JPH08134065A - Production of 3'-amino-3'-deoxynucleoside and intermediate for synthesizing the same - Google Patents

Abstract

PURPOSE: To easily and efficiently obtain a lactone derivative useful as a raw material for synthesizing the subject compound having useful physiological activity such as antineoplastic activity, or as an intermediate for synthesizing other physiologically active substances. CONSTITUTION: This intermediate, a 3-amino-3-deoxy-D-ribono-1,4-lactone derivative, is expressed by formula I (R<1> and R<4> are each H, an acyl, an alkyl, silyl, etc., i.e., a protecting group for hydroxyl group; R<2> and R<3> are each H, an alkyl, an alkenyl, an acyl, an aryl, etc.; R<2> and R<4> or R<3> and R<4> may be combined to form isopropylidene, methylidene, etc.), e.g. a compound of formula II. The compound of formula I is obtained via a compound of formula IV (R<5> is H, an acyl, sulfonate, etc.), a compound of formula V, etc., from a compound of formula III as starting material. The objective 3'-amino-3'-deoxynucleoside is obtained from the compound of formula I as the starting material.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a 3-amino-3-deoxy-D-ribono-1,4-lactone derivative represented by the formula (1). The present invention also relates to a method for producing a compound of formula (1) and a method for producing a 3'-amino-3'-deoxynucleoside represented by formula (7).

[0002]

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[0003]

2. Description of the Related Art In recent years, basic research and synthetic chemical research on nucleic acid-related compounds and amino acid-related compounds, which are important as bioactive components, have been actively conducted in the fields of organic industrial chemicals, pharmaceuticals, agricultural chemicals and the like. In particular, the nucleic acid-related compound is a compound that has been particularly attracting attention in recent years because it can be expected to have antitumor activity, antiviral activity, particularly anti-HIV activity. The saccharides that are the starting materials or constituent units for organic synthesis of such nucleic acid-related compounds are mainly commonly available sugars such as D-glucose, D-mannose or D-galactose, or It is a derivative thereof. However, in order to efficiently synthesize a useful nucleic acid-related compound, rare saccharides, unnatural saccharides and their derivatives, which have been difficult to obtain in addition to the above-mentioned sugars, are used as a starting material or a structural unit. It is often effective to do so. Therefore, rare sugars,
There is a strong demand in the art for development of a synthetic method capable of easily supplying a large amount of non-natural sugars and their derivatives, and their industrial utility is extremely great.

The above-mentioned synthetically effective derivative is 3-amino-3-deoxy-ribono-represented by the formula (1).
There are 1,4-lactone derivatives, which are expected to be widely available as starting materials for synthesizing various useful compounds such as nucleic acids.

On the other hand, nucleic acid-related compounds include 3'-amino-3'-deoxynucleosides, and among them, 3'-amino-3'-deoxyadenosine has been found to have antitumor activity and puromycin. It is also expected to be a compound that inhibits the protein synthesis pathway as a related compound. Further, in recent years, it has been noted that an antisense oligonucleotide acts as an antiviral agent, but an oligomer having a 3'-amino-3'-deoxynucleoside as a constituent unit can be expected to have the same usefulness.

[0006] Conventional synthetic methods for 3'-amino-3'-deoxyadenosine include, for example, a method derived from adenosine (Tetrahedron Lett. 30: 2329, 1989).
Year) and xylose as a starting material, followed by an acylated derivative and a coupling reaction with a nucleic acid base (JOURNAL OF MEDICAL CHEMISTRY, vol. 22, p. 882, 1979). However, the former is a 3'-amino-other than 3'-amino-3'-deoxyadenosine.
Since it cannot be applied to the synthesis of 3'-deoxynucleoside, there is a problem in versatility. Further, the latter is applicable to the synthesis of various 3'-amino-3'-deoxynucleosides, and thus has great versatility, but has problems in some steps in terms of complexity of purification, selectivity and yield. . Therefore, a highly versatile synthetic method for 3′-amino-3′-deoxynucleosides has been earnestly desired.

Further, the above 3-amino-3-deoxy-D
The -ribono-1,4-lactone derivative (1) is not only a raw material for synthesizing the 3'-amino-3'-deoxynucleoside (7) but also useful as a synthetic intermediate for other physiologically active substances, and thus is versatile. There is a strong demand for a high synthesis method.

[0008]

The present invention has been made in view of the above points, and a first object thereof is a 3-amino-3-deoxy-D-ribono-1,4-lactone derivative (1 ) Is to provide.

A second object is to provide a method for easily and selectively synthesizing 3-amino-3-deoxy-D-ribono-1,4-lactone derivative (1) from easily available raw materials. Is.

Further, a third object of the present invention is 3'-amino-
It is intended to provide a method for synthesizing a 3′-deoxynucleoside derivative.

[0011]

Means for Solving the Problems As a result of intensive studies to achieve the above object, the present inventor has used levoglucosenone, which is easily obtained as a thermal decomposition product of cellulose, as a starting material, and efficiently uses 3-amino- A method for synthesizing a 3-deoxy-D-ribono-1,4-lactone derivative (1) was developed.

Furthermore, the above-mentioned synthetic method efficiently provides the 3-amino-3-deoxy-D-ribono-1,4-lactone derivative (1).

The present inventors have also developed a method for synthesizing a 3'-amino-3'-deoxynucleoside derivative using the above compound (1) as a starting material.

That is, the above problem is solved by the following (I) to (I
V) is solved.

(I) 3-amino-represented by the following formula (1)
3-deoxy-D-ribono-1,4-lactone derivative.

[0016]

[Chemical 17]

However, R ¹ and R ⁴ represent a hydrogen atom or a protective group for a hydroxyl group such as an acyl group, an alkyl group, a silyl group, an aralkyl group, a sulfonic acid group, a phosphoryl group and a formyl group, and R ² and R ³ Represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, a silyl group, an aryl group, an aralkyl group, an alkyloxycarbonyl group, an aryloxycarbonyl group, an alkylsulfonyl group or an arylsulfonyl group. In addition, R ² and R ⁴ or R
³ and R ⁴ may together form an isopropylidene group, an ethylidene group, a methylidene group, or an alkylidene group such as a benzylidene group and a cyclohexylidene group.

(II) 3-amino-represented by the following formula (1)
A method for producing a 3-deoxy-D-ribono-1,4-lactone derivative, comprising:

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However, R ¹ , R ² , R ³ and R ⁴ are (I)
As defined in.

(A) As shown in the following reaction formula, the compound represented by the formula (2) has a cis-positioned N-substituted amino group at the 4-position of the double bond and a cis-positioned hydroxyl group at the 3-position. Adding to obtain a compound represented by formula (3),

[Chemical 19]

However, R ⁵ represents a hydrogen atom or a hydroxyl-protecting group such as an acyl group, an alkyl group, a silyl group, an aralkyl group, a sulfonic acid group, a phosphoryl group or a formyl group, and R 5
² represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, a silyl group, an aryl group, an aralkyl group, an alkyloxycarbonyl group, an aryloxycarbonyl group, an alkylsulfonyl group or an arylsulfonyl group.

(B) As shown in the following reaction formula, the 3-position hydroxyl group and 4-position amino group of the compound of formula (3) are protected to produce a compound of formula (4), and then the 2-position of Removing the protective group of the hydroxyl group to obtain a compound represented by the following formula (5):

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However, R ⁵ is as defined above,
R ² , R ³ and R ⁴ are as defined above in (I).

(C) As represented by the following reaction formula, the hydroxyl group at the 2-position of the compound of the following formula (5) is oxidized to give the following formula (6)
A step of obtaining a compound represented by:

[Chemical 21]

However, R ² , R ³ and R ⁴ are as defined above in (I).

(D) Formula (6) as shown in the following reaction formula
Oxygen is introduced between the 1-position and 2-position of the compound (1), further hydrolyzed, and ring-closed again to give a compound represented by the formula (1 ′), and then hydroxy of the 5-position of the compound (1 ′). Protects the hydroxyl group of the methyl machine, 3-amino-represented by the formula (1)
Step of obtaining 3-deoxy-D-ribono-1,4-lactone derivative (1)

[Chemical formula 22]

However, R ¹ , R ² , R ³ and R ⁴ are
As defined above in (I). And 3-amino-3-deoxy-D-ribono-
A method for producing a 1,4-lactone derivative (1).

(III) A method for producing a 3'-amino-3'-deoxynucleoside represented by the following formula (7),

[Chemical formula 23]

However, B represents a nucleic acid base.

(A) a step of reducing the carbonyl group at the 1-position of the compound of formula (1 ') as shown in the following reaction formula to obtain a compound of the following formula (8),

[Chemical formula 24]

However, R ² , R ³ and R ⁴ are as defined above in (I).

(B) protecting the 1- and 5-position hydroxyl groups of the compound of formula (8) with an acyl group as represented by the following reaction formula to obtain a compound of formula (9) ,

[Chemical 25]

However, R ⁸ represents an acyl group, and R ² , R ³
And R ⁴ are as defined in (I) above.

(C) As represented by the following reaction formula, a compound represented by the formula (10) is prepared by removing the protective group of the 2-position hydroxyl group and the 3-position N-substituted amino group of the compound of the formula (9). A compound having the formula (11) is prepared by introducing an acyl group into the 2-position hydroxyl group and a trifluoroacetyl group into the 3-position amino group,

[Chemical formula 26]

However, R ⁸ and R ⁹ represent an acyl group.

(D) As represented by the following reaction formula, the formula (1
The compound of 1) and a nucleobase are subjected to a coupling reaction to produce a compound represented by the formula (12), and the protecting groups for the hydroxyl group and the N-substituted amino group are eliminated to give a compound represented by the formula (7). To obtain the compound to be treated

[Chemical 27]

However, R ⁸ and R ⁹ represent an acyl group, and B
Represents a nucleobase.

A process for producing 3'-amino-3'-deoxynucleoside (7), which comprises:

(IV) A method for producing a 3'-amino-3'-deoxynucleoside represented by the following formula (7),

[Chemical 28]

However, B represents a nucleic acid base.

(I) a step of reducing the carbonyl group at the 1-position of formula (1 ') as represented by the following reaction formula to obtain a compound represented by the following formula (8),

[Chemical 29]

However, R ² , R ³ and R ⁴ are as defined in claim 1.

(Ii) As represented by the following reaction formula, the protecting groups at the 2- and 3-positions of the compound of the formula (8) are eliminated and the 1, 2, 3 and 5 positions are protected by an acyl group. To obtain a compound represented by the formula (13):

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However, R ⁸ represents an acyl group.

(Iii) As shown in the following reaction formula, the compound of formula (13) and a nucleobase are subjected to a coupling reaction to produce a compound of formula (14). Removing the protecting group of to obtain a compound represented by formula (7)

[Chemical 31]

However, R ⁸ represents an acyl group and B represents a nucleobase.

A process for producing 3'-amino-3'-deoxynucleoside (7), characterized by comprising:

The present invention will be described in detail below.

In the present invention, the nucleobase means a purine or pyrimidine base, and specifically adenine, guanine, cytosine, uracil, thymine and the like.

In the present invention, the alkyl group has 1 carbon atom.
1 to 10, preferably 1 to 6, linear, branched or cyclic saturated hydrocarbons.

The alkenyl group means an unsaturated hydrocarbon having 2 to 10 carbon atoms, preferably 2 to 6 straight chain, branched or cyclic double bond.

The alkynyl group means an unsaturated hydrocarbon having 2 to 10 carbon atoms, preferably 2 to 6 linear or branched one or more triple bonds.

The aryl group has a carbon number of 6 to 12,
It preferably means 6 to 8 aromatic hydrocarbons, which may or may not have substituents.

The alkoxy group means a group containing a straight or branched saturated or unsaturated hydrocarbon having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms.

The aralkyl group means a linear, branched, or cyclic alkyl group, alkenyl group, and alkynyl group having 7 to 25 carbon atoms, preferably 7 to 20 carbon atoms substituted with an aryl group (alkyl group, An alkenyl group, an alkynyl group, and an aryl group have the same meanings as above.).

The silyl group means an organosilyl group containing 3 kinds of alkyl or aryl groups having 1 to 30 carbon atoms, preferably 3 to 18 carbon atoms (the alkyl group and the aryl group have the same meanings as described above). ). Specifically, trimethylsilyl group, triethylsilyl group, triphenylsilyl group, tert-butyldimethylsilyl group, tert
-Butyldiphenylsilyl group and the like.

The acyl group means an alkylcarbonyl group having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, or an arylcarbonyl group (the alkyl group and the aryl group have the same meanings as described above).

The alkyloxycarbonyl group has 1 carbon atom.
To 10, preferably 1 to 6 alkyl groups (the alkyl groups have the same meanings as above). For example, a methoxycarbonyl group, an ethoxycarbonyl group,
There is a t-butoxycarbonyl group and the like.

The aryloxycarbonyl group has 6 carbon atoms.
To 15 and preferably 6 to 10 aryl groups (aryl groups have the same meaning as above). For example, there is a phenoxycarbonyl group or the like.

The alkylsulfonyl group has 1 carbon atom.
To 10, preferably 1 to 6 sulfonyl groups having an alkyl group (the alkyl group has the same meaning as above). For example, there are a methanesulfonyl group, an ethanesulfonyl group and the like.

The arylsulfonyl group has 6 to 1 carbon atoms.
A sulfonyl group having 5, preferably 6 to 10 aryl groups. (Aryl group has the same meaning as above). For example, there are a benzenesulfonyl group, a p-toluenesulfonyl group and the like.

