JP2005132775A - Furanosyladenine derivative and method for producing the same, and 3'-amino-3'-deoxyadenosine compound and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a precursor for producing a 3'-amino-3'-deoxyadenosine compound. <P>SOLUTION: The precursor is a furanosyladenine derivative of general formula(1)[ wherein, R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>and R<SP>4</SP>are each H, a halogen atom, heterocyclic group, (halogen-substituted) alkyl, (halogen-substituted) alkenyl, (halogen-substituted) alkynyl, (halogen-substituted) aryl, (halogen-substituted) aralkyl, amino, thiocarbamoyl, mercapto or a C(O)R<SP>5</SP>group ( R<SP>5</SP>is phenyl or a 1-6C alkyl ); X is a protonic acid group; and n is 0 or 1 ]. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a furanosyl adenine derivative and a method for producing the same, and a 3'-amino-3'-deoxyadenosine compound and a method for producing the same.

The 3′-amino-3′-deoxyadenosine compound represented by the following general formula (A) has not only been found to have antitumor activity, but is also used as a raw material for producing various adenosine nucleic acid derivatives. In particular, it is useful as a raw material for the synthesis of puromycin, an antibiotic that acts as a protein synthesis inhibitor (see, for example, Non-Patent Document 1 and Non-Patent Document 2).

  In addition, antisense oligonucleotides comprising 3'-amino-3'-deoxyadenosine compounds as building blocks have high binding performance to target DNA and RNA, so development of antiviral agents applying this property, etc. From the point of view, its usefulness is expected (for example, see Non-Patent Document 3).

On the other hand, as a method for producing a 3′-amino-3′-deoxyadenosine compound, a method using natural adenosine as a raw material (see, for example, Non-Patent Document 1 and Non-Patent Document 2), or 3 ′ from D-xylose. A method of obtaining a derivative of -amino-3′-deoxyribose and subjecting it to a nucleobase coupling reaction (for example, see Non-Patent Document 4) is known. In addition, a method of obtaining a 3′-diacylimide-3′-deoxyribose derivative from D-xylose and coupling it with adenine (for example, see Patent Document 1), or a method using levoglucosenone as a raw material (for example, And Patent Document 2) are also known.
JP-A-9-110893 JP-A-8-134065 MJRobins, RWMiles, MCSamano, RLKaspar, J.Org.Chem., 2001,66,8204-8210 NQN-Trung, O.Botta, S.Terenzi, P.Strazewski, J.Org.Chem., 2003,68,2038-2041 S.Gryaznov, JKChen, J.Am.Chem.Soc., 1994,116,3143-3144 A. Okuszek, JGVerkade, J. Med. Chem., 1979, 22, 882-885

  However, in the production methods described in Non-Patent Document 1 and Non-Patent Document 2, it is necessary to selectively aminate and deoxygenate the 3 'position rather than the 2' position of adenosine. For this reason, Non-Patent Document 1 requires a process using dimethylborane bromide, which is a pyrophoric reagent. On the other hand, in the method described in Non-Patent Document 2, a step of isomerizing the by-product protected at the 3 'position to the target compound protected at the 2' position is essential. Furthermore, in these methods, a side reaction in which the 2'-position reacts is unavoidable due to the reaction mechanism, and it is difficult to apply to gene synthesis and pharmaceutical use that require high purity.

In addition, in the production method described in Non-Patent Document 4, the production process is long and complicated, and there is a problem in terms of selectivity and yield in the coupling reaction. Furthermore, in the manufacturing method described in Patent Document 1, although high selectivity is obtained in the coupling reaction, there is a problem that the manufacturing process is long and complicated. Furthermore, the production method described in Patent Document 2 is not suitable for industrial production because it requires a process using highly toxic osmium tetroxide and an oxidation reaction at -80 to -40 ° C. . Furthermore, in the above-described production method, only the deoxyadenosine compound in which R ¹ and R ² are hydrogen atoms has been reported in the deoxyadenosine compound adenosine represented by the general formula (A). Therefore, it is desired to create a precursor that can easily and inexpensively produce a 3′-amino-3′-deoxyadenosine compound.

  This invention is made | formed in view of the said problem, and provides the precursor for manufacturing a 3'-amino-3'-deoxyadenosine compound simply and cheaply, and the manufacturing method of this precursor. Objective. Another object of the present invention is to provide a 3'-amino-3'-deoxyadenosine compound and a method for producing such a compound easily and inexpensively.

