JP2007153876A - Nucleic acid bases having perfluoroalkyl group and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for simply and efficiently producing nucleic acid bases having a perfluoroalkyl group. <P>SOLUTION: The method for efficiently producing the perfluoroalkyl nucleic acid bases useful as a medicinal intermediate is carried out as follows. Halogenated perfluoroalkyls are reacted with nucleic acid bases (e.g. uracils, cytosines, adenines, guanines, hypoxanthines or xanthines, etc.) in the presence of sulfoxides, a peroxide and an iron compound. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a method for producing nucleobases having a perfluoroalkyl group.

  Nucleobases substituted with a perfluoroalkyl group are important compounds as intermediates for producing pharmaceuticals or medical and agrochemicals. Particularly, nucleobases having a trifluoromethyl group are useful compounds. For this reason, many studies have been made on methods for producing trifluoromethyl-substituted nucleobases.

  For example, with respect to a method for producing 5-trifluoromethyluracil which is important as an intermediate for anticancer agents, antiviral agents, etc., Patent Document 1 discloses 5-trifluoromethyl obtained by reaction of α-trifluoromethylacrylic acid and urea. A method for obtaining 5-trifluoromethyluracil by reacting methyl-5,6-dihydrouracil with dimethyl sulfoxide and iodine using concentrated sulfuric acid as a catalyst is disclosed. Patent Document 2 discloses a method of reacting 5-iodouracils with copper iodide and methyl fluorosulfonyldifluoroacetate to convert them into 5-trifluoromethyluracils. Further, in Patent Document 3, thymine is chlorinated with chlorine gas to 2,4-dichloro-5-trichloromethylpyrimidine, and further fluorinated with anhydrous hydrogen fluoride or antimony trifluoride in the presence of antimony pentachloride. , A process for producing 5-trifluoromethyluracil by treatment with water is disclosed. However, each method has a problem in that it uses a large number of steps and uses anhydrous hydrogen fluoride and an antimony compound which are difficult to use industrially. Non-Patent Document 1 discloses a method of trifluoromethylating the 5-position of 3 ', 5'-diacetyl-2'-deoxyuridine with trifluoroacetic acid and xenon difluoride. However, since this method also uses a special reactant, it is difficult to use industrially.

  Regarding the method for producing 5-trifluoromethylcytosine, Non-Patent Document 2 describes 4-amino-2-chloro-5 obtained by reaction of 2,4-dichloro-5-trifluoromethylpyrimidine and liquid ammonia. A method for obtaining 5-trifluoromethylcytosine by hydrolyzing trifluoromethylpyrimidine and treating with ion exchange resin is disclosed. However, this method has a problem in that the number of steps including a raw material manufacturing step is large.

  Regarding the method for producing purines having a trifluoromethyl group, for example, Non-Patent Document 3 discloses that 8-trifluoromethyl is obtained by reacting 4,5-diaminopyrimidine with trifluoroacetic acid or trifluoroacetic anhydride. Methods for obtaining adenine, 2,6-diamino-8-trifluoromethylpurine, 8-trifluoromethyl hypoxanthine are disclosed. Non-Patent Document 4 discloses 2,4-diamino-5-trifluoroacetamino-6 obtained by reaction of 2,4,5-triamino-6-oxo-1,6-dihydropyrimidine and trifluoroacetic acid. A method for obtaining 8-trifluoromethylguanine by reacting -oxo-1,6-dihydropyrimidine with trifluoroacetic anhydride is disclosed. However, each method has an industrial problem in that the number of steps including the production of raw materials is large.

  As a method for directly perfluoroalkylating these nucleobases, for example, in Patent Document 4, purines are reacted with N, O-bis (trimethylsilyl) trifluoroacetamide using pyridine and trimethylchlorosilane as a catalyst. , A method of obtaining a purine having a perfluoroalkyl group at the 8-position or 2-position by reacting bis (perfluoroalkyl) peroxide is disclosed. However, this method has a problem in that di (haloacyl) peroxide, which is difficult to use industrially, a fluorocarbon solvent, and structural isomers having different substitution positions are produced. Further, in Non-Patent Documents 5 and 6, uracil anion is electrochemically generated and reacted with perfluorobutane iodide, thereby producing 8-perfluorobutyluracil, 8-perfluorobutyl hypoxanthine and 8-perfluorocarbon. A method for obtaining a fluorobutylxanthine salt is disclosed. However, this method has a problem in that an electrochemical method that is difficult to use industrially and a product can be obtained as a salt of the supporting electrolyte.

  Non-patent document 7 discloses that 8-trifluoromethyltheophylline obtained by the reaction of 5,6-diamino-1,3-dimethyluracil and trifluoroacetic anhydride is potassium iodide and iodide in N, N-dimethylformamide. A method for obtaining 8-trifluoromethylcaffeine by reacting with methyl is disclosed. However, this method is industrially problematic in that the number of steps including the production of raw material production steps is large.

  Regarding perfluoroalkylation using halogenated perfluoroalkyl, non-patent document 8 describes that 2 ′, 3 ′, 5′-tri-O-acetyl-iodinated nucleosides and copper powder in hexamethylphosphoric triamide. And trifluoromethyl iodide are reacted to give 2 ′, 3 ′, 5′-tri-O-acetyl-trifluoromethyl nucleosides, which are deprotected to give trifluoromethyl nucleosides. A method of obtaining is disclosed. However, this method also has a problem in that it has many steps and uses hexamethylphosphoric triamide which is difficult to use industrially.

  Non-patent documents 9 and 10 disclose a method using perfluorobutyl iodide or perfluoropropyl iodide which is liquid at room temperature using dimethyl sulfoxide, aqueous hydrogen peroxide, and iron (II) sulfate. However, the substrates are limited to pyrroles, indoles and substituted benzenes. Further, there is no description of a trifluoromethylation reaction using a perfluoroalkyl halide that is gaseous at room temperature, for example, trifluoromethyl iodide.

JP 2001-247551 A JP 11-246590 A JP-A-6-73023 Journal of Organic Chemistry, 53, 4582-4585, 1988 Journal of Medicinal Chemistry, 13, 151-152, 1970 Journal of the American Chemical Society, 80, 5744-5752, 1957 Justice Libigs Analder der Chemie, 726, 201-215, 1969 JP-A-5-1066 Tetrahedron Letters, 33, 7351-7354, 1992 Tetrahedron, 56, 2655-2664, 2000 Journal of Medicinal Chemistry, 36, 2639-2644, 1993 Journal of the Chemical Society, Perkin Transaction 1, 2755-2761, 1980 Tetrahedron Letters, 34, 3799-3800, 1993 Journal of Organic Chemistry, 62, 7128-7136, 1997

  An object of the present invention is to provide a simple and efficient method for producing nucleobases having a perfluoroalkyl group.

  As a result of intensive studies to solve the above-mentioned problems, the inventors of the present invention have made perfluoroalkyl in one step by using perfluoroalkyl halides in the presence of sulfoxides, peroxides and iron compounds. The inventors have found that nucleobases having a perfluoroalkyl group can be produced very easily, and have completed the present invention.

  That is, the present invention relates to the general formula (1)

[Wherein, R ^1a and R ^1b represent an alkyl group having 1 to 12 carbon atoms or an optionally substituted phenyl group. In the presence of sulfoxides, peroxides and iron compounds represented by general formula (2)

[Wherein, Rf represents a perfluoroalkyl group having 1 to 6 carbon atoms, and X represents a halogen atom. ] The manufacturing method of the nucleobase which has a perfluoroalkyl group characterized by reacting perfluoroalkyl halide represented by this, and nucleobase.

  The present invention also provides a compound represented by the general formula (9)

[Wherein, Rf represents the same content as described above, R ²² and R ²³ represent a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms, and R ²⁴ represents an optionally substituted carbon number. 1 to 6 alkyl group, an optionally substituted amino group or an optionally substituted alkoxycarbonyl group having 2 to 5 carbon atoms. However, when R ²² and R ²³ are hydrogen atoms, R ²⁴ represents an optionally substituted alkoxycarbonyl group having 2 to 5 carbon atoms. It is a 5-perfluoroalkyluracil characterized by being represented by this.

  Furthermore, the present invention provides a compound of the general formula (10)

[Wherein Rf represents the same content as described above, and R ²⁵ , R ²⁶ and R ²⁷ represent a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms. However, R ²⁵ , R ²⁶ and R ²⁷ are not hydrogen atoms at the same time. It is 8-perfluoroalkylxanthines characterized by these. The present invention is described in further detail below.

  In the present invention, the raw material nucleobase and the product nucleobase having a perfluoroalkyl group may be a mixture of tautomers such as keto and enol. Sexual bodies are also included in the present invention. In the specification and claims of the present application, a keto body is used for convenience.

Specific examples of the alkyl group having 1 to 12 carbon atoms represented by R ^1a and R ^1b include a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group, and a sec-butyl group. Tert-butyl group, cyclobutyl group, cyclopropylmethyl group, dodecyl group and the like. Specific examples of the optionally substituted phenyl group represented by R ^1a and R ^1b include a phenyl group, a p-tolyl group, an m-tolyl group, and an o-tolyl group. R ^1a and R ^1b are preferably a methyl group, a butyl group, a dodecyl group, a phenyl group, and a p-tolyl group, and more preferably a methyl group, a butyl group, and a phenyl group in terms of a good yield.

  Specific examples of the perfluoroalkyl group having 1 to 6 carbon atoms represented by Rf include trifluoromethyl group, perfluoroethyl group, perfluoropropyl group, perfluoroisopropyl group, perfluorocyclopropyl group, perfluorobutyl group. Perfluoroisobutyl group, perfluoro-sec-butyl group, perfluoro-tert-butyl group, perfluorocyclobutyl group, perfluorocyclopropylmethyl group, perfluoropentyl group, perfluoro-1,1-dimethylpropyl group Perfluoro-1,2-dimethylpropyl group, perfluoroneopentyl group, perfluoro-1-methylbutyl group, perfluoro-2-methylbutyl group, perfluoro-3-methylbutyl group, perfluorocyclobutylmethyl group, perfluoro Fluoro-2-si Ropropylethyl group, perfluorocyclopentyl group, perfluorohexyl group, perfluoro-1-methylpentyl group, perfluoro-2-methylpentyl group, perfluoro-3-methylpentyl group, perfluoroisohexyl group, perfluoro -1,1-dimethylbutyl group, perfluoro-1,2-dimethylbutyl group, perfluoro-2,2-dimethylbutyl group, perfluoro-1,3-dimethylbutyl group, perfluoro-2,3-dimethyl Butyl group, perfluoro-3,3-dimethylbutyl group, perfluoro-1-ethylbutyl group, perfluoro-2-ethylbutyl group, perfluoro-1,1,2-trimethylpropyl group, perfluoro-1,2, 2-trimethylpropyl group, perfluoro-1-ethyl-1-methylpropyl group, Fluoro-1-ethyl-2-methylpropyl group or a perfluoroalkyl cyclohexyl group can be exemplified.

  The trifluoromethyl group, perfluoroethyl group, perfluoropropyl group, perfluoroisopropyl group, perfluorobutyl group, perfluoroisobutyl group, perfluoro-sec- in terms of good performance as a pharmaceutical and good yield. A butyl group, a perfluoro-tert-butyl group or a perfluorohexyl group is desirable, and a trifluoromethyl group or a perfluoroethyl group is more desirable.

  X represents a halogen atom, and specific examples include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. An iodine atom or a bromine atom is desirable in terms of a good yield, and an iodine atom is more desirable.

  The nucleobases in the present invention are uracils, pseudouracils, thymines, cytosines, adenines, guanines, hypopoxes whose basic skeletons are shown in (N-1) to (N-8) shown in Table 1. Xanthines and xanthines can be exemplified.

  Among these, as nucleobases, uracils, cytosines, adenines, guanines, hypoxanthines and xanthines represented by the general formulas (3) to (8) are preferable, and the performance as pharmaceuticals is good. In particular, uracils represented by the general formula (3) are particularly preferable.

[Wherein R ² represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms or a protecting group for a nitrogen atom, and R ³ represents a hydrogen atom, optionally substituted carbon number 1 R ⁶ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, a substituted group, and an analog thereof. An optionally substituted alkoxy group having 1 to 4 carbon atoms, an optionally substituted amino group, a carboxy group, an optionally substituted carbamoyl group or an optionally substituted alkoxycarbonyl group having 2 to 5 carbon atoms; R ⁵ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, a nitrogen atom protecting group or a pentose residue, and its analogs, and R ⁶ represents a hydrogen atom, substituted From 1 carbon Alkyl group, may be substituted amino group, a carboxy group, an alkoxycarbonyl group having 2 to 5 carbon atoms which may optionally be good carbamoyl group or a substituted optionally substituted, R ⁷ and R ^8, R ⁹ represents a hydrogen atom or a nitrogen atom protecting group, and R ⁹ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, a nitrogen atom protecting group or a pentose residue and its analogs. , R ¹⁰ is a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted amino group, a carboxy group, an optionally substituted carbamoyl group, or an optionally substituted group. indicates an alkoxycarbonyl group having 2 to 5 carbon atoms, R ¹¹ and R ¹² represents a hydrogen atom or a protecting group for a nitrogen atom, R ¹³ is a hydrogen atom, it may be substituted A protecting group from the prime 1 6 alkyl group or a nitrogen atom, R ¹⁴ is a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, protecting group or pentose residue of the nitrogen atoms and R ¹⁵ and R ¹⁶ represent a hydrogen atom or a nitrogen atom protecting group, and R ¹⁷ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms or a nitrogen atom protection. R ¹⁸ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, a nitrogen atom protecting group or a pentose residue, and analogs thereof, and R ¹⁹ represents a hydrogen atom. Represents an optionally substituted alkyl group having 1 to 6 carbon atoms or a protecting group for nitrogen atom, and R ²⁰ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, and protecting a nitrogen atom. Groups or pentose residues and The indicated analogs, R ²¹ represents a hydrogen atom, an optionally substituted from a good 1 -C 6 alkyl group or a protecting group of the nitrogen atom. ].

Specific examples of the optionally substituted alkyl group represented by R ² and R ³ in the general formula (3) include a methyl group, an ethyl group, a propyl group, an isopropyl group, Examples include cyclopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, cyclobutyl group, cyclopropylmethyl group, pentyl group, neopentyl group, hexyl group, cyclohexyl group and the like. In addition, these alkyl groups may be substituted with a halogen atom, and specifically include a chloromethyl group, a 2-chloroethyl group, a 3-chloropropyl group, a difluoromethyl group, a 3-fluoropropyl group, a trifluoro group. A methyl group, 2-fluoroethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group and the like can be exemplified.