Further, the alkylidene group has 1 to 1 carbon atoms.
0, preferably 1 to 8 is a divalent group represented by RR'C <, and R and R'represent an alkyl group or, together, represent a saturated cyclic hydrocarbon. Specifically, it represents an isopropylidene group, an ethylidene group, a methylidene group, a cyclohexylidene group, or a benzylidene group.

Further, halogen means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

Further, the base is an organic base or an inorganic base, and specific examples thereof include triethylamine, imidazole, n-butylamine, pyridine, aqueous ammonia, sodium hydrogencarbonate and potassium hydrogencarbonate.

In the present invention, the ether solvent means diethyl ether, tetrahydrofuran, dioxane and the like.

The hydrocarbon solvent means hexane, benzene, toluene, xylene and the like.

The halogen solvent means carbon tetrachloride, chloroform, methylene chloride, 1,2-dichloroethane and the like.

The aprotic polar solvent means N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like.

The basic solvent means pyridine, piperidine,
A solvent such as triethylamine or aqueous ammonia.

In the first aspect of the present invention, 3-amino-3
-Deoxy-ribono-1,4-lactone derivative (1) is provided.

The compound (1) has an O-substituted hydroxyl group at the 2-position,
Each having an N-substituted amino group in the α-configuration at the 3-position and 4
Having an O-substituted hydroxymethyl group in the β-configuration at position 5
It is a compound having a membered ring lactone structure.

In the present invention, the compound (1) has a hydroxyl group at the 2-position, an amino group at the 3-position, a hydroxyl group at the 5-position, or is substituted with various substituents. These substituents are commonly used as protective groups for hydroxyl groups,
Or, as long as it is a general protective group for an amino group, it is not particularly limited, but examples thereof include the following.

R ¹ which is a hydroxyl group-protecting group at the 5 position represents a hydrogen atom or a hydroxyl group-protecting group such as an acyl group, an alkyl group, a silyl group, an aralkyl group, a sulfonic acid group, a phosphoryl group and a formyl group. Of these, an acyl group and a formyl group are preferred.

R ² and R which are protecting groups for the amino group at the 3-position
³ may be the same or different, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, a silyl group, an aryl group, an aralkyl group, an alkyloxycarbonyl group, an aryloxycarbonyl group, an alkylsulfonyl group, an arylsulfonyl group. Represent Preferably, it is an alkyloxycarbonyl group.

Examples of R ⁴ which is a hydroxyl-protecting group at the 2-position include the same groups as R ¹ above, but a particularly preferred group is an acyl group.

In the present invention, R ² and R ⁴ or R ³
And R ⁴ may together form an alkylidene group. The alkylidene group is not particularly limited as long as it is a common one, but an isopropylidene group, a benzylidene group, an ethylidene group, a methylidene group, and a cyclohexylidene group are preferable, and an isopropylidene group is particularly preferable.

In the second aspect of the present invention, there is provided a method for producing the above compound (1).

The method for producing the compound (1) will be described below along with each step.

First, in the present invention, as shown in the following reaction formula, using levoglucosenone represented by the formula (15) as a starting material, the carbonyl group at the 2-position of this compound is reduced to give 1,6-anhydro-3. , 4-dideoxy-β-D
-Threo-hex-3-enopyranose (16). Then, the β-configuration hydroxyl group of the compound (16) is protected to give a compound (2).

[0080]

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However, R ⁵ is as defined above.

The reduction reaction of the levoglucosenone (15) can be carried out according to the methods described in Japanese Patent Application Nos. 2-272186, 3-77380 and 3-162604. That is, the carbonyl group at the 2-position may be reduced to the β-coordinated hydroxyl group with a metal hydride such as lithium aluminum hydride or sodium borohydride in a suitable ether-based solvent such as ether or tetrahydrofuran.

Next, the obtained 1,6-anhydro-3,4-dideoxy-β-D- represented by the above formula (16) is obtained.
Protects the hydroxyl group at the 2-position of threo-hex-3-enopyranose. In the present invention, the hydroxyl protecting group R ⁵ is not particularly limited. The protecting groups mentioned above for the R ¹ group or R ⁴ group in the description of the compound (1) are applicable as they are (however, when they are divalent groups). Specifically, for example, a silyl-based protecting group such as a t-butyldiphenylsilyl group or a t-butyldimethylsilyl group, an aralkyl group such as a benzyl group, or an acyl group such as an acetyl group, a benzoyl group or a pivaloyl group. Protecting groups of the system may be suitably used.

As the conditions for the reaction of introducing the protecting group, the conditions for protecting a general hydroxyl group corresponding to each protecting group can be used. For example, when a silyl-based protecting group is introduced, a desired silyl halide (for example, t-) in a halogen-based solvent such as chloroform or an aprotic polar solvent such as N, N-dimethylformamide (DMF) is used. Butyldiphenylsilyl chloride, etc.) may be allowed to act in the presence of a base such as imidazole. The reaction temperature and reaction time in this case are not particularly limited, but are 0
C. to 100.degree. C. for 1 to 24 hours is preferred. Especially 2
It is preferable to react at 0 ° C. to 50 ° C. for 1 to 20 hours. Further, the silyl halide and the base are added in 1 to 5 equivalents, preferably 1 to 3 equivalents, based on the compound (16).

When an acyl group is introduced, the compound (16) may be reacted with carboxylic acid anhydride, carboxylic acid chloride or carboxylic acid in the presence of a base in a suitable solvent. As the reaction solvent, all organic solvents that can be used for ordinary acylation of hydroxyl groups can be applied. For example, in this reaction, an aprotic organic solvent is preferable, and a halogen solvent and a basic solvent are particularly preferable. Examples of these solvents are methylene chloride or chloroform, or pyridine or piperidine.

This reaction is carried out in the presence of a base in order to trap the acid produced as the reaction proceeds. The base that can be used is not particularly limited as long as it does not trap an acid and inhibits this reaction, but a tertiary amine is preferable. Particularly preferred is pyridine or triethylamine. If a basic solvent such as pyridine is used as the solvent, a base is not particularly required, but if another aprotic solvent is used, it is necessary to add a base such as a tertiary amine in advance. Further, when the acylation reaction is performed with an acid anhydride in an organic solvent other than the basic solvent, it is preferable to add N, N-dimethylaminopyridine or the like as a catalyst for the acylation. The amount of each reagent used for acylation is 1 to 5 equivalents, preferably 1 to 2 equivalents of the acylating agent based on the compound (16). It is preferable to use the same amount.
When N, N-dimethylaminopyridine or the like is used as a catalyst for acylation, 0.01 to 0.5 equivalent,
Preferably 0.01 to 0.2 equivalent is added.

The reaction conditions may be those suitable for each acylation reaction. For example, when an acid anhydride is used as the acylating agent, the reaction temperature is preferably 0 ° C to 60 ° C, particularly preferably 0 ° C to 30 ° C. The reaction time is preferably 1 to 24 hours, particularly preferably 3 to 10 hours.

Further, when introducing an aralkyl group such as a benzyl group, a halogenated aralkyl such as a benzyl halide is allowed to act in the presence of a strong base such as sodium amide in an aprotic polar solvent such as DMF. Good. In this case, the reaction temperature and the reaction time are −20 ° C. to 50 ° C., 1 to 24 hours, preferably 0 to 30 ° C.,
1 to 10 hours. The amount of each reagent used is 1 to 2 equivalents, preferably 1 to 1.5 equivalents of the strong base, and 1 to 3 equivalents, preferably 1 to 3 equivalents of the aralkyl halide, based on the compound (16). It is 2 equivalents.

In the present invention, it is not always necessary to introduce a protecting group, and the compound (16) may be used as it is. That is, the hydroxyl group at the 2-position of the compound (16) may be left free and the step (a) described below may be carried out. However,
In the aminohydroxylation reaction of step (a), it is preferable to protect the hydroxyl group at the 2-position in order to efficiently and selectively introduce the N-substituted amino group at the 4-position. Furthermore, in the present invention, in order to selectively obtain the compound of the formula (3) described later in the highest yield selectively, the protecting group is sterically bulky t-butyldiphenylsilyl for the reason described in the step (a). Groups are preferred.

By the above method, 1,6 represented by the equation (2)
-Anhydro-3,4-dideoxy-β-D-threo-
A compound in which the hydroxyl group of hexo-3-enopyranose is protected is obtained.

In the step (a), the 1,6-anhydro-3,4-dideoxy-β-D-threo-hex-3-enopyranose derivative represented by the above-mentioned formula (2) is obtained. It is a step of cis-adding a hydroxyl group at the 3-position of the double bond between the 3- and 4-positions and an amino group at the 4-position in the α configuration.

In the following, in order to simplify the explanation, the substituent on the amino group introduced by aminohydroxylation is represented by R ² .

In this reaction, the compound of the formula (2) is treated with osmium tetroxide as a catalyst, for example, a chloramine derivative (R
¹⁰ SO ₂ NClNa) or N-chloro-N-carbamate (R ¹¹ OC (O) NClNa) by treatment with a co-oxidant that serves as a source of amino groups. That is, it is carried out under the same conditions as in ordinary aminohydroxylation.

The cooxidant that can be used in this step is not particularly limited as long as it can be used for aminohydroxylation. For example, the chloramine derivative (R ¹⁰ SO
₂ NClNa) or N-chloro-N-carbamyl acid salt (R ¹¹ OC (O) NClNa) can be used. Here, in the present invention, R ¹⁰ is preferably an aryl group or an alkyl group, and particularly preferably an aryl group. Specific examples include phenyl, o-tolyl, p-tolyl, p-chlorophenyl, p-nitrophenyl, o-carboalkoxyphenyl, and the like. In the present invention, R ¹¹ is
An alkyl group or an aralkyl group is preferred. Specific examples thereof include a methyl group, an ethyl group, an isopropyl group, a t-butyl group and a benzyl group. In the present invention,
As described above, various co-oxidizing agents can be used, and depending on the co-oxidizing agent used, N- added on the carbon atom at the 4-position can be used.
Different substituted amino groups. For example, chloramine-T (R ¹⁰
= P-tolyl group) is used as the co-oxidizing agent, the compound becomes a compound to which p-toluenesulfonamide is added (a compound in which R ² is a paratoluenesulfonyl group in the formula (3)). Also, N-chloro-N-carbamate (R ¹¹ prepared from t-butyl carbamate and t-butyl hypochlorite
When OC (O) NClNa and R ¹¹ is a t-butyl group is used as a co-oxidant, a compound to which t-butoxycarbonylamide is added (a compound of the formula (3) in which R ² is a t-butoxycarbonyl group) )become.

The co-oxidant is 1 based on the compound (2).
Use more than equivalent. It is preferable to use 1 to 5 equivalents, and it is more preferable to use 1 to 2 equivalents. Further, the cooxidant is more effective when used as a silver salt obtained by adding silver nitrate.

Osmium tetroxide used in this reaction acts as a catalyst. The amount of osmium tetroxide is not particularly limited as long as it is an effective amount as a catalyst, but it is 0.
05 to 0.5 equivalents are preferred and 0.05 to 0.3 equivalents are particularly preferred.

This reaction is generally carried out in a protic polar solvent such as water or alcohol, but it should be carried out in a two-layer system of water and an organic solvent immiscible with a phase transfer catalyst. Is also possible. As the organic solvent immiscible with water, a halogen-based solvent such as chloroform or methylene chloride can be preferably used. The phase transfer catalyst is not particularly limited, but benzyltriethylammonium chloride and the like are preferable.

The reaction temperature is not particularly limited, but 0 ° C to 100 ° C can be preferably used. The temperature is preferably 0 ° C to 60 ° C, particularly preferably 10 ° C to 30 ° C.

The reaction time is from 1 hour to 7 days, preferably from 24 to 96 hours.

Here, the N- introduced by this reaction
The regioselectivity of substituted amino groups and hydroxyl groups depends on the substituents on the double bond carbon. This is due to the bulkiness of the imide group of imidoosmium trioxide represented by the following formula (17), which is produced as an intermediate in this reaction.

[0101]

[Chemical 33]

However, R ² is as defined above.

That is, in Compound (2), consider the case where the carbon atom side at the 3-position is sterically crowded compared to the carbon atom side at the 4-position because R ⁵ is substituted with the hydroxyl group at the 2-position. Then, as shown in the following formula, an intermediate (18) having a bulky imide group bonded to a carbon atom at the 4-position, which is more sterically hindered, is obtained. Regarding steric crowding on the α side and β side of the ring, compound (2)
Compared to the plane, it has a structure in which the β plane is three-dimensionally crowded. In particular, the tendency that the β side becomes crowded by the substitution of the R ⁵ group becomes remarkable. Therefore, imidoosmium trioxide (17) attacks the double bond from the α-face of the ring (in the reaction formula below, the attack from the α-face is represented by a dotted arrow. , The side of the ring where the 6-anhydro bond is located is the β-face, and the face of the opposite ring is the α-face).

[0104]

Embedded image

However, R ² and R ⁵ are as defined above.

Therefore, in this step, R ⁵ is preferably as sterically bulky as possible.

Thus, in this reaction, a compound (3) having an N-substituted amino group at the 4-position carbon atom and a hydroxyl group at the 3-position carbon atom in the α configuration is obtained.

Thus, 4 represented by the equation (3) is obtained.
-Amino-1,6-anhydro-4-deoxy-β-D
-A compound in which the hydroxyl group at the 2-position and the N-substituted amino group at the 4-position of altropyranose are protected is obtained.

In step (b), a protecting group is introduced into the 3-position hydroxyl group and 4-position N-substituted amino group of compound (3) obtained in step (a) to give compound (4), and then 2 In this step, the protecting group R ^{5 at the position} is eliminated.

