JP2001233890A - Sulfonylated nucleoside derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an intermediate for efficiently producing medicines, for example, nucleic acid antiviral agent and the like. SOLUTION: The objective sulfnonylated nucleoside derivative is represented by general formula (I) [wherein R1 is a 1-30C alkyl, a 2-30C alkenyl, a 2-30C non-aromatic heterocyclic hydrocarbon group, a 5-30C aryl, a 3-21C substituted silyl group, a 1-7C sulfonyl group or 1-30C hydroxycarbonyl group; in R2, R3, R4 and R5, R2 and R5 are each independently from each other a 1-20C acyloxy group or -OSO2R7, when R3 and R4 are each simultaneously H wherein R7 is a 1-7C alkyl, a 5-10C aryl group, a 2-7C non-aromatic heterocyclic hydrocarbon group].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel sulfonylated nucleoside derivative useful as a raw material for producing a pharmaceutical intermediate or the like.

[0002]

2. Description of the Related Art Many novel nucleic acid antiviral drugs used for the treatment of viral diseases are currently under development. In the production of these drugs, natural nucleic acids or natural carbohydrates are used as raw materials in multiple steps. In general, a method of synthesizing with a low yield is used. For example, Biochem. Palmacol.
36 (17), 2719 (1987) and Tokiko 6-1
No. 3547 discloses a compound represented by the following formula.

[0003]

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(Where L represents a hydrogen atom or an NH ₂ group, and when L represents a hydrogen atom, R represents an NH ₂ group;
Represents a hydrogen atom or a fluorine atom, Y represents a hydrogen atom or a fluorine atom, provided that X and Y are not both hydrogen atoms, and when L represents an NH ₂ group, R represents an OH group or Represents an NH ₂ group, X represents a fluorine atom, and Y represents a hydrogen atom)

[0005] This compound is known to be useful as a nucleic acid antiviral drug. The publications listed above contain 6-
Amino-9- (3'-deoxyarabinofuranosyl)-
9-H- 5 purine 'position hydroxyl group is protected with dimethoxytrityl chloride, 2' position hydroxyl group is triflate derivatized, fluorine group is introduced at the 2 'position by SN ₂ reaction with tetra -n- butylammonium fluoride , 2 'of 2', 3'-deoxyadenosine by a method in which the dimethoxytrityl protecting group at the 5'-position is removed by dichloroacetic acid.
It is described that -β-fluoro isomer, that is, a compound in which X is a fluorine atom and Y is a hydrogen atom in the above formula, is synthesized. It's not an easy way.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a production intermediate capable of efficiently producing a pharmaceutical compound such as a nucleic acid antiviral drug.

[0007]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have developed a novel sulfonylated nucleoside derivative having a specific structure from nucleic acid derivatives such as rodenosine and its analogous compounds. It has been found that a virus agent can be produced efficiently. The present invention has been completed based on the above findings. That is, the present invention provides the following general formula (I)

[0008]

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Wherein R ¹ is an alkyl group having 1 to 30 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, a non-aromatic heterocyclic hydrocarbon group having 2 to 30 carbon atoms, and an aryl having 5 to 30 carbon atoms. Group, substituted silyl group having 3 to 21 carbon atoms, 1 carbon atom
And R ² , R ³ , R ⁴ and R ⁵ represent R ² and R ⁵
Are simultaneously hydrogen atoms, R ³ and R ⁴ are each independently an acyloxy group having 1 to 20 carbon atoms or —OSO
Indicates ₂ R ⁷ group, each R ² and R ⁵ when R ³ and R ⁴ are not hydrogen atoms at the same time independently represents an acyloxy group, or -OSO ₂ R ⁷ group having 1 to 20 carbon atoms, wherein R ⁷ represents an alkyl group having 1 to ⁷ carbon atoms, an aryl group having 5 to 10 carbon atoms, and a non-aromatic heterocyclic hydrocarbon group having 2 to 7 carbon atoms]. is there.

[0010]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. In the formulas (I) and (Ia), R ¹ has 1 to 30 carbon atoms.
Alkyl group, alkenyl group having 2 to 30 carbon atoms, non-aromatic heterocyclic hydrocarbon group having 2 to 30 carbon atoms, 5 to 3 carbon atoms
An aryl group having 0, a substituted silyl group having 3 to 21 carbon atoms, a sulfonyl group having 1 to 7 carbon atoms or 1 to 30 carbon atoms
R ² , R ³ , R ⁴ and R
^5, when R ² and R ⁵ are not hydrogen atoms at the same time R ³ and R
⁴ each independently represents an acyloxy group, or -OSO ₂ R ⁷ group having 1 to 20 carbon atoms, when R ³ and R ⁴ are hydrogen atoms at the same time R ² and R ⁵ are 1 to carbon atoms independently 20 represents an acyloxy group or —OSO ₂ R ⁷ group, wherein R ⁷ is an alkyl group having 1 to 7 carbon atoms, and 5 carbon atoms;
And a non-aromatic heterocyclic hydrocarbon group having 2 to 7 carbon atoms.