Specific examples of the protecting group for the nitrogen atom represented by R ² and R ³ include an acetyl group, a propionyl group, a pivaloyl group, a propargyl group, a benzoyl group, a p-phenylbenzoyl group, a benzyl group, and a p-methoxybenzyl group. , Trityl group, 4,4′-dimethoxytrityl group, methoxyethoxymethyl group, phenyloxycarbonyl group, benzyloxycarbonyl group, tert-butoxycarbonyl group, 9-fluorenylmethoxycarbonyl group, allyl group, p-methoxyphenyl Group, trifluoroacetyl group, methoxymethyl group, 2- (trimethylsilyl) ethoxymethyl group, allyloxycarbonyl group, trichloroethoxycarbonyl group and the like.

R ² is preferably a hydrogen atom or a methyl group in terms of good yield.

Specific examples of the pentose residue represented by R ³ and its analogs include (P-1) to (P-401) described in Tables 2 to 16. The black circles in (P-1) to (P-401) are nitrogen atoms to which nucleobases bind, Me is a methyl group, Et is an ethyl group, Pr is a propyl group, ⁱ Pr is an isopropyl group, and Bu is butyl ^group, t Bu is tert- butyl group, Ph refers to a phenyl group, TMS is trimethylsilyl group, TBDPS is tert- butyldiphenylsilyl group, Ts represents a tosyl group.

  The free hydroxyl group in these pentose residues is a general-purpose protecting group such as benzoyl group, p-chlorobenzoyl group, toluyl group, benzyl group, tert-butylcarbonyl group, tert-butyldimethylsilyl group. Acetyl group, mesyl group, benzyloxycarbonyl group, tert-butyldiphenylsilyl group, trimethylsilyl group, tosyl group, tert-butylcarbonyl group, p-methoxyphenylcarbonyl group, p-monomethoxytrityl group, di (p-methoxy) ) Trityl group, p-chlorophenylcarbonyl group, m-trifluoromethylcarbonyl group, pivaloyl group, (9-fluorenyl) methoxycarbonyl group, (biphenyl-4-yl) carbonyl group, formyl group, (2-naphthyl) carbonyl group Tert-butyldimethylsilyl group Triisopropylsilyl group, tripropylsilyl group, triphenylmethyl group, butyl group, an ethylcarbonyl group, a propyl group, a nonyl group, may be protected with p- methoxyphenyl group.

  Further, when there are hydroxyl groups at both the 2'-position and the 3'-position, they may be jointly protected with an isopropylidene group or the like to form a ring. The free amino group is a general-purpose protecting group such as a trifluoromethylcarbonyl group, 2,4-dinitrophenyl group, tosyl group, acetyl group, benzyloxycarbonyl group, triphenylmethyl group, benzoyl group, benzyl group. And may be protected with an adamantylcarbonyl group, a butylcarbonyl group, a phthaloyl group, a tetrabromophthaloyl group, or the like. The free mercapto group may be protected with a general-purpose protecting group such as 2,4,6-triisopropylphenyl group, benzoyl group, benzyl group, acetyl group and the like.

R ³ is a hydrogen atom, methyl group, (P-34), (P-35), (P-75), (P-100), (P- 101), (P-123), (P-152), (P-153), (P-314) or (P-315) is desirable.

In the general formula (3), as the optionally substituted alkyl group represented by R ⁴ having 1 to 6 carbon atoms, specifically, the optionally substituted carbon number described in the description of R ² 1 to 6 alkyl groups can be exemplified.

  Specific examples of the optionally substituted alkoxy group having 1 to 4 carbon atoms include methoxy group, ethoxy group, propoxy group, isopropyloxy group, cyclopropyloxy group, butoxy group, isobutyloxy group, sec-butyloxy group. Group, tert-butyloxy group, cyclobutyloxy group, cyclopropylmethyloxy group and the like. In addition, these alkoxy groups may be substituted with a halogen atom, and specifically include a chloromethoxy group, 2-chloroethoxy group, 3-chloropropoxy group, difluoromethoxy group, 3-fluoropropoxy group, trifluoromethoxy. Group, 2-fluoroethoxy group, 2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group and the like.

Examples of the optionally substituted amino group represented by R ⁴ include an amino group which may be substituted with an alkyl group having 1 to 4 carbon atoms, specifically, an amino group, methylamino Group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, sec-butylamino group, tert-butylamino group, N, N-dimethylamino group, N, N-diethylamino group, N , N-dipropylamino group, N, N-diisopropylamino group, N, N-dibutylamino group, N, N-diisobutylamino group, N, N-di-sec-butylamino group, N, N-di- Examples thereof include a tert-butylamino group.

  Further, it may be substituted with a protecting group for nitrogen atom, specifically, acetylamino group, propionylamino group, pivaloylamino group, propargylamino group, benzoylamino group, p-phenylbenzoylamino group, benzylamino group, p-methoxybenzylamino group, tritylamino group, 4,4′-dimethoxytritylamino group, methoxyethoxymethylamino group, phenyloxycarbonylamino group, benzyloxycarbonylamino group, tert-butoxycarbonylamino group, 9-fluore Nylmethoxycarbonylamino group, allylamino group, p-methoxyphenylamino group, trifluoroacetylamino group, methoxymethylamino group, 2- (trimethylsilyl) ethoxymethylamino group, allyloxycarbonylamino group, trichloro Ethoxycarbonylamino group and the like.

As the optionally substituted carbamoyl group represented by R ⁴ , a carbamoyl group optionally substituted with an alkyl group having 1 to 4 carbon atoms on the nitrogen atom can be exemplified. Specifically, the carbamoyl group can be exemplified. Group, N-methylcarbamoyl group, N-ethylcarbamoyl group, N-propylcarbamoyl group, N-isopropylcarbamoyl group, N-butylcarbamoyl group, N, N-dimethylcarbamoyl group, N, N-diethylcarbamoyl group, N, Examples thereof include N-dipropylcarbamoyl group, N, N-diisopropylcarbamoyl group, N, N-dibutylcarbamoyl group and the like.

Specific examples of the optionally substituted alkoxycarbonyl group having 2 to 5 carbon atoms represented by R ⁴ include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropyloxycarbonyl group, a butyloxycarbonyl group, Examples thereof include isobutyloxycarbonyl group, sec-butyloxycarbonyl group, tert-butyloxycarbonyl group and the like. In addition, these alkoxycarbonyl groups may be substituted with a halogen atom, specifically, 2-chloroethoxycarbonyl group, 3-chloropropyloxycarbonyl group, difluoromethoxycarbonyl group, 3-fluoropropyloxycarbonyl group. Group, trifluoromethoxycarbonyl group, 2-fluoroethoxycarbonyl group, 2,2,2-trifluoroethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group and the like.

R ⁴ is preferably a hydrogen atom, a 2-chloroethyl group, an amino group, a tert-butoxycarbonylamino group, or a carboxy group in terms of a good yield.

As the optionally substituted alkyl group having 1 to 6 carbon atoms represented by R ⁵ in the general formula (4), specifically, the optionally substituted carbon atom 1 described in the description of R ² To 6 alkyl groups. Specific examples of the protecting group for nitrogen represented by R ⁵ include the protecting groups for nitrogen described in the description of R ² . Specific examples of the pentose residue represented by R ⁵ and its analogs include (P-1) to (P-401) described in the description of R ³ . R ⁵ is a hydrogen atom, a methyl group, (P-34), (P-35), (P-75), (P-100), (P- 101), (P-123), (P-152), (P-153), (P-314) or (P-315) is desirable.

As the optionally substituted alkyl group having 1 to 6 carbon atoms represented by R ⁶ in the general formula (4), specifically, the optionally substituted carbon atom 1 described in the description of R ² To 6 alkyl groups. Specific examples of the optionally substituted amino group represented by R ⁶ include the optionally substituted amino group described in the description of R ⁴ . Specific examples of the optionally substituted carbamoyl group represented by R ⁶ include the optionally substituted carbamoyl group described in the description of R ⁴ . As the optionally substituted alkoxycarbonyl group having 2 to 5 carbon atoms represented by R ⁶ , specifically, the optionally substituted alkoxycarbonyl group having 2 to 5 carbon atoms described in the description of R ⁴ Can be illustrated. R ⁶ is preferably a hydrogen atom, a 2-chloroethyl group, an amino group, a tert-butoxycarbonylamino group, or a carboxy group in terms of a good yield.

Specific examples of the protecting group for nitrogen atom represented by R ⁷ and R ⁸ in the general formula (4) include the protecting group for nitrogen atom described in the description of R ² . R ⁷ and R ⁸ are preferably a hydrogen atom or an acetyl group in terms of good yield.

As the optionally substituted alkyl group having 1 to 6 carbon atoms represented by R ⁹ in the general formula (5), specifically, the optionally substituted carbon atom 1 described in the description of R ² To 6 alkyl groups. Specific examples of the protecting group for nitrogen represented by R ⁹ include the protecting groups for nitrogen described in the description of R ² . Specific examples of the pentose residue represented by R ⁹ and its analogs include (P-1) to (P-401) described in the description of R ³ . R ⁹ is a hydrogen atom, a methyl group, (P-34), (P-35), (P-75), (P-100), (P- 101), (P-123), (P-152), (P-153), (P-314) or (P-315) is desirable.

The alkyl group having 1 to 6 carbon atoms which may be substituted represented by R ¹⁰ in the general formula (5) is specifically 1 carbon atom which may be substituted as described in the description of R ^2. To 6 alkyl groups. Specific examples of the optionally substituted amino group represented by R ¹⁰ include the optionally substituted amino groups described in the description of R ⁴ . Specific examples of the optionally substituted carbamoyl group represented by R ¹⁰ include the optionally substituted carbamoyl group described in the description of R ⁴ . The optionally substituted alkoxycarbonyl group having 2 to 5 carbon atoms represented by R ¹⁰ is specifically an optionally substituted alkoxycarbonyl group having 2 to 5 carbon atoms described in the description of R ^4. Can be illustrated. R ¹⁰ is preferably a hydrogen atom, a 2-chloroethyl group, an amino group, a tert-butoxycarbonylamino group, or a carboxy group in terms of a good yield.

Specific examples of the protecting group for nitrogen atoms represented by R ¹¹ and R ¹² in the general formula (5) include the protecting groups for nitrogen atoms described in the description of R ² . R ¹¹ and R ¹² are preferably a hydrogen atom or an acetyl group in terms of good yield.

As the optionally substituted alkyl group having 1 to 6 carbon atoms represented by R ¹³ in the general formula (6), specifically, the optionally substituted carbon atom 1 described in the description of R ² To 6 alkyl groups. Specific examples of the protecting group for nitrogen represented by R ¹³ include the protecting groups for nitrogen described in the description of R ² . R ¹³ is preferably a hydrogen atom or a methyl group in terms of good yield.

As the optionally substituted alkyl group having 1 to 6 carbon atoms represented by R ¹⁴ in the general formula (6), specifically, the optionally substituted carbon atom 1 described in the description of R ² To 6 alkyl groups. Specific examples of the protecting group for nitrogen represented by R ¹⁴ include the protecting groups for nitrogen described in the description of R ² . Specific examples of the pentose residue represented by R ¹⁴ and its analogs include (P-1) to (P-401) described in the description of R ³ . R ¹⁴ is useful as a medical pesticide or an intermediate thereof, and is a hydrogen atom, a methyl group, (P-34), (P-35), (P-75), (P-100), (P- 101), (P-123), (P-152), (P-153), (P-314) or (P-315) is desirable.

Specific examples of the protecting group for nitrogen represented by R ¹⁵ and R ¹⁶ in formula (6) include the protecting groups for nitrogen described in the description of R ² . R ¹⁵ and R ¹⁶ are preferably a hydrogen atom or an acetyl group in terms of good yield.

As the optionally substituted alkyl group having 1 to 6 carbon atoms represented by R ¹⁷ in the general formula (7), specifically, the optionally substituted carbon atom 1 described in the description of R ² To 6 alkyl groups. Specific examples of the protecting group for nitrogen represented by R ¹⁷ include the protecting groups for nitrogen described in the description of R ² . R ¹⁷ is preferably a hydrogen atom or a methyl group in terms of a good yield.

As the optionally substituted alkyl group having 1 to 6 carbon atoms represented by R ¹⁸ in the general formula (7), specifically, the optionally substituted carbon atom 1 described in the description of R ² To 6 alkyl groups. Specific examples of the protecting group for nitrogen represented by R ¹⁸ include the protecting groups for nitrogen described in the description of R ² . Specific examples of the pentose residue represented by R ¹⁸ and its analogs include (P-1) to (P-401) described in the description of R ³ . R ¹⁸ is a hydrogen atom, methyl group, (P-34), (P-35), (P-75), (P-100), (P- 101), (P-123), (P-152), (P-153), (P-314) or (P-315) is desirable.

As the optionally substituted alkyl group having 1 to 6 carbon atoms represented by R ¹⁹ in the general formula (8), specifically, the optionally substituted carbon atom 1 described in the description of R ² To 6 alkyl groups. Specific examples of the protecting group for nitrogen represented by R ¹⁹ include the protecting groups for nitrogen described in the description of R ² . R ¹⁹ is preferably a hydrogen atom or a methyl group in terms of good yield.

As the optionally substituted alkyl group having 1 to 6 carbon atoms represented by R ²⁰ in the general formula (8), specifically, the optionally substituted carbon atom 1 described in the description of R ² To 6 alkyl groups. Specific examples of the protecting group for nitrogen represented by R ²⁰ include the protecting groups for nitrogen described in the description of R ² . The pentose residues and analogs thereof represented by R ^20, specifically, can be exemplified by those described in the description of ^{R 3} (P-1) to (P-401). R ²⁰ is, in terms useful as medicines, agricultural chemicals and intermediates thereof, a hydrogen atom, a methyl group, (P-34), ( P-35), (P-75), (P-100), (P- 101), (P-123), (P-152), (P-153), (P-314) or (P-315) is desirable.

As the optionally substituted alkyl group having 1 to 6 carbon atoms represented by R ²¹ in the general formula (8), specifically, the optionally substituted carbon atom 1 described in the description of R ² To 6 alkyl groups. Specific examples of the protecting group for nitrogen represented by R ²¹ include the protecting groups for nitrogen described in the description of R ² . R ²¹ is preferably a hydrogen atom or a methyl group in terms of good yield.

