JP6253169B2 - Method for producing cyclic hemiacetal compound - Google Patents

Description

  The present invention relates to a method for producing a cyclic hemiacetal compound.

Sugar is an essential component (gene and cell component) that constitutes a living body, and also becomes energy. As research on rare sugars with low abundance in nature progresses, some of the rare sugars have postprandial blood glucose level-inhibiting action, fat accumulation-inhibiting action, arteriosclerosis-preventing action, blood pressure-inhibiting action, antioxidant action, etc. It has been reported that there is. Rare sugars are also attracting attention as new functional materials that are expected to prevent metabolic syndrome. Furthermore, it has been found that some rare sugars induce the expression of pest defense-related genes such as rice and also have a growth regulating action on plants.
In addition, L-nucleoside analogs are useful as excellent antiviral agents and can be easily synthesized from L-ribose. However, L-ribose is expensive. For this reason, research has been conducted on synthetic methods for alternative L-nucleoside analogues and stereoselective synthesis of L-ribose and derivatives (for example, see Non-patent Document 1).
For this reason, the demand for derivatives of various sugars including rare sugars is increasing more than ever.

  On the other hand, research on synthesizing sugars by organic synthesis (see Non-Patent Documents 2 and 3) is also known.

Tetrahedron, 2011, 67, p. 4031-4035 J. et al. Chem. Soc. C, 1967, p. 1186-1187 J. et al. Chem. Soc. Chem. Commun. 1986, p. 11,885-11,887

The method described in Non-Patent Document 2 is a reaction in which acetal is hydrolyzed under acidic conditions, tosylate is eliminated, and a 5-membered ring is formed. However, this method has a low yield. On the other hand, the method described in Non-Patent Document 3 is a reaction in which acetal is hydrolyzed under acidic conditions and cyclized to a 6-membered ring. However, this method has a limited compound structure to be cyclized. In addition, special 2,2,2-trifluoroethanol is used as a nucleophile under basic conditions, and the reaction conditions are also limited.
In addition, physiologically active substances in pharmaceuticals, agricultural chemicals, and the like have greatly different effects on living bodies depending on the three-dimensional structure of the compound. For this reason, it is necessary to selectively synthesize only one stereoisomer. Moreover, it is required to convert one stereoisomer to the other stereoisomer (for example, D-form-L conversion) under mild reaction conditions and in a short process.

Therefore, an object of the present invention is to provide a production method capable of synthesizing a cyclic hemiacetal compound in a simple and high yield under mild conditions.
Furthermore, it is an object to provide a method for producing a cyclic hemiacetal compound that can be applied even when a stereoisomer such as a sugar has to be considered, is excellent in stereoselectivity, and can be mass-produced. To do.

  The present inventors examined various methods for converting D-ribofuranose to L-lyxofuranose in order to convert from one stereoisomer to the other. . As a result, the inventors have found a method of directly cyclizing a carbonyl group of an aldehyde in a saccharide linear structure from an oxime form obtained by oximation, and have further studied the present invention.

According to the present invention, the following means are provided:
<1> A method for producing a compound represented by the following general formula (II), wherein a compound represented by the following general formula (I) is reacted under acidic conditions.

In the general formula (I) and (II), L represents a halogen atom or -OSO ₂ Ra. R ^N represents -Rb, the -ORb or -N (Rb) (Rc). Here, Ra represents a halogen atom, an aliphatic group, an aryl group or a heterocyclic group, and Rb and Rc each independently represent a hydrogen atom, an aliphatic group, an acyl group, an aryl group or a heterocyclic group. R ¹ represents a hydrogen atom, an aliphatic group, an aryl group or a heterocyclic group. X represents a single bond or —C (R ^XA ) (R ^XB ) —. R ^{2A to} R ^4A , R ^{2B to} R ^4B , R ^XA and R ^XB each independently represent a hydrogen atom or a substituent. R ^2A and R ^2B , R ^3A and R ^3B , R ^XA and R ^XB may jointly form a methylidene group represented by ═O or ═C (Rd) (Re), , R ^{2A to} R ^4A , R ^{2B to} R ^4B , R ^XA and R ^XB may be bonded to each other to form a ring. Rd and Re each independently represent a hydrogen atom or a substituent.
<2> The compound represented by the general formula (I) is a compound represented by the following general formula (IA), and the compound represented by the general formula (II) is represented by the following general formula (IIA). <1> The production method according to <1>.

In formula (IA) and ^{(IIA), L, R N} , R 1, R 2A ~R 4A and ^R 2B ^{to R 4B} is, ^L in the general formula (I) and ^{(II), R N, R} 1, R ^2A to R ^4A and ^R 2B ^{to R 4B} is as defined above.
<3> L is a halogen atom or -OSO ₂ Ra, is ^{R N} is -Rb, -ORb or -N (Rb) (Rc), wherein, Ra is a halogen atom, an alkyl group, an alkenyl A group, an aryl group or a heterocyclic group, wherein Rb and Rc are each independently a hydrogen atom, an alkyl group, an alkenyl group, an acyl group, an aryl group or a heterocyclic group;
R ¹ is a hydrogen atom, an alkyl group, an alkenyl group or an aryl group, X is a single bond or —C (R ^XA ) (R ^XB ) —, and R ^2A , R ^2B , R ^3A , R ^3B , R ^XA and R ^XB are each independently a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group, an alkenyl group, an aryl group, a heterocyclic group, an alkoxy group, an alkenyloxy group, an aryloxy group, an acyloxy group, an alkylsulfonyloxy Group, arylsulfonyloxy group, silyloxy group, amino group, acylamino group, cyano group or azide group, and R ^4A and R ^4B are each independently a hydrogen atom, an alkyl group, an alkenyl group, an aryl group or a heterocyclic group. Yes,
Here, even if R ^2A and R ^2B , R ^3A and R ^3B , R ^XA and R ^XB jointly form a methylidene group represented by ═O or ═C (Rd) (Re) Or at least two of R ^{2A to} R ^4A , R ^{2B to} R ^4B , R ^XA and R ^XB may be bonded to each other to form a ring, in which case Rd and Re are each independently A hydrogen atom or an alkyl group,
The manufacturing method as described in <1>.
<4> ^{R N} is an -ORb <1> ~ The process according to any one of <3>.
<5> The production method according to any one of <1> to <4>, wherein R ¹ is a hydrogen atom.
The production method according to <6> L is any one of a _{-OSO 2 Ra <1> ~ <} 5>.
<7> The production according to any one of <1> to <6>, wherein one of R ^4A and R ^4B is a hydrogen atom and the other is a substituent, or R ^4A and R ^4B are different substituents. Method.
<8> At least one of R ^2A , R ^3A , R ^2B and R ^3B is a hydroxyl group, alkoxy group, alkenyloxy group, aryloxy group, acyloxy group, silyloxy group, alkylsulfonyloxy group or arylsulfonyloxy group < The manufacturing method according to any one of 1> to <7>.
<9> L is a -OSO ₂ Ra, ^{R N} is a -ORb, ^{R 1} is hydrogen ^{atom, R 2A, R 3A, R} 2B and ^{R 3B} are each independently a hydrogen atom, a hydroxyl group , An alkoxy group, an alkenyloxy group, an aryloxy group, an acyloxy group, an alkylsulfonyloxy group or an arylsulfonyloxy group, and any one of R ^4A and R ^4B is a hydrogen atom and the other is an alkyl group <1> to The manufacturing method as described in any one of <8>.
<10> The production method according to <2>, wherein the reaction is performed after the compound represented by the general formula (IA) is produced from the compound represented by the following general formula (IIIA).

In the general formula (IIIA), ^{R 1} has the same meaning as ^{R 1} in the general formula (I). R ^{2Ax to} R ^4Ax and R ^{2Bx to} R ^4Bx each independently represent a hydrogen atom or a substituent. R ^2Ax and R ^2Bx , R ^3Ax and R ^3Bx may jointly form a methylidene group represented by ═O or ═C (Rdx) (Rex), and R ^{2Ax to} R ^{4Ax And} at least two of R ^{2Bx to} R ^4Bx may be bonded to each other to form a ring. Rdx and Rex each independently represent a hydrogen atom or a substituent.
<11> The production method according to any one of <1> to <10>, wherein the reaction is performed in the presence of water.
<12> The production method according to any one of <1> to <11>, wherein the reaction is performed in the presence of an aldehyde compound.
<13> The production method according to any one of <1> to <12>, wherein the reaction is performed in the presence of glyoxylic acid.

  In the present specification, each substituent may be further substituted with a substituent unless otherwise specified. In addition, when a plurality of groups having the same symbol are present, it means that these groups may be the same or different from each other unless otherwise specified.

According to the present invention, it is possible to provide a production method capable of synthesizing a cyclic hemiacetal compound in a simple and high yield under mild conditions.
In addition, the present invention can be applied even when a stereoisomer such as a sugar has to be considered, and can provide a method for producing a cyclic hemiacetal compound that is excellent in stereoselectivity and can be mass-produced.
These and other features and advantages of the present invention will become more apparent from the following description.