  As a result of intensive studies to achieve the above object, the present inventors can achieve the above object by using a furanosyl adenine derivative as a novel precursor of a 3′-amino-3′-deoxyadenosine compound. The present invention has been completed.

That is, the present invention provides furanosyl adenine derivatives represented by the following general formulas (1) to (3), which are novel precursors of 3′-amino-3′-deoxyadenosine compounds.

The furanosyl adenine derivative represented by the above general formula (1) can be produced by a method of reacting a xylonucleotide represented by the following general formula (5) with thionyl chloride, and represented by the above general formula (2). The furanosyl adenine derivative to be produced can be produced by a method in which the furanosyl adenine derivative represented by the general formula (1) is reacted with benzyl isocyanate. The furanosyl adenine derivative represented by the general formula (3) is produced by a method in which the furanosyl adenine derivative represented by the general formula (2) and a base are reacted in an aprotic organic solvent. Is possible.

The present invention also provides a 3′-amino-3′-deoxyadenosine compound represented by the following general formula (4).

  Furthermore, the 3′-amino-3′-deoxyadenosine compound represented by the general formula (4) is obtained by reacting the xylonucleotide represented by the general formula (5) with thionyl chloride, It can be produced by reacting, further reacting with a base in an aprotic organic solvent, hydrolyzing and then hydrogenating.

  In the conventional method for producing a 3′-amino-3′-deoxyadenosine compound, a by-product is produced due to the difficulty of the regioselective reaction as described above, and the production process is complicated. There are problems such as. In contrast, in the production method of the present invention, a furanosyl adenine derivative substituted with a sulfinyl group is first obtained as a reaction intermediate from the starting compound xylonucleotide. Since such a furanosyl adenine derivative has a 3 ′, 5′-O-sulfinyl group excellent as a leaving group and a hydroxyl group only at the 2 ′ position, a stereoselective reaction and a regioselective reaction become possible. -Amino-3'-deoxyadenosine compound can be easily obtained. Therefore, according to this production method, the 3'-amino-3'-deoxyadenosine compound can be produced easily and inexpensively.

In the above general formulas (1) to (5), R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, a halogen atom, a heterocyclic group, or an alkyl group which may be substituted with a halogen atom. An alkenyl group optionally substituted with a halogen atom, an alkynyl group optionally substituted with a halogen atom, an aryl group optionally substituted with a halogen atom, an aralkyl group optionally substituted with a halogen atom, an amino Group, thiocarbamoyl group, mercapto group or —C (O) R ⁵ group (R ⁵ represents a phenyl group or an alkyl group having 1 to 6 carbon atoms), X represents a protonic acid, and n represents 0 or 1, respectively. Show. However, in the compounds represented by the general formulas (3) and (4), except when R ¹ , R ² , R ³ and R ⁴ are hydrogen atoms at the same time, in the production method of these compounds, R ¹ , R ² , R ³ and R ⁴ may be hydrogen atoms at the same time.

In the general formulas (1) to (5), X is a protonic acid such as HCl, HBr, H ₂ SO ₄ , H ₃ PO ₄ , CH ₃ COOH, CH ₃ SO ₃ H (X is preferably HCl or HBr). .) N represents 0 or 1, for example, the furanosyl adenine derivative represented by the general formula (1) when n is 0 is represented by the following general formula (1a), n is 1, and The furanosyl adenine derivative represented by the general formula (1) when X is HCl is represented by the following general formula (1b).

  According to the present invention, a 3'-amino-3'-deoxyadenosine compound and a method for producing such a compound easily and inexpensively are provided. Also provided are furanosyl adenine derivatives useful as precursors for producing 3'-amino-3'-deoxyadenosine compounds and methods for producing the same.

  Hereinafter, a furanosyl adenine derivative according to the present invention and a method for producing the same, and a method for producing a 3'-amino-3'-deoxyadenosine compound and a 3'-amino-3'-deoxyadenosine compound using the furanosyl adenine derivative are described below. explain.