As the protective group for the hydroxyl group at the 3-position and the protective group for the N-substituted amino group at the 4-position, those suitable for the protective group for the hydroxyl group and those suitable for the protective group for the N-substituted amino group should be introduced independently. However, in the present invention, it is preferable to protect the hydroxyl group at the 3-position and the N-substituted amino group at the 4-position as an acetal by introducing an alkylidene group capable of protecting the hydroxyl group and the N-substituted amino group at once.

Introduction of an alkylidene group is achieved by subjecting compound (3) to a usual acetalization reaction using an organic acid such as p-toluenesulfonic acid or acetic acid or an inorganic acid such as hydrochloric acid or sulfuric acid as a catalyst. It As the acetalizing agent, 2,2-dimethoxypropane, 2,2-dimethoxymethane, dimethoxybenzyl and the like can be preferably used.
Preferably 2,2-dimethoxypropane is used.
When 2,2-dimethoxypropane is used, the compound has a hydroxyl group at the 3-position and an N-substituted amino group at the 4-position protected with isopropylidene.

As the reaction solvent, benzene, toluene,
Hydrocarbon-based organic solvents such as hexane and ether-based organic solvents such as tetrahydrofuran and 1,4-dioxane can be used. The amount of acid catalyst is preferably 0.05 to 0.5 equivalents, more preferably 0.05 to 0.2 equivalents. The reaction temperature is also not particularly limited, but is 3
0 to 150 ° C. is preferable, and 60 to 1 is particularly preferable.
It is 20 ° C. The reaction time is 1 to 48 hours, preferably 1 to 24 hours.

When protecting the hydroxyl group at the 3-position and the N-substituted amino group at the 4-position with a group other than an alkylidene group, a group suitable for a hydroxyl-protecting group and a protecting group for an N-substituted amino group are independently selected. A suitable one can also be introduced. For example, in order to introduce a protective group into a hydroxyl group, the method described in the introduction of the R ⁵ group can be applied as it is. Also,
In order to introduce a protecting group into the N-substituted amino group, a usual method for introducing a protecting group for an amino group can be used as it is. For example, an acyl protecting group can be introduced by using an acid anhydride, an acid halide or the like, and an aralkyl group can be introduced by using an aralkyl halide (eg, benzyl chloride, trityl chloride etc.) in the presence of a strong base. . Further, the order of introduction of the protective group for the hydroxyl group and the protective group for the N-substituted amino group may be either first.

Next, the protective group R ⁵ for the hydroxyl group at the 2-position of the obtained compound (4) is deprotected.

Removal of the protecting group must be appropriately selected depending on the R ⁵ group. For example, in the case of an organosilyl group such as t-butyldiphenylsilyl group, these groups are eliminated by reacting with tetrabutylammonium fluoride or a fluoride such as hydrofluoric acid in a suitable organic solvent. it can. This elimination reaction can also be carried out in a basic solution such as pyridine. In addition to the above-mentioned fluorides, organic acids such as acetic acid and hydrochloric acid, acids such as mineral acids and Lewis acids, and proton-type cation exchange resins can also be used to eliminate the silyl group. As the solvent that can be used for elimination of the silyl group, for example, an ether solvent such as tetrahydrofuran or diethyl ether, a halogen solvent such as chloroform, or acetonitrile can be used.

The amount of the above-mentioned fluoride, acid, ion exchange resin or the like that can be used for elimination of the silyl group is 1 to 5 equivalents, preferably 1 to 3 equivalents based on the compound (4).
It is equivalent. The reaction conditions also vary depending on the reagents used, but are preferably 0 ° C to 100 ° C for 1 to 42 hours, more preferably 0 ° C to 50 ° C for 1 to 30 hours.

When R ⁵ is an acyl-based protecting group,
All reactions capable of removing an acyl group can be applied. For example, hydrochloric acid, sulfuric acid, an H ⁺ type cation exchange resin or the like may be allowed to act in a protic organic solvent such as water or alcohol. When deprotecting under basic conditions, a base may be allowed to act in a protic organic solvent such as alcohol. Examples of the base that can be used include hydroxides and alkoxides of alkali metals and alkaline earth metals, and ammonia water. Specific examples of hydroxides and alkoxides include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium methoxide, and sodium ethoxide.

The reaction time and reaction temperature may be appropriately selected depending on the acid or base used. Specifically, in the case of deprotection using an acid catalyst, the reaction temperature is preferably 0 ° C to 70 ° C,
C. to 40.degree. C. are particularly preferred. The reaction time is 30
Minutes to 24 hours, preferably 1 hour to 18 hours. Also, similar reaction conditions can be used in the reaction under basic conditions.

When the step (a) is carried out using the compound (2) as a starting material, elimination of the R ⁵ group can be omitted.

Step (c) is a step of oxidizing the hydroxyl group at the 2-position of the compound represented by the formula (5) obtained in step (b) to convert it into a carbonyl group.

Any oxidation method can be used in this step as long as it can oxidize a hydroxyl group to a carbonyl group. Although there are many such reactions, typical examples are given below.

1) dicyclohexylcarbodiimide,
Oxidation with dimethylsulfoxide in combination with acetic anhydride, phosphorus pentoxide, trifluoroacetic anhydride, oxalyl chloride, halogen, etc.

2) Chromium (VI) oxide represented by Jones oxidation, dichromate, chromium oxide-pyridine complex (Collins reagent), pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), etc. Chromic acid oxidation.

3) Oxidation with manganese dioxide.

4) Oxidation with hypohalite, halogenate or the like.

5) Oppenauer oxidation or oxidation with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).

6) Oxidation with a transition metal catalyst such as ruthenium tetroxide, platinum catalyst and palladium catalyst.

7) Oxidation with silver carbonate, copper (II) salt, lead tetraacetate, etc.

The reaction conditions such as the amount of the reagent, the solvent, the reaction temperature, the reaction time and the like differ depending on each oxidation method. Therefore, the conditions suitable for each oxidation reaction may be appropriately selected and used.
It is not particularly limited. For the oxidation reaction in this step, a method by so-called Swern oxidation using dimethyl sulfoxide and oxalyl chloride can be preferably used. In this method, oxalyl chloride and dimethyl sulfoxide are mixed at a temperature below freezing, and then the above formula (5) is used.
Is added, and after the reaction, the reaction is treated with a base such as triethylamine. Oxalyl chloride and dimethyl sulfoxide may be 1 equivalent or more with respect to the compound (5), preferably 1 to 5 equivalents, and particularly preferably 2 to 3 equivalents. The reaction temperature is preferably −100 ° C. to 0 ° C., and −80 to −40 ° C. is particularly desirable. The reaction time is not particularly limited,
0.5 to 24 hours are desirable and 0.5 to 5 hours are particularly preferred. In addition to the above triethylamine, the base is 4
-Dimethylaminopyridine and the like can be preferably used. Dichloromethane can be preferably used as the solvent.

In step (d), oxygen is inserted between the 1-position and 2-position of the compound represented by formula (6) obtained in step (c), further hydrolyzed and recyclized to give γ. Generate a lactone ring.

This step is not particularly limited as long as it is a method of introducing oxygen into the α-position of the carbonyl group, but a method using peracid, so-called Baeyer-Villiger oxidation is effective.
This method is carried out by reacting compound (6) with peracid. As the peracid, m-chloroperbenzoic acid, a methanol solution of magnesium permonophthalate, or the like can be preferably used. In the present invention, it is particularly preferable to use a methanol solution of magnesium permonophthalate. For example, when magnesium permonophthalate is used as an oxidant, the amount used may be 0.5 equivalent or more,
0.5 to 5 equivalents are desirable, and 0.6 to 3 equivalents are particularly preferred. The reaction temperature is preferably 0 ° C to 60 ° C, particularly preferably 20 ° C to 40 ° C. The reaction time is preferably 10 hours or longer, preferably 10 to 48 hours, particularly preferably 10 to 24 hours. In this step, as a by-product, a compound in which the hydroxymethyl group at the 5-position of the compound of the above formula (6) is formyl esterified is also obtained, which is easily separated by column chromatography or the like. can do.

The above-mentioned formyl ester compound can be treated as the compound (6) by treating it under the condition of acid hydrolysis. As the acid for hydrolysis, any general acid catalyst such as hydrochloric acid, sulfuric acid, or Amberlite IR-120B (proton type) can be used. Any solvent may be used as long as it is a solvent used in general acid hydrolysis such as water or alcohol. The reaction temperature may be 0 to 100 ° C., but it is preferably about room temperature. The reaction time is preferably about 1 to 20 hours. Moreover, this formyl ester can be used as it is in the method for producing 3'-amino-3'-deoxynucleoside (7) described later.

As described above, 3-amino-3-deoxy-D- which is useful as a synthetic intermediate for physiologically active substances
A ribono-1,4-lactone derivative (1 ′) (in the above formula (1), R ¹ is a hydrogen atom) can be produced.

The compound (1 ′) obtained by this reaction has various protective groups introduced into the hydroxyl group of the hydroxymethyl group at the 5-position,
3-amino-3-deoxy-D- which is a compound of the present invention
The ribono-1,4-lactone derivative (1) can be produced. Various substituents are the same as the substituent R ⁵ explained in the production of the compound (2), and the introduction method thereof is the same as the introduction method of the R ⁵ group described in the production of the compound (2). Can be applied.

3-Amino-3-deoxy-D-ribono-
The 1,4-lactone derivative is known as a strong inhibitor of proteases and is a useful physiologically active substance itself, and can be easily produced by the method of the present invention.

The product obtained in each step of the present invention can be purified by a conventional purification means such as column chromatography or recrystallization.

In the third aspect of the present invention, 3'-amino-
A first method for producing a 3'-deoxynucleoside derivative is provided.

The first method for producing the 3'-amino-3'-deoxynucleoside derivative of the present invention will be described below in accordance with each step.

In the present invention, various 3-amino-3-deoxy-D-ribono-1,4-lactone derivative (1) can be used as a starting material. However, in the present invention, in the compound represented by the formula (1), R ¹ is a hydrogen atom, R ² is a protecting group for an amino group, and R ³ and R ⁴ together form an alkylidene group. It is particularly preferred to use the compounds mentioned above. Here, the case where (1 ′) is used as the starting material will be described. In addition, in the following description, in order to simplify the description, the substituent R ² or R ³ is R ⁴
Together with represents an alkylidene group, R ³ and R ⁴
To form an alkylidene group.

In the step (A), the above-mentioned step (d)
The carbonyl group of the γ-lactone ring of the compound represented by the above formula (1 ′) obtained in step 1 is reduced and converted to lactol.

In this step, a general reduction reaction which can convert a carbonyl group into an alcohol can be preferably used. For example, a reduction reaction using a metal hydride as a reducing agent can be mentioned. In this reaction, the reduction reaction using diisobutylaluminum hydride is particularly effective. That is, the compound of formula (1 ′) is dissolved in a suitable solvent and isobutylaluminum hydride is allowed to act on it. The amount of isobutylaluminum hydride used may be 3 equivalents or more and 3 to 1
0 equivalents are preferred and 5 to 10 equivalents are particularly preferred. The reaction solvent is preferably an ether solvent such as diethyl ether or tetrahydrofuran. The reaction temperature is from 0 ° C to -10
0 ° C. may be preferably used. More preferably, it is -50 ° C to -80 ° C, and particularly preferably -70 ° C to -80.
° C. The reaction time is not particularly limited, but is 1 to 20.
The time is preferably 1 to 5 hours.

In this step, the formyl ester form of (1 ') obtained in the above step (d) or a mixture of the formyl ester form and the compound (1') can be used as a starting material. The reaction conditions are the same as those for the reduction reaction of the above compound (1 ′).

Further, in the present invention, various compounds (1 ′)
Other than 3-amino-3-deoxy-D-ribono-1,4
-The lactone derivative (1) can be used as a starting material. In this step, among the compounds represented by the formula (1 ′), a compound in which R ² is a protecting group for an amino group and R ³ and R ⁴ together form an alkylidene group is used. Is particularly preferable.

In step (B), the hydroxyl groups at the 1-position and 5-position of the compound represented by the above formula (8) obtained in step (A) are protected with an acyl group.

This reaction can be carried out using a usual acylation reaction. For example, R described in the production of compound (2)
^{As one} group, a method of introducing an acyl group can be mentioned. Particularly in the present invention, a method using an acid halide is effective. For example, this reaction can be carried out by dissolving the compound represented by the formula (8) in a basic solvent such as pyridine, adding a pyridine solution of an acid halide under ice cooling, then returning to room temperature and continuing stirring. . The acid halide is preferably an acid chloride, particularly benzoyl chloride,
Paranitrobenzoyl chloride, acetyl chloride and the like are preferable. The amount of the acid halide may be 2 equivalents or more, preferably 2 to 5 equivalents, particularly preferably 2 to 3 equivalents. The reaction temperature is not particularly limited, but it is 0 ° C to 70 ° C.
℃, preferably 0 ℃ to 50 ℃, particularly preferably 20 ℃
To 40 ° C. The reaction time is 1 to 24 hours,
5 to 15 hours are preferred and 5 to 10 hours are particularly preferred.

In the step (C), the protecting groups at the 2- and 3-positions of the compound represented by the formula (8) obtained in the step (B) are eliminated, and the 3-position is replaced with a trifluoroacetyl group and the 2-position. Is a step of protecting with an acyl group.

First, elimination of the protective group for the hydroxyl group at the 2-position of the compound represented by formula (8) will be described.

The elimination reaction of the protecting group needs to be appropriately selected depending on the R ⁴ group. Specifically, the elimination reaction of the R ⁵ group described in the above-mentioned step (b) can be mentioned. The elimination reaction may be performed according to the reaction conditions described in step (b) above.