In the compounds of the above formulas (I) and (Ia), the groups defined by R ^{1 to} R ⁵ will be specifically described below. The “alkyl group having 1 to 30 carbon atoms” or the “alkenyl group having 2 to 30 carbon atoms” may be any of linear, branched or cyclic. "A non-aromatic heterocyclic hydrocarbon group having 2 to 30 carbon atoms" means at least one carbon atom.
One represents a saturated or unsaturated cyclic hydrocarbon group substituted with a hetero atom such as an oxygen atom, a nitrogen atom, or a sulfur atom. "An aryl group having 5 to 30 carbon atoms" refers to a nitrogen atom,
A monocyclic or condensed polycyclic aromatic hydrocarbon group which may contain one or two or more hetero atoms such as an oxygen atom and a sulfur atom.

"Substituted silyl group having 3 to 21 carbon atoms"
The term refers to one in which one or more hydrogen atoms of silyl (—SiH ₃ ) are substituted with an alkyl group, an aryl group, an alkoxy group, or the like having 1 to 7 carbon atoms. The "sulfonyl group having 1 to 7 carbon atoms" refers to an alkyl group having 1 to 7 carbon atoms or 5 to 5 carbon atoms.
7 having an aryl group or the like. "C 1-3
"Oxycarbonyl group having 0 carbon atoms" means an alkyl group having 1 to 29 carbon atoms, an alkenyl group having 2 to 29 carbon atoms, or 5 to 29 carbon atoms.
Those having 29 aryl groups and the like are shown. The functional group may have one or more optional substituents as long as the substituted state is within the above-defined range. When it has two or more substituents, they may be the same or different. The position of the substituent is not particularly limited, and the substituent can be located at any substitutable site. Although the type of the substituent is not particularly limited, for example, an alkyl group, an alkoxy group, an aryl group, a silyl group, a silyloxy group, a nitro group, an alkylene group, an arylene group, a hydroxy group, an amino group, a cyano group, a halogen atom, and a sulfonyl group , A sulfinyl group, an alkoxycarbonyl group, an oxycarbonyl group, an alkenyl group and the like. Here, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Further, the substituents exemplified above may be further substituted by one or more other substituents.
Examples of such a substituent include, for example, an alkoxyalkyl group, a halogenated alkyl group, a halogenated arylalkyl group, a heteroarylalkyl group alkoxycycloalkyl group, an arylalkoxy group, a halogenated alkoxy group, a halogenated aryl group, and an alkoxyl group. Examples include an aryl group, an alkylaryl group, an alkylsilyl group, an arylsilyl group, an arylalkylene group, an alkylarylene group, and an alkoxyarylene group. The substituents of the functional groups described above are for illustrative purposes only, and are not limited thereto.

Specific examples of the functional group of R ^{1 in} the general formula (I) include the following. 1-30 carbon atoms
Examples of the alkyl group include a methyl group, a methoxymethyl group, a (phenyldimethylsilyl) methoxymethyl group, an ethoxymethyl group, a benzoylmethyl group, a p-methoxybenzyloxymethyl group, a (4-methoxyphenoxy) methyl group, and guaiacol Methyl group, t-butoxymethyl group, 4-pentyloxymethyl group, 2-methoxyethoxymethyl group, 2-trimethylsilylethoxymethyl group, benzyl group, p-methoxybenzyl group, 3,4-
Dimethoxybenzyl group, p-chlorobenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, p-cyanobenzyl group, p-phenylbenzyl group, diphenylmethyl group, triphenylmethyl group, α-naphthyldiphenylmethyl group, p-methoxyphenyldiphenylmethyl group, di (p-methoxyphenyl) phenylmethyl group, tri (p
-Methoxyphenyl) methyl group, di (4-methoxyphenyl) methyl group, 4,4 ', 4 "-tris (benzoyloxyphenyl) methyl group, 1,1-bis (4-methoxyphenyl) -1'-pyrenylmethyl Group, 9-anthryl group, 1-ethoxyethyl group, 1- (2-chloroethoxy) ethyl group, 1-methyl-1-methoxyethyl group, 1
-Methyl-1-benzyloxyethyl group, 2-trimethylsilylethyl group, t-butyl group, trimethylsilyloxymethyl group, dimethyl (t-butyl) silyloxymethyl group, dimethyl (1,1,2-trimethylpropyl)
A silyloxymethyl group, a diphenyl (t-butyl) silyloxymethyl group, and the like.

Examples of the non-aromatic heterocyclic hydrocarbon group having 2 to 30 carbon atoms include cycloalkyl groups such as 1-methoxycyclohexyl group; 1,4-dioxan-2-yl group, tetrahydropyranyl group and tetrahydrofuran group. And the like. Examples of the substituted silyl group having 3 to 21 carbon atoms include trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethyl (t-butyl) silyl, and dimethyl (1 , 1,2-Trimethylpropyl) silyl group, diphenyl (t-butyl) silyl group, tribenzylsilyl group, tri-p-xylylsilyl group, triphenylsilyl group, diphenylmethylsilyl group, (t-butyl) methoxyphenylsilyl And the like.