<< Method for Producing Cyclic Hemiacetal Compound >>
The production method of the present invention is a production method in which a compound represented by the following general formula (I) is reacted under acidic conditions to synthesize a compound represented by the following general formula (II).

In the general formula (I) and (II), L represents a halogen atom or -OSO ₂ Ra. R ^N represents -Rb, the -ORb or -N (Rb) (Rc). Here, Ra represents a halogen atom, an aliphatic group, an aryl group or a heterocyclic group, and Rb and Rc each independently represent a hydrogen atom, an aliphatic group, an acyl group, an aryl group or a heterocyclic group. R ¹ represents a hydrogen atom, an aliphatic group, an aryl group or a heterocyclic group. X represents a single bond or —C (R ^XA ) (R ^XB ) —. R ^{2A to} R ^4A , R ^{2B to} R ^4B , R ^XA and R ^XB each independently represent a hydrogen atom or a substituent. R ^2A and R ^2B , R ^3A and R ^3B , R ^XA and R ^XB may jointly form a methylidene group represented by ═O or ═C (Rd) (Re), , R ^{2A to} R ^4A , R ^{2B to} R ^4B , R ^XA and R ^XB may be bonded to each other to form a ring. Rd and Re each independently represent a hydrogen atom or a substituent.

This reaction, as shown below, under acidic conditions, general formula (I)> in the C = ^N-R N is hydrolysed> C = O, and the cyclization via the hydrolysis intermediate It progresses by doing.

As noted above, the moieties involved in the reaction are the carbon atom to which R ^4A , R ^4B and L are attached and the carbon atom> C = N—R ^N. The carbon atom to which R ^4A , R ^4B and L are bonded undergoes a nucleophilic attack by the oxygen atom of the carbonyl, resulting in absolute conformational inversion (Walden inversion). In the general formula (II), the carbon atom to which R ¹ and OH are bonded may have an α- or β-anomer upon cyclization. However, since R ^2A , R ^2B , X moiety, R ^3A and R ^3B are not involved in the reaction, the absolute conformation is retained.
In addition, said hydrolysis intermediate body is an intermediate body which arises temporarily in said reaction system (reaction liquid).

In the present invention, the absolute conformations of R ^2A , R ^2B , X moiety, R ^3A and R ^3B are retained, and only the absolute conformation of the carbon atom to which R ^4A , R ^4B and L are attached is inverted. For this reason, for example, a D-form-L form conversion which synthesize | combines a L-lyxofuranose derivative from a D-ribofuranose derivative is attained.

  Here, Bz represents a benzoyl group.

  Hereinafter, the compound represented by the general formula (I) used in the production method of the present invention, the compound represented by the general formula (II) produced by the production method of the present invention, reaction conditions and the general formula (I) Will be described in the order of the method of synthesizing the compounds represented by formula (1).

<Compound represented by formula (I)>

L represents a halogen atom or —OSO ₂ Ra. Among them, in the present invention, _-OSO 2 Ra are preferred.
The halogen atom is preferably a chlorine atom, a bromine atom or an iodine atom, more preferably a bromine atom or an iodine atom, and even more preferably an iodine atom.

Ra in —OSO ₂ Ra represents a halogen atom, an aliphatic group, an aryl group or a heterocyclic group.
The halogen atom in Ra is preferably a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, more preferably a fluorine atom or a chlorine atom.
The aliphatic group is preferably an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, or a cycloalkenyl group. Of these, the alkyl group preferably has 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, and n-hexyl. The alkenyl group preferably has 2 to 6 carbon atoms, and examples thereof include vinyl, allyl, 1-propenyl, and 2-propenyl. The number of carbon atoms of the alkynyl group is preferably 2 to 6, and examples thereof include ethynyl and 2-propynyl. The number of carbon atoms of the cycloalkyl group is preferably 3 to 8, and examples thereof include cyclopropyl, cyclopentyl, and cyclohexyl. The number of carbon atoms of the cycloalkenyl group is preferably 5 to 10, and examples thereof include cyclopentenyl and cyclohexenyl.
6-20 are preferable and, as for carbon number of an aryl group, 6-12 are more preferable, for example, phenyl and naphthyl are mentioned.
The heterocyclic group is preferably one in which the atom bonded to the sulfur atom of SO ₂ is a carbon atom, and the hetero atom constituting the heterocyclic ring of the heterocyclic group is an oxygen atom, a sulfur atom, or a nitrogen atom and is a 5- or 6-membered ring And a ring such as a benzene ring may be condensed. The heterocyclic ring of the heterocyclic group may be a saturated ring, an unsaturated ring or an aromatic ring. As for carbon number of a heterocyclic group, 0-20 are preferable. Examples of such heterocycle include furan ring, thiophene ring, pyrrole ring, imidazole ring, pyridine ring, pyrimidine ring, pyrazine ring, triazine ring, indole ring, benzofuran ring, benzothiophene ring, tetrahydrofuran ring, pyrrole ring, Examples include a piperazine ring and a morpholine ring.

Each group in Ra may be further substituted with a substituent. Examples of such a substituent include a halogen atom, an alkoxy group, an aryloxy group in addition to the aliphatic group, aryl group, and heterocyclic group mentioned above. Group, alkylthio group, arylthio group, amino group (including alkylamino group, arylamino group and heterocyclic amino group in addition to —NH ₂ ), acyl group, acyloxy group, acylamino group, sulfonamide group, carbamoyl group, sulfamoyl group , Alkoxycarbonyl group, aryloxycarbonyl group, ureido group, urethane group, alkyl or aryl sulfonyl group, alkyl or aryl sulfinyl group, alkyl or aryl sulfonyloxy group, alkyl or aryl sulfinyloxy group, silyl group, silyloxy Group, cyano group, nitro group, sulfo group, carboxy group, hydroxy group, azide group, hydrazino group.

  These substituents preferably have 25 or less carbon atoms, more preferably 12 or less. Among them, the aliphatic part of the group having an aliphatic part preferably has 1 to 6 carbon atoms, the aryl part of the group having an aryl part preferably has 6 to 20 carbon atoms, and the heterocyclic ring of the group having a heterocyclic part. As for carbon number of a part, 0-20 are preferable. For example, in the case of an acyl group and an alkylcarbonyl group, the number of carbon atoms of “alkyl” is preferably 1 to 6. When the total number of carbon atoms of the carbonyl group is 1, the preferable number of carbon atoms of the “alkylcarbonyl group” is 2 to 2. 7

  Among these, the substituent that may be further substituted on each group in Ra is preferably an electron-withdrawing group, and is a halogen atom, acyl group, acyloxy group, sulfonamido group, carbamoyl group, sulfamoyl group, alkoxycarbonyl group. , Aryloxycarbonyl group, ureido group, urethane group, alkyl or aryl sulfonyl group, alkyl or aryl sulfinyl group, cyano group, nitro group, sulfo group and carboxy group.

  Ra is preferably a halogen atom, an alkyl group, an alkenyl group, an aryl group or a heterocyclic group, more preferably a halogen atom, an alkyl group, an aryl group or an aromatic heterocyclic group (heteroaryl group), and an alkyl group or an aryl group. Further preferred is an aryl group. Among them, a halogen atom, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a carbamoyl group, a sulfamoyl group, an alkyl or aryl sulfonyl group, an alkyl or aryl sulfinyl group, or an aryl group substituted with a cyano group is preferable. As for the number of these substituents substituted to an aryl group, 1-5 are preferable. Especially, when a halogen atom substitutes, 2-5 are preferable and, as for the number of halogen atoms, 3-5 are more preferable.

  Particularly preferable Ra is an alkyl group substituted with 1 to 9 halogen atoms, a phenyl group substituted with 1 to 5 halogen atoms, and a phenyl group substituted with 2 to 5 halogen atoms is particularly preferred. Most preferred is a phenyl group substituted with 3 to 5 atoms.

R ^N represents -Rb, the -ORb or -N (Rb) (Rc). Here, Rb and Rc each independently represents a hydrogen atom, an aliphatic group, an acyl group, an aryl group or a heterocyclic group. Preferred examples of the aliphatic group, aryl group and heterocyclic group for Rb and Rc include those exemplified for the aliphatic group, aryl group and heterocyclic group for Ra.

The acyl group may be an aliphatic acyl group or an aromatic acyl group. An alkylcarbonyl group or an arylcarbonyl group is preferred. Here, the “aliphatic acyl group” means an acyl group having an “aliphatic group” in Rb and Rc, and is an aliphatic group —C (═O) —.
The number of carbon atoms of the acyl group is preferably 2-20, and among these, the number of carbon atoms of the aromatic acyl group containing an arylcarbonyl group is preferably 6-20, and the aliphatic acyl group is preferably 2-10. The “aliphatic group” of the aliphatic group —C (═O) — and the “aryl” group in the “aromatic” group part of the aromatic acyl group are the preferred ranges mentioned for the aliphatic group and aryl group in Ra, and Specific exemplary groups are preferably applied.