Further, for example, the elimination of the alkylidene group of the compound in which the R ³ group and the R ⁴ group are combined to form an alkylidene group, which is particularly preferred in the production method of the present invention, is p-
This can be achieved by hydrolysis using an organic acid such as toluenesulfonic acid or trifluoroacetic acid or an inorganic acid such as hydrochloric acid or sulfuric acid in an aqueous solution. The amount of acid may be 1 equivalent or more, preferably 3 to 10 equivalents, and 5 to 10 equivalents.
Equivalent weights are particularly preferred. Furthermore, the reaction time is 1 to 24 hours,
It is preferably 1 to 15 hours, particularly preferably 1 to 5 hours. The reaction temperature is not particularly limited, but is 10 to 50 ° C, preferably 10 to 30 ° C.

When the protective group for the hydroxyl group is eliminated, the protective group for the amino group at the 3-position may be eliminated.

This gives 3-amino-3-deoxy-
A compound in which the 2-hydroxyl group of the D-ribose derivative is deprotected is obtained.

Next, elimination of the protecting group for the amino group at the 3-position of the obtained compound will be described. Also in this step, the method of elimination depends on the protective group. The reaction is appropriately selected depending on the amino group to be deprotected. For example, when chloramine-T is used as the co-oxidant in step (a), p- is used for the amino group.
Since the toluenesulfonyl group is bonded, photolysis or Birch reduction is used for elimination of this group. For example, the former irradiates light having a wavelength in the ultraviolet region with a high-pressure mercury lamp in an organic solvent containing water (for example, methanol or ethanol). In this photolysis, it is preferable to use a photosensitizer. As the photosensitizer, 1,5-dimethoxynaphthalene or 1,4-dimethoxybenzene can be preferably used. It is also preferable to add a reducing agent such as sodium borohydride.

The reaction time is 1 to 24 hours, preferably 1
The reaction temperature is 10 to 50 ° C., preferably 10 to 30 ° C., although the reaction temperature is not particularly limited.

When N-chloro-N-carbamate (R ¹¹ = t-butyl group) is used as the co-oxidant, t
-Butoxycarbonyl group bound to an amino group,
For deprotection of these, an acid catalyst such as hydrochloric acid or trifluoroacetic acid may be used. These acids include 1N hydrochloric acid,
It is preferable to use a 90% -trifluoroacetic acid aqueous solution. The reaction conditions vary depending on the acid used, but generally, all the conditions for eliminating the t-butoxycarbonyl group can be used. For example, the reaction solvent may be a halogen-based organic solvent such as chloroform or methylene chloride. When trifluoroacetic acid is used, it is not necessary to use a solvent. Further, the reaction time is 1 to 24 hours, preferably 1 to 15 hours, and the reaction temperature is not particularly limited, but is 10 to 50 ° C., preferably 10 to 30 ° C.

As described above, the amount of the reaction reagent, the solvent, the reaction time, the reaction temperature, etc. are different depending on the respective methods, and therefore may be appropriately selected depending on the protecting group and are not particularly limited. . Either the amino-protecting group or the hydroxyl-protecting group may be deprotected first.

When the protective group R ² for the amino group is eliminated by eliminating the protective group for the hydroxyl group at the 2-position of the above compound (8), it is not necessary to deprotect the amino group.

Accordingly, D- represented by the above (10)
A ribose derivative is obtained.

Next, a trifluoromethylcarbonyl group is introduced into the amino group of the compound (10) thus obtained, and an acyl group is introduced into the hydroxyl group at the 3-position.

In order to introduce a trifluoromethylcarbonyl group into the 4-position amino group, the compound (10) is dissolved in pyridine and trifluoroacetic anhydride is added under ice cooling. The amount of trifluoroacetic anhydride should be 1 equivalent or more, preferably 1 to 10 equivalents, particularly 3 to 10 equivalents.

The reaction temperature is -10 ° C to 50 ° C, preferably 0 ° C to 50 ° C, and particularly preferably 20 ° C to 40 ° C. The reaction time is 1 hour to 24 hours, preferably 1 to 10 hours.

Then, an acyl group is introduced into the hydroxyl group at the 3-position by applying a usual acylation reaction to the obtained compound. In the present invention, acylation with an acid halide is preferred. As the acid halide, acid chloride is preferable, and benzoyl chloride, paranitrobenzoyl chloride, acetyl chloride and the like are particularly preferable. Benzoyl chloride is particularly preferred in the present invention. The amount of acid halide is 2
It is sufficient if it is at least equivalent, preferably 2 to 50 equivalents, particularly 10 to 50 equivalents. The reaction temperature is not particularly limited, but it is 0 ° C to 70 ° C, preferably 0 ° C to 50 ° C.
C., particularly preferably 20 to 40.degree. The reaction time is from 1 hour to 5 days, preferably from 1 day to 5 days, particularly preferably from 1 to 3 days. This gives formula (11)
A compound represented by

In the step (D), the compound represented by the above formula (11) obtained in the step (C) is coupled with a nucleobase at the 1-position, and further all protecting groups are removed to remove the 3'-amino group. This is a step of producing -3'-deoxynucleoside.

The condensation reaction between the compound of formula (11) and the nucleobase is carried out in an aprotic solvent in the presence of Lewis acids using the nucleobase in an amount equal to or more than that of the compound (11). The Lewis acids used are not particularly limited, but include, for example, trimethylsilyl trifluoromethanesulfonate,
Tin tetrachloride, titanium tetrachloride and the like are preferable. The amount of the Lewis acid catalyst may be 1 equivalent or more, and 1 to 5 equivalents, and more preferably 1 to 3 equivalents can be used. The amount of the nucleobase may be 1 equivalent or more, preferably 1 to 3 equivalents, particularly preferably 1 to 2 equivalents. The reaction temperature and the reaction time are not particularly limited, but 0 ° C to 100 ° C is preferable, and 4
Particularly preferred is 0 ° C to 100 ° C. Depending on the solvent used, it is carried out at the reflux temperature. The reaction time is preferably 1 to 48 hours, particularly preferably 5 to 24 hours. The solvent for this condensation reaction is an aprotic solvent, and for example, chloroform, methylene chloride, 1,2-dichloroethane, acetonitrile and the like are used.

In this step, the nucleobase can be used in the reaction either as it is or as an active nucleobase in a silylated form or a salt form. For example, as a method of silylation for activation and a salt form,
The following examples can be given, but not limited to these.

<Method for Silylating Nucleobase> Silylation can be performed, for example, by the method disclosed by Vorbruggen et al.
m. Ber. 1981, 114, p. 1234). That is, this is a method in which trimethylsilyl chloride is added to a hexamethyldisilazane suspension of a nucleic acid base, and the mixture is heated under reflux in an argon gas atmosphere.

<Method of Forming Nucleic Acid Base in Salt Form> This method includes (i) the method of the inventors (Japanese Patent Laid-Open No. 2-17199, Chem. Le.
tt. 1989, p. 235), ie, a method of reacting a suspension of nucleobase with alcohol or water with one equivalent of metal hydroxide or alcoholate, (ii) Kazimierczuk et al. (J. Am. Chem. Soc 1984 Vol. 106, page 6379) That is, there is a method of reacting a nucleobase with a metal hydride in a reaction system to produce a salt.

Examples of the nucleobase include thymine, uracil and cytosine obtained by decomposing naturally occurring nucleic acid.
Adenine, guanine, hypoxanthine, xanthine, or those obtained by synthesizing these bases by a usual method can be used. Alternatively, a nucleobase that is not derived from a natural product and is completely synthetically obtained can be used. In the present invention, it is preferable to use nucleobases of thymine, uracil, adenine and cytosine.

In this reaction, it is particularly preferable to add tin tetrachloride as a Lewis acid by adding a 1,2-dichloroethane solution of the compound of the above formula (11) to a nucleic acid base activated with a trimethylsilyl group or the like.

Next, the protecting group is removed and the 3'-amino-
The process of producing 3'-deoxynucleoside (7) will be described.

For the elimination of the protecting group, all the conditions used for elimination of the acyl group can be used. In the present invention, an acyl group elimination reaction under basic conditions can be preferably used. For example, the alkaline elimination conditions for the acyl group described in the elimination of R ^{5 in} the above step (b) can be used as they are.
By deprotecting the acyl group under this basic condition, the protecting groups for the amino group and the hydroxyl group can be simultaneously deprotected. As an example, the protecting group can be removed by adding n-butylamine to the compound (12) after the coupling reaction and heating the mixture to react. In this case, the amount of n-butylamine may be 4 equivalents or more, preferably 10 to 200 equivalents, particularly preferably 50 to 200 equivalents. The reaction temperature and reaction time are not particularly limited, but are 30 ° C.
To 100 ° C, especially 50 ° C to 70 ° C, for 1 to 3 days is preferred, and for 2 to 3 days is particularly preferred. As a result, the 3'-amino-3'-deoxynucleoside represented by the above formula (7) can be obtained.

Further, in the present invention, various 3-amino-3
The -deoxy-D-ribono-1,4-lactone derivative (1) can be used as a starting material. Therefore,
When the compound (1) other than the compound (1 ′) is used as a starting material, only the hydroxyl group at the 1-position is protected with an acyl group in the step (B). In the step (D), it may be necessary to deprotect the R ¹ groups separately and independently. In that case, an appropriate elimination reaction is performed depending on the protecting group. For example,
If R ¹ group is a group listed above, since the R ¹ group is a group having the same meaning as R ⁵ groups, mentioned earlier steps (b) R ⁵
The conditions for leaving the group can be applied as they are.

The product obtained in each step of the present invention can be purified by a conventional purification means such as column chromatography or recrystallization. In particular, this first production method has a remarkable feature that the product obtained in each step is easily purified.

In the fourth aspect of the present invention, 3'-amino-
A second method of making a 3'-deoxynucleoside derivative is provided.

The second method for producing the 3'-amino-3'-deoxynucleoside derivative of the present invention will be described below along with each step.

Even in the second production method of the present invention, various 3-amino-3-deoxy-D-ribono-
The 1,4-lactone derivative (1) can be used as a starting material. However, in the present invention, among the compounds represented by formula (1), R ¹ is a hydrogen atom, a protecting group of R ² is an amino group, form an alkylidene group R ^3及 beauty R ⁴ together It is particularly preferable to use the compound described below.
Here, the case where (1 ′) is used as the starting material will be described. Further, in the following description, in order to simplify the description, when the substituent R ² or R ³ together with R ⁴ represents an alkylidene group, R ³ and R ⁴ form an alkylidene group. .

Step (i) is a step of reducing the carbonyl group of the γ-lactone ring of the compound represented by the above formula (1 ′) obtained in the above step (d) to convert it to lactol, This is exactly the same as the first method for producing the 3'-amino-3'-deoxynucleoside derivative.

Also in this step, various 3-amino-3-deoxy-ribono-1,4-lactone derivatives (1) other than the compound (1 ′) are used as starting materials in the same manner as in the above-mentioned first production method. be able to. In this step, among the compounds represented by the formula (1 ′), a compound in which R ² is a protecting group for an amino group and R ³ and R ⁴ together form an alkylidene group is used. Is particularly preferable.

In the step (ii), the protecting group for the hydroxyl group at the 2-position and the protecting group for the amino group at the 3-position of the compound represented by the formula (8) obtained in the step (i) are eliminated, and 1,2
And a hydroxyl group at the 5-position and an amino group at the 3-position are protected with an acyl group to obtain a compound represented by the formula (13).

In the present invention, elimination of the protective groups at the 2- and 3-positions and protection of the hydroxyl groups at the 1,2- and 5-positions and the amino group at the 3-position with an acyl group may be carried out in one step, After deprotection, the deprotected form may be isolated and further acylated.

For example, in the case where the R ³ group and the R ⁴ group together form an alkylidene group, which is particularly preferred in the production method of the present invention, the R ² group is further protected with a t-butoxycarbonyl group. The compounds described above can be deprotected and acylated at the same time. Specifically, the compound (1 ′) substituted as described above is anhydrous in the presence of an inorganic acid such as hydrochloric acid or sulfuric acid or an organic acid such as acetic acid or trifluoroacetic acid in a solvent such as acetic acid. The reaction can be carried out by acting an acylating agent such as acetic acid. The reaction time is 1 to 48 hours, preferably 1 to 24 hours, and the reaction temperature is not particularly limited and is 10 to 50 ° C, preferably 10 to 30 ° C.

On the other hand, the deprotection of the protective groups at the 2 and 3 positions and the acylation may be carried out separately. In this case, the deprotection at the 2- and 3-positions and the acylation of the hydroxyl groups at the 1,2- and 5-positions and the amino group at the 3-position are carried out by the elimination method described in the step (C) of the first production method. The method of acylation can be applied as it is.

As described above, the desired compound (13)
Can be obtained.

In step (iii), the compound (13) obtained in step (ii) is coupled with a nucleobase at the 1-position and further all protecting groups are eliminated to give 3-amino-3'-deoxynucleoside. Is a process of manufacturing.

In this step, the coupling reaction with the nucleic acid base and the method for removing the protective group described in the step (D) of the first production method can be applied as they are.

As a result, 3'represented by the above formula (7) is obtained.
An -amino-3'-deoxynucleoside derivative can be obtained.

The product obtained in each step of the present invention can be purified by a conventional purification means such as column chromatography or recrystallization.

[0187] In the method for producing a 3'-amino-3'-deoxynucleoside derivative of the present invention, the second production method is to obtain the desired compound from compound (1 ') in a short number of steps of 3 steps. It is possible and has excellent economic efficiency.

