WO2000039144A1 - Process for the preparation of fluorinated derivatives of nucleosides or sugars - Google Patents

Abstract

A process for efficiently preparing nucleoside or sugar derivatives whose secondary hydroxyl groups are selectively replaced by fluorine atoms, which comprises reacting a nucleoside or sugar derivative bearing secondary hydroxyl groups with a sulfonyl fluoride such as a perfluoroalkanesulfonyl fluoride or alkanesulfonyl fluoride in the presence of a base. This process is an uncostly, safe and industrially advantageous one permitting one-step fluorination of the above hydroxyl groups, thus being extremely useful for the preparation of intermediates for various drugs including antivirals.

Description

 Description Method for producing fluorinated derivatives of nucleosides or sugars

 The present invention relates to an industrially useful method for producing a nucleoside or saccharide derivative in which a secondary hydroxyl group is substituted by a fluorine atom. INDUSTRIAL APPLICABILITY According to the present invention, 9-1 (2,3-dideoxy-12-fluoro-β-D-threo-penttofuranosyl) adenine (“F dd A may be abbreviated as “dd A.”) can be industrially advantageously produced.

Background art

 Conventionally, various methods have been used as a method for substituting a hydroxyl group of a nucleoside or a sugar derivative with a fluorine atom (for example, see JA Wilkinson, Chem. Rev., 92, 505-519 (1982)). . In a generally known method, two or more steps are required to replace the hydroxyl group of a nucleoside or a sugar derivative with a fluorine atom. A method using DAST (getylaminosulfur trifluoride) is known as a laboratory-excellent method for fluorinating in one step, but this compound is unstable and its toxicity is high. Due to the danger, it is not produced in large quantities and is not an industrially useful method.

 Other known fluorination methods (Bull. Soc. Chim. Belg., 103, 453, 1994; Tetrahedron Letters, vol. 36, No. 15, pp. 2611-2614, 1995; Nucleosides & Nucleotides, 15 (1-3 ), 739-742 (1996)), but some of them have not been applied to the secondary hydroxyl group of nucleoside disaccharides.

Therefore, the fluorine substitution described above can be widely applied to nucleic acid and sugar derivatives. There is a need for an industrially advantageous and safe method for producing compounds.

Problems of the Invention

 An object of the present invention relates to a method for producing a nucleoside or a sugar derivative in which a secondary hydroxyl group has been substituted with a fluorine atom, and in particular, can be fluorinated in one step, is low in cost, is safe, and is industrially useful. Another object of the present invention is to provide an effective method for producing various useful nucleic acid derivatives such as intermediates for producing the above-mentioned medicines (eg, FddA).

Disclosure of the invention

 The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that a secondary hydroxyl group of a nucleotide or a sugar derivative, a perfluoroalkane, norefonynolefnoreolide, or an The secondary hydroxyl group in a nucleoside or sugar derivative is stereospecifically substituted with a fluorine atom in one step by reacting with snorephonylfluoride such as recantholephoninolefnoreolide in the presence of a base. It was found that the present invention was completed. Sulfonyl fluoride is available at a low cost and can be used safely, and the present invention is an industrially excellent production method. As a result, it is expected to be used or used as an intermediate for the production of various drugs as described above. That is, the present invention provides a nucleoside or a sugar derivative represented by the following general formula (I):

[式中、

[Where,

 A is a hydrogen atom or a methyl group having a protected hydroxyl group, B is a nucleobase (including a derivative thereof) or a protected hydroxyl group, R is a hydroxyl-protecting group, and Y and X are any. One represents a hydroxyl group and the other represents a hydrogen atom or a protected hydroxyl group; or

 A and R together form a cyclic acetal represented by the following general formula (III) (R and R-both represent a hydrogen atom or a methyl group, or Represents a hydrogen atom, and the other represents a methyl group or a phenyl group, respectively.), B, Y and X have the same meanings as above.

(Yes)

Or

And Y represents a hydroxyl group, and X and B together form a cyclic acetal represented by the following general formula (IV). (Where both R ₃ and R ₄ represent a hydrogen atom or a methyl group. , Or one of them represents a hydrogen atom and the other represents a methyl group or a phenyl group, respectively), and A and R have the same meanings as described in any of the above-mentioned (a) and (b). ]

(IV) A nucleoside represented by the following general formula (II), which is characterized by reacting snorehoninolefluoride, for example, perfluoroalkanesulfoninolefluoride or alkanesulfonylfluoride in the presence of a base. Or a method for producing a sugar derivative. That is, sulfonyl fluoride is used as a fluorinating agent, and the 2′-position or 3′-position hydroxyl group is selectively substituted with a fluorine atom.

 A

 [Wherein AB and R represent the same meaning as described above, and one of Y ′ and X ′ represents a fluorine atom, and the other represents a hydrogen atom or a protected hydroxyl group, respectively. When Y ′ represents a fluorine atom, X ′ and B may be combined to form a cyclic acetal represented by the above general formula (IV) (R and R are the same as described above).

 For the preparation of FddA, it is preferred to use as starting material a compound in which B is adenine or 6-logenopurine in the 3-configuration.

In the case of adenine, a compound represented by the general formula (Π) (where Υ ′ is a hydrogen atom and X ′ is a fluorine atom having 8 positions) is produced, and if a protecting group is present in the hydroxyl group, this is By desorption, it can be easily led to F dc! A. In this case, when Y ′ is not a hydrogen atom but a hydroxyl group (protected or unprotected), the hydroxyl group is dehydroxylated by a conventional method, and the 5′-position hydroxyl group is protected as necessary. Alternatively, when a protecting group is present, it can be desorbed and treated in the same manner to lead to FddA. On the other hand, when a compound in which B is 6-logenopurine such as 6-chloromouth purine is used as a starting material, the obtained compound (Π) can be obtained in the same manner by the method described later or other known methods. Can lead to F dd A. The present invention also includes the following contents.

 1. In the above-mentioned production method, when the produced nucleoside or saccharide derivative represented by the general formula (II) is used and has a protective group in the hydroxyl group, it is preferably produced by subjecting the hydroxyl group to a deprotection step. A fluorinated nucleoside derivative represented by the following general formula (V) and the production method.

[In the formula, B ′ represents a nucleic acid base, Y ″ and X ″ each represent a fluorine atom, and the other represents a hydrogen atom or a hydroxyl group. ]

 However, the above sugar derivative further includes a condensation step with the nucleic acid base represented by B ′.

 From sugar derivatives, known routes (VE Marquez et al., J. Med. Chem., 33, 978 (1990); KA Watanabe et al., Carbohydr. Res., 42, 233 (1975), etc.) Fdd A can be easily produced by using the above method. Utilizing such a known method, a desired fluorinated nucleoside derivative such as FddA can be produced.

2. Nucleoside derivative represented by the general formula (Π) obtained by the above-mentioned production method (where A is a hydrogen atom, B is 6-logenopurine, Y ′ is a hydrogen atom or a protected hydroxyl group) , X ′ represents a fluorine atom), and the 6-position halogen atom is replaced by a hydrogen atom, an amino group, a hydroxyl group, Azide group, a substituent represented by the formula 〇, subjected to the step of substituting with any of substituents represented by the substituents and NHR ⁴ formula SR ^4, a manufacturing method of the described for producing the substituted compound . In this case, if the compound has a 5′-protecting group (R), the method may include a step of deprotecting the protecting group before or after the reaction for substituting with the substituent.

R ⁴ represents a lower alkyl group (C 15) in which a fuunyl group or the like may have a substituent.

 3. The nucleoside derivative (when Υ ′ represents a protected hydroxyl group and X ′ represents a fluorine atom) obtained by the above production method is further subjected to a step of dehydroxylating the hydroxyl group. A method for producing a 3'-dehydroxylated product.