Examples of the oxycarbonyl group having 1 to 30 carbon atoms include methoxycarbonyl, ethoxycarbonyl, trifluoromethoxycarbonyl, isobutyloxycarbonyl, t-butyloxycarbonyl, vinyloxycarbonyl, allyloxy Examples include a carbonyl group, a phenyloxycarbonyl group, a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, and a 1-naphthoxycarbonyl group. Examples of the sulfonyl group having 1 to 7 carbon atoms include a benzylsulfonyl group,
Examples include a methanesulfonyl group and a tosyl group. Examples of the alkenyl group having 2 to 30 carbon atoms include a vinyl group,
Examples include an allyl group and a 2-cyclohexenyl group. Examples of the aryl group having 5 to 30 carbon atoms include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a p-methoxyphenyl group, a 2,4-dinitrophenyl group, a 2-pyridyl group, a 3-pyridyl group, 8- (1) -quinolyl group and the like.

In the above functional groups, R ¹ is preferably a substituted or unsubstituted benzyl group or a substituted or unsubstituted triphenylmethyl group, and more specifically, triphenylmethyl group, 4-methoxyphenyl. Diphenylmethyl group, di (4-methoxyphenyl) phenylmethyl group, tri (4-methoxyphenyl) methyl group, di (4-
A methoxyphenyl) methyl group is preferred, and a triphenylmethyl group is more preferred. R in the above general formula (I)
The acyloxy group having 1 to 20 carbon atoms of ² , R ³ , R ⁴ and R ⁵ is represented by the following general formula (III):

[0018]

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Wherein R ⁶ is an alkyl group having 1 to 19 carbon atoms, an alkenyl group having 2 to 19 carbon atoms, and 2 to 19 carbon atoms.
A non-aromatic heterocyclic hydrocarbon group and an aryl group having 5 to 19 carbon atoms]. Here, “C 1 to C 19
Alkyl group "or" alkenyl group having 2 to 19 carbon atoms "
May be any of linear, branched or cyclic.
“A non-aromatic heterocyclic hydrocarbon group having 2 to 19 carbon atoms” means that at least one of carbon atoms is an oxygen atom, a nitrogen atom,
A saturated or unsaturated cyclic hydrocarbon group substituted with a hetero atom such as a sulfur atom. The “aryl group having 5 to 19 carbon atoms” is a monocyclic or condensed polycyclic aromatic hydrocarbon which may contain one or more hetero atoms such as a nitrogen atom, an oxygen atom and a sulfur atom. Represents a group.

The above functional group may have one or more optional substituents as long as the state of substitution is within the range defined above. When having two or more substituents,
They may be the same or different. The position of the substituent is not limited, and the substituent can be located at any substitutable site. Although the type of the substituent is not particularly limited, for example, an alkyl group, an alkoxy group, an aryl group, a silyl group, a silyloxy group, a nitro group, an alkylene group, an arylene group, a hydroxy group, an amino group, a cyano group, a halogen atom, and a sulfonyl group , A sulfinyl group, an alkoxycarbonyl group, an oxycarbonyl group, an alkenyl group and the like. Here, examples of the halogen atom include those described above.

Further, the substituents exemplified above may be further substituted with one or more other substituents.
Examples of such a substituent include an alkoxyalkyl group, a halogenated alkyl group, a halogenated arylalkyl group, a heteroarylalkyl group, an alkoxycycloalkyl group, an arylalkoxy group, a halogenated alkoxy group, a halogenated aryl group, and an alkoxyaryl. Group,
Alkylaryl group, alkylsilyl group, arylsilyl group, arylalkylene group, alkylarylene group,
An alkoxyarylene group can be exemplified. The substituents described above are for illustration only and are not limiting.

Specific examples of the functional group of R ^{6 in} the general formula (III) include the following. Carbon number 1-19
Examples of the alkyl group include a methyl group, a methoxymethyl group, a (phenyldimethylsilyl) methoxymethyl group, an ethoxymethyl group, a benzoylmethyl group, a p-methoxybenzyloxymethyl group, a (4-methoxyphenoxy) methyl group, and guaiacol Methyl group, t-butoxymethyl group, 4-pentyloxymethyl group, 2-methoxyethoxymethyl group, 2-trimethylsilylethoxymethyl group, benzyl group, p-methoxybenzyl group, 3,4-
Dimethoxybenzyl group, p-chlorobenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, p-cyanobenzyl group, p-phenylbenzyl group, diphenylmethyl group, triphenylmethyl group, α-naphthyldiphenylmethyl group, p-methoxyphenyldiphenylmethyl group, di (p-methoxyphenyl) phenylmethyl group, tri (p
-Methoxyphenyl) methyl group, di (4-methoxyphenyl) methyl group, 4,4 ', 4 "-tris (benzoyloxyphenyl) methyl group, 1,1-bis (4-methoxyphenyl) -1'-pyrenylmethyl Group, 9-anthryl group, 1-ethoxyethyl group, 1- (2-chloroethoxy) ethyl group, 1-methyl-1-methoxyethyl group, 1
-Methyl-1-benzyloxyethyl group, 2-trimethylsilylethyl group, t-butyl group, 1-methoxycyclohexyl group, trimethylsilyloxymethyl group, dimethyl (t-butyl) silyloxymethyl group, dimethyl (1,1,2 -Trimethylpropyl) silyloxymethyl group, diphenyl (t-butyl) silyloxymethyl group and the like.

The alkenyl group having 2 to 19 carbon atoms includes
For example, a vinyl group, an allyl group, a 2-cyclohexenyl group and the like can be mentioned. Examples of the non-aromatic heterocyclic hydrocarbon group having 2 to 19 carbon atoms include, for example, 1,4-dioxane-2-
Examples thereof include an yl group, a tetrahydropyranyl group, and a tetrahydrofuranyl group.