[0188]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

[0189]

【Example】

Example 1 (Step a) Synthesis of 1,6-anhydro-2-t-butyldiphenylsilyl-4-deoxy-4-t-butylcarbamide-β-D-altropyranose (3a) t-butylcarbamate 3.51 g ( (30 mmol) in 20 ml of methanol, and under ice cooling, t-butyl hypochlorite 3.39 m
l (30 mmol) was gradually added dropwise. After 30 minutes, 1.26 g of sodium hydroxide was dissolved in 40 ml of methanol and added dropwise to this mixed solution. Further, stirring was continued for 1 hour and the solvent was distilled off to obtain a white solid. To this solid was added 80 ml of acetonitrile, 5.21 g (30 mmol) of silver nitrate was added, and the mixture was vigorously stirred for 30 minutes. To this mixed solution, 1,6-anhydro-2-t-butyldiphenylsilyl-3,4-dideoxy-β-D-threo-hex-3-enopyranose (2a) represented by the following formula: 7.21 g (20 mmol) Then, 2 ml (2 mmol) of a t-butyl alcohol solution of osmium tetroxide and 1.7 ml of water were added, and the mixture was stirred at room temperature for 3 days. After the reaction, it was filtered through Celite, and 5%
50 ml of an aqueous sodium sulfite solution was added to the mixture, and the mixture was refluxed for 3 hours. Then, the mixture was concentrated at 50 ° C. or lower, liquid-extracted with dichloromethane, the organic solvent phase was dried, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 2: 1-
The fraction containing impurities was purified by recrystallization with a mixed solvent of hexane-ethyl acetate (3: 1-6: 1) to give 1,6-anhydro-2- represented by the following formula. 5.87 g (yield 59.8%) of t-butyldiphenylsilyl-4-deoxy-4-t-butylcarbamide-β-D-altropyranose (3a) was obtained.

[0190]

Embedded image

(Physical properties) ¹ H-NMR (CDCl ₃ ): δ tBu, 1.42 (9H, s); tBu, 1.0
9 (9H, s); OH, 2.07 (1H, br. D); NH, 4.78 (1H, br.
d); phenyl-o position; 7.75-7.70 (4H, m); phenyl-m, p position;
7.48-7.36 (6H, m); H-1, 5.01 (1H, d, J = 1.6 Hz); H-2,
3.49 (1H, dd, J = 8.2, 1.6 Hz); H-3, 4.05 (1H, m); H-
4, 3.98 (1H, m); H-5, 4.52 (1H, d, J = 5.5Hz); H-6, 3.8
4-3.73 (2H, m). Melting point 170-171.5 ℃ [α] ²⁵ _D -54.3 ° (C = 0.56, CHCl 3) Elemental analysis C ₂₇ H ₃₇ O ₆ NSi theoretical value C: 64.91 H:
7.44 N: 2.80 Found C: 64.80 H: 7.43 N: 2.86 (Step b) 1,6-anhydro-4-deoxy-3,4
-Isopropylidene-4-t-butylcarbamide-β-
Synthesis of D-altropyranose (5a) 1,6-anhydro-2-t-butyldiphenylsilyl-4-deoxy-4-t-butylcarbamide-β-D-
20 ml (163 ml) of 2,2-dimethoxypropane was added to 30 ml of a benzene solution containing 2.4 g (5 mmol) of altropyranose (3a).
mmol) and 10 p-toluenesulfonic acid as an acid catalyst.
0 mg was added and the mixture was refluxed for 3 hours for reaction. After the reaction, aqueous sodium hydrogen carbonate solution and dichloromethane were added to the mixed solution, liquid separation extraction was performed, the organic phase was dried, and the solvent was distilled off.
A residue was obtained. This residue was dissolved in 30 ml of tetrahydrofuran, and 6 ml (6 mmol) of 1.0 M tetrabutylammonium fluoride-tetrahydrofuran solution was added,
It was stirred for 30 minutes. After the reaction, a sodium hydrogen carbonate aqueous solution and dichloromethane were added to the mixed solution, liquid separation extraction was performed, the organic solvent phase was dried, and the solvent was distilled off to obtain a residue. This residue was purified by silica gel column chromatography (hexane-ethyl acetate = 2: 1), and the following formula 1,6-anhydro-4-deoxy-3,4-isopropylidene-4-t was used.
-Butylcarbamide-β-D-altropyranose (5
a) 0.94 g (yield 62.7%) was obtained.

[0192]

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(Physical properties) ¹ H-NMR (CDCl ₃ ): δ tBu, 1.49 (9H, s); Me, 1.72-
1.41 (6H, br. M); OH, 2.48 (1H, d, J = 9.2 Hz)); H-1,
5.53 (1H, d, J = 3.8 Hz); H-2, 4, 6, 3.97-3.71 (4H, m);
H-3, 4.16 (1H, dd, 7.3, 1.9 Hz); H-5, 4.92 (1H, m). IR ν _max (KBr Disk): 3460 (br), 2978 (m), 1694 (s),
1458 (w), 1394 (s), 1369 (s), 1334 (w), 1249 (m), 1158
(s), 1077 (s), 977 (m), 946 (w), 890 (m), 859 (w), 830
(w), 774 (m), 688 (w). Melting point 103-105 ° C [α] ²⁵ _D -218.9 ° (C 0.52, CHCl ₃ ) Elemental analysis C ₁₄ H ₂₃ O ₆ N Theoretical value C: 55.81 H: 7.67
N: 4.64 Found C: 55.64 H: 7.54 N: 4.75 (Step c) 1,6-anhydro-4-deoxy-3,4
-Isopropylidene-4-t-butylcarbamide-β-
Synthesis of D-glyceropyrano-2-ulose (6a) Oxalyl chloride 0.46 g (3.6 mmol) was added to dichloromethane 8
A solution prepared by dissolving 0.64 g (8.2 mmol) of dimethyl sulfoxide in 4 ml of dichloromethane was slowly added dropwise over 5 minutes in a cooling bath at -60 ° C, and the mixture was stirred for 15 minutes. 1,6-anhydro-4-deoxy-3,4-isopropylidene-4-t was added to this mixed solution.
-Butylcarbamide-β-D-altropyranose (5
a) A solution of 0.45 g (1.5 mmol) dissolved in 8 ml of dichloromethane was added dropwise over 3 minutes, and then the mixture was stirred for 40 minutes.
Furthermore, 2.3 g of triethylamine was added, the cooling bath was removed, and the reaction temperature was raised to room temperature. When the reaction solution reached room temperature, water and dichloromethane were added for liquid separation and extraction, the organic solvent phase was dried, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane-ethyl acetate). = 3: 1),
0.40 g (yield 88.3%) of 6-anhydro-4-deoxy-3,4-isopropylidene-4-t-butylcarbamide-β-D-glyceropyrano-2-ulose (6a) was obtained.

[0194]

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(Physical properties) ¹ H-NMR (CDCl ₃ ): δ tBu, 1.53 (9H, s); Me, 1.72-1.
40 (6H, br. M); H-1,5.28 (1H, s); H-3, 4.58 (1H,
d, 7.8 Hz); H-4, 4.30 (1H, d, 7.8 Hz), H-5, 5.50 (1
H, br.s); H-6, 3.93 (1H, s); H-6, 3.91 (1H, s) .IR νmax (KBr Disk): 2976 (m), 2942 (w), 2914 (w) , 1
746 (s), 1694 (s), 1483 (w), 1396 (m), 1371 (s), 1307
(m), 1238 (m), 1174 (m), 1147 (m), 1112 (m), 1093 (m),
969 (s), 922 (w), 888 (w), 872 (m), 808 (m), 756 (m), 62
7 (w). Melting point 159-160.5 ℃ [α] ²⁵ _D -125.5 ° (C 0.51, CHCl ₃ ) Elemental analysis C ₁₄ H ₂₁ O ₆ N Theoretical value C: 56.21 H: 7.05
N: 4.68 Found C: 55.97 H: 6.93 N: 4.70 (Step d) 3-deoxy-2,3-isopropylidene-
Synthesis of 3-t-butylcarbamide-D-ribono-1,4-lactone (1a) 1,6-anhydro-4-deoxy-3,4-isopropylidene-4-t-butylcarbamide-β-D-glyceropyrano -2-Ulose (6a) 0.49 g (1.6 mmol) was dissolved in dichloromethane 2 ml and ice-cooled, and magnesium permonophthalate hexahydrate 0.59 g (1.2 mmol) was dissolved in methanol 4 ml and added. Bring the temperature back to room temperature and stir overnight. After the reaction, the precipitate is filtered off and the solvent of the filtrate is distilled off to obtain a residue. Ethyl acetate was added to this residue, the resulting insoluble material was filtered off, the solvent in the filtrate was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate = 1: 1) to give 3-deoxy. -2,3-Isopropylidene-3-t-butylcarbamide-D-ribono-1,4-lactone (1a) was obtained. As a by-product, 3-deoxy-5-formyl-2,3-isopropylidene-3-t-butylcarbamide-D-ribono-1,4 was used.
-Lactone (1b) was also obtained.

[0196]

[Chemical 38]

(Physical Properties) Compound (1a) ¹ H-NMR (CDCl ₃ ): δ tBu, 1.49 (9H, s); Me, 1.54 (6H,
s); OH, 2.68 (1H, br.s); H-2, 4, 4.91-4.59 (2H, m);
H-3, 4.50 (1H, dd, J = 15.6, 7.1 Hz); H-5, 4.08-3.71
(2H, m) .IR ν _max (KBr Disk): 3440 (m), 2984 (m), 2942 (w), 1
789 (s), 1713 (s), 1692 (s), 1479 (w), 1460 (w), 1381
(s), 1371 (s), 1253 (s), 1170 (s), 1108 (w), 1085 (s),
1019 (w), 984 (w), 920 (w), 847 (w), 810 (w), 772 (w). Compound (1b) ¹ H-NMR (CDCl ₃ ): δ tBu, 1.50 (9H, s); Me, 1.55 (6H,
s); H-2, 4, 5.04-4.71 (2H, m); H-3, 5, 4.61-3.95 (3
H, m); CHO, 8.06 (1H, s). IR ν _max (KBr Disk): 2976 (w), 1787 (s), 1727 (s), 1
707 (s), 1460 (w), 1390 (s), 1371 (s), 1251 (m), 1191
(w), 1170 (s), 1112 (m), 1085 (m), 1062 (w), 942 (w), 8
47 (w), 770 (w), 752 (w), 669 (w). Example 2 This example uses chloramine-T as a co-oxidant in the cis-aminohydroxylation reaction of step a. And was carried out by a reaction similar to that in Example 1.

(Step a) 1,6-anhydro-2-O-
t-butyldiphenylsilyl-4-deoxy-4-p-
Synthesis of Toluenesulfonamide-β-D-Altropyranose (3b) 1,6-Anhydro-2-Ot-butyldiphenylsilyl-3,4-dideoxy-β-D-threo-hexo-
4.12 g (11.25 mmol) of 3-enopyranose (2a) was added to t
-Butyl alcohol was dissolved in 54 ml, and to this was added an aqueous solution of 3.18 g of chloramine-T.trihydrate dissolved in 54 ml of water. Then t of 0.1 molar osmium tetroxide
-Butyl alcohol solution (9 ml) was added, and the mixture was stirred at room temperature for 18 hours. After adding 9 ml of 45% sodium thiosulfate aqueous solution and stirring at room temperature for 10 minutes, the solvent was distilled off from the reaction solution under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate = 4: 1). ), 1,6-anhydro-represented by the following formula:
2-Ot-butyldiphenylsilyl-4-deoxy-
4.11 g (yield 74.2%) of 4-p-toluenesulfonamide-β-D-altropyranose (3b) was obtained. this is,
It was recrystallized from a mixed solvent of hexane-ethyl acetate.

[0199]

[Chemical Formula 39]

(Physical properties) Melting point: 156.5-160.0 ° C. [α] ²⁸ _D -52.0 ° (C 0.96, CHCl ₃ ) IR ν _max (KBr Disk) 3572 (m), 3542 (m), 3250
(m), 3074 (m), 3048 (m), 2956 (s), 2896 (m), 2862
(m), 1968 (w), 1901 (w), 1754 (w), 1601 (w), 1591
(w), 1489 (m), 1470 (m), 1446 (m), 1429 (m), 1400
(m), 1348 (m), 1332 (s), 1307 (m), 1274 (w), 1234
(w), 11 74 (s), 1122 (s), 1093 (s), 1004 (s), 977
(m), 938 (s), 861 (s), 818 (s), 783 (s), 743 (s),
702 (s), 681 (s), 658 (w), 630 (m), 613 (m), 578
(w), 555 (m), 545 (m), 503 (s) ¹ H-NMR: δ t-Bu; 1.07 (9H, s), OH; 1.94 (1H, d, J
= 7.5 Hz), NH; 4.89 (1H, d, J = 7.4 Hz), CH ₃ of Ts;
2.43 (3H, S), aromatic ring of Ts and Ph; 7.73-7.67 (6H,
m), 7.48-7.37 (6H, m), 7.30 (2H, d, J = 8.4 Hz),
1st place; 4.98 (1H, d, J = 1.5 Hz), 2nd place; 3.39 (1H, dd,
J = 8.4, 1.5 Hz), 3rd place; 3.90 (1H, ddd, J = 8.
4, 7.5, 5.7 Hz), 4th place; 3.49 (1H, ddd, J = 7.4,
5.7, 2.2 Hz), 5th place; 4.25 (1H, ddd, J = 4.8, 2.6,
2.2 Hz), 6-position; 3.72-3.65 (2H, m) (step b) 1,6-anhydro-2-Ot-butyldiphenylsilyl-4-deoxy-3,4-O, N-isopropylidene- 4-p-toluenesulfonamide-β-D
-Synthesis of altropyranose (4b) 1,6-anhydro-2-Ot-butyldiphenylsilyl-4-deoxy-4-p-toluenesulfonamide-
β-D-Altropyranose (3a) 7.50 g (13.54 mm
ol) was dissolved in 90 ml of toluene, and 8.47 g (81.33 mmol) of 2,2-dimethoxypropane and 0.04 g (0.21 mmol) of p-toluenesulfonic acid monohydrate were added thereto, and the mixture was kept in an argon atmosphere for 1 hour. The mixture was heated to reflux (at this time, the toluene solvent liquefied by the cooling device was passed through zeolite A-4 and returned to the reaction system to adsorb and remove methanol and water generated by the reaction, thereby removing methanol and dehydration in the reaction system. Operation was performed). After allowing to cool, the reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatograph (hexane-ethyl acetate = 4: 1) to give 1,6-anhydro-2.
-Ot-butyldiphenylsilyl-4-deoxy-
3,4-O, N-isopropylidene-4-p-toluenesulfonamide-β-D-altropyranose (4b) 8.
08 g was quantitatively obtained.

