s), 3.73 (1H, dd, J = 6.0, 11.0 Hz), 3.86 (1H, dd, J = 4.0) , 11.0 Hz), 4.46 (1H, dd, J = 3.8, 5.6 Hz), 4.46 (2H, s), 4.68 (2H, dd, J = 11.2, 18. 4Hz), 5.03-5.05 (1H, m), 5.43 (1H, d, J = 3.8 Hz), 7.24-7.37 (12H, m), 7.97 (2H, d, J = 8.2 Hz), 9.59 (1H, s)

Reference example 1
[A] Synthesis of (3R, 4S, 5R) -4- (benzyloxy) -5-((benzyloxy) methyl) -3-fluorothiolan-2-ol and its alkoxy form

  Reaction of (2S, 3R, 4S) -3,5-bis (benzyloxy) -2-fluoro-4-((4-methylbenzenesulfonyl) oxy) pentanal with 15% aqueous sodium hydrogen sulfide solution as follows Was synthesized.

(2S, 3R, 4S) -3,5-bis (benzyloxy) -2-fluoro-4-((4-methylbenzenesulfonyl) oxy) pentanal 0.13 g of N, N-dimethylformamide in 0.53 mL solution At 10 ° C. or lower, 15% sodium hydrogen sulfide aqueous solution (0.15 mL) was dropped, and the mixture was stirred at 25 ° C. for 1 hour. To the reaction mixture, 20 mL of ethyl acetate and 20 mL of saturated aqueous sodium chloride solution were added, and the aqueous layer was removed. The organic layer was washed successively with an aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/2) to give (3R, 4S, 5R) -4- (benzyloxy) as a colorless oil. 80 mg of) -5-((benzyloxy) methyl) -3-fluorothiolan-2-ol was obtained.
As a result of measuring ¹ H-NMR, it was an anomeric mixture of about 74:26.

¹ H-NMR (CDCl ₃ ) δ value:
3.05 (0.74H, d, J = 6.3 Hz), 3.32 (0.26H, dd, J = 7.9, 10.0 Hz), 3.45 (0.26H, dd, J = 5.1, 10.1 Hz), 3.58-3.82 (2.74 H, m), 4.20 (0.74 H, ddd, J = 2.8, 7.5, 26.7 Hz), 4 .29 (0.26H, brs), 4.45-4.69 (4H, m), 4.94 (0.26H, dt, J = 4.0, 48.0 Hz), 4.97 (0. 74H, dt, J = 2.3, 51.0 Hz), 5.22 (0.74H, t, J = 5.5 Hz), 5.34 (0.26H, ddd, J = 2.3, 4.. 2, 14.4 Hz), 7.24-7.37 (10H, m)

(3R, 4S, 5R) -4- (Benzyloxy) -5-((benzyloxy) methyl) -3-fluorothiolan-2-ol in a solution of 0.33 g of ethyl acetate in 10 mL of ethyl acetate at 10 ° C. or lower and N, N -Dimethylaminopyridine 0.026g, pyridine 0.4mL, and acetic anhydride 0.48mL were added, and it stirred at 25 degreeC for 30 minutes, Then, it left still for 2 days. To the reaction solution, 10 mL of ethyl acetate and 20 mL of 0.5N hydrochloric acid water were added, and the aqueous layer was removed. The organic layer was washed 4 times with an aqueous sodium bicarbonate solution and then dried over sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/3) to give colorless oily (3R, 4S, 5R) -4- (benzyloxy 0.28 g of) -5-((benzyloxy) methyl) -3-fluorothiolan-2-yl acetate was obtained.
As a result of measuring ¹ H-NMR, it was an anomeric mixture of about 83:17.

¹ H-NMR (CDCl ₃ ) δ value:
2.04 (2.49 H, s), 2.14 (0.51 H, s), 3.52 (0.34 H, d, J = 5.5 Hz), 3.61 (0.83 H, dd, J = 7.8, 11.1 Hz), 3.73-3.80 (1.66 H, m), 3.84-3.92 (0.17 H, m), 4.01-4.16 (1 H, m) 4.47-4.75 (4H, m), 5.04 (0.83H, dt, J = 2.3, 48.0 Hz), 5.10 (0.17H, dt, J = 4. 1,51.0 Hz), 5.98 (0.83 H, dd, J = 1.9, 10.3 Hz), 6.19 (0.17 H, dd, J = 4.5, 8.3 Hz), 7 .27-7.37 (10H, m)

[B] Synthesis of Raw Material The raw material (2S, 3R, 4S) -3,5-bis (benzyloxy) -2-fluoro-4-((4-methylbenzenesulfonyl) oxy) pentanal is as follows: Thus, it was synthesized in a plurality of steps.

To a solution of 50.1 g of (3S, 4S, 5S) -4- (benzyloxy) -5-((benzyloxy) methyl) -2-methoxyoxolan-3-ol synthesized in Example 2 in 500 mL of dichloromethane, 10 117 ° C. of pyridine and 36.6 mL of trifluoromethanesulfonic anhydride were successively added dropwise at a temperature of 0 ° C. or lower, and the mixture was stirred at 25 ° C. for 1 hour. About 300 mL of dichloromethane was distilled off under reduced pressure, 700 mL of ethyl acetate and 700 mL of 5 wt% sodium chloride aqueous solution were added, and the aqueous layer was removed. The organic layer was washed with 0.5N aqueous hydrochloric acid (twice), aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to give a colorless oil (3S, 4R, 5S). ) -4- (Benzyloxy) -5-((benzyloxy) methyl) -2-methoxyoxolan-3-yl trifluoromethanesulfonate 72.8 g was obtained.
As a result of measuring ¹ H-NMR, it was an anomeric mixture of about 50:50.

¹ H-NMR (CDCl ₃ ) δ value:
3.41 (1.5H, s), 3.45 (1.5H, s), 3.57-3.77 (2H, m), 4.21 (0.5H, dd, J = 1.8) , 5.9Hz), 4.31-4.37 (0.5H, m), 4.43-4.72 (5H, m), 5.05-5.07 (1H, m), 5.16. -5.19 (1H, m), 7.23-7.27 (10H, m)

  (3S, 4R, 5S) -4- (Benzyloxy) -5-((benzyloxy) methyl) -2-methoxyoxolan-3-yl trifluoromethanesulfone was added to 1 L of a tetrahydrofuran solution of 1 mol / L tetrabutylammonium fluoride. 72.8 g of natto was dissolved and stirred at 50 ° C. for 18.5 hours, and tetrahydrofuran was distilled off under reduced pressure. To the residue was added 1 L of ethyl acetate and 500 mL of water, and the aqueous layer was removed. The organic layer was washed successively with water (twice) and saturated aqueous sodium chloride solution and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/3) to give (2S, 3R, 4R, 5S) -3- (benzyloxy) as a colorless oil. ) -2-((benzyloxy) methyl) -4-fluoro-5-methoxyoxolane (13.1 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ value:
3.37 (3H, s), 3.67 (1H, ddd, J = 1.3, 7.9, 10.4 Hz), 3.77 (1H, dd, J = 3.7, 10.4 Hz) 4.30 (1H, ddd, J = 4.0, 7.1, 20.8 Hz), 4.42 (1H, dt, J = 3.7, 7.5 Hz), 4.52 (2H, dd , J = 2.9, 12.0 Hz), 4.66 (2H, dd, J = 8.0, 12.1 Hz), 4.80 (1H, ddd, J = 0.8, 4.0, 54) .8 Hz), 5.08 (1 H, d, J = 9.9 Hz), 7.24-7.36 (10 H, m)

  (2S, 3R, 4R, 5S) -3- (Benzyloxy) -2-((benzyloxy) methyl) -4-fluoro-5-methoxyoxolane in 40 mL of trifluoroacetic acid at 10 ° C. or less 6.1 mL of water was added dropwise and stirred at 25 ° C. for 5 hours. The reaction solution was slowly added to a mixture of ethyl acetate 400 mL / water 400 mL / sodium bicarbonate 44 g, and the aqueous layer was removed. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate / hexane to give (2S, 3R, 4R, 5S) -4- (benzyloxy) -5-((benzyloxy) methyl) -3- 2.6 g of white crystals of fluorooxolan-2-ol was obtained.

¹ H-NMR (CDCl ₃ ) δ value:
2.92 (1H, brs), 3.63-3.70 (1H, m), 3.76 (1H, dd, J = 2.6, 10.5), 4.37 (1H, ddd, J = 4.1, 7.0, 20.2 Hz), 4.49-4.58 (3H, m), 4.66 (1H, dd, J = 11, 9, 23.1 Hz), 4.93 ( 1H, ddd, J = 0.89, 4.1, 52.6 Hz), 5.56 (1H, d, J = 1.6, 9.9 Hz), 7.27-7.37 (10 H, m)

(2S, 3R, 4R, 5S) -4- (benzyloxy) -5-((benzyloxy) methyl) -3-fluorooxolan-2-ol 3.5 g of methanol 35 mL / tetrahydrofuran 25 mL 4 mL, 2.7 g of p-toluenesulfonic acid monohydrate and 1.6 g of O-methylhydroxylamine hydrochloride were added at 25 ° C., and the mixture was stirred at 25 ° C. for 2 hours. After most of the solvent was distilled off under reduced pressure, 200 mL of ethyl acetate and 200 mL of water were added to the residue, and the aqueous layer was removed. The organic layer was washed successively with 10% aqueous sodium chloride solution (twice), 1N aqueous hydrochloric acid solution (twice), aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. 3.75 g of yellow oily (2S, 3R, 4S) -1,3-bis (benzyloxy) -4-fluoro-4-((methoxyimino) methyl) butan-2-ol was obtained.
As a result of measuring ¹ H-NMR, it was an about 87:13 oxime isomer mixture.