Examples of the aryl group having 5 to 19 carbon atoms include a phenyl group, a 1-naphthyl group, a 2-naphthyl group,
p-methoxyphenyl group, 2,4-dinitrophenyl group, 2-pyridyl group, 3-pyridyl group, 8- (1) -quinolyl group and the like. Among them, as R ⁶ , a t-butyl group, an ethyl group, a methyl group and the like are preferable, and a methyl group is more preferable. That is, the acyloxy group of R ^{2 to} R ⁵ is preferably one having 5 or less carbon atoms, and among them, an acetyloxy group is most preferred.

In the general formula (I), as the —OSO ₂ R ⁷ group of R ² , R ³ , R ⁴ and R ⁵ , R ⁷ has 1 to 1 carbon atoms.
And an alkyl group having 7 carbon atoms, an aryl group having 5 to 10 carbon atoms, and a non-aromatic heterocyclic hydrocarbon group having 2 to 7 carbon atoms. The alkyl group having 1 to 7 carbon atoms may be linear, branched, or cyclic, and may have one or more substituents. Specific examples include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, a butyl group, a benzyl group and the like. Among these, a methyl group is preferred. The aryl group having 5 to 10 carbon atoms represents a monocyclic or condensed polycyclic aromatic hydrocarbon group which may contain one or more hetero atoms such as a nitrogen atom, an oxygen atom and a sulfur atom. Specifically, for example, a phenyl group, p-
Examples thereof include a tolyl group, a p-bromophenyl group, and a 2-pyridyl group. The non-aromatic heterocyclic hydrocarbon group having 2 to 7 carbon atoms represents a saturated or unsaturated cyclic hydrocarbon group in which at least one of carbon atoms is substituted with a hetero atom such as an oxygen atom, a nitrogen atom, and a sulfur atom. Specifically, for example, an imidazolyl group, a pyrazolyl group, a tetrahydrofuranyl group and the like are mentioned, and an imidazolyl group is preferable. In the above-mentioned definitions of the substituents of R ^{1 to} R ⁷ , groups not specifically shown are selected from the above-described atoms and groups in any combination or according to generally known common sense.
As the sulfonylated nucleoside derivative of the formula (I),
The compound represented by the formula (Ia) is represented by the following formula (I-
b):

[0026]

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Wherein R ^{1 to} R ⁵ are as defined above. ]
A compound represented by the following formula (Ic):

[0028]

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Wherein R ^{1 to} R ⁵ are as defined above. ]
A compound represented by the following formula (Id):

[0030]

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Wherein R ^{1 to} R ⁵ are as defined above. ]
And a plurality of stereoisomers such as a compound represented by the formula (Ia), and among them, the sulfonylated nucleoside derivative of the formula (Ia) is preferable. The method for synthesizing the sulfonylated nucleoside derivative represented by the above general formula (I) of the present invention will be described according to the following reaction formula A, taking the adenosine derivative of the formula (1) as an example.

[0032]

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Wherein R ^{1 to} R ⁵ are as defined above,
^8, R ^9, R ¹⁰ and R ^11, R ⁹ and R ¹⁰ when R ⁸ and R ¹¹ are not hydrogen atoms at the same time is independently an acyloxy group or a -OSO ₃ X group having 1 to 20 carbon atoms , R ⁹ and R ¹⁰ are simultaneously a hydrogen atom, R ⁸ and R ¹¹ each independently represent an acyloxy group having 1 to 20 carbon atoms or a —OSO ₃ X group, and R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ is a group represented by R ¹² and R ^{15 which} are simultaneously a hydrogen atom;
R ¹³ and R ¹⁴ each independently represent a hydroxyl group or an acyloxy group having 1 to 20 carbon atoms. When R ¹³ and R ¹⁴ are simultaneously a hydrogen atom, R ¹² and R ¹⁵ each independently represent a hydroxyl group or 1 carbon atom. And the acyloxy group having 1 to 20 carbon atoms has the same meaning as the acyloxy group having 1 to 20 carbon atoms in the formula (I), and X represents a hydrogen atom, an alkali metal atom, an alkaline earth A metal atom or R ¹⁶ R ¹⁷ R ¹⁸ R ¹⁹ N ⁺ , wherein R ^{16 to} R ¹⁹ are each independently a hydrogen atom, methyl, ethyl, propyl,
An alkyl group having 1 to 8 carbon atoms such as butyl; an aryl group having 6 to 12 carbon atoms such as phenyl and naphthyl; or an aralkyl group having 7 to 25 carbon atoms such as benzyl. ]

In the above formula, examples of the atom represented by X or an ammonium ion substance include the following. A hydrogen atom; an alkali metal atom such as lithium, potassium and sodium; an alkaline earth metal atom such as magnesium and calcium; or tetramethylammonium, tetraethylammonium, tetrapropylammonium, tetrabutylammonium, tetrapentylammonium, tetrahexylammonium, tetra Compounds represented by the formula R ¹⁶ R ¹⁷ R ¹⁸ R ¹⁹ N ⁺ such as heptyl ammonium, tetraoctyl ammonium, trimethyl octyl ammonium, cyclohexyl trimethyl ammonium, phenyl trimethyl ammonium and the like can be mentioned. Among these, compounds represented by the formula R ¹⁶ R ¹⁷ R ¹⁸ R ¹⁹ N ⁺ such as tetraethylammonium and tetrabutylammonium are preferable, and tetrabutylammonium is particularly preferable.

