MX2008006012A

MX2008006012A - Nucleic acid base having perfluoroalkyl group and method for producing the same.

Info

Publication number: MX2008006012A
Application number: MX2008006012A
Authority: MX
Inventors: Tetsu Yamakawa; Kyoko Yamamoto; Daisuke Uraguchi; Kenji Tokuhisa
Original assignee: Tosoh Corp
Priority date: 2005-11-09
Filing date: 2006-11-06
Publication date: 2008-09-11

Abstract

It is intended to provide a simple and efficient method for producing a nucleic acid base having a perfluoroalkyl group. In the presence of a sulfoxide, a peroxide and an iron compound, by reacting a halogenated perfluoroalkyl and a nucleic acid base (for example, a uracil, a cytosine, an adenine, a guanine, a hypoxanthine, a xanthine or the like), a perfluoroalkyl nucleic acid base useful as a pharmaceutical intermediate is economically produced.

Description

NUCLEOBASE THAT HAS PERFLUOROALQUILO GROUP AND PROCEDURE TO PRODUCE IT TECHNICAL FIELD The present invention relates to a process for producing a nucleobase having a perfluoroalkyl group.

BACKGROUND OF THE INVENTION Nucleobases substituted with a perfluoroalkyl group are important compounds as drugs and intermediates for obtaining medicinal and agronomic chemical agents, and nucleobases having a trifluoromethyl group are particularly useful compounds. Therefore, many studies have been carried out on the procedures for producing the nucleobases substituted with trifluoromethyl. With respect to a method for producing 5-trifluoromethyl-uracil, which is important as an intermediate for obtaining an anti-cancer agent, an antiviral agent or the like, for example, Patent Document 1 describes a method for producing 5-trifluoromethyluracil by reacting 5- trifluoromethyl-5,6-dihydrouracil, which is obtained by a reaction of α-trifluoromethyl-acrylic acid and urea, with dimethyl sulfoxide and iodine, in the presence of concentrated sulfuric acid as a catalyst. In addition, the Patent document 2 discloses a method for reacting 5-iodouracils with copper iodide and methyl fluorosulfonylldifluoroacetate, to convert them into 5-trifluoromethyluracils. In addition, patent document 3 discloses a method for producing 5-trifluoromethyluracil in which thymine is chlorinated with chlorine gas to form 2,4-dichloro-5-trichloromethylpyrimidine, and then fluorinated with anhydrous hydrofluoric acid or antimony trifluoride in conjunction with antimony pentachloride, followed by treatment with water. However, these methods have the problem that they include multiple steps and the latter method uses anhydrous hydrofluoric acid and the antimony compound, which are difficult to handle industrially. In addition, non-patent document 1 describes a method for trifluoromethylar 3 ', 5'-diacetyl-2'-deoxyhydine in the 5-position with trifluoroacetic acid and xenon difluoride. However, this method also uses a special reagent that is difficult to use industrially. In addition, with respect to a method for producing 5-trifluoromethylcytosine, non-patent document 2 describes a method for producing 5-trifluoromethylcytosine by hydrolyzing 4-amino-2-chloro-5-trifluoromethylpyrimidine, obtained by a reaction of 2,4-dichloro- 5-trifluoromethylpyrimidine and liquid ammonia, and treating it with an ion exchange resin. However, this method has the problem of multiple steps that include the production of raw materials. With respect to a method for producing a purine compound having a trifluoromethyl group, for example, the non-patent document 3 describes a method for producing 8-trifluoromethyladenine, 2,6-diamino-8-trifluoromethylpurine and 8-trifluoromethylhypoxanthine by reacting 4,5-diaminopyrimidines with trifluoroacetic acid or trifluoroacetic anhydride. Non-patent document 4 describes a method for producing 8-trifluoromethylguanine by reacting 2,4-diamino-5-trifluoroacetamino-6-oxo-1,6-dihydropyrimidine, which is obtained by a 2,4,5-triamine- 6-oxo-1, 6-dihydropyrimidine and trifluoroacetic acid, with trifluoroacetic anhydride. However, all of these methods also have the multi-step industrial scale problem that includes the production of raw materials. With respect to the direct perfluoroalkylation of these nucleobases, for example, the patent document 4 describes a method for producing purines having a perfluoroalkyl group in the 8-position or the 2-position, by reacting the purines with N, O-bis (trimethylsilyl ) trifluoroacetamide, in the presence of pyridine and trimethylchlorosilane as catalysts, and then reacting the resulting product with bis (perfluoroalkyl) peroxide. However, this method has the problem that it uses di (haloacyl) peroxide. which is difficult to handle industrially, since it uses a chlorofluorocarbon solvent and forms regioisomers with the substituent in the different positions. In addition, non-patent documents 5 and 6 disclose a method for producing salts of 5-perfluorobutyluracil, 8-perfluorobutylhipoxanthin and 8-perfluorobutylxanthine, by forming an anion of uracil electrochemically, followed by reaction with perfluorobutyl iodide. However, this method has the problem of which uses the electrochemical technique, which is difficult to use industrially and whose resulting product is a salt of a supporting electrolyte. Non-patent document 7 describes a method for producing 8-trifluoromethylcaffeine by reacting 8-trifluoromethylteophylline, obtained by a reaction of 5,6-diamino-1,3-dimethylduracil and trifluoroacetic anhydride, with potassium carbonate and methyl iodide in ?,? - dimethylformamide. However, this method has the problem on an industrial scale of multiple steps that include the production of raw materials. With respect to perfluoroalkylation with a perfluoroalkyl halide, the non-patent document 8 describes a method for obtaining trifluoromethyl nucleosides by reacting 2 ', 3', 5'-tri-0-acetylated iodonucleosides with copper powder and trifluoromethyl iodide in triamide hexamethylphosphoric, to obtain 2 ', 3', 5'-tri-0-acetylated trifluoromethylnucleosides, and followed by their deprotection. However, this method also has multi-step problems and the use of hexamethylphosphoric triamide, which is difficult to use industrially. In addition, non-patent documents 9 and 10 describe a process using perfluorobutyl iodide or perfluoropropyl iodide, which is liquid at room temperature, using dimethyl sulfoxide, hydrogen peroxide and ferric sulfate. However, the substrates are restricted to pyrroles, indoles and substituted benzenes. In addition, there is no disclosure with respect to trifluoromethylation using a perfluoroalkyl halide, which is a gas at room temperature, for example trifluoromethyl iodide.

Patent Document 1: JP-A-2001 -247551. Patent Document 2: JP-A-11-246590. Patent Document 3: JP-A-6-73023. Non-Patent Document 1: Journal of Organic Chemistry, Vol. 53, p. 4582, in 1988. Non-patent document 2: Journal of Medicinal Chemistry Vol.13, p. 151-152, in 1970. Non-patent document 3: Journal of the American Chemical Society, Vol. 80 p. 5744-5752, in 1957. Non-patent document 4: Justus Libigs Annalen der Chemie, vol. 726, p. 201-215, in 1969. Patent Document 4: JP-A-5-1066. Non-patent document 5: Tetrahedron Letters, Vol. 33, p. 7351 -7354, in 1992. Non-patent document 6: Tetrahedron, Vol. 26 p. 2655-2664, in 2000. Non-patent document 7: Journal of Medicinal Chemistry, Vol. 36, p. 2639-2644, in 1993. Non-patent document 8: Journal of the Chemical Society, Perkin Transaction, p. 2755-2761, in 1980. Non-patent document 9: Tetrahedron Letters, Vol 34, No. 23, p. 3799-3800, in 1993. Non-patent document 10: Journal of Organic Chemistry, Vol. 62, p. 7128-7136, in 1997.

BRIEF DESCRIPTION OF THE INVENTION Objective of the Invention An objective of the present invention is to provide a simple and efficient process for producing a nucleobase having a perfluoroalkyl group.

Means for carrying out the objective In order to achieve the above objective, the inventors of the present invention have carried out extensive and intensive studies, and as a result found that a nucleobase can be perfluoroalkylated in a step with a perfluoroalkyl halide, in the presence of a sulfoxide, a peroxide and an iron compound, thus producing in a very simple manner the nucleobase having a perfluoroalkyl group, in order to carry out the present invention. Particularly, the present invention has the following aspects: 1. A process for producing a nucleobase having a perfluoroalkyl group, the method comprising: performing a reaction of a nucleobase with a perfluoroalkyl halide represented by the general formula (2): Rf- X (2) wherein Rf is a perfluoroalkyl group of C1-C6 and X is a halogen atom, in the presence of a sulfoxide represented by the general formula (1): R1a-S-R1 b II 0 (1) wherein each of R1a and R1b is a C1-C12 alkyl group or an optionally substituted phenyl group, a peroxide and an iron compound. 2. The process according to aspect 1 above, wherein the reaction is carried out in the presence of an acid. 3. The process according to aspect 1 or 2 above, wherein the nucleobase are uracils represented by the general formula (3): wherein R2 is a hydrogen atom, an optionally substituted C1-C6 alkyl group, or a nitrogen protecting group, R3 is a hydrogen atom, an optionally substituted C1-C6 alkyl group, a nitrogen protecting group, or a pentose residue or analogue thereof, and R 4 is a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted amino group, a carboxy group, a carbamoyl group optionally substituted, or an optionally substituted C2-C5 alkoxycarbonyl group; cytosines represented by the general formula (4). wherein R5 is a hydrogen atom, an optionally substituted C1-C6 alkyl group, a nitrogen protecting group, or a pentose residue or analog thereof, R6 is a hydrogen atom, a C1-C6 alkyl group optionally substituted , an optionally substituted amino group, a carboxy group, an optionally substituted carbamoyl group, or an optionally substituted C2-C5 alkoxycarbonyl group, and each of R7 and R8 is a hydrogen atom or a nitrogen protecting group; Adenines represented by the general formula (5): wherein R9 is a hydrogen atom, an optionally substituted C1-C6 alkyl group, a nitrogen protecting group, or a pentose residue or analog thereof, R10 is a hydrogen atom, a substituted C1-C6 alkyl group optionally, an optionally substituted amino group, a carboxy group, an optionally substituted carbamoyl group, or an optionally substituted C2-C5 alkoxycarbonyl group, and each of R11 and R2 is a hydrogen atom or a nitrogen protecting group; guanines represented by the general formula (6): wherein R 13 is a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group or a nitrogen protecting group, R 4 is a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, a nitrogen protecting group, or a pentose residue or analogue thereof, and each of R15 and R16 is a hydrogen atom or a nitrogen protecting group; a hypoxanthine compound represented by the general formula (7): wherein R 17 is a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, or a nitrogen protecting group, and R 8 is a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, a nitrogen protecting group , or a pentose residue or analogue thereof; or xanthines represented by the general formula (8): wherein R19 is a hydrogen atom, an optionally substituted C1-C6 alkyl group, or a nitrogen protecting group; R is a hydrogen atom, a C1-C6 alkyl group optionally substituted, a nitrogen protecting group, or a pentose residue or analog thereof; and R21 is a hydrogen atom, an optionally substituted C1-C6 alkyl group, or a nitrogen protecting group. 4. The method according to aspect 3 above, wherein the nucleobase are uracils represented by the general formula (3): wherein R2, R3 and R4 are the same as defined above. 5. The process according to any of aspects 1 to 4 above, wherein X is iodine or bromine. 6. The process according to any of aspects 1 to 5 above, wherein Rf is a trifluoromethyl group or a perfluoroethyl group. 7. The process according to any of aspects 1 to 6 above, wherein the iron compound is ferric sulfate, ferric ammonium sulfate, ferric tetrafluoroborate, ferric chloride, ferric bromide, ferric iodide, ferric acetate, ferric oxalate, bis (acetylacetonate) iron (II), ferrocene, bis (n5-pentamethylcyclopentadienyl) iron, or iron powder. 8. The process according to aspect 7 above, wherein the iron compound is ferric sulfate, ferric ammonium sulfate, ferric tetrafluoroborate, ferrocene, or iron powder. 9. The process according to any of aspects 1 to 8 above, wherein the peroxide is hydrogen peroxide, a mixture of hydrogen peroxide and urea, tert-butyl peroxide or peroxyacetic acid. 10. The process according to aspect 9 above, wherein the peroxide is hydrogen peroxide, or a mixture of hydrogen peroxide and urea. 1 1. The procedure according to any of the aspects 2 to 10 above, wherein the 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 or trifluoroacetic acid. 12. The process according to aspect 1 1 above, wherein the acid is sulfuric acid, tetrafluoroboric acid, or trifluoromethanesulfonic acid. 13. The process according to any of aspects 1 to 12 above, wherein each of R1a and R1 b is a methyl group, a butyl group or a phenyl group. 14. The process according to any of aspects 1 to 13 above, wherein the reaction temperature is from 20 ° C to 100 ° C. 15. The process according to any of aspects 1 to 14 above, wherein the reaction pressure is from atmospheric pressure (0.1 MPa) to 1.0 MPa. 16. The 5-perfluoroalkyluracils represented by the general formula (9): wherein Rf is a perfluoroalkyl group of C1-C6, each of R22 and R23 is a hydrogen atom or an optionally substituted C1_6 alkyl group, and R24 is an optionally substituted C1_6 alkyl group, an optionally substituted amino group, or optionally substituted C2-C5 alkoxycarbonyl group, provided that when R22 and R23 are a hydrogen atom, R24 is an optionally substituted C2-C5 alkoxycarbonyl group. 17. The 8-perfluoroalkylxanthines represented by the general formula (10): wherein Rf is a perfluoroalkyl group of C1-C6, and each of R25, R26 and R27 is a hydrogen atom or an optionally substituted C1-C6 alkyl group, provided that R25, R26 and R27 are not all together an atom of hydrogen.