  Rb and Rc are preferably a hydrogen atom, an aliphatic group (in particular, an alkyl group or an alkenyl group), an acyl group, an aryl group, or a heterocyclic group.

Here,> C═N— ^RN is a protecting group for a carbonyl group, where> C═O, and is deprotected under acidic conditions, so that> C═N—R ^N becomes> C═O. R ^N, the stability of the compound represented by the general formula (I), i.e., affect the stability of the> C = ^N-R N. In terms of this stability, ^{R N} is -ORb or -N (Rb) (Rc) is preferred. On the other hand,> C = the ^{N-R N>} in terms of ease of deprotection reaction to C = O is, ^{R N} is preferably -Rb or -ORb. For this reason, -ORb is particularly preferable in terms of satisfying both stability and ease of deprotection.

  Rb and Rc are preferably an aliphatic group, an aryl group or a heterocyclic group, more preferably an aliphatic group or an aryl group, still more preferably an aliphatic group, and particularly preferably an alkyl group. The aliphatic group in Rb and Rc preferably has 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms, still more preferably a methyl group, an ethyl group, an n-propyl group, or an isopropyl group, a methyl group or an ethyl group Groups are particularly preferred and methyl groups are most preferred.

R ¹ represents a hydrogen atom, an aliphatic group (preferably an alkyl group or an alkenyl group), an aryl group or a heterocyclic group. Examples of the aliphatic group, aryl group and heterocyclic group include those exemplified for the aliphatic group, aryl group and heterocyclic group in Ra, and are preferred.
R ¹ is preferably a hydrogen atom, an aliphatic group (preferably an alkyl group, an alkenyl group) or an aryl group, more preferably a hydrogen atom or an aliphatic group, and most preferably a hydrogen atom from the viewpoint of reactivity.

X represents a single bond or —C (R ^XA ) (R ^XB ) —. In the present invention, X is preferably a single bond.

R ^{2A to} R ^4A , R ^{2B to} R ^4B , R ^XA and R ^XB each independently represent a hydrogen atom or a substituent.
R ^{2A to} R ^4A , R ^{2B to} R ^4B , R ^XA and R ^XB are a hydrogen atom, a hydroxyl group, a halogen atom, an aliphatic group (preferably an alkyl group or an alkenyl group), an aryl group, a heterocyclic group, an alkoxy group, An alkenyloxy group, an aryloxy group, an acyloxy group, an alkylsulfonyloxy group, an arylsulfonyloxy group, a silyloxy group, an amino group, an acylamino group, a cyano group, or an azido group is preferable, and an aliphatic group (preferably an alkyl group or an alkenyl group) An aryl group, heterocyclic group, amino group, halogen atom, hydroxyl group, alkoxy group, alkenyloxy group, aryloxy group, acyloxy group, alkylsulfonyloxy group, arylsulfonyloxy group, cyano group or azide group is preferred.

Here, the amino group includes an alkylamino group, an arylamino group, and a heterocyclic amino group in addition to —NH ₂ .

Among R ^{2A to} R ^4A , R ^{2B to} R ^4B , R ^XA and R ^XB , R ^2A , R ^3A , R ^2B , R ^3B , R ^XA and R ^XB are a hydrogen atom, a hydroxyl group, a halogen atom, and an aliphatic group (Preferably alkyl group, alkenyl group), aryl group, heterocyclic group, alkoxy group, alkenyloxy group, aryloxy group, acyloxy group, alkylsulfonyloxy group, arylsulfonyloxy group, silyloxy group, amino group, acylamino group, A cyano group or an azide group is preferable, and R ^4A and R ^4B are preferably a hydrogen atom, an aliphatic group (preferably an alkyl group or an alkenyl group), an aryl group, or a heterocyclic group.

Of each group, the halogen atom, aliphatic group, aryl group, and heterocyclic group are preferably a halogen atom, an aliphatic group, an aryl group, and a heterocyclic group in Ra, and preferably include the range of carbon number.
Further, the carbon number of the alkyl part of the alkoxy group, alkenyloxy group, aryloxy group, alkylsulfonyloxy group, arylsulfonyloxy group, and the carbon number of the aryl part are such that the carbon number in the preferred range of the alkyl group and aryl group in Ra is as follows. preferable. The number of carbon atoms in the “acyl” part of the acylamino group and acyloxy group is preferably within the preferable range of the acyl group in Rb and Rc.

  Here, examples of the acyl group include acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, pivaloyl group, heptanoyl group, acrylic group, methacryl group, cyclohexanoyl group, benzoyl group, and naphthoyl group.

  3-20 are preferable and, as for carbon number of a silyloxy group, 3-10 are more preferable. As silyloxy group, trialkylsilyloxy group, dialkylbenzylsilyloxy group, dialkylarylsilyloxy group, alkyldiarylsilyloxy group, triarylsilyloxy group, trialkoxysilyloxy group, dialkoxyalkylsilyloxy group or arylsilyl An oxy group, an alkoxydialkylsilyloxy group or a diarylsilyloxy group can be mentioned.

  As for carbon number of an amino group, 0-20 are preferable. Examples of the amino group include amino, methylamino, dimethylamino, methylethylamino, dibutylamino, octylamino, phenylamino, and naphthylamino.

  Aliphatic groups, aryl groups, heterocyclic groups, alkoxy groups, alkenyloxy groups, aryloxy groups, acyloxy groups, alkylsulfonyloxy groups, arylsulfonyloxy groups, silyloxy groups, amino groups, and acylamino groups are further substituted with substituents. Examples of such substituents include hydroxyl group, halogen atom, aliphatic group, aryl group, heterocyclic group, alkoxy group, alkenyloxy group, aryloxy group, acyloxy group, alkylsulfonyloxy group, arylsulfonyl Oxy, silyloxy, amino, acylamino, cyano, acyl, sulfonamido, carbamoyl, sulfamoyl, alkoxycarbonyl, aryloxycarbonyl, ureido, urethane, alkyl or aryl sulfoni Group, a sulfinyl group of alkyl or aryl, nitro group, a sulfo group and a carboxy group.

  These substituents which may be further substituted preferably have 25 or less carbon atoms, more preferably 12 or less. Among them, the aliphatic part of the group having an aliphatic part preferably has 1 to 6 carbon atoms, the aryl part of the group having an aryl part preferably has 6 to 20 carbon atoms, and the heterocyclic ring of the group having a heterocyclic part. As for carbon number of a part, 0-20 are preferable.

As the substituent that each group of R ^2A , R ^2B , R ^3A , R ^3B , R ^XA and R ^XB may have, an alkyl group, an aryl group or a halogen atom is preferable.

R ^{2A to} R ^4A and R ^{XA in} the R ^A series group and R ^{2B to} R ^4B and R ^{XB in} the R ^B series group, wherein either the R ^A series group or the R ^B series group is a substituent In the case, the remaining series of groups are preferably hydrogen atoms.

However, in R ^2A and R ^2B, it is also preferable that both are substituents. As such substituents, one is a substituent selected from an alkyl group and an aryl group, and the other is R ^2A. And a substituent bonded to the carbon atom to which R ^2B is bonded and an oxygen atom (for example, a hydroxyl group, an alkoxy group, an alkenyloxy group, an aryloxy group, an acyloxy group, an alkylsulfonyloxy group, an arylsulfonyloxy group, R ^2A and R ^2B are preferably linked to a substituent on the carbon atom adjacent to the carbon atom to which R ^2A and R ^2B are bonded to form a methylenedioxy ring or an ethylenedioxy ring.

In the present invention, when X is —C (R ^XA ) (R ^XB ) —, at least one of R ^{2A to} R ^4A , R ^{2B to} R ^4B , R ^XA and R ^XB is a hydroxyl group, an alkoxy group, an alkenyloxy Group, aryloxy group, acyloxy group, silyloxy group, alkylsulfonyloxy group or arylsulfonyloxy group is preferred. When X is a single bond, at least one of R ^{2A to} R ^4A and R ^{2B to} R ^4B is a hydroxyl group, an alkoxy group, an alkenyloxy group, an aryloxy group, an acyloxy group, a silyloxy group, an alkylsulfonyloxy group, or An arylsulfonyloxy group is preferred.
At least one of R ^2A , R ^2B , R ^3A and R ^3B is more preferably a hydroxyl group, alkoxy group, alkenyloxy group, aryloxy group, acyloxy group, silyloxy group, alkylsulfonyloxy group or arylsulfonyloxy group. R ^2A , R ^2B , R ^3A and R ^3B are each independently a hydrogen atom, a hydroxyl group, an alkoxy group, an alkenyloxy group, an aryloxy group, an acyloxy group, an alkylsulfonyloxy group or an arylsulfonyloxy group. preferable.
In the present invention, those having at least two of these preferred groups are more preferred.

Here, as described above, the alkoxy group is preferably not only an unsubstituted alkoxy group but also a methoxy group substituted with an aryl group, that is, —O—CH ₂ —Ar, and particularly preferably a benzyloxy group. Ar represents an aryl group and is preferably a phenyl group which may have a substituent. Examples of the substituent include the substituents described above, which may further substitute each group.