In the general formula (9), the optionally substituted alkyl group having 1 to 6 carbon atoms represented by R ²² and R ²³ may be substituted as described in the description of R ^2. Good alkyl groups having 1 to 6 carbon atoms can be exemplified. R ²² and R ²³ may be any of the above alkyl groups, but are preferably a methyl group or an ethyl group in that physiological activity can be expected. In the general formula (9), as the optionally substituted alkyl group represented by R ²⁴ having 1 to 6 carbon atoms, specifically, the optionally substituted carbon number described in the description of R ² 1 to 6 alkyl groups can be exemplified. Specific examples of the optionally substituted amino group represented by R ²⁴ include the optionally substituted amino groups described in the description of R ⁴ . As the optionally substituted alkoxycarbonyl group having 2 to 5 carbon atoms represented by R ²⁴ , specifically, the optionally substituted alkoxycarbonyl group having 2 to 5 carbon atoms described in the description of R ⁴ Can be illustrated. R ²⁴ is preferably an amino group substituted with a methyl group, an ethyl group, an amino group, or a protecting group, from the viewpoint of being useful as a pharmaceutical or agricultural chemical or an intermediate thereof.

In the general formula (10), the optionally substituted alkyl group having 1 to 6 carbon atoms represented by R ²⁵ , R ²⁶ and R ²⁷ is specifically the substituted group described in the description of R ^2. Examples thereof may include an alkyl group having 1 to 6 carbon atoms. R ²⁵ , R ²⁶ and R ²⁷ are preferably a methyl group or an ethyl group in that performance as a sustained release agent can be expected.

  Next, the production method of the present invention will be described in detail.

  When uracils of general formula (3) are used as raw materials, the production process is shown by the following [Step-A], and 5-perfluoroalkyluracils represented by general formula (11) are obtained as products. It is done.

[Wherein R ² , R ³ , R ⁴ , Rf and X have the same contents as described above. ]
In [Step-A], the sulfoxide (1) may be used as a solvent as it is, but a solvent that does not harm the reaction can also be used. Specifically, water, N, N-dimethylformamide, acetic acid, trifluoroacetic acid, tetrahydrofuran, diethyl ether, ethyl acetate, acetone, 1,4-dioxane, tert-butyl alcohol, ethanol, methanol, isopropyl alcohol, trifluoro Ethanol, hexamethylphosphoric triamide, N-methyl-2-pyrrolidone, N, N, N ′, N′-tetramethylurea, N, N′-dimethylpropyleneurea, etc. can be mentioned, and these are combined appropriately. It may be used. From the viewpoint of good yield, it is desirable to use water, sulfoxides (1) or a mixed solvent of water and sulfoxides (1).

  The molar ratio of uracils (3) to sulfoxides (1) is preferably 1: 1 to 1: 200, and more preferably 1:10 to 1: 100 in terms of good yield.

  The molar ratio of the uracils (3) and the perfluoroalkyl halides (2) is preferably 1: 1 to 1: 100, and more preferably 1: 1.5 to 1:10 in terms of good yield.

  Examples of the peroxide include hydrogen peroxide, hydrogen peroxide-urea complex, tert-butyl peroxide, and peracetic acid, and these may be used in combination as necessary. Hydrogen peroxide or hydrogen peroxide-urea complex is desirable in terms of good yield.

  Hydrogen peroxide may be diluted with water. The concentration at that time may be 3 to 70% by weight, but a commercially available 35% by weight may be used as it is. It is further desirable to dilute with water to 10 to 30% by weight in terms of good yield and safety.

  The molar ratio of uracils (3) and peroxide is preferably 1: 0.1 to 1:10, and more preferably 1: 1.5 to 1: 3 in terms of good yield.

The iron compound is preferably an iron (II) salt in terms of a good yield. For example, iron (II) sulfate, iron (II) ammonium sulfate, iron (II) tetrafluoroborate, iron (II) chloride, bromide Inorganic acid salts such as iron (II) or iron (II) iodide, iron (II) acetate, iron (II) oxalate, iron (II) bisacetylacetonate, ferrocene or bis (η ⁵ -pentamethylcyclo Pentadienyl) organometallic compounds such as iron can be exemplified, and these may be used in appropriate combination. In addition, iron (II) salts can be generated in the system by combining iron powder, iron (0) compound or iron (I) salt and an oxidizing reagent such as peroxide. In this case, hydrogen peroxide used for the reaction can be used as it is as an oxidizing reagent. It is desirable to use iron (II) sulfate, iron (II) ammonium sulfate, iron (II) tetrafluoroborate, ferrocene or iron powder in terms of good yield.

  These iron compounds may be used as solids, but can also be used as solutions. When used as a solution, the solvent may be either the sulfoxides (1) or the above-mentioned solvents, but water is particularly preferable. In this case, the concentration of the iron compound solution is preferably 0.1 to 10 mol / L, and more preferably 0.5 to 5 mol / L in terms of a good yield.

  The molar ratio between the uracils (3) and the iron compound is preferably 1: 0.01 to 1:10, and more preferably 1: 0.1 to 1: 1 in terms of a good yield.

  The reaction temperature can be carried out at a temperature appropriately selected from the range of 20 ° C to 100 ° C. 20 ° C to 70 ° C is desirable in terms of good yield.

  When the reaction is performed in a closed system, the reaction can be performed at a pressure appropriately selected from the range of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even at atmospheric pressure. The atmosphere during the reaction may be an inert gas such as argon or nitrogen, but the reaction proceeds sufficiently even in the air.

  When the perfluoroalkyl halides of the general formula (2) are gaseous at room temperature, they may be used as they are. At that time, it may be diluted with a gas such as argon, nitrogen, air, helium, oxygen, or the like to be a mixed gas, and can be used as a gas having a mole fraction of the perfluoroalkyl halide (2) of 1 to 100%. . When the reaction is carried out in a closed system, perfluoroalkyl halides (2) or a mixed gas thereof can be used as a reaction atmosphere. The pressure at that time can be carried out at a pressure appropriately selected from the range of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even at atmospheric pressure. Alternatively, perfluoroalkyl halides (2) or a mixed gas thereof may be bubbled and introduced into the reaction solution in an open system. The introduction rate of the halogenated perfluoroalkyls (2) or mixed gas at that time depends on the scale of the reaction, the amount of catalyst, the reaction temperature, and the mole fraction of the halogenated perfluoroalkyls (2) in the mixed gas. Can be selected from the range of 1 mL to 200 mL per minute.

  In this method, the yield of the target product can be improved by adding an acid. Acids include inorganic acids such as sulfuric acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, hexafluorophosphoric acid or tetrafluoroboric acid, formic acid, acetic acid, propionic acid, oxalic acid, p-toluenesulfone Examples thereof include organic acids such as acid, trifluoromethanesulfonic acid and trifluoroacetic acid, and these may be used in combination as appropriate. It is desirable to use sulfuric acid, tetrafluoroboric acid or trifluoromethanesulfonic acid in terms of good yield.

  Further, an acidic salt of sulfuric acid may be used. Examples of the acid salt include tetramethylammonium hydrogensulfate, tetraethylammonium hydrogensulfate, tetrabutylammonium hydrogensulfate, and tetraphenylphosphonium hydrogensulfate.

  These acids may be used after diluting. The solvent at that time may be sulfoxides (1) or the above-mentioned solvent, and among them, water, sulfoxides (1) or a mixed solvent of water and sulfoxides (1) is desirable.

  The molar ratio of the uracils (3) and the acid is preferably 1: 0.001 to 1: 5, and more preferably 1: 0.01 to 1: 2 in terms of a good yield.

  The method for isolating the target product from the solution after the reaction is not particularly limited, but may be a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation. The object can be obtained.

  When the cytosine of the general formula (4) is used as a raw material, the production process is shown by the following [Step-B], and a 5-perfluoroalkylcytosine represented by the general formula (12) is obtained as a product. It is done.

[Wherein R ⁵ , R ⁶ , R ⁷ , R ⁸ , Rf and X have the same contents as described above. ]
In [Step-B], the sulfoxide (1) may be used as a solvent as it is, but a solvent that does not harm the reaction can also be used. Specifically, water, N, N-dimethylformamide, acetic acid, trifluoroacetic acid, tetrahydrofuran, diethyl ether, ethyl acetate, acetone, 1,4-dioxane, tert-butyl alcohol, ethanol, methanol, isopropyl alcohol, trifluoro Ethanol, hexamethylphosphoric triamide, N-methyl-2-pyrrolidone, N, N, N ′, N′-tetramethylurea, N, N′-dimethylpropyleneurea, etc. can be mentioned, and these are combined appropriately. It may be used. From the viewpoint of good yield, it is desirable to use water, sulfoxides (1) or a mixed solvent of water and sulfoxides (1).

  The molar ratio of cytosines (4) and sulfoxides (1) is preferably 1: 1 to 1: 200, and more preferably 1:10 to 1: 100 in terms of good yield.

  The molar ratio of cytosines (4) and perfluoroalkyl halides (2) is preferably 1: 1 to 1: 100, and more preferably 1: 1.5 to 1:10 in terms of good yield.

  Examples of the peroxide include hydrogen peroxide, hydrogen peroxide-urea complex, tert-butyl peroxide, and peracetic acid, and these may be used in combination as necessary. Hydrogen peroxide is desirable because of its good yield.

  Hydrogen peroxide may be diluted with water. The concentration at that time may be 3 to 70% by weight, but a commercially available 35% by weight may be used as it is. It is further desirable to dilute with water to 10 to 30% by weight in terms of good yield and safety.

  The molar ratio of cytosines (4) and peroxide is preferably from 1: 0.1 to 1:10, and more preferably from 1: 1.5 to 1: 3 in terms of good yield.

The iron compound is preferably an iron (II) salt in terms of a good yield. For example, iron (II) sulfate, iron (II) ammonium sulfate, iron (II) tetrafluoroborate, iron (II) chloride, bromide Inorganic acid salts such as iron (II) or iron (II) iodide, iron (II) acetate, iron (II) oxalate, iron (II) bisacetylacetonate, ferrocene or bis (η ⁵ -pentamethylcyclo Pentadienyl) organometallic compounds such as iron can be exemplified, and these may be used in appropriate combination. In addition, iron (II) salts can be generated in the system by combining iron powder, iron (0) compound or iron (I) salt and an oxidizing reagent such as peroxide. In this case, hydrogen peroxide used for the reaction can be used as it is as an oxidizing reagent. It is desirable to use iron (II) sulfate in terms of a good yield.

  These iron compounds may be used as solids, but can also be used as solutions. When used as a solution, the solvent may be either the sulfoxides (1) or the above-mentioned solvents, but water is particularly preferable. In this case, the concentration of the iron compound solution is preferably 0.1 to 10 mol / L, and more preferably 0.5 to 5 mol / L.

  The molar ratio between the cytosines (4) and the iron compound is preferably 1: 0.01 to 1:10, and more preferably 1: 0.1 to 1: 1 in terms of a good yield.

  The reaction temperature can be carried out at a temperature appropriately selected from the range of 20 ° C to 100 ° C. 20 ° C to 70 ° C is desirable in terms of good yield.

  When the reaction is performed in a closed system, the reaction can be performed at a pressure appropriately selected from the range of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even at atmospheric pressure. The atmosphere during the reaction may be an inert gas such as argon or nitrogen, but the reaction proceeds sufficiently even in the air.

  When the perfluoroalkyl halides of the general formula (2) are gaseous at room temperature, they may be used as they are. At that time, it may be diluted with a gas such as argon, nitrogen, air, helium, oxygen, or the like to be a mixed gas, and can be used as a gas having a mole fraction of the perfluoroalkyl halide (2) of 1 to 100%. . When the reaction is carried out in a closed system, perfluoroalkyl halides (2) or a mixed gas thereof can be used as a reaction atmosphere. The pressure at that time can be carried out at a pressure appropriately selected from the range of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even at atmospheric pressure. Alternatively, perfluoroalkyl halides (2) or a mixed gas thereof may be bubbled and introduced into the reaction solution in an open system. The introduction rate of the halogenated perfluoroalkyls (2) or mixed gas at that time depends on the scale of the reaction, the amount of catalyst, the reaction temperature, and the mole fraction of the halogenated perfluoroalkyls (2) in the mixed gas. Can be selected from the range of 1 mL to 200 mL per minute.

  In this method, the yield of the target product can be improved by adding an acid. Acids include inorganic acids such as sulfuric acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, hexafluorophosphoric acid or tetrafluoroboric acid, formic acid, acetic acid, propionic acid, oxalic acid, p-toluenesulfone Examples thereof include organic acids such as acid, trifluoromethanesulfonic acid and trifluoroacetic acid, and these may be used in combination as appropriate. It is desirable to use sulfuric acid in terms of good yield.

These acids may be used after diluting. The solvent at that time may be sulfoxides (1) or the above-mentioned solvent, and among them, water, sulfoxides (1) or a mixed solvent of water and sulfoxides (1) is desirable.
Is desirable.

  The molar ratio of cytosine (4) and acid is preferably from 1: 0.001 to 1: 5, and more preferably from 1: 0.01 to 1: 2 in terms of good yield.

  The method for isolating the target product from the solution after the reaction is not particularly limited, but may be a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation. The object can be obtained.

  When the adenine of the general formula (5) is used as a raw material, the production process is shown by the following [Step-C], and an 8-perfluoroalkyladenine represented by the general formula (13) is obtained as a product. It is done.

[Wherein R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , Rf and X have the same contents as described above. ]
In [Step-C], the sulfoxide (1) may be used as a solvent as it is, but a solvent that does not harm the reaction can also be used. Specifically, water, N, N-dimethylformamide, acetic acid, trifluoroacetic acid, tetrahydrofuran, diethyl ether, ethyl acetate, acetone, 1,4-dioxane, tert-butyl alcohol, ethanol, methanol, isopropyl alcohol, trifluoro Ethanol, hexamethylphosphoric triamide, N-methyl-2-pyrrolidone, N, N, N ′, N′-tetramethylurea, N, N′-dimethylpropyleneurea, etc. can be mentioned, and these are combined appropriately. It may be used. From the viewpoint of good yield, it is desirable to use water, sulfoxides (1) or a mixed solvent of water and sulfoxides (1).

  The molar ratio of adenine (5) to sulfoxide (1) is preferably 1: 1 to 1: 200, and more preferably 1:10 to 1: 100 in terms of good yield.

  The molar ratio of adenine (5) to halogenated perfluoroalkyl (2) is preferably 1: 1 to 1: 100, and more preferably 1: 1.5 to 1:10 in terms of good yield.

  Examples of the peroxide include hydrogen peroxide, hydrogen peroxide-urea complex, tert-butyl peroxide, and peracetic acid, and these may be used in combination as necessary. Hydrogen peroxide is desirable because of its good yield.