EFFECTS OF THE INVENTION The present invention makes possible the economic and high-yield production of a nucleobase having a perfluoroalkyl group, which is a compound useful as a drug or as an intermediate for obtaining medicinal and agronomic agents.

DETAILED DESCRIPTION OF THE INVENTION Next, the present invention will be described in greater detail. In the present invention, the nucleobase as a raw material and the nucleobase having a perfluoroalkyl group as a product, can be a mixture of tautomers such as a keto form and an enol form, and the present invention includes said tautomers. For convenience, in the part descriptive and in the claims of the present application are described in the keto form. Specific examples of the C 1 -C 12 alkyl group denoted by each of R 1a and R 1b include a methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopropylbutyl, dodecyl group, etc. . Specific examples of the optionally substituted phenyl group denoted by each of R 1a and R b include a phenyl group, p-tolyl, m-tolyl, o-tolyl, and the like. Each of R a and R b is preferably a methyl, butyl, dodecyl, phenyl, or p-tolyl group, preferably a methyl, butyl or phenyl group, to obtain a good yield. Specific examples of the perfluoroalkyl group of C 1 -C 6 denoted by Rf include a trifluoromethyl, perfluoroethyl, perfluoropropyl, perfluoroisopropyl, perfluorocyclopropyl, pefluoro butyl, perfluoroisobutyl, perfluoro-sec-butyl, perfluoro-tert-butyl, perfluorocyclobutyl, perfluorocyclopropylmethyl, perfluoropentyl group, perfluoro-1, 1-dimethylpropyl, perfluoro-1,2-dimethylpropyl, perfluoroneopentyl, perfluoro-1-methylbutyl, perfluoro-2-methylbutyl, perfluoro-3-methylbutyl, perfluorocyclobutylmethyl, perfluoro-2-cyclopropylethyl, perfluorocyclopentyl, perfluorohexyl, perfluoro- 1-methylpentyl, perfluoro-2-methylpentyl, perfluoro-3-methylpentyl, perfluoroisohexyl, perfluoro-1, 1-dimethylbutyl, perfluoro-1,2-dimethylbutyl, perfluoro-2,2-dimethylbutyl, perfluoro-, 3-dimethylbutyl, perfluoro -2,3-dimethylbutyl, perfluoro-3,3-dimethylbutyl, perfluoro-1-ethylbutyl, perfluoro-2-ethylbutyl, perfluoro-1,2,3-trimethylpropyl, perfluoro-1, 2,2-trimethylpropyl, perfluoro-1-et-1-methylpropyl, perfluoro-1-ethyl-2-methylpropyl, perfluoro-cyclohexyl, and the like. To obtain a good performance as a drug and a good yield, the Rf is preferably a trifluoromethyl, perfluoroethyl, perfluoropropyl, perfluoroisopropyl, perfluorobutyl, perfluoroisobutyl, perfluoro-sec-butyl, perfluoro-tert-butyl or perfluorohexyl group, preferably a trifluoromethyl or perfluoroethyl group . X is a halogen atom and specific examples thereof include a fluorine, chlorine, bromine and iodine atom. For a good yield, X is preferably an iodine atom or a bromine atom, preferably an iodine atom. Examples of the nucleobase in the present invention include uracils, pseudouracils, thymines, cytosines, adenines, guanines, hypoxanthines and xanthines, whose basic skeletons are (N-1) to (N-8), respectively, as shown in the table 1.

TABLE 1 Of these, the nucleobases uracils, cytosines, adenines, guanines, hypoxanthines or xanthines represented by the general formulas (3) to (8) are preferred, respectively, and in terms of good performance as drugs, the uracils represented by the general formula (3), among others. wherein R 2 is a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group or a nitrogen protecting group, R 3 is a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, a nitrogen protecting group, or a pentose residue or analogue thereof, R 4 is a hydrogen atom, a C 1 -C 6 alkyl group optionally substituted, a C 1 -C 4 alkoxy group optionally substituted, a group optionally substituted amino, a carboxy group, an optionally substituted carbamoyl group, or an optionally substituted C2-C5 alkoxycarbonyl group, R5 is a hydrogen atom, an optionally substituted C1-C6 alkyl group, a nitrogen protecting group, or a pentose residue or analogue thereof, R6 is a hydrogen atom, an optionally substituted C1-C6 alkyl group, an optionally substituted amino group, a carboxy group, an optionally substituted carbamoyl group, or a substituted C2-C5 alkoxycarbonyl group optionally, each of R7 and R8 is a hydrogen atom, or a nitrogen protecting group, R9 is a hydrogen atom, an optionally substituted C1-C6 alkyl group, a nitrogen protecting group, or a pentose residue or analogue thereof, R 0 is a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted amino group, a carboxy group, an optional substituted carbamoyl group or an optionally substituted C2-C5 alkoxycarbonyl group, each of R1 and R2 is a hydrogen atom, or a nitrogen protecting group, R13 is a hydrogen atom, an optionally substituted C1-C6 alkyl group, or a nitrogen protecting group, R 4 is a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, a nitrogen protecting group, or a pentose residue or analog thereof, each of R 15 and R 16 is an atom of hydrogen, or a nitrogen protecting group, R 7 is a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, or a nitrogen protecting group, R 8 is a hydrogen atom, a C 1 -C 6 alkyl group optionally substituted, a nitrogen protecting group, or a pentose residue or analogue thereof, R19 is a hydrogen atom, an optionally substituted C1-C6 alkyl group, or a nitrogen protecting group, R20 is a hydrogen atom, an alkyl group of C1-C6 optionally substituted, a nitrogen protecting group, or a pentose residue or analog thereof, and R21 is a hydrogen atom, an optionally substituted C1-C6 alkyl group, or a nitrogen protecting group. Specific examples of the optionally substituted C1-C6 alkyl group, denoted by each of R2 and R3 in the general formula (3), include a methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl group, tert-butyl, cyclobutyl, cyclopropylmethyl, pentyl, neopentyl, hexyl, cyclohexyl, and the like. In addition, each of these alkyl groups may be substituted with a halogen atom; Specific examples of the substituted alkyl group include a chloromethyl, 2-chloroethyl, 3-chloropropyl, difluoro methyl, 3-fluoropropyl, trifluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl group, and the like. Specific examples of the nitrogen protecting group denoted by each of R2 and R3 include an acetyl, propionyl, pivaloyl, propargyl, benzoyl, p-phenylbenzoyl, benzyl, p-methoxybenzyl, trityl, 4,4'-dimethoxytrityl, methoxyethoxymethyl group, phenyloxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, allyl, p-methoxyphenyl, trifluoroacetyl, methoxymethyl, 2- (trimethylsilyl) ethoxymethyl, allyloxycarbonyl, trichloroethoxycarbonyl, and the like.

Preferably, R2 is a hydrogen atom or a methyl group, to obtain a good yield. Specific examples of the pentose residue and its analogues, denoted by R3, include (P-1) to (P-401), shown in Tables 2 to 16. It should be noted that in (P-1) to (P-) 401), a bold circle is a nitrogen atom to which the nucleobase is attached, Me is a methyl group, Et is an ethyl group, Pr is a propyl group, 'Pr is an isopropyl group, Bu is a butyl group, 'Bu is a tert-butyl group, Ph is a phenyl group, TMS is a trimethylsilyl group, TBDPS is a tert-butyldiphenylsilyl group, and Ts is a tosyl group. In addition, a free hydroxyl group in the pentose residue may be protected with a generally used protecting group, such as a benzoyl, p-chlorobenzoyl, toluyl, benzyl, tert-butylcarbonyl, tert-butyldimethylsilyl, acetyl, mesyl, benzyloxycarbonyl, tertiary group. -butyldiphenylsilyl, trimethylsilyl, tosyl, tert-butylcarbonyl, p-methoxyphenylcarbonyl, p-monomethoxytrityl, di- (p-methoxy) trityl, chlorophenylcarbonyl, m-trifluoromethylcarbonyl, pivaloyl, (9-fluorenyl) methoxycarbonyl, (biphenyl-4-) il) carbonyl formyl, (2-naphthyl) carbonyl, tert-butyldimethylsilyl, triisopropylsilyl, tripropylsilyl, triphenylmethyl, butylcarbonyl, ethylcarbonyl, propylcarbonyl, nonylcarbonyl, or p-methoxyphenyl. In addition, when the hydroxyl groups exist in both position 2 'as in position 3,' can be protected together by means of an isopropylidene group or the like to form a ring. In addition, a free amino group may be protected with a generally used protecting group, such as a trifluoromethylcarbonyl, 2,4-dinitrophenyl, tosyl, acetyl, benzyloxycarbonyl, triphenylmethyl, benzoyl, benzyl, adamantylcarbonyl, butylcarbonyl, phthaloyl, tetrabromophthaloyl group. In addition, a free mercapto group can be protected with a generally used protecting group, such as a 2,4,6-triisopropylphenyl, benzoyl, benzyl or acetyl group.