Among R ^{2A to} R ^4A , R ^{2B to} R ^4B , R ^XA and R ^XB , R ^4A and R ^4B are cyclized because they are bonded to the carbon atom to which L which is released by the reaction is bonded. Affects reaction.
For this reason, R ^4A and R ^4B are preferably groups that enhance the stability of the carbocation generated on the carbon atom to which L is bonded. For example, a group that can be conjugated with a cation on this carbon, such as an aryl group or an allyl group. preferable.

Further, the carbon atom to which L is attached, resulting from carbonyl (rose) -O ^- the ion ^{attacks, R 4A} and ^{R 4B} are sterically small groups are ^preferred, either one of ^{R 4A} and ^{R 4B} Is more preferably a hydrogen atom.
When either one of R ^4A and R ^4B is a hydrogen atom for the above reasons, the remaining one is preferably a hydrogen atom or an alkyl group, more preferably an alkyl group. Of these, the alkyl group is preferably an alkyl group having a substituent in addition to the unsubstituted alkyl group. Among them, the alkyl group is preferably a methyl group or —CH ₂ —O—Ry. Here, Ry is preferably a hydrogen atom, an aliphatic group, an aryl group, a heterocyclic group, an acyl group, an alkyl or aryl sulfonyl group, a carbamoyl group or a sulfamoyl group. The aryl group, heterocyclic group, and alkyl or aryl sulfonyl group in Ry are preferably the aryl group, heterocyclic group, and alkyl or aryl sulfonyl group in Ra, and the acyl group in Ry is the acyl group in Rb and Rc. Preferably mentioned. Note that the aliphatic group is preferably —CH ₂ —Ar in the above —O—CH ₂ —Ar.

Here, when one of R ^4A and R ^4B is a hydrogen atom and the other is a substituent, or when R ^4A and R ^4B are different substituents, the carbon atom to which R ^4A and R ^4B are bonded is an asymmetric carbon It becomes an atom, and the absolute conformation is reversed by the cyclization reaction, and D-form-L-form conversion becomes possible, which is preferable.

R ^2A and R ^2B , R ^3A and R ^3B , R ^XA and R ^XB may jointly form a methylidene group represented by ═O or ═C (Rd) (Re), , R ^{2A to} R ^4A , R ^{2B to} R ^4B , R ^XA and R ^XB may be bonded to each other to form a ring. Here, Rd and Re each independently represent a hydrogen atom or a substituent.
Examples of the substituent in Rd and Re include substituents that may further substitute each group in R ^{2A to} R ^4A , R ^{2B to} R ^4B , R ^XA and R ^XB . Rd and Re are preferably a hydrogen atom or an alkyl group, and more preferably a hydrogen atom.

As a ring formed by combining at least two of R ^{2A to} R ^4A , R ^{2B to} R ^4B , R ^XA and R ^XB with each other, a benzene ring, a cycloalkane (eg, cyclopentane, cyclohexane), a heterocycle (preferably Is a heterocycle exemplified in Ra). Among them, groups on adjacent carbon atoms are bonded to each other to form —O—C (Rα1) (Rβ1) —C (Rα2) (Rβ2) —O—, —O—C (Rα1) (Rβ1) —. O- or _{-CH 2 -O-C (Rα1)} (Rβ1) which -O- in a ring are preferred. Here, Rα1, Rα2, Rβ1 and Rβ2 each independently represent a hydrogen atom, an alkyl group or an aryl group. In particular, when R ^4A or R ^4B and R ^3A or R ^3B are bonded to each other, it is preferable to form a ring with * —CH ₂ —O—C (Rα1) (Rβ1) —O — **. When groups on adjacent carbon atoms among R ^{2A to} R ^3A , R ^{2B to} R ^3B , R ^XA and R ^XB are bonded to each other, —O—C (Rα1) (Rβ1) —C (Rα2) ( Rβ2) —O—, —O—C (Rα1) (Rβ1) —O— preferably form a ring, and —O—C (Rα1) (Rβ1) —O— more preferably form a ring. . Note that * is a bond bonded to the carbon atom to which R ^4A or R ^4B is bonded, and ** is a bond bonded to the carbon atom to which R ^3A or R ^3B is bonded.

<Compound represented by formula (II)>

In formula ^{(II), R 1, X} , R 2A ~R 4A and ^R 2B ^{to R 4B} is ^R 1 in the general formula ^{(I), X,} it is synonymous with R 2A ^{to R 4A} and ^R 2B ^{to R 4B} The preferred range is also the same.

  The compound represented by the general formula (I) is preferably a compound represented by the following general formula (IA). In this case, the compound obtained as a result of the reaction is a compound represented by the following general formula (IIA).

In formula (IA) and ^{(IIA), L, R N} , R 1, R 2A ~R 4A and ^R 2B ^{to R 4B} is, ^L in the general formula (I) and ^{(II), R N, R} 1, has the same meaning as R ^2A to R ^4A and ^R 2B ^{to R 4B,} the preferred range is also the same.

  Specific examples of the compound represented by the general formula (I) are shown as stereoisomers below. In addition, this invention is not limited by this, In the following specific examples, the isomer from which a three-dimensional structure differs is also mentioned. Further, in addition to some of the three-dimensional structures described as representatives, naturally, compounds of different three-dimensional structures having the same substituents are also exemplified, and are merely omitted for the convenience of the specification sheet.

Specific examples of the compound represented by the general formula (II) are shown below as stereoisomers.
In this invention, since it is natural that the compound represented by general formula (II) obtained from the compound represented by the said general formula (I) is mentioned as an exemplary compound, it abbreviate | omits.

<Reaction conditions>
The compound represented by general formula (II) can be produced by reacting the compound represented by general formula (I) under acidic conditions.
Examples of the solvent (reaction solvent) used in this reaction include aliphatic hydrocarbon compounds, halogenated hydrocarbon compounds, alcohol compounds, ether compounds, ester compounds, ketone compounds, nitrile compounds, amide compounds, sulfoxide compounds, aromatic compounds. Group hydrocarbon compounds, urea compounds and water. These solvents may be used as a mixture.

  Specific examples of these reaction solvents include pentane, hexane, heptane, methylene chloride, chloroform, methanol, ethanol, isopropanol, n-butanol, t-butanol, diethyl ether, methyl-t-butyl ether, tetrahydrofuran, and dioxane. , Ethyl acetate, isopropyl acetate, butyl acetate, acetone, methyl ethyl ketone, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, N-ethylpyrrolidone, 1,3-dimethyl-2-imidazolide Non, dimethyl sulfoxide, benzene, toluene, xylene, chlorobenzene, and water can be mentioned.

  The reaction solvent is preferably a water-soluble solvent, preferably a nitrile compound, a ketone compound or an alcohol compound, more preferably a nitrile compound or a ketone compound, specifically acetonitrile or acetone is preferable, and acetonitrile is particularly preferable.

In the present invention,> the C = ^N-R N since the> deprotected C = O, the reaction is preferably carried out in the presence of water.
The amount of water contained in the reaction solvent is preferably 1 to 70 mL, more preferably 1 to 50 mL, and even more preferably 1 to 20 mL with respect to 100 mL of the organic solvent.

  The amount of the solvent used is not particularly limited, and is 1 to 50 times the amount of the compound represented by the general formula (I) (volume / weight, hereinafter abbreviated as v / w). 1) to 15 times (v / w) is preferable.

  The reaction of the present invention is carried out under acidic conditions, and the acid used may be either organic or inorganic. Examples of inorganic acids include hydrochloric acid, sulfuric acid, and phosphoric acid, and examples of organic acids include aliphatic or aromatic carboxylic acids including glyoxylic acid, and aliphatic or aromatic sulfonic acids. Specific examples of the aliphatic or aromatic carboxylic acid and the aliphatic or aromatic sulfonic acid include glyoxylic acid, acetic acid, trifluoromethanesulfonic acid, benzoic acid, benzenesulfonic acid, and toluenesulfonic acid, and glyoxylic acid is preferable. .

  The amount of the acid used is preferably 0.1 times mol or more, more preferably 1 time mol or more, and particularly preferably 1.5 times mol or more based on the compound represented by the general formula (I). As an upper limit, 100 times mole or less is preferable, 60 times mole or less is more preferable, and 40 times mole or less is especially preferable.

In the present invention, to capture the NH ₂ -R ^N caused by deprotection, shifting the equilibrium of the reaction to deprotection side, in order to accelerate the reaction, it is preferable to add a carbonyl compound. Examples of the carbonyl compound include ketone compounds such as acetone and 2-butanone, and aldehyde compounds such as formaldehyde, benzaldehyde, glyoxal and glyoxylic acid, aldehyde compounds are preferable, and glyoxylic acid is more preferable.
In the present invention, acid and may be a compound having both a carbonyl compound by capturing NH ₂ -R ^N shift the equilibrium of the reaction to deprotection side. Such a compound is a compound having a sulfo group or a carboxy group and a carbonyl group in the molecule, and glyoxylic acid has both functions. In addition to glyoxylic acid, pyruvic acid, 2-oxobutanoic acid, 2-oxoglutamic acid, acetone dicarboxylic acid, acetoacetic acid, oxalacetic acid, ketopinic acid, 2-formylpropionic acid and the like can be mentioned.