¹ H-NMR (CDCl ₃ ) δ value:
2.45 (0.87H, d, J = 6.9 Hz), 2.57 (0.13H, d, J = 5.5 Hz), 3.45-3.56 (2H, m), 3.82 -3.91 (1H, m), 3.85 (0.39H, s), 3.88 (2.61H, s), 3.96-4.03 (1H, m), 4.46-4 .60 (3H, m), 4.72-4.80 (1H, m), 5.13 (0.87H, ddd, J = 4.9, 7.3, 45.9 Hz), 5.75 ( 0.13H, ddd, J = 3.3, 6.0, 47.2 Hz), 6.93 (0.13H, dd, J = 6.0, 9.6 Hz), 7.23-7.52 ( 10H, m), 7.50 (0.87H, dd, J = 6.5, 7.2 Hz)

A solution of 2.0 g of (2S, 3R, 4S) -1,3-bis (benzyloxy) -4-fluoro-4-((methoxyimino) methyl) butan-2-ol in 4.0 mL of acetonitrile / 2.0 mL of tetrahydrofuran To the mixture, 1.6 g of 4-toluenesulfonyl chloride and 1.14 mL of N-methylimidazole were added at 10 ° C. or lower, and the mixture was stirred at 25 ° C. for 4 hours. 50 mL of ethyl acetate and 50 mL of 1N hydrochloric acid were added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed successively with 1N aqueous hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/3) to give colorless oily (2S, 3R, 4S) -1,3-bis (benzyloxy) -4-fluoro- 2.6 g of 5- (methoxyimino) pentan-2-yl 4-methylbenzenesulfonate was obtained.
As a result of measuring ¹ H-NMR, it was an about 87:13 oxime isomer mixture.

¹ H-NMR (CDCl ₃ ) δ value:
2.33 (0.13H, s), 2.35 (0.87H, s), 3.62-3.75 (2H, m), 3.81 (0.13H, s), 3.85 ( 0.87H, s), 4.07-4.23 (2H, m), 4.32-4.44 (2H, m), 4.52-4.65 (2H, m), 4.70- 4.79 (1H, m), 4,98 (0.87H, ddd, J = 45.7, 7.4, 4.9 Hz), 5.61 (0.13H, ddd, J = 3.0, 5.8, 47.0 Hz), 6.81 (0.13 H, dd, J = 5.8, 9, 6 Hz), 7.12-7.36 (12 H, m), 7.37 (0.87 H) , Dd, J = 6.1, 7.3 Hz), 7.71 (2H, d, J = 8.3 Hz)

  (2S, 3R, 4S) -1,3-bis (benzyloxy) -4-fluoro-5- (methoxyimino) pentan-2-yl 4-methylbenzenesulfonate in a solution of 2.5 g of acetone in 50 mL of acetone and 30 mL of formalin and 1.1 mL of 2N hydrochloric acid was added, and the mixture was stirred at 25 ° C. for 1 hour, and then allowed to stand overnight. 200 mL of ethyl acetate and 200 mL of aqueous sodium bicarbonate were added, and the aqueous layer was removed. The organic layer was washed with water (twice) and saturated aqueous sodium chloride solution and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/2 → 1/1) to give a colorless oily (2S, 3R, 4S) -3,5- 1.3 g of bis (benzyloxy) -2-fluoro-4-[(4-methylbenzenesulfonyl) oxy] pentanal was obtained.

¹ H-NMR (CDCl ₃ ) δ value:
2.35 (3H, s), 3.64 (1H, ddd, J = 0.95, 4.7, 11.1 Hz), 3.73 (1H, dd, J = 4.6, 11.1 Hz) 4.20 (1H, ddd, J = 2.9, 5.8, 20.7 Hz), 4.37 (2H, s), 4.54 (2H, dd, J = 11.4, 28.1 Hz) ), 4.83-5.01 (2H, m), 7.15-7.35 (12H, m), 7.72 (2H, d, J = 8.3 Hz), 9.60 (1H, J) = 7.8Hz)

Reference example 2
[A] Synthesis of (3R, 4R, 5S) -3,4-dimethoxy-5- (methoxymethyl) thiolan-2-ol and its alkoxy form

  It was synthesized by reacting (2R, 3R, 4R) -1,3,4-trimethoxy-5-oxopentan-2-yl 4-methylbenzenesulfonate with a 15% aqueous sodium hydrogen sulfide solution as follows. .

(2R, 3R, 4R) -1,3,4-Trimethoxy-5-oxopentan-2-yl 4-methylbenzenesulfonate To a solution of 1.85 g of N, N-dimethylformamide in 53.4 mL at 10 ° C. or lower. Then, 2.4 mL of a 15% aqueous sodium hydrogen sulfide solution was added dropwise, and the mixture was stirred at 25 ° C for 1.5 hours. To the reaction mixture, 200 mL of dichloromethane and 200 mL of a saturated aqueous sodium chloride solution were added, and the aqueous layer was removed. The organic layer was washed three times with an aqueous sodium hydrogen carbonate solution and once with a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give (3R, 4R, 5S) -3,4. -0.87 g of a crude product of -dimethoxy-5- (methoxymethyl) thiolan-2-ol was obtained.
To a solution of 0.54 g of this crude product in 54 mL of dichloromethane was added 1.0 mL of pyridine, 1.2 mL of acetic anhydride and 67 mg of 4- (N, N-dimethylamino) pyridine at 25 ° C., and the mixture was stirred at room temperature for 30 minutes and then overnight. Left to stand. To the reaction solution, 50 mL of 0.5N hydrochloric acid was added, and the aqueous layer was removed. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution (4 times) and saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/3) to give a pale yellow oily (3R, 4R, 5S) -3,4-dimethoxy. 0.50 g of -5- (methoxymethyl) thiolan-2-yl acetate was obtained.
As a result of measuring ¹ H-NMR, it was an anomeric mixture of about 50:50.

¹ H-NMR (CDCl ₃ ) δ value:
2.10 (1.5 H, s), 2.13 (1.5 H, s), 3.27-3.33 (0.5 H, m), 3.36 (1.5 H, s), 3. 37-3.49 (1H, m), 3.39 (1.5 H, s), 3.42 (1.5 H, s), 3.46 (1.5 H, s), 3.47 (1. 5H, s), 3.53 (1.5H, s), 3.62-3.78 (2.5H, m), 3.88 (0.5H, dd, J = 4.2, 8.7 Hz) ), 4.00 (0.5H, dd, J = 2.7, 4.6 Hz), 5.95 (0.5H, d, J = 2.6 Hz), 6.11 (0.5H, d, J = 4.2Hz)

[B] Synthesis of Raw Material In addition, the raw material (2R, 3R, 4R) -1,3,4-trimethoxy-5-oxopentan-2-yl 4-methylbenzenesulfonate is prepared as follows. Synthesized in the process.

  First, (3R, 4S, 5R) -3,4-dimethoxy-5- (methoxymethyl) oxolan-2-ol, which is a starting material, was synthesized by the following route under known conditions or similar conditions. .

  Here, the first reaction is, for example, Journal of Organic Chemistry, 1992, 57, p. 5899-5907, the second reaction is described, for example, in Biomacromolecules, 2010, 11, p. In 2415-2421, the third reaction is described in, for example, Tetrahedron, 1994, 50, p. 5361-5368.

(3R, 4S, 5R) -3,4-dimethoxy-5- (methoxymethyl) oxolan-2-ol 1.42 g of methanol in 24 mL solution of pyridine 3.8 mL, p-toluenesulfonic acid monohydrate 9 g and O-benzylhydroxylamine 1.55 g were added at 25 ° C., and the mixture was stirred at 25 ° C. for 1 hour. About 15 mL of methanol was distilled off under reduced pressure, 200 mL of ethyl acetate and 200 mL of water were added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed successively with 10% aqueous sodium chloride solution (twice), 1N aqueous hydrochloric acid (twice), aqueous sodium bicarbonate and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.79 g of a crude product of (benzyloxy) ((2S, 3S, 4R) -2,3,5-trimethoxy-4-hydroxypentylidene) amine as a pale yellow oil. This crude product was used in the next step without further purification.
As a result of measuring ¹ H-NMR, it was an about 83:17 oxime isomer mixture.

¹ H-NMR (CDCl ₃ ) δ value:
2.52 (0.83H, d, J = 5.3 Hz), 2.74 (0.17H, d, J = 2.7 Hz), 3.31 (2.49 H, s), 3.34-3 .49 (4.53H, m), 3.37 (2.49H), 3.50 (2.49H, s), 3.90-3.96 (1H, m), 3.99 (0.83H) , Dd, J = 5.0, 7.9 Hz), 4.66 (0.17H, dd, J = 4.0, 6.3 Hz), 5.13-5.15 (2H, m), 6. 87 (0.17H, d, J = 6.3 Hz), 7.28-7.37 (5H, m), 7.47 (0.83H, d, J = 8.0 Hz)

(Benzyloxy) ((2S, 3S, 4R) -2,3,5-trimethoxy-4-hydroxypentylidene) amine (1.8 g) in a solution of 1.8 g of acetonyl in 11 mL of 4-methylbenzenesulfonyl chloride 2 at 5 ° C. .3 g and 2.3 mL of N-methylimidazole were added dropwise, stirred at 25 ° C. for 30 minutes, and allowed to stand overnight. 200 mL of ethyl acetate and 200 mL of water were added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed successively with 10% aqueous sodium chloride solution (twice), 1N aqueous hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue is purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/3 → 1/2) to give (2R, 3R, 4S) -1,3,4-trimethoxy-5- Each of the two isomers of ((benzyloxy) imino) pentan-2-yl 4-methylbenzenesulfonate was 2.3 g (developing solvent: ethyl acetate / hexane = 1/2, TLC Rf = 0.54). Component) and 0.47 g (developing solvent: component of TLC Rf = 0.44 in ethyl acetate / hexane = 1/2).
As a result of measuring ¹ H-NMR, each component was a single isomer.