First, about furanosyl adenine derivatives represented by general formulas (1) to (3) and R ^{1 to} R ⁴ of the 3′-amino-3′-deoxyadenosine compound represented by general formula (4) in the present invention. explain. R ^{1 to} R ⁴ in the general formulas (1) to (4) are each independently substituted with a hydrogen atom, a halogen atom, a heterocyclic group, an alkyl group which may be substituted with a halogen atom, or a halogen atom. An alkenyl group which may be substituted with a halogen atom, an aryl group which may be substituted with a halogen atom, an aralkyl group which may be substituted with a halogen atom, an amino group, a thiocarbamoyl group, a mercapto group , -C (O) R ⁵ group. However, in the compounds represented by the general formulas (3) and (4), the case where R ^{1 to} R ⁴ are simultaneously hydrogen atoms is excluded.

Here, examples of the halogen atom as R ^{1 to} R ⁴ and the halogen atom that substitutes the alkyl group, alkenyl group, alkynyl group, aryl group, and aralkyl group include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Of these, a fluorine atom or an iodine atom is preferred.

  The alkyl group is preferably a linear, cyclic or branched alkyl group having 1 to 20 carbon atoms, more preferably a linear, cyclic or branched alkyl group having 1 to 12 carbon atoms, 1-6 linear, cyclic or branched alkyl groups are more preferred. Suitable alkyl groups include, for example, a methyl group, an ethyl group, a propyl group, a butyl group, and a cyclopropyl group. The alkyl group may be substituted with a halogen atom, and an alkyl group substituted with a fluorine atom such as a trifluoromethyl group is preferred.

  The alkenyl group is preferably a linear, cyclic or branched alkenyl group having 2 to 20 carbon atoms, more preferably a linear, cyclic or branched alkenyl group having 2 to 12 carbon atoms, 2-6 linear, cyclic or branched alkenyl groups are more preferred. Suitable alkenyl groups include, for example, ethenyl, propenyl, and butenyl groups. The alkenyl group may be substituted with a halogen atom, and an ethenyl group substituted with a bromine atom such as a 2-bromoethenyl group is preferred.

  The alkynyl group is preferably a linear, cyclic or branched alkynyl group having 2 to 20 carbon atoms, more preferably a linear, cyclic or branched alkynyl group having 2 to 12 carbon atoms, 2-6 linear, cyclic or branched alkynyl groups are more preferred. Suitable alkynyl groups include, for example, ethynyl group, propynyl group, butynyl group. The alkynyl group may be substituted with a halogen atom, and examples thereof include an ethynyl group substituted with a fluorine atom or a bromine atom.

  The heterocyclic group means a monovalent group obtained by removing one hydrogen atom from a heterocyclic compound. For example, a heterocyclic group such as furan, thiophene, oxazole, imidazole, thiazole, pyridine, pyrimidine, pyrazine, piperazine, or triazine. Monovalent group obtained by removing one hydrogen atom from a monocyclic compound, one hydrogen atom from a condensed heterocyclic compound such as benzofuran, benzothiophene, indole, benzothiazole, benzimidazole, quinoline, dibenzofuran, carbazole, purine, etc. Excluded are monovalent groups.

  The aryl group means a monovalent group obtained by removing one hydrogen atom from an aromatic hydrocarbon, and examples thereof include a phenyl group, a tolyl group, a xylyl group, a biphenylyl group, a naphthyl group, an anthryl group, and a phenanthryl group. The aryl group may be substituted with a halogen atom, for example, a phenyl group substituted with a fluorine atom or a chlorine atom at the p-position, a phenyl group substituted with a chlorine atom at the 3,4-position, A phenyl group substituted with a fluoromethyl group can be mentioned.

  The aralkyl group means a monovalent group in which an alkyl group is bonded to an aryl group, and examples thereof include a benzyl group, a phenylethyl group, an α-methylphenyl group, a 1-methyl-1-phenylethyl group, and a diphenylmethyl group. It is done. The aralkyl group may be substituted with a halogen atom, and examples thereof include a benzyl group in which the aromatic ring is substituted at the 3rd and 4th positions with a chlorine atom.

^{R 5} constituting the -C (O) ^{R 5} group is a phenyl group or an alkyl group having 1 to 6 carbon atoms. R ⁵ is preferably a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an n-pentyl group, a phenyl group or the like.

R ¹ is preferably a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a benzyl group, a phenyl group, or —C (O) R ⁵ group, and R ² is preferably a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. , A benzyl group, a phenyl group, or a —C (O) R ⁵ group. R ³ is preferably hydrogen, amino group, thiocarbamoyl group, mercapto group, halogen atom or —C (O) R ⁵ group, and R ⁴ is preferably hydrogen atom or halogen atom.