As the adenosine derivative (1), specifically, for example, 5'-O-trityladenosine, 5'-O-
Dimethoxytrityl adenosine, 5'-O-monomethoxytrityl adenosine, 5'-O-toluoyl adenosine, 5'-O-t-butyldimethylsilyl adenosine and the like. These can be easily synthesized from adenosine in one or several steps by a known method. Adenosine may be a commercially available one, or can be obtained by a known method. Instead of adenosine, those which are stereoisomeric at the 1'-position, 2'-position, 3'-position and 4'-position can also be used.

[Step A-1] The 1,3,2-dioxathiolane oxide derivative of the formula (2) can be prepared by adding, for example, K.I. B. Sha
rpless et al. [J. Am. Chem. Soc. , 11
0, 7538 (1988)]. [Step A-2] A 1,3,2-dioxathiolane oxide derivative of the formula (2) is converted into a compound, for example, in the presence of a RuCl ₃ catalyst.
By a known oxidation reaction using an oxidizing agent such as sodium periodate and sodium hypochlorite, 1,3,3 of the formula (3)
A 2-dioxathiolane-2,2-dioxide derivative can be obtained.

[Step A-3] In the production of the sulfated nucleoside derivative of the formula (4) from the 1,3,2-dioxathiolane-2,2-dioxide derivative of the formula (3), a commonly used acyloxylating agent is used. Can be implemented. As the acyloxylating agent, the following general formula (V):

[0038]

Embedded image R ⁶ COOX (V)

Wherein R ⁶ and X are as defined above. ] Can be used. [Step A-4] A hydroxy nucleoside derivative of the formula (5) can be produced by reacting an acidic substance such as sulfuric acid with the sulfated nucleoside derivative of the formula (4). [Step A-5]

The production of the sulfonylated nucleoside derivative of the formula (Ia) from the hydroxy nucleoside derivative of the formula (5) uses an alkylsulfonic acid derivative or an arylsulfonic acid derivative.

Examples of the alkylsulfonic acid-derived or arylsulfonic acid derivative used for carrying out the reaction of the present invention include the following. Alkylsulfonic acid halides such as methanesulfonyl chloride; arylsulfonic acid derivatives such as p-toluenesulfonyl chloride, phenylsulfonyl chloride, 4-bromophenylsulfonyl chloride, 1-imidazoylsulfonyl chloride; alkylsulfonic acid derivatives such as methanesulfonyl anhydride Anhydride; arylsulfonic acid derivative anhydrides such as anhydrous p-toluenesulfonyl, anhydrous phenylsulfonyl, and anhydrous 4-bromophenylsulfonyl. Among them, from the viewpoint of industrial versatility, methanesulfonyl chloride or p-
Toluenesulfonyl chloride is preferred, and methanesulfonyl chloride is more preferred. Further, the reaction may be carried out using sulfuryl chloride and imidazole.

The amount of the alkyl sulfonic acid derivative or the aryl sulfonic acid derivative to be used in carrying out the reaction of the present invention is not particularly limited, and is usually based on 1 mol of the hydroxynucleoside derivative of the formula (5) serving as a substrate. The molar ratio is selected in the range of 1 to 100 times, preferably 1 to 10 times, and more preferably 1 to 5 times. In addition, there is no restriction on the mixing order when the hydroxynucleoside derivative of the formula (5) is reacted with the alkylsulfonic acid derivative or the arylsulfonic acid derivative.

Further, a base may coexist in the reaction system. Examples of the base include secondary amines having a hydrocarbon group having 2 to 22 carbon atoms such as diethylamine and diisopropylamine; triethylamine, tripropylamine,
Carbon such as triisopropylamine, tributylamine, triisobutylamine, trioctylamine, N, N-dimethylaniline, 1-methylpyrrolidine, 1-methylpiperidine, 1-methyl-2-pyrrolidone, 1-methyl-2-piperidone A tertiary amine having a hydrocarbon group of the number 3 to 24; pyridine, 2-picoline, 3-picoline, 4-
Heterocyclic aromatic compounds such as picoline and 1-methylpyrrole are exemplified. Among these, triethylamine and pyridine are preferable, and pyridine is more preferable.

The use of a reaction solvent is not essential, but can be used if necessary. Examples of the solvent include aliphatic hydrocarbons such as hexane, heptane and octane; aromatic hydrocarbons such as toluene and xylene; ketones such as acetone, diethyl ketone and methyl ethyl ketone; diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran; Ethers such as dioxane;
Esters such as ethyl acetate and butyl acetate; amides such as dimethylformamide and dimethylacetamide; secondary amines such as diethylamine and diisopropylamine; triethylamine, tripropylamine, triisopropylamine, tributylamine, triisobutylamine and trioctylamine , N, N-dimethylaniline, 1-methylpyrrolidine, 1-methylpiperidine, 1-methyl-
Tertiary amines such as 2-pyrrolidone and 1-methyl-2-piperidone; pyridine, 2-picoline, 3-picoline, 4-
Heterocyclic aromatic compounds such as picoline and 1-methylpyrrole; dimethylsulfoxide, sulfolane, N-methylpyrrolidone and the like, or compounds which are by-produced during the production of the hydroxy nucleoside derivative of the formula (5) as a raw material. Among these, more preferred solvents are ethers, amines and heterocyclic aromatic compounds, and specific compounds thereof include triethylamine and pyridine, with pyridine being particularly preferred.