  Hydrogen peroxide may be diluted with water. The concentration at that time may be 3 to 70% by weight, but a commercially available 35% by weight may be used as it is. It is further desirable to dilute with water to 10 to 30% by weight in terms of good yield and safety.

  The molar ratio of adenine (5) and peroxide is preferably from 1: 0.1 to 1:10, and more preferably from 1: 1.5 to 1: 3 in terms of good yield.

The iron compound is preferably an iron (II) salt in terms of a good yield. For example, iron (II) sulfate, iron (II) ammonium sulfate, iron (II) tetrafluoroborate, iron (II) chloride, bromide Inorganic acid salts such as iron (II) or iron (II) iodide, iron (II) acetate, iron (II) oxalate, iron (II) bisacetylacetonate, ferrocene or bis (η ⁵ -pentamethylcyclo Pentadienyl) organometallic compounds such as iron can be exemplified, and these may be used in appropriate combination. In addition, iron (II) salts can be generated in the system by combining iron powder, iron (0) compound or iron (I) salt and an oxidizing reagent such as peroxide. In this case, hydrogen peroxide used for the reaction can be used as it is as an oxidizing reagent. It is desirable to use iron (II) sulfate in terms of a good yield.

  These iron compounds may be used as solids, but can also be used as solutions. When used as a solution, the solvent may be either the sulfoxides (1) or the above-mentioned solvents, but water is particularly preferable. In this case, the concentration of the iron compound solution is preferably 0.1 to 10 mol / L, and more preferably 0.5 to 5 mol / L.

  The molar ratio of the adenine (5) and the iron compound is preferably 1: 0.01 to 1:10, and more preferably 1: 0.1 to 1: 1 in terms of a good yield.

  The reaction temperature can be carried out at a temperature appropriately selected from the range of 20 ° C to 100 ° C. 20 ° C to 70 ° C is desirable in terms of good yield.

  When the reaction is performed in a closed system, the reaction can be performed at a pressure appropriately selected from the range of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even at atmospheric pressure. The atmosphere during the reaction may be an inert gas such as argon or nitrogen, but the reaction proceeds sufficiently even in the air.

  When the perfluoroalkyl halides of the general formula (2) are gaseous at room temperature, they may be used as they are. At that time, it may be diluted with a gas such as argon, nitrogen, air, helium, oxygen, or the like to be a mixed gas, and can be used as a gas having a mole fraction of the perfluoroalkyl halide (2) of 1 to 100%. . When the reaction is carried out in a closed system, perfluoroalkyl halides (2) or a mixed gas thereof can be used as a reaction atmosphere. The pressure at that time can be carried out at a pressure appropriately selected from the range of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even at atmospheric pressure. Alternatively, perfluoroalkyl halides (2) or a mixed gas thereof may be bubbled and introduced into the reaction solution in an open system. The introduction rate of the halogenated perfluoroalkyls (2) or mixed gas at that time depends on the scale of the reaction, the amount of catalyst, the reaction temperature, and the mole fraction of the halogenated perfluoroalkyls (2) in the mixed gas. Can be selected from the range of 1 mL to 200 mL per minute.

  In this method, the yield of the target product can be improved by adding an acid. Acids include inorganic acids such as sulfuric acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, hexafluorophosphoric acid or tetrafluoroboric acid, formic acid, acetic acid, propionic acid, oxalic acid, p-toluenesulfone Examples thereof include organic acids such as acid, trifluoromethanesulfonic acid and trifluoroacetic acid, and these may be used in combination as appropriate. It is desirable to use sulfuric acid in terms of good yield.

  These acids may be used after diluting. The solvent at that time may be sulfoxides (1) or the above-mentioned solvent, and among them, water, sulfoxides (1) or a mixed solvent of water and sulfoxides (1) is desirable.

The molar ratio of adenine (5) and acid is preferably from 1: 0.001 to 1: 5, and more preferably from 1: 0.01 to 1: 2 in terms of a good yield.
The method for isolating the target product from the solution after the reaction is not particularly limited, but may be a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation. The object can be obtained.

  When the guanine of the general formula (6) is used as a raw material, the production process is shown by the following [Step-D], and an 8-perfluoroalkylguanine represented by the general formula (14) is obtained as a product. It is done.

[Wherein, R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , Rf and X have the same contents as described above. In [Step-D], the sulfoxide (1) may be used as a solvent as it is, but a solvent that does not harm the reaction can also be used. Specifically, water, N, N-dimethylformamide, acetic acid, trifluoroacetic acid, tetrahydrofuran, diethyl ether, ethyl acetate, acetone, 1,4-dioxane, tert-butyl alcohol, ethanol, methanol, isopropyl alcohol, trifluoro Ethanol, hexamethylphosphoric triamide, N-methyl-2-pyrrolidone, N, N, N ′, N′-tetramethylurea, N, N′-dimethylpropyleneurea, etc. can be mentioned, and these are combined appropriately. It may be used. From the viewpoint of good yield, it is desirable to use water, sulfoxides (1) or a mixed solvent of water and sulfoxides (1).

  The molar ratio of guanines (6) to sulfoxides (1) is preferably 1: 1 to 1: 5000, and more preferably 1:10 to 1: 3000 in terms of good yield.

  The molar ratio of guanines (6) and halogenated perfluoroalkyls (2) is preferably 1: 1 to 1: 100, and more preferably 1: 1.5 to 1:10 in terms of good yield.

  Examples of the peroxide include hydrogen peroxide, hydrogen peroxide-urea complex, tert-butyl peroxide, and peracetic acid, and these may be used in combination as necessary. Hydrogen peroxide is desirable because of its good yield.

  Hydrogen peroxide may be diluted with water. The concentration at that time may be 3 to 70% by weight, but a commercially available 35% by weight may be used as it is. It is further desirable to dilute with water to 10 to 30% by weight in terms of good yield and safety.

  The molar ratio between the guanines (6) and the peroxide is preferably 1: 0.1 to 1:10, and more preferably 1: 1.5 to 1: 3 in terms of a good yield.

The iron compound is preferably an iron (II) salt in terms of a good yield. For example, iron (II) sulfate, iron (II) ammonium sulfate, iron (II) tetrafluoroborate, iron (II) chloride, bromide Inorganic acid salts such as iron (II) or iron (II) iodide, iron (II) acetate, iron (II) oxalate, iron (II) bisacetylacetonate, ferrocene or bis (η ⁵ -pentamethylcyclo Pentadienyl) organometallic compounds such as iron can be exemplified, and these may be used in appropriate combination. In addition, iron (II) salts can be generated in the system by combining iron powder, iron (0) compound or iron (I) salt and an oxidizing reagent such as peroxide. In this case, hydrogen peroxide used for the reaction can be used as it is as an oxidizing reagent. It is desirable to use iron (II) sulfate in terms of a good yield.

  These iron compounds may be used as solids, but can also be used as solutions. When used as a solution, the solvent may be either the sulfoxides (1) or the above-mentioned solvents, but water is particularly preferable. In this case, the concentration of the iron compound solution is preferably 0.1 to 10 mol / L, and more preferably 0.5 to 5 mol / L.

  The molar ratio of the guanines (6) to the iron compound is preferably 1: 0.01 to 1:10, and more preferably 1: 0.1 to 1: 1 in terms of a good yield.

  The reaction temperature can be carried out at a temperature appropriately selected from the range of 20 ° C to 100 ° C. 20 ° C to 70 ° C is desirable in terms of good yield.

  When the reaction is performed in a closed system, the reaction can be performed at a pressure appropriately selected from the range of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even at atmospheric pressure. The atmosphere during the reaction may be an inert gas such as argon or nitrogen, but the reaction proceeds sufficiently even in the air.

  When the perfluoroalkyl halides of the general formula (2) are gaseous at room temperature, they may be used as they are. At that time, it may be diluted with a gas such as argon, nitrogen, air, helium, oxygen, or the like to be a mixed gas, and can be used as a gas having a mole fraction of the perfluoroalkyl halide (2) of 1 to 100%. . When the reaction is carried out in a closed system, perfluoroalkyl halides (2) or a mixed gas thereof can be used as a reaction atmosphere. The pressure at that time can be carried out at a pressure appropriately selected from the range of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even at atmospheric pressure. Alternatively, perfluoroalkyl halides (2) or a mixed gas thereof may be bubbled and introduced into the reaction solution in an open system. The introduction rate of the halogenated perfluoroalkyls (2) or mixed gas at that time depends on the scale of the reaction, the amount of catalyst, the reaction temperature, and the mole fraction of the halogenated perfluoroalkyls (2) in the mixed gas. Can be selected from the range of 1 mL to 200 mL per minute.

  In this method, the yield of the target product can be improved by adding an acid. Acids include inorganic acids such as sulfuric acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, hexafluorophosphoric acid or tetrafluoroboric acid, formic acid, acetic acid, propionic acid, oxalic acid, p-toluenesulfone Examples thereof include organic acids such as acid, trifluoromethanesulfonic acid and trifluoroacetic acid, and these may be used in combination as appropriate. It is desirable to use sulfuric acid in terms of good yield.

These acids may be used after diluting. The solvent at that time may be sulfoxides (1) or the above-mentioned solvent, and among them, water, sulfoxides (1) or a mixed solvent of water and sulfoxides (1) is desirable.
The molar ratio between the guanines (6) and the acid is preferably 1: 0.001 to 1: 5, and more preferably 1: 0.01 to 1: 2 in terms of a good yield.

  The method for isolating the target product from the solution after the reaction is not particularly limited, but may be a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation. The object can be obtained.

  When the hypoxanthine of the general formula (7) is used as a raw material, the production process is shown by the following [Step-E], and the product is an 8-perfluoroalkyl hypoxanthine represented by the general formula (15). Is obtained.

[Wherein R ¹⁷ , R ¹⁸ , Rf and X represent the same contents as described above. ]
In [Step-E], the sulfoxide (1) may be used as a solvent as it is, but a solvent that does not harm the reaction can also be used. Specifically, water, N, N-dimethylformamide, acetic acid, trifluoroacetic acid, tetrahydrofuran, diethyl ether, ethyl acetate, acetone, 1,4-dioxane, tert-butyl alcohol, ethanol, methanol, isopropyl alcohol, trifluoro Ethanol, hexamethylphosphoric triamide, N-methyl-2-pyrrolidone, N, N, N ′, N′-tetramethylurea, N, N′-dimethylpropyleneurea, etc. can be mentioned, and these are combined appropriately. It may be used. From the viewpoint of good yield, it is desirable to use water, sulfoxides (1) or a mixed solvent of water and sulfoxides (1).

  The molar ratio of hypoxanthines (7) and sulfoxides (1) is preferably 1: 1 to 1: 200, and more preferably 1:10 to 1: 100 in terms of good yield.

  The molar ratio of hypoxanthines (7) and perfluoroalkyl halides (2) is preferably 1: 1 to 1: 100, and more preferably 1: 1.5 to 1:10 in terms of good yield. .

  Examples of the peroxide include hydrogen peroxide, hydrogen peroxide-urea complex, tert-butyl peroxide, and peracetic acid, and these may be used in combination as necessary. Hydrogen peroxide is desirable because of its good yield.

  Hydrogen peroxide may be diluted with water. The concentration at that time may be 3 to 70% by weight, but a commercially available 35% by weight may be used as it is. It is further desirable to dilute with water to 10 to 30% by weight in terms of good yield and safety.

  The molar ratio of hypoxanthines (7) and peroxide is preferably 1: 0.1 to 1:10, and more preferably 1: 1.5 to 1: 3 in terms of good yield.

The iron compound is preferably an iron (II) salt in terms of a good yield. For example, iron (II) sulfate, iron (II) ammonium sulfate, iron (II) tetrafluoroborate, iron (II) chloride, bromide Inorganic acid salts such as iron (II) or iron (II) iodide, iron (II) acetate, iron (II) oxalate, iron (II) bisacetylacetonate, ferrocene or bis (η ⁵ -pentamethylcyclo Pentadienyl) organometallic compounds such as iron can be exemplified, and these may be used in appropriate combination. In addition, iron (II) salts can be generated in the system by combining iron powder, iron (0) compound or iron (I) salt and an oxidizing reagent such as peroxide. In this case, hydrogen peroxide used for the reaction can be used as it is as an oxidizing reagent. It is desirable to use iron (II) sulfate or ferrocene in terms of a good yield.

  These iron compounds may be used as solids, but can also be used as solutions. When used as a solution, the solvent may be either the sulfoxide (1) or the above-mentioned solvent, but water is particularly preferable. In this case, the concentration of the iron compound solution is preferably 0.1 to 10 mol / L, and more preferably 0.5 to 5 mol / L.

  The molar ratio between the hypoxanthines (7) and the iron compound is preferably 1: 0.01 to 1:10, and more preferably 1: 0.1 to 1: 1 in terms of a good yield.

  The reaction temperature can be carried out at a temperature appropriately selected from the range of 20 ° C to 100 ° C. 20 ° C to 70 ° C is desirable in terms of good yield.

  When the reaction is performed in a closed system, the reaction can be performed at a pressure appropriately selected from the range of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even at atmospheric pressure. The atmosphere during the reaction may be an inert gas such as argon or nitrogen, but the reaction proceeds sufficiently even in the air.

  When the perfluoroalkyl halides of the general formula (2) are gaseous at room temperature, they may be used as they are. At that time, it may be diluted with a gas such as argon, nitrogen, air, helium, oxygen, or the like to be a mixed gas, and can be used as a gas having a mole fraction of the perfluoroalkyl halide (2) of 1 to 100%. . When the reaction is carried out in a closed system, perfluoroalkyl halides (2) or a mixed gas thereof can be used as a reaction atmosphere. The pressure at that time can be carried out at a pressure appropriately selected from the range of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even at atmospheric pressure. Alternatively, perfluoroalkyl halides (2) or a mixed gas thereof may be bubbled and introduced into the reaction solution in an open system. The introduction rate of the halogenated perfluoroalkyls (2) or mixed gas at that time depends on the scale of the reaction, the amount of catalyst, the reaction temperature, and the mole fraction of the halogenated perfluoroalkyls (2) in the mixed gas. Can be selected from the range of 1 mL to 200 mL per minute.

  In this method, the yield of the target product can be improved by adding an acid. Acids include inorganic acids such as sulfuric acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, hexafluorophosphoric acid or tetrafluoroboric acid, formic acid, acetic acid, propionic acid, oxalic acid, p-toluenesulfone Examples thereof include organic acids such as acid, trifluoromethanesulfonic acid and trifluoroacetic acid, and these may be used in combination as appropriate. It is desirable to use sulfuric acid in terms of good yield.