[0201]

[Chemical 40]

(Physical properties) Melting point: 49.0-51.0 ° C. [α] ²⁷ _D -89.8 ° (C 0.90, CHCl ₃ ) IR ν _max (KBr Disk) 3074 (s), 3052 (s), 2936
(s), 2898 (s), 2862 (s), 2744 (w), 2712 (w), 2590
(w), 2322 (w), 1966 (w), 1910 (w), 1829 (w), 1777
(w), 1738 (w), 1738 (w), 1657 (w), 1601 (s), 1570
(w), 1475 (s), 1431 (s), 1334 (br), 1296 (s), 1234
(s), 1 093 (br), 982 (br), 959 (s), 884 (s), 855
(s), 822 (s), 795 (s), 743 (s), 677 (br), 644 (s),
611 (s), 598 (s), 576 (s), 553 (s), 487 (s), 418
(s) ¹ H-NMR: δ CH ₃ of Isop; 1.53 (3H, S), 1.44 (3H,
S), CH ₃ of Ts; 2.41 (3H, S), aromatic ring of Ts and Ph; 7.7
2-7.65 (6H, m), 7.45-7.34 (6H, m), 7.25 (2H, d, J
= 8.3 Hz), 1st place; 4.93 (1H, d, J = 2.6 Hz), 2nd place;
3.72 (1H, dd, J = 5.4, 2.6 Hz), 3rd place; 4.32 (1H, dd,
J = 7.0, 5.4 Hz), 4th place; 3.81 (1H, d, J = 7.0 H
z), 5-position; 4.82 (1H, br), 6-position; 3.77-3.74 (2H, m) (continued from step b) 1,6-anhydro-4-deoxy-
Synthesis of 3,4-O, N-isopropylidene-4-p-toluenesulfonamide-β-D-altropyranose (5b) 1,6-anhydro-2-Ot-butyldiphenylsilyl-4-deoxy 8.08 g (13.61 mmol) of 3,3,4-O, N-isopropylidene-4-p-toluenesulfonamide-β-D-altropyranose (4b) was dissolved in 150 ml of tetrahydrofuran, and tetrabutylammonium fluoride was added thereto. 1 molar solution of tetrahydrofuran 1
5.3 ml was added, and the mixture was stirred at room temperature for 5 hours in an argon atmosphere. Amberlite IR-120B (H
⁽⁺ Type) cation exchange resin was added to trap tetrabutylammonium ion, saturated aqueous sodium hydrogencarbonate solution was added thereto, and the solvent was distilled off under reduced pressure. The residue was purified by using a silica gel column chromatograph (hexane-ethyl acetate = 1: 5), and 1,6 represented by the following formula
-Anhydro-4-deoxy-3,4-O, N-isopropylidene-4-p-toluenesulfonamide-β-D-
4.39 g (91.2%) of altropyranose (5b) was obtained. This was recrystallized from a hexane-methylene chloride mixed solvent.

[0203]

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(Physical properties) Melting point: 174.0-174.6 ° C. [α] ²⁷ _D -109 ° (C 0.32, CHCl ₃ ) IR ν _max (KBr Disk) 3438 (s), 3030 (w), 2996
(w), 2946 (m), 2366 (w), 1601 (w), 1493 (w), 1469
(w), 1373 (w), 1359 (m), 1342 (s), 1309 (w), 1290
(w), 1276 (w), 1255 (w), 1236 (m), 1214 (m), 1172
(m), 1156 (s), 1137 (m), 1108 (s), 1094 (s), 1083
(m), 10 25 (m), 1015 (m), 996 (w), 967 (m), 940
(w), 872 (w), 864 (w), 841 (w), 826 (w), 810 (w),
797 (w), 729 (w), 708 (w), 700 (w), 671 (s), 638
(w), 600 (s), 580 (s), 555 (s), 487 (w), 443 (w),
408 (w) ¹ H-NMR: δ CH ₃ of Isop; 1.72 (3H, S), 1.53 (3H,
S), CH ₃ of Ts; 2.45 (3H, S), Ts aromatic ring; 7.76 (2
H, d, J = 8.2 Hz), 7.33 (2H, d, J = 8.2 Hz), OH;
2.37 (1H, d, J = 2.4 Hz), 1st place; 5.46 (1H, d, J =
3.9 Hz), 2nd and 4th; 3.82-3.75 (2H, m), 3rd;
4.08 (1H, dd, J = 7.0, 2.9 Hz), 5th place; 4.84 (1H, d
d, J = 5.3, 1.2 Hz), 6th place; 3.79 (1H, d, J = 8.0 H
z), 3.73 (1H, dd, 8.0, 1.2 Hz) (Step c) 1,6-anhydro-4-deoxy-3,4
Synthesis of -O, N-isopropylidene-4-p-toluenesulfonamide-β-D-ribo-hex-2-pyranourose (6b) Oxalyl chloride 7.71 ml (78.00 mmol) was dissolved in dry methylene chloride 205 ml. Then, a solution prepared by dissolving 12.75 ml (175.39 mmol) of dimethyl sulfoxide in 41 ml of dry methylene chloride was added dropwise thereto at −70 ° C. in a nitrogen atmosphere. Two
After stirring for 1 minute, 1,6-anhydro-4-deoxy-3,
4-O, N-isopropylidene-4-p-toluenesulfonamide-β-D-altropyranose (5b) 27.72
A solution of g (78.00 mmol) in 181 ml of dry methylene chloride was added dropwise. After further stirring for 1.5 hours, 60.00 ml (429.0 mmol) of triethylamine was added dropwise and stirred for 5 minutes. Then, the temperature is raised to room temperature, the solvent is distilled off from the reaction solution under reduced pressure, and the residue is purified by using a silica gel column chromatograph (hexane: ethyl acetate = 1: 1) to obtain a compound represented by the following formula 1 , 6-Anhydro-4-deoxy-3,4-O, N-isopropylidene-4-p-
27.01 g (yield 98.0%) of toluenesulfonamide-β-D-ribo-hex-2-pyranourose (6b) was obtained. This was recrystallized from a hexane-methylene chloride mixed solvent.

[0205]

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(Physical properties) Melting point: 190.4-192.0 ° C. [α] ²⁷ _D -169 ° (C 0.95, CHCl ₃ ) IR ν _max (KBr Disk) 3428 (w), 2974 (w), 2910
(w), 1756 (s), 1601 (m), 1493 (w), 1460 (w), 1390
(w), 1359 (s), 1342 (s), 1303 (w), 1261 (w), 1220
(s), 1154 (s), 1120 (s), 1087 (s), 1038 (s), 1023
(s), 973 (s), 922 (s), 872 (m), 859 (m), 835 (m),
808 (s), 787 (m), 708 (s), 669 (s), 642 (s), 584
(s), 565 (w), 549 (s), 526 (w), 485 (w), 439 (w) ¹ H-NMR: δ CH ₃ of Isop; 1.63 (3H, S), 1.57 (3H,
S), CH ₃ of Ts; 2.45 (3H, S), Ts aromatic ring; 7.76 (2
H, d, J = 8.2 Hz), 7.33 (2H, d, J = 8.2 Hz), 1st place;
5.56 (1H, s), 3rd place; 4.30 (1H, d, J = 7.6 Hz), 4
Position; 4.61 (1H, dd, J = 7.6, 0.7 Hz), 5th position; 5.31 (1
H, d dd, J = 3.2, 3.2, 0.7 Hz), 6th place; 3.94 (2H, d,
J = 3.2 Hz) (Step d) 3-deoxy-2,3-O, N-isopropylidene-3-p-toluenesulfonamide-D-ribo-
Synthesis of 1,4-lactone (1c) 1,6-anhydro-4-deoxy-3,4-O, N-
Isopropylidene-4-p-toluenesulfonamide-β
-D-ribo-hex-2-pyranourose (6a) 6.55
g (18.55 mmol) of methylene chloride 56 ml and methanol 1
Dissolve in 67 ml, and in an ice bath magnesium monoperoxyphthalate (hexahydrate) 11.05 g (80%, 17.88 mmol)
Was added, and the mixture was stirred at room temperature for 2 days in an argon atmosphere. After removing the precipitate by filtration, the solvent was distilled off from the filtrate under reduced pressure and the residue was dried, and the residue was purified using a silica gel column chromatograph (hexane: ethyl acetate = 2-1: 1). 5.08 g (yield 80.2%) of 3-deoxy-2,3-O, N-isopropylidene-3-p-toluenesulfonamido-D-ribo-1,4-lactone (1c) represented by the formula was obtained. It was This was recrystallized from a hexane-methylene chloride mixed solvent.

[0207]

[Chemical 43]

(Physical properties) Melting point: 158.0-160.0 ° C. [α] ²⁷ _D -89.3 ° (C 0.51, CHCl ₃ ) IR ν _max (KBr Disk) 3460 (br), 3014 (m), 2984
(m), 2928 (m), 2878 (m), 1775 (s), 1601 (m), 1493
(w), 1464 (w), 1402 (w), 1375 (s), 1348 (s), 1307
(w), 1259 (m), 1218 (s), 1154 (s), 1122 (s), 1091
(s), 1079 (s), 1062 (m), 1040 (s), 1015 (s), 990
(m), 96 5 (m), 920 (m), 870 (m), 837 (m), 806 (m),
774 (m), 712 (s), 671 (s), 640 (w), 627 (w), 601
(s), 561 (s), 549 (s), 497 (w), 474 (w) ¹ H-NMR: δCH ₃ of Isop; 1.61 (3H, S), 1.50 (3H,
S), CH ₃ of Ts; 2.45 (3H, S), aromatic ring of Ts; 7.75-7.72
(2H, m), 7.35 (2H, dd, J = 8.2, 0.4 Hz), OH; 2.
33 (1H, dd, J = 5.7, 5.0 Hz), 2nd place; 4.80 (1H, d, J
= 7.5 Hz), 3rd place; 4.56 (1H, dd, J = 7.5, 1.2 Hz),
4th; 5.03 (1H, br), 5th; 4.02 (1H, ddd, J = 12.
2, 5.0, 2.2 Hz), 3.91 (1H, ddd, J = 12.2, 5.7, 1.3
Hz) ¹³ C-NMR: δ 174.4 (1C), 144.5 (1C), 137.3 (1C), 1
30.04 (2C), 127.5 (2C), 100.4 (1C), 85.3 (1C), 74.
7 (1C), 62.2 (1C), 61.0 (1C), 29.5 (1C), 25.6 (1
C), 21.6 (1C) Example 3 <3-1> (Step A) 3-deoxy-2,3-isopropylidene-
Synthesis of 3-t-butylcarbamide-D-ribose (8a) 3-deoxy-2,3-isopropylidene-3-t-butylcarbamyl-ribono-1,4-lactone (1a) and 3-deoxy. A mixture of -5-formyl-2,3-isopropylidene-3-t-butylcarbamyl-ribono-1,4-lactone (1b) (0.25 g) was dissolved in distilled tetrahydrofuran (35 ml), and the temperature was adjusted to -78 ° C. , 1.5 M
Diisobutylaluminium hydride 3.5 ml (5.3 mmo
l) was added dropwise little by little and stirred for 1 hour. After the reaction, a small amount of water was added to raise the temperature of the reaction solution to room temperature, and when bubbles were not generated, a large amount of tetrahydrofuran was added and the mixture was dried over magnesium sulfate, and the insoluble material was filtered off. The filtrate was mixed with a washing solution that was sufficiently recovered from an insoluble matter with an organic solvent such as tetrahydrofuran and chloroform, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 1: 1). Purified and represented by the following formula: 3-deoxy-2,3-isopropylidene-3-t-butylcarbamide-D-ribose (8a) 0.15 g (step d of Example 1 and two steps of this step) (Total yield of 31%) was obtained.