  The amount of the carbonyl compound used is preferably 0.5 times mol or more, more preferably 1 time mol or more, and particularly preferably 1.5 times mol or more based on the compound represented by the general formula (I). As an upper limit, 100 times mole or less is preferable, 60 times mole or less is more preferable, and 40 times mole or less is especially preferable.

  The reaction temperature is preferably 0 ° C. or higher, more preferably 30 ° C. or higher, and further preferably 50 ° C. or higher. As an upper limit, 120 degrees C or less is preferable, 100 degrees C or less is more preferable, and 80 degrees C or less is further more preferable. The reaction time is preferably 5 minutes or longer. The upper limit is preferably within 50 hours, more preferably within 24 hours, and even more preferably within 6 hours.

<< Method for Producing Compound Represented by Formula (I) >>
The compound represented by the general formula (I) is preferably synthesized using a compound represented by the following general formula (III).

In general formula (III), ^{R 1} has the same meaning as ^{R 1} in the general formula (I). Xx represents a single bond or —C (R ^XAx ) (R ^XBx ) —. R ^{2Ax to} R ^4Ax , R ^{2Bx to} R ^4Bx , R ^XAx and R ^XBx each independently represent a hydrogen atom or a substituent. R ^2Ax and R ^2Bx , R ^3Ax and R ^3Bx , R ^XAx and R ^XBx may cooperate with each other to form a methylidene group represented by ═O or ═C (Rdx) (Rex). , R ^{2Ax to} R ^4Ax , R ^{2Bx to} R ^4Bx , R ^XAx and R ^XBx may be bonded to each other to form a ring. Rdx and Rex each independently represent a hydrogen atom or a substituent.

Here, Xx, R ^{2Ax to} R ^4Ax , R ^{2Bx to} R ^4Bx , R ^XAx , R ^XBx , Rdx and Rex are X, R ^{2A to} R ^4A , R ^{2B to} R ^4B , R ^XA in the general formula (I) , R ^XB , Rd and Re, and the preferred range is also the same.

  The compound represented by the general formula (III) is preferably a compound represented by the following general formula (IIIA).

In the general formula (IIIA), ^{R 1} has the same meaning as ^{R 1} in the general formula (I). R ^{2Ax to} R ^4Ax and R ^{2Bx to} R ^4Bx each independently represent a hydrogen atom or a substituent. R ^2Ax and R ^2Bx , R ^3Ax and R ^3Bx may jointly form a methylidene group represented by ═O or ═C (Rdx) (Rex), and R ^{2Ax to} R ^{4Ax And} at least two of R ^{2Bx to} R ^4Bx may be bonded to each other to form a ring. Rdx and Rex each independently represent a hydrogen atom or a substituent.

Here, R ^{2Ax to} R ^4Ax , R ^{2Bx to} R ^4Bx , R ^XAx , R ^XBx , Rdx and Rex are R ^{2Ax to} R ^4Ax , R ^{2Bx to} R ^4Bx , R ^XAx , R ^XBx , It is synonymous with Rdx and Rex, and its preferable range is also the same.

  The synthetic route for synthesizing the compound represented by the general formula (I) from the compound represented by the general formula (III) is preferably the following synthetic route.

Here, Ra is in the compound represented by ^{R N} and _Y-SO 2 -Ra in the compound represented by _NH 2 -R ^N, has the same meaning as ^{R N} and Ra in formula (I), preferable range The same. Y represents a halogen atom (a fluorine atom, a chlorine atom, a bromine atom or an iodine atom is preferable, and a bromine atom is more preferable). In the general formulas (III ′), (I-1) and (I-2), R ¹ , Xx, R ^{2Ax to} R ^4Ax and R ^{2Bx to} R ^4Bx are R ¹ , Xx, R ^2AX to R ^4AX and ^R 2BX ^{to R 4BX} and are synonymous, and preferred ranges are also the same. Formula (III '), (I- 1), has the same meaning as ^{R N R N} in the general formula (I) in (I-2), and the preferred range is also the same. Ra in general formula (I-1) is synonymous with Ra in general formula (I), and its preferable range is also the same.

As described above, first, the general formula is reacted with a compound represented by NH ₂ represented by -R ^N compound (III), to obtain a compound represented by the general formula (III '). Then, the hydroxyl group (—OH) on the carbon atom to which R ^4Ax and R ^4Bx are bonded is reacted with a compound represented by (a) Y—SO ₂ —Ra to form —O—SO ₂ —Ra. The compound represented by the general formula (I-1) is synthesized, or (b) is converted to a halogen atom with a halogenating agent such as thionyl chloride. A compound is synthesized.

  Moreover, the synthetic route which synthesize | combines the compound represented by general formula (IA) from the compound represented by general formula (IIIA) is represented as the following synthetic route.

Here, the general formula ^{(IIIA ') R 1, R} 2Ax ~R 4Ax and ^R 2BX ^{to R 4BX} in is located in the general formula (III) in ^{R 1, R} 2Ax ^{~R 4Ax} and ^R 2BX ^{to R 4BX} synonymous The preferred range is also the same. Is ^{R N} in the general formula (IIIA ') it has the same meaning as ^{R N} in formula (I), and preferred ranges are also the same.

<Production of compound represented by formula (III ')>
Formula (III ') The compound represented by the general formula (III) compounds represented by, it is preferably synthesized by reacting a compound represented by NH ₂ -R ^N.
As the compound represented by the general formula (III), for example, a commonly used pyranose compound or furanose can be used.

A compound represented by NH ₂ -R ^N, if ^{R N} is _-Rb, a primary amine compound represented by NH 2 -Rb. Specifically, the primary amine compound is preferably methylamine, ethylamine, vinylamine, cyclopentylamine, cyclohexylamine, aniline, toluidine, 1-naphthylamine, 2-aminopyrimidine, 2-aminotriazine, and methylamine or ethylamine is preferred. Especially preferred.

A compound represented by NH ₂ -R ^N, if ^{R N} is _-ORb, a hydroxylamine compound represented by NH 2 -ORb. The compound represented by NH ₂ —ORb is specifically hydroxylamine, O-methylhydroxylamine, O-ethylhydroxylamine, O-phenylhydroxylamine, O-tritylhydroxylamine, or O-benzylhydroxylamine. Preferably, O-methylhydroxylamine or O-benzylhydroxylamine is more preferable, and O-methylhydroxylamine is particularly preferable.

NH compounds represented by ₂ -R ^N, if ^{R N} is -N (Rb) _(Rc), a hydrazine compound represented by NH 2 -N (Rb) (Rc ). Specifically, the hydrazine compound is preferably hydrazine, N-methylhydrazine, N, N-dimethylhydrazine, or phenylhydrazine, and more preferably N-methylhydrazine or N, N-dimethylhydrazine.

A compound represented by NH ₂ -R ^N are may be a salt. Examples of such a salt include hydrochloride.

The compound represented by the general formula (III ′) can be synthesized in a high yield by the reaction of an aldehyde or ketone with an acetal or ketal, and is represented by the obtained general formula (III ′). The compound is stable.
For this reason, even in the subsequent reaction conditions for obtaining the compound represented by the general formula (I), the> C = N- ^RN portion is stable. In addition, the compound represented by the general formula (I) is reacted under acidic conditions, and the compound represented by the general formula (II) is synthesized via an aldehyde or ketone intermediate obtained by deprotection. This reaction also proceeds under mild conditions.

  Examples of the reaction solvent include aliphatic hydrocarbon compounds, halogenated hydrocarbon compounds, alcohol compounds, ether compounds, ester compounds, nitrile compounds, amide compounds, sulfoxide compounds, aromatic hydrocarbon compounds, heteroaromatic compounds, and water. It is done. These solvents may be used as a mixture. Although the usage-amount of a solvent is not specifically limited, It should just be 1-50 times amount (v / w) with respect to the compound represented by general formula (III), and 1-15 times amount (v / w). Is preferred.

The amount of NH ₂ -R ^N compounds represented by the for general formula (III) compounds represented by is preferably at least 1-fold mol, more preferably at least 2-fold moles, particularly more than 3 times the molar preferable. As an upper limit, 10 times mole or less is preferable, 5 times mole or less is more preferable, and 3 times mole or less is especially preferable. When using a salt of the compound represented by NH ₂ -R ^N, it is preferable to add a base. Examples of the base include organic or inorganic bases, and tertiary amines (for example, triethylamine), basic heterocyclic compounds having a nitrogen atom as a ring atom, or sodium hydrogen carbonate are preferable. The amount of the base to the compound represented by NH ₂ -R ^N, preferably more than 1-fold molar, more preferably at least 1.5 moles, more preferably twice or more moles, at least 3-fold molar Particularly preferred. As an upper limit, 10 times mole or less is preferable, 5 times mole or less is more preferable, and 3 times mole or less is especially preferable.