Component of Rf (ethyl acetate / hexane = 1/2) = 0.54
¹ H-NMR (CDCl ₃ ) δ value:
2.42 (3H, s), 3.21 (3H, s), 3.23 (3H, s), 3.27 (3H, s), 3.45-3.53 (2H, m), 3 .69 (1H, dd, J = 3.2, 11.6 Hz), 3.85 (1H, dd, J = 3.2, 7.7 Hz), 4.86 (1H, ddd, J = 3.0) , 4.2, 7.0 Hz), 5.12 (2H, s), 7.26-7.36 (7H, m), 7.40 (1H, d, J = 7.7 Hz), 7.82. (2H, d, J = 8.4Hz)

Component of Rf (ethyl acetate / hexane = 1/2) = 0.44
¹ H-NMR (CDCl ₃ ) δ value:
2.42 (3H, s), 3.08 (3H, s), 3.24 (3H, s), 3.28 (3H, s), 3.48 (1H, dd, J = 4.1) 11.8 Hz), 3.71 (1H, dd, J = 2.7, 11.8 Hz), 3.75 (1H, dd, J = 2.2, 7.6 Hz), 4.55 (1H, dd) , J = 2.2, 5.5 Hz), 4.84 (1H, ddd, J = 3.0, 4.2, 7.4 Hz), 5.13 (2H, d, J = 2.1 Hz), 6.84 (1H, d, J = 5.5 Hz), 7.26-7.36 (7H, m), 7.81 (2H, d, J = 8.3 Hz)

  (2R, 3R, 4S) -1,3,4-trimethoxy-5-((benzyloxy) imino) pentan-2-yl 4-methylbenzenesulfonate 2.49 g of acetone in 44 mL solution Were added with 27.6 mL of 37% formalin aqueous solution and 1.38 mL of 2N aqueous hydrochloric acid, stirred at 25 ° C. for 1 hour, and allowed to stand overnight. After distilling off about 25 mL of acetone under reduced pressure, 200 mL of dichloromethane and 200 mL of aqueous sodium hydrogen carbonate solution were added, and the aqueous layer was removed. The organic layer was washed successively with water (twice) and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/2 → 1/1) to give (2R, 3R, 4R) -1,3,4- 1.85 g of trimethoxy-5-oxopentan-2-yl 4-methylbenzenesulfonate was obtained.

¹ H-NMR (CDCl ₃ ) δ value:
2.44 (3H, s), 3.19 (3H, s), 3.27 (3H, s), 3.48 (3H, s), 3.53 (1H, dd, J = 4.5, 11.7 Hz), 3.69-3.75 (2 H, m), 3.88 (1 H, dd, J = 3.0, 6.9 Hz), 4.87 (1 H, ddd, J = 3.1) , 4.2, 7.1 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.82 (2H, d, J = 8.2 Hz), 9.76 (1H, d, J = 0.9Hz)

Example 3
[A] Synthesis of (3R, 4R, 5S) -3,4-dipropoxy-5- (propoxymethyl) thiolan-2-ol and its alkoxy form

  The synthesis was performed by reacting (2R, 3R, 4R) -1,3,4-tripropoxy-5-oxopentan-2-yl methanesulfonate with a 15% aqueous sodium hydrogen sulfide solution as follows.

(2R, 3R, 4R) -1,3,4-Tripropoxy-5-oxopentan-2-yl methanesulfonate 5.7 g of N, N-dimethylformamide in 159 mL solution at 10 ° C. or less, 15% sulfurization 7.2 mL of aqueous sodium hydride solution was added dropwise and stirred at 25 ° C. for 1 hour. To the reaction mixture, 300 mL of ethyl acetate and 300 mL of a saturated aqueous sodium chloride solution were added, and the aqueous layer was removed. The organic layer was sequentially washed three times with an aqueous sodium hydrogen carbonate solution and once with a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/5 → 1/4) to give (3R, 4R, 5S) -3,4-dipropoxy. 1. 2-g isomers of -5- (propoxymethyl) thiolan-2-ol (developing solvent: TLC Rf = 0.48 component in ethyl acetate / hexane = 1/5) and 2. 1 g (developing solvent: component of TLC Rf = 0.34 in ethyl acetate / hexane = 1/5) was obtained.
As a result of measuring ¹ H-NMR, each component was a single isomer.

Component of Rf (ethyl acetate / hexane = 1/5) = 0.48
¹ H-NMR (CDCl ₃ ) δ value:
0.91 (3H, t, J = 7.4 Hz), 0.92 (6H, t, J = 7.4 Hz), 1.52-1.65 (6H, m), 3.30-3.40 (2H, m), 3.42-3.62 (7H, m), 3.82 (1H, dd, J = 6.1, 9.7 Hz), 4.11 (2H, d, J = 9. 3Hz), 5.34 (1H, td, J = 1.1, 12.2 Hz)

Component of Rf (ethyl acetate / hexane = 1/5) = 0.34
¹ H-NMR (CDCl ₃ ) δ value:
0.88-0.97 (9H, m), 1.53-1.71 (6H, m), 3.36 (1H, dd, J = 4.7, 9.4 Hz), 3.43-3 .66 (9H, m), 3.86 (1H, dd, J = 4.0, 7.0 Hz), 3.98 (1H, dd, J = 4.7, 7.0 Hz), 5.19 ( 1H, dd, J = 4.0, 8.0 Hz)

To a solution of 1.8 g of (3R, 4R, 5S) -3,4-dipropoxy-5- (propoxymethyl) thiolan-2-ol (component of Rf = 0.48) in 35 mL of ethyl acetate at 25 ° C. 4 mL, 2.9 mL of acetic anhydride, and 0.16 g of 4- (N, N-dimethylamino) pyridine were added, and the mixture was stirred at room temperature for 30 minutes and allowed to stand overnight. To the reaction solution, 100 mL of 0.5N hydrochloric acid was added, and the aqueous layer was removed. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution (4 times) and saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/5) to give a pale yellow oily (3R, 4R, 5S) -3,4-dipropoxy. 1.7 g of -5- (propoxymethyl) thiolan-2-yl acetate was obtained.
As a result of measuring ¹ H-NMR, it was almost a single anomer.

¹ H-NMR (CDCl ₃ ) δ value:
0.88-0.95 (9H, m), 1.51-1.65 (6H, m), 2.08 (3H, s), 3.36-3.81 (10H, m), 4. 06 (1H, dd, J = 3.0, 5.3 Hz), 5.89 (1H, d, J = 3.0 Hz)

(3R, 4R, 5S) -3,4-dipropoxy-5- (propoxymethyl) thiolan-2-ol (component of Rf = 0.34) 2.1 g of ethyl acetate in 42 mL solution at 25 ° C. 9 mL, 3.4 mL of acetic anhydride, and 0.19 g of 4- (N, N-dimethylamino) pyridine were added, and the mixture was stirred at room temperature for 30 minutes and allowed to stand overnight. To the reaction solution, 100 mL of 0.5N hydrochloric acid was added, and the aqueous layer was removed. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution (4 times) and saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/4) to give (3R, 4R, 5S) -3,4-dipropoxy as a pale yellow oil. 1.8 g of -5- (propoxymethyl) thiolan-2-yl acetate was obtained.
As a result of measuring ¹ H-NMR, it was almost a single anomer.

¹ H-NMR (CDCl ₃ ) δ value:
0.89-0.95 (9H, m), 1.51-1.64 (6H, m), 2.11 (3H, s), 3.30 (1H, dt, J = 5.5, 7 .3 Hz), 3.39-3.75 (8 H, m), 3.84 (1 H, dd, J = 7.0, 9.0 Hz), 3.93 (1 H, dd, J = 4.2) 9.0 Hz), 6.09 (1H, d, J = 4.2 Hz)

To a solution of 0.33 g of (3R, 4R, 5S) -3,4-dipropoxy-5- (propoxymethyl) thiolan-2-yl acetate in 3.3 mL of methanol was added 0.14 mL of acetyl chloride dropwise at 5 ° C., and 25 Stir for 2 hours at ° C. To the reaction solution, 10 mL of ethyl acetate and 10 mL of aqueous sodium hydrogen carbonate solution were added, and the aqueous layer was removed. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/10) to give (3R, 4R, 5S) -3,4-dipropoxy-5- (propoxy). 0.12 g (developing solvent: component of TLC Rf = 0.68 in ethyl acetate / hexane = 1/5) and 0.16 g (developing solvent) of two isomers of methyl) -2-methoxythiolane : TLC Rf = 0.59 component in ethyl acetate / hexane = 1/3).
As a result of measuring ¹ H-NMR, each component was a single isomer.

Component of Rf (ethyl acetate / hexane = 1/5) = 0.68
¹ H-NMR (CDCl ₃ ) δ value:
0.91 (3H, t, J = 7.4 Hz), 0.92 (3H, t, J = 7.4 Hz), 0.93 (3H, t, J = 7.4 Hz), 1.52-1 .67 (6H, m), 3.32 (3H, s), 3.36-3.76 (10H, m), 3.92 (1H, dd, J = 3.3, 6.0 Hz), 4. .85 (1H, d, J = 3.3 Hz)

Component of Rf (ethyl acetate / hexane = 1/5) = 0.59
¹ H-NMR (CDCl ₃ ) δ value:
0.87-0.96 (9H, m), 1.52-1.71 (6H, m), 3.23-3.32 (1H, m), 3.34-3.58 (4H, m) ), 3.37 (3H, s), 3.54-3.72 (4H, m), 3.89 (1H, dd, J = 5.7, 8.5 Hz), 3.94 (1H, dd) , J = 3.7, 8.5 Hz), 4.78 (1H, d, J = 3.6 Hz)

[B] Synthesis of Raw Material In addition, the raw material (2R, 3R, 4R) -1,3,4-tripropoxy-5-oxopentan-2-yl methanesulfonate is produced in a plurality of steps as follows. Synthesized.