 4. A fluorinated nucleoside derivative or Fdd obtained by any of the production methods described above.

 5. The sugar derivative similarly produced is 3-deoxy-3-fluoro-1,2: 5,6-di-isopropylidene-one-D-dalcofuranose and a fluorinated nucleoside produced using the same. Derivative or FddA.

Embodiment

 In the nucleoside or sugar derivative represented by the above general formula (I) used as a starting material of the present invention, when the above general formula (I) represents a nucleoside derivative, B is a purine base ゃ pyrimidine Represents a nucleic acid base such as a base or a derivative thereof. In the present invention, the term “nucleobase” includes the nucleic acid base itself and the derivative of such a nucleobase, but in the description of the specification, the terms “nucleobase” and “nucleic acid derivative” in a narrow sense, respectively, are used. When describing "", terms such as "nucleobase", "nucleobase (derivative)", and "derivative thereof" are used.

Specifically, pyrimidine bases such as pyrimidine, thymine, cytosine, Peracyl and the like, and the purin bases include purin, adenine, guanine, xanthine, hypoxanthine and the like. Examples of B include a nucleobase derivative in which a hydrogen atom, a hydroxyl group, an amino group, or the like of the nucleobase is substituted with another appropriate substituent. Examples of such a substituent preferably include a hydrogen atom, an amino group, a hydroxyl group, a halogen atom (such as a chlorine atom), an alkyl group having 11 to 10 carbon atoms, and a nitrogen atom.

 Representative nucleobase derivatives include adenine, guanine, hypoxanthine, 6-halogenoprine, peracyl, thymine and the like, in particular, because of their versatility as intermediates for drug production.

 When these nucleobases or derivatives thereof have a reactive functional group, they may be protected with a protecting group generally used in nucleic acid synthesis. When the protecting group is a protecting group for a hydroxyl group, for example, an acetyl group such as an acetyl group or a benzoyl group, an alkenyl group such as a methoxymethyl group or an aryl group, or an aralkyl group such as a benzyl group or a triphenylmethyl group. And the like. In the case of an amino-protecting group, examples thereof include an acetyl group, an benzoyl group and other aralkyl groups, and a benzyl group and other aralkyl groups. These protecting groups may have a suitable substituent such as a halogen atom, an alkyl group having 15 to 15 carbon atoms, or an alkyloxy group having 1 to 5 carbon atoms. When the general formula (I) represents a sugar derivative, B represents a protected hydroxyl group. Examples of the hydroxyl-protecting group include acetyl groups such as acetyl group and benzoyl group (having 11 to 10 carbon atoms), alkyl groups such as methyl group and aryl group, and aralkyl groups such as benzyl group and triphenylmethyl group. And silyl groups such as trimethylsilyl group and triethylsilyl group.

Incidentally, these protecting groups a halogen atom, an alkyl group having 1 one 5 carbon atoms, which may have a suitable substituent such as Arukiruokishi group with carbon number i one ₅ (main butoxy, etc.). In the above general formula (I), R represents a hydroxyl-protecting group. As the hydroxyl-protecting group, as described above, preferably, an acetyl group, an alkyl group such as a benzoyl group, an alkyl group such as a methyl group or an aryl group, an aralkyl group such as a benzyl group or a trimethyl group are preferable. And silyl groups such as trimethylsilyl. As described above, these protecting groups may have a substituent such as a halogen atom, an alkyl group having 15 to 15 carbon atoms, or an alkyloxy group having 1 to 5 carbon atoms (such as methoxy). As a protecting reagent for protecting, a reagent known as a reagent for protecting a hydroxyl group, for example, an acylating agent, an alkylating agent, an aralkylating agent, an organic silylating agent and the like are appropriately used. In the general formula (I), A represents a hydrogen atom or a methyl group having a protected hydroxyl group (that is, R′—O—CH ₂ —). Examples of the hydroxyl-protecting group (R ′) include, as described above, for example, an acetyl group, an alkyl group such as a benzoyl group, an alkyl group such as a methyl group and an aryl group, and an aralkyl group such as a benzyl group and a triphenylmethyl group. And the like. That is, when A is a methyl group having a protected hydroxyl group, A is, for example, an acetyloxymethyl group such as an acetyloxymethyl group or a benzoyloxymethyl group, or a benzyloxymethyl group. And an aralkyloxymethyl group such as a trityloxymethyl group. Further, the protective group (R ′) may have a substituent such as a halogen atom, an alkyl group having 115 carbon atoms, or an alkyloxy group having 15 carbon atoms (such as methoxy).

 In addition, in the above general formula (I), A and R do not represent the above (instead of each other), and A and R together form a cyclic acetal represented by the following general formula (III). Can also.

0

Ye I In the general formula (III), R 1 and R 2 both represent a hydrogen atom or a methyl group, or one of them represents a hydrogen atom and the other represents a methyl group or a phenyl group. Further, the above and R ₂ may have a substituent such as a halogen atom, an alkyl group having 115 carbon atoms, or an alkyloxy group having 115 carbon atoms.

 The cyclic acetal represented by the general formula (III) has a form in which an adjacent hydroxyl group is protected by a protecting group. In this case, the hydroxyl group can be deprotected by an ordinary method for deprotecting a protecting group.

 In the general formula (I), one of Y and X represents a hydroxyl group, and the other represents a hydrogen atom or a protected hydroxyl group. Examples of the hydroxyl-protecting group include an acetyl group, an benzoyl group and other such acyl groups, a methyl group and an alkyl group such as an aryl group, and a benzyl group and an aralkyl group such as a triphenylmethyl group. Further, these protecting groups may have a substituent such as a halogen atom, an alkyl group having 115 carbon atoms, or an alkyloxy group having 15 carbon atoms (such as a methoxy group).

 In addition, in the above general formula (I), when Y represents a hydroxyl group, X and B do not represent the above, and X and B together form a cyclic acetal represented by the following general formula (IV) You can also.

上記一般式 （IV) 中、 R .，及び は、 両方が水素原子若しくはメチ ル基を表すか、 又は何れか一方が水素原子を表し他方がメチル基若し くはフエ二ル基を表す _Q また、 上記 R ;及び R は、 ハロゲン原子、 炭 素数 1 一 5のアルキル基、 炭素数 1 一 5のアルキルォキシ基等の置換 基を有していてもよい。 一般式 （IV) で示される環状ァセタールは、 隣接水酸基が保護基で 保護された形態となつており、 この場合水酸基の保護基を脱保護する 場合の通常の方法により脱保護することができる。

In the general formula (IV), R., And are both represent represent or either one Ku is Wakashi methyl group the other represents a hydrogen atom phenylene Le based on hydrogen atom or a methylation group _Q R and R may have a substituent such as a halogen atom, an alkyl group having 115 carbon atoms, or an alkyloxy group having 115 carbon atoms. The cyclic acetal represented by the general formula (IV) has a form in which an adjacent hydroxyl group is protected by a protecting group. In this case, the hydroxyl group can be deprotected by a usual method for deprotecting a protecting group.

 As described above, the general formula (I) also includes a compound represented by the following formula.

 (I-3)

(Wherein, R, RR, R ₃ , RA, B, X and Y have the same meanings as described above.)

B, X, and Y in the above general formula (I) may have any of three or three configurations. Specifically, it is represented by any of the following general formulas (VI) to (XIII).

 (VI) (VII) (VIII) (IX)

 In the case where Y is a hydroxyl group and X is combined with B to form a cyclic acetal represented by the above general formula (IV), the general formula (I) is replaced by the general formula (VII) , (VIII), (X) or (XIII).