  The reaction temperature is preferably −10 ° C. or higher, more preferably −5 ° C. or higher, and particularly preferably 0 ° C. or higher. As an upper limit, 100 degrees C or less is preferable, 80 degrees C or less is more preferable, and 60 degrees C or less is especially preferable. The reaction time is preferably 5 minutes or longer. The upper limit is preferably within 50 hours, more preferably within 24 hours, and particularly preferably within 6 hours.

<Production of compound represented by formula (I)>
The compound represented by the general formula (I) is preferably synthesized by converting the hydroxyl group of the compound represented by the general formula (III ′) to L. Here, L is a halogen atom or —OSO ₂ Ra.

(A) Sulfonylation reaction (Method for producing compound represented by formula (I-1))
When the hydroxyl group of the compound represented by the general formula (III ′) is converted to —OSO ₂ —Ra, Y—SO ₂ —Ra or O (SO ₂ —Ra) ₂ is represented by the general formula (III ′). It is preferable to sulfonylate the hydroxyl group in the represented compound. Here, Y is a halogen atom.

  Examples of the reaction solvent include aliphatic hydrocarbon compounds, halogenated hydrocarbon compounds, alcohol compounds, ether compounds, ester compounds, nitrile compounds, amide compounds, sulfoxide compounds, aromatic hydrocarbon compounds, heteroaromatic compounds, and water. It is done. These solvents may be used as a mixture. Although the usage-amount of a solvent is not specifically limited, It should just be 1-50 times amount (v / w) with respect to the compound represented by general formula (III '), and 1-15 times amount (v / w) ) Is preferred.

The amount of the sulfonylating agent represented by Y—SO ₂ —Ra is preferably 0.8 times mol or more and more preferably 1 time mol or more based on the compound represented by the general formula (III ′). 1.2 times mole or more is especially preferable. As an upper limit, 10 times mole or less is preferable, 4 times mole or less is more preferable, and 2 times mole or less is especially preferable.

Since the acid of HY is generated as the reaction proceeds, it is preferable to use a base in order to neutralize it.
Examples of the base include organic or inorganic bases such as tertiary amines that do not react with Y—SO ₂ —Ra, basic heterocyclic compounds having a nitrogen atom as a ring constituent atom, triethylamine, pyridine. And N-methylimidazole are preferred. The usage-amount of a base should just be 0.8-10 times mole with respect to the compound represented by general formula (III '), 0.8-4.0 times mole is preferable, and 1.0-3 A molar ratio of 0.0 is more preferable.

(B) Halogenation reaction (production method of the compound represented by formula (I-2))
When converting the hydroxyl group of the compound represented by the general formula (III ′) to a halogen atom, it is preferable to halogenate the hydroxyl group in the compound represented by the general formula (III ′) with a halogenating agent.

  Examples of the reaction solvent include aliphatic hydrocarbon compounds, halogenated hydrocarbon compounds, ether compounds, ester compounds, ketone compounds, nitrile compounds, amide compounds, sulfoxide compounds, aromatic hydrocarbon compounds, urea compounds, and water. These solvents may be used as a mixture. Although the usage-amount of a solvent is not specifically limited, It should just be 1-50 times amount (v / w) with respect to the compound represented by general formula (III '), and 1-15 times amount (v / w) ) Is preferred.

Examples of the halogenating agent include commonly used chlorinating agents and brominating agents.
As chlorinating agents, phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride, Vilsmeier reagent (N, N-dimethylformamide-phosphorus pentachloride, N, N-dimethylformamide-phosphorus oxychloride, etc.), Rydon reagent (Ph ₃ PCl) ₂ , triphenylphosphine-carbon tetrachloride), thionyl chloride and sulfuryl chloride, and the like, and sulfuryl chloride, phosphorus trichloride or thionyl chloride is preferable.
Examples of brominating agents include phosphorus tribromide, N, N-dimethylformamide-phosphorous tribromide, triphenylphosphine-carbon tetrabromide, and triphenylphosphine dibromide.

  The amount of the halogenating agent used is preferably 0.8 times mol or more, more preferably 1 time mol or more, and particularly preferably 1.2 times mol or more based on the compound represented by the general formula (III '). As an upper limit, 10 times mole or less is preferable, 5 times mole or less is more preferable, and 2 times mole or less is especially preferable.

Since the acid of HY is generated as the reaction proceeds, it is preferable to use a base in order to neutralize it.
Examples of the base include organic or inorganic bases, such as tertiary amines and basic heterocyclic compounds having a nitrogen atom as a ring constituent atom, and triethylamine, pyridine and N-methylimidazole are preferred. The amount of the base used is preferably 0.8 times mol or more and particularly preferably 1 time mol or more with respect to the compound represented by the general formula (III ′). As an upper limit, 50 times mole or less is preferable, 20 times mole or less is more preferable, and 10 times mole or less is especially preferable.

In this reaction, it is preferable to add a salt. Examples of the salt include lithium chloride, lithium bromide, sodium bromide, calcium bromide, and pyridine hydrochloride. In this halogenation reaction, an epimer mixture is usually obtained. In order to improve the purity of the compound represented by the general formula (I-2), it is preferable to use sulfuryl chloride and lithium chloride in combination.
The amount of the salt used is preferably 0.5 times mol or more, more preferably 0.8 times mol or more, and particularly preferably 1 time mol or more with respect to the compound represented by the general formula (III ′). As an upper limit, 20 times mole or less is preferable, 5 times mole or less is more preferable, and 3 times mole or less is especially preferable.

  The reaction temperature is preferably −50 ° C. or higher, more preferably −40 ° C. or higher, and particularly preferably −30 ° C. or higher. As an upper limit, 80 degrees C or less is preferable, 60 degrees C or less is more preferable, and 40 degrees C or less is especially preferable. The reaction time is preferably 5 minutes or longer. The upper limit is preferably within 50 hours, more preferably within 24 hours, and particularly preferably within 6 hours.

<< Use of Compound Represented by General Formula (II) >>
The compound represented by the general formula (II) is an L-nucleoside useful as an antiviral agent [for example, all of Tetrahedron, 2011, 67, p. 4031-4035, 2′-fluoro-5-methyl-β-L-arabinofuranosyl lysine and L-2 ′, 3′-dideoxy-2 ′, 3′-didehydro, useful for hepatitis B virus -5-fluorocytidine, a compound useful for the production of 1- (β-L-ribofuranosyl) -1,2,4-triazole-3-carboxamide and its valine ester precursors exhibiting hepatitis C virus activity is there.

  In addition, by applying it to the production of rare sugars with low abundance in nature, research on postprandial blood glucose level increase action, fat accumulation inhibition action, arteriosclerosis prevention action, blood pressure rise prevention action and antioxidant action by these rare sugars It is possible to supply a large amount at a low cost for research as a new functional material expected for development and countermeasures for metabolic syndrome. In addition, plants can be supplied in a large amount at a low cost for inducing expression of pest defense-related genes such as rice and studying growth regulation.

  Below, based on an Example, it demonstrates in detail about this invention. However, the present invention is not construed as being limited thereby.

  The synthesized compound was purified or measured using the following measuring instrument.

(Measurement equipment used)
Column chromatography Measuring instrument: Preparative chromatograph W-Prep 2XY (trade name) manufactured by Yamazen
Chromatographic carrier: silica gel

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

Example 1
Exemplified compound (II-1) was synthesized from Exemplified compound (I-3) under the following reaction conditions.

A mixture of 1.00 g of exemplary compound (I-3), 10 mL of acetonitrile, and 1.51 mL of 50% glyoxylic acid aqueous solution (10 molar equivalents) was heated and stirred at 70 ° C. for 14 hours. Thereafter, 20 mL of ethyl acetate was added to the reaction solution, followed by liquid separation. The organic layer was washed with water, an aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 73/27 to 52/48) to obtain 0.32 g (51% yield) of amorphous exemplified compound (II-1). As a result of measuring ¹ H-NMR, the anomeric ratio was 3: 1.

¹ H-NMR (CDCl ₃ ) δ value: 8.10-7.87 (6H, m), 7.64-7.29 (9H, m), 6.14-6.08 (1H, m), 5.78-5.71 (1H, m), 5.64 (0.75H, dd, J = 1.8, 5.4Hz), 5.46 (0.25H, t, J = 5.1Hz) , 5.00 (0.75H, dd, J = 5.7, 12.3 Hz), 4.82-4.60 (2.25H, m), 3.30 (0.25H, d, J = 11) .1 Hz), 3.14 (0.75 H, d, J = 2.7 Hz)

  The exemplified compound (I-3) used was synthesized by the following synthesis route.