Moreover, as a suitable combination of R ^{1 to} R ⁴ , R ¹ , R ² , R ³ and R ⁴ shown in Table 1 can be arbitrarily selected and combined, but R ¹ , R ² , R 4 ³ and R ⁴ are hydrogen atoms (excluding the compounds represented by the above general formulas (3) and (4)), and R ¹ and R ² are methyl groups, and R ³ and R ⁴ A compound in which is a hydrogen atom is more preferred.

  Next, the manufacturing method of the furanosyl adenine derivative based on this invention is demonstrated.

  The furanosyl adenine derivative represented by the general formula (1) (hereinafter referred to as “furanosyl adenine derivative (1)”), that is, 3 ′, 5′-O-sulfinylxyloadenosine derivative is a novel nucleoside derivative.

  The furanosyl adenine derivative (1) is obtained by reacting a xylonucleoside represented by the above general formula (5) (hereinafter referred to as “xylon nucleoside (5)”) with thionyl chloride in an aprotic organic solvent. be able to. The amount of thionyl chloride used is equal to or more than that of xylonucleotide (5), preferably 4 times equivalent. The aprotic organic solvent may be a mixed solvent, and for example, a mixed solvent of acetylonitrile and ether (for example, 1,3-dioxolane) is preferable. The furanosyl adenine derivative (1) can be easily taken out and purified only by a recrystallization operation using a ketone solvent such as 4-methyl-2-pentanone or methyl ethyl ketone.

  The furanosyl adenine derivative (1) has a structure in which a sulfinyl group is bonded at the 3 'position and a furanose hydroxyl group is present at the 2' position. That is, the furanosyl adenine derivative (1) has a sulfinyl group that is a good leaving group and a hydroxyl group that allows easy introduction of a substituent. Therefore, the furanosyl adenine derivative (1) is suitable as a precursor that can be produced easily and inexpensively for a 3'-amino-3'-deoxyadenosine compound.

  The structure of the furanosyl adenine derivative (1) can be confirmed by infrared absorption spectrum (IR), nuclear magnetic resonance (NMR), mass spectrometry (MS), etc., and the purity is TLC, IR, HPLC, NMR It can be measured by melting point measurement or the like.

The xylonucleoside (5) can be obtained by glycosidically bonding D-xylose and a purine compound. Literature (C. Nakayama and M. Saneyoshi, Nucleosides & Nucleotides, 1982, 1, 139-146 and MS Motawia, M. Meldal, M. Sofan, P. Stein, EB Pedersen, C. Nielsen, 1995, 265-270) An outline of a reaction scheme for obtaining xylonucleoside (5) from D-xylose (6) is shown below.

  In the above reaction scheme, the bond represented by the wavy line means that the bond is formed toward the upper surface or the lower surface of the surface formed by the five-membered ring. MeOH means methanol, Bz-Cl means benzoyl chloride, Bz means benzoyl group, MeCN means acetonitrile, and NaOMe means sodium methoxide.

  The furanosyl adenine derivative represented by the general formula (2) (hereinafter referred to as “furanosyl adenine derivative (2)”) is converted into the furanosyl adenine derivative (1) in an aprotic organic solvent in the presence of a base. It can be obtained by reacting benzyl isocyanate. The furanosyl adenine derivative (2) can be easily taken out and purified only by a recrystallization operation using a ketone solvent such as 4-methyl-2-pentanone or methyl ethyl ketone.

  The furanosyl adenine derivative (2) is a carbamate obtained by reacting the 2′-position hydroxyl group of the furanosyl adenine derivative (1) with the isocyanate group of benzyl isocyanate. Further, since the furanosyl adenine derivative (2) has a benzylamino group having an unpaired electron at the 2 ′ position, the unpaired electron attacks the 3 ′ position in a stereoselective and regioselective manner to form a sulfinyl group. Desorption is possible. Therefore, the furanosyl adenine derivative (2) is suitable as a precursor that can be produced easily and inexpensively for the 3'-amino-3'-deoxyadenosine compound.

  Examples of the base include triethylamine, N, N-dimethylaminopyridine (DMAP), and the aprotic solvent may be a mixed solvent. For example, a mixed solvent of acetylonitrile and ether (for example, tetrahydrofuran) is preferable. .