TABLE 3 TABLE 4 TABLE 6 TABLE 7 TABLE 8 TABLE 9 TABLE 10 (P-226) (P-227) (P-228) (P-229) (P-262) (P-253) TABLE 11 TABLE 12 TABLE 14 TABLE 15 R3 is preferably 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), for its usefulness as a medicinal or agronomic chemical agent, or an intermediary thereof. Specific examples of the optionally substituted C 1 -C 6 alkyl group denoted by R 4 in the general formula (3) include the optionally substituted C 1 -C 6 alkyl groups mentioned in the description of R 2. Specific examples of the optionally substituted C 1 -C 4 alkoxy group include a methoxy, ethoxy, propoxy, isopropyloxy, cyclopropyloxy, butoxy, isobutyloxy, sec-butyloxy, tert-butyloxy, cyclobutyloxy, cyclopropylmethyloxy, and the like. In addition, each of these alkoxy groups may be substituted with a halogen atom, and specific examples include a chloromethoxy, 2-chloroethoxy, 3-chloropropoxy, difluoromethoxy, 3- group. fluoropropoxy, trifluoromethyloxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, and the like. Examples of the optionally substituted amino group denoted by R 4 include an amino group which may be substituted with a C 1 -C 4 alkyl group, and specific examples thereof include an amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino group , sec-butylamino, tert-butylamino,?,? - dimethylamino, N, N-diethylamino,?,? - dipropylamino, N, N-diisopropylamino,?,? -dibutylamino, N, N-diisobutylamino, N, N-di -sec-butylamino, N, N-di-tert-butylamino, and so on. In addition, the amino group may be substituted with a nitrogen protecting group, and specific examples of the substituted amino group include an acetylamino, propionylamino group, pivaloylamino, propargylamino, benzoylamino, p-phenylbenzoylamino, benzylamino, methoxybenzylamino, tritylamino, 4,4'-dimethoxytritylamino, methoxyethoxymethylamino, phenyloxycarbonylamino, benzyloxycarbonylamino, tert-butoxycarbonylamino, 9-fluorenylmethoxy-carbonylamino, allylamino, p-methoxyphenylamino, trifluoroacetylamino, methoxymethylamino, 2- (trimethylsilyl) ethoxymethylamino, allyloxycarbonylamino, trichloroethoxycarbonylamino, and the like. An example of the substituted carbamoyl group optionally denoted by R 4 includes a carbamoyl group which may be substituted with a C 1 -C 4 alkyl group at the nitrogen atom, and specific examples thereof include a carbamoyl group, N-methylcarbamoyl, N-ethylcarbamoyl , N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, ?,? - dimethylcarbamoyl,?,? - diethylcarbamoyl,?,? - dipropylcarbamoyl,?,? - diisopropylcarbamoyl,?,? - dibutylcarbamoyl, and the like. Specific examples of the optionally substituted C2-C5 alkoxycarbonyl group denoted by R4 include a methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropyloxycarbonyl, butylcarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, tert-butyloxycarbonyl group, and the like. In addition, each of these alkoxycarbonyl groups may be substituted with a halogen atom; Specific examples of the substituted alkoxycarbonyl group include a 2-chloroethoxycarbonyl, 3-chloropropyloxycarbonyl, difluoromethoxycarbonyl, 3-fluoropropyloxycarbonyl, trifluoromethoxycarbonyl, 2-fluoroethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 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, to obtain a good yield. Specific examples of the optionally substituted C 1 -C 6 alkyl group denoted by R 5 in the general formula (4) include the optionally substituted C 1 -C 6 alkyl groups mentioned in the description of R 2. Specific examples of the nitrogen protecting group denoted by R5 include the nitrogen protecting groups mentioned in the description of R2. Specific examples of the pentose residues and their analogs, denoted by R5, include (P-1) to (P-401) mentioned in the description of R3. R5 is preferably a hydrogen atom, a group methyl, (P-34), (P-35), (P-75), (P-100), (P-101), (P-123), (P-152), (P-153), (P-314), or (P-315), for its usefulness as a medicinal or agronomic chemical agent, or an intermediary thereof. Specific examples of the optionally substituted C 1 -C 6 alkyl group denoted by R 6 in the general formula (4) include the optionally substituted C 1 -C 6 alkyl groups mentioned in the description of R 2. Specific examples of the optionally substituted amino group denoted by R6 include the optionally substituted amino groups mentioned in the description of R4. Specific examples of the optionally substituted carbamoyl group denoted by R6 include the optionally substituted carbamoyl groups mentioned in the description of R4. Specific examples of the optionally substituted C2-C5 alkoxycarbonyl group denoted by R6 include the optionally substituted C2-C5 alkoxycarbonyl groups mentioned in the description of R4. R6 is preferably a hydrogen atom, a 2-chloroethyl, amino, tert-butoxycarbonylamino or carboxy group, to obtain a good yield. Specific examples of the nitrogen protecting group denoted by each of R7 and R8 in the general formula (4) include the nitrogen protecting groups mentioned in the description of R2. Each of R7 and R8 is preferably a hydrogen atom or an acetyl group, to obtain a good yield. Specific examples of the optionally substituted C 1 -C 6 alkyl group denoted by R 9 in the general formula (5) include the groups optionally substituted C1-C5 alkyl mentioned in the description of R2. Specific examples of the nitrogen protecting group denoted by R9 include the nitrogen protecting groups mentioned in the description of R2. Specific examples of the pentose residues and their analogues denoted by R9 include (P-1) to (P-401) mentioned in the description of R3. Preferably, R9 is a hydrogen atom, a methyl group, (P-34), (P-35) (P-75), (P-100), (P-101), (P-123), (P -152), (P- 53), (P-314), or (P-315), for their usefulness as medicinal or agronomic chemical agents, or intermediates thereof. Specific examples of the optionally substituted C 1 -C 6 alkyl group denoted by R 10 in the general formula (5) include the optionally substituted substituted C 1 -C 6 alkyl groups in the description of R2. Specific examples of the optionally substituted amino group denoted by R 10 include the optionally substituted amino groups mentioned in the description of R 4. Specific examples of the optionally substituted carbamoyl group denoted by R 10 include the optionally substituted carbamoyl groups mentioned in the description of R 4. Specific examples of the optionally substituted C2-C5 alkoxycarbonyl group denoted by R10 include the optionally substituted C2-C5 alkoxycarbonyl groups mentioned in the description of R4. Preferably, R10 is a hydrogen atom, a 2-chloroethyl, amino, tert-butoxycarbonylamino, or carboxy group, to obtain a good yield. Specific examples of the nitrogen protecting group denoted by each of R11 and R12 in the general formula (5), include the nitrogen protecting groups mentioned in the description of R2. Preferably, each of R11 and R12 is a hydrogen atom or an acetyl group, to obtain a good yield. Specific examples of the optionally substituted C 1 -C 6 alkyl group denoted by R 13 in the general formula (6) include the optionally substituted C 1 -C 6 alkyl groups mentioned in the description of R 2. Specific examples of the nitrogen protecting group denoted by R13 include the nitrogen protecting groups mentioned in the description of R2. R13 is preferably a hydrogen atom or a methyl group, to obtain a good yield. Specific examples of the optionally substituted C 1 -C 6 alkyl group denoted by R 4 in the general formula (6) include the optionally substituted C 1 -C 6 alkyl groups mentioned in the description of R 2. Specific examples of the nitrogen protecting group denoted by R 14 include the nitrogen protecting groups mentioned in the description of R 2. Specific examples of the pentose residues and their analogs denoted by R 14 include (P-1) to (P-401), mentioned in the description of R 3. R 14 is preferably 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), for their usefulness as medicinal or agronomic chemical agents, or intermediates thereof. Specific examples of the nitrogen protecting group denoted by each of R15 and R16 in the general formula (6), include the nitrogen protecting group mentioned in the description of R2. Each of R15 and R16 is preferably a hydrogen atom or an acetyl group, to obtain a good yield. Specific examples of the optionally substituted C 1 -C 6 alkyl group denoted by R 7 in the general formula (7) include the optionally substituted C 1 -C 6 alkyl groups mentioned in the description of R 2. Specific examples of the nitrogen protecting group denoted by R17 include the nitrogen protecting groups mentioned in the description of R2. Preferably, R17 is a hydrogen atom or a methyl group, to obtain a good yield. Specific examples of the optionally substituted C 1 -C 6 alkyl group denoted by R 18 in the general formula (7) include the optionally substituted C 1 -C 6 alkyl groups mentioned in the description of R 2. Specific examples of the nitrogen protecting group denoted by R18 include the nitrogen protecting groups mentioned in the description of R2. Specific examples of the pentose residues and their analogs denoted by R18 include (P-1) to (P-401) mentioned in the description of R3. R 8 is preferably 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-3 5), for their usefulness as medicinal or agronomic chemical agents, or intermediates thereof. Specific examples of the substituted C1-C6 alkyl group optionally denoted by R19 in the general formula (8), include the optionally substituted C1-C6 alkyl groups mentioned in the description of R2. Specific examples of the nitrogen protecting group denoted by R 9 include the nitrogen protecting groups mentioned in the description of R2. Preferably, R19 is a hydrogen atom or a methyl group, to obtain a good yield. Specific examples of the optionally substituted C 1 -C 6 alkyl group denoted by R 20 in the general formula (8) include the optionally substituted C 1 -C 6 alkyl groups mentioned in the description of R 2. Specific examples of the nitrogen protecting group denoted by R20 include the nitrogen protecting groups mentioned in the description of R2. Specific examples of the pentose residues and their analogs denoted by R20 include (P-1) to (P-401) mentioned in the description of R3. R20 is preferably a hydrogen atom, a methyl group, (P-34), (P-35), (P-75), (P- 00), (P-101), (P-123), (P-152), (P-) 153), (P-314), or (P-315), for their usefulness as medicinal or agronomic chemical agents, or intermediates thereof. Specific examples of the optionally substituted C 1 -C 6 alkyl group denoted by R 2 in the general formula (8) include the optionally substituted C 1 -C 6 alkyl groups mentioned in the description of R 2. Specific examples of the nitrogen protecting group denoted by R21 include the nitrogen protecting groups mentioned in the description of R2. Preferably, R21 is a hydrogen atom or a group methyl, to obtain good performance. Specific examples of the optionally substituted C 1 -C 6 alkyl group denoted by each of R 22 or R 23 in the general formula (9) include the optionally substituted C 1 -C 6 alkyl groups mentioned in the description of R 2. Each of R22 and R23 can be any of the alkyl groups described above, preferably is a methyl or ethyl group as a function of promising physiological activity. Specific examples of the optionally substituted C 1 -C 6 alkyl group, denoted by R 24 in the general formula (9), include the optionally substituted C 1 -C 6 alkyl groups mentioned in the description of R 2. Specific examples of the optionally substituted amino group denoted by R24 include the optionally substituted amino groups mentioned in the description of R4. Specific examples of the optionally substituted C2-C5 alkoxycarbonyl group denoted by R24 include the optionally substituted C2-C5 alkoxycarbonyl groups mentioned in the description of R4. Preferably, R24 is a methyl, ethyl, amino or amino group substituted with a protecting group, for its utility as medicinal or agronomic chemical agents, or intermediates thereof. Specific examples of the optionally substituted C 1 -C 6 alkyl group denoted by each of R 25, R 26 and R 27 in the general formula (10), include the optionally substituted C 1 -C 6 alkyl groups mentioned in the description of R 2. Each of R25, R26 and R27 is preferably a methyl or ethyl group, depending on performance promising as a sustained release preparation. Next, the production method of the present invention will be described in detail. When the uracils of the general formula (3) are used as raw material, the production process is shown in the following procedure A, and 5-perfluoroalkyluracils represented by the formula (11) are obtained.

