JP2006022009A - METHOD FOR PRODUCING 3-FLUORO-2,3-DIDEOXY-beta-D-RIBOFURANOSYL-TYPE NUCLEOSIDE DERIVATIVE - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a 3-fluoro-2,3-dideoxy-β-D-ribofuranosyl-type nucleoside derivative, capable of industrially producing the derivative, especially 3'-fluoro-2',3'-dideoxyguanosine, at a low cost. <P>SOLUTION: This 3-fluoro-2,3-dideoxy-β-D-ribofuranosyl-type nucleoside derivative is produced by reacting a 3-halogeno-3-dideoxy-β-D-xylofuranosyl-type nucleoside derivative with sulfur tetrafluoride (SF<SB>4</SB>), so as to convert the xylofuranosyl-type derivative into a 2-halogeno-2,3-dideoxy-3-fluoro-β-D-arabinofuranosyl-type nucleoside derivative with high regioselectivity, and then conducting, irrespective of order, a process (1) for subjecting a halogen atom at the 2'-position to dehalogenation, a process (2) for subjecting a protective group for a hydroxy group at the 5'-position to deprotection, and, if necessary, a process (3) for conducting at least any one of protection, deprotection, and modification of a nucleic-acid base or its derivative. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for producing a 3-fluoro-2,3-dideoxy-β-D-ribofuranosyl nucleoside derivative.

  3-Fluoro-2,3-dideoxy-β-D-ribofuranosyl nucleoside derivatives are attracting attention because of their antitumor activity and strong antiviral activity against human immunodeficiency virus (HIV) (for example, 3′- For fluoro-2 ′, 3′-dideoxyadenosine, refer to Patent Document 1, for 3′-fluoro-2 ′, 3′-dideoxyguanosine, for Patent Document 2, 3′-fluoro-2 ′, 3′-dideoxyinosine. (Refer nonpatent literature 1).

As an efficient method for synthesizing these series of 3-fluoro-2,3-dideoxy-β-D-ribofuranosyl nucleoside derivatives, a hydroxyl group or a silyloxy group obtained by silylation of a hydroxyl group at the 2′-α position By reacting a 3-halogeno-3-deoxy-β-D-xylofuranosyl nucleoside derivative having a halogen atom other than a fluorine atom at the β-position with a dialkylaminosulfur trifluoride, the halogen atom is transferred to the 2′-β-position. Converted to a 2-halogeno-2,3-dideoxy-3-fluoro-β-D-arabinofuranosyl nucleoside derivative in which the 3′-α position is fluorinated, and the halogen atom at the 2 ′ position is dehalogenated, 3-fluoro-2,3-dideoxy-β-D-ribofuranosyl-type nucleoside induction by deprotecting the protecting group at the 5′-position hydroxyl group A method of synthesizing a conductor has been reported (Patent Document 3, Non-Patent Document 2).
East German Patent No. 158903 Specification East German Patent No. 209197 Specification JP 2001-122891 Journal of Medicinal Chemistry (USA), 1989, Vol. 32, No. 8, p.1743-9 Nucleosides, Nucleotides & Nucleic Acids (USA), 2003, Vol. 22, No. 5-8, p.711-713

  The synthesis methods disclosed in Patent Document 3 and Non-Patent Document 2 are efficient synthesis methods at the laboratory level, but it is necessary to use a very expensive dialkylaminosulfur trifluoride for industrial use. In practice, it could not be an industrial production method.

  Furthermore, since this reaction proceeds via a bromonium ion (divalent bromine cation) when the 3′-β position is a bromine atom as a transition state of the reaction (see the figure below), the target 2′-β There was a problem of by-production of 2′-α-fluoro-3′-β-bromo, which is a positional isomer of -bromo-3′-α-fluoro. In fact, the regioselectivity (2′-β-bromo) when 9- (3-bromo-3-deoxy-β-D-xylofuranosyl) guanine derivative specifically targeted in the present invention is reacted with diethylaminosulfur trifluoride. -3′-α-fluoro form: 2′-α-fluoro-3′-β-bromo form) is as low as 2.9: 1 (see Comparative Example 1), and as a result A 2,3-dideoxy-β-D-ribofuranosyl nucleoside derivative could not be obtained in good yield.

本発明の目的は、工業的な使用において非常に高価なジアルキルアミノサルファートリフルオリドの使用を回避し、さらに目的とする２’−β−ハロゲノ−３’−α−フルオロ体が高い位置選択性で得られる脱ヒドロキシフッ素化剤を見出すことである。その結果として、所望の３−フルオロ−２，３−ジデオキシ−β−Ｄ−リボフラノシル型ヌクレオシド誘導体を工業的に低コストで製造できる方法を提供することである。

The object of the present invention is to avoid the use of dialkylaminosulfur trifluoride which is very expensive in industrial use, and further, the target 2′-β-halogeno-3′-α-fluoro compound has high regioselectivity. It is to find the resulting dehydroxyfluorinating agent. As a result, it is to provide a method capable of industrially producing a desired 3-fluoro-2,3-dideoxy-β-D-ribofuranosyl nucleoside derivative at low cost.

As a result of intensive studies to solve the above problems, the inventors of the present invention have a 3-halogeno-3-hydroxy group at the 2′-α position and a halogen atom other than a fluorine atom at the 3′-β position. By reacting a deoxy-β-D-xylofuranosyl-type nucleoside derivative with sulfur tetrafluoride (SF ₄ ) that can be used relatively inexpensively for industrial use, a halogen atom is rearranged to the 2′-β position. It was found that a 2-halogeno-2,3-dideoxy-3-fluoro-β-D-arabinofuranosyl nucleoside derivative having a fluorinated '-α-position can be obtained satisfactorily. Furthermore, the regioselectivity is very high when the 9- (3-bromo-3-deoxy-β-D-xylofuranosyl) guanine derivative specifically targeted in the present invention is reacted with sulfur tetrafluoride (see Example 1). As a dehydroxyfluorinating agent, sulfur tetrafluoride was found to be significantly superior to dialkylaminosulfur trifluoride.