When the general formula (I) represents a nucleoside derivative, those having A as a hydrogen atom and B as having three configurations are generally used. At this time, X and Y may have any configuration of α or / 3. If the above is specifically represented by a general formula, it can be represented by any of the following general formulas (XIV) to (XVII).

 (XVI I)

(XIV) When the compound represented by the general formula (I) is a nucleoside derivative, a method generally used in the synthesis of a nucleoside derivative (for example, “Chemistry of Nucleosides ana Nucleotides”, Vol. 1, LB Townsend, According to Ed., Plenum Press, New York (1988), 1-281), any compound can be synthesized. As typical examples of the nucleotide derivatives produced here, 6-chloro- _9- [3-deoxy-5-O- (triphenylmethyl) -i3-D-erythrotropen-tofurano-sinore] -1 9 H—purine, 6—chloro 9— [3-doxy 5—O-acetyl-1 i3—D—erythropentafuranosyl] 1 9 H—purine, 9—1—3—doxy— 5 — O—acetyl-] 3 — D—erythrobentofuranosyl] adenine (5′—O—acetyl_3′—deoxyadenosine), 5′—O—triphenylmethyl-3′—0—be Nzir 1-6 ク ル ブ リ ブ リ ブ リ ボ 等.

 In addition, when the compound represented by the general formula (I) is a sugar derivative, a method used in the synthesis of a sugar derivative (eg, “Preparative Carbohydrate Chemistry”, S. Hanessian, Ed., Marcel Dekkei ', New York (1997) 4) Therefore, any compound can be synthesized.

 As typical sugar derivatives produced here, there can be mentioned, for example, 3-deoxy-3-phenylene 1,2: 5,6—di-isopropyridene-hi-D-gunolecofuranose. .

In the present invention, sulfonylfluoride used for the fluorinating agent includes, in particular, benzoylfluoride Although sulfonyl fluoride can be mentioned, it is not particularly limited. Preferred examples thereof include a sulfonyl fluoride compound represented by the following general formula (XXX).

〇

 ^ II

 R? -S-F

 (I

 〇

(XXX)

 ぺ As a compound of the formula (XXX) represented by the above formula, R 5 is a saturated or unsaturated, straight-chain or unsaturated, C 1 -C 12 carbon atom Compounds representing a branched perfluoroalkyl group can be preferably mentioned. '

On the other hand, alkanesulfonyl fluoride can also be used. In the compound (XXX) represented by the above formula, R ₅ is a saturated or unsaturated, linear or branched chain having 11 to 12 carbon atoms. And a compound which may have a substituent. Regarding the substituent in this case, a part of the fluorine atom may be substituted with a hydrogen atom, or may be substituted with a halogen atom other than a fluorine atom, a carboxyl group, or the like. Further, as for the substituent R, one or more of the C—C bonds present therein may be a group substituted by a C—O—C bond.

In particular, tri-norenolenolides such as tri-norenolenolenolides, trinolenolenoleolides, 1-butanesnolehoninolenolenoleolides, and one-octane snorehonolenolenoleolides. Kansonorehoninorefunoreido, Belfluro (4-methyl-13,6-dioxacto-7-ene) Sulfonylfluoride, 5-halogeno (e.g.) Noroleol 3—Alkanesulfonyl fluorides such as oxantopenthnolehoninolefnoreolide and fluorosulfonyl (diphnoleo) acetic acid ester (methyl ester, etc.) are readily available on an industrial scale, and are cost effective. Particularly useful. Of course, not limited to this, sulfonyl fluoride having an arbitrary number of carbon atoms can also be used.

 When sulfonyl fluoride is used in the present invention, it is usually used in the range of 0.1 to 10 equivalents to the substrate. Preferably, it is used in the range of 0.5 to 5 equivalents, more preferably 1 to 4 equivalents.

 The base used in the production method of the present invention is not particularly limited, but preferred examples thereof include amines (including salts thereof), metal hydroxides, metal alkoxides, ion exchange resins, and carbonates. , Phosphates, acetates and the like. Of these, amines and the like are particularly preferable in that there are many types and an optimal one can be selected for the substrate. Examples of the amines include hydroxyamine, ammonia or a salt thereof, primary to quaternary organic amine or a salt thereof, an ion exchange resin, and a resin of a polymerized amine. Is mentioned. Specific examples include triethylamine, tributynoleamine, trioctylamine, N, N—dimethinolecyclohexinoleamine, N, N—getinolecyclohexylamine, N-ethylethylisopropylamine, 1,8—diazabicyclo [5,4,0] indecku 7-ene, 1-ethylbiperidine, 2,2,6,6-tetramethylbiperidine, 1,1,3,3-tetramethyldanidine, 2, 4, 6-collidine, polyvinylpyridine and the like.

 The amines used in the present invention include those in the form of a salt. Examples of the salt include a hydrochloride, a tosylate, a tartrate and the like.

The base is usually used in the range of 0.1 to 10 equivalents to the substrate. It is preferably used in the range of 0.5 to 5 equivalents, more preferably 1 to 4 equivalents. It is.

 In the present invention, the fluorination reaction using sulfonyl fluoride can be performed in an appropriate solvent, but is preferably toluene, benzotrifluoride, ethyl acetate, methylene chloride, methyl-t-butyl ether. The reaction can be carried out in an organic solvent such as tetrahydrofuran, acetonitrinole, and acetone. The reaction temperature is usually in the range of −40 ° C. to the reflux temperature of the solvent used. Preferably, the temperature is from 20 ° C. to the solvent reflux temperature.

 After the completion of the reaction, the reaction mixture is neutralized with a base or sulfonic acid, if necessary, and subjected to the above-mentioned general formula (II ) Can be extracted.

The compound represented by the general formula (II) obtained by the production method of the present invention is a compound in which the hydroxyl group in the general formula (I) is stereospecifically substituted with a fluorine atom. Substituents other than the hydroxyl group to be substituted maintain their respective positions and α or; Specifically, it is represented by any of the following formulas (XVIII) to (XXV).

 (XX ェ) ((XXλ 丄 丄 I 丄)) (XXIV) (XXV) wherein Υ is a hydroxyl group, and X and と are combined to form a cyclic acetal represented by the above general formula (IV) When the compound is formed, the compound represented by the general formula (II) has a stereo configuration represented by the general formula (XIX), (XX), (XXII) or (XXV).

 When the compound represented by the general formula (I) is a nucleoside derivative, as described above, a compound in which Α is a hydrogen atom and B has 13 configurations is generally used (X and Y are α or). Any of the three configurations may be held. ). In this case, the general formula (II) is represented by any of the following general formulas (XXVI) to (XXIX).

The hydroxyl-protecting group of the compound represented by the general formula (II) is an ordinary one. It can be deprotected by law. For example, when the hydroxyl-protecting group is an acetyl group, an benzoyl group, or another such acyl group, an alcohol such as methanol or a protic solvent such as water, or an alkali such as ammonia or sodium hydroxide is used. In the case of aralkyl groups such as benzyl group and triphenylmethyl group, deprotection can be easily performed by treating with an acid such as hydrochloric acid or acetic acid, or by reducing in the presence of a reduction catalyst. be able to. When the nucleic acid group has a protecting group, the protecting group can be similarly deprotected by a usual method.

 In addition, a substituent of a nucleic acid base (including a derivative thereof) may be derived to another appropriate substituent, for example, a halogen atom at the 6-position may be substituted with an amino group, or a hydroxyl group of Y ′ or X ′ may be removed. The desired fluorinated nucleoside derivative can be converted to a desired fluorine-containing nucleoside derivative by, for example, dehydroxylating the 3′-hydroxyl group (protected or unprotected).