Procedure A wherein R2, R3, R4, Rf and X are the same as described above. In process A, the sulfoxides (1) can be used as the solvent as such, but it is also possible to use a solvent that does not adversely affect the reaction. Specific examples of the solvent include water,?,? -dimethylformamide, acetic acid, trifluoroacetic acid, tetrahydrate breakage, diethyl ether, ethyl acetate, acetone, 1,4-dioxane, tert-butyl alcohol, ethanol, methanol, isopropyl alcohol, trifluoroethanol, hexamethylphosphoric triamide, N-methyl-2-pyrrolidone,?,?,? ',?' - tetramethylurea,?,? '- dimethylpropyleneurea, etc., and these can be used appropriately in combination. Preferably, the solvent is water, the sulfoxides (1), or a solvent mixture of water and the sulfoxides (1), to obtain a good yield. The molar ratio of the uracils (3) to the sulfoxide (1) is preferably from 1: 1 to 1: 200, preferably from 1: 13 to 1: 100, to obtain a good yield. The molar ratio of the uracils (3) to the perfluoroalkyl halides (2) is preferably from 1: 1 to 1: 100, preferably from 1: 1.5 to 1: 10, to obtain a good yield. Examples of the peroxides include hydrogen peroxide, a mixture of hydrogen peroxide and urea, tert-butyl peroxide, peroxyacetic acid, etc., and these may be suitably used in combination. Preferably, the peroxide is hydrogen peroxide, or a mixture of hydrogen peroxide and urea, to obtain a good yield. Hydrogen peroxide can be used after dilution with water. In this case, the concentration can be from 3% to 70% by weight, but commercially available 35% by weight hydrogen peroxide can be used as such. It is more preferable to dilute the hydrogen peroxide with water of 10% to 30% by weight to obtain a good yield and safety. The molar ratio of the uracils (3) to the peroxides is preferably from 1: 0.1 to 1:10, preferably from 1: 1.5 to 1: 3, to obtain a good yield.

The iron compound is preferably an iron (II) salt to obtain a good yield, and examples thereof include inorganic acid salts such as ferric sulfate, ferric ammonium sulfate, ferric tetrafluoroborate, ferric chloride, ferric bromide and ferric iodide, and organometallic compounds such as ferric acetate, ferric oxalate, bis (acetylacetonate) iron, ferrocene and bis- (n5-pentamethylcyclopentadienyl) iron, and these may be suitably used in combination. In addition, iron powder, an iron compound (0) or iron salt (I), in combination with an oxidizing reagent such as a peroxide, can be used to generate an iron (II) salt in the system . In this case, the hydrogen peroxide used for the reaction can also be used as the oxidizing agent as such. The iron compound is preferably ferric sulfate, ferric ammonium sulfate, ferric tetrafluoroborate, ferrocene, or iron powder, to obtain a good yield. These iron compounds can be used in the solid state as such, but they can also be used in the form of a solution. When used as a solution, the solvent to be used may be any of the sulfoxides (1) and the solvents described above, and water is preferred. In this case, the concentration of the iron compound solution is preferably 0.1 mol / l to 10 mol / l, preferably 0.5 to 5 mol / l, to obtain a good yield. The molar ratio of the uracils (3) to the iron compounds is preferably from 1: 0.01 to 1: 10, preferably from 1: 0.1 to 1: 1, for get good performance The reaction can be carried out at a temperature optionally selected from the scale of 20 ° C to 100 ° C. Preferably, the temperature is from 20 ° C to 70 ° C to obtain good performance. In case of carrying out the reaction in a closed system, the reaction can be carried out under a pressure optionally selected from the scale of atmospheric pressure (0.1 MPa) to 1.0 MPa, and the reaction proceeds sufficiently even under atmospheric pressure. In addition, the atmosphere of the reaction may be an inert gas such as argon or nitrogen, but the reaction proceeds sufficiently even in an air atmosphere. When the perfluoroalkyl halides of the general formula (2) are gases at room temperature, they can be used in the gaseous state as such. In this case they can be used as a mixture of gases after being diluted with a gas such as argon, nitrogen, air, helium or oxygen, wherein the mole fraction of the perfluoroalkyl halides (2) is from 1% to 100%. When the reaction is carried out in a closed system, the perfluoroalkyl halides (2) or the gas mixture thereof can be used as a reaction atmosphere. In this case, the pressure can optionally be selected from the scale of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even under atmospheric pressure. On the other hand, the perfluoroalkyl halides (2) or the gas mixture thereof can be introduced by bubbling them into a reaction solution in an open system. In this case, the speed of introduction of the perfluoroalkyl halides (2) or the gas mixture thereof, can be selected from the scale of 1 ml / min to 200 ml / min, although it depends on the scale of the reaction, the amount of the catalyst, the temperature of reaction and the molar fraction of the perfluoroalkyl halides (2) in the gas mixture. In accordance with the process of the present invention, the desired product yield can be improved by adding an acid. Examples of the acid include inorganic acids, such as sulfuric acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, hexafluorophosphoric acid and tetrafluoroboric acid, and organic acids such as formic acid, acetic acid, propionic acid, acid oxalic, p-toluenesulfonic acid, trifluoromethanesulfonic acid and trifluoroacetic acid. These can be used appropriately in combination. It is preferable to use sulfuric acid, tetrafluoroboric acid or trifluoromethanesulfonic acid, to obtain a good yield. In addition, an acid salt of sulfuric acid can also be used. Examples of the acid salt include tetramethylammonium acid sulfate, tetraethylammonium acid sulfate, tetrabutylammonium acid sulfate, tetraphenyl phosphonium acid sulfate, and the like. These acids can be used after dilution. A solvent in this case can be selected from the sulfoxides (1) and the solvents described above, and water, and the sulfoxide compound (1) or a solvent mixture of water and the sulfoxide compound (1) is preferred.

The molar ratio of the uracils (3) to the acids is preferably from 1: 0.001 to 1: 5, preferably from 1: 0.01 to 1: 2, to obtain a good yield. There are no particular restrictions on the method of isolating the desired product from the solution after the reaction, and the desired product can be obtained by some generally used method, such as solvent extraction, column chromatography, preparative thin layer chromatography, chromatography. of preparative liquids, recrystallization and sublimation. When the cytosines of the general formula (4) are used as raw material, the production process is shown in the following procedure B, and 5-perfluoroalkylcytosines represented by the general formula (12) are obtained.

Procedure B (4) (12) wherein R5, R6, R7, R8, Rf and X are the same as described above. In process B, the sulfoxides (1) can be used as solvent as such, but it is also possible to use a solvent that does not adversely affect the reaction. Specific examples of the solvent include water, α, β-dimethylformamide, acetic acid, trifluoroacetic acid, tetrahydrofuran, diethyl ether, ethyl acetate, acetone, 1,4-dioxane, tert-butyl alcohol, ethanol, methanol, isopropyl alcohol, trifluoroethanol , hexamethylphosphoric triamide, N-methyl-2-pyrrolidone,?,?,? ',?' - tetramethylurea,?,? '- dimethylpropyleneurea, etc., and these may be suitably used in combination. Preferably, the solvent is water, the sulfoxides (1), or a solvent mixture of water and the sulfoxides (1), to obtain a good yield. The molar ratio of the cytosines (4) to the sulfoxides (1) is preferably from 1: 1 to 1: 200, preferably from 1: 10 to 1: 100, to obtain a good yield. The molar ratio of the cytosines (4) to the perfluoroalkyl halides (2) is preferably from 1: 1 to 1: 100, preferably from 1: 1.5 to 1: 10, to obtain a good yield. Examples of the peroxides include hydrogen peroxide, a mixture of hydrogen peroxide and urea, tert-butyl peroxide, peroxyacetic acid, etc., and these may be suitably used in combination. Preferably, the peroxide is hydrogen peroxide to obtain a good yield. Hydrogen peroxide can be used after dilution with water. In this case, the concentration can be from 3% to 70% by weight, but there can be used as such the commercially available 35% by weight hydrogen peroxide. It is more preferable to dilute the hydrogen peroxide with water of 10% to 30% by weight to obtain a good yield and safety. The molar ratio of the cytosines (4) to the peroxides is preferably from 1: 0.1 to 1:10, preferably from 1: 1.5 to 1: 3, to obtain a good yield. The iron compound is preferably an iron (II) salt to obtain a good yield, and examples thereof include inorganic acid salts such as ferric sulfate, ferric ammonium sulfate, ferric tetrafluoroborate, ferric chloride, ferric bromide and ferric iodide, and organometallic compounds such as ferric acetate, ferric oxalate, bis (acetylacetonate) iron, ferrocene and bis- (n5-pentamethylcyclopentadienyl) iron, and these may be suitably used in combination. In addition, iron powder, an iron compound (0) or iron salt (I), in combination with an oxidizing reagent such as a peroxide, can be used to generate an iron (II) salt in the system . In this case, the hydrogen peroxide used for the reaction can also be used as the oxidizing agent as such. The iron compound is preferably ferric sulfate to obtain a good yield. These iron compounds can be used in the solid state as such, but they can also be used in the form of a solution. When used in the form of a solution, the solvent to be used may be any of the sulfoxides (1) and the solvents described above, and Water. In this case, the concentration of the iron compound solution is preferably 0.1 mol / l to 10 mol / l, preferably 0.5 mol / l to 5 mol / l. The molar ratio of the cytosines (4) to the iron compounds is preferably from 1: 0.01 to 1: 10, preferably from 1: 0.1 to 1: 1, to obtain a good yield. The reaction can be carried out at a temperature optionally selected from the scale of 20 ° C to 100 ° C. Preferably, the temperature is from 20 ° C to 70 ° C to obtain good performance. If the reaction is carried out in a closed system, the reaction can be carried out under a pressure optionally selected from the scale of atmospheric pressure (0.1 MPa) at 1.0 MPa, and the reaction proceeds sufficiently even under atmospheric pressure. In addition, the atmosphere of the reaction may be an inert gas such as argon or nitrogen, but the reaction proceeds sufficiently even in an air atmosphere. When the perfluoroalkyl halides of the general formula (2) are gases at room temperature, they can be used in the gaseous state as such. In this case they can be used as a mixture of gases after being diluted with a gas such as argon, nitrogen, air, helium or oxygen, wherein the mole fraction of the perfluoroalkyl halides (2) is from 1% to 100%. When the reaction is carried out in a closed system, the perfluoroalkyl halides (2) or the gas mixture thereof can be used as a reaction atmosphere. In this case, the pressure it can optionally select from the scale of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even under atmospheric pressure. On the other hand, the perfluoroalkyl halides (2) or the gas mixture thereof can be introduced by bubbling them into a reaction solution in an open system. In this case, the rate of introduction of the perfluoroalkyl halides (2) or the gas mixture thereof can be selected from the scale of 1 ml / min to 200 ml / min, although it depends on the scale of the reaction, the amount of the catalyst, the reaction temperature and the mole fraction of the perfluoroalkyl halides (2) in the gas mixture. In accordance with the process of the present invention, the desired product yield can be improved by adding an acid. Examples of the acid include inorganic acids, such as sulfuric acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, hexafluorophosphoric acid and tetrafluoroboric acid, and organic acids such as formic acid, acetic acid, propionic acid, acid oxalic, p-toluenesulfonic acid, trifluoromethanesulfonic acid and trifluoroacetic acid. These can be used appropriately in combination. It is preferable to use sulfuric acid to obtain good performance. These acids can be used after dilution. A solvent in this case can be selected from the sulfoxides (1) and the solvents described above, and water, and the sulfoxides (1) or a solvent mixture of water and the sulfoxides (1) are preferred.