First, (3R, 4S, 5R) -3,4-dipropoxy-5- (propoxymethyl) oxolan-2-ol which is a starting material is similar to the route described in Reference Example 2 under conditions known in the literature or similar thereto. It was synthesized under the conditions of

(3R, 4S, 5R) -3,4-dipropoxy-5- (propoxymethyl) oxolan-2-ol In a solution of 5.2 g of methanol in 63 mL of methanol, 9.9 mL of pyridine, p-toluenesulfonic acid monohydrate 4 9.9 g and O-methylhydroxylamine hydrochloride 2.8 g were added at 25 ° C. and stirred at 25 ° C. for 1 hour. After about 40 mL of methanol was distilled off under reduced pressure, 200 mL of ethyl acetate and 200 mL of water were added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed successively with 10% aqueous sodium chloride solution (twice), 1N aqueous hydrochloric acid (twice), aqueous sodium bicarbonate and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 5.6 g of a crude product of methoxy ((2S, 3S, 4R) -2,3,5-tripropoxy-4-hydroxypentylidene) amine as a pale yellow oil. This crude product was used in the next step without further purification.
As a result of measuring ¹ H-NMR, it was about 77:23 oxime isomer mixture.

¹ H-NMR (CDCl ₃ ) δ value:
0.91 (3H, t, J = 7.3 Hz), 0.92 (6H, t, J = 7.3 Hz), 1.51-1.68 (6H, m), 2.30 (1H, bs) ), 3.28-3.73 (9H, m), 3.87 (2.31H, s), 3.89 (0.69H, s), 3.89-3.97 (1H, m), 4.06 (0.77H, dd, J = 5.6, 8.0 Hz), 4.72 (0.23H, dd, J = 4.8, 6.5 Hz), 6.80 (0.23H, d, J = 6.5 Hz), 7.38 (0.77 H, d, J = 8.1 Hz)

To a solution of 5.6 g of crude methoxy ((2S, 3S, 4R) -2,3,5-tripropoxy-4-hydroxypentylidene) amine in 92 mL of ethyl acetate, 2.2 mL of methanesulfonyl chloride and triethylamine at 5 ° C. 4.2 mL was dripped and it stirred at 25 degreeC for 1.5 hours. To the reaction mixture, 100 mL of ethyl acetate and 200 mL of water were added, and the aqueous layer was removed. The organic layer was washed successively with 10% aqueous sodium chloride solution (twice), 1N aqueous hydrochloric acid, aqueous sodium bicarbonate and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. By distilling off the solvent under reduced pressure, a crude product of light yellow oily (2R, 3R, 4S) -1,3,4-tripropoxy-5- (methoxyimino) pentan-2-yl methanesulfonate 7.0 g Got. This crude product was used in the next step without further purification.
As a result of measuring ¹ H-NMR, it was an about 85:15 oxime isomer mixture.

¹ H-NMR (CDCl ₃ ) δ value:
0.87-0.96 (9H, m), 1.53-1.66 (6H, m), 1.49-1.60 (6H, m), 3.09 (0.45H, s), 3.11 (2.55H, s), 3.21-3.83 (10H, m), 3.88 (2.55H, s), 3.90 (0.45H, s), 4.02 ( 0.85H, dd, J = 4.2, 7.8 Hz), 4.65 (0.15H, dd, J = 2.7, 5.7 Hz), 4.83-4.91 (1H, m) 6.83 (0.15H, d, J = 5.7 Hz), 7.38 (0.85H, d, J = 7.8 Hz)

  (2R, 3R, 4S) -1,3,4-Tripropoxy-5- (methoxyimino) pentan-2-yl methanesulfonate crude 7.0 g in acetone 138 mL solution, 37% formalin aqueous solution 92 mL and 2N 4.6 mL of aqueous hydrochloric acid was added, and the mixture was stirred at 25 ° C. for 5 hours and then allowed to stand overnight. After about 80 mL of acetone was distilled off under reduced pressure, 200 mL of ethyl acetate and 200 mL of an aqueous sodium hydrogen carbonate solution were added, and the aqueous layer was removed. The organic layer was washed successively with water (twice) and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue is purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/5 → 1/2) to give (2R, 3R, 4R) -1,3,4- light orange oil. 6.0 g of tripropoxy-5-oxopentan-2-yl methanesulfonate was obtained.

¹ H-NMR (CDCl ₃ ) δ value:
0.88 (3H, t, J = 7.4 Hz), 0.92 (3H, t, J = 7.4 Hz), 0.96 (3H, t, J = 7.4 Hz), 1.50-1 .74 (6H, m), 3.09 (3H, s), 3.32-3.83 (10H, m), 3.89 (1H, dd, J = 1.0, 3.8 Hz), 4 .02 (1H, dd, J = 3.9, 5.8 Hz), 4.90 (1H, dt, J = 3.6, 6.0 Hz), 9.81 (1H, d, J = 1.1 Hz) )

Example 4
[A] Synthesis of (3R, 4R, 5S) -3,4-dibutoxy-5- (butoxymethyl) thiolan-2-ol and its alkoxy form

  The synthesis was performed by reacting (2R, 3R, 4R) -1,3,4-tributoxy-5-oxopentan-2-yl methanesulfonate with a 15% aqueous sodium hydrogen sulfide solution as follows.

(2R, 3R, 4R) -1,3,4-Tributoxy-5-oxopentan-2-yl methanesulfonate 4.6% in N, N-dimethylformamide 116 mL solution at 10 ° C. or less, 15% hydrogen sulfide A sodium aqueous solution (5.5 mL) was added dropwise, and the mixture was stirred at 25 ° C. for 1 hour. To the reaction mixture, 300 mL of ethyl acetate and 300 mL of a saturated aqueous sodium chloride solution were added, and the aqueous layer was removed. The organic layer was washed three times with an aqueous sodium hydrogen carbonate solution and once with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate to give (3R, 4R, 5S) -3,4-dibutoxy-5- (butoxymethyl). ) A crude solution of thiolan-2-ol was obtained.
To this crude solution, 5.7 mL of pyridine, 6.0 mL of acetic anhydride and 0.32 g of 4- (N, N-dimethylamino) pyridine were added at 25 ° C., and the mixture was stirred at room temperature for 30 minutes and then allowed to stand overnight. . To the reaction solution, 300 mL of 0.5N hydrochloric acid was added, and the aqueous layer was removed. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution (4 times) and saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/8) to give (3R, 4R, 5S) -3,4-dibutoxy as a pale yellow oil. 3.8 g of -5- (butoxymethyl) thiolan-2-yl acetate was obtained.
As a result of measuring ¹ H-NMR, it was an anomeric mixture of about 52:48.

¹ H-NMR (CDCl ₃ ) δ value:
0.88-0.95 (9H, m), 1.30-1.46 (6H, m), 1.49-1.60 (6H, m), 2.08 (1.56H, s), 2.11 (1.44H, s), 3.25-3.31 (0.48H, m), 3.39-3.85 (9.52H, m), 3.92 (0.48H, dd) , J = 4.2, 9.0 Hz), 4.04 (0.52H, dd, J = 3.0, 5.3 Hz), 5.88 (0.48H, d, J = 3.0 Hz), 6.08 (0.52H, d, J = 4.1 Hz)

(3R, 4R, 5S) -3,4-dibutoxy-5- (butoxymethyl) thiolan-2-ol crude 1.8 g of acetyl chloride 0.7 mL was added dropwise at 5 ° C. to 17 mL of methanol, 25 The mixture was stirred at 0 ° C. for 30 minutes and then allowed to stand overnight. 50 mL of ethyl acetate and 50 mL of aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the aqueous layer was removed. The organic layer was washed sequentially with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain about 3.7 g of a residue. By purifying 1.5 g of this residue by column chromatography (developing solvent: ethyl acetate / hexane = 1/1), (3R, 4R, 5S) -3,4-dibutoxy-5- (butoxymethyl)- Two isomers of 2-methoxythiolane, 0.20 g (developing solvent: component of TLC Rf = 0.59 in 1/115) and 0.42 g (developing solvent: ethyl acetate) / Hexane = 1/15 component of TLC Rf = 0.48).
As a result of measuring ¹ H-NMR, each component was a single isomer.

Component of Rf (ethyl acetate / hexane = 1/15) = 0.59
¹ H-NMR (CDCl ₃ ) δ value:
0.91 (6H, t, J = 7.3 Hz), 0.92 (3H, t, J = 7.3 Hz), 1.30-1.41 (6H, m), 1.49-1.59 (6H, m), 3.32 (3H, s), 3.41-3.74 (10H, m), 3.91 (1H, dd, J = 3.3, 6.0 Hz), 4.84 (1H, d, J = 3.3Hz)

Component of Rf (ethyl acetate / hexane = 1/15) = 0.48
¹ H-NMR (CDCl ₃ ) δ value:
0.91 (6H, t, J = 7.3 Hz), 0.92 (3H, t, J = 7.3 Hz), 1.31-1.43 (6H, m), 1.49-1.64 (6H, m), 3.21-3.31 (1H, m), 3.36 (3H, s), 3.38-3.52 (4H, m), 3.57-3.75 (4H , M), 3.87 (1H, dd, J = 5.7, 8.6 Hz), 3.93 (1H, dd, J = 3.6, 8.6 Hz), 4.77 (1H, d, J = 3.6Hz)

Example 5
[A] Synthesis of (3R, 4R, 5S) -3,4-bis (pentyloxy) -5-((pentyloxy) methyl) thiolan-2-ol and its alkoxy form

  Synthesis by reacting (2R, 3R, 4R) -1,3,4-tris (pentyloxy) -5-oxopentan-2-yl methanesulfonate with a 15% aqueous sodium hydrogen sulfide solution as follows. did.