  And (1) a step of dehalogenating a 2′-position halogen atom using the obtained 2-halogeno-2,3-dideoxy-3-fluoro-β-D-arabinofuranosyl nucleoside derivative, 2) Deprotecting the 5′-position protecting group and, if necessary, (3) performing at least one of protection, deprotection or modification of the nucleobase or derivative thereof in any order. It has been found that 3-fluoro-2,3-dideoxy-β-D-ribofuranosyl-type nucleoside derivatives can be produced industrially at low cost.

  In the production of 3′-fluoro-2 ′, 3′-dideoxyguanosine, which is particularly targeted in the present invention, the selectivity of each step is high and impurities that are difficult to separate are hardly produced as by-products. This is a very useful method for industrial production of ', 3'-dideoxyguanosine.

  That is, the present invention relates to the general formula [I]

［式中、Ｂは核酸塩基またはその誘導体を表し、Ｘは塩素原子、臭素原子またはヨウ素原子を表し、Ｒは水酸基の保護基を表す］で示される３−ハロゲノ−３−デオキシ−β−Ｄ−キシロフラノシル型ヌクレオシド誘導体をサルファーテトラフルオリド（ＳＦ₄）と反応させることにより、一般式［ＩＩ］

[Wherein B represents a nucleobase or a derivative thereof, X represents a chlorine atom, a bromine atom, or an iodine atom, and R represents a protecting group for a hydroxyl group], 3-halogeno-3-deoxy-β-D - a xylofuranosyl nucleoside derivative by reaction with sulfur tetrafluoride (SF _4), the general formula [II]

［式中、Ｂは核酸塩基またはその誘導体を表し、Ｘは塩素原子、臭素原子またはヨウ素原子を表し、Ｒは水酸基の保護基を表す］で示される２−ハロゲノ−２，３−ジデオキシ−３−フルオロ−β−Ｄ−アラビノフラノシル型ヌクレオシド誘導体を製造する方法を包含する。

[Wherein, B represents a nucleobase or a derivative thereof, X represents a chlorine atom, a bromine atom, or an iodine atom, and R represents a hydroxyl-protecting group] 2-halogeno-2,3-dideoxy-3 A method for producing a fluoro-β-D-arabinofuranosyl-type nucleoside derivative.

  Further, the present invention provides a compound represented by the general formula [III]

［式中、Ｒは水酸基の保護基を表し、Ｒ’はアミノ基の保護基を表す］で示される９−（３−ブロモ−３−デオキシ−β−Ｄ−キシロフラノシル）グアニン誘導体をサルファーテトラフルオリド（ＳＦ₄）と反応させることにより、一般式［ＩＶ］

[Wherein R represents a protecting group for a hydroxyl group and R ′ represents a protecting group for an amino group] A 9- (3-bromo-3-deoxy-β-D-xylofuranosyl) guanine derivative represented by the formula: (SF ₄ ) to give a compound of the general formula [IV]

［式中、Ｒは水酸基の保護基を表し、Ｒ’はアミノ基の保護基を表す］で示される９−（２−ブロモ−２，３−ジデオキシ−３−フルオロ−β−Ｄ−アラビノフラノシル）グアニン誘導体を製造する方法を包含する。

[Wherein, R represents a hydroxyl-protecting group, and R ′ represents an amino-protecting group] 9- (2-bromo-2,3-dideoxy-3-fluoro-β-D-arabino A method for producing a furanosyl) guanine derivative.

  The present invention also uses the 2-halogeno-2,3-dideoxy-3-fluoro-β-D-arabinofuranosyl-type nucleoside derivative produced as described above, and the following (1), (2) and If necessary, the steps of (3) are performed in random order, so that the general formula [V]

［式中、Ｂ'は核酸塩基またはその誘導体を表す］で示される３−フルオロ−２，３−ジデオキシ−β−Ｄ−リボフラノシル型ヌクレオシド誘導体を製造する方法を包含する。
（１）２'位ハロゲン原子を脱ハロゲン化する工程、
（２）５'位水酸基の保護基を脱保護する工程、
（３）核酸塩基またはその誘導体の保護、脱保護または修飾の内、少なくとも何れか一つを行う工程。

[Wherein B ′ represents a nucleobase or a derivative thereof] includes a method for producing a 3-fluoro-2,3-dideoxy-β-D-ribofuranosyl-type nucleoside derivative represented by the formula:
(1) a step of dehalogenating a 2′-position halogen atom;
(2) a step of deprotecting the protecting group for the 5′-position hydroxyl group,
(3) A step of performing at least one of protection, deprotection or modification of a nucleobase or a derivative thereof.

  In addition, the present invention uses the 9- (2-bromo-2,3-dideoxy-3-fluoro-β-D-arabinofuranosyl) guanine derivative produced as described above, and the following (1), ( By performing the steps of 2) and (3) in random order, the formula [VI]

で示される３’−フルオロ−２’，３’−ジデオキシグアノシンを製造する方法を包含する。
（１）２'位臭素原子を脱臭素化する工程、
（２）５'位水酸基の保護基を脱保護する工程、
（３）グアニン誘導体の２位アミノ基の保護基を脱保護する工程。

The method of manufacturing 3'-fluoro-2 ', 3'-dideoxyguanosine shown by these is included.
(1) a step of debromination of a 2′-position bromine atom;
(2) a step of deprotecting the protecting group for the 5′-position hydroxyl group,
(3) A step of deprotecting the protecting group of the 2-position amino group of the guanine derivative.