 That is, the nucleoside or saccharide derivative represented by the general formula (II) produced by the production method of the present invention can be converted into a fluorine derivative represented by the following general formula (V) by a method known to those skilled in the art. Nucleoside derivatives. For example, when A is a hydrogen atom and R is a hydroxyl-protecting group in the general formula (I), the 5′-position can be deprotected by an ordinary deprotection method. When any of Y ′ and X ′ is a protected hydroxyl group, it is similarly converted to a hydroxyl group from which the protective group has been removed by the deprotection step.

 On the other hand, when B represents a hydrogen atom, the desired fluorinated nucleoside derivative (V) is obtained by a condensation step of this sugar derivative and a salt represented by B ′ (adenine, 6-halogenoprin, etc.). Can be manufactured. The condensation step can be carried out using a known method (see "Chemistry of Nucleosides and Nucleotides", Vol. 1, LB Townsend, Ed, Plenum Press, New York (1988), 1-281).

For example, if the base is 6-logenopurine, the halogen atom Can be converted into a substituent. In particular, when FddA is produced, it must be subjected to the following 6-amination step (see, for example, VE Marquez et al., J. Med. Chem., 33, 978 (1990)). ).

(V) In the above formula, B ′ represents a nucleobase (including a derivative thereof), Y ″ and X ″ each represent a fluorine atom, and the other represents a hydrogen atom or a hydroxyl group. The compound represented by the general formula (V) is an important compound particularly for pharmaceutical use. For example, a compound in which B ′ is a 3 configuration adenine, X ″ is a 3 configuration fluorine atom, and Y ″ is a hydrogen atom, 9— (2,3-didoxy-1-2-funolelo jS — D— treopen tofurano sinole) Adenine (FddA) is known to have potent antiviral activity against human immunodeficiency virus (HIV). According to the present invention, such an important active ingredient as a medicament can be effectively and easily produced. Among the compounds represented by the above general formula (Π), for example, A is a hydrogen atom, B is adenine in a 6-position, X ′ is a fluorine atom in a] configuration, and Y ′ is a hydrogen atom. By deprotecting R, which is a protecting group for the hydroxyl group at the 5′-position, from the compound of formula (1), FddA can be easily derived. In this case, when Y 'is not a hydrogen atom but a hydroxyl group (protected or unprotected), a step of dehydroxylating this hydroxyl group is required. The protection and deprotection of the hydroxyl group can be appropriately performed as necessary. The above B is 6-halogenoprin in j3 configuration instead of adenine in 3 configuration. In this case, FddA can be produced by aminating the halogen atom at the 6-position of the obtained nucleoside derivative by a known method (such as treatment with ammonia / alcohol). In this case, when γ ′ is not a hydrogen atom but a hydroxyl group (protected or unprotected), a step of dehydroxylating this hydroxyl group is required. The dehydration step may be performed before or after the amination step. In this case, of course, the protection and deprotection of the hydroxyl group can be appropriately carried out as required. Further, when the above B represents a hydrogen atom in the above, a sugar derivative is obtained. If necessary, FddA can be produced by aminating the halogen atom at the 6-position in the same manner.

 The 6-position amination can be carried out by a halogen atom-amino group substitution reaction step of a nucleoside derivative known per se, in which case the 5′-position hydroxyl group is protected even if it is protected. It may not be protected, and if protected, the 5 ′ position may be subjected to the deprotection step after the amination step.

 In the above, when Y ′ is a hydroxyl group protected in place of a hydrogen atom, this hydroxyl group (protection) is subjected to a 3′-position dehydroxylation step (for example, Maruyama et al., Chem. Pharm. Bull., 47, 966- 970 (1999)). When performing this step, it is preferable that the 5′-hydroxyl group is protected, and in this case, the protecting group may be deprotected thereafter. In this step, of course, B may be the above-mentioned halogenoprin, and in such a case, the above-mentioned 6-position amination step is required.

 In addition, for example, the compound described in the general formula (II) can be used to guide FddA according to the method described in Examples below.

Further, among the compounds represented by the general formula (II), for example, A is water Compounds in which B is a peracyl or thymine in the | 3 configuration, Y 'is a fluorine atom in the α configuration, and X' is a hydrogen atom, R is a protecting group for the hydroxyl group at the 5'-position. Deprotection easily leads to 2 ', 3,1-dideoxy 3'-fluorouridine, 3,1-deoxy-13'-fluorothymidine, which is known to have antiviral activity. be able to. When the general formula (II) represents a sugar derivative, the compound represented by the general formula (II) is useful, for example, as an intermediate of a nucleoside derivative. By conducting a condensation reaction (coupling reaction) with a nucleobase derivative from such a sugar derivative, a target nucleoside derivative can be obtained. Then, similarly, deprotection of a protecting group of a hydroxyl group or a nucleic acid base, derivation of a substituent to another suitable substituent, or dehydroxylation of a hydroxyl group of X ′ or Y ′ is performed. Thus, it can be converted into a desired fluorine-containing nucleoside derivative represented by the general formula (V).

 For example, FddA can be derived from a sugar derivative by the method described in VE Marquez et al., Synthesis (1991), 1005 or VE Marquez et al., J. Med. Chem., 33, 978 (1990). it can.

 The following method can be used to produce FddA and related compounds using a derivative in which B is 6-halogenoprin.

The compound represented by the following general formula (Π-1) may be subjected to the step of substituting the halogen atom at the 6-position with a Z group to remove the 5′-position as necessary, or the 5′-position may be unprotected. Then, FddA or a related compound can be produced by subjecting the halogen atom at the 6-position to a Z group substitution reaction.

(JL'2 ') in the above formula, Q a is halogen atom, Z is a hydrogen atom, an amino group, hydroxyl group, azide de group, substituents of the formula OR ^4, represented by the formula SR ⁴ substituent And R is any of the substituents represented by the formula NH R ⁴ , R is a protecting group for a hydroxyl group, and has the same meaning as described above.

 The substitution at the 6-position and the logen atom with the Z group can be carried out using a substitution reaction known per se. For example, when producing the nucleoside derivative represented by the general formula (（-2), the compound represented by the general formula (Π-1) may be subjected to, for example, the following reaction step.

In the case of ∑ = amino group, treat with ammonia dissolved in alcohol such as methanol under pressure. In the case of z = hydroxyl group, it is treated with an aqueous solution of hydroxide such as sodium hydroxide or hydroxide.

 When z is a hydrogen atom, the compound is treated with hydrogen in the presence of a reduction catalyst such as palladium carbon. If z = azide group, treat with an alkali metal azide such as sodium azide or lithium azide in a solvent that dissolves the metal azide such as dimethylformamide.

If Z = OR ⁴ or SR ⁴ , the corresponding alkyl alcohol or alkyl thiol is activated with an alkali metal halide such as sodium halide and treated with this.

For Z = NHR ^4, alkyl amines (Arukiruamin corresponding to substituent to Mechiruamin like object), preferably treated in an inert solvent medium such as dimethyl formamidine de.

In the above formula, R ⁴ may have a substituent such as a fuunyl group, or a lower alkyl group having 15 to 15 carbon atoms (eg, a methyl group, an ethyl group, a propyl group, a butyl group, a benzyl group, etc.). ).

 Further, when the compound represented by the general formula (Π-2) is subjected to a deprotection reaction, for example, when the scale is an acetyl group such as acetyl or benzoyl, the compound is treated with alcohol (sodium hydroxide, potassium hydroxide, etc.). When R is an alkyl group such as methoxymethyl or aryl, treatment with an acid such as hydrochloric acid or acetic acid results in reduction of palladium carbon or Raney nickel when R is an aralkyl group such as benzyl or trimethylmethyl. If R is a silyl group such as trimethylsilyl, it is easily treated with hydrogen or in the presence of a catalyst, if necessary, with an acid such as acetic acid, etc., and then easily treated with tetraammonium fluoride. The nucleoside derivative represented by the formula (III-3) can be produced.