(2R, 3R, 4R) -1,3,4-Tris (pentyloxy) -5-oxopentan-2-yl methanesulfonate in a solution of 6.6 g of N, N-dimethylformamide at 150 ° C. 6.7 mL of 15% aqueous sodium hydrogen sulfide solution was added dropwise, and the mixture was stirred at 25 ° C. for 1.5 hours. To the reaction mixture, 300 mL of ethyl acetate and 300 mL of a saturated aqueous sodium chloride solution were added, and the aqueous layer was removed. The organic layer was washed with an aqueous sodium hydrogen carbonate solution three times and a saturated aqueous sodium chloride solution once, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 5.5 g of a crude product of (3R, 4R, 5S) -3,4-bis (pentyloxy) -5-((pentyloxy) methyl) thiolan-2-ol.
To a solution of 2.8 g of this crude product in 37 mL of ethyl acetate, 3.0 mL of pyridine, 3.5 mL of acetic anhydride and 192 mg of 4- (N, N-dimethylamino) pyridine were added at 25 ° C., stirred for 30 minutes, and then brought to room temperature. Left overnight. 150 mL of ethyl acetate and 200 mL of 0.5N aqueous hydrochloric acid were added to the reaction solution, and the aqueous layer was removed. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution (4 times) and saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/10) to give (3R, 4R, 5S) -3,4-bis (pentyloxy) 2.35 g of -5-((pentyloxy) methyl) thiolan-2-yl acetate was obtained.
As a result of measuring ¹ H-NMR, it was an anomeric mixture of about 53:47.

¹ H-NMR (CDCl ₃ ) δ value:
0.88-0.93 (9H, m), 1.28-1.38 (12H, m), 1.50-1.61 (6H, m), 2.08 (1.59H, s), 2.11 (1.41H, s), 3.25-3.32 (0.53H, m), 3.39-3.85 (9.47H, m), 3.92 (0.47H, dd) , J = 4.2, 9.0 Hz), 4.04 (0.53H, dd, J = 3.1, 5.3 Hz), 5.90 (0.53H, d, J = 3.0 Hz), 6.08 (0.47H, d, J = 4.2 Hz)

To a solution of 2.7 g of the crude product of (3R, 4R, 5S) -3,4-bis (pentyloxy) -5-((pentyloxy) methyl) thiolan-2-ol obtained in 24 mL of methanol at 5 ° C. Then, 1.0 mL of acetyl chloride was added dropwise, stirred at 25 ° C. for 2 hours, and allowed to stand overnight. To the reaction solution, 70 mL of ethyl acetate and 70 mL of an aqueous sodium hydrogen carbonate solution were added, and the aqueous layer was removed. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/15) to give pale yellow (3R, 4R, 5S) -3,4- 2.3 g of bis (pentyloxy) -5-((pentyloxy) methyl) -2-methoxythiolane was obtained.
As a result of measuring ¹ H-NMR, it was an anomeric mixture of about 55:45.

¹ H-NMR (CDCl ₃ ) δ value:
0.87-0.96 (9H, m), 1.26-1.36 (12H, m), 1.52-1.64 (6H, m), 3.25 (0.55H, dd, J) = 6.4, 13.5 Hz), 3.32 (1.35 H, s), 3.36 (1.65 H, s), 3.41-3.74 (9 H, m), 3.85-4 0.00 (1.45 H, m), 4.77 (0.55 H, d, J = 3.6 Hz), 4.84 (0.45 H, d, J = 3.3 Hz)

Example 6
[A] Synthesis of (3S, 4S, 5R) -3,4-dibutoxy-5- (butoxymethyl) thiolan-2-ol and its alkoxy form

  The synthesis was performed by reacting (2S, 3S, 4S) -1,3,4-tributoxy-5-oxopentan-2-yl methanesulfonate with a 15% aqueous sodium hydrogen sulfide solution as follows.

(2S, 3S, 4S) -1,3,4-Tributoxy-5-oxopentan-2-yl methanesulfonate 9.7 g of N, N-dimethylformamide in 245 mL solution at 10 ° C. or lower, 15% hydrogen sulfide 11.0 mL of sodium aqueous solution was dripped, and it stirred at 25 degreeC for 1 hour. To the reaction mixture were added 350 mL of ethyl acetate and 350 mL of a saturated aqueous sodium chloride solution, and the aqueous layer was removed. The organic layer was washed with an aqueous sodium hydrogen carbonate solution three times and a saturated aqueous sodium chloride solution once, then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain (3S, 4S, 5R) -3,4. -8.4 g of a crude product of dibutoxy-5- (butoxymethyl) thiolan-2-ol was obtained. By purifying 2.8 g of this crude product by column chromatography (developing solvent: ethyl acetate / hexane = 1/9), almost single (3S, 4S, 5R) -3,4-dibutoxy-5- ( 1.1 g of the anomeric isomer of butoxymethyl) thiolan-2-ol was obtained.
To a solution of 1.1 g of this single anomeric isomer in 17 mL of ethyl acetate, 1.4 mL of pyridine, 1.6 mL of acetic anhydride and 87 mg of 4- (N, N-dimethylamino) pyridine were added at 25 ° C. After stirring for hours, it was allowed to stand overnight. 50 mL of ethyl acetate and 70 mL of 0.5N aqueous hydrochloric acid were added to the reaction solution, and the aqueous layer was removed. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution (4 times) and saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/8) to give a pale yellow oily (3S, 4S, 5R) -3,4-dibutoxy. 1.2 g of -5- (butoxymethyl) thiolan-2-yl acetate was obtained.
As a result of measuring ¹ H-NMR, it seemed that isomerization at the anomeric position partially progressed, and it was an anomeric mixture of about 79:21.

¹ H-NMR (CDCl ₃ ) δ value:
0.88-0.95 (9H, m), 1.30-1.46 (6H, m), 1.49-1.60 (6H, m), 2.08 (2.37H, s), 2.11 (0.63H, s), 3.25-3.31 (0.21H, m), 3.39-3.85 (9.79H, m), 3.92 (0.21H, dd) , J = 4.2, 9.0 Hz), 4.04 (0.79H, dd, J = 3.0, 5.5 Hz), 5.88 (0.79H, d, J = 3.0 Hz), 6.08 (0.21H, d, J = 4.2 Hz)

  2.4 mL of acetyl chloride was added dropwise at 5 ° C. to a 56 mL methanol solution of 5.8 g of a crude product of (3S, 4S, 5R) -3,4-dibutoxy-5- (butoxymethyl) thiolan-2-ol, 25 Stir for 2 hours at ° C. To the reaction solution, 160 mL of ethyl acetate and 160 mL of an aqueous sodium hydrogen carbonate solution were added, and the aqueous layer was removed. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/15) to give (3S, 4S, 5R) -3,4-dibutoxy-5- (butoxy 4.8 g of a mixture of two isomers of methyl) -2-methoxythiolane (developing solvent: component of TLC Rf = 0.45 and component of Rf = 0.36 in ethyl acetate / hexane = 1/15) Obtained. This mixture was further purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/15) to obtain a component having Rf = 0.36 as a single anomer.

¹ H-NMR (CDCl ₃ ) δ value:
0.91 (6H, t, J = 7.3 Hz), 0.92 (3H, t, J = 7.3 Hz), 1.31-1.46 (6H, m), 1.49-1.66 (6H, m), 3.25 (1H, dt, J = 5.2, 6.7 Hz), 3.36 (3H, s), 3.38-3.52 (4H, m), 3.57 −3.76 (4H, m), 3.87 (1H, dd, J = 5.7, 8.6 Hz), 3.92 (1H, dd, J = 3.6, 8.5 Hz), 4. 77 (1H, d, J = 3.6 Hz)

Example 7
[A] Synthesis of (3R, 4R, 5R) -3,4-dibutoxy-5- (butoxymethyl) thiolan-2-ol and its alkoxy form

  Synthesis was carried out by reacting (2S, 3R, 4R) -1,3,4-tributoxy-5-oxopentan-2-yl methanesulfonate with a 15% aqueous sodium hydrogen sulfide solution as follows.

(2S, 3R, 4R) -1,3,4-Tributoxy-5-oxopentan-2-yl Methanesulfonate (5.0 g) in N, N-dimethylformamide (63 mL) solution at 10 ° C. or lower and 15% hydrogen sulfide A sodium aqueous solution (5.9 mL) was added dropwise, and the mixture was stirred at 25 ° C. for 1.0 hour. Ethyl acetate and water were added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution twice, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 3.8 g of a crude product of (3R, 4R, 5R) -3,4-dibutoxy-5- (butoxymethyl) thiolan-2-ol.
As a result of measuring ¹ H-NMR, it was an anomeric mixture of about 78:22. The obtained residue was purified by column chromatography to obtain 1.83 g of a colorless oily anomer ratio ratio of about 82:18 and 0.35 g of a colorless oily anomer ratio ratio of about 91: 9.

¹ H-NMR (CDCl ₃ ) δ value:
0.87-0.97 (9H, m), 1.30-1.45 (6H, m), 1.49-1.64 (6H, m), 3.10 (0.18H, d, J = 9.6 Hz), 3.37-3.77 (8.82 H, m), 3.82- 3.88 (0.36 H, m), 3.91 (0.82 H, d, J = 12. 6 Hz), 3.96-4.04 (1.82 H, m), 5.20 (0.82 H, d, J = 12.6 Hz), 5.55 (0.18 H, dd, J = 4.4). , 9.4 Hz).

(3R, 4R, 5R) -3,4-dibutoxy-5- (butoxymethyl) thiolan-2-ol (anomeric mixing ratio 91: 9) 350 mg of ethyl acetate in 5 mL solution at 25 ° C. with pyridine 0.32 mL and 4 -12 mg of (N, N-dimethylamino) pyridine was added, and 0.19 mL of acetic anhydride was added at 0 ° C. After stirring at 25 ° C. for 75 minutes, ethyl acetate and water were added to the reaction solution, and the aqueous layer was removed. The organic layer was washed successively with hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography to obtain a total of 331 mg of (3R, 4R, 5R) -3,4-dibutoxy-5- (butoxymethyl) thiolan-2-yl acetate. Obtained.
As a result of measuring ¹ H-NMR, it was an anomeric mixture of about 97: 3 (171 mg) and about 81:19 (160 mg).