 According to the present invention, 3-fluoro-2,3-dideoxy-β-D-ribofuranosyl-type nucleoside derivatives, particularly 3′-fluoro-2 ′, 3′-dideoxyguanosine, are industrially much lower than before. Can be manufactured at cost.

  Hereinafter, the method for producing the 3-fluoro-2,3-dideoxy-β-D-ribofuranosyl nucleoside derivative of the present invention will be described in detail.

  Examples of B of the 3-halogeno-3-deoxy-β-D-xylofuranosyl nucleoside derivative represented by the general formula [I] include nucleobases such as pyrimidine bases and purine bases or derivatives thereof. Examples of the pyrimidine base include uracil, thymine, and cytosine. Examples of the purine base include adenine, guanine, hypoxanthine, and xanthine. Examples of the nucleobase derivative include derivatives in which a hydrogen atom, a hydroxyl group, an amino group, or the like of a nucleobase such as a pyrimidine base or a purine base is substituted with an appropriate substituent. Group, halogen atom, alkyl group having 1 to 10 carbon atoms, vinyl group having 1 to 10 carbon atoms, nitro group and the like. The nucleobase or derivative thereof may be protected with a protecting group generally used in the field of nucleic acid-related substance synthesis. Examples of the hydroxyl-protecting group include acyl groups such as acetyl group and benzoyl group, alkyl groups such as methoxymethyl group and allyl group, and aralkyl groups such as benzyl group and triphenylmethyl group. Examples of the protecting group for amino group include acyl groups such as acetyl group and benzoyl group, and aralkyl groups such as benzyl group. These protecting groups may have an appropriate substituent such as a halogen atom, an alkyl group having 1 to 5 carbon atoms, or an alkyloxy group having 1 to 5 carbon atoms. B is particularly preferably a purine base and a derivative in which the purine base is substituted with an appropriate substituent.

  Examples of X of the 3-halogeno-3-deoxy-β-D-xylofuranosyl nucleoside derivative represented by the general formula [I] include a chlorine atom, a bromine atom and an iodine atom which are halogen atoms other than a fluorine atom. Among these, a bromine atom and an iodine atom are preferable, and a bromine atom is particularly preferable. As the reason why a bromine atom is particularly preferable, among the 3-halogeno-3-deoxy-β-D-xylofuranosyl-type nucleoside derivatives represented by the general formula [I], a nucleoside derivative in which the 3′-position halogen atom is a bromine atom is easy Among the 2-halogeno-2,3-dideoxy-3-fluoro-β-D-arabinofuranosyl nucleoside derivatives represented by the general formula [II], the 2′-position halogen atom is For example, the dehalogenation of a nucleoside derivative that is a bromine atom easily proceeds.

  As R of the 3-halogeno-3-deoxy-β-D-xylofuranosyl nucleoside derivative represented by the general formula [I], an acyl group such as an acetyl group or a benzoyl group, an alkyl group such as a methoxymethyl group or an allyl group, Examples thereof include aralkyl groups such as a benzyl group and a triphenylmethyl group. These protecting groups may have an appropriate substituent such as a halogen atom, an alkyl group having 1 to 5 carbon atoms, or an alkyloxy group having 1 to 5 carbon atoms.

  Among the 3-halogeno-3-deoxy-β-D-xylofuranosyl nucleoside derivatives represented by the general formula [I], 9- (3-bromo-3-deoxy-β-D- represented by the general formula [III] The xylofuranosyl) guanine derivative is one of the reaction substrates of the present invention because of its very high regioselectivity when reacted with sulfur tetrafluoride. The 9- (3-bromo-3-deoxy-β-D-xylofuranosyl) guanine derivative represented by the general formula [III] is converted into the 9- (2-bromo represented by the general formula [IV] by the production method of the present invention. -2,3-dideoxy-3-fluoro-β-D-arabinofuranosyl) guanine derivative. R in the general formula [III] and the general formula [IV] represents a hydroxyl-protecting group, and R of the 3-halogeno-3-deoxy-β-D-xylofuranosyl nucleoside derivative represented by the above general formula [I]. Is the same. R ′ in general formula [III] and general formula [IV] represents an amino-protecting group, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, t-butyl group. C1-C10 alkyl group such as benzyl group, trityl group, 4-monomethoxytrityl group, 4,4′-dimethoxytrityl group, etc., aralkyl group having 7 to 22 carbon atoms, formyl group, acetyl group, pivaloyl And carbamoyl groups such as benzoyl group, benzyloxycarbonyl group, t-butoxycarbonyl group, methoxycarbonyl group and the like. As the amino-protecting group, an acyl group is preferable, and an acetyl group is more preferable. These protecting groups may have an appropriate substituent such as a halogen atom, an alkyl group having 1 to 5 carbon atoms, or an alkyloxy group having 1 to 5 carbon atoms.