On the other hand, the order of the substitution reaction and the deprotection reaction from the compound (Π-1) is changed, and the compound (Π-1) is first subjected to the 5′-position deprotection reaction as described above to obtain the compound represented by the general formula When the compound represented by (Π-2 ′) is produced, and then subjected to the reaction of substituting the substituent Q with the Z group as described above, the nucleoside derivative represented by the above general formula (Π-3) is also obtained. Can be manufactured.

 In the production of the nucleoside derivative, when the compound (保護) is a compound having a hydroxyl group or a protected hydroxyl group at the 3′-position, the hydroxyl group (protected or unprotected) is dehydroxylated. The above-mentioned FddA or a related compound can be produced. For this dehydroxylation, a method known per se can be used, but dehydroxylation can also be carried out by introducing an appropriate leaving group.

 In this case, the protecting groups at the 5'-position and the 3'-position should be different from each other so that they cannot be simultaneously deprotected under the same conditions, and those which can deprotect only the 3'-position should be selected. There is a need to. For example, an acetyl group such as an acetyl group or a benzoyl group as a protecting group at the 3′-position, and an aralkyl group such as a trityl group or a benzyl group which may have a substituent as the protecting group at the 5′-position. Combinations of groups can be employed.

Preferred embodiment

 Hereinafter, the present invention will be described in detail with reference to Examples and Reference Examples. However, these Examples do not limit the present invention at all.

Reference Example 1>

 6—Black mouth 9—1 [3-Doxy 5— O— (triphenylmethyl) 1 / 3—D—Eritroventfuranosyl] 1 9 H—brin

6-Black mouth 9-1 (3-Doxy j8—D—Elitroventfuranosyl) — 9H—Purine 1.38 g (5.1 Ommo 1) is dissolved in 4 mL of dry dimethylformamide, and After adding 2.3 ml (16.5 mm o 1) of triethylamine and 0.424 g (3.47 mm o 1) of 4-dimethylaminopyridine, 4.79 g (16.8 mm o) of trityl chloride o 1) was added, and the mixture was reacted at 50 ° C for about 16.5 hours. After cooling, 8 ml of water was added, and the solvent was distilled off four times. The residue was dissolved in 10 Om1 of methylene chloride and 5 Om1 of water. The layers were separated and the organic layer was washed four times with 50 ml of water, dried over anhydrous sodium sulfate and filtered. Filter the filtrate Apply to a Ricagel column (100 g silica gel), methylene chloride, then 1-1

Elution was performed with a 0% methanol Z methylene chloride solution. The solvent was distilled off to obtain 2.71 g (purity 85.3%, yield 88.5%) of the desired product as an oil.

¹ H-NiVIR (300 MHz, CDC 1;) δ: 8.64 (1H, s, H2), 8.40 (1H, s, H8), 7.41-7 . 2 1 (15H, m, 5'OTr), 6.04 (1H, d, J = 2.2Hz, HI '), 4.87 (1H, m, H2 '), 4.73 (1H, m, H4'), 3.44 (1H, dd, J = 10.6, 3.1Hz, H5'a), 3.33 (1H, dd, J = 10.6, 4.6Hz, H5'b), 2.30 (1H, ddd, J = 13.3, 7.7, 5.6H z, H3, a), 2.17 (1H, ddd, J = 13.3, 6.5, 3.9Hz, H3'b).

IR (KB r, cm " ¹ ): 3 3 5 4 3 0 5 9 1 5 9 2 1 5 6 2 1 4 9 1 1 4 4 9 1 4 0 0 1 ... 206, 1130, 1107, 1108, 952, 766, 748, 704, 634.

 U V (M e OH) λ max: 207 (1 og £ 2.27), 26.5 (1 og £ 0.31) nm.

 MS (E S I) m / z: 5 1 3 (M + H)

<Example 1>

 6 — Black mouth 9 — [2, _ 3 — Didoxy 1 2 — — Funoleo mouth 5 — O— (triphenylmethyl) mono — D— Treopenp Tofurano 9 Hpurine

6-Black 9-1 [3-Doxy 5 — O— (triphenylmethyl) — I3— D—Erythro-bentofuranosyl] -19H—purine 2.0 duram (3.90 mm 01) is dissolved in tonoleen 20 milliliters, and N—ethylpyperidin 1.07 Milliliters (7.80 mmo 1) was added. At room temperature, perfluoro-1-butanesulfoninolephnolide 2.80 milliliter (15.6 mmol) was added dropwise to this mixture with stirring, and the mixture was heated to 40 ° C and cooled to 40 ° C. Stirred for 0 hours. When the reaction mixture was analyzed by high performance liquid chromatography (HPLC), the target compound was obtained at an area ratio of 60.4%. The desired product was isolated and purified by recrystallization. Example 2 (Step 1)>

 9-1- [2,3-dideoxy-2-fluoro-5-O- (triphenylmethyl) -1-] 3-D-treopentofuranosyl] adenine

 6—Chlorol 9-1 [2,3-dideoxy-l 2-fluoro-5-O— (triphenylmethyl) 11-D—treopenttofuranosyl] — 9 H—purin ll O mg (0.2 14 Dissolve mm o 1) in 17.2 ml of a 20% ammonia / methanol solution and place in a sealed tube at 60 °. And left for 1 晚. After cooling, the reaction mixture was concentrated, azeotroped with toluene, and the resulting crystals were filtered. Drying under reduced pressure at room temperature gave 82.3 mg of a white solid (purity 74.4%, yield 57.7%).

'H-NMR (300MHz, CDC13) 5: 8.33 (1H, s, H2), 8.06 (1Η, d, J = 3.0ΗΗ, Η 8), 7.5 2-7. 20 (10 Η, m, 5 Ό Τ r), 6.33 (1 Η, dd, J = 19.9, 2.9 Η, Η 1 '), 6.18 (2Η, bs, 6-ΝΝ!), 5.20 (1Η, md, J = 53.8 8Η, Η2'), 4.40 ( 1 Η, m, Η 4 '), 3.46 (1 Η, dd, J = 10.0, 6.5 Η Η, Η 5' a), 3.27 (1, -Ι, dd , J = 10.0, 4.1Η, H5'b), 2.50 (1Η, dddd, J = 35.5, 14.9, 9.0, 5.4Η) ,, Η 3 'a), 2.31 (1 Η, dddd, J = 27.5, 14.9, 4.8, 1.4 Hz, H3'b).

 IR (KBr, cm '): 3151, 1649, 1599, 15578, 1403, 1063, 703.

 U V (M eO H) λ max: 208 (1 o g f 2.19), 25 9

(1 o g f 0.58) n m.

M S (E S I) m / z: 496 (M + H) +.

<Example 2 (Step 2)>

 9-1- (2,3-dideoxy-1 2-fluoro-j3-D-treopent furanosyl) adenine (F d d A)

 9 1 [2,3-Dideoxy 2 -fluoro-5 -O- (triphenylmethyl) 1 -D-treopentofuranosyl] adenine 35.3 mg (0.071 0 mm o 1) of acetic acid 1 After stirring at room temperature for about 4 hours, the mixture was stirred at 80 ° C for about 3 hours. Acetic acid (1.0 ml) was added, the mixture was cooled to room temperature, concentrated, and the residue was purified by preparative silica gel plate (91% methylene chloride Z ethanol). After extracting the fraction of the target substance with methanol, the solvent was distilled off to obtain the target substance as a white solid in a total of 11.1 mg (yield: 61.5%). Product physical data were consistent with known literature values.