The molar ratio of the cytosines (4) to the acids is preferably from 1: 0.001 to 1: 5, preferably from 1: 0.01 to 1: 2, to obtain a good yield. There are no particular restrictions on the method of isolating the desired product from the solution after the reaction, and the desired product can be obtained by some generally used method, such as solvent extraction, column chromatography, preparative thin layer chromatography, chromatography. of preparative liquids, recrystallization and sublimation. When the adenines of the general formula (5) are used as raw material, the production process is shown in the following procedure C, and 8-perfluoroalkyladenines represented by the general formula (13) are obtained. (5) (13) wherein R9, R10, R11, R12, Rf and X are the same as described above.

In process C, the sulfoxides (1) can be used as solvent as such, but it is also possible to use a solvent that does not adversely affect the reaction. Specific examples of the solvent include water, α, β-dimethylformamide, acetic acid, trifluoroacetic acid, tetrahydrofuran, diethyl ether, ethyl acetate, acetone, 1,4-dioxane, tert-butyl alcohol, ethanol, methanol, isopropyl alcohol, trifluoroethanol , hexamethylphosphoric triamide, N-methyl-2-pyrrolidone,?,?,? ',?' - tetramethylurea,?,? '- dimethylpropyleneurea, etc., and these may be suitably used in combination. Preferably, the solvent is water, the sulfoxides (1), or a solvent mixture of water and the sulfoxides (1), to obtain a good yield. The molar ratio of the adenines (5) to the sulfoxides (1) is preferably from 1: 1 to 1: 200, preferably from 1: 10 to 1: 100, to obtain a good yield. The molar ratio of the adenines (5) to the perfluoroalkyl halides (2) is preferably from 1: 1 to 1: 100, preferably from 1: .5 to 1: 10, to obtain a good yield. Examples of the peroxides include hydrogen peroxide, a mixture of hydrogen peroxide and urea, tert-butyl peroxide, peroxyacetic acid, etc., and these may be suitably used in combination. Preferably, the peroxide is hydrogen peroxide to obtain a good yield. Hydrogen peroxide can be used after dilution with Water. In this case, the concentration can be from 3% to 70% by weight, but commercially available 35% by weight hydrogen peroxide can be used as such. It is more preferable to dilute the hydrogen peroxide with water of 10% to 30% by weight to obtain a good yield and safety. The molar ratio of the adenines (5) to the peroxides is preferably from 1: 0.1 to 1:10, preferably from 1: 1.5 to 1: 3, to obtain a good yield. The iron compound is preferably an iron (II) salt to obtain a good yield, and examples thereof include inorganic acid salts such as ferric sulfate, ferric ammonium sulfate, ferric tetrafluoroborate, ferric chloride, ferric bromide and ferric iodide, and organometallic compounds such as ferric acetate, ferric oxalate, bis (acetylacetonate) iron (II), ferrocene and bis- (q5-pentamethylcyclopentadienyl) -iron, and these may be suitably used in combination. In addition, iron powder, an iron compound (0) or iron salt (I), in combination with an oxidizing reagent such as a peroxide, can be used to generate an iron (II) salt in the system . In this case, the hydrogen peroxide used for the reaction can also be used as the oxidizing agent as such. The iron compound is preferably ferric sulfate to obtain a good yield. These iron compounds can be used in the solid state as such, but they can also be used in the form of a solution. When used as a solution, the solvent to be used can be any of the sulfoxides (1) and the solvents described above, and water is preferred. In this case, the concentration of the solution of the iron compound is preferably from 0.1 mol / l to 10 mol / l, preferably from 0.5 mol / l to 5 mol / l. The molar ratio of the adenines (5) to the iron compounds is preferably from 1: 0.01 to 1: 10, preferably from 1: 0.1 to 1: 1, to obtain a good yield. The reaction can be carried out at a temperature optionally selected from the scale of 20 ° C to 100 ° C. Preferably, the temperature is from 20 ° C to 70 ° C to obtain good performance. In case of carrying out the reaction in a closed system, the reaction can be carried out under a pressure optionally selected from the scale of atmospheric pressure (0.1 MPa) to 1.0 MPa, and the reaction proceeds sufficiently even under atmospheric pressure. In addition, the atmosphere of the reaction may be an inert gas such as argon or nitrogen, but the reaction proceeds sufficiently even in an air atmosphere. When the perfluoroalkyl halides of the general formula (2) are gases at room temperature, they can be used in the gaseous state as such. In this case they can be used as a mixture of gases after being diluted with a gas such as argon, nitrogen, air, helium or oxygen, wherein the mole fraction of the perfluoroalkyl halides (2) is from 1% to 100%. When the reaction is carried out in a closed system, the perfluoroalkyl halides (2) or the gas mixture thereof are They can use as a reaction atmosphere. In this case, the pressure can optionally be selected from the scale of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even under atmospheric pressure. On the other hand, the perfluoroalkyl halides (2) or the gas mixture thereof can be introduced by bubbling them into a reaction solution in an open system. In this case, the rate of introduction of the perfluoroalkyl halides (2) or the gas mixture thereof can be selected from the scale of 1 ml / min to 200 ml / min, although it depends on the scale of the reaction, the amount of the catalyst, the reaction temperature and the mole fraction of the perfluoroalkyl halides (2) in the gas mixture. In accordance with the process of the present invention, the desired product yield can be improved by adding an acid. Examples of the acid include inorganic acids, such as sulfuric acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, hexafluorophosphoric acid and tetrafluoroboric acid, and organic acids such as formic acid, acetic acid, propionic acid, acid oxalic, p-toluenesulfonic acid, trifluoromethanesulfonic acid and trifluoroacetic acid. These can be used appropriately in combination. It is preferable to use sulfuric acid to obtain good performance. These acids can be used after dilution. A solvent in this case can be selected from the sulfoxides (1) and the above-described solvents, and water, and sulfoxides (1) or a mixture are preferred. solvent of water and sulfoxides (1). The molar ratio of the adenines (5) to the acids is preferably from 1: 0.001 to 1: 5, preferably from 1: 0.01 to 1: 2, to obtain a good yield. There are no particular restrictions on the method of isolating the desired product from the solution after the reaction, and the desired product can be obtained by some generally used method, such as solvent extraction, column chromatography, preparative thin layer chromatography, chromatography. of preparative liquids, recrystallization and sublimation. When the guanines of the general formula (6) are used as raw material, the production process is shown in the following procedure D, and 8-perfluoroalkylguanines represented by the general formula (14) are obtained.

Procedure D (6) (14) wherein R13, R4, R5, R16, Rf and X are the same as described above.