  The 3-halogeno-3-deoxy-β-D-xylofuranosyl nucleoside derivative represented by the general formula [I] is a method described in Nucleosides & Nucleotides (USA), 1996, Vol. 15, p31-45, etc. It can be easily prepared according to known methods. For example, a 9- (3-bromo-3-deoxy-β-D-xylofuranosyl) guanine derivative represented by the general formula [III], particularly 2-N-acetyl-9- (5-O-acetyl-3-bromo- 3-deoxy-β-D-xylofuranosyl) guanine is 2-N-acetyl-9- (2,5-di-O-acetyl-3-bromo, wherein both the 2′-position and the 5′-position are protected with an acetyl group. -3-deoxy-β-D-xylofuranosyl) guanine according to known methods (see for example J. Chem. Soc., Perkin Trans. I (UK), 1980, No. 2, p. 563-573), It can be easily produced by selectively deprotecting the 2′-position acetyl group with hydroxylamine or the like. In addition, 2-N-acetyl-9- (2,5-di-O-acetyl-3-bromo-3-deoxy-β-D-xylofuranosyl) guanine in which both the 2′-position and the 5′-position are protected with an acetyl group Can be easily produced according to the method described in Nucleosides, Nucleotides & Nucleic Acids (USA), 1996, Vol. 15, No. 1-3, p.31-45.

  The 2-halogeno-2,3-dideoxy-3-fluoro-β-D-arabinofuranosyl nucleoside derivative represented by the general formula [II] is a 3-halogeno-3-deoxy represented by the general formula [I]. It can be produced by reacting a -β-D-xylofuranosyl-type nucleoside derivative with sulfur tetrafluoride.

  B, X and R of the 2-halogeno-2,3-dideoxy-3-fluoro-β-D-arabinofuranosyl nucleoside derivative represented by the general formula [II] are represented by the above general formula [I]. The same as B, X and R of the 3-halogeno-3-deoxy-β-D-xylofuranosyl nucleoside derivative.

Sulfur tetrafluoride (SF ₄ ) can be easily produced according to the method described in Organic Reactions, Vol. 21, WG Dauben, Ed., John Wiley & Sons, New York (1974), 1-124. it can.

The amount of sulfur tetrafluoride (SF ₄ ) used is not particularly limited, but is 1 with respect to 1 mol of the 3-halogeno-3-deoxy-β-D-xylofuranosyl nucleoside derivative represented by the general formula [I]. What is necessary is just to use 1 mol or more normally, and 1 to 30 mol is preferable, and especially 1 to 20 mol is more preferable. From the viewpoint of industrially producing 3-fluoro-2,3-dideoxy-β-D-ribofuranosyl-type nucleoside derivatives, particularly 3′-fluoro-2 ′, 3′-dideoxyguanosine, 3 The use of 15 mol or less per 1 mol of the -halogeno-3-deoxy-β-D-xylofuranosyl nucleoside derivative is more preferable.

  The dehydroxyfluorination reaction involving rearrangement of the present invention can be carried out in the presence of a suitable base, and the conversion rate and selectivity of the reaction can be improved. Such bases include organic bases such as triethylamine, diisopropylethylamine, pyridine or 2,6-lutidine, and inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate. Of course, it is not necessary to add a base when the conversion rate and selectivity of the reaction are sufficiently satisfactory. Among the 3-halogeno-3-deoxy-β-D-xylofuranosyl-type nucleoside derivatives represented by the general formula [I], it involves rearrangement of 9- (3-bromo-3-deoxy-β-D-xylofuranosyl) guanine derivatives. In the dehydroxyfluorination reaction, the reaction proceeds well without intentionally adding a base.

  The dehydroxyfluorination reaction involving rearrangement of the present invention can be carried out using an appropriate reaction solvent, such as aliphatic hydrocarbons such as n-hexane, cyclohexane and n-heptane, benzene , Aromatic hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, ethers such as diethyl ether, tetrahydrofuran and tert-butyl methyl ether, acetonitrile and propionitrile And nitriles such as Among these, n-heptane, toluene, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran and acetonitrile are preferable, and toluene, methylene chloride, 1,2-dichloroethane and acetonitrile are more preferable. These reaction solvents can be used alone or in combination.

  Although there is no restriction | limiting in particular as the usage-amount of a reaction solvent, 0.1 L (liter) or more with respect to 1 mol of 3-halogeno-3-deoxy- (beta) -D-xylofuranosyl type nucleoside derivatives shown by General formula [1]. May be used, and usually 0.2 to 50 L is preferable, and 0.3 to 25 L is more preferable.

  As temperature conditions, it is -100 to +100 degreeC, Usually, -80 to +80 degreeC is preferable, and -60 to +60 degreeC is especially more preferable. The reason why the temperature range of −60 to + 60 ° C. is particularly preferable is that the reaction rate is sufficiently fast, good selectivity and good yield, and 2-halogeno-2,3-dideoxy- represented by the general formula [II] It is mentioned that a 3-fluoro-β-D-arabinofuranosyl type nucleoside derivative is obtained. A pressure-resistant reaction vessel can be used when the reaction is performed at a temperature higher than the boiling point of sulfur tetrafluoride (−38 ° C.).

  The reaction time is 0.1 to 72 hours, but it varies depending on the substrate and reaction conditions, so the progress of the reaction is traced by analytical means such as thin layer chromatography, liquid chromatography, and NMR, and the raw materials are almost lost. Preferably, the end point is the end point.

  As an optimal combination of reaction substrate and reaction conditions, among 3-halogeno-3-deoxy-β-D-xylofuranosyl nucleoside derivatives represented by the general formula [I], 9- (3-bromo-3-deoxy- [beta] -D-xylofuranosyl) guanine derivatives, in particular 2-N-acetyl-9- (5-O-acetyl-3-bromo-3-deoxy- [beta] -D-xylofuranosyl) guanine, with respect to 1 mol; Examples include dissolving in 3 to 25 L of toluene, methylene chloride, 1,2-dichloroethane or acetonitrile and reacting with 15 mol or less of sulfur tetrafluoride at −60 to + 60 ° C. for 0.1 to 72 hours. Under such conditions, the target compound can be produced particularly smoothly and with high selectivity.