<Example 2 (Step 3)>

 9-1 (2,3—Dideoxy 1—2-Funoleo 3—D—Threopent furanosyl) Adenine (F d dA)

 6—Black mouth 9— [2,3-Dideoxy 2-funoleol 5—O— (Triphenylmethyl) mono jS—D—Threopentofuranosyl] —9 H—purine 3.65 g

(7.09 mmo 1) was dissolved in methanol (18 ml) containing 0.5 equivalents of hydrochloric acid and toluene (18 ml) and stirred at room temperature for 4 hours. This was treated with 2 equivalents of poly (4-vinylvinylidine), and the filtrate was concentrated under reduced pressure. Residue in methanol 200m

1 and toluene dissolved in 200 ml of 1, 40 to 6 in the presence of 3.5 atm of ammonia 0. Stirred at C for 5 days. The reaction mixture was concentrated under reduced pressure, and an 80% aqueous acetone solution was added to the residue to produce crystals, which were filtered. The obtained crystals were dried and analyzed. As a result, the target compound, FddA, was obtained in two steps with a yield of 73%. <Example 3>

 6-chloro 9-1- [2,3-dideoxy 2-phenoleol-5-O —— (triphenylmethyl) -β-D-treopentofurano 9Η-purine

 6-Chlorol 9- [3-Doxy-1 5-〇1- (triphenylmethyl) -1 3—D-Erythrobentofurano Sinore] 1-9 プ リ -Prin 100.0 Gram (19.49) mmol) was dissolved in 100 milliliters of toluene, and N, N-dimethinolecyclohexylamine 5.96 milliliters (38.99 milliliters) was added. To this mixture at room temperature, perfluoro-1-butanesulfonyl fluoride 7.78 milliliters (38.99 mmo1) was added dropwise with stirring, and the mixture was heated to 50 and heated for 24 hours. Stirred. The reaction was stopped by adding 25 milliliters of a 10% aqueous ammonium chloride solution to the reaction mixture, and the organic layer was separated. The organic layer was washed sequentially with 25 milliliters of a 10% aqueous ammonium chloride solution and 25 milliliters of water. When the organic layer was analyzed by HPLC, the desired product was obtained in a yield of 57.6%.

<Reference Example 2> 39144

 PCT / JP99 / 06500

6—Black mouth 9—1 [3-Doxy 5—O—acetyl—D—Elit mouth—ventfurano 9 H—brine

6-Chloro-9— [3-Doxy-d-D-erythro-pentofuranosyl] —9H-purine was reacted with acetyl chloride in dry dimethylformamide in the presence of pyridine at room temperature. The resulting reaction mixture was treated with water, and the product was extracted with methylene chloride. Subjected oily substance obtained by concentrating the extracted organic layer silica force gel strength Ramuku Roma Togurafi one, and eluted with hexane mixed solution to acetic acid Echiruno _n scratch. The eluate containing the desired compound was collected, and the residue obtained by concentrating the eluate was recrystallized twice from ethyl acetate and n-hexane to obtain the desired product.

¹ H-NMR (300 MHz, CDC 13) δ: 8.75 (1 1, s, H 2), 8.43 (1 H, s, H 8), 6.04 ( 1 H, d, J = 2.3 Hz, HI '), 4.87 (1H, m, H2'), 4.8 1 (1H, m, H4 '), 4.4 2 (1H, dd,] = 12.4, 3.0Hz, H5'a), 4.31 (1H, dd, J-12.4, 4.4Hz, H 5'b), 2.24 (2H, m, H3 '), 2.07 (3H, s, 5 HAc) ₀

<Example 4>

 6 —Chloro 9 1 2, _ 3 —Dideoxy 2 —Phenylol 5 —O—A-cetyl—β — Ό—Tropenpentofurano — 9 ΗPrin

6 — Black mouth — 9 — [3 — Doxy 1 5 — 1-acetyl-; / 39144

 PCT / JP99 / 06500 Retroventofuranosyl] — 9 H—purine 200 milligrams dissolved in benzotrifluoride 4.0 milliliters, and N, N—dimethylcyclohexylamine 0.16 I added the Milli-Ri-t-Nore. To this mixture at room temperature was added dropwise 0.25 milliliter of perfluoro-1-monobutanesulfonolenefluoride with stirring, and the mixture was stirred at 25 C for 24 hours, and then heated to 50 C. Stirred for 20 hours. When the reaction mixture was analyzed by HPLC, the desired product was obtained with an area ratio of 49.3%. The target compound was isolated and purified by recrystallization from ethyl acetate and n-hexane.

'H-NMR (300 MHz, CDC 13) δ: 8.74 (1Η, s, H 2), 8.45 (1Η, d, J = 2.7 Hz, H 8), 6.43 (1H, dd, J = 18.9, 3.1Hz, HI *), 5.32 (1H, ddd, J = 54.2, 9.9 , 4.3 H z, H 2 '), 5.1 1 (1 H, t, J = 5.8 Hz, 5 Ό H), 4.26 (1 H, m, H 4'), 3.75—3.58 (2H, m, H5'ab), 2.71 -2.50 (1H, m, H3'a), 2.42 -2.2 2 (1 H, m, H 3 'b), 2.13

(3H, s, 5'OAc).

<Example 5>

 9-1- [2,3-dideoxy-1-fluoro-5—O—acetyl—jS—D—furanosyl on treopen] adenine

9 [3—Doxy 5 — 0—Acetyl 3 — D—Eri Troben O 00/39144

 PCT / JP99 / 06500 Tofuranosyl] 100 mg of adenine in tetrahydrofuran 3.

4 Dissolve in milliliter, and add N, N-dimethylcyclohexylamine 0,

166 Milliliters (0.68 mmo1) was added. To this mixture, at room temperature, was added dropwise, with stirring, benzofluorene-1-butanesulfoninolefluoride 0.127 milliliter (0.68 mm 01) at 5 ° C.

After stirring for 2 hours, additional N, N-dimethylcyclohexylamine was added.

1 6 6 Milli-liter (0.68 mmol) and benzofluorone 1-butanesulfoninolephnoleide 0.127 Milli-liter (0.68 mmo)

1) was added. This mixture was stirred at 50 ° C. for 20 hours and analyzed by HPLC, whereby the target product was obtained at an area ratio of 7.8%.

<Example 6>

 6—Kurorow 9 1 (5—〇1 1 Tri-Feninole Metinole 3—O—Ben

Lou 2—Doxy 2 —Fluoro / 3 / D—Dara Vino Furano

9 H—purine

5'—O—Tri-Feninole Metinole 3'—O—Benzoinole 6—Krolov. Dissolve 1.0 g (1.55 mmo 1) of phosphorus riboside in 10 ml of toluene and add N, N-dimethylcyclohexylamine 0.47 ml of toluene (3.10 mmo 1) was added. To this mixture, at room temperature, was added dropwise, while stirring, a mixture of benolefnoroleol 1-butanes-le-honinolefnorleolide 0.58 milliliter (3.10 mmo1) and stirring at 50 ° C. time Stirred. The reaction mixture was quenched with 10 milliliters of saturated aqueous sodium bicarbonate solution to terminate the reaction, and then added with 10 milliliters of toluene and 2 ° milliliters of ethyl acetate. The organic layer was separated. The organic layer was washed successively with 10 milliliters of a 5% aqueous solution of citric acid and 10 milliliters of a saturated aqueous solution of sodium bicarbonate. When this organic layer was analyzed by HPLC, the target product was obtained in a yield of 66.2%. The desired product was isolated and purified by silica gel column chromatography.