  These acids may be used after diluting. The solvent at that time may be sulfoxides (1) or the above-mentioned solvent, and among them, water, sulfoxides (1) or a mixed solvent of water and sulfoxides (1) is desirable.

  The molar ratio between the hypoxanthines (7) and the acid is preferably 1: 0.001 to 1: 5, and more preferably 1: 0.01 to 1: 2 in terms of a good yield.

  The method for isolating the target product from the solution after the reaction is not particularly limited, but may be a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation. The object can be obtained.

  When the xanthine of the general formula (8) is used as a raw material, the production process is shown by the following [Step-F], and an 8-perfluoroalkylxanthine represented by the general formula (16) is obtained as a product. It is done.

[Wherein R ¹⁹ , R ²⁰ , R ²¹ , Rf and X have the same contents as described above. ]
In [Step-F], the sulfoxides (1) may be used as they are, but a solvent that does not harm the reaction can also be used. Specifically, water, N, N-dimethylformamide, acetic acid, trifluoroacetic acid, tetrahydrofuran, diethyl ether, ethyl acetate, acetone, 1,4-dioxane, tert-butyl alcohol, ethanol, methanol, isopropyl alcohol, trifluoro Ethanol, hexamethylphosphoric triamide, N-methyl-2-pyrrolidone, N, N, N ′, N′-tetramethylurea, N, N′-dimethylpropyleneurea, etc. can be mentioned, and these are combined appropriately. It may be used. From the viewpoint of good yield, it is desirable to use water, sulfoxides (1) or a mixed solvent of water and sulfoxides (1).
The molar ratio of xanthines (8) and sulfoxides (1) is preferably from 1: 1 to 1: 5000, and more preferably from 1:10 to 1: 1000 in terms of good yield.

  The molar ratio of the xanthines (8) and the perfluoroalkyl halides (2) is preferably 1: 1 to 1: 100, and more preferably 1: 1.5 to 1:10 in terms of good yield.

  Examples of the peroxide include hydrogen peroxide, hydrogen peroxide-urea complex, tert-butyl peroxide, and peracetic acid, and these may be used in combination as necessary. Hydrogen peroxide is desirable because of its good yield.

  Hydrogen peroxide may be diluted with water. The concentration at that time may be 3 to 70% by weight, but a commercially available 35% by weight may be used as it is. It is further desirable to dilute with water to 10 to 30% by weight in terms of good yield and safety.

  The molar ratio of xanthines (8) and peroxide is preferably from 1: 0.1 to 1:10, and more preferably from 1: 1.5 to 1: 3 in terms of good yield.

The iron compound is preferably an iron (II) salt in terms of a good yield. For example, iron (II) sulfate, iron (II) ammonium sulfate, iron (II) tetrafluoroborate, iron (II) chloride, bromide Inorganic acid salts such as iron (II) or iron (II) iodide, iron (II) acetate, iron (II) oxalate, iron (II) bisacetylacetonate, ferrocene or bis (η ⁵ -pentamethylcyclo Pentadienyl) organometallic compounds such as iron can be exemplified, and these may be used in appropriate combination. In addition, iron (II) salts can be generated in the system by combining iron powder, iron (0) compound or iron (I) salt and an oxidizing reagent such as peroxide. In this case, hydrogen peroxide used for the reaction can be used as it is as an oxidizing reagent. It is desirable to use iron (II) sulfate, iron (II) tetrafluoroborate, ferrocene or iron powder in terms of good yield.

  These iron compounds may be used as solids, but can also be used as solutions. When used as a solution, the solvent may be either the sulfoxides (1) or the above-mentioned solvents, but water is particularly preferable. In this case, the concentration of the iron compound solution is preferably 0.1 to 10 mol / L, and more preferably 0.5 to 5 mol / L.

  The molar ratio of the xanthines (8) and the iron compound is preferably 1: 0.01 to 1:10, and more preferably 1: 0.1 to 1: 1 in terms of a good yield.

  The reaction temperature can be carried out at a temperature appropriately selected from the range of 20 ° C to 100 ° C. 20 ° C to 70 ° C is desirable in terms of good yield.

  When the reaction is performed in a closed system, the reaction can be performed at a pressure appropriately selected from the range of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even at atmospheric pressure. The atmosphere during the reaction may be an inert gas such as argon or nitrogen, but the reaction proceeds sufficiently even in the air.

  When the perfluoroalkyl halides of the general formula (2) are gaseous at room temperature, they may be used as they are. At that time, it may be diluted with a gas such as argon, nitrogen, air, helium, oxygen, or the like to be a mixed gas, and can be used as a gas having a mole fraction of the perfluoroalkyl halide (2) of 1 to 100%. . When the reaction is carried out in a closed system, perfluoroalkyl halides (2) or a mixed gas thereof can be used as a reaction atmosphere. The pressure at that time can be carried out at a pressure appropriately selected from the range of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even at atmospheric pressure. Alternatively, perfluoroalkyl halides (2) or a mixed gas thereof may be bubbled and introduced into the reaction solution in an open system. The introduction rate of the halogenated perfluoroalkyls (2) or mixed gas at that time depends on the scale of the reaction, the amount of catalyst, the reaction temperature, and the mole fraction of the halogenated perfluoroalkyls (2) in the mixed gas. Can be selected from the range of 1 mL to 200 mL per minute.

  In this method, the yield of the target product can be improved by adding an acid. Acids include inorganic acids such as sulfuric acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, hexafluorophosphoric acid or tetrafluoroboric acid, formic acid, acetic acid, propionic acid, oxalic acid, p-toluenesulfone Examples thereof include organic acids such as acid, trifluoromethanesulfonic acid and trifluoroacetic acid, and these may be used in combination as appropriate. It is desirable to use sulfuric acid or tetrafluoroboric acid in terms of a good yield.

  These acids may be used after diluting. The solvent at that time may be sulfoxides (1) or the above-mentioned solvent, and among them, water, sulfoxides (1) or a mixed solvent of water and sulfoxides (1) is desirable.

  The molar ratio between the xanthines (8) and the acid is preferably 1: 0.001 to 1: 5, and more preferably 1: 0.01 to 1: 2 in terms of a good yield.

  The method for isolating the target product from the solution after the reaction is not particularly limited, but may be a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation. The object can be obtained.

  Among the compounds obtained by the above production method, 5-perfluoroalkyluracils represented by the general formula (9) and 8-perfluoroalkylxanthines represented by the general formula (10) are novel compounds. It is expected to be used as an intermediate for producing pharmaceuticals or medical pesticides.

  INDUSTRIAL APPLICABILITY According to the present invention, nucleobases having a perfluoroalkyl group, which is a compound useful as a pharmaceutical or medical / agrochemical production intermediate, can be obtained in a high yield and with good economic efficiency.

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

  Example 1

In a 50 mL two-necked flask equipped with a magnetic rotor, 0.11 g (1.0 mmol) of uracil was weighed, and the inside of the container was replaced with argon. 2.0 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of 2.1 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 mL of 30% aqueous hydrogen peroxide, and 1.0 mol / L aqueous iron (II) sulfate solution 0 .3 mL was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The formation of 5-trifluoromethyluracil was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 94%). Preparative thin layer chromatography gave 5-trifluoromethyluracil as a white solid (0.17 g, 93% yield).

¹ H-NMR (heavy acetone): δ 8.09 (s, 1H), 10.5 (brs, 2H). ¹³ C-NMR (heavy acetone): δ 104.0 (q, J _CF = 32.4 Hz), 123.6 (q, J _CF = 268.2 Hz), 144.2 (q, J _CF = 5.9 Hz) 150.9, 160.2.
¹⁹ F-NMR (heavy acetone): δ-64.1.
MS (m / z): 180 [M] ^<+> .

(Example 2)
The same operation as in Example 1 was carried out except that a 1.0 mol / L iron (II) ammonium sulfate aqueous solution was used instead of the 1.0 mol / L iron (II) sulfate aqueous solution to produce 5-trifluoromethyluracil. Confirmed (production rate 80%).

(Example 3)
In a 50 mL two-necked flask equipped with a magnetic rotor, 0.11 g (1.0 mmol) of uracil and 0.028 g (0.5 mmol) of iron powder were weighed, and the inside of the container was replaced with argon. 2.0 mL of dimethyl sulfoxide, 2.0 mL of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide and 0.2 mL of 30% hydrogen peroxide water were added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. By performing the same operation as in Example 1, production of 5-trifluoromethyluracil was confirmed (production rate: 32%).

Example 4
In a 50 mL two-necked flask equipped with a magnetic rotor, 0.11 g (1.0 mmol) of uracil was weighed, and the inside of the container was replaced with argon. 42% tetrafluoroboric acid aqueous solution 0.21 mL, dimethyl sulfoxide 2.0 mL, trifluoromethyl iodide 2.0 mol / L dimethyl sulfoxide solution 3.0 mL, 1.0 mol / L iron (II) tetrafluoroborate aqueous solution 0 .3 mL and 30% hydrogen peroxide water 0.2 mL were added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. By performing the same operation as in Example 1, the production of 5-trifluoromethyluracil was confirmed (production rate 94%).

(Example 5)
In a 50 mL two-necked flask equipped with a magnetic rotor, 0.11 g (1.0 mmol) of uracil was weighed, and the inside of the container was replaced with argon. 2.0 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 3.0 mL of 2.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.12 g of hydrogen peroxide-urea complex and 1 mol / L iron (II) sulfate aqueous solution 0.3 mL was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. By performing the same operation as in Example 1, the production of 5-trifluoromethyluracil was confirmed (production rate 70%).

(Example 6)
Except that dimethyl sulfoxide was used in place of the 1N dimethyl sulfoxide solution of sulfuric acid, the same operation as in Example 1 was performed to confirm the formation of 5-trifluoromethyluracil (production rate: 38%).

(Example 7)
In a 50 mL two-necked flask equipped with a magnetic rotor, 0.11 g (1.0 mmol) of uracil was weighed, and the inside of the container was replaced with trifluoromethyl iodide. Dibutyl sulfoxide 5.0 mL, concentrated sulfuric acid 0.053 mL, 30% aqueous hydrogen peroxide 0.2 mL and 1.0 mol / L iron (II) sulfate aqueous solution 0.3 mL were added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The formation of 5-trifluoromethyluracil was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 0.2%).

(Example 8)
In a 50 mL two-necked flask equipped with a magnetic rotor, 0.11 g (1.0 mmol) of uracil was weighed, and the inside of the container was replaced with trifluoromethyl iodide. Diphenyl sulfoxide 5.0 g, concentrated sulfuric acid 0.053 mL, 30% aqueous hydrogen peroxide 0.2 mL and 1.0 mol / L iron (II) sulfate aqueous solution 0.3 mL were added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The formation of 5-trifluoromethyluracil was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 0.5%).

Example 9
All operations were the same as in Example 1 except that the reaction was performed in air without replacing with argon, and the production of 5-trifluoromethyluracil was confirmed (production rate: 76%).

(Example 10)
In a 100 mL two-necked flask equipped with a magnetic rotor, 1.1 g (10 mmol) of uracil was weighed, and the inside of the container was replaced with argon. 20 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 22.5 mL of dimethyl sulfoxide, 7.5 mL of 2.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 2.0 mL of 30% aqueous hydrogen peroxide and 1.0 mol / L iron sulfate ( II) 3.0 mL of aqueous solution was added. After stirring at 40 to 50 ° C. for 30 minutes, the reaction solution was cooled to room temperature. By performing the same operation as in Example 1, the production of 5-trifluoromethyluracil was confirmed (production rate 94%).

(Example 11)
In a 100 mL two-necked flask equipped with a magnetic rotor, 1.1 g (10 mmol) of uracil was weighed, and the inside of the container was replaced with argon. Concentrated sulfuric acid 0.055 mL, dimethyl sulfoxide 9 mL, trifluoromethyl iodide 24.5 mmol, 30% aqueous hydrogen peroxide 2.0 mL and 1.0 mol / L iron (II) sulfate aqueous solution 1.5 mL were added. After stirring for 10 minutes at 60 to 70 ° C., the reaction solution was cooled to room temperature. By performing the same operation as in Example 1, production of 5-trifluoromethyluracil was confirmed (production rate 97%).

(Example 12)
To a 300 mL two-necked flask equipped with a magnetic rotor, 11.2 g (100 mmol) of uracil was weighed, and the inside of the container was replaced with argon. Dimethyl sulfoxide (80 mL), concentrated sulfuric acid (0.55 mL), trifluoromethyl iodide (245 mmol), 30% aqueous hydrogen peroxide (20 mL) and 1.5 mol / L iron (II) sulfate aqueous solution (10 mL) were added. After stirring at 60 to 70 ° C. for 100 minutes, the reaction solution was cooled to room temperature. By performing the same operation as in Example 1, production of 5-trifluoromethyluracil was confirmed (production rate 97%).

  (Example 13)

In a 50 mL two-necked flask equipped with a magnetic rotor, 0.11 g (1.0 mmol) of uracil was weighed, and the inside of the container was replaced with argon. 2.0 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 1.3 mL of tridecafluoro-1-iodohexane, 1.2 mL of dimethyl sulfoxide, 0.3 mL of 1.0 mol / L aqueous iron (II) sulfate solution and 30% hydrogen peroxide solution 0.2 mL was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. Formation of 5-perfluorohexyluracil was confirmed by ¹⁹ F-NMR using benzotrifroid as an internal standard substance (production rate 29%). Column chromatography afforded 5-perfluorohexyluracil as a white solid (0.107 g, 25% yield).

¹ H-NMR (deuterated chloroform): δ 8.01 (d, J _HF = 5.7 Hz, 1 H), 11.59 (brs, 1 H), 11.80 (d, J _HF = 4.8 Hz, 1 H).
¹⁹ F-NMR (deuterated chloroform): δ-126.1 (q, J _FF = 7.0 Hz, 2F), −122.8 (brs, 2F), −122.1 (brs, 2F), −121. 2 (brs, 2F), - 108.5 (m, 2F), - 80.5 (t, J FF = 9.5Hz, 3F) MS (m / z): 430 [M] +.

  (Example 14)

In a 50 mL two-necked flask equipped with a magnetic rotor, 0.18 g (1.0 mmol) of 6-trifluoromethyluracil and 0.058 g (0.3 mmol) of ferrocene were weighed, and the inside of the container was replaced with argon. 1.8 mL of dimethyl sulfoxide, 2.0 mL of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of a 2.1 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide and 0.2 mL of 30% aqueous hydrogen peroxide were added. After stirring at 60 to 70 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The formation of 5,6-bis (trifluoromethyl) uracil was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 63%). Preparative thin layer chromatography gave 5,6-bis (trifluoromethyl) uracil as a white solid (0.12 g, 48% yield).