¹ H-NMR (CDCl ₃ ) δ value:
0.87-0.97 (9H, m), 1.29-1.64 (12H, m), 2.07 (2.43H, s), 2.10 (0.57H, s), 3. 36-3.66 (8H, m), 3.73 (0.19H, dd, J = 4.7, 9.5 Hz), 3.81 (0.81H, dd, J = 5.4, 9.. 0 Hz), 3.94 (0.81 H, t, J = 5.3 Hz), 3.96 (0.19 H, dd, J = 4.5, 9.3 Hz), 4.08 (0.19 H, dd) , J = 7.5, 9.3 Hz), 4.13 (0.81 H, dd, J = 2.7, 5.1 Hz), 5.88 (0.89 H, d, J = 2.7 Hz), 6.07 (0.19H, d, J = 4.5 Hz)

  By repeating purification of (3R, 4R, 5R) -3,4-dibutoxy-5- (butoxymethyl) thiolan-2-yl acetate synthesized by the same method as described above by column chromatography, the anomeric ratio is reduced to about 189 mg of a 22:78 mixture was obtained.

(3R, 4R, 5R) -3,4-dibutoxy-5- (butoxymethyl) thiolan-2-ol (anomer mixing ratio 82:18) 1.0 g of acetyl chloride 0.85 mL at 5 ° C. in 15 mL of methanol Was dropped and left at 25 ° C. overnight. Ethyl acetate and water were added to the reaction solution, and the aqueous layer was removed. The organic layer was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography to obtain two components (2R, 3R, 4R) -3,4-dibutoxy-2- (butoxymethyl) -5-methoxythiolane. , 0.58 g (developing solvent: component of TLC Rf = 0.37 in ethyl acetate / hexane = 5/95) and 0.34 g (developing solvent: TLC Rf = 0 in ethyl acetate / hexane = 5/95) .23 component).
As a result of measuring ¹ H-NMR, each component was a single isomer.

Component of Rf (ethyl acetate / hexane = 5/95) = 0.37
¹ H-NMR (CDCl ₃ ) δ value:
0.88-0.96 (9H, m), 1.30-1.45 (6H, m), 1.50-1.62 (6H, m), 3.31 (3H, s), 3. 40-3.65 (8H, m), 3.80-3.87 (1H, m), 3.88-3.98 (1H, m), 4.85 (1H, d, J = 2.7 Hz) )

Component of Rf (ethyl acetate / hexane = 5/95) = 0.23
¹ H-NMR (CDCl ₃ ) δ value:
0.87-0.96 (9H, m), 1.30-1.44 (6H, m), 1.49-1.66 (6H, m), 3.37 (3H, s), 3. 40-3.68 (8H, m), 3.76 (1H, dd, J = 4.6, 9.4 Hz), 3.92 (1H, dd, J = 4.2, 9.0 Hz), 4 .13 (1H, dd, J = 7.8, 9.0 Hz), 4.78 (1H, d, J = 4.2 Hz)

Example 8
[A] Synthesis of (3S, 4R, 5R) -3,4-dibutoxy-5- (butoxymethyl) thiolan-2-ol and its alkoxy form

  Synthesis was carried out by reacting (2S, 3R, 4S) -1,3,4-tributoxy-5-oxopentan-2-yl methanesulfonate with a 15% aqueous sodium hydrogen sulfide solution as follows.

(2S, 3R, 4S) -1,3,4-Tributoxy-5-oxopentan-2-yl methanesulfonate 6.3 g of N, N-dimethylformamide in 160 mL solution at 10 ° C. or less, 15% hydrogen sulfide 6.3 mL of sodium aqueous solution was dripped, and it stirred at 25 degreeC for 1.5 hours. To the reaction mixture, 400 mL of ethyl acetate and 400 mL of saturated aqueous sodium chloride solution were added, and the aqueous layer was removed. The organic layer was washed with an aqueous sodium hydrogen carbonate solution twice and a saturated aqueous sodium chloride solution once, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 5.6 g of a crude product of (3S, 4R, 5R) -3,4-dibutoxy-5- (butoxymethyl) thiolan-2-ol.
As a result of measuring ¹ H-NMR, it was an anomeric mixture of about 65:35.

¹ H-NMR (CDCl ₃ ) δ value:
0.89-0.96 (9H, m), 1.33-1.45 (6H, m), 1.50-1.64 (6H, m), 2.16 (0.35H, d, J) = 5.8 Hz), 3.41-3.91 (10H, m), 4.12-4.17 (1H, m), 4.29 (1H, d, J = 11.9 Hz), 5.30. −5.33 (0.35H, m), 5.33 (0.65H, dd, J = 3.8, 11.9 Hz)

(3S, 4R, 5R) -3,4-dibutoxy-5- (butoxymethyl) thiolan-2-ol crude 0.85 g of ethyl acetate in 13 mL solution at 25 ° C. with 3.0 mL of pyridine and acetic anhydride. 0 mL and 66 mg of 4- (N, N-dimethylamino) pyridine were added, stirred for 30 minutes, and allowed to stand at room temperature for 2.5 days. To the reaction solution, 30 mL of ethyl acetate and 1N aqueous hydrochloric acid were added, and the aqueous layer was removed. The organic layer was washed successively with 1N aqueous hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 1/8) to give (3S, 4R, 5R) -3,4-dibutoxy-5- ( 0.48 g of butoxymethyl) thiolan-2-yl acetate was obtained.
As a result of measuring ¹ H-NMR, it was an anomeric mixture of about 79:21.

¹ H-NMR (CDCl ₃ ) δ value:
0.89-0.95 (9H, m), 1.32-1.46 (6H, m), 1.49-1.60 (6H, m), 2.07 (0.63H, s), 2.09 (2.37H, s), 3.41-3.60 (8H, m), 3.78-3.95 (2H, m), 4.06-4.10 (1H, m), 5.90 (0.21H, d, J = 3.9 Hz), 6.23 (0.79H, d, J = 4.9 Hz)

(3S, 4R, 5R) -3,4-Dibutoxy-5- (butoxymethyl) thiolan-2-ol A crude product of 3.7 g of methanol in 38 mL was added dropwise with 1.57 mL of acetyl chloride at 5 ° C., 25 The mixture was stirred at 0 ° C. for 30 minutes and then allowed to stand overnight. Ethyl acetate 100mL and sodium hydrogencarbonate aqueous solution 100mL were added to the reaction liquid, and the aqueous layer was removed. The organic layer was washed successively with an aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain about 3.7 g of a residue. By purifying 1.5 g of this residue by column chromatography (developing solvent: ethyl acetate / hexane = 1/15), (3S, 4R, 5R) -3,4-dibutoxy-5- (butoxymethyl)- 0.82 g of 2-methoxythiolane was obtained.
As a result of measuring ¹ H-NMR, it was almost a single anomer.

¹ H-NMR (CDCl ₃ ) δ value:
0.89-0.95 (9H, m), 1.34-1.43 (6H, m), 1.50-1.59 (6H, m), 3.33 (3H, s), 3. 43 (2H, t, J = 6.5 Hz), 3.50-3.71 (6H, m), 3.80 (1H, dd, J = 5.8, 9.2 Hz), 3.90 (1H , T, J = 3.6 Hz), 4.07 (1H, dd, J = 3.3, 5.4 Hz), 4.98 (1H, d, J = 3.9 Hz)

In addition, the raw materials in Examples 4 to 8 are the corresponding 3,4-dialkoxy-5-alkoxymethyloxolane-2-ol according to conditions known in the literature or similar conditions as in the route described in Reference Example 2. This was obtained by synthesizing the corresponding 1,3,4-trialkoxy-5-oxoalkane-2-yl methanesulfonate by the same method as in Example 3 .

Example 9
[A] Synthesis of (3R, 4S, 5R) -3,4-dibutoxy-5- (butoxymethyl) thiolan-2-ol and its alkoxy form

  The synthesis was performed by reacting (2R, 3S, 4S) -4-bromo-2,3,5-tributoxypentanal with a 15% aqueous sodium hydrogen sulfide solution as follows.

(2R, 3S, 4S) -4-Bromo-2,3,5-tributoxypentanal (0.99 g) in a solution of N, N-dimethylformamide (26 mL) at 10 ° C. or less, 2.0 M hydrochloric acid (0.26 mL) and 15 A 1.17 mL aqueous sodium hydrogen sulfide solution was added dropwise, and the mixture was stirred at 25 ° C. for 1 hour. To the reaction mixture, 60 mL of ethyl acetate and 30 mL of a saturated aqueous sodium chloride solution were added, and the aqueous layer was removed. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 0.79 g of a crude product of (3R, 4S, 5R) -3,4-dibutoxy-5- (butoxymethyl) thiolan-2-ol.
As a result of measuring ¹ H-NMR, β form: (2S, 3R, 4S, 5R) -3,4-dibutoxy-5- (butoxymethyl) thiolan-2-ol and α form: (2R, 3R, 4S, 5R) -3,4-dibutoxy-5- (butoxymethyl) thiolan-2-ol was an anomeric mixture with a ratio of about 65:35.