  The structure of the furanosyl adenine derivative (2) can be confirmed by infrared absorption spectrum (IR), nuclear magnetic resonance (NMR), mass spectrometry (MS), etc., and the purity is TLC, IR, HPLC, NMR It can be measured by melting point measurement or the like.

  The furanosyl adenine derivative represented by the general formula (3) (hereinafter referred to as “furanosyl adenine derivative (3)”) is obtained by reacting the furanosyl adenine derivative (2) with a base in an aprotic solvent. Can be obtained. This reaction condition is preferably performed under mild conditions, for example, 0 to 40 ° C. The furanosyl adenine derivative (3) can be easily taken out and purified by column chromatography.

  In the furanosyl adenine derivative (3), the unpaired electron of the benzylamino group of the furanosyl adenine derivative (2) attacks nucleophilically at the 3 ′ position, and the sulfinyl group is eliminated to react stereoselectively and regioselectively. It is the obtained oxazolidininone. In addition, the furanosyl adenine derivative (3) can be converted to an amino group at the 3 'position by opening the oxazolidininone by hydrolysis and then hydrogenating it. Therefore, the furanosyl adenine derivative (3) is suitable as a precursor that can be produced easily and inexpensively for the 3'-amino-3'-deoxyadenosine compound.

  Examples of the aprotic organic solvent include dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone, dimethylaminoimidazole (DMI), ethylene glycol dimethyl ether, and the like.

  As the base, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, disodium hydrogen phosphate, dipotassium hydrogen phosphate and the like can be used, and the amount used is a furanosyl adenine derivative ( It is equivalent or more to 2), preferably 2.2 times equivalent.

  The structure of the furanosyl adenine derivative (3) can be confirmed by infrared absorption spectrum (IR), nuclear magnetic resonance (NMR), mass spectrometry (MS), etc., and the purity is TLC, IR, HPLC, NMR It can be measured by melting point measurement or the like.

Next, a method for producing a 3′-amino-3′-deoxyadenosine compound according to the present invention will be described. A method for producing a 3′-amino-3′-deoxyadenosine compound will be described according to a reaction scheme.

  In the above reaction scheme, when xylonucleotide (5) is reacted with thionyl chloride, furanosyl adenine derivative (1) is produced as an intermediate, and when further reacted with benzyl isocyanate, furanosyl adenine derivative (2) is produced as an intermediate. When obtained and further reacted with a base in an aprotic organic solvent, a furanosyl adenine derivative (3) is formed as an intermediate, which is further hydrolyzed and then hydrogenated to give 3'-amino-3'-deoxy. An adenosine compound is obtained. The reaction for obtaining the furanosyl adenine derivative (1), the reaction for obtaining the furanosyl adenine derivative (2), and the reaction for obtaining the furanosyl adenine derivative (3) can be performed by the same method as described above.

  Further, in the reaction for obtaining a 3′-amino-3′-deoxyadenosine compound from the furanosyl adenine derivative (3), which is a reaction intermediate, in accordance with the method described in Non-Patent Document 1, a furanosyl adenine derivative ( After hydrolyzing 3) in the presence of a base, a 3′-amino-3′-deoxyadenosine compound can be produced with high selectivity and easily by hydrogenation in the presence of a Pd catalyst. This 3'-amino-3'-deoxyadenosine compound can be easily separated and purified by combining separation operations by column chromatography.

  In the above production method, a series of reactions may be performed by adding all raw material compounds, or the raw material compounds may be sequentially added and reacted. In this case, the 3'-amino-3'-deoxyadenosine compound may be separated and purified after all the reactions are completed. Further, separation and purification may be performed for each reaction step, and the reaction may be sequentially performed using the obtained reaction intermediate.

  The structure of the 3′-amino-3′-deoxyadenosine compound thus obtained can be confirmed by infrared absorption spectrum (IR), nuclear magnetic resonance (NMR), mass spectrometry (MS), or the like. The purity can be measured by TLC, IR, HPLC, NMR, melting point measurement or the like.

  As described above, since xylonucleosides can be synthesized using D-xylose as a raw material, the 3′-amino-3′-deoxyadenosine compound represented by the general formula (4) is obtained using D-xylose as a starting material. Synthesis is possible by a production method including the production steps described above.

  In such a production method, the starting material D-xylose is inexpensive, the reaction can be performed under mild conditions, and the precursor and the final product can be easily purified by recrystallization operation, column chromatography or the like. Therefore, the synthesis process is not complicated, and a 3′-amino-3′-deoxyadenosine compound can be provided simply and inexpensively.