In process D, the sulfoxides (1) can be used as the solvent as such, but it is also possible to use a solvent that does not adversely affect the reaction. Specific examples of the solvent include water, α, γ-dimethylformamide, acetic acid, trifluoroacetic acid, tetrahydrofuran, diethyl ether, ethyl acetate, acetone, 1,4-dioxane, tert-butyl alcohol, ethanol, methanol, alcohol sootylic acid, trifluoroethanol, hexamethylphosphoric triamide, N-methyl-2-pyrrolidone,?,?,? ',?' -tetramethylurea,?,? '-dimethylpropyleneurea, and the like, and these may be suitably used in combination. Preferably, the solvent is water, the sulfoxides (1), or a solvent mixture of water and the sulfoxides (1), to obtain a good yield. The molar ratio of the guanines (6) to the sulfoxides (1) is preferably from 1: 1 to 1: 5000, preferably from 1: 10 to 1: 3000, to obtain a good yield. The molar ratio of the guanines (6) to the perfluoroalkyl halides (2) is preferably from 1: 1 to 1: 100, preferably from 1: 1.5 to 1: 10, to obtain a good yield. Examples of the peroxides include hydrogen peroxide, a mixture of hydrogen peroxide and urea, tert-butyl peroxide, peroxyacetic acid, etc., and these may be suitably used in combination. Preferably, the peroxide is hydrogen peroxide to obtain a good yield. Hydrogen peroxide can be used after dilution with Water. In this case, the concentration can be from 3% to 70% by weight, but commercially available 35% by weight hydrogen peroxide can be used as such. It is more preferable to dilute the hydrogen peroxide with water of 10% to 30% by weight to obtain a good yield and safety. The molar ratio of the guanines (6) to the peroxides is preferably from 1: 0.1 to 1: 10, preferably from 1: 1.5 to 1: 3, to obtain a good yield. The iron compound is preferably an iron (II) salt to obtain a good yield, and examples thereof include inorganic acid salts such as ferric sulfate, ferric ammonium sulfate, ferric tetrafluoroborate, ferric chloride, ferric bromide and ferric iodide, and organometallic compounds such as ferric acetate, ferric oxalate, bis (acetylacetonate) iron (II), ferrocene and bis- (q5-pentamethylcyclopentadienyl) -iron, and these may be suitably used in combination. In addition, iron powder, an iron compound (0) or iron salt (I), in combination with an oxidizing reagent such as a peroxide, can be used to generate an iron (II) salt in the system . In this case, the hydrogen peroxide used for the reaction can also be used as the oxidizing agent as such. The iron compound is preferably ferric sulfate to obtain a good yield. These iron compounds can be used in the solid state as such, but they can also be used in the form of a solution. When used as a solution, the solvent to be used can be any of the suifoxides (1) and the solvents described above, and water is preferred. In this case, the concentration of the solution of the iron compound is preferably from 0.1 mol / l to 10 mol / l, preferably from 0.5 mol / l to 5 mol / l. The molar ratio of the guanines (6) to the iron compounds is preferably from 1: 0.01 to 1: 10, preferably from 1: 0.1 to 1: 1, to obtain a good yield. The reaction can be carried out at a temperature optionally selected from the scale of 20 ° C to 100 ° C. Preferably, the temperature is from 20 ° C to 70 ° C to obtain good performance. In case of carrying out the reaction in a closed system, the reaction can be carried out under a pressure optionally selected from the scale of atmospheric pressure (0.1 MPa) to 1.0 MPa, and the reaction proceeds sufficiently even under atmospheric pressure. In addition, the atmosphere of the reaction may be an inert gas such as argon or nitrogen, but the reaction proceeds sufficiently even in an air atmosphere. When the perfluoroalkyl halides of the general formula (2) are gases at room temperature, they can be used in the gaseous state as such. In this case they can be used as a mixture of gases after being diluted with a gas such as argon, nitrogen, air, helium or oxygen, wherein the mole fraction of the perfluoroalkyl halides (2) is from 1% to 100%. When the reaction is carried out in a closed system, the perfluoroalkyl halides (2) or the gas mixture thereof are They can use as a reaction atmosphere. In this case, the pressure can optionally be selected from the scale of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even under atmospheric pressure. On the other hand, the perfluoroalkyl halides (2) or the gas mixture thereof can be introduced by bubbling them into a reaction solution in an open system. In this case, the rate of introduction of the perfluoroalkyl halides (2) or the gas mixture thereof can be selected from the scale of 1 ml / min to 200 ml / min, although it depends on the scale of the reaction, the amount of the catalyst, the reaction temperature and the mole fraction of the perfluoroalkyl halides (2) in the gas mixture. In accordance with the process of the present invention, the desired product yield can be improved by adding an acid. Examples of the acid include inorganic acids, such as sulfuric acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, hexafluorophosphoric acid and tetrafluoroboric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid and trifluoroacetic acid. These can be used appropriately in combination. It is preferable to use sulfuric acid to obtain good performance. These acids can be used after dilution. A solvent in this case can be selected from the sulfoxides (1) and the solvents described above, and water, and sulfoxides (1) or a mixture are preferred. solvent of water and sulfoxides (1). The molar ratio of the guanines (6) to the acids is preferably from 1: 0.001 to 1: 5, preferably from 1: 0.01 to 1: 2, to obtain a good yield. There are no particular restrictions on the method of isolating the desired product from the solution after the reaction, and the desired product can be obtained by some generally used method, such as solvent extraction, column chromatography, preparative thin layer chromatography, chromatography. of preparative liquids, recrystallization and sublimation. When the hypoxanthines of the general formula (7) are used as raw material, the production process is shown in the following procedure E, and 8-perfluoroalkylhypoxanthines represented by the general formula (5) are obtained.

Procedure E (7) (15) wherein R17, R18, Rf and X are the same as described above.

In process E, sulfoxides (1) can be used as a solvent as such, but it is also possible to use a solvent that does not adversely affect the reaction. Specific examples of the solvent include water, α, β-dimethylformamide, acetic acid, trifluoroacetic acid, tetrahydrofuran, diethyl ether, ethyl acetate, acetone, 1,4-dioxane, tert-butyl alcohol, ethanol, methanol, isopropyl alcohol, trifluoroethanol , hexamethylphosphoric triamide, N-methyl-2-pyrrolidone,?,?,? ',?' - tetramethylurea,?,? '- dimethylpropyleneurea, etc., and these may be suitably used in combination. Preferably, the solvent is water, the sulfoxides (1), or a solvent mixture of water and the sulfoxides (1), to obtain a good yield. The molar ratio of the hypoxanthines (7) to the sulfoxides (1) is preferably from 1: 1 to 1: 200, preferably from 1: 10 to 1: 100, to obtain a good yield. The molar ratio of the hypoxanthines (7) to the perfluoroalkyl halides (2) is preferably from 1: 1 to 1: 100, preferably from 1: 1.5 to 1: 10, to obtain a good yield. Examples of the peroxides include hydrogen peroxide, a mixture of hydrogen peroxide and urea, tert-butyl peroxide, peroxyacetic acid, etc., and these may be suitably used in combination. Preferably, the peroxide is hydrogen peroxide to obtain a good yield. Hydrogen peroxide can be used after dilution with Water. In this case, the concentration can be from 3% to 70% by weight, but commercially available 35% by weight hydrogen peroxide can be used as such. It is more preferable to dilute the hydrogen peroxide with water of 10% to 30% by weight to obtain a good yield and safety. The molar ratio of the hypoxanthines (7) to the peroxides is preferably from 1: 0.1 to 1:10, preferably from 1: 1.5 to 1: 3, to obtain a good yield. The iron compound is preferably an iron (II) salt to obtain a good yield, and examples thereof include salts of inorganic acid such as ferric sulfate, ferric ammonium sulfate, ferric tetrafluoroborate, ferric chloride, ferric bromide and ferric iodide, and organometallic compounds such as ferric acetate, ferric oxalate, bis (acetylacetonate) iron (II), ferrocene and bis- (n5-pentamethylcyclopentadienyl) -iron, and these may be suitably used in combination. In addition, iron powder, an iron compound (0) or iron salt (I), in combination with an oxidizing reagent such as a peroxide, can be used to generate an iron (II) salt in the system . In this case, the hydrogen peroxide used for the reaction can also be used as the oxidizing agent as such. The iron compound is preferably ferric sulfate or ferrocene to obtain a good yield. These iron compounds can be used in the solid state as such, but they can also be used in the form of a solution. When used as a solution, the solvent to be used can be any of the sulfoxides (1) and the solvents described above, and water is preferred. In this case, the concentration of the iron compound solution is preferably from 0.1 mol / l to 10 mol / l, preferably from 0.5 mol / l to 5 mol / l. The molar ratio of the hypoxanthines (7) to the iron compounds is preferably from 1: 0.01 to 1: 10, preferably from 1: 0.1 to 1: 1, to obtain a good yield. The reaction can be carried out at a temperature optionally selected from the scale of 20 ° C to 100 ° C. Preferably, the temperature is from 20 ° C to 70 ° C to obtain good performance. If the reaction is carried out in a closed system, the reaction can be carried out under a pressure optionally selected from the scale of atmospheric pressure (0.1 MPa) at 1.0 MPa, and the reaction proceeds sufficiently even under atmospheric pressure. In addition, the atmosphere of the reaction may be an inert gas such as argon or nitrogen, but the reaction proceeds sufficiently even in an air atmosphere. When the perfluoroalkyl halides of the general formula (2) are gases at room temperature, they can be used in the gaseous state as such. In this case they can be used as a mixture of gases after being diluted with a gas such as argon, nitrogen, air, helium or oxygen, wherein the mole fraction of the perfluoroalkyl halides (2) is from 1% to 100%. When the reaction is carried out in a closed system, the perfluoroalkyl halides (2) or the gas mixture thereof are They can use as a reaction atmosphere. In this case, the pressure can optionally be selected from the scale of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even under atmospheric pressure. On the other hand, the perfluoroalkyl halides (2) or the gas mixture thereof can be introduced by bubbling them into a reaction solution in an open system. In this case, the rate of introduction of the perfluoroalkyl halides (2) or the gas mixture thereof can be selected from the scale of 1 ml / min to 200 ml / min, although it depends on the scale of the reaction, the amount of the catalyst, the reaction temperature and the mole fraction of the perfluoroalkyl halides (2) in the gas mixture. In accordance with the process of the present invention, the desired product yield can be improved by adding an acid. Examples of the acid include inorganic acids, such as sulfuric acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, hexafluorophosphoric acid and tetrafluoroboric acid, and organic acids such as formic acid, acetic acid, propionic acid, acid oxalic, p-toluenesulfonic acid, trifluoromethanesulfonic acid and trifluoroacetic acid. These can be used appropriately in combination. It is preferable to use sulfuric acid to obtain good performance. These acids can be used after dilution. A solvent in this case can be selected from the sulfoxides (1) and the solvents described above, and water, and sulfoxides (1) or a mixture are preferred. solvent of water and sulfoxides (1). The molar ratio of hypoxanthines (7) to acids is preferably from 1: 0.001 to 1: 5, preferably from 1: 0.01 to 1: 2, to obtain a good yield. There are no particular restrictions on the method of isolating the desired product from the solution after the reaction, and the desired product can be obtained by some generally used method, such as solvent extraction, column chromatography, preparative thin layer chromatography, chromatography. of preparative liquids, recrystallization and sublimation. When the xanthines of the general formula (8) are used as raw material, the production process is shown in the following procedure F, and 8-perfluoroalkylxanthines represented by the general formula (16) are obtained.

Procedure F (8) (16) where R 9, R 20, R 2, R f and X are the same as described above.