The reaction is sufficiently carried out even at a reaction temperature of 0 ° C. or lower, but the reaction is usually carried out at a temperature of 0 ° C. or higher in order to further increase the reaction rate. Preferably it is 0-100 degreeC, More preferably, it is 0.
To room temperature, particularly preferably room temperature. The reaction time depends on the reaction temperature, but is usually in the range of 0.1 to 200 hours, preferably 0.5 to 100 hours. From the reaction solution, formula (I)
The method for separating the sulfonylated nucleoside derivative of -a) can be carried out by a commonly known method such as crystallization, extraction, adsorption, and column separation.

According to the above-mentioned method, a sulfonylated nucleoside derivative represented by the general formula (I) is obtained. This novel compound is useful as an intermediate for organic chemicals, and also as an intermediate for the production of pharmaceuticals and agricultural chemicals. In particular, it can be effectively used as an intermediate of rodenosine showing anti-HIV activity. Hereinafter, a method for producing rhodenosin from the sulfonylated nucleoside derivative represented by the general formula (Ia) of the present invention will be described in accordance with Reaction Formula B, but is limited to the specific production method shown in Reaction Formula B below. It will not be done. It should be understood that reaction conditions and reaction reagents can be appropriately selected by those skilled in the art, and that the methods described below can be appropriately modified or modified.

[0047]

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[Wherein, R ^{1 to} R ⁵ are as defined above. ]

[Step B-1] The sulfonated nucleoside derivative of the formula (Ia) is closed with a base to produce a β-epoxide compound of the formula (6). Examples of the base used for ring closure include sodium hydride, sodium amide, metal alkoxide and the like, and among them, metal alkoxide is preferable.

[Step B-2] The fluorination reaction from the β-epoxide compound of the formula (6) to the difluoride compound of the formula (7) is performed, for example, according to R. L. Tolman et al. [J. Med.
Chem. , 15, 1092 (1972)] or A.I. M. Kawasaki et al. [J. Med. Che
m. , 36, 831 (1993)]. That is, first, the 3′-position is fluorinated to obtain a fluorohydrin compound, and then the generated hydroxyl group is fluorinated after introducing a leaving group.

The fluorination reaction at the 3'-position is carried out, for example, by reacting a β-epoxide compound of the formula (6) with at least an equimolar amount of a fluorine donor in a solvent inert under the reaction conditions. . As the fluorine donor, for example, potassium fluoride, sodium fluoride, cesium fluoride, tetraalkylammonium fluoride (in this case,
Examples of the alkyl include methyl, ethyl, propyl, butyl and the like, and among them, butyl is preferable.) Or a polyhydrodiene fluoride such as pyridinium polyhydrodiene fluoride, KHF ₂ or tetraalkylammonium bifluoride. . As the solvent, chlorinated hydrocarbons such as methylene chloride; ethers such as tetrahydrofuran; nitrile compounds such as acetonitrile; alcohols such as butanol; polyol-based solvents such as ethylene glycol and mixtures thereof can be suitably used.

By the above reaction, a fluorohydrin compound can be obtained from the β-epoxide compound of the formula (6). A commonly used leaving group such as a trifluoromethanesulfonyl group, a p-bromobenzenesulfonyl group, an imidazolylsulfonyl group, a p-toluenesulfonyl group is introduced into a hydroxyl group of the fluorohydrin compound, and the fluorinating agent is allowed to act again. And a difluoride compound of the formula (7). As the fluorinating agent, among the above, tri- or tetra- having 1 to 8 carbon atoms.
Alkyl ammonium is preferred, especially tetrabutylammonium fluoride. Reaction temperature is from 0 ° C to 8
0 ° C. and the reaction time are preferably 1 to 8 hours.

[Step B-3] The dehydrofluorination reaction from the difluoride compound of the formula (7) to the vinyl fluoride compound of the formula (8) is performed, for example, as described in P.S. L. J. Coe et al. Fl
uorine. Chem. , 69, 19 (1994). Examples of the base used for dehydrofluorination include sodium hydride, sodium amide, metal alkoxide and the like, and among them, metal alkoxide is preferable. Examples of such a metal alkoxide include potassium t-butoxide, sodium t-butoxide, lithium t-butoxide and the like. Among them, potassium t-butoxide is preferable. The amount of the metal alkoxide to be used is not particularly limited as long as it is at least equimolar to the difluoride compound of the formula (7), but is preferably in the range of 1 to 5 times, more preferably 2 to 3 times.

As the solvent, methanol, ethanol,
Alcohols such as propanol, butanol and benzyl alcohol; phenols such as phenol and 4-methoxyphenol; aromatic hydrocarbons such as benzene, toluene and xylene; diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran and 1,4-dioxane Ethers; nitrogen-containing polar solvents such as N, N-dimethylformamide; and sulfur-containing polar solvents such as dimethylsulfoxide. The reaction temperature is usually
The range is 20 to 80 ° C, preferably 20 to 40 ° C.