¹ H-NMR (CDCl ₃ ) δ value:
0.91-0.96 (9H, m), 1.30-1.45 (6H, m), 1.50-1.64 (6H, m), 2.52 (0.65H, d, J) = 6.3 Hz), 3.27-3.72 (9 H, m), 3.84 (0.35 H, d, J = 3.8 Hz), 3.95-4.11 (2 H, m), 5 .16 (0.65H, dd, J = 1.2, 6.3 Hz), 5.32 (0.35H, ddd, J = 0.9, 4.5, 11.7 Hz)

A crude product of 0.83 g of (3R, 4S, 5R) -3,4-dibutoxy-5- (butoxymethyl) thiolan-2-ol and 0.03 g of 4- (N, N-dimethylamino) pyridine in 10 mL of ethyl acetate To the solution, 2.4 mL of acetic anhydride was added and stirred at 25 ° C. for 30 minutes.
As a result of measuring ¹ H-NMR, it was an anomeric mixture of about 42:58. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 3/97 → 24/76) to obtain α-anomer: (2S, 3R, 4S, 5R). 0.30 g of 3,4-dibutoxy-5- (butoxymethyl) thiolan-2-yl acetate (developing solvent: component of TLC Rf = 0.2 in ethyl acetate / hexane = 1/9), and β-anomer : (2R, 3R, 4S, 5R) -3,4-dibutoxy-5- (butoxymethyl) thiolan-2-yl acetate 0.47 g (developing solvent: TLC Rf = 0 in ethyl acetate / hexane = 1/9) .3 component).

α-anomer
¹ H-NMR (CDCl ₃ ) δ value:
0.88-0.96 (9H, m), 1.32-1.46 (6H, m), 1.49-1.64 (6H, m), 2.11 (3H, s), 3. 41-3.60 (7H, m), 3.64-3.72 (2H, m), 3.85-4.00 (1H, m), 6.20 (1H, m)

β-anomer
¹ H-NMR (CDCl ₃ ) δ value:
0.88-0.96 (9H, m), 1.32-1.46 (6H, m), 1.49-1.60 (6H, m), 2.07 (3H, s); 41-3.72 (8H, m), 3.75-3.82 (2H, m), 4.01 (1H, dd, J = 1.8, 3.3 Hz), 5.89 (1H, d , J = 1.8Hz)

To a solution of 0.73 g of a crude product of (3R, 4S, 5R) -3,4-dibutoxy-5- (butoxymethyl) thiolan-2-ol in 8 mL of methanol was added dropwise 0.34 mL of acetyl chloride at 5 ° C., 25 After stirring at 5 ° C. for 5 hours, 20 mL of toluene was added and allowed to stand overnight. Ethyl acetate and water were added to the reaction solution, and the aqueous layer was removed. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. As a result of measuring ¹ H-NMR of the obtained residue, it was an anomeric mixture of about 3:97.
By purifying the obtained residue by column chromatography (developing solvent: ethyl acetate / hexane = 0/100 → 13/87), α-anomer: (2S, 3R, 4S, 5R) -3,4- 0.027 g of dibutoxy-5- (butoxymethyl) -2-methoxythiolane (developing solvent: component of TLC Rf = 0.2 in ethyl acetate / hexane = 1/9) and β-anomer: (2R, 3R, 4S, 5R) -3,4-dibutoxy-5- (butoxymethyl) -2-methoxythiolane 0.77 g (developing solvent: component of TLC Rf = 0.45 in ethyl acetate / hexane = 1/9) )

α-anomer
¹ H-NMR (CDCl ₃ ) δ value:
0.87-0.95 (9H, m), 1.30-1.45 (6H, m), 1.50-1.70 (6H, m), 3.37 (3H, s), 3. 42-3.70 (9H, m), 3.88 (1H, t, J = 4.5 Hz), 3.94 (1H, dd, J = 2.7, 4.5 Hz), 5.52 (1H , D, J = 4.2 Hz)

β-anomer
¹ H-NMR (CDCl ₃ ) δ value:
0.87-0.95 (9H, m), 1.30-1.45 (6H, m), 1.49-1.64 (6H, m), 3.31 (3H, s), 3. 40-3.71 (8H, m), 3.75-4.00 (2H, m), 3.98 (1H, dd, J = 1.8, 3.3 Hz), 4.86 (1H, d , J = 1.8Hz)

[B] Synthesis of raw material The raw material (2R, 3S, 4S) -4-bromo-2,3,5-tributoxypentanal was synthesized in a plurality of steps as follows.

  First, (3R, 4R, 5R) -3,4-dibutoxy-5- (butoxymethyl) oxolan-2-ol, which is a starting material, was synthesized by the following route under conditions known in the literature or similar conditions thereto. .

(3R, 4R, 5R) -3,4-dibutoxy-5- (butoxymethyl) oxolan-2-ol 3.1 g of methanol in 38 mL solution was added pyridine 6.2 mL, p-toluenesulfonic acid monohydrate 3 0.1 g and O-methylhydroxylamine hydrochloride 1.8 g were added at 25 ° C. and stirred at 25 ° C. for 5 minutes. After about 30 mL of methanol was distilled off under reduced pressure, 10 mL of toluene, 40 mL of ethyl acetate and 40 mL of water were added to the reaction mixture, and the aqueous layer was removed. The organic layer was washed successively with 0.5N aqueous hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give colorless oily methoxy ((2S, 3R, 4R) -2,3,5-Tributoxy-4-hydroxypentylidene) amine 4.5 g was obtained. This crude product was used in the next step without further purification.
As a result of measuring ¹ H-NMR, it was a mixture of oxime isomers A and B of about 81:19.

¹ H-NMR (CDCl ₃ ) δ value:
0.88-0.94 (9H, m), 1.30-1.43 (6H, m), 1.46-1.62 (6H, m), 2.65 (0.81H, d, J = 4.7 Hz), 2.71 (0.19 H, d, J = 5.4 Hz), 3.33-3.60 (8 H, m), 3.62-3.79 (2 H, m), 3 .87 (2.43 H, s), 3.89 (0.57 H, s), 4.10 (0.81 H, dd, J = 4.0, 8.1 Hz), 4.80 (0.19 H, dd, J = 2.6, 6.5 Hz), 6.79 (0.19 H, d, J = 6.5 Hz), 7.35 (0.81 H, d, J = 8.1 Hz)

To an 18 mL acetonitrile solution of 4.5 g of methoxy ((2S, 3R, 4R) -2,3,5-tributoxy-4-hydroxypentylidene) amine crude and 3.64 g of 2,4,5-trichlorobenzenesulfonyl chloride 1.91 mL of N-methylimidazole was added dropwise at 3 ° C., and the mixture was stirred at 25 ° C. for 2 hours. Then, 0.67 g of 2,4,5-trichlorobenzenesulfonyl chloride was added, and the mixture was stirred at 25 ° C. for 1 hour. To the reaction mixture were added 18 mL of toluene, 18 mL of ethyl acetate and 18 mL of water, and the precipitated insoluble material was separated by filtration. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a pale yellow oily (2R, 3S, 4S) -1,3,4-tributoxy. 7.9 g of a crude product of -5- (methoxyimino) pentan-2-yl 2,4,5-trichlorobenzene-1-sulfonate was obtained. This crude product was used in the next step without further purification.
As a result of measuring ¹ H-NMR, it was an about 84:16 oxime isomer mixture.

¹ H-NMR (CDCl ₃ ) δ value:
0.84-0.94 (9H, m), 1.16-1.56 (12H, m), 3.21-3.83 (10H, m), 3.86 (2.52H, s), 3.87 (0.48H, s), 4.68 (0.16H, dd, J = 5.1, 6.6 Hz), 4.84-4.92 (0, 84H, m), 6.64 (0.16H, d, J = 6.6 Hz), 7.19 (0.83H, d, J = 7.7 Hz), 7.63 (0.16H, s), 7.64 (0.83H, s), 8.14 (1H, s)

(2R, 3S, 4S) -1,3,4-Tributoxy-5- (methoxyimino) pentan-2-yl 2,4,5 Trichlorobenzene-1-sulfonate crude 7.9 g of dimethylimidazolidinone 14 mL To the solution was added a solution of 2.09 g of lithium bromide in 7 mL of dimethylimidazolidinone and stirred at 50 ° C. for 10 hours. To the reaction mixture were added 60 mL of toluene and 40 mL of water, the aqueous layer was removed, the organic layer was washed successively with water and a saturated aqueous sodium chloride solution, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 2/98 → 23/77) to give (2S, 3S, 4S) -4-bromo-2,3 as a colorless oil. , 5-Tributoxypentylidene) (methoxy) amine 1.44 g.
As a result of measuring ¹ H-NMR, it was an about 92: 8 oxime isomer mixture.

¹ H-NMR (CDCl ₃ ) δ value:
0.87-0.95 (9H, m), 1.28-1.61 (12H, m), 3.35-3.61 (8H, m), 3.64-3.90 (2H, m ), 3.89 (3H, s), 3.99 (0.98H, dd, J = 8.1, 8.1 Hz), 4.36-4.45 (0, 08H, m), 4.48. (0.98H, ddd, J = 2.1, 5.7, 9.0 Hz), 4.75 (0.98H, dd, J = 7.7, 7.7 Hz), 6.68 (0.08H) , D, J = 7.8 Hz), 7.30 (0.92H, d, J = 7.8 Hz)

  (2S, 3S, 4S) -4-Bromo-2,3,5-tributoxypentylidene) (methoxy) amine in 1.44 g of 28 mL of acetone, 2.78 mL of 37% formalin aqueous solution and 1N aqueous hydrochloric acid 1. After adding 8 mL and stirring at 25 degreeC for 13.5 hours, it stirred at 40 degreeC for 1 hour. After diluting with 25 mL of ethyl acetate, the solvent was distilled off under reduced pressure, ethyl acetate and 1.0 M hydrochloric acid were further added, and the aqueous layer was removed. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (developing solvent: ethyl acetate / hexane = 5/95 → 26/74) to give (2R, 3S, 4S) -4-bromo-2,3 as a colorless oil. , 5-tributoxypentanal 0.99 g was obtained.