In process F, the sulfoxides (1) can be used as the solvent as such, but it is also possible to use a solvent that does not adversely affect the reaction. Specific examples of the solvent include water, α, β-dimethylformamide, acetic acid, trifluoroacetic acid, tetrahydrofuran, diethyl ether, ethyl acetate, acetone, 1,4-dioxane, tert-butyl alcohol, ethanol, methanol, isopropyl alcohol, trifluoroethanol , hexamethylphosphoric triamide, N-methyl-2-pyrrolidone,?,?,? ',?' - tetramethylurea,?,? '- dimethylpropyleneurea, etc., and these may be suitably used in combination. Preferably, the solvent is water, the sulfoxides (1), or a solvent mixture of water and the sulfoxides (1), to obtain a good yield. The molar ratio of the xanthines (8) to the sulfoxides (1) is preferably from 1: 1 to 1: 5000, preferably from 1: 10 to 1: 1000, to obtain a good yield. The molar ratio of the xanthines (8) to the perfluoroalkyl halides (2) is preferably from 1: 1 to 1: 100, preferably from 1: 1.5 to 1: 10, to obtain a good yield. Examples of the peroxides include hydrogen peroxide, a mixture of hydrogen peroxide and urea, tert-butyl peroxide, peroxyacetic acid, etc., and these may be suitably used in combination. Preferably, the peroxide is hydrogen peroxide to obtain a good yield. Hydrogen peroxide can be used after dilution with Water. In this case, the concentration can be from 3% to 70% by weight, but commercially available 35% by weight hydrogen peroxide can be used as such. It is more preferable to dilute the hydrogen peroxide with water of 10% to 30% by weight to obtain a good yield and safety. The molar ratio of the xanthines (8) to the peroxides is preferably from 1: 0.1 to 1:10, preferably from 1: 1.5 to 1: 3, to obtain a good yield. The iron compound is preferably an iron (II) salt to obtain a good yield, and examples thereof include inorganic acid salts such as ferric sulfate, ferric ammonium sulfate, ferric tetrafluoroborate, ferric chloride, ferric bromide and ferric iodide, and organometallic compounds such as ferric acetate, ferric oxalate, bis (acetylacetonate) iron (II), ferrocene and bis- (q5-pentamethylcyclopentadienyl) -iron, and these may be suitably used in combination. In addition, iron powder, an iron compound (0) or iron salt (I), in combination with an oxidizing reagent such as a peroxide, can be used to generate an iron (II) salt in the system . In this case, the hydrogen peroxide used for the reaction can also be used as the oxidizing agent as such. The iron compound is preferably ferric sulfate, ferric tetrafluoroborate, ferrocene, or an iron powder, to obtain a good yield. These iron compounds can be used in the solid state as such, but they can also be used in the form of a solution. When they are used in the form of a solution, the solvent to be used can be any of the sulfoxides (1) and the solvents described above, and water is preferred. In this case, the concentration of the iron compound solution is preferably 0.1 mol / l to 10 mol / l, preferably 0.5 mol / l to 5 mol / l. The molar ratio of the xanthines (8) to the iron compounds is preferably from 1: 0.01 to 1: 10, preferably from 1: 0.1 to 1: 1, to obtain a good yield. The reaction can be carried out at a temperature optionally selected from the scale of 20 ° C to 100 ° C. Preferably, the temperature is from 20 ° C to 70 ° C to obtain good performance. If the reaction is carried out in a closed system, the reaction can be carried out under a pressure optionally selected from the scale of atmospheric pressure (0.1 MPa) to 1.0 MPa., and the reaction proceeds sufficiently even under atmospheric pressure. In addition, the atmosphere of the reaction may be an inert gas such as argon or nitrogen, but the reaction proceeds sufficiently even in an air atmosphere. When the perfluoroalkyl halides of the general formula (2) are gases at room temperature, they can be used in the gaseous state as such. In this case they can be used as a mixture of gases after being diluted with a gas such as argon, nitrogen, air, helium or oxygen, wherein the mole fraction of the perfluoroalkyl halides (2) is from 1% to 100%. When the reaction is carried out in a closed system, the Perfluoroalkyl halides (2) or the gas mixture thereof can be used as a reaction atmosphere. In this case, the pressure can optionally be selected from the scale of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even under atmospheric pressure. On the other hand, the perfluoroalkyl halides (2) or the gas mixture thereof can be introduced by bubbling them into a reaction solution in an open system. In this case, the rate of introduction of the perfluoroalkyl halides (2) or the gas mixture thereof can be selected from the scale of 1 ml / min to 200 ml / min, although it depends on the scale of the reaction, the amount of the catalyst, the reaction temperature and the mole fraction of the perfluoroalkyl halides (2) in the gas mixture. In accordance with the process of the present invention, the desired product yield can be improved by adding an acid. Examples of the acid include inorganic acids, such as sulfuric acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, hexafluorophosphoric acid and tetrafluoroboric acid, and organic acids such as formic acid, acetic acid, propionic acid, acid oxalic, p-toluenesulfonic acid, trifluoromethanesulfonic acid and trifluoroacetic acid. These can be used appropriately in combination. It is preferable to use sulfuric acid or tetrafluoroboric acid to obtain a good yield. These acids can be used after dilution. A solvent in this case it can be selected from the sulfoxides (1) and the solvents described above, and water, and sulfoxides (1) or a solvent mixture of water and the sulfoxide compound (1) are preferred. The molar ratio of the xanthines (8) to the acids is preferably from 1: 0.001 to 1: 5, preferably from 1: 0.01 to 1: 2, to obtain a good yield. There are no particular restrictions on the method of isolating the desired product from the solution after the reaction, and the desired product can be obtained by some generally used method, such as solvent extraction, column chromatography, preparative thin layer chromatography, chromatography. of preparative liquids, recrystallization and sublimation. Of the compounds obtained by means of the production methods described above, the 5-perfluoroalkyluracils represented by the general formula (9) and the 8-perfluoroalkylxanthines represented by the general formula (10), are novel compounds and are expected to be used as drugs or as intermediaries of chemical medicinal and agronomic agents.

EXAMPLES The present invention will now be described in detail with reference to the examples, but it should be understood that this invention is not restricted in any way to these examples.

EXAMPLE 1 0.1 1 g (1.0 mmol) of uracil were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 2.0 ml of a solution of 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 2.1 mol / l, 0.2 ml of an aqueous solution of hydrogen peroxide 30%, and 0.3 ml of an aqueous solution of ferric sulfate 1.0 mol / l. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 5-trifluoromethyl-uracil was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 94%). The 5-trifluoromethyluracil was obtained as a white solid by preparative thin layer chromatography (0. 7 g, yield: 93%). 1 H-NMR (deuterated acetone): d 8.09 (s, 1 H), 10.5 (brs, 2H). 13C-NMR (deuterated acetone): d 104.0 (q, JCF = 32.4HZ), 1 23.6 (q, JCF = 268.2HZ), 144.2 (q, JCF = 5.9HZ), 1 50.9, 160.2. 19F-NMR (deuterated acetone): d -64.1. MS (m / z): 1 80 [M] +.

EXAMPLE 2 The formation of 5-trifluoromethyluracil was confirmed in the same manner as in Example 1 (yield according to 19F-NMR: 80%), except that an aqueous solution of 1.0 mol / L ammonium sulfate was used instead of the aqueous solution of ferric sulphate 1.0 mol / l.

EXAMPLE 3 0.1 1 g (1.0 mmol) of uracil and 0.028 g (0.5 mmol) of iron powder were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor; the atmosphere of the flask was replaced with argon. The following materials were added: 2.0 ml of dimethyl sulfoxide, 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l, and 0.2 ml of an aqueous solution of 30% hydrogen peroxide. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 5-trifluoromethyluracil was confirmed in the same manner as in Example 1 (yield according to 9F-NMR: 32%).

EXAMPLE 4 0.1 1 g (1.0 mmol) of uracil were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 0.21 ml of an aqueous solution of 42% tetrafluoroboric acid, 2.0 ml of dimethyl sulfoxide, 3.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 2.0 mol / l, 0.3 ml of a solution water of ferric tetrafluoroborate 1.0 milligrams per liter, and 0.2 ml of an aqueous solution of 30% hydrogen peroxide. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 5-trifluoromethyluracil was confirmed in the same manner as in Example 1 (yield according to 19F-NMR: 94%).

EXAMPLE 5 0.11 g (1.0 mmol) of uracil were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 3.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 2.0 mol / l, 0.12 g of a mixture of hydrogen peroxide and urea, and 0.3 ml of an aqueous solution of ferric sulfate 1 mol / l. The mixture was stirred a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 5-trifluoromethyluracil was confirmed in the same manner as in Example 1 (yield according to 19F-NMR: 70%).

EXAMPLE 6 The formation of 5-trifluoromethyluracil was confirmed in exactly the same manner as in Example 1 (yield according to 9F-NMR: 38%), except that dimethyl sulfoxide was used in place of the solution of sulfuric acid in 1 N dimethyl sulfoxide. .

EXAMPLE 7 0.11 g (1.0 mmol) of uracil were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with trifluoromethyl iodide. The following materials were added: 5.0 ml of dibutyl sulfoxide, 0.053 ml of concentrated sulfuric acid, 0.2 ml of a 30% aqueous solution of hydrogen peroxide, and 0.3 ml of an aqueous solution of ferric sulfate 1.0 mol / I. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 5-trifluoromethyluracil was confirmed by 19F-NMR with 2.2.2- Trifluoroethanol as internal standard (yield according to 19F-NMR: 0.2%).

EXAMPLE 8 0.11 g (1.0 mmol) of uracil were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with trifluoromethyl iodide. The following materials were added: 5.0 g of diphenyl sulfoxide, 0.053 ml of concentrated sulfuric acid, 0.2 ml of a 30% aqueous solution of hydrogen peroxide, and 0.3 ml of an aqueous solution of ferric sulfate 1.0 mol / l. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 5-trifluoromethyluracil was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 0.5%).

EXAMPLE 9 The formation of 5-trifluoromethyluracil was confirmed in exactly the same manner as in Example 1 (yield according to 19F-NMR: 76%), except that the reaction was carried out in an air atmosphere without replacement with argon.

EXAMPLE 10 1 .1 g (10 mmol) of uracil were weighed and placed in a 100 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 20 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 22.5 ml of dimethyl sulfoxide, 7.5 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 2.0 mol / l, 2.0 ml of an aqueous solution of 30% hydrogen peroxide, and 3.0 ml of an aqueous solution of ferric sulfate 1.0 mol / l. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 30 minutes and then the resulting solution was cooled to room temperature. The formation of 5-trifluoromethyluracil was confirmed in the same manner as in Example 1 (yield according to 19F-NMR: 94%).

EXAMPLE 11 1.1 g (10 mmol) of uracil were weighed and placed in a 100 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 0.055 ml of concentrated sulfuric acid, 9 ml of dimethyl sulfoxide, 24.5 mmol of trifluoromethyl iodide, 2.0 ml of a 30% aqueous solution of hydrogen peroxide, and 1.5 ml of an aqueous solution of ferric sulfate 1.0 mol / l. The mixture was stirred at a temperature of 60 ° C to 70 C for 10 minutes and then the resulting solution was cooled to room temperature. The formation of 5-trifluoromethyluracil was confirmed in the same manner as in Example 1 (yield according to 9F-NMR: 97%).

EXAMPLE 12 1.2 g (100 mmol) of uracil were weighed and 300 ml two-necked flask equipped with a magnetic rotor was placed, and the atmosphere in the flask was replaced with argon. The following materials were added: 80 ml of dimethyl sulfoxide, 0.55 ml of concentrated sulfuric acid, 245 mmol of trifluoromethyl iodide, 20 ml of a 30% aqueous solution of hydrogen peroxide, and 10 ml of an aqueous solution of ferric sulfate 1.5 mol / I. The mixture was stirred at a temperature of 60 ° C to 70 ° C for 100 minutes and then the resulting solution was cooled to room temperature. The formation of 5-trifluoromethyluracil was confirmed in the same manner as in Example 1 (yield according to 19F-NMR: 97%).