To a 1.3 mL acetic acid suspension of 5.0 g of 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose was added dropwise 2.9 mL of 30% hydrogen bromide / acetic acid at room temperature. And stirred at room temperature for 3 hours. After adding 20 mL of toluene and 20 mL of water to the reaction mixture and stirring for 5 minutes, the water tank was removed. The obtained organic layer was washed with 20 mL of 10% aqueous sodium hydrogen carbonate solution, and the solvent was evaporated under reduced pressure. To the obtained oily substance, 10 mL of acetonitrile and 10 mL of 10% aqueous sodium hydrogen carbonate solution were added, and the mixture was stirred at room temperature for 1 hour and allowed to stand overnight. After adding 20 mL of toluene and 10 mL of water to the reaction mixture and stirring for 5 minutes, the aqueous layer was removed, the solvent was distilled off under reduced pressure, and colorless oil containing 2,3,5-tri-O-benzoyl-D-ribofuranose was obtained. I got a thing.
The colorless oil was used as such for the next reaction.

To the colorless oil obtained above, 1.3 g of O-methylhydroxylamine hydrochloride and 5.0 mL of methanol were added, and 1.8 mL of triethylamine was added dropwise under ice cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture, 10 mL of toluene and 10 mL of 10% aqueous sodium chloride solution were added, the aqueous layer was removed, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/0 to 2/1) to give (2R, 3R, 4S) -2-hydroxy-5- (methoxyimino) as a colorless oil. 2.7 g of pentane-1,3,4-triyl = tribenzoate was obtained.
As a result of measuring ¹ H-NMR, the syn / anti ratio was 4: 1.

¹ H-NMR (CDCl ₃ ) δ value: 8.05-8.01 (4H, m), 799-7.94 (2H, m), 7.62-7.35 (9.8 H, m) ), 6.92 (0.2 H, d, J = 5.9 Hz), 6.57 (0.2 H, dd, J = 5.9, 2.6 Hz), 6.16 (0.8 H, dd, J = 6.6, 3.3 Hz), 5.87 (0.2 H, dd, J = 8.9, 3.0 Hz), 5.81 (0.8 H, dd, J = 7.9, 3.). 3Hz), 4.68-4.62 (1H, m), 4.46-4.31 (2H, m), 4.03 (0.6H, s), 3.92 (2.4H, s) , 3.24 (0.2H, brs), 3.06 (0.8H, brs)

  (2R, 3R, 4S) -2-hydroxy-5- (methoxyimino) pentane-1,3,4-triyl = tribenzoate 2.7 g, acetonitrile 5 mL, N-methylimidazole 0.5 mL and 2,4,4 A mixture of 1.7 g of 5-trichlorobenzenesulfonyl chloride was stirred at room temperature for 8 hours and allowed to stand at room temperature for 3 days. Ethyl acetate and water were added to the reaction mixture, the organic layer was separated, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/0 to 3/1) to give (2R, 3R, 4S) -5- (methoxyimino) -2- ( 3.0 g of ((2,4,5-trichlorobenzene) sulfonyl) oxy) pentane-1,3,4-triyl = tribenzoate was obtained.

¹ H-NMR (CDCl ₃ ) δ value: 8.08-7.96 (5H, m), 7.91-7.88 (2H, m), 7.64-7.33 (10.75H, m ), 6.91 (0.25 H, d, J = 5.9 Hz), 6.55 (0.25 H, t, J = 5.3 Hz), 6.06-5.95 (1.75 H, m) 5.55-5.49 (0.75H, m), 5.48-5.42 (0.25H, m), 4.91-4.84 (1H, m), 4.69-4. 62 (1H, m), 3.97 (0.75H, s), 3.85 (2.25H, s)

Example 2
Exemplified compound (II-1) was synthesized from Exemplified compound (I-2) under the following reaction conditions.

  A mixture of 0.26 g of exemplary compound (I-2), 2.6 mL of acetonitrile, and 0.41 mL (10 molar equivalent) of 50% aqueous glyoxylic acid solution was heated and stirred at 70 ° C. for 24 hours. Thereafter, ethyl acetate was added to the reaction solution to separate the layers. The organic layer was washed with water, a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution in this order, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 73/27 to 52/48) to obtain 0.087 g (yield 51%) of amorphous exemplified compound (II-1).

  Exemplified compound (I-2) was synthesized from (2R, 3R, 4S) -2-hydroxy-5- (methoxyimino) pentane-1,3,4-triyl in the synthesis of exemplified compound (I-3). The tribenzoate was synthesized in the same manner as Exemplified Compound (I-3) except that 2,5-dichlorobenzenesulfonyl chloride was used instead of 2,4,5-trichlorobenzenesulfonyl chloride.

Exemplary Compound (I-2)
¹ H-NMR (CDCl ₃ ) δ value: 8.10-7.90 (7H, m), 7.64-7.38 (10H, m), 7.27-7.20 (2H, m), 6.90 (0.25H, d, J = 5.7 Hz), 6.55 (0.25H, dd, J = 4.8, 5.7 Hz), 6.07-5.90 (1.75H, m), 5.56-5.50 (0.75H, m), 5.49-5.43 (0.25H, m), 4.90-4.84 (1.00H, m), 4. 68-4.54 (1.00H, m), 3.96 (0.75H, s), 3.85 (2.25H, s)

Example 3
Exemplified compound (II-1) was synthesized from Exemplified compound (I-1) under the following reaction conditions.

  A mixture of 0.45 g of exemplary compound (I-1), acetonitrile 4.5 mL, 50% glyoxylic acid aqueous solution 0.75 mL (10 molar equivalent) was heated and stirred at 70 ° C. for 5 hours, and then heated and stirred at 100 ° C. for 19 hours. . Thereafter, ethyl acetate was added to the reaction solution to separate the layers. The organic layer was washed with water, a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution in this order, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 73/27 to 52/48) to obtain 0.136 g (43% yield) of amorphous exemplified compound (II-1).

  Exemplified compound (I-1) was synthesized from (2R, 3R, 4S) -2-hydroxy-5- (methoxyimino) pentane-1,3,4-triyl in the synthesis of exemplified compound (I-3). The tribenzoate was synthesized in the same manner as the exemplary compound (I-3) except that 4-chlorobenzenesulfonyl chloride was used instead of 2,4,5-trichlorobenzenesulfonyl chloride.

Exemplary Compound (I-1)
¹ H-NMR (CDCl ₃ ) δ value: 8.10-7.89 (6H, m), 7.83-7.76 (2H, m), 7.65-7.55 (3H, m), 7.50-7.40 (7H, m), 7.34-7.28 (2H, m), 6.85 (0.25H, d, J = 5.7 Hz), 6.51 (0.25H) , Dd, J = 4.8, 5.7 Hz), 6.04-5.92 (1.75 H, m), 5.47-5.40 (0.75 H, m), 5.40-5. 34 (0.25H, m), 4.92-4.83 (1.00H, m), 4.60-4.48 (1.00H, m), 3.94 (0.75H, s), 3.85 (2.25H, s)

Example 4
Exemplified compound (II-3) was synthesized from exemplified compound (I-21) by the following reaction.

A mixture of 0.72 g of exemplary compound (I-21), 7.2 mL of acetonitrile, and 1.15 mL (10 molar equivalent) of 50% aqueous glyoxylic acid solution was heated and stirred at 70 ° C. for 5 hours. Thereafter, ethyl acetate was added to the reaction solution to separate the layers. The organic layer was washed with water, a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution in this order, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 69/31 to 48/52) to obtain 0.260 g (yield 59%) of oily exemplified compound (II-3). As a result of measuring ¹ H-NMR, the anomeric ratio was 1: 1.

¹ H-NMR (CDCl ₃ ) δ value: 7.38-7.28 (15H, m), 5.51 (0.5H, d, J = 2.4 Hz), 5.26 (0.5H, dd) , J = 4.2, 12.0 Hz), 4.87-4.44 (6H, m), 4.29-4.21 (1H, m), 4.16-4.08 (1H, m) , 3.93-3.89 (1H, m), 3.85-3.67 (2H, m)

  The exemplified compound (I-21) used was synthesized by the following synthesis route.

In addition, Exemplified Compound (I-21) is an example of 1-O instead of 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose in the synthesis of Exemplified Compound (I-3). The compound was synthesized in the same manner as Exemplified Compound (I-3) except that -acetyl-2,3,5-tri-O-benzyl-D-ribofuranose was used. As a result of measuring ¹ H-NMR, the isomer ratio was 4: 1.