[0209]

[Chemical 44]

(Physical properties) ¹ H-NMR (CDCl ₃ ): δ tBu, 1.48 (9H, s); Me, 1.69,
1.63, 1.59, 1.45 (1.5H, s); H-1, 5.44, 5.40 (0.5H,
α and β, s); H-2, 4, 4.58-4.45 (2H, m); H-3,
4.33 (1H, m); H-5, 3.96-3.71 (2H, m). IR ν _max (Film): 3396 (br), 2980 (m), 2940 (m), 1707
(s), 1688 (s), 1475 (w), 1460 (w), 1396 (s), 1369 (s), 1
257 (m), 1214 (w), 1160 (m), 1077 (s), 880 (w), 864 (w),
770 (w). [Α] ²⁵ _D -52.7 ° (C 0.27, CHCl ₃ ) Elemental analysis C ₁₃ H ₂₃ O ₆ N Theoretical value C: 53.98 H: 7.99
N: 4.84 Found C: 53.92 H: 7.73 N: 4.86 (Step B) 3-deoxy-2,3-isopropylidene-
1,5-dibenzoyl-3-t-butylcarbamyl-D
-Ribose (9a) 3-deoxy-2,3-isopropylidene-3-t-butylcarbamyl-D-ribose (8a) 63 mg (0.22 mmo
l) was dissolved in 2 ml of dry pyridine, and 99 mg (0.70 mmol) of benzoyl chloride was dissolved in 2 ml of dry pyridine and added dropwise under ice cooling, and the mixture was stirred at room temperature overnight. After the reaction, the mixture was dried under reduced pressure, sodium borohydride aqueous solution and chloroform were added to the residue, and liquid separation extraction was performed. After the organic solvent phase was dried, the solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate = 2: 1) to give 1,5-benzoyl-3 represented by the following formula. −
Deoxy-2,3-isopropylidene-3-t-butylcarbamyl-D-ribose (9a) 98 mg (yield 90.9%)
I got

[0211]

Embedded image

(Physical properties) ¹ H-NMR (CDCl ₃ ): δ Phenyl-o position, 8.14-7.86 (4H, m);
Phenyl-m, p position, 7.64-7.31 (6H, m); tBu, 1.48 (9H,
s); Me, 1.76-1.43 (6H, br.m); H-1, 6.55 (1H, d, J = 6.0
Hz); H-2, 4.85 (1H, d, J = 6.1 Hz); H-3, 4,5, 4.81
-4.35 (4H, m). IR νmax (KBr Disk): 2980 (m), 1794 (w), 1723 (s), 1
603 (w), 1586 (w), 1560 (w), 1543 (w), 1508 (w), 1454
(m), 1369 (m), 1317 (m), 1272 (s), 1164 (m), 1091 (w),
1069 (m), 1027 (m), 946 (m), 864 (w), 804 (w), 772 (w),
710 (s), 687 (w). [Α] ²⁵ _D 6.5 ° (C 0.16, CHCl ₃ ). (Step C) 3-Amino-3-deoxy-1,2,5-tribenzoyl-3-trifluoro Synthesis of acetyl-D-ribose (11a) To 98 mg (0.2 mmol) of 1,5-benzoyl-3-deoxy-2,3-isopropylidene-3-t-butylcarbamyl-D-ribose (9a) was obtained. 0.5% (3.9 mmol) of 90% trifluoroacetic acid aqueous solution was added, and the mixture was vigorously stirred at room temperature for 3 hours, and then volatile components were sufficiently distilled off under reduced pressure.
A residue was obtained. To this residue, 1 ml of dry pyridine and 0.75 ml (5.3 mmol) of trifluoroacetic anhydride were added under ice cooling, and then stirred at room temperature for 3 days. After the reaction, the volatile components were distilled off under reduced pressure, water was added, and sodium borohydride was added little by little until the pH reached about 7. Further, dichloromethane was added, liquid separation extraction was carried out, the organic solvent phase was dried, and then the solvent was distilled off under reduced pressure to obtain a residue. This residue was subjected to a simple purification operation by silica gel column chromatography (hexane-ethyl acetate = 3: 2), the obtained mixture was dissolved in 2 ml of dry pyridine, and 0.1 g of benzoyl chloride was added.
(0.7 mmol) was added under ice cooling, the temperature was returned to room temperature, and the mixture was stirred overnight. After the reaction, the volatile components were sufficiently distilled off under reduced pressure, water and dichloromethane were added to the obtained residue, liquid separation extraction was carried out, the organic solvent phase was dried, and then the solvent and volatile components were distilled off, and the residue was removed. Got This residue was purified by silica gel column chromatography (hexane-ethyl acetate = 3: 1), and 3-amino-3-deoxy-1,2,5-tribenzoyl-3-trifluoroacetyl- represented by the following formula. 62 mg (yield 56.5%) of D-ribose (11a) was obtained.

[0213]

Embedded image

(Physical properties) ¹ H-NMR (CDCl ₃ ): δ Phenyl-o position, 8.18-7.88 (6H, m);
Phenyl-m, p position, 7.69-7.28 (9H, m); CF ₃ CONH, 6.74 (1
H, d, J = 8.4 Hz); H-1, 6.59 (1H, s); H-2, 5.73 (1H,
d, J = 4.8 Hz); H-3, 5.21 (1H, ddd, J = 8.6, 8.6, 4.8 H
z); H-4, 4.63 (1H, m); H-5, 4.71 (1H, dd, J = 3.8, 11.7
Hz); H-5, 4.51 (1H, dd, J = 11.8, 4.5 Hz). IR ν _max (KBr Disk): 1731 (s), 1655 (w), 1636 (w), 1
603 (m), 1560 (m), 1508 (w), 1491 (w), 1475 (w), 1454
(w), 1421 (m), 1396 (w), 1319 (m), 1270 (s), 1180 (m),
1096 (m), 1069 (m), 1025 (m), 948 (m), 748 (w), 708 (s),
687 (w), 518 (w). Elemental analysis C ₂₈ H ₂₂ O ₈ F ₃ N theoretical value C: 60.33 H:
3.96 N: 2.51 Actual value C: 60.46 H: 4.13 N: 2.57 [α] ²⁵ _D 43.5 ° (c 0.24, CHCl ₃ ) (Process D) Synthesis of 3'-amino-3'-deoxyadenosine (7a) Argon stream N ⁶ -benzoyl adenine 35.9 mg (0.
15 mmol), a mixed solution of 0.75 ml of 1,1,1,3,3,3-hexamethyldisilazane and 0.33 ml of dry pyridine was added, and the mixture was heated and refluxed for 4 hours. Then, the reaction solution was air-cooled, the volatile components were sufficiently distilled off under reduced pressure, and 0.9 ml of distilled 1,2-dichloroethane was added to the obtained residue.
3-amino-3-deoxy-1,2,5-
44.0 mg (0.08 mmol) of tribenzoyl-3-trifluoroacetyl-D-ribose (9a) was dissolved in 1.5 ml of distilled 1,2-dichloroethane and added, and 0.2 ml of a 1M tin tetrachloride-dichloromethane solution (0.20 mmol). ),
Stir overnight under reflux conditions. After completion of the reaction, distilled 1,2-dichloroethane was added to the reaction solution, solids were filtered off, 1,2-dichloroethane and sodium borohydride aqueous solution were added to the filtrate, and liquid separation extraction was performed. Further, the aqueous phase was extracted several times with a mixed solution of chloroform-methanol = 20: 1, these organic solvent phases were mixed and dried, and then the solvent was distilled off under reduced pressure to obtain a residue. The residue was purified by silica gel (Iatro beads) column chromatography (chloroform-methanol = 20: 1),
7.2 mg of 29.7 mg of the obtained solid was added to n-butylamine.
30 μl and 200 μl of methanol were added and refluxed for 3 days.
After the reaction, the solvent and volatile components were distilled off, the residue was thoroughly washed with methanol and dichloromethane, and dried under reduced pressure to give 3'-amino-3'-deoxyadenosine (7a) 2.6 mg represented by the following formula. (Yield 50.9%) was obtained.

(Physical properties) ¹ H-NMR (D ₂ O): δ H-8, 8.21 (1 H, s); H-2, 8.10 (1
H, s); H-1 ', 5.98 (1H, d, J = 3.2 Hz); H-2', 4.51 (1
H, dd, J = 5.6, 3.2 Hz); H-3 ', 3.52 (1H, dd, J = 7.2,
5.6 Hz); H-4 ', 3.97 (1H, m); H-5', 3.84 (1H, dd, J = 1
2.9, 2.3 Hz); H-5 ', 3.69 (1H, dd, J = 13.0, 4.0 Hz). Melting point 266-268 ° C [α] ²⁵ _D -36.3 ° C (C 0.20, 0.1N HCl)

[Chemical 47]

<3-2> (Step D) 3'-amino-3'-deoxycytidine (7
Synthesis of b) N ⁴ acetylcytosine 459 mg (0.15 mm) in an argon stream.
ol), a mixed solution of 20 ml of 1,1,1,3,3,3-hexamethyldisilazane and 1.0 ml of trimethylsilyl chloride was added, and the mixture was heated and refluxed for 2 hours and 20 minutes. Then, the reaction liquid was air-cooled and the volatile components were sufficiently distilled off under reduced pressure. To the obtained residue, 2.0 g of Molecular Sieves 4A was added and further dried. Then, 950 mg of 3-amino-3-deoxy-1,2,5-tribenzoyl-3-trifluoroacetyl-D-ribose represented by the above formula (11a).
A solution of (2.56 mmol) in 50 ml of distilled 1,2-dichloroethane was added, 10 ml (10 mmol) of 1M tin tetrachloride-dichloromethane solution was further added, and the mixture was stirred overnight under reflux conditions. After completion of the reaction, the reaction solution was poured into an aqueous sodium borohydride solution, a chloroform-methanol 10: 1 solution was further added, and liquid separation extraction was performed 5 times. After drying the organic solvent layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol = 10: 1). next,
To the obtained solid (616 mg) were added methanol (18.8 ml) and 0.1N sodium methoxide (18.8 ml), and the mixture was reacted at 80 ° C for 2 hours.
After the reaction, the solvent and volatile components were distilled off, and the obtained residue was subjected to silica gel (iatro beads) column chromatography (chloroform-methanol-ammonia water = 60:
The resulting product was purified by 20: 1) to obtain 171 mg of 3'-amino-3'-deoxycytidine (7b) represented by the following formula. Furthermore, unreacted product was recovered and methanol 18.8 ml and 0.1N
After adding 18.8 ml of sodium methoxide and reacting at 80 ° C. for 4 days, 1.9 ml of 1N sodium methoxide was added and reacted at 80 ° C. for 1 day. After the reaction, the solvent and the volatile components were distilled off, and the obtained residue was purified by silica gel (Iatro beads) column chromatography (chloroform-methanol-ammonia water = 60: 20: 1) and represented by the following formula 3 '-Amino-3-deoxycytidine was obtained. The total yield of 3'-amino-3-deoxycytidine (7b) in this step was 310 mg (yield 56.1%).

(Physical properties) ¹ H-NMR (D ² O): δ H-6, 7.90 (1 H, d, J = 7.6 Hz); H
-5, 5.99 (1H, d, J = 7.6Hz); H-1 ', 5.81 (1H, d, J = 1.5
Hz); H-2 ', 4.25 (1H, dd, J = 5.5, 1.4Hz); H-3', 3.37
(1H, dd, J = 9.2, 5.5Hz); H-4 ', 4.03 (1H, m); H-5',
3.99 (1H, m), H-5 ', 3.83 (1H, dd, J = 12.9, 4.4Hz).

Embedded image

<3-3> (Step D) 3'-amino-3'-deoxyuridine (7
c) Synthesis of uracil 544 mg (4.86 mmol) in an argon stream
A mixed solution of 30 ml of 1,1,3,3,3-hexamethyldisilazane and 1.0 ml of trimethylsilyl chloride was added, and the mixture was heated and refluxed for 2 hours and 45 minutes. Then, the reaction liquid was air-cooled and the volatile components were sufficiently distilled off under reduced pressure. In the obtained residue,
1.0 g (2.70 mmol) of 3-amino-3-deoxy-1,2, -tribenzoyl-3-trifluoroacetyl-D-ribose represented by the above formula (11a) was distilled.
-Add the one dissolved in 45 ml of dichloroethane and add 1 more
Tin tetrachloride-dichloromethane solution of M 5.7 ml (5.70 mmo
l) was added and the mixture was stirred overnight under reflux conditions. After the reaction was completed, the reaction solution was poured into an aqueous sodium borohydride solution,
Further, a chloroform-methanol = 10: 1 solution was added and liquid separation extraction was performed three times. After the organic solvent layer was subjected to dry treatment, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol 10: 1). Out of 746 mg of the obtained solid
498 mg was taken, 16.8 ml of methanol and 16.8 ml of 0.1N sodium methoxide were added thereto, and the mixture was reacted at 80 ° C. overnight. After the reaction, the solvent and volatile components were distilled off, and the resulting residue was subjected to silica gel (iatro beads) column chromatography (chloroform-methanol-aqueous ammonia = 60: 2).
0: 1) and 3′-amino-3′-deoxyuridine (7c) represented by the following formula: 286 mg (yield 65.2%
) Got.

(Physical properties) ¹ H-NMR (D ₂ O) δ H-6, 7.89 (1 H, d, J = 8.2 Hz); H-
5, 5.88 (1H, d, J = 7.9Hz); H-1 ', 5.87 (1H, d, J = 2.8H
z); H-2 ', 4.51 (1H, dd, J = 6.0,2.7Hz); H-3', 3.69 (1
H, dd, J = 7.9,6.3Hz); H-4 ', 4.19 (1H, m); H-5', 3.99
(1H, dd, J = 12.9, 2.7Hz); H-5 ', 3.84 (1H, dd, J = 12.9,
4.2Hz).

[Chemical 49]

Example 4 (Step i) 3-Amino-3-deoxy-1,2,3,5
-Tetraacetyl-D-ribose (13a) Synthesis of 3-deoxy-2,3-isopropylidene-3-t-butylcarbamide-D-ribose (8a) 46 mg (0.16 mmol) obtained in Step A of Example 3 Acetic acid 1.2 ml and acetic anhydride
0.5 ml was added, this was ice-cooled, and then 3 drops of sulfuric acid were added with a Pasteur pipette. The mixed solution was returned to room temperature and stirred overnight. Then, the reaction solution was poured into a saturated sodium borohydride aqueous solution, and when the pH was 7 or lower, sodium borohydride was added until the pH became 7 or higher. Chloroform was added to this solution, liquid separation and extraction operations were performed, the organic solvent layer was briefly treated with magnesium sulfate, and thin layer chromatography confirmed that the components of the solution were single, and the solvent was removed. And vacuum dried to give 3-amino-3-deoxy-1,2,3,5-tetraacetyl-D represented by the following formula.
-44 mg (87.1% yield) of ribose (13a) was obtained.