  There is no particular limitation on the post-treatment, but usually the reaction end solution is poured into an aqueous solution of an inorganic base (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate or potassium carbonate), and an organic solvent (eg, toluene, chloride, etc.). The crude product can be obtained by extraction with methylene, chloroform or ethyl acetate. If necessary, the crude product is subjected to purification operations such as activated carbon treatment, recrystallization or column chromatography to give the desired 2-halogeno-2,3-dideoxy-3-fluoro represented by the general formula [II]. A -β-D-arabinofuranosyl nucleoside derivative can be obtained with high chemical purity.

  A 2-halogeno-2,3-dideoxy-3-fluoro-β-D-arabinofuranosyl-type nucleoside derivative represented by the general formula [II] obtained by the dehydroxyfluorination reaction involving rearrangement of the present invention is used. And (1) a step of dehalogenating a 2′-position halogen atom, (2) a step of deprotecting a protecting group for the 5′-position hydroxyl group, and (3) a nucleobase or a derivative thereof as required. 3-Fluoro-2,3-dideoxy-β-D-ribofuranosyl-type nucleoside derivative represented by the general formula [V] by performing at least one of the steps of protection, deprotection or modification in random order Can be manufactured. Each of these steps is, for example, a method described in JP-A-2001-122891, Nucleosides, Nucleotides & Nucleic Acids (USA), 2003, Vol. 22, No. 5-8, p.711-713, etc. This can be done by methods known to those skilled in the art.

  That is, the dehalogenation step (1) involves radical reduction using tri-n-butyltin hydride, hypophosphorous acid, etc. (see Tetrahedron Letters (UK), 2001, Vol. 42, p7605-7608), palladium Dehalogenation can be achieved by catalytic hydrogen reduction using carbon or the like as a catalyst.

 In the deprotection step (2), when the hydroxyl protecting group is, for example, an acyl group such as an acetyl group or a benzoyl group, an alkali such as ammonia, sodium hydroxide, potassium hydroxide, sodium methoxide or potassium methoxide is used. In addition, when the hydroxyl protecting group is an aralkyl group such as benzyl group or triphenylmethyl group, it is treated with an acid such as hydrochloric acid or acetic acid, or palladium carbon is used as a catalyst. Deprotection can be achieved by catalytic hydrogenolysis or the like.

 Of the protection, deprotection or modification of (3), the deprotection step can be deprotected in the same manner as the deprotection step of (2), and the protection and modification steps are generally used in the field of synthesis of nucleic acid-related substances. Any desired 3-fluoro-2,3-dideoxy-β-D-ribofuranosyl-type nucleoside derivative can be produced by a method that has been adopted by the public.

  For example, among 2-halogeno-2,3-dideoxy-3-fluoro-β-D-arabinofuranosyl nucleoside derivatives represented by the general formula [II], 9- (2 represented by the general formula [IV] -Bromo-2,3-dideoxy-3-fluoro-β-D-arabinofuranosyl) guanine derivatives, in particular 2-N-acetyl-9- (5-O-acetyl-2-bromo-2,3-dideoxy -3-Fluoro-β-D-arabinofuranosyl) guanine debrominated the 2 ′ bromine atom by radical reduction of hypophosphorous acid and 5 ′ O-acetyl group and 2-position N-acetyl of guanine By simultaneously deacetylating the group by ammonia treatment, 3′-fluoro-2 ′, 3′-dideoxyguanosine represented by the general formula [VI] can be produced.

  Examples of B ′ of the 3-fluoro-2,3-dideoxy-β-D-ribofuranosyl nucleoside derivative represented by the general formula [V] include nucleobases such as pyrimidine bases and purine bases or derivatives thereof. Examples of the pyrimidine base include uracil, thymine, and cytosine. Examples of the purine base include adenine, guanine, hypoxanthine, and xanthine. Examples of the nucleobase derivative include derivatives in which a hydrogen atom, a hydroxyl group, an amino group, or the like of a nucleobase such as a pyrimidine base or a purine base is substituted with an appropriate substituent. Group, halogen atom, alkyl group having 1 to 10 carbon atoms, vinyl group having 1 to 10 carbon atoms, nitro group and the like. The nucleobase or derivative thereof may be protected with a protecting group generally used in the field of nucleic acid-related substance synthesis. Examples of the hydroxyl-protecting group include acyl groups such as acetyl group and benzoyl group, alkyl groups such as methoxymethyl group and allyl group, and aralkyl groups such as benzyl group and triphenylmethyl group. Examples of the protecting group for amino group include acyl groups such as acetyl group and benzoyl group, and aralkyl groups such as benzyl group. These protecting groups may have an appropriate substituent such as a halogen atom, an alkyl group having 1 to 5 carbon atoms, or an alkyloxy group having 1 to 5 carbon atoms.

Hereinafter, the embodiments of the present invention will be specifically described by way of examples. However, the present invention is not limited to these examples.
<Reference Example 1>
Preparation of 2-N-acetyl-9- (5-O-acetyl-3-bromo-3-deoxy-β-D-xylofuranosyl) guanine

２−Ｎ−アセチル−９−（２，５−ジ−Ｏ−アセチル−３−ブロモ−３−デオキシ−β−Ｄ−キシロフラノシル）グアニン（９４４ｍｇ、２．０ｍｍｏｌ）のエタノール（２０ｍＬ）懸濁液に、塩酸ヒドロキシルアミン（２７８ｍｇ、４．０ｍｍｏｌ）とトリエチルアミン（０．５５８ｍＬ、４．０ｍｍｏｌ）を加え、室温で１４時間撹拌した。得られた懸濁液から固体をろ取し、減圧下乾燥させることで目的物（６１８ｍｇ、収率７２％）を白色固体として得た。
¹H-NMR (DMSO-d6) : d 2.06 (s, 3H), d 2.19 (s, 3H), d 4.32―4.40 (m, 2H), d 4.50―4.57 (m, 1H), d 4.63 (d-d, 1H, J=5.2, 3.7 Hz), d 4.83―4.88 (m, 1H), d 5.75 (d, 1H, J=3.8 Hz), d 6.51―6.55 (m, 1H), d 8.18 (s, 1H), d 11.77 (br, 1H), d 12.10 (br, 1H).
ESIMS m/z: 430 (M+H).