<Example 7 (Step 1)>

 9-1- (5-O-triphenylinolemethinole-1-dioxy-2-fluoro-3) -D-arabinofuranosyl) adenine

 6—Black mouth 9— (5—O-triphenylinone 3—O—Venzoyl 1—2-Doxy 1—2-Fluoro 1 β-1 D—Alara pino furanosyl) — 9Η— Purine (3.15 g, 4.98 mmol) is dissolved in 100 ml of methanolic ammonia (saturated at 0 ° C) and left in a sealed tube at 100 ° C for 2 days. did. After cooling, the solvent was carefully distilled off and the residue was dissolved in 100 ml of chloroform. The insoluble matter was removed by filtration, and the solution was applied to a silica gel column (3.5 × 50 cm), and eluted with a 3-10% ethanol / dichloromethane solution (4000 ml). The fractions of the product were collected and the solution was concentrated to give white crystals (1.87 g, 3.66 mmol 1, 73%).

Melting point: 20.5-22.5 ° C.

<Example 7 (Step 2)>

 9— (5—O—triphenylmethyl-1-3-phenyloxycarbinoleoxy-1-2-deoxy-2-fluoro j8—D—arapino furanosyl) adenine

27-mg of 4-dimethylaminoviridine was dissolved in 10 ml of anhydrous acetonitrile, and 9- (5-O-triphenylmethyl-2-de) was added to this solution. 2 -Fluoro] 3 -D-arabinofuranosyl) adenine (4 19 mg, 0.82 mmo 1) was suspended therein. Next, 0.22 ml of phenoxythiocarbonyl chloride was added with stirring, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, the residue was dissolved in 20 ml of chloroform-form, and subjected to chromatography on a silica gel column (2.5 x 32 cm). 0 ml). Fractions of the product were collected and the solvent was distilled off to give the caramel-like target. Yield 490 mg (FW: 61.564, 0.80 mmo1, 97%).

 <Example 7 (Step 3)>

 9 — (5 —〇 triphenylmethyl 1, 3 — dideoxy 2 — fluorool ί3 — D— treopen tofuranosyl) adenine

 9 — (5 — O— triphenylenolemethyl-3 — phenoxythiocarbonioxy 1 — doxy 2 —fluoro jS — D—arabino furanosil) adenine (386 mg, 0.63 mm o 1) was suspended in 4 ml of dry tonolene, and azobisisobutyronitrile (60 mg) and tris (trimethylsilyl) silane (0.6 ml) were added thereto. The mixture was heated at 100 ° C under a nitrogen stream. Stirred for 30 minutes. After cooling, the precipitated crystals were collected by filtration, washed with toluene, and dried. Yield 229 mg (0.46 mmo1, 73%).

Melting point: 2 26-22 9 ° C.

'H-NMR (CDC lr δ: 8.36 (1 H, s, Η 2), 8.07 (1, d, J = 2.6 Η,, 8), 7.1- 7.6 (ca20 0, Τr), 6.33 (1Η, dd, J = 17, J = 3.0 Η, Η1 '), 5.70 (2Η, b r.s, Ν Ν 2), 5.2 2 (1 Η, m, J = 43.6 Η,, Η 2 '), 4.4 (1 Η, m, Η 4'), 3.4 6 (1Η, dd, J = 8.2, J = 5.9Η, Η5'a), 3.26 (1Η, dd, J = 8.2, J = 3.2Η) , H 5 'b), 2.2 — 2.6 5 (2 H, m, H 3 ').

Example 7 (Step 4)>

 9-1- (2,3-dideoxy phnoreo-l-β-D-—treopent furanosyl) adenine (FddA)

 9- (5—O—triphenylmethyl-2,3—dideoxy—2—fluorone ^ —D—treopentofurano sinole) adenine (300 mg, 0.605 mmo 1) in methanol (18 ml), concentrated hydrochloric acid (1.2 ml) was added thereto, and the mixture was stirred and dissolved. The mixture was stirred at room temperature for one and a half hours, to which 4 ml of Amberlite IR400B (〇Ac-type) was calorie, and the mixture was stirred for 5 minutes. The resin was removed by filtration, the filtrate was concentrated to about 2 ml, 40 ml of water was added, and the mixture was washed three times with 10 ml of chloroform. The aqueous layer was concentrated to give prism crystals.

Yield First crystal 1 1 6 mg Second crystal 丄 9 mg ₀

Total yield 135 mg (FW: 2532, 0.533 mmo1, 88%).

 (Example 8)

 6—Black mouth 9—1— [2, —3—Dideoxy 1 2 Funole 1-5—O— (Triphenylmethyl) 1 / 3—D—Toleo-bent Furano 1 9H—Prince

6—Crow 9— [3—Doxy 5—Primary (Triphenyl) / 39144

 PCT / JP99 / 06500

— D—Erytrofuranto furanosyl] — 9 H—purine 51.3 milligrams (0.1 mm 01) are dissolved in 0.5 milliliters of toluene and N, N —Dimethylcyclohexylamine 0.30 Milliliter (2.0 mmo 1) was added. To this mixture, at room temperature, perfluoro (4-methyl-3,6-dioxoctol 7-ene) snorephonylfluoride 89.2 milligrams (0.2 mmo 1) was added dropwise with stirring, The temperature was raised to 50 ° C and the mixture was stirred for 23 hours. When the reaction mixture was analyzed by HPLC, the desired product was obtained in a yield of 27.5%.

 (Example 9)

 6-chloro 9- [2,3-dideoxy 2--fluoro-5-O- (tri-phenylmethyl) -β_-1 D-treopentofuranosyl] -19-purine

6—Chloro 9— [3-Doxy 5—O— (triphenylmethyl) —D—erythroventofuranosyl] 1 9H—Prin 51.3 migrogram (0.1 mmo 1) Was dissolved in 0.5 milliliters of toluene, and N, N-dimethylcyclohexynoleamine 0.30 milliliters (2.0 mmo 1) was added. To this mixture, at room temperature, was added dropwise 55.2 mg (0.2 mmo1) of 5-oxopentafluoro-3-oloxapentane sulfonylfluoride while stirring, and the temperature was raised to 50 C. And stirred for 23 hours. The reaction mixture was analyzed by HPLC. Was obtained in a yield of 20.2%.

 (Example 10)

 6 — Black mouth 1 9 1 [2,3-Dideoxy 1 2 -Fluoro 5 -〇 1 (Triphenylmethyltinole) 11 D-Treobent furanosyl] — 9 H-purine

6—Chlorol 9—1 [3-Doxy 5—O— (triphenylmethinole) 1 / 3—D—Erythrobentofuranosyl] 1 9H—Prin 51.3 Milligram (0.1 mmo 1) is dissolved in 0.5 ml of toluene, and N, N-dimethyinolecyclohexynoleamin 0.03 mm (1 mmo 1) Was added. To this mixture at room temperature was added dropwise perfluorooctane snolephonyl funoreolide 0.055 milliliter (0.2 mmol) while stirring, and the temperature was raised to 50 ° C. The mixture was stirred for 72 hours. When the reaction mixture was analyzed by HPLC, the desired product was obtained in a yield of 39.4%.

 (Example 11)

6-Chloro-9-1_ [2, —3-didoxy __2—Fluoro-5-〇-1- (triphenylmethyl) 11 D Reobent Furano 1 9H-purine

 6—Chlorol 9— [3-Doxy-5-O— (triphenylenolemethyl) -jS—D—Erythrobentofuranosyl] —9 H—purine 51.3

 Three

The regram (0.1 mmo1) was dissolved in 0.5 ml of toluene and 0.5 milliliter of triethylamine, and 0.028 milliliter of triethylamine was added (0.2 mmo1). To this mixture, at room temperature, 38.4 milligrams (0.2 mmo1) of methyl fluorosulfonyl (difluoro) acetate was added dropwise with stirring, and the mixture was heated to 50 ° C and stirred for 74 hours. did. When the reaction mixture was analyzed by HPLC, the desired product was obtained in a yield of 28.1%.