[0221]

Embedded image

(Physical properties) ¹ H-NMR (CDCl ₃ ): δ H-1 (α-OAc), 6.44 (0.22H, d,
J = 4.3 Hz); H-1 (β-OAc), 6.12 (0.78H, s); CONH
(α), 5.96 (0.22H, d, J = 7.7 Hz); CONH (β), 5.65
(0.78H, d, J = 8.9 Hz); H-2 (α), 5.26 (0.22H, dd, J =
7.7, 4.3 Hz); H-2 (β), 5.08 (0.78H, d, J = 4.9 Hz);
H-3 (β), 4.89 (0.78H, ddd, J = 8.9, 8.9, 4.6 Hz); H-
3 (α), 4.63 (0.22H, ddd, J = 7.9, 7.9, 3.9 Hz); H-4,
5, 4.11-4.05 (3H, m); CH ₃ CO, 2.24-1.98 (12H, m). IR ν _max (film): 1746 (s), 1663 (m), 1543 (m), 1435
(w), 1375 (m), 1224 (s), 1106 (w), 1071 (w), 1027 (m), 9
67 (w). (Step ii) 9- (3-amino-3-deoxy-2,3,
Synthesis of 5-triacetyl-D-ribosyl) -N ⁶ -benzoyladenine (14a) N ⁶ -benzoyladenine 155.0 mg in an argon stream.
To (0.65 mmol), 5.0 ml of 1,1,1,3,3,3-hexamethyldisilazane and 1.1 ml of dry pyridine were added, heated and refluxed for 3 hours. Then, the reaction liquid was air-cooled and the volatile component was distilled off under reduced pressure. To the obtained residue, 3-amino-3-deoxy-1,2,3,5-tetraacetyl-D
A solution of 151. mg (0.48 mmol) of ribose dissolved in 15 ml of distilled 1,2-dichloroethane was added. Further, 0.85 ml of 1M tin tetrachloride-dichloromethane solution was added, and the reaction was carried out at 70 ° C. overnight. After the reaction was completed, a chloroform-ethanol = 10: 1 solution was added to the reaction solution, and the solid was separated by filtration.
50 ml of a saturated sodium hydride aqueous solution was added to the filtrate, the mixture was stirred, and a chloroform-methane ball = 10: 1 solution was further added for liquid separation and extraction. This liquid separation extraction operation was repeated 3 times, the organic solvent layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-methanol = 15: 1), and further purified by NH silica (silica gel surface aminopropylated) gel column chromatography (chloroform-methanol = 20: 1). 9- (3
-Amino-3-deoxy-2,3,5-triacetyl-
D-ribosyl) -N ⁶ -benzoyladenine (14a)
103.1 mg (yield 43.6%) and 9- (3-amino-3-deoxy-2,3,5-triacetyl-D-ribosyl) adenine (14b) 20.8 mg (yield 11.1%) were obtained. (14
Total yield of a and 14b 54.7%)

[Chemical 51]

(Physical Properties) Compound (12a): ¹ H-NMR (CDCl ₃ ): δ Ph-o, 8.03 (2H, d, J = 7.0 Hz) ,; P
hm, p, 7.63-7.50 (3H, m); PhCONH, 8.98 (1H, s); MeC
ONH, 5.60 (1H, d, J = 8.8 Hz); H-8, 8.85 (1H, s); H-
2, 8.16 (1H, s); H-1 ', 6.11 (1H, d, J = 1.7 Hz); H-
2 ', 5.76 (1H, dd, J = 6.1, 1.8 Hz); H-3', 5.42 (1H,
m); H-4 ', 5', 4.33-4.37 (2H, m); H-5 ', 4.55 (1H, d,
J = 10.1 Hz), CH ₃ CO, 2.23 (3H, s); CH ₃ CO, 2.08 (6
H, s). IR νmax (KBr Disk): 1738 (m), 1657 (w), 1613 (w), 1
578 (w), 1510 (w), 1456 (w), 1377 (w), 1228 (w), 1052
(m). [α] ²⁵ _D -4.7 ° (C 0.21, MeOH). Compound (12b) ¹ H-NMR (CDCl ₃ + CD ₃ OD): δ H-8, 8.25 (1H, s); H- 2,
8.04 (1H, s); MeCONH, 7.39 (1H, d, J = 8.7 Hz); H-
1 ', 6.04 (1H, d, J = 2.6 Hz); H-2', 5.53 (1H, dd, J =
6.2, 2.6 Hz); H-3 ', 5.06 (1H, m); H-4', 5 ', 4.32-4.
12 (2H, m); H-5 ', 4.40 (1H, dd, J = 14.4, 4.5 Hz), CH
₃ CO, 2.12 (3H, s); CH ₃ CO, 2.04 (3H, s); CH ₃ CO,
1.97 (3H, s). (Step iii) Synthesis of 3′-amino-3′-deoxyadenosine (7) 9- (3-amino-3-deoxy-2,3,5-triacetyl-D-ribosyl- N ⁶ -benzoyl adenine (1
2a) 0.3 ml of 4.1N sodium methoxide-methanol solution was added to 20.2 mg (0.04 mmol), and 1.3 m of methanol was added.
l was added, and the mixture was reacted under reflux conditions for 15 hours. After the reaction,
Chloroform-methanol-25% aqueous ammonia = 6
About 2 ml of a mixed solution of 0: 20: 1 was added, and the mixture was purified by iatrobeads column chromatography (chloroform-methanol-25% ammonia water = 30: 10: 1).
3'-amino-3'-deoxyadenosine (7) 9.2mg
(Yield 85.2%) was obtained.

(Physical properties) ¹ H-NMR (D ₂ O): δ H-8, 8.21 (1H, s); H-2, 8.10 (1
H, s); H-1 ', 5.98 (1H, d, J = 3.2 Hz); H-2', 4.51 (1
H, dd, J = 5.6, 3.2 Hz); H-3 ', 3.52 (1H, dd, J = 7.2
, 5.6); H-4 ', 3.97 (1H, m); H-5', 3.84 (1H, dd, J
= 7.2, 5.6 Hz); H-5 ', 3.69 (1H, dd, J = 13.0, 4.0 H
z).

[0225]

INDUSTRIAL APPLICABILITY As described above, according to the present invention, there is provided a synthetic method for easily and efficiently obtaining 3'-amino-3'-deoxynucleoside having useful physiological activities including antitumor activity. . In addition, the present invention is characterized by being applicable to the synthesis of various aminonucleoside compounds and having high versatility since it has oxyamination or a coupling reaction between sugar and nucleic acid base as a constituent element.

The 3-amino-3-deoxy-ribono-1,4-lactone derivative (1) not only serves as a starting material for synthesizing the 3'-amino-3'-deoxynucleoside of the formula (7). It is also useful as a synthetic intermediate for other physiologically active substances. For example, α-hydroxy-β-amino acid compounds are known to exhibit a protease-inhibiting effect on HIV-1 (Proc. Natl. Ac.
ad. Sci, USA, 86, 9752 (1989))
However, this α-hydroxy-β-amino acid compound can be synthesized from the compound of (1).

Furthermore, the 3-amino-3-deoxy-ribono-1,4-lactone derivative is known as a potent inhibitor of proteases (Bioorg. Med. Chem. L.).
ett. , 2,1235, (1992)), and compounds useful as spacers for immobilizing useful physiologically active substances such as nucleosides on polymer compounds (Polym.Pr.
ep. Jpn. , 34, 2497, (1985)),
It can be a raw material for the synthesis of β-amino acid oligopeptide derivatives.

In the method for producing a 3'-amino-3'-deoxynucleoside derivative of the present invention, the first production method has a remarkable feature that the product obtained in each step is easy to purify. There is. In addition, the second production method can obtain the target compound from the compound (1 ′) in a short number of steps of 3 steps, and is excellent in economical efficiency and the like. As described above, the present invention provides a useful 3-amino-3-deoxy-D-ribono-1,4-lactone derivative (1), and a method for producing the compound simply and efficiently. Provided.

Front page continuation (72) Inventor Takashi Ebata 1-1 Murasakicho, Takatsuki-shi, Osaka Japan Tobacco Inc. Pharmaceutical Research Institute

Claims (4)

[Claims] 1. A 3-amino-3-deoxy-D-ribono-1,4-lactone derivative represented by the following formula (1). Embedded image However, R ¹ and R ⁴ represent a hydrogen atom or a hydroxyl group-protecting group such as an acyl group, an alkyl group, a silyl group, an aralkyl group, a sulfonic acid group, a phosphoryl group and a formyl group, and R ² and R ³ represent hydrogen. An atom or an alkyl group, an alkenyl group, an alkynyl group, an acyl group, a silyl group, an aryl group, an aralkyl group, an alkyloxycarbonyl group, an aryloxycarbonyl group, an alkylsulfonyl group, and an arylsulfonyl group. Further, R ² and R ⁴ or R ³ and R ⁴ may be combined together to form an alkylidene group such as an isopropylidene group, an ethylidene group, a methylidene group, a cyclohexylidene group or a benzylidene group. 2. A method for producing a 3-amino-3-deoxy-D-ribono-1,4-lactone derivative represented by the following formula (1), wherein: However, R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1. (A) An N-substituted amino group having an α configuration at the 4-position of the double bond of the compound represented by the formula (2) as shown in the following reaction formula, and a hydroxyl group having the α configuration at the 3-position are cis-added. , Formula (3)
A step of obtaining a compound represented by: However, R ⁵ is a hydrogen atom or an acyl group, an alkyl group, a silyl group, an aralkyl group, a sulfonic acid group, a phosphoryl group,
R ² represents a protective group for a hydroxyl group such as a formyl group, and R ² represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, a silyl group, an aryl group, an aralkyl group, an alkyloxycarbonyl group, an aryloxycarbonyl group, an alkyl It represents a sulfonyl group or an arylsulfonyl group. (B) protecting the 3-position hydroxyl group and 4-position amino group of the compound of formula (3) as shown in the following reaction formula to produce a compound of formula (4), and then protecting the 2-position hydroxyl group. Removing the group to obtain a compound represented by the following formula (5): However, R ⁵ is as defined above in the step (a),
R ² , R ³ and R ⁴ are as defined above in claim 1. (C) a step of oxidizing the hydroxyl group at the 2-position of the compound of the following formula (5) to obtain a compound of the following formula (6) as represented by the following reaction formula: However, R ² , R ³ and R ⁴ are as defined in claim 1. (D) 1 of the compound of formula (6) as shown in the following reaction formula
Introducing oxygen between the 2-position and the 2-position, further hydrolyzing and reclosing the ring to obtain a compound represented by the formula (1 ′), and then,
A step of protecting the hydroxyl group of the hydroxymethyl group at the 5-position of the compound (1 ′) to obtain the 3-amino-3-deoxy-D-ribono-1,4-lactone derivative (1) represented by the formula (1). [Chemical 6] However, R ¹ , R ² , R ³ and R ⁴ are as defined in claim 1. And a method for producing a 3-amino-3-deoxy-D-ribono-1,4-lactone derivative (1). 3. A 3'-amino-3 'represented by the following formula (7):
A method for producing deoxynucleosides, which comprises: However, B represents a nucleic acid base. (A) a step of reducing the carbonyl group at the 1-position of formula (1 ′) as shown in the following reaction formula to obtain a compound represented by the following formula (8): However, R ² , R ³ and R ⁴ are as defined above in claim 1. (B) protecting the 1- and 5-position hydroxyl groups of the compound of formula (8) with an acyl group as represented by the following reaction formula to obtain a compound of formula (9): 9] However, R ⁸ represents an acyl group, and R ² , R ³ and R ⁴ are as previously defined in claim 1. (C) The compound of formula (10) is produced by removing the protecting group of the 2-position hydroxyl group and 3-position N-substituted amino group of the compound of formula (9) as represented by the following reaction formula: Then, a step of introducing an acyl group into the 2-position hydroxyl group and a trifluoroacetyl group into the 3-position amino group to obtain a compound represented by the formula (11): However, R ⁸ and R ⁹ represent an acyl group. (D) A compound represented by the formula (12) is produced by subjecting a compound of the formula (11) and a nucleobase to a coupling reaction as represented by the following reaction formula, and further a hydroxyl group and an N-substituted amino group. A step of removing the protecting group of to obtain a compound represented by the formula (7): However, R ⁸ and R ⁹ represent an acyl group, and B represents a nucleobase. And 3'-amino-
Process for producing 3'-deoxynucleoside (7). 4. A 3'-amino-represented by the following formula (7):
A method for producing a 3'-deoxynucleoside, which comprises: However, B represents a nucleic acid base. (I) a step of reducing the carbonyl group at the 1-position of formula (1 ′) as shown in the following reaction formula to obtain a compound represented by the following formula (8): However, R ² , R ³ and R ⁴ are as defined in claim 1. (Ii) As represented by the following reaction formula, the protecting groups at the 2-position and 3-position of the compound of formula (8) are eliminated, and
Protecting the 2, 3 and 5 positions with an acyl group to obtain a compound represented by the formula (13): However, R ⁸ represents an acyl group. (Iii) As represented by the following reaction formula, the compound of formula (13) and a nucleobase are subjected to a coupling reaction to produce a compound of formula (14), which is further protected by a hydroxyl group and an amino group. To obtain a compound represented by the formula (7): However, R ⁸ represents an acyl group and B represents a nucleobase. And a method for producing 3′-amino-3′-deoxynucleoside (7).