  The obtained 3'-amino-3'-deoxyadenosine compound is useful as a raw material for producing adenosine nucleic acid derivatives and as a synthetic raw material for puromycin, which is an antibiotic that acts as a protein synthesis inhibitor.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.

[Production of furanosyl adenine derivative]
(Example 1)
Preparation of 9- (3 ′, 5′-O-sulfinyl-β-D-xylofuranosyl) adenine 9- (β-D-xylofuranosyl) adenine (2.67 g, 10.0 mMol), acetonitrile (10 mL) and 1,3 -Thionyl chloride (3.57 g, 30 mMol) was added to a mixed solution of dioxolane (4 ml) and pyridine (2.37 g, 30 mMol), and the mixture was stirred at 25 ° C for 4 hours. To the reaction solution were added sodium bicarbonate (10.1 g) and water (46 mL), and the mixture was extracted twice with ethyl acetate (46 mL). The solvent was distilled off under reduced pressure, and the resulting crude product was recrystallized and purified with 4-methyl-2-pentanone and dried under reduced pressure to give 9- (3 ′, 5′-O-sulfinyl-β-D- 2.62 g (yield 83.4%) of white powder of xylofuranosyl) adenine was obtained.

The measurement results of melting point (Mp), ¹ H-NMR and mass spectrometry are shown below.
Mp (4-methyl-2-pentanone): 229 ° C.
¹ H-NMR (DMSO-d ₆ , ppm): δ 8.22 (s, 1H, 2-H), 8.20 (s, 1H, 8-H), 7.37 (bs, 2H, NH ₂ ) 6.48 (d, 1H, J = 4.0 Hz, OH), 6.09 (bs, 1H, H-1 ′), 4.98 (dd, 1H, J = 13.3 Hz and 1.9 Hz, H-4) '), 4.87 (d, 1H, J = 2.4Hz, H-3'), 4.63 (d, 1H, J = 2.8Hz, H-2 '), 4.51 (d, 1H, J = 1.8Hz, H-5 '), 4.36 (d, 1H, J = 13.1Hz, H-5'),
MS (m / z,%): 314 ([M + H] ⁺ ) (100), 165 (15), 120 (35), 89 (56), 77 (59).

(Example 2)
Preparation of 9- [2-O- (N-benzylcarbonyl) -3 ′, 5′-O-sulfinyl-β-D-xylofuranosyl] adenine 9- (3 ′, 5′-O-sulfinyl-β-D- Benzyl isocyanate (2.66 g, 20 mMol) was added to a mixed solution of xylofuranosyl) adenine (3.13 g, 10 mMol), triethylamine (1.52 g, 15 mMol), acetonitrile (50 mL), and tetrahydrofuran (50 mL) at 25 ° C. For 21 hours. Ethanol (10 mL) was added to the reaction solution, and the mixture was stirred at 25 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, recrystallized and purified with the resulting crude product 4-methyl-2-pentanone, and dried under reduced pressure to give 9- [2-O- (N-benzylcarbonyl) -3 ′, 5 4.18 g (yield 93.7%) of white powder of '-O-sulfinyl-β-D-xylofuranosyl] adenine was obtained.

The measurement results of melting point (Mp), ¹ H-NMR and mass spectrometry are shown below.
Mp (4-methyl-2-pentanone): 174 ° C.
¹ H-NMR (DMSO-d ₆ , ppm): δ 8.23 (t, J = 6.2 Hz, 1H, 2-H), 8.20 (pseudo-s, 2H, H-2 and H-8), _{7.38 (bs, 2H, NH 2} ), 7.29 (m, 5H, Ph-H), 6.25 (d, 1H, J = 1.8Hz, H-1 '), 5.48 (s, 1H, H-2 ′), 5.12 (d, 1H, J = 2.4 Hz, H-3 ′), 4.97 (dd, 1H, J = 13.3 Hz and 2.0 Hz, H-5 ′), 4 45 (pseudo-s, 1H, H-5 ′), 4.35 (d, 1H, J = 13.4 Hz, H-5 ′), 4.23 (d, 2H, J = 6.1 Hz, Ph-CH ₂ ),
¹³ C-NMR (DMSO-d ₆ , ppm): δ 156.0, 154.4, 153.0, 149.1, 138.9, 137.7, 128.2, 127.1, 126.9, 118 .5, 86.7, 80.4, 72.9, 69.3, 55.4, 44.0,
MS (m / z,%): 447 ([M + H] ⁺ ) (93), 312 (54), 307 (33), 01 (100), 89 (65).