 (Example 12)

 5 '— O— Triphenylamine 2 ,, 3 ′ — Didoxy 1 3 ”— Fluorouridine

 5'-O-triphenylmethynolate 2'-Doxy-l-xylofuranosylperacil 200 milligrams were dissolved in tetrahydrofuran 2.0 milliliters, and N, N- Dimethylenocyclohexinoreamin 0.26 milliliter was added. To this mixture was added 0.32 milliliter of perfluoro-1-butanesulfonylfluoride at room temperature, and the mixture was stirred under reflux for 48 hours. When the reaction mixture was analyzed by HPLC, the desired product was obtained at an area ratio of 20.8%.

The 5'-protected hydroxyl group at the target product obtained in this manner is treated with a method known as the 5'-position deprotection method for nucleotides, for example, by treating it with an acid such as hydrochloric acid or acetic acid. Easily converted to 2 ', 3'-didoxy 3'-fluoridine by reduction in the presence of a reduction catalyst Can be

(Example 13)

 3-Doxy 3-Fluoro-1, 2: 5, 6 1-O-O-isopropylidene 1-1 D-Darcofuranose

1,2: 5,6-Di-O-isopropylidene-Hi-D-alofuranose 5.0 g (19.2 mmol) was dissolved in toluene 50 milliliters, and N, N-dimethyl was dissolved. Cyclohexylamine 5. Milliliter tongue (38. 4 mmo1) was added. To this mixture, at room temperature, was added dropwise with stirring 6.9 liters of butanes honolehonolefluoride 6.9 milliliters (38. 4 mmo1), and the temperature was raised to 50 ° C. And stirred for 64 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture to stop the reaction, and the toluene layer was separated. The lower layer was extracted with toluene, and the extracted organic layers were combined and washed twice with a saturated aqueous solution of ammonium chloride. The oily substance obtained by concentrating the extracted organic layer was applied to a silica gel column, and eluted with a mixed solution of ethyl acetate and methylene chloride. The eluate containing the desired compound was collected and concentrated to give an oily target in a yield of 47.3%.

A known method from the sugar derivative obtained as described above (VE Marquez et al., J. Med. Chem., 33, 978 (1990); A. Watanabe et al., Carbohydr. Res. (1975), 42, See 233 etc. ) Can be used to easily produce FddA. Here, at least a condensation step with a 6-halogenoprine derivative and a 3′-position dehydroxylation step are included.

The invention's effect

 According to the present invention, a compound in which the hydroxyl group is selectively and effectively substituted with a fluorine atom can be easily produced from a nucleoside or a sugar derivative having a secondary hydroxyl group. In particular, a fluorine atom can be stereospecifically substituted in one step, and a low-cost, safe, and industrially superior production method is provided.

 As a result, the present invention is extremely useful in the production of various pharmaceutical intermediates including FddA.

Claims

A nucleoside or a sugar derivative represented by the following general formula (I) Ichijinji

of [Where, A. A is a hydrogen atom or a methyl group having a protected hydroxyl group, B is a nucleobase (including a derivative thereof) or a protected hydroxyl group, R is a hydroxyl-protecting group, and Y and X are any of One represents a hydroxyl group and the other represents a hydrogen atom or a protected hydroxyl group; or A and R together form a cyclic acetal represented by the following general formula (III) (R and R both represent a hydrogen atom or a methyl group, or one of them represents a hydrogen atom. And the other represents a methyl group or a phenyl group, respectively.), B, Y and X represent the same meaning as described above.

Yeee Or C. Y represents a hydroxyl group, and X and B are integrally represented by the following general formula (IV). (R ₃ and R both represent a hydrogen atom or a methyl group, or one of them represents a hydrogen atom, and the other represents a methyl group or a phenyl group, respectively.) , A and R have the same meanings as in any of the above. ]

 (IV) A method for producing a nucleoside or a sugar derivative represented by the following general formula (II), which comprises reacting a sulfonyl fluoride with a base.

[In the formula, A, B and R represent the same meaning as described above, and one of Y ′ and X ′ represents a fluorine atom, and the other represents a hydrogen atom or a protected hydroxyl group, respectively. ]  Further, when Y ′ is a protected hydroxyl group, the method may include a step of deprotecting the protective group to produce an unprotected Y ′ hydroxyl group. 2. Sunorehonorenorehonoride is Benorefolenorreolo Anorecansnorehoni Force or trifluoromethanesulfoninolefluoride, at least one of rufluoride and alkanesulfonylfluoride, phenol fluorene 1—butanesulfoninolefluoride and benzolefluorinone 1—octanesnorefonino Lefnoreolide, Penolenovoleo mouth (4—methinole 3, 6—dioxactone 7—one) Sulfoninolephnoleoride, 5—Nologenoktakhnolelow 3—Oxapentance norehonino 2. The production method according to claim 1, wherein the production method is any one of refnoleolide and fluorosulfonyl (diphnoleo mouth) acetate. 3. The production method according to claim 1, wherein the base present in the reaction with the sulfonyl fluoride is an amide. Amines include those in salt form. 4. The method according to claim 1, wherein the nucleobase is adenine or 6-halogenoprin. 5. The production method according to claim 1, wherein Y represents a hydrogen atom or a protected hydroxyl group, X represents a hydroxyl group, Y ′ represents a hydrogen atom or a protected hydroxyl group, and X ′ represents a fluorine atom.  Further, when Y ′ is a protected hydroxyl group, the method may include a step of deprotecting the protective group to produce an unprotected Y ′ hydroxyl group. 6. The nucleoside or saccharide derivative represented by the general formula (II) obtained by the production method according to claim 1 is subjected to a deprotection step of a hydroxyl group to obtain a fluorine represented by the following general formula (V). 2. The production method according to claim 1, wherein the nucleoside derivative is produced. However, for sugar derivatives, the condensation step with the nucleic acid base represented by B ' At least c H

[In the formula, B 'represents a nucleic acid base, Y "and X" each represent a fluorine atom, and the other represents a hydrogen atom or a hydroxyl group. ] 7. A nucleoside derivative represented by the general formula (Π) obtained by the production method according to claim 1, wherein A is a hydrogen atom, B is 6-halogenopurine, and Y ′ is a hydroxyl group or a protected a hydroxyl group, a X 'is a fluorine atom, a represents.) respectively, 6-position a halogen atom and a hydrogen atom, an amino group, a hydroxyl group, an azide group, a substituent of the formula OR ^4, substitution of formula SR ⁴ subjected to the step of substituting with any of substituents represented by the group, and NH R ^4, the method of claim 1 wherein manufacturing the substituents. When it has a 5′-protecting group (R), it may include a step of deprotecting the protecting group before or after the reaction of substituting with the substituent. R ⁴ represents a lower alkyl group which may have a fluorine group. 8. The nucleoside derivative (π) (Y ′ represents a protected hydroxyl group and X ′ represents a fluorine atom) obtained by the production method according to claim 1, and the hydroxyl group at the Y ′ position is dehydroxoxyl. 2. The production method according to claim 1, wherein the 3′-position dehydroxylated product is produced by the step of oxidizing. When R is a protecting group, the method may include a step of removing the protecting group. 9. A fluorinated nucleoside derivative or FddA characterized by being obtained by the production method according to claim 68 10. The sugar derivative produced is 3-doxy-3-fluoro-1,2 The production method according to claim 1, wherein the production method is 5, 6-di-iso-isopropylidene-α-D-dalcofuranose. 11. The method according to claim 10, further comprising a step of condensing with a 6-logenopurine derivative or an adenine derivative and a step of dehydroxylating at the 3′-position to produce FddA, and the FddA obtained by the method.