¹ H-NMR (heavy acetone): δ 10.73 (brs, 2H).
¹³ C-NMR (heavy acetone): δ 102.5 (q, J _CF = 32.7 Hz), 120.6 (q, J _CF = 277.3 Hz), 123.2 (q, J _CF = 270.2 Hz) , 147.0 (q, J _CF = 37.0 Hz), 152.3, 161.2.
¹⁹ F-NMR (heavy acetone): δ-64.8 (q, J _FF = 14.6 Hz), -58.4 (q, J _FF = 14.6 Hz).
MS (m / z): 248 [M] ^<+> .

  (Example 15)

In a 50 mL two-necked flask equipped with a magnetic rotor, 0.17 g (1.0 mmol) of 6-methoxycarbonyluracil and 0.058 g (0.3 mmol) of ferrocene were weighed, and the inside of the container was replaced with argon. 1.8 mL of dimethyl sulfoxide, 2.0 mL of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide and 0.2 mL of 30% hydrogen peroxide water were added. After stirring at 60 to 70 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 6-methoxycarbonyl-5-trifluoromethyluracil was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 84%). Column chromatography gave 6-methoxycarbonyl-5-trifluoromethyluracil as a white solid (0.20 g, 80% yield).

¹ H-NMR (heavy acetone): δ 3.94 (s, 3H), 10.70 (s, 1H), 11.10 (brs, 1H).
¹³ C-NMR (heavy acetone): δ 54.5, 100.8 (q, J _CF = 32.2 Hz), 123.1 (q, J _CF = 269.7 Hz), 147.4 (q, J _CF = 3.52 Hz), 149.9, 160.1, 161.6.
¹⁹ F-NMR (heavy acetone): δ-60.6.
MS (m / z): 238 [M] ^<+> .

  (Example 16)

In a 50 mL two-necked flask equipped with a magnetic rotor, 0.14 g (1.0 mmol) of 1,3-dimethyluracil was weighed, and the inside of the container was replaced with argon. 2.0 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 mL of 30% aqueous hydrogen peroxide and 1.0 mol / L aqueous iron (II) sulfate solution 0 .3 mL was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The formation of 1,3-dimethyl-5-trifluoromethyluracil was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 78%). Preparative thin layer chromatography gave 1,3-dimethyl-5-trifluoromethyluracil as a white solid (0.12 g, 44% yield).

¹ H-NMR (heavy acetone): δ 3.25 (s, 3H), 3.51 (s, 3H), 8.23 (q, J _HF = 1.05 Hz, 1H).
¹³ C-NMR (deuterated _{acetone): δ27.8,37.6,102.9 (q, J CF} = 32.3Hz), 123.8 (q, J CF = 268.4Hz), 146.4 (q , J _CF = 5.91 Hz), 151.9, 159.5.
¹⁹ F-NMR (heavy acetone): δ-60.6.
MS (m / z): 208 [M] ^&lt; ^{+ &gt};.

  (Example 17)

In a 50 mL two-necked flask equipped with a magnetic rotor, 0.16 g (1.0 mmol) of 6-amino-1,3-dimethyluracil was weighed, and the inside of the container was replaced with argon. 2.0 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of 2.1 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 mL of 30% aqueous hydrogen peroxide, and 1.0 mol / L aqueous iron (II) sulfate solution 0 .3 mL was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 6-amino-1,3-dimethyl-5-trifluoromethyluracil was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 95%). Column chromatography gave 6-amino-1,3-dimethyl-5-trifluoromethyluracil as a white solid (0.20 g, 95% yield).

¹ H-NMR (deuterated chloroform): δ 3.29 (s, 3H), 3.53 (s, 3H), 6.20 (s, 2H).
¹³ C-NMR (deuterated chloroform): δ 28.0, 29.7, 80.5 (q, J _CF = 30.2 Hz), 125.5 (q, J _CF = 269.1 Hz), 150.4, 153 .2, 159.8.
¹⁹ F-NMR (deuterated chloroform): δ-54.9.
MS (m / z): 223 [M] ^<+> .

  (Example 18)

To a 50 mL two-necked flask equipped with a magnetic rotor, 0.26 g (1.0 mmol) of 6-tert-butoxycarbonylamino-1,3-dimethyluracil was weighed, and the inside of the container was replaced with argon. 2.0 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of 2.1 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 mL of 30% aqueous hydrogen peroxide, and 1.0 mol / L aqueous iron (II) sulfate solution 0 .3 mL was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 6-tert-butoxycarbonylamino-1,3-dimethyl-5-trifluoromethyluracil was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 95 %). Column chromatography gave 6-tert-butoxycarbonylamino-1,3-dimethyl-5-trifluoromethyluracil as a white solid (0.30 g, 93% yield).

¹ H-NMR (deuterated chloroform): δ 1.51 (s, 9H), 3.32 (s, 3H), 3.46 (s, 3H), 6.89 (brs, 1H).
¹³ C-NMR (heavy _{chloroform): δ27.9,28.5,32.2,84.2,98.4 (q, J CF} = 22.8Hz), 122.8 (q, J CF = 271. 5 Hz), 147.5, 150.6, 151.3, 158.6.
¹⁹ F-NMR (deuterated chloroform): δ-54.8.
MS (m / z): 250 [M-OC 4 H 9] +.

  (Example 19)

In a 50 mL two-necked flask equipped with a magnetic rotor, 0.16 g (1.0 mmol) of 6- (2-chloromethyl) uracil and 0.058 g (0.3 mmol) of ferrocene were weighed, and the inside of the container was replaced with argon. . 1.8 mL of dimethyl sulfoxide, 2.0 mL of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of a 2.1 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide and 0.2 mL of 30% aqueous hydrogen peroxide were added. After stirring at 60 to 70 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 6- (2-chloromethyl) -5-trifluoromethyluracil was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 55%). Preparative thin layer chromatography gave 6- (2-chloromethyl) -5-trifluoromethyluracil as a white solid (0.10 g, 45% yield).

¹ H-NMR (deuterated dimethyl sulfoxide): δ 4.47 (s, 2H), 11.78 (brs, 1H), 11.82 (brs, 1H).
¹³ C-NMR (deuterated dimethyl sulfoxide): δ 38.8, 100.9 (q, J _CF = 30.7 Hz), 123.6 (q, J _CF = 270.9 Hz), 150.3, 153.9, 160.9.
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-56.5.
MS (m / z): 228 [M] ^<+> .

  (Example 20)

In a 50 mL two-necked flask equipped with a magnetic rotor, 0.17 g (1.0 mmol) of 6-carboxyuracil and 0.058 g (0.3 mmol) of ferrocene were weighed, and the inside of the container was replaced with argon. 1.8 mL of dimethyl sulfoxide, 2.0 mL of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide and 0.2 mL of 30% hydrogen peroxide water were added. After stirring at 60 to 70 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 6-carboxy-5-trifluoromethyluracil was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 95%). By column chromatography, 6-carboxy-5-trifluoromethyluracil was obtained (0.076 g, yield 34%).

¹ H-NMR (deuterated dimethyl sulfoxide): δ 11.71 (brs, 1H), 12.13 (brs, 1H).
¹³ C-NMR (deuterated dimethyl sulfoxide): δ 97.2 (q, J _CF = 31.5 Hz), 122.9 (q, J _CF = 269.9 Hz), 149.8, 150.3, 160.6, 162.3.
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-58.6.
MS (m / z): 223 [M-H] ^<+> .

  (Example 21)

In a 50 mL two-necked flask equipped with a magnetic rotor, 0.24 g (1.0 mmol) of uridine was weighed, and the inside of the container was replaced with argon. 1.5 mL of dimethyl sulfoxide, 2 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 1 mL of 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 mL of 1 mol / L iron (II) sulfate aqueous solution and 30% hydrogen peroxide 0.2 mL of water was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 5-trifluoromethyluridine was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 51%). Column chromatography gave 5-trifluoromethyluridine (0.071 g, 23% yield).

¹ H-NMR (deuterated dimethyl sulfoxide): δ 2.84 (brs, 3H), 3.88 (m, 3H), 4.60 (m, 1H), 4.32 (d, J = 13.6 Hz, 2H) ), 4.60 (brs, 1H), 5.88 (d, J = 13.6 Hz, 1H), 8.88 (s, 1H).
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-61.8.

  (Example 22)

A 50 mL two-necked flask equipped with a magnetic rotor was weighed with 0.37 g (1.0 mmol) of 2 ′, 3 ′, 5′-tri-O-acetyluridine and 0.058 g (0.3 mmol) of ferrocene. The inside was replaced with argon. 1.8 mL of dimethyl sulfoxide, 2.0 mL of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of a 2.1 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide and 0.2 mL of 30% aqueous hydrogen peroxide were added. After stirring at 60 to 70 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The formation of 5-trifluoromethyl-2 ′, 3 ′, 5′-tri-O-acetyluridine was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (Production rate 45%). By column chromatography, 5-trifluoromethyl-2 ′, 3 ′, 5′-tri-O-acetyluridine was obtained as a white solid (0.17 g, yield 40%).

¹ H-NMR (deuterated chloroform): δ 2.11 (s, 3H), 2.13 (s, 3H), 2.14 (s, 3H), 4.34 (d, J = 13.6 Hz, 1H) , 4.43 (m, 1H), 4.43 (dd, J = 3.2 Hz, 13.6 Hz, 1H), 5.34 (t, J = 5.4 Hz, 1H), 5.37 (t, J = 5.4 Hz, 1H), 6.07 (d, J = 5.4 Hz, 1H), 8.01 (s, 1H), 9.48 (s, 1H).
¹³ C-NMR (deuterated chloroform): δ 20.3, 20.4, 62.7, 69.9, 73.2, 80.5, 87.7, 106.2 (q, J _CF = 33.3 Hz) 121.6 (q, J _CF = 270.3 Hz), 140.2 (q, J _CF = 6.0 Hz), 149.3, 158.0, 169.6, 169.7, 170.2.
¹⁹ F-NMR (deuterated chloroform): δ-64.0.

  (Example 23)

In a 50 mL two-necked flask equipped with a magnetic rotor, 0.23 g (1.0 mmol) of 2′-deoxyuridine was weighed, and the inside of the container was replaced with argon. 2.0 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of 2.1 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 mL of 30% aqueous hydrogen peroxide, and 1.0 mol / L aqueous iron (II) sulfate solution 0 .3 mL was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. Using 2,2,2-trifluoroethanol as an internal standard substance, the production of 5-trifluoromethyl-2′-deoxyuridine was confirmed by ¹⁹ F-NMR (production rate 85%). Column chromatography yielded 5-trifluoromethyl-2′-deoxyuridine as a white solid (0.17 g, yield 58%).

¹ H-NMR (deuterated chloroform): δ 2.35 (ddd, J = 6.10 Hz, 6.25 Hz, 13.53 Hz, 1 H), 2.39 (ddd, J = 3.61 Hz, 6.25 Hz, 13. 53 Hz, 1H), 3.86 (dd, J = 11.7 Hz, 15.3 Hz, 2H), 4.02 (dd, J = 3.61 Hz, 6.10 Hz, 1H), 4.46 (brs, 2H) ), 4.53 (brs, 1H), 6.27 (t, J = 6.25 Hz, 1H), 8.84 (s, 1H), 10.45 (s, 1H).
¹³ C-NMR (deuterated chloroform): δ 42.0, 62.0, 71.4, 86.9, 89.0, 104.5 (q, J _CF = 32.4 Hz), 123.7 (q, J _CF = 268.6 Hz), 143.1 (q, J _CF = 5.66 Hz), 150.5, 159.4.
¹⁹ F-NMR (deuterated chloroform): δ-63.7.

  (Example 24)

Weigh out 0.32 g (1.0 mmol) of 3 ′, 5′-di-O-acetyl-2′-deoxyuridine and 0.058 g (0.3 mmol) of ferrocene in a 50 mL two-necked flask equipped with a magnetic rotor. The inside of the container was replaced with argon. 1.8 mL of dimethyl sulfoxide, 2.0 mL of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of a 2.1 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide and 0.2 mL of 30% aqueous hydrogen peroxide were added. The mixture was stirred at 60 to 70 ° C. for 20 minutes, and then the reaction solution was cooled to room temperature. Using trifluoroethanol as an internal standard substance, production of 5-trifluoromethyl-3 ′, 5′-di-O-acetyl-2′-deoxyuridine was confirmed by ¹⁹ F-NMR (production rate: 75%). By column chromatography, 5-trifluoromethyl-3 ′, 5′-di-O-acetyl-2′-deoxyuridine was obtained as a white solid (0.19 g, yield 50%).

¹ H-NMR (deuterated chloroform): δ 2.10 (s, 3H), 2.13 (s, 3H), 2.19 (ddd, J = 6.63 Hz, 8.00 Hz, 14.34 Hz, 1H), 2.63 (ddd, J = 1.96 Hz, 5.72 Hz, 14.34 Hz, 1H), 4.28-4.37 (m, 2H), 4.44 (dd, J = 2.66 Hz, 11. 77 Hz, 1H), 5.23 (td, J = 1.96 Hz, 6.63 Hz, 1H), 6.28 (dd, J = 5.72 Hz, 8.00 Hz, 1H), 8.09 (s, 1H) ), 9.27 (s, 1H).
¹³ C-NMR (deuterated chloroform): δ 20.5, 20.9, 38.7, 63.7, 74.0, 83.1, 86.1, 105.7 (q, J _CF = 33.3 Hz) , 121.7 (q, J _CF = 270.2 Hz), 140.0 (q, J _CF = 5.91 Hz), 149.2, 158.1, 170.2, 170.4.
¹⁹ F-NMR (deuterated chloroform): δ-63.7.

  (Example 25)

In a 50 mL two-necked flask equipped with a magnetic rotor, 0.11 g (1.0 mmol) of cytosine was weighed, and the inside of the container was replaced with argon. 2.0 mL of dimethyl sulfoxide, 2.0 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 mL of 30% hydrogen peroxide and 1.0 mol / L sulfuric acid 0.3 mL of iron (II) aqueous solution was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 5-trifluoromethylcytosine was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 27%). Column chromatography gave 5-trifluoromethylcytosine as a white solid (0.010 g, yield 5.6%).

¹ H-NMR (deuterated dimethyl sulfoxide): δ 6.95 (brs, 2H), 7.72 (brs, 2H), 7.95 (s, 1H).
¹³ C-NMR (deuterated dimethyl sulfoxide): δ 94.3 (q, J _CF = 33.5 Hz), 124.2 (q, J _CF = 268.7 Hz), 145.8, 156.0, 161.5. ¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-60.8.
MS (m / z): 181 [M] ^<+> .