Compound (I-21 ′)
¹ H-NMR (CDCl ₃ ) δ value: 7.44 (0.8 H, d, J = 8.1 Hz), 7.37-7.15 (15 H, m), 6.89 (0.2 H, d , J = 6.6 Hz), 5.02 (0.2H, dd, J = 2.4, 6.6 Hz), 4.79-4.42 (6H, m), 4.33 (0.8H, dd, J = 3.3, 8.1 Hz), 3.88 (2.4 H, s), 3.87 (0.6 H, s), 3.89-3.76 (2 H, m), 3. 66-3.54 (2H, m), 2.68 (0.2H, d, J = 5.7 Hz), 2.58 (0.8H, d, J = 4.8 Hz)

Exemplary Compound (I-21)
¹ H-NMR (CDCl ₃ ) δ value: 8.08 (0.8 H, s), 8.06 (0.2 H, s), 7.35-7.22 (14 H, m), 7.16 ( 0.8H, d, J = 7.5 Hz), 7.10-7.06 (2H, m), 6.69 (0.2H, d, J = 6.6 Hz), 5.04-4.96. (1H, m), 4.81 (0.2H, dd, J = 5.4, 6.6 Hz), 4.74-4.58 (3H, m), 4.41-4.32 (1H, m), 4.20 (2H, s), 4.06-3.94 (1.8H, m), 3.89 (2.4H, s), 3.87 (0.6H, s), 3 .74-3.66 (1.2 H, m), 3.52 (0.8 H, dd, J = 3.0, 11.4 Hz)

Example 5
Exemplified compound (II-1) was synthesized from Exemplified compound (I-3) under the following reaction conditions.

A mixture of 1.00 g of exemplary compound (I-3), 10 mL of acetone, 1.08 mL (10 molar equivalent) of 35% aqueous formaldehyde solution, and 0.14 mL of 1 mol / L hydrochloric acid was heated and stirred at 70 ° C. for 15 hours. Thereafter, 20 mL of ethyl acetate was added to the reaction solution, followed by liquid separation. The organic layer was washed with water, a sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution in this order, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 73/27 to 52/48) to obtain 0.38 g (yield 60%) of amorphous exemplified compound (II-1). As a result of measuring ¹ H-NMR, the anomeric ratio was 2: 1.

Comparative Example 1
J. et al. Chem. Soc. , C.I. 1967, p. A synthesis method described in 1186 to 1187 is shown below.
A solution obtained by adding 1.5 g of acetal compound (VIII) to 60 mL of acetone and 5N sulfonic acid (10 mL) were mixed, and the mixture was heated and stirred for 6 hours under reflux. The resulting product was separated with chloroform and chromatographed using 50 g of silica gel. A mixture of acetal compound (VIII) and aldehyde compound (IX) is obtained from the eluent of benzene-ether (19: 1), and slurry-like 2,3,3 is obtained from the eluent of benzene-ether (85:15). 201 mg of 5-tri-O-benzyl-L-lyxofuranose (XI) was obtained. Further, the mixture of the acetal compound (VIII) and the aldehyde compound (IX) was repeatedly purified by chromatography to obtain 895 mg of a mixture of the acetal compound (VIII) and the aldehyde compound (IX).
The yield based on the acetal compound (VIII) was calculated to be 20%.

Bn is a benzyl group (—CH ₂ —C ₆ H ₅ ), and Ts is a tosyl group (—SO ₂ C ₆ H ₄ —p—CH ₃ ).

As is clear from Examples 1 to 5 and Comparative Example 1, the production method of the present invention is a production method that is easy, high yield, excellent in stereoselectivity, and capable of mass production under mild conditions. I understand that.
In particular, when mass production is performed, a yield improvement of 10% or more results in a significant cost reduction.
In this way, by applying the production method of the present invention to the production of rare sugars having a small abundance in nature, it becomes possible to supply a large amount of rare sugars that are finding various effects at low cost. It turns out that it is useful for promotion of development.

  While this invention has been described in conjunction with its embodiments, we do not intend to limit our invention in any detail of the description unless otherwise specified and are contrary to the spirit and scope of the invention as set forth in the appended claims. I think it should be interpreted widely.

  This application claims the priority based on Japanese Patent Application No. 2014-194394 for which it applied for a patent in Japan on September 24, 2014, and this is referred to here for the contents of this description. Capture as part.

Claims (13)

The manufacturing method of the compound represented with the following general formula (II) with which the compound represented with the following general formula (I) is made to react on acidic conditions.

In the general formula (I) and (II), L represents a halogen atom or -OSO ₂ Ra. R ^N represents -Rb, the -ORb or -N (Rb) (Rc). Here, Ra represents a halogen atom, an aliphatic group, an aryl group or a heterocyclic group, and Rb and Rc each independently represent a hydrogen atom, an aliphatic group, an acyl group, an aryl group or a heterocyclic group. R ¹ represents a hydrogen atom, an aliphatic group, an aryl group or a heterocyclic group. X represents a single bond or —C (R ^XA ) (R ^XB ) —. R ^{2A to} R ^4A , R ^{2B to} R ^4B , R ^XA and R ^XB each independently represent a hydrogen atom or a substituent. R ^2A and R ^2B , R ^3A and R ^3B , R ^XA and R ^XB may jointly form a methylidene group represented by ═O or ═C (Rd) (Re), , R ^{2A to} R ^4A , R ^{2B to} R ^4B , R ^XA and R ^XB may be bonded to each other to form a ring. Rd and Re each independently represent a hydrogen atom or a substituent. The compound represented by the general formula (I) is a compound represented by the following general formula (IA), and the compound represented by the general formula (II) is represented by the following general formula (IIA). The manufacturing method of Claim 1 which is a compound.

In the general formulas (IA) and (IIA), L, R ^N , R ¹ , R ^{2A to} R ^4A and R ^{2B to} R ^4B are L, R ^N , R ^{1 in the} general formulas (I) and (II), respectively. the same meanings as ^R 2A ^{to R 4A} and ^R 2B ^{to R 4B.} Wherein L is a halogen atom or -OSO ₂ Ra, wherein ^{R N} is -Rb, a -ORb or -N (Rb) (Rc), wherein, Ra is a halogen atom, an alkyl group, an alkenyl group An aryl group or a heterocyclic group, wherein Rb and Rc are each independently a hydrogen atom, an alkyl group, an alkenyl group, an acyl group, an aryl group or a heterocyclic group;
The R ¹ is a hydrogen atom, an alkyl group, an alkenyl group or an aryl group, the X is a single bond or —C (R ^XA ) (R ^XB ) —, and the R ^2A , R ^3A and R ^2B , R ^3B , R ^XA and R ^XB are each independently a hydrogen atom, hydroxyl group, halogen atom, alkyl group, alkenyl group, aryl group, heterocyclic group, alkoxy group, alkenyloxy group, aryloxy group, acyloxy group, An alkylsulfonyloxy group, an arylsulfonyloxy group, a silyloxy group, an amino group, an acylamino group, a cyano group, or an azide group, and each of the R ^4A and R ^4B independently represents a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, or A heterocyclic group,
Here, even if R ^2A and R ^2B , R ^3A and R ^3B , R ^XA and R ^XB jointly form a methylidene group represented by ═O or ═C (Rd) (Re) Or at least two of R ^{2A to} R ^4A , R ^{2B to} R ^4B , R ^XA and R ^XB may be bonded to each other to form a ring, in which case Rd and Re are each independently A hydrogen atom or an alkyl group,
The manufacturing method according to claim 1. Wherein ^{R N} is The process according to claim 1 which is the -ORb. Wherein R ¹ is The process according to claim 1 is a hydrogen atom. Wherein L is A process according to any one of claims 1-5 wherein a -OSO ₂ Ra. The production method according to claim 1, wherein one of R ^4A and R ^4B is a hydrogen atom and the other is a substituent, or R ^4A and R ^4B are different substituents. 2. At least one of the R ^2A , R ^3A , R ^2B and R ^3B is a hydroxyl group, alkoxy group, alkenyloxy group, aryloxy group, acyloxy group, silyloxy group, alkylsulfonyloxy group or arylsulfonyloxy group. The manufacturing method of any one of -7. Wherein L is the -OSO ₂ Ra, wherein ^{R N} is said -ORb, wherein ^{R 1} is a hydrogen atom, the ^{R 2A, R 3A, R 2B} and ^{R 3B} are each independently a hydrogen atom, A hydroxyl group, an alkoxy group, an alkenyloxy group, an aryloxy group, an acyloxy group, an alkylsulfonyloxy group or an arylsulfonyloxy group, wherein one of the R ^4A and R ^4B is a hydrogen atom and the other is an alkyl group. The manufacturing method of any one of 1-8. The manufacturing method of Claim 2 which performs the said reaction, after manufacturing the compound represented by the said general formula (IA) from the compound represented with the following general formula (IIIA).

In the general formula (IIIA), ^{R 1} has the same meaning as ^{R 1} in the general formula (I). R ^{2Ax to} R ^4Ax and R ^{2Bx to} R ^4Bx each independently represent a hydrogen atom or a substituent. R ^2Ax and R ^2Bx , R ^3Ax and R ^3Bx may jointly form a methylidene group represented by ═O or ═C (Rdx) (Rex), and R ^{2Ax to} R ^{4Ax And} at least two of R ^{2Bx to} R ^4Bx may be bonded to each other to form a ring. Rdx and Rex each independently represent a hydrogen atom or a substituent.   The manufacturing method of any one of Claims 1-10 which perform the said reaction in water presence.   The production method according to claim 1, wherein the reaction is performed in the presence of an aldehyde compound.   The manufacturing method of any one of Claims 1-12 which perform the said reaction in glyoxylic acid presence.