[Step B-4] The hydrogenation reaction and deprotection reaction of the vinyl fluoride compound of the formula (8) to rodenosine can be carried out by a known method, for example, A.I. Tetrahedron. Lett. , 39,1657
(1998) and the like. As the hydrogenation catalyst used in this reaction, a commonly used catalyst known per se can be used.For example, alkali metals, alkaline earth metals, zinc, aluminum, iridium, chromium, tin, iron, titanium, copper Metals such as Rhodium complex, Ruthenium complex, Platinum complex, etc. Catalysts for uniform catalytic hydrogenation; Non-uniformity using metals such as Palladium, Platinum, Rhodium, Ruthenium, Nickel, Chromium, etc. System-catalyzed hydrogenation catalysts and the like. Moreover, you may reduce with a metal hydride, such as sodium hydride and sodium borohydride. Among these, it is preferable to use a heterogeneous catalytic hydrogenation catalyst because of its high selectivity and reproducibility in many cases.

Examples of such a catalyst include palladium, platinum, rhodium, ruthenium, nickel and the like.
A heterogeneous catalytic hydrogenation catalyst such as a chromium-based catalyst may be mentioned, and among them, a palladium-based catalyst is preferable. Examples of the palladium-based catalyst include palladium-carbon, palladium-barium sulfate, palladium-calcium carbonate, and the like, with palladium-carbon being preferred. The amount of the catalyst to be used is generally 0.1 to 10 parts by weight, preferably 1 to 3 parts by weight, per 1 part by weight of the substrate. As the solvent, for example, methanol, ethanol, propanol,
Examples thereof include aliphatic alcohols such as butanol and acetic acid, and among them, aliphatic alcohols such as methanol, ethanol, propanol and butanol are preferable. The pressure condition used for this reaction is usually from normal pressure to 3 kg / cm.
It is in the range of ² , but preferably around normal pressure. The reaction temperature is usually in the range of room temperature to 50 ° C, but preferably around room temperature. The deprotection reaction may be appropriately selected from known methods depending on the introduced protecting group and used.

[0057]

EXAMPLES The embodiments of the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples unless it exceeds the gist thereof. A sulfonylated nucleoside derivative represented by the general formula (1) was synthesized by the following steps. In the formula, “Ph” represents a phenyl group, “Ph ₃ C” represents a trityl group (hereinafter sometimes referred to as “Tr”), “Ac” represents an acetyl group, and “Ms” represents methane. A sulfonyl group;
"e" represents a methyl group, and "Bu" represents a butyl group.

[0058]

Embedded image

Reference Example 1 From compound (B) to compound (A)
Compound (B) 0.65 in a two-necked flask having an inner volume of 10 ml
35 g (0.75 mmol) was charged and the inside was replaced with nitrogen. 1.7 ml of a tetrahydrofuran solution prepared in 0.44 M of sulfuric acid and 0.48 M of water was added dropwise, and the solution was added at room temperature.
Stir for 1 hour. The reaction was followed by HPLC. After extraction with chloroform / water, the mixture was neutralized with an aqueous sodium hydrogen carbonate solution, and the solvent was distilled off. Purification was performed by silica gel column chromatography (chloroform / methanol = 95/5). The product is a powder. Yield 0.1284 g (0.
23 mmol), and the yield was 31.3%. Identification is ¹ H
-NMR and ¹³ C-NMR were used. According to the analysis by liquid chromatography, the purity was 99% or more.

The NMR spectrum of the compound (A) is shown below. ¹ H-NMR (CDCl ₃ ); Chemical Shi
ft (Intensity, Multiplicity
y, JHH, assignment) 8.28 (1H, s, 2-H), 7.91 (1H, s,
8-H), 7.42 (6H, dd, 8.2 & 1.7, T
r), 7.26 (3H, m, Tr), 6.27 (2H,
_{s, NH 2), 6.09 (} 1H, d, 2.2,1-
H), 5.60 (1H, s, OH), 5.36 (1H,
dd, 4.4 & 3.0, 3'-H), 4.83 (1H,
dd, 9.9 & 5.2, 4'-H), 4.65 (1H,
t, 2.5, 2'-H), 3.49 (1H, dd, 9.
8 & 5.4, 5'-H), 3.36 (1H, 9.9 &
5.5, 5'-H), 1.75 (3H, s, OAc).

¹³ C-NMR (CDCl ₃ ); Chemi
cal Shift (assignment) 169.6 (Ac), 155.6 (6-C), 152.
6 (2-C), 148.5 (4-C), 143.3 (T
r-1), 138.4 (8-C), 128.6 (Tr-
3), 127.8 (Tr-2), 127.2 (Tr-
4), 119.7 (5-C), 91.1 (4'-C),
_{87.1 (CPh 3), 80.5 (} 1'-C), 78.
7 (3'-C), 77.2 (2'-C), 61.1
(5'-C), 20.5 (Me).