EXAMPLE 13 0.11 g (1.0 mmol) of uracil were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere of the flask was replaced with argon. The following materials were added: 2.0 ml of a solution of sulfuric acid in 1 N dimethyl suifoxide, 1.3 ml of tridecafluoro-1-iodohexane, 1.2 ml of dimethyl suifoxide, 0.3 ml of an aqueous solution of ferric sulfate 1.0 mol / I, and 0.2 ml of an aqueous solution of 30% hydrogen peroxide. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 5-perfluorohexyluracil was confirmed by means of 19 F-NMR with benzotrifluoride as internal standard (yield according to 19 F-NMR: 29%). The 5-perfluorohexyluracil was obtained as a white solid by column chromatography (1 .107 g, yield: 25%). 1 H-NMR (deuterated chloroform): 8.01 (d, JHF = 5.7HZ, 1 H), 1.59 (brs, 1 H), 1.80 (d, JHF = 4.8HZ, 1 H). 19 F-NMR (deuterated chloroform): d-126.1 (q, JFF = 7.0HZ, 2F), - 122.8 (brs, 2F), -122.1 (brs, 2F), - 121.2 (brs, 2F), -108.5 (m , 2F), -80.5 (t, JFF = 9.5Hz, 3F). MS (m / z): 430 [M] +.

EXAMPLE 14 0.18 g (1.0 mmol) of 6-trifluoromethyluracil and 0.058 g were weighed. (0.3 mmol) of ferrocene and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 1.8 ml dimethyl sulfoxide2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 2.1 mol / l, and 0.2 ml of a 30% aqueous solution of hydrogen peroxide. The mixture was stirred at a temperature of 60 ° C to 70 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 5,6-bis (trifluoromethyl) uracil was confirmed by means of 19 F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 9F-NMR: 63%). The 5,6-bis (trifluoromethyl) uracil was obtained as a white solid by preparative thin layer chromatography (0.12 g, yield: 48%). H-NMR (deuterated acetone): d 10.73 (brs, 2F). 13, C-NMR (deuterated acetone): d 102.5 (q, JCF = 32.7Hz), 120.6 JCF = 277.3Hz), 123.2 (q, JCF = 270.2Hz), 147.0 (q, JCF = 37.0Hz), 152.3, .2. 19, F-NMR (deuterated acetone): d -64.8 (q, JFF = 4.6Hz), -58.4 (q, JFF = 14.6Hz). MS (m / z): 248 [M] +.

EXAMPLE 15 0.17 g (1.0 mmol) of 6-methoxycarbonyluracil and 0.058 g (0.3 mmol) of ferrocene were weighed, and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 1.8 ml of dimethyl sulfoxide, 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l, and 0.2 ml. of an aqueous solution of 30% hydrogen peroxide. The mixture was stirred at a temperature of 60 ° C to 70 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 6-methoxycarbonyl-5-trifluoromethyluracil was confirmed by means of 19 F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 84%). The 6-methoxycarbonyl-5-trifluoromethyluracil was obtained as a white solid by column chromatography (0.20 g, yield: 80%). 1 H-NMR (deuterated acetone): d 3.94 (s, 3 H), 10.70 (s, 1 H), 1 .10 (brs, 1 H). 13C-NMR (deuterated acetone): d 54.5, 100.8 (q, JCF = 32.3 2Hz), 123.1 (q, JCF = 269.7Hz), 147.4 (q, JCF = 3.52Hz), 149.9, 160.1, 161.6. 19 F-NMR (deuterated acetone): d -60.6. MS (m / z): 238 [M] +.

EXAMPLE 16 0.14 g (1.0 mmol) of 1,3-dimethyluracil were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 2.0 ml of a solution of sulfuric acid in 1N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l, 0.2 ml of an aqueous solution of hydrogen peroxide to 30%, and 0.3 ml of an aqueous solution of ferric sulfate 1.0 mol / l. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 1,3-dimethyl-5-trifluoromethyluracil was confirmed by means of 19 F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 78%). The 1,3-dimethyl-5-trifluoromethyluracil was obtained as a white solid by preparative thin layer chromatography (0.12 g, yield: 44%). 1 H-NMR (deuterated acetone): d 3.25 (s, 3 H), 3.51 (s, 3 H), 8.23 (q, JHF = 1.05 Hz, 1 H). 13C-NMR (deuterated acetone): d 27.8, 37.6, 102.9 (q, JCF = 32.2 Hz, 123.8 (q, JCF = 268.4Hz), 146.4 (q, JCF = 5.91 Hz), 151.9, 159.5, 19F-NMR ( deuterated acetone): d -60.6 MS (m / z): 208 [M] +.

EXAMPLE 17 0.16 g (1.0 mmol) of 6-amino-1,3-dimethyluracil were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 2.1 mol / l, 0.2 ml of an aqueous solution of hydrogen peroxide to 30%, and 0.3 ml of an aqueous solution of ferric sulfate 1.0 mol / l. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 6-amino-1,3-dimethyl-5-trifluoromethyluracil was confirmed by means of 19F-NMR with 2,2,2-trifluoroethanol as standard. internal (yield according to 9F-RMN: 95%). The 6-amino-1,3-dimethyl-5-trifluoromethyluracil was obtained as a white solid by column chromatography (0.20 g, yield: 95%). H-NMR (deuterated chloroform): d 3.29 (s, 3H), 3.53 (s, 3H), 6. 20 (s, 2H). 13 C-NMR (deuterated chloroform): d 28.0, 29.7, 80.5 (q, JCF = 30.2HZ), 125.5 (q, JCF = 269.1 Hz), 1 50.4, 1 53.2, 1 59.8. 9F-NMR (deuterated chloroform): d -54.9. MS (m / z): 223 [M] +.

EXAMPLE 18 0.26 g (1.0 mmol) of 6-tert-butoxycarbonylamino-1,3-dimethyluracil were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 2.1 mol / l, 0.2 ml of an aqueous solution of peroxide of hydrogen at 30%, and 0.3 ml of an aqueous solution of ferric sulfate 1.0 moles / I. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 6-tert-butoxycarbonylamino-1,3-dimethyl-5-trifluoromethyluracil was confirmed by means of 9F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 95%). The 6-tert-butoxycarbonylamino-1,3-dimethyl-5-trifluoromethyluracil was obtained as a white solid by column chromatography (0.30 g, yield: 93%). 1 H-NMR (deuterated chloroform): d 1.51 (s, 9H), 3.32 (s, 3H), 3.46 (s, 3H), 6.89 (brs, 1 H). 13 C-NMR (deuterated chloroform): d 27.9, 28.5, 32.2, 84.2, 98.4 (q, JCF = 22.8HZ), 122.8 (q, JCF = 271.5Hz), 147.5, 150.6, 151.3, 158.6. 19F-NMR (deuterated chloroform): d -54.8. MS (m / z): 250 [M-OC4H9] +.

EXAMPLE 19 0.16 g (1.0 mmol) of 6- (2-chloromethyl) uracil and 0.058 g (0.3 mmol) of ferrocene were weighed, and placed in a 50-ml two-necked flask equipped with a magnetic rotor, and the atmosphere of the flask it was replaced with argon. The following materials were added: 1.8 ml of dimethyl sulfoxide, 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1. 0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 2.1 mol / l and 0.2 ml of a 30% aqueous solution of hydrogen peroxide. The mixture was stirred at a temperature of 60 ° C to 70 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 6- (2-chloromethyl) -5-trifluoromethyluracil was confirmed by means of 19 F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 55%). 6- (2-Chloromethyl) -5-trifluoromethyluracil was obtained as a white solid by preparative thin layer chromatography (0.10 g, yield: 45%). 1 H-NMR (deuterated dimethyl sulfoxide): d 4.47 (s, 2 H), 1 1 .78 (brs, 1 H), 1 1 .82 (brs, 1 H). 13 C-NMR (deuterated dimethyl sulfoxide): d 38.8, 100.9 (q, JCF = 30.7HZ), 123.6 (q, JCF = 270.9HZ), 150.3, 153.9, 160.9. 19 F-NMR (deuterated dimethyl sulfoxide): d -56.5. MS (m / z): 228 [M] +.

EXAMPLE 20 0.17 g (1.0 mmol) of 6-carboxyuracil and 0.058 g (0.3 mmol) of ferrocene were weighed and placed in a 50 ml two-necked flask. equipped with a magnetic rotor, and the atmosphere of the flask was replaced with argon. The following materials were added: 1.8 ml of dimethyl sulfoxide, 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l and 0.2 ml of a aqueous solution of 30% hydrogen peroxide. The mixture was stirred at a temperature of 60 ° C to 70 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 6-carboxy-5-trifluoromethyluracil was confirmed by means of 9F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 9F-NMR: 95%). The 6-carboxy-5-trifluoromethyluracil was obtained by column chromatography (0.076 g, yield: 34%). H-NMR (deuterated dimethyl sulfoxide): d 1 1 .71 (brs, 1 H), 12.13 (brs, 1 H). 13 C-NMR (deuterated dimethyl sulfoxide): d 97.2 (q, JCF = 31.5Hz), 122.9 (q, JCF = 269.9HZ), 149.8, 150.3, 160.6, 162.3. 19 F-NMR (deuterated dimethyl sulfoxide): d-58.6. MS (m / z): 223 [M-H] +.

EXAMPLE 21 0.24 g (1.0 mmol) of uridine were weighed and placed in a 50 ml two neck flask equipped with a magnetic rotor, and the atmosphere of the flask was replaced with argon. The following materials were added: 1.5 ml of dimethyl sulfoxide, 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l, 0.3 ml of an aqueous solution of ferric sulfate 1 mol / l, and 0.2 ml of an aqueous solution of 30% hydrogen peroxide. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 5-trifluoromethyluridine was confirmed by means of 9F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 51%). The 5-trifluoromethyluridine was obtained by column chromatography (0.071 g, yield: 23%). 1 H-NMR (deuterated dimethyl sulfoxide): d 2.84 (brs, 3H), 3.88 (m, 3H), 4.60 (m, 1 H), 4.32 (d, J = 13.6Hz, 2H), 4.60 (brs, 1 H), 5.88 (d, J = 13.6Hz, 1 H), 8.88 (s) , 1 HOUR). 19 F-NMR (deuterated dimethyl sulfoxide): d-61 .8.

EXAMPLE 22 Weighed 0.37 g (1.0 mmol) of 2 '> 3'.5'-tri-0-acetyluridine and 0.058 g (0.3 mmol) of ferrocene were placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 1.8 ml of dimethyl sulfoxide, 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 2.1 mol / l, and 0.2 ml. of an aqueous solution of 30