¹ H-NMR (CDCl ₃ ) δ value:
0.88-0.95 (9H, m), 1.28-1.44 (6H, m), 1.48-1.65 (6H, m), 3.38-3.82 (9H, m) ), 3.94 (1H, dd, J = 2.0, 8.0 Hz), 4.42 (1H, ddd, J = 3.0, 6.0, 11.4 Hz), 9.80 (1H, d, J = 2.1 Hz)

As apparent from Examples 1-9, by reaction with a chain-like compound represented by a general formula (I) and sulfur compounds, as soon thiolane ring when the sulfur compound reacts is formed. Moreover, this reaction can produce a compound represented by the general formula (II) useful as a thionucleoside synthesis intermediate under a mild condition and with a high yield.
Also, compounds and derived compounds other than thio nucleosides represented by one general formula (II) is also potentially useful pharmaceutical, it is also useful as a precursor of pharmaceuticals.
Incidentally, it is possible to a compound represented by a general formula (II) as a starting material, by a method according to the prior art or, to synthesize thio nucleosides are expected as useful physiologically active substances. Thus, the compounds represented by one to a manufacturing method sequence of the compound represented by one general formula (II) general formula (II) are useful.

Claims (21)

The manufacturing method of the compound represented by the following general formula (II) through the process with which the compound represented by the following general formula (I) is made to react with hydrogen sulfide or its salt.

In the general formulas (I) and (II), R ¹ represents a hydrogen atom, an alkyl group or an acyl group, R ² represents —O—R ^2a or a fluorine atom, R ² ′ represents —O—R ^2a , A fluorine atom or = O is represented. Here, R ^2a represents a hydrogen atom, —CH ₂ —R ^2b or an acyl group. R ^2b , R ³ and R ⁵ each independently represents a hydrogen atom, an alkyl group, a vinyl group or an aryl group, and X represents a leaving group. Here, the bond from R ² ′ to the thiolane ring represents a single bond or a double bond.
The acyl group in R ¹ and R ^2a , the alkyl group in R ¹ , and the alkyl group and aryl group in R ^2b , R ³ and R ⁵ are a halogen atom, an alkyl group, an aryl group, a heterocyclic group, an alkoxy group , An aryloxy group, an alkylthio group or an arylthio group may be substituted.
However, when R ¹ is an unsubstituted alkyl group and R ² ′ is —O—R ^2a , R ^2a is a hydrogen atom, —CH ₂ —R ^2b or an acyl group, and R ^2b is an alkyl group. Group, a vinyl group or an aryl group, when R ¹ is a substituted alkyl group and R ² ′ is —O—R ^2a , R ^2a is a hydrogen atom, —CH ₂ —R ^2b or an acyl group. R ^2b is a hydrogen atom, an alkyl group or a vinyl group, and when R ¹ is a hydrogen atom or an acyl group, R ² ′ is ═O. The production method according to claim 1, wherein the compound represented by the general formula (II) is a compound represented by any one of the following general formulas (II-1) to (II-10).

In formula (II-1) ~ (II -5), R 1, R 2b, R 3 and ^{R 5, R} 1, ^R 2b in the formula (II), the same meaning as ^{R 3} and ^{R 5} . R ^2c represents an alkyl group or an aryl group.
In General Formulas (II-6) to (II-10), R ¹¹ represents an alkyl group, and R ²¹ , R ³¹ and R ⁵¹ each independently represents an alkyl group.
Note that the alkyl group in R ¹¹ , R ^2c , R ²¹ , R ³¹ and R ⁵¹ and the aryl group in R ^2c are a halogen atom, an alkyl group, an aryl group, a heterocyclic group, an alkoxy group, an aryloxy group, an alkylthio group. Group or arylthio group may be substituted. R ² ′ in the general formula (II) is —O—CH ₂ —R ^2b or an arylcarbonyloxy group, and R ^2b is a hydrogen atom, an alkyl group, a vinyl group, or an aryl group, or The method according to claim 1, wherein the compound represented by the general formula (II) is represented by the general formula (II-1) or (II-2), and the R ^2c is an aryl group. . The R ¹¹ is a methyl group, the R ²¹ is an alkyl group having 2 to 10 carbon atoms, and R ³¹ and R ⁵¹ are each independently an alkyl group having 1 to 10 carbon atoms. The manufacturing method as described in. 5. The production method according to claim 2, wherein R ²¹ , R ^31, and R ⁵¹ are all the same substituent. In the step of reacting the compound represented by the general formula (I) with the hydrogen sulfide or a salt thereof, a compound represented by the following general formula (IIA) is synthesized, and then represented by the general formula (IIA). The manufacturing method of any one of Claims 1-5 which synthesize | combines the compound represented by the said general formula (II) through the process of alkylating or acylating a compound.

In formula ^(IIA), R 2, ^{R 3} and ^{R 5} have the same meanings as ^R 2, ^{R 3} and ^{R 5} in the general formula (I). When R ² ′ in the general formula (II) is a hydroxy group or when the compound represented by the general formula (II) is represented by the general formula (II-3), the general formula (I) A step of dealkylating a compound represented by the following general formula (II-a) obtained through the step of reacting the compound represented by the hydrogen sulfide or a salt thereof, or the following general formula (II- The manufacturing method of Claim 1 or 2 which manufactures the compound represented by the following general formula (II-c) at the process of deacylating the compound represented by b).

In formula (II-a) ~ (II -c), R 1, R 3 and ^{R 5} have the same meanings as ^R 1, ^{R 3} and ^{R 5} in the general formula (II). R ^2b has the same meaning as ^{R 2b} in the formula (II-1). R ^2c have the same meanings as ^{R 2c} in the formula (II-2). When R ² ′ in the general formula (II) is ═O or the compound represented by the general formula (II) is represented by the general formula (II-5), Through the step of oxidizing the compound represented by the following general formula (II-c ′) obtained through the step of reacting the compound represented by hydrogen sulfide or a salt thereof with the following general formula (II) The production method according to claim 1 or 2, wherein the compound represented by II-d) is produced.

In formula (II-c ') and ^{(II-d), R 1} , R 3 and ^{R 5} have the same meanings as ^R 1, ^{R 3} and ^{R 5} in the general formula (II). R ¹ ′ represents an alkyl group or an acyl group.
The alkyl group and acyl group in R ¹ ′ may be substituted with a halogen atom, alkyl group, aryl group, heterocyclic group, alkoxy group, aryloxy group, alkylthio group or arylthio group. Wherein R ¹ is a hydrogen atom, a manufacturing method according to any one of claims 1 to 3 or 6 to 8 is an acetyl group or a methyl group.   Said X is a halogen atom, an alkylsulfonyloxy group, or an arylsulfonyloxy group, The manufacturing method of any one of Claims 1-9. In the hydrogen sulfide or a salt thereof, method for producing M is according to any one of claims 1 to 10, a MSH or M _{2 S} is an alkali metal. A compound represented by the following general formula (II ′ ).

'In, ^{R 1} represents a hydrogen atom, an alkyl group or an acyl ^{group, R} 2 "is ^{-O-R 2a} formula (II)' or other represents = O. In this ^{case, R 2a} 'represents a hydrogen atom , —CH ₂ —R ^2b ′ or an acyl group, R ^2b ′ represents a vinyl group, and R ³ and R ⁵ each independently represents a hydrogen atom, an alkyl group, a vinyl group or an aryl group. , R ² ″ to the thiolane ring represents a single bond or a double bond.
The acyl group in R ¹ and R ^2a ′ , the alkyl group in R ¹ , and the alkyl group and aryl group in R ³ and R ⁵ are halogen atoms, alkyl groups, aryl groups, heterocyclic groups, alkoxy groups, aryl groups oxy group, an alkylthio group or an arylthio group, but it may also be substituted. The compound according to claim 12 , wherein R ² ″ is ═O. Under following general formula (II-2 ') ~ ( II-5'), (II-7) or other (II-10) or by represented Ru of compounds of.

In the general formulas ( II-2 ′ ) to (II-5 ′), R ¹ represents a hydrogen atom, an alkyl group or an acyl group , R ^1c represents an alkyl group, and R ³⁰ and R ⁵⁰ are each independently aryl. R ^2c represents an alkyl group or an aryl group.
In formula (II-7) Contact and ^{(II-10), R 11} represents an alkyl ^{group, R 21,} R ³¹ and ^{R 51} are to display the alkyl group each independently.
Incidentally, acyl group in ^{R 1, R 1, R 1c} , R 11, R 2c, an alkyl group definitive in R ^{21, R 31} and R ^{5 1,} as well ^as the aryl group in R ^{2c, R 30} and ^{R 50} is halogen atom, an alkyl group, an aryl group, a heterocyclic group, an alkoxy group, an aryloxy group, an alkylthio group or an arylthio group but it may also be substituted. Wherein the compound is a compound represented by the general formula (II-5 '), wherein R ¹ is a hydrogen atom, a methyl group or an acetyl group, 請 Motomeko R ³⁰ and R ⁵⁰ are Ru der phenyl group 14. The compound according to 14 . The compound is a compound represented by general formula (II-7) or (II-10), wherein R ^{1 1} is a methyl group, and the R ²¹ , R ³¹ and R ^{5 are} The compound according to claim 14 , wherein each ¹ is independently an alkyl group having 1 to 10 carbon atoms. The compound according to claim 14 or 16, wherein the compound is a compound represented by the general formula (II-7), and the R ²¹ , R ³¹ and R ⁵¹ are each independently the same substituent. The alkyl group definitive in ^{R 1c} and R ^{1 1} is The compound of claim 14 which is an unsubstituted alkyl group. The selected Ru of compounds from under Symbol.

The selected Ru of compounds from under Symbol.

In the general formulas (II-X-1) to (II-X-5), R ^x1 represents a methyl group, and R ^x2 represents a propyl group, a butyl group, or a pentyl group. Before hear compounds A compound according to any one of claims 12 to 20 is a thio nucleoside synthesis intermediates.