Example 1 Synthesis of sulfonylated nucleoside derivative (I-1) from compound (A) In a two-necked flask having an internal volume of 10 mL, 0.0161 g (0.029 mmol) of hydroxynucleoside derivative (A) was placed.
l) was added and the inside was replaced with nitrogen. 1.8 ml of pyridine
And cooled to 0 ° C. externally. 0.0136g
(0.12 mmol) of methanesulfonyl chloride,
Stirred at room temperature for 4 hours. The reaction was followed by HPLC. Extracted with water and chloroform, neutralized, washed with water,
After drying, the solvent was distilled off. After drying under reduced pressure, the target product was obtained as a powder. Identification was performed by ¹ H-NMR and ¹³ C-NMR. The yield is 0.0184 g (0.029 mmol),
The yield was 100%. According to the analysis by liquid chromatography, the purity was 99% or more.

The sulfonylated nucleoside derivative (I-
The NMR spectrum of 1) is shown below. ¹ H-NMR (CDCl ₃ ); Chemical Shi
ft (Intensity, Multiplicity
y, JHH, assignment) 8.29 (1H, s, 2-H), 7.83 (1H, s,
8-H), 7.85 (6H, m, Tr), Tr, 7.2
6 (9H, m, Tr), 6.26 (1H, d, 2.1,
1'-H), 5.80 (2H , s, NH 2), 5.62
(1H, t, 2.0, 2'-H), 5.54 (1H, d
d, 4.1 & 1.9, 3'-H), 4.69 (1H, d
d, 8.9 & 4.8, 4'-H), 3.55 (1H, d
d, 9.7 & 5.7, 5'-H), 3.39 (1H, d
d, 9.8 & 5.9, 5'-H), 3.31 (3H,
s, Ms), 1.79 (3H, s, Ac). ¹³ C-NMR (CDCl ₃ ); Chemical Sh
if (assignment) 169.0 (Ac), 155.4 (6-C), 153.
2 (2-C), 149.7 (4-C), 143.2 (T
r-1), 135.9 (8-C), 128.6 (Tr-
3), 127.9 (Tr-2), 127.3 (Tr-
4), 119.5 (5-C), 87.9 (4'-C),
87.3 (CPh ₃ ), 83.3 (1′-C), 80.
3 (3'-C), 77.2 (2'-C), 60.6
(5'-C), 38.6 (Ms), 20.3 (Me).

Continued on the front page (72) Inventor Masaki Takai 1000 Kamoshita-cho, Aoba-ku, Yokohama-shi, Kanagawa Prefecture Inside the Yokohama Research Laboratory, Mitsubishi Chemical Corporation (72) Inventor Takeshi Nakato 8-3-1 Chuo, Ami-cho, Inashiki-gun, Ibaraki Prefecture Mitsubishi Chemical Corporation Tsukuba Research Laboratory (72) Inventor Machiko Narita 8-3-1 Chuo, Ami-cho, Inashiki-gun, Ibaraki Prefecture Mitsubishi Chemical Corporation Tsukuba Research Laboratory (72) Inventor Yuji Ohgome Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa 1000 address Mitsubishi Chemical Corporation Yokohama Research Laboratory F-term (reference) 4C057 AA18 BB02 BB05 CC02 CC03 DD01 GG10 LL29

Claims (7)

[Claims] 1. A compound of the general formula (I): [Wherein, R ¹ is an alkyl group having 1 to 30 carbon atoms, and 2 carbon atoms.
An alkenyl group having from 30 to 30 carbon atoms, a non-aromatic heterocyclic hydrocarbon group having from 2 to 30 carbon atoms, an aryl group having from 5 to 30 carbon atoms, a substituted silyl group having from 3 to 21 carbon atoms, and a sulfonyl group having from 1 to 7 carbon atoms or indicates oxycarbonyl group having 1 to 30 carbon atoms, R ^2, R ^3, R ⁴ and R ^5, carbon atoms R ³ and R ⁴ are each independently when R ² and R ⁵ are not hydrogen atoms at the same time 1
Shows an acyloxy group, or -OSO ₂ R ⁷ groups to 20, R ² and R ⁵ when R ³ and R ⁴ are not hydrogen atoms at the same time
Each independently represents an acyloxy group having 1 to 20 carbon atoms or a -OSO ₂ R ⁷ group, wherein R ⁷ represents 1 to 20 carbon atoms;
7 alkyl groups, 5-10 carbon atoms, and non-aromatic heterocyclic hydrocarbon groups having 2-7 carbon atoms]. 2. A compound of the general formula (Ia): [Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁷ have the same meanings as in the above formula (I)]. 3. The sulfonylated nucleoside derivative according to claim 1, wherein R ¹ is an optionally substituted benzyl group. 4. The sulfonylated nucleoside derivative according to claim 1, wherein R ¹ is an optionally substituted triphenylmethyl group. 5. The sulfonylated nucleoside derivative according to claim 1, wherein the acyloxy group of R ^{2 to} R ⁵ has 5 or less carbon atoms. 6. The sulfonylated nucleoside derivative according to claim 1, wherein the acyloxy group of R ^{2 to} R ⁵ is an acetyloxy group. 7. In the general formula (Ia), R ¹ is a triphenylmethyl group, R ² is an acetyloxy group, R ⁵ is a methanesulfonyloxy group, and R ³ and R ⁴ are hydrogen. The sulfonylated nucleoside derivative according to claim 2, which is an atom.