  (Example 26)

N ⁴ -acetylcytosine 0.15 g (1.0 mmol) was weighed into a 50 mL two-necked flask equipped with a magnetic rotor, and the inside of the container was replaced with argon. 17 mL of dimethyl sulfoxide, 2.0 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 mL of 30% hydrogen peroxide and 1.0 mol / L iron sulfate ( II) 0.3 mL of aqueous solution was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. Using 2,2,2-trifluoroethanol as an internal standard substance, production of N ⁴ -acetyl-5-trifluoromethylcytosine was confirmed by ¹⁹ F-NMR (production rate 35%). By column chromatography, N ⁴ -acetyl-5-trifluoromethylcytosine was obtained as a white solid (0.067 g, yield 30%).

¹ H-NMR (deuterated dimethyl sulfoxide): δ 2.56 (s, 3H), 8.04 (s, 1H), 11.58 (brs, 2H).
¹³ C-NMR (deuterated dimethyl sulfoxide): δ 23.0, 102.3 (q, J _CF = 31.9 Hz), 123.4 (q, J _CF = 268.8 Hz), 144.7 (q, J _CF = 5.6 Hz), 151.2, 160.5, 172.1.
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-61.8.
MS (m / z): 224 [M + H] ^< +>.

  (Example 27)

In a 50 mL two-necked flask equipped with a magnetic rotor, 0.24 g (1.0 mmol) of cytidine was weighed, and the inside of the container was replaced with argon. Add 4.0 mL of dimethyl sulfoxide, 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 mL of a 1.0 mol / L aqueous iron (II) sulfate solution and 0.2 mL of 30% hydrogen peroxide solution. It was. The mixture was stirred at 40 to 50 ° C. for 20 minutes, and the reaction solution was cooled to room temperature. Using trifluoroethanol as an internal standard substance, the production of 5-trifluoromethylcytidine was confirmed by ¹⁹ F-NMR (production rate: 24%). Column chromatography yielded 5-trifluoromethylcytidine (0.034 g, 11% yield).

¹ H-NMR (deuterated dimethyl sulfoxide): δ 3.52 (m, 1H), 3.70 (m, 1H), 3.96 (m, 3H), 5.00 (d, J = 13.6 Hz, 1H ), 5.28 (t, J = 5.4 Hz, 1H), 5.48 (d, J = 13.6 Hz, 1H), 5.76 (m, 1H), 7.16 (brs, 1H), 7.72 (brs, 2H), 8.84 (s, 1H).
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-60.9.

  (Example 28)

In a 50 mL two-necked flask equipped with a magnetic rotor, 0.15 g (1.0 mmol) of 2′-deoxycytidine was weighed, and the inside of the container was replaced with argon. 2.0 mL of dimethyl sulfoxide, 2.0 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 mL of 30% hydrogen peroxide and 1.0 mol / L sulfuric acid 0.3 mL of iron (II) aqueous solution was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. Production of 5-trifluoromethyl-2′-deoxycytidine was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate: 11%). Column chromatography gave 5-trifluoromethyl-2′-deoxycytidine as a white solid (0.01 g, yield 3.3%).
¹ H-NMR (deuterated dimethyl sulfoxide): δ 2.16 (m, 2H), 3.62 (m, 2H), 3.82 (m, 1H), 4.20 (m, 1H), 5.06 ( d, J = 12.5 Hz, 1H), 5.19 (d, J = 12.5 Hz, 1H), 6.04 (t, J = 5.6 Hz, 1H), 7.04 (brs, 1H), 7.64 (brs, 2H), 8.60 (s, 1H).
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-60.8.

  (Example 29)

Adenine 0.13 g (1.0 mmol) was weighed into a 50 mL two-necked flask equipped with a magnetic rotor, and the inside of the container was replaced with argon. 2.0 mL of dimethyl sulfoxide, 2.0 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 mL of 30% hydrogen peroxide and 1.0 mol / L sulfuric acid 0.3 mL of iron (II) aqueous solution was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 8-trifluoromethyladenine was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 26%). Preparative thin layer chromatography gave 8-trifluoromethyladenine as a white solid (0.02 g, 10% yield).

¹ H-NMR (deuterated dimethyl sulfoxide): δ 8.31 (s, 1H), 14.08 (brs, 2H).
¹³ C-NMR (deuterated dimethyl sulfoxide): δ 119.9, 121.0 (q, J _CF = 270.2 Hz), 147.1, 147.1, 150.9, 156.8.
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-62.9.
MS (m / z): 203 [M] ⁺
(Example 30)

Adenosine 0.27 g (1.0 mmol) was weighed into a 50 mL two-necked flask equipped with a magnetic rotor, and the inside of the container was replaced with argon. Add 4.0 mL of dimethyl sulfoxide, 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 mL of a 1.0 mol / L aqueous iron (II) sulfate solution and 0.2 mL of 30% hydrogen peroxide solution. It was. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 8-trifluoromethyladenosine was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate: 6.7%). Column chromatography gave 8-trifluoromethyladenosine as a white solid (0.01 g, yield 3.1%).

¹ H-NMR (deuterated dimethyl sulfoxide): δ 3.62 (m, 2H), 4.04 (m, 1H), 4.23 (m, 1H), 5.05 (dd, 1H), 5.24 ( m, 1H), 5.52 (m, 2H), 5.81 (d, 1H), 7.92 (brs, 2H), 8.24 (s, 1H).
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-60.2.

  (Example 31)

In a 50 mL two-necked flask equipped with a magnetic rotor, 0.15 g (1.0 mmol) of 2,6-diaminopurine was weighed, and the inside of the container was replaced with argon. Add 4.0 mL of dimethyl sulfoxide, 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 mL of a 1.0 mol / L aqueous iron (II) sulfate solution and 0.2 mL of 30% hydrogen peroxide solution. It was. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 2,6-diamino-8-trifluoromethylpurine was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 45%). Column chromatography gave 2,6-diamino-8-trifluoromethylpurine as a white solid (0.050 g, 23% yield).

¹ H-NMR (deuterated dimethyl sulfoxide): δ 6.17 (s, 2H), 7.26 (s, 2H),
12.2 (brs, 1H).
¹³ C-NMR (deuterated dimethyl sulfoxide): δ 114.8, 116.0 (q, J _CF = 269.1 Hz), 144.3, 152.7, 157.0, 161.7.
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-62.6.
MS (m / z): 218 [M] ^<+> .

  (Example 32)

In a 50 mL two-necked flask equipped with a magnetic rotor, 0.15 g (1.0 mmol) of 2,6-diaminopurine was weighed, and the inside of the container was replaced with argon. 3.0 mL of dimethyl sulfoxide, 2.0 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 1.3 mL of tridecafluoro-1-iodohexane, 0.3 mL of 1.0 mol / L iron (II) sulfate aqueous solution and 30% hydrogen peroxide solution 0.2 mL was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 2,6-diamino-8-perfluorohexylpurine was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 10%). By column chromatography, 2,6-diamino-8-perfluorohexylpurine was obtained as a white solid (0.018 g, yield 4.0%).

¹ H-NMR (deuterated dimethyl sulfoxide): δ 6.20 (s, 2H), 7.31 (s, 2H), 12.2 (brs, 1H).
¹⁹ F-NMR (deuterated dimethyl sulfoxide): δ-126.2 (q, J _FF = 4.7 Hz, 2F), -122.9 (brs, 2F), -121.9 (m, 4F), -108 .9 (m, 2F), -80.7 (t, J _FF = 9.5 Hz, 3F)
MS (m / z): 469 [M + H] ^< +>.

  (Example 33)

In a 500 mL two-necked flask equipped with a magnetic rotor, 0.15 g (1.0 mmol) of guanine was weighed, and the inside of the container was replaced with argon. 197 mL of dimethyl sulfoxide, 2.0 mL of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 mL of 30% hydrogen peroxide and 1.0 mol / L iron sulfate ( II) 0.3 mL of aqueous solution was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 8-trifluoromethylguanine was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 46%). Column chromatography yielded 8-trifluoromethylguanine as a white solid (0.019 g, 9% yield).

¹ H-NMR (deuterated dimethyl sulfoxide): δ 6.60 (brs, 2H), 10.81 (brs, 1H), 13.73 (brs, 1H).
¹³ C-NMR (deuterated dimethyl sulfoxide): δ 116.3, 119.2 (q, J _CF = 269.3 Hz), 134.9 (q, J _CF = 40.7 Hz), 152.8, 154.7, 156.6.
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-63.0.
MS (m / z): 218 [M-H] -.

  (Example 34)

In a 50 mL two-necked flask equipped with a magnetic rotor, 0.41 g (1.0 mmol) of 2 ′, 3 ′, 5′-tri-O-acetylguanosine was weighed, and the inside of the container was replaced with argon. 2.0 mL of dimethyl sulfoxide, 2.0 mL of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 mL of a 1.0 mol / L aqueous iron (II) sulfate solution and 30 mL A 0.2% aqueous hydrogen peroxide solution was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 8-trifluoromethyl-2 ′, 3 ′, 5′-tri-O-acetylguanosine was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (Production rate 51%). Silica gel column chromatography gave 8-trifluoromethyl-2 ′, 3 ′, 5′-tri-O-acetylguanosine as a yellow solid (0.22 g, 47% yield).

¹ H-NMR (deuterated chloroform): δ 2.03 (s, 3H), 2.13 (s, 3H), 2.16 (s, 3H), 4.30 (m, 1H), 4.44 (m , 2H), 5.87 (t, J = 5.0 Hz, 1H), 5.94 (d, J = 5.0 Hz, 1H), 6.47 (brs, 2H), 12.1 (s, 1H) ).
¹³ C-NMR (deuterated chloroform): δ 20.3, 20.5, 20.6, 62.9, 70.6, 71.6, 77.2, 80.6, 87.6, 116.4, 118 .3 (q, J _CF = 270.5 Hz), 152.6, 154.6, 158.9, 169.5, 169.5, 170.8.
¹⁹ F-NMR (deuterated chloroform): δ-61.5.

  (Example 35)

In a 50 mL two-necked flask equipped with a magnetic rotor, 0.39 g (1.0 mmol) of 2 ′, 3 ′, 5′-tri-O-acetylinosine was weighed, and the inside of the container was replaced with argon. 5.0 mL of dimethyl sulfoxide, 2.0 mL of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 mL and 30 mL of a 1.0 mol / L aqueous iron (II) sulfate solution A 0.2% aqueous hydrogen peroxide solution was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 8-trifluoromethyl-2 ′, 3 ′, 5′-tri-O-acetylinosine was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (Production rate 7.0%). By column chromatography, 8-trifluoromethyl-2 ′, 3 ′, 5′-tri-O-acetylinosine was obtained (0.018 g, yield 4.0%).

¹ H-NMR (deuterated dimethyl sulfoxide): δ 2.08 (s, 6H), 2.16 (s, 3H), 4.35-4.45 (m, 2H), 4.51 (dd, J = 3 .6, 11.3 Hz, 1H) 5.73 (dd, J = 5.5, 5.6 Hz, 1H), 6.08 (d, J = 5.5 Hz, 1H), 6.27 (dd, J = 5.6 Hz, 1H), 8.26 (s, 1H), 12.49 (brs, 1H).
¹³ C-NMR (deuterated dimethyl sulfoxide): δ 20.2, 20.5, 20.7, 62.8, 70.3, 72.0, 80.7, 88.0, 118.1 (q, J _CF = 271.7 Hz), 124.2, 138.2 (q, J _CF = 40.7 Hz), 147.2, 150.1, 158.6, 169.2, 169.5, 170.5.
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-61.5.

  (Example 36)

In a 50 mL two-necked flask equipped with a magnetic rotor, 0.14 g (1.0 mmol) of hypoxanthine and 0.058 g (0.3 mmol) of ferrocene were weighed, and the inside of the container was replaced with argon. 2.0 mL of dimethyl sulfoxide, 2.0 mL of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide and 0.2 mL of 30% hydrogen peroxide water were added. After stirring at 60 to 70 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 8-trifluoromethyl hypoxanthine was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate: 24%). By column chromatography, 8-trifluoromethyl hypoxanthine was obtained (0.026 g, yield 13%).

¹ H-NMR (deuterated dimethyl sulfoxide): δ 8.13 (s, 1H), 12.52 (s, 1H), 14.89 (brs, 1H).
¹³ C-NMR (deuterated dimethyl sulfoxide): δ 119.0 (q, J _CF = 270.1 Hz), 122.6, 138.0 (q, J _CF = 41.2 Hz), 147.6, 152.3 156.4.
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-63.2.
MS (m / z): 205 [M + H] &lt; ⁺ &gt;.

  (Example 37)

0.19 g (1.0 mmol) of xanthine was weighed into a 100 mL two-necked flask equipped with a magnetic rotor, and the inside of the container was replaced with argon. 47 mL of dimethyl sulfoxide, 2.0 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 mL of 30% hydrogen peroxide and 1.0 mol / L iron sulfate ( II) 0.3 mL of aqueous solution was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 8-trifluoromethylxanthine was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 44%). 8-Trifluoromethylxanthine was obtained by column chromatography (0.044 g, yield 20%).

¹ H-NMR (deuterated dimethyl sulfoxide): δ 11.16 (s, 1H), 11.83 (s, 1H), 15.07 (brs, 1H).
¹³ C-NMR (deuterated dimethyl sulfoxide): δ 110.0, 118.7 (q, J _CF = 269.9 Hz), 138.0 (q, J _CF = 41.1 Hz), 148.1, 151.7, 156.2.
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-63.1.
MS (m / z): 221 [M + H] ^< +>.

  (Example 38)

Caffeine 0.19 g (1.0 mmol) was weighed into a 50 mL two-necked flask equipped with a magnetic rotor, and the inside of the container was replaced with argon. 2.0 mL of dimethyl sulfoxide, 2.0 mL of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 mL of a 1.0 mol / L aqueous iron (II) sulfate solution and 30 A 0.2% aqueous hydrogen peroxide solution was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 8-trifluoromethylcaffeine was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate: 17%). Column chromatography yielded 8-trifluoromethyl caffeine as a white solid (0.033 g, 13% yield).

¹ H-NMR (heavy acetone): δ 3.33 (s, 3H), 3.52 (s, 3H), 4.21 (q, J _HF = 1.25 Hz, 3H).
¹³ C-NMR (deuterated _{acetone): δ27.8,29.7,33.3 (q, J CF} = 1.98Hz), 110.3,119.2 (q, J CF = 270.2Hz), 138 .4 (q, J _CF = 39.6 Hz), 147.0.
¹⁹ F-NMR (heavy acetone): δ-62.1 (d, J _HF = 1.25 Hz)
MS (m / z): 262 [M] ^<+> .