To a suspension of 2-N-acetyl-9- (2,5-di-O-acetyl-3-bromo-3-deoxy-β-D-xylofuranosyl) guanine (944 mg, 2.0 mmol) in ethanol (20 mL). Hydroxylamine hydrochloride (278 mg, 4.0 mmol) and triethylamine (0.558 mL, 4.0 mmol) were added, and the mixture was stirred at room temperature for 14 hours. A solid was collected from the obtained suspension by filtration and dried under reduced pressure to obtain the desired product (618 mg, yield 72%) as a white solid.
¹ H-NMR (DMSO-d6): d 2.06 (s, 3H), d 2.19 (s, 3H), d 4.32-4.40 (m, 2H), d 4.50-4.57 (m, 1H), d 4.63 (dd , 1H, J = 5.2, 3.7 Hz), d 4.83-4.88 (m, 1H), d 5.75 (d, 1H, J = 3.8 Hz), d 6.51-6.55 (m, 1H), d 8.18 (s, 1H ), d 11.77 (br, 1H), d 12.10 (br, 1H).
ESIMS m / z: 430 (M + H).

Production of 2-N-acetyl-9- (5-O-acetyl-2-bromo-2,3-dideoxy-3-fluoro-β-D-arabinofuranosyl) guanine by sulfur tetrafluoride (SF ₄ )

ステンレス鋼（ＳＵＳ）製耐圧反応容器に、１．０グラムの２−Ｎ−アセチル−９−（５−Ｏ−アセチル−３−ブロモ−３−デオキシ−β−Ｄ−キシロフラノシル）グアニン（純度９７％）を加え、２３．３ミリリットルの塩化メチレンを加えて溶解し、−７８℃に冷却して２．７グラムのサルファーテトラフルオリド（ＳＦ₄）をボンベから吹き込み、室温で１７時間攪拌した。反応終了液を氷水で冷却した８０ミリリットルの飽和炭酸水素ナトリウム水溶液に注ぎ込み、１０ミリリットルの塩化メチレンを加えて抽出し、有機層を回収し、再度、水層を２０ミリリットルのクロロホルムで抽出した。回収した有機層を合わせて減圧下濃縮し、さらに真空乾燥し、粗生成物１．０グラムを得た。有機物の回収率は定量的であった。粗生成物の液体クロマトグラフィー (Inertsil ODS-2, MeCN : 0.1M Na₂HPO₄ aq = 1 : 4, isocratic, 0.5 ml/min, 260 nm)により変換率と位置選択性（２’−β−ブロモ−３’−α−フルオロ体：２’−α−フルオロ−３’−β−ブロモ体）を測定したところ、変換率は９０％で、位置選択性は７．８：１であった。¹Ｈ−ＮＭＲスペクトルを下に示す。
¹H-NMR (DMSO-d6) : d 2.05 (s, 3H), d 2.22 (s, 3H), d 4.32―4.44 (m, 2H), d 4.45―4.50 (m, 1H), d 5.31 (d-t, 1H, J=18.9, 6.8 Hz), d 6.00 (d-t, 1H, J=55.0, 6.4 Hz), d 6.36 (d, 1H, J=6.8 Hz), d 8.14 (s, 1H), d 11.61 (br, 1H).
ESIMS m/z: 432 (M+H).
＜比較例１＞
ジエチルアミノサルファートリフルオリド（ＤＡＳＴ）による２−Ｎ−アセチル−９−（５−Ｏ−アセチル−２−ブロモ−２，３−ジデオキシ−３−フルオロ−β−Ｄ−アラビノフラノシル）グアニンの製造

In a pressure resistant reaction vessel made of stainless steel (SUS), 1.0 gram of 2-N-acetyl-9- (5-O-acetyl-3-bromo-3-deoxy-β-D-xylofuranosyl) guanine (purity 97% ), 23.3 milliliters of methylene chloride was added and dissolved, cooled to −78 ° C., 2.7 grams of sulfur tetrafluoride (SF ₄ ) was blown from the bomb, and the mixture was stirred at room temperature for 17 hours. The reaction-terminated liquid was poured into 80 ml of a saturated aqueous sodium hydrogen carbonate solution cooled with ice water, extracted by adding 10 ml of methylene chloride, the organic layer was recovered, and the aqueous layer was extracted again with 20 ml of chloroform. The collected organic layers were combined, concentrated under reduced pressure, and further vacuum dried to obtain 1.0 gram of a crude product. The organic recovery was quantitative. Conversion and regioselectivity (2'-β-) of the crude product by liquid chromatography (Inertsil ODS-2, MeCN: 0.1M Na ₂ HPO ₄ aq = 1: 4, isocratic, 0.5 ml / min, 260 nm) Bromo-3′-α-fluoro product: 2′-α-fluoro-3′-β-bromo product) was measured, and the conversion was 90% and the regioselectivity was 7.8: 1. ¹ H-NMR spectrum is shown below.
¹ H-NMR (DMSO-d6): d 2.05 (s, 3H), d 2.22 (s, 3H), d 4.32-4.44 (m, 2H), d 4.45-4.50 (m, 1H), d 5.31 (dt , 1H, J = 18.9, 6.8 Hz), d 6.00 (dt, 1H, J = 55.0, 6.4 Hz), d 6.36 (d, 1H, J = 6.8 Hz), d 8.14 (s, 1H), d 11.61 ( br, 1H).
ESIMS m / z: 432 (M + H).
<Comparative Example 1>
Production of 2-N-acetyl-9- (5-O-acetyl-2-bromo-2,3-dideoxy-3-fluoro-β-D-arabinofuranosyl) guanine with diethylaminosulfur trifluoride (DAST)