(Example 3)
Preparation of 9- [3- (benzylamino) -3-N, 2-O-carbonyl-3-deoxy-β-D-ribofuranosyl] adenine 9- [2-O- (N-benzylcarbonyl) -3 ′, 5′-O-sulfinyl-β-D-xylofuranosyl] adenine (4.46 g, 10 mMol) and N, N-dimethylformamide (100 mL) were mixed, and potassium hydrogen carbonate (4.50 g, 45 mMol) was added. Stir at 25 ° C. for 11 days. The insoluble inorganic salt in the reaction solution was separated by filtration, then the filtrate was concentrated under reduced pressure, and the obtained crude product was purified using silica gel column chromatography to obtain 9- [3- (benzylamino) -3-N. , 2-O-carbonyl-3-deoxy-β-D-ribofuranosyl] adenine was obtained as a white powder (2.30 g, yield 60.2%). In addition, it was confirmed that the spectral data of adenine obtained by the above production method was consistent with the data described in Non-Patent Document 1.

Claims (13)

A furanosyl adenine derivative represented by the following general formula (1).

[Wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, a halogen atom, a heterocyclic group, an alkyl group which may be substituted with a halogen atom, or a halogen atom. An alkenyl group, an alkynyl group optionally substituted with a halogen atom, an aryl group optionally substituted with a halogen atom, an aralkyl group optionally substituted with a halogen atom, an amino group, a thiocarbamoyl group, a mercapto group, or- C (O) R ⁵ group (R ⁵ represents a phenyl group or an alkyl group having 1 to 6 carbon atoms), X represents a protonic acid, and n represents 0 or 1, respectively. ] A furanosyl adenine derivative represented by the following general formula (2).

[Wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, a halogen atom, a heterocyclic group, an alkyl group which may be substituted with a halogen atom, or a halogen atom. An alkenyl group, an alkynyl group optionally substituted with a halogen atom, an aryl group optionally substituted with a halogen atom, an aralkyl group optionally substituted with a halogen atom, an amino group, a thiocarbamoyl group, a mercapto group, or- C (O) R ⁵ group (R ⁵ represents a phenyl group or an alkyl group having 1 to 6 carbon atoms), X represents a protonic acid, and n represents 0 or 1, respectively. ] A furanosyl adenine derivative represented by the following general formula (3).

[Wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, a halogen atom, a heterocyclic group, an alkyl group which may be substituted with a halogen atom, or a halogen atom. An alkenyl group, an alkynyl group optionally substituted with a halogen atom, an aryl group optionally substituted with a halogen atom, an aralkyl group optionally substituted with a halogen atom, an amino group, a thiocarbamoyl group, a mercapto group, or- C (O) R ⁵ group (R ⁵ represents a phenyl group or an alkyl group having 1 to 6 carbon atoms), X represents a protonic acid, and n represents 0 or 1, respectively. However, the case where R ¹ , R ² , R ³ and R ⁴ are hydrogen atoms at the same time is excluded. ] R ¹ and / or R ² is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a benzyl group, a phenyl group and a group selected from the group consisting of —C (O) R ⁵ groups (R ⁵ is a phenyl group or a carbon number) The furanosyl adenine derivative according to claim 1, wherein the furanosyl adenine derivative is represented by 1 to 6 alkyl groups. R ³ is a group selected from the group consisting of a hydrogen atom, a halogen atom, an amino group, a thiocarbamoyl group, a mercapto group, and —C (O) R ⁵ group (R ⁵ represents a phenyl group or an alkyl group having 1 to 6 carbon atoms). The furanosyl adenine derivative according to any one of claims 1 to 4, which is characterized by: The furanosyl adenine derivative according to any one of claims 1 to 5, wherein R ⁴ is a group selected from the group consisting of a hydrogen atom and a halogen atom. R ¹ and R ² are hydrogen atoms, and R ³ is a group selected from the group consisting of hydrogen atoms, halogen atoms, amino groups, thiocarbamoyl groups, mercapto groups, and —C (O) R ⁵ groups (R ⁵ is phenyl A furanosyl adenine derivative according to claim 1, wherein R ⁴ is a hydrogen atom or a halogen atom. R ¹ and R ² are methyl groups, and R ³ is a group selected from the group consisting of a hydrogen atom, a halogen atom, an amino group, a thiocarbamoyl group, a mercapto group, and a —C (O) R ⁵ group (R ⁵ is a phenyl group) A furanosyl adenine derivative according to claim 1, wherein R ⁴ is a hydrogen atom or a halogen atom. A 3′-amino-3′-deoxyadenosine compound represented by the following general formula (4).

[Wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, a halogen atom, a heterocyclic group, an alkyl group which may be substituted with a halogen atom, or a halogen atom. An alkenyl group, an alkynyl group optionally substituted with a halogen atom, an aryl group optionally substituted with a halogen atom, an aralkyl group optionally substituted with a halogen atom, an amino group, a thiocarbamoyl group, a mercapto group, or- C (O) R ⁵ group (R ⁵ represents a phenyl group or an alkyl group having 1 to 6 carbon atoms), X represents a protonic acid, and n represents 0 or 1, respectively. However, the case where R ¹ , R ² , R ³ and R ⁴ are hydrogen atoms at the same time is excluded. ] A method for producing a furanosyl adenine derivative, wherein a furanosyl adenine derivative represented by the following general formula (1) is obtained by reacting a xylonucleotide represented by the following general formula (5) with thionyl chloride.

[Wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, a halogen atom, a heterocyclic group, an alkyl group which may be substituted with a halogen atom, or a halogen atom. An alkenyl group, an alkynyl group optionally substituted with a halogen atom, an aryl group optionally substituted with a halogen atom, an aralkyl group optionally substituted with a halogen atom, an amino group, a thiocarbamoyl group, a mercapto group, or- C (O) R ⁵ group (R ⁵ represents a phenyl group or an alkyl group having 1 to 6 carbon atoms), X represents a protonic acid, and n represents 0 or 1, respectively. ] A method for producing a furanosyl adenine derivative, wherein a furanosyl adenine derivative represented by the following general formula (2) is obtained by reacting a furanosyl adenine derivative represented by the following general formula (1) with benzyl isocyanate.

[Wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, a halogen atom, a heterocyclic group, an alkyl group which may be substituted with a halogen atom, or a halogen atom. An alkenyl group, an alkynyl group optionally substituted with a halogen atom, an aryl group optionally substituted with a halogen atom, an aralkyl group optionally substituted with a halogen atom, an amino group, a thiocarbamoyl group, a mercapto group, or- C (O) R ⁵ group (R ⁵ represents a phenyl group or an alkyl group having 1 to 6 carbon atoms), X represents a protonic acid, and n represents 0 or 1, respectively. ] A furanosyl adenine derivative represented by the following general formula (3) is obtained by reacting a furanosyl adenine derivative represented by the following general formula (2) with a base in an aprotic organic solvent. A method for producing a derivative.

[Wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, a halogen atom, a heterocyclic group, an alkyl group which may be substituted with a halogen atom, or a halogen atom. An alkenyl group, an alkynyl group optionally substituted with a halogen atom, an aryl group optionally substituted with a halogen atom, an aralkyl group optionally substituted with a halogen atom, an amino group, a thiocarbamoyl group, a mercapto group, or- C (O) R ⁵ group (R ⁵ represents a phenyl group or an alkyl group having 1 to 6 carbon atoms), X represents a protonic acid, and n represents 0 or 1, respectively. ] A xylonucleotide represented by the following general formula (5) is reacted with thionyl chloride, further reacted with benzyl isocyanate, further reacted with a base in an aprotic organic solvent, hydrolyzed and then hydrogenated. The manufacturing method of the 3'-amino-3'-deoxyadenosine compound which obtains the 3'-amino-3'-deoxyadenosine compound represented by following General formula (4) by this.

[Wherein R ¹ , R ² , R ³ and R ⁴ are each independently a hydrogen atom, a halogen atom, a heterocyclic group, an alkyl group which may be substituted with a halogen atom, or a halogen atom. An alkenyl group, an alkynyl group optionally substituted with a halogen atom, an aryl group optionally substituted with a halogen atom, an aralkyl group optionally substituted with a halogen atom, an amino group, a thiocarbamoyl group, a mercapto group, or- C (O) R ⁵ group (R ⁵ represents a phenyl group or an alkyl group having 1 to 6 carbon atoms), X represents a protonic acid, and n represents 0 or 1, respectively. ]