(Example 39)
The production of 8-trifluoromethyl caffeine was confirmed by performing the same operation as in Example 38 except that 0.5 mL of 1N dimethylsulfoxide solution of sulfuric acid was used instead of 2.0 mL of 1N dimethylsulfoxide solution of sulfuric acid. (Production rate 48%).

(Example 40)
In a 100 mL two-necked flask equipped with a magnetic rotor, 1.94 g (10 mmol) of caffeine was weighed, and the inside of the container was replaced with argon. 20 mL of dimethyl sulfoxide, 20 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 10 mL of 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 3.0 mL of 1.0 mol / L aqueous iron (II) sulfate solution and 30% hydrogen peroxide solution 2 0.0 mL was added. After stirring at 50 to 60 ° C. for 60 minutes, the reaction solution was cooled to room temperature. The production of 8-trifluoromethylcaffeine was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 20%).

(Example 41)
1.94 g (10 mmol) of caffeine was weighed into a 300 mL two-necked flask equipped with a magnetic rotor, and the inside of the container was replaced with argon. Dimethyl sulfoxide (50 mL), sulfuric acid (0.055 mL), gaseous trifluoromethyl iodide (30 mmol), 1.0 mol / L iron (II) sulfate aqueous solution (3.0 mL) and 30% aqueous hydrogen peroxide (2.0 mL) were added. After stirring at 50 to 60 ° C. for 60 minutes, the reaction solution was cooled to room temperature. The production of 8-trifluoromethylcaffeine was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate: 23%).

(Example 42)
Production of 8-trifluoromethylcaffeine was carried out in the same manner as in Example 41 except that a 1.0 mol / L iron (II) ammonium sulfate aqueous solution was used instead of the 1.0 mol / L iron (II) sulfate aqueous solution. (Production rate 15%) was confirmed.

(Example 43)
Caffeine 0.19 g (1.0 mmol) was weighed into a 50 mL two-necked flask equipped with a magnetic rotor, and the inside of the container was replaced with argon. 42% tetrafluoroboric acid aqueous solution 0.21 mL, dimethyl sulfoxide 4.0 mL, trifluoromethyl iodide 3.0 mol / L dimethyl sulfoxide solution 1.0 mL, 1.0 mol / L iron (II) tetrafluoroborate aqueous solution 0 .3 mL and 30% hydrogen peroxide water 0.2 mL were added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 8-trifluoromethylcaffeine was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 11%).

(Example 44)
Caffeine 0.19 g (1.0 mmol) was weighed into a 50 mL two-necked flask equipped with a magnetic rotor, and the inside of the container was replaced with argon. 0.016 g (0.3 mmol) of iron powder, 2.0 mL of dimethyl sulfoxide, 2.0 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of a 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide and 30% hydrogen peroxide 0.2 mL of water was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 8-trifluoromethylcaffeine was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 37%).

(Example 45)
Caffeine 0.19 g (1.0 mmol) and ferrocene 0.056 g (0.3 mmol) were weighed into a 50 mL two-necked flask equipped with a magnetic rotor, and the inside of the container was replaced with argon. 2.0 mL of dimethyl sulfoxide, 2.0 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 mL of 1.0 mol / L aqueous iron (II) sulfate solution and 0.2 mL of hydrogen oxide was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 8-trifluoromethylcaffeine was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate: 17%).

(Example 46)
All operations were performed in the same manner as in Example 41 except that the reaction was performed in air without replacing with argon, and production of 8-trifluoromethylcaffeine was confirmed (production rate: 13%).

  (Example 47)

Caffeine 0.18 g (1.0 mmol) was weighed into a 50 mL two-necked flask equipped with a magnetic rotor, and the inside of the container was replaced with argon. 3.0 mL of dimethyl sulfoxide, 2.0 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 1.3 mL of tridecafluoro-1-iodohexane, 0.3 mL of 1.0 mol / L iron (II) sulfate aqueous solution and 30% hydrogen peroxide solution 0 .2 mL was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 8-perfluorohexyl caffeine was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 30%). Column chromatography yielded 8-perfluorohexyl caffeine as a white solid (0.077 g, 15% yield).

¹ H-NMR (heavy acetone): δ 3.33 (s, 3H), 3.52 (s, 3H), 4.21 (s, 3H).
¹⁹ F-NMR (heavy acetone): δ-125.9 (m, 2F), -122.8 (s, 2F), -122.0 (m, 2F), -114.2 (m, 4F), −80.5 (q, J _FF = 9.4 Hz, 3F).
MS (m / z): 513 [M + H] ^< +>.

  (Example 48)

Theobromine 0.18 g (1.0 mmol) was weighed into a 50 mL two-necked flask equipped with a magnetic rotor, and the inside of the container was replaced with argon. 17 mL of dimethyl sulfoxide, 2.0 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.3 mL of 1.0 mol / L iron (II) sulfate aqueous solution and 30% excess 0.2 mL of hydrogen oxide water was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 8-trifluoromethyl theobromine was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 12%). Column chromatography yielded 8-trifluoromethyl theobromine as a white solid (0.024 g, 10% yield).

¹ H-NMR (deuterated dimethyl sulfoxide): δ 3.34 (s, 3H), 4.04 (s, J = 1.7 Hz, 3H), 11.48 (brs, 1H).
¹³ C-NMR (deuterated dimethyl sulfoxide): δ 33.1 (q, J _CF = 1.9 Hz), 42.1, 109.9 (q, J _CF = 1.9 Hz), 118.2 (q, J _CF = 270.7 Hz), 137.0 (q, J _CF = 39.2 Hz), 147.5, 150.6, 155.2.
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-61.6.
MS (m / z): 248 [M] ^<+> .

  (Example 49)

Theophylline 0.18 g (1.0 mmol) was weighed into a 50 mL two-necked flask equipped with a magnetic rotor, and the inside of the container was replaced with argon. 2.0 mL of dimethyl sulfoxide, 2.0 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 mL of 3.0 mol / L dimethyl sulfoxide solution of trifluoromethyl iodide, 0.2 mL of 30% hydrogen peroxide and 1.0 mol / L sulfuric acid 0.3 mL of iron (II) aqueous solution was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 8-trifluoromethyltheophylline was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 48%). Column chromatography gave 8-trifluoromethyl theophylline as a white solid (0.086 g, 35% yield).

¹ H-NMR (deuterated dimethyl sulfoxide): δ 3.24 (s, 3H), 3.42 (s, 3H), 15.2 (brs, 1H).
¹³ C-NMR (deuterated dimethyl sulfoxide): δ 27.9, 29.9, 109.1, 118.2 (q, J _CF = 270.0 Hz), 137.3 (q, J _CF = 37.2 Hz), 146.8, 150.9, 154.6.
¹⁹ F-NMR (heavy dimethyl sulfoxide): δ-62.3.
MS (m / z): 248 [M] ^<+> .

  (Example 50)

Theophylline 0.18 g (1.0 mmol) was weighed into a 50 mL two-necked flask equipped with a magnetic rotor, and the inside of the container was replaced with argon. 3.0 mL of dimethyl sulfoxide, 2.0 mL of 1N dimethyl sulfoxide solution of sulfuric acid, 1.3 mL of tridecafluoro-1-iodohexane, 0.3 mL of 1.0 mol / L iron (II) sulfate aqueous solution and 30% hydrogen peroxide solution 0 .2 mL was added. After stirring at 40 to 50 ° C. for 20 minutes, the reaction solution was cooled to room temperature. The production of 8-perfluorohexyltheophylline was confirmed by ¹⁹ F-NMR using 2,2,2-trifluoroethanol as an internal standard substance (production rate 12%). Column chromatography yielded 8-perfluorohexyltheophylline as a white solid (0.02 g, 4.0% yield).

¹ H-NMR (heavy acetone): δ 3.34 (s, 3H), 3.57 (s, 3H), 14.2 (brs, 1H).
¹⁹ F-NMR (heavy acetone): δ-127.0 (m, 2F), -123.6 (brs, 2F), -122.9 (m, 2F), -122.4 (brs, 2F), −112.3 (m, 2F), −81.9 (t, J _FF = 7.1 Hz, 3F).
MS (m / z): 499 [M + H] ^< +>.

  (Example 51)

The same operation as in Example 22 was carried out except that 0.16 g of 6- (2-chloroethyl) uracil was used instead of 0.37 g of 2 ′, 3 ′, 5′-tri-O-acetyluridine, and 6- ( Formation of 2-chloroethyl) -5-trifluoromethyluracil was confirmed (production rate 55%). Then, 6- (2-chloroethyl) -5-trifluoromethyluracil was obtained as a white solid by preparative thin layer chromatography (0.10 g, yield 45%).

Claims (17)

General formula (1)

[Wherein, R ^1a and R ^1b represent an alkyl group having 1 to 12 carbon atoms or an optionally substituted phenyl group. In the presence of sulfoxides, peroxides and iron compounds represented by general formula (2)

[Wherein, Rf represents a perfluoroalkyl group having 1 to 6 carbon atoms, and X represents a halogen atom. ] The manufacturing method of the nucleobase which has a perfluoroalkyl group characterized by reacting perfluoroalkyl halide represented by this, and nucleobase. The process according to claim 1, wherein the reaction is carried out in the presence of an acid. Nucleobase is represented by the general formula (3)

[Wherein R ² represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms or a protecting group for a nitrogen atom, and R ³ represents a hydrogen atom, optionally substituted carbon number 1 R ⁶ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, a substituted group, and an analog thereof. And an optionally substituted alkoxy group having 1 to 4 carbon atoms, an optionally substituted amino group, a carboxy group, an optionally substituted carbamoyl group or an optionally substituted alkoxycarbonyl group having 2 to 5 carbon atoms. ] Uracil represented by the general formula (4)

[Wherein R ⁵ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, a nitrogen atom protecting group or a pentose residue, and analogs thereof, and R ⁶ represents a hydrogen atom An optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted amino group, a carboxy group, an optionally substituted carbamoyl group, or an optionally substituted alkoxy having 2 to 5 carbon atoms Represents a carbonyl group, and R ⁷ and R ⁸ represent a protecting group for a hydrogen atom or a nitrogen atom. A cytosine represented by the general formula (5)

[Wherein R ⁹ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, a protecting group for nitrogen atom or a pentose residue and its analogs, and R ¹⁰ represents a hydrogen atom An optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted amino group, a carboxy group, an optionally substituted carbamoyl group, or an optionally substituted alkoxy having 2 to 5 carbon atoms Represents a carbonyl group, and R ¹¹ and R ¹² represent a protecting group for a hydrogen atom or a nitrogen atom. Adenine represented by the general formula (6)

[Wherein, R ¹³ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms or a protecting group for a nitrogen atom, and R ¹⁴ represents a hydrogen atom, optionally substituted carbon number 1 6 alkyl group, a protecting group or pentose residues and analogs thereof of the nitrogen atom, R ¹⁵ and R ¹⁶ represents a hydrogen atom or a protecting group for a nitrogen atom. A guanine represented by the general formula (7)

[Wherein R ¹⁷ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms or a protecting group for a nitrogen atom, and R ¹⁸ represents a hydrogen atom, optionally substituted carbon number 1 To 6 alkyl groups, nitrogen atom protecting groups or pentose residues and analogs thereof. Or a hypoxanthine represented by the general formula (8)

[Wherein R ¹⁹ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms or a protecting group for a nitrogen atom, and R ²⁰ represents a hydrogen atom, optionally substituted carbon number 1 And R ²¹ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms or a nitrogen atom, and a nitrogen atom protecting group or a pentose residue and analogs thereof. Indicates a group. The production method according to claim 1, wherein the xanthines are represented by the formula: Nucleobase is represented by the general formula (3)

[Wherein R ² , R ³ and R ⁴ have the same contents as described above. ] The manufacturing method in any one of Claim 1 to 3 characterized by the above-mentioned. The production method according to claim 1, wherein X is iodine or bromine. Rf is a trifluoromethyl group or a perfluoroethyl group, The manufacturing method in any one of Claim 1 to 5 characterized by the above-mentioned. The iron compound is iron (II) sulfate, iron (II) sulfate, iron (II) tetrafluoroborate, iron (II) chloride, iron (II) bromide, iron (II) iodide, iron acetate (II) ), Iron (II) oxalate, iron (II) bisacetylacetonate, ferrocene, bis (η ⁵ -pentamethylcyclopentadienyl) iron or iron powder, The manufacturing method in any one. The production according to any one of claims 1 to 7, characterized in that the iron compound is iron (II) sulfate, iron (II) ammonium sulfate, iron (II) tetrafluoroborate, ferrocene or iron powder. Method. The production method according to claim 1, wherein the peroxide is hydrogen peroxide, hydrogen peroxide-urea complex, tert-butyl peroxide, or peracetic acid. The production method according to any one of claims 1 to 9, wherein the peroxide is hydrogen peroxide or a hydrogen peroxide-urea complex. Acid is sulfuric acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, hexafluorophosphoric acid, tetrafluoroboric acid, formic acid, acetic acid, propionic acid, oxalic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid The production method according to claim 2, wherein the production method is trifluoroacetic acid. The method according to any one of claims 2 to 11, wherein the acid is sulfuric acid, tetrafluoroboric acid or trifluoromethanesulfonic acid. The production method according to any one of claims 1 to 12, wherein R ^1a and R ^1b are a methyl group, a butyl group, or a phenyl group. The process according to any one of claims 1 to 13, wherein the reaction temperature is from 20 ° C to 100 ° C. The method according to any one of claims 1 to 14, wherein the reaction pressure is from atmospheric pressure (0.1 MPa) to 1.0 MPa. General formula (9)

[Wherein, Rf represents a perfluoroalkyl group having 1 to 6 carbon atoms, R ²² and R ²³ represent a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms, and R ²⁴ is substituted. An optionally substituted alkyl group having 1 to 6 carbon atoms, an optionally substituted amino group, or an optionally substituted alkoxy group having 2 to 5 carbon atoms is shown. However, when R ²² and R ²³ are hydrogen atoms, R ²⁴ represents an optionally substituted alkoxycarbonyl group having 2 to 5 carbon atoms. ] The 5-perfluoroalkyl uracils characterized by these. General formula (10)

[Wherein, Rf represents a perfluoroalkyl group having 1 to 6 carbon atoms, and R ²⁵ , R ²⁶ and R ²⁷ represent a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms. However, R ²⁵ , R ²⁶ and R ²⁷ are not hydrogen atoms at the same time. 8-Perfluoroalkylxanthines characterized by the above-mentioned.