２−Ｎ−アセチル−９−（５−Ｏ−アセチル−３−ブロモ−３−デオキシ−β−Ｄ−キシロフラノシル）グアニン（８６０．４ｍｇ、２．０ｍｍｏｌ）のジクロロメタン（１０ｍＬ）溶液を０℃に冷却した後、ジエチルアミノサルファートリフルオリド（０．９８ｍＬ、１０．０ｍｍｏｌ）をゆっくり滴下し、滴下後４０℃で２時間撹拌した。得られた溶液を飽和炭酸水素ナトリウム水溶液（２０ｍＬ）に滴下し、ジクロロメタン（１０ｍＬ）を加え分層した。水層にジクロロメタン（２０ｍＬ）を加え再抽出し、得られた二つの有機層を混合し、飽和塩化アンモニウム水溶液（５ｍＬ）で洗浄した後、無水硫酸ナトリウムで乾燥させ、減圧下濃縮した。クロマトグラフィー（シリカゲル２０ｇ;溶出液１６:１ジクロロメタン−メタノール）により精製し、目的物（５８８．４ｍｇ、収率６８％）を白色固体として得た。なおフッ素化の位置選択性は３’Ｆ：２’Ｆ＝２．９：１であった。
¹H-NMR (DMSO-d6) : d 2.05 (s, 3H), d 2.22 (s, 3H), d 4.32―4.44 (m, 2H), d 4.45―4.50 (m, 1H), d 5.31 (d-t, 1H, J=18.9, 6.8 Hz), d 6.00 (d-t, 1H, J=55.0, 6.4 Hz), d 6.36 (d, 1H, J=6.8 Hz), d 8.14 (s, 1H), d 11.61 (br, 1H).
ESIMS m/z: 432 (M+H).

A solution of 2-N-acetyl-9- (5-O-acetyl-3-bromo-3-deoxy-β-D-xylofuranosyl) guanine (860.4 mg, 2.0 mmol) in dichloromethane (10 mL) was cooled to 0 ° C. Then, diethylaminosulfur trifluoride (0.98 mL, 10.0 mmol) was slowly added dropwise, and the mixture was stirred at 40 ° C. for 2 hours. The obtained solution was added dropwise to a saturated aqueous sodium hydrogen carbonate solution (20 mL), and dichloromethane (10 mL) was added to separate the layers. Dichloromethane (20 mL) was added to the aqueous layer for re-extraction, and the resulting two organic layers were mixed, washed with a saturated aqueous ammonium chloride solution (5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by chromatography (silica gel 20 g; eluent 16: 1 dichloromethane-methanol) gave the desired product (588.4 mg, yield 68%) as a white solid. The regioselectivity of fluorination was 3′F: 2′F = 2.9: 1.
¹ H-NMR (DMSO-d6): d 2.05 (s, 3H), d 2.22 (s, 3H), d 4.32-4.44 (m, 2H), d 4.45-4.50 (m, 1H), d 5.31 (dt , 1H, J = 18.9, 6.8 Hz), d 6.00 (dt, 1H, J = 55.0, 6.4 Hz), d 6.36 (d, 1H, J = 6.8 Hz), d 8.14 (s, 1H), d 11.61 ( br, 1H).
ESIMS m / z: 432 (M + H).

 Preparation of 2-N-acetyl-9- (5-O-acetyl-2,3-dideoxy-3-fluoro-β-D-arabinofuranosyl) guanine

２−Ｎ−アセチル−９−（５−Ｏ−アセチル−２−ブロモ−２，３−ジデオキシ−３−フルオロ−β−Ｄ−アラビノフラノシル）グアニン（２２４．７ｍｇ、０．５２ｍｍｏｌ）のアセトニトリル（２．２５ｍＬ）溶液に、５０％次亜リン酸水溶液（２０５．０ｍｇ、１．５６ｍｍｏｌ）と水（１．１２５ｍＬ）とトリエチルアミン（０．２１６ｍＬ、１．５６ｍｍｏｌ）を加えた後、２，２'−アゾビス（２−アミジノプロパン）二塩酸塩を加え、７０℃で３時間撹拌した。反応液を減圧下濃縮し、クロマトグラフィー（シリカゲル２０ｇ;溶出液はジクロロメタン−メタノール混合溶媒を使用し、比率を６６:１、３３：１、２０：１と順に変化させた）により精製し、目的物（１８０ｍｇ、収率９８％）を白色固体として得た。
¹H-NMR (DMSO-d6) : d 2.04 (s, 3H), d 2.19 (s, 3H), d 2.65―2.80 (m, 1H), d 2.90―3.10 (m, 1H), d 4.18―4.25 (m, 2H), d 4.35―4.45 (m, 1H), d 5.45―5.63 (m, 1H), d 6.24―6.29 (m, 1H), d 8.23 (s, 1H), d 11.68 (br, 1H).
ESIMS m/z: 354 (M+H).

2-N-acetyl-9- (5-O-acetyl-2-bromo-2,3-dideoxy-3-fluoro-β-D-arabinofuranosyl) guanine (224.7 mg, 0.52 mmol) in acetonitrile (2.25 mL) solution was added 50% aqueous hypophosphorous acid solution (205.0 mg, 1.56 mmol), water (1.125 mL) and triethylamine (0.216 mL, 1.56 mmol), followed by 2,2 '-Azobis (2-amidinopropane) dihydrochloride was added and stirred at 70 ° C for 3 hours. The reaction solution was concentrated under reduced pressure and purified by chromatography (silica gel 20 g; eluent was a dichloromethane-methanol mixed solvent, and the ratio was changed in the order of 66: 1, 33: 1, 20: 1). Product (180 mg, 98% yield) was obtained as a white solid.
¹ H-NMR (DMSO-d6): d 2.04 (s, 3H), d 2.19 (s, 3H), d 2.65-2.80 (m, 1H), d 2.90-3.10 (m, 1H), d 4.18-4.25 (m, 2H), d 4.35―4.45 (m, 1H), d 5.45―5.63 (m, 1H), d 6.24―6.29 (m, 1H), d 8.23 (s, 1H), d 11.68 (br, 1H ).
ESIMS m / z: 354 (M + H).

 Production of 3'α-fluoro-2 ', 3'-dideoxyguanosine

２−Ｎ−アセチル−９−（５−Ｏ−アセチル−２，３−ジデオキシ−３−フルオロ−β−Ｄ−アラビノフラノシル）グアニン（１０ｍｇ、０．０２８ｍｍｏｌ）に２．０ｍｏｌ／Ｌのアンモニアメタノール溶液（１ｍＬ、２ｍｍｏｌ）を加え、室温で３時間撹拌した。反応液を減圧下濃縮し、クロマトグラフィー（シリカゲル５ｇ;溶出液４：１ジクロロメタン−メタノール）により精製し、目的物（６．２ｍｇ、収率８２％）を白色固体として得た。
¹H-NMR (DMSO-d6) : d 2.50―2.67 (m, 1H), d 2.70―2.90 (m, 1H), d 3.50―3.60 (m, 2H), d 4.16 (d-t, 1H, J=27.0, 4.9 Hz), d 5.15 (t, 1H, J=5.4 Hz), d 5.38 (d-d, 1H, J=53.6, 4.3 Hz), d 6.15 (d-d, 1H, J=9.4, 5.6 Hz), d 6.49 (br, 2H), d 10.54 (br, 1H).
ESIMS m/z: 270 (M+H).

2-N-acetyl-9- (5-O-acetyl-2,3-dideoxy-3-fluoro-β-D-arabinofuranosyl) guanine (10 mg, 0.028 mmol) in 2.0 mol / L ammonia Methanol solution (1 mL, 2 mmol) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by chromatography (silica gel 5 g; eluent 4: 1 dichloromethane-methanol) to obtain the desired product (6.2 mg, yield 82%) as a white solid.
¹ H-NMR (DMSO-d6): d 2.50-2.67 (m, 1H), d 2.70-2.90 (m, 1H), d 3.50-3.60 (m, 2H), d 4.16 (dt, 1H, J = 27.0 , 4.9 Hz), d 5.15 (t, 1H, J = 5.4 Hz), d 5.38 (dd, 1H, J = 53.6, 4.3 Hz), d 6.15 (dd, 1H, J = 9.4, 5.6 Hz), d 6.49 (br, 2H), d 10.54 (br, 1H).
ESIMS m / z: 270 (M + H).

Claims (4)

Formula [I]

[Wherein B represents a nucleobase or a derivative thereof, X represents a chlorine atom, a bromine atom, or an iodine atom, and R represents a protecting group for a hydroxyl group], 3-halogeno-3-deoxy-β-D - a xylofuranosyl nucleoside derivative by reaction with sulfur tetrafluoride (SF _4), the general formula [II]

[Wherein, B represents a nucleobase or a derivative thereof, X represents a chlorine atom, a bromine atom, or an iodine atom, and R represents a hydroxyl-protecting group] 2-halogeno-2,3-dideoxy-3 A method for producing a fluoro-β-D-arabinofuranosyl nucleoside derivative. Formula [III]

[Wherein R represents a protecting group for a hydroxyl group and R ′ represents a protecting group for an amino group] A 9- (3-bromo-3-deoxy-β-D-xylofuranosyl) guanine derivative represented by the formula: (SF ₄ ) to give a compound of the general formula [IV]

[Wherein, R represents a hydroxyl-protecting group, and R ′ represents an amino-protecting group] 9- (2-bromo-2,3-dideoxy-3-fluoro-β-D-arabino A method for producing a furanosyl) guanine derivative. Using the 2-halogeno-2,3-dideoxy-3-fluoro-β-D-arabinofuranosyl nucleoside derivative prepared according to claim 1, the following (1), (2) and, if necessary, (3) are carried out in any order, so that the general formula [V]

A method for producing a 3-fluoro-2,3-dideoxy-β-D-ribofuranosyl nucleoside derivative represented by the formula:
(1) a step of dehalogenating a 2′-position halogen atom;
(2) a step of deprotecting the protecting group for the 5′-position hydroxyl group,
(3) A step of performing at least one of protection, deprotection or modification of a nucleobase or a derivative thereof. Using 9- (2-bromo-2,3-dideoxy-3-fluoro-β-D-arabinofuranosyl) guanine derivative produced according to claim 2, the following (1), (2) and ( By performing the steps of 3) in random order, the formula [VI]

A method for producing 3′-fluoro-2 ′, 3′-dideoxyguanosine represented by the formula:
(1) a step of debromination of a 2′-position bromine atom;
(2) a step of deprotecting the protecting group for the 5′-position hydroxyl group,
(3) A step of deprotecting the protecting group of the 2-position amino group of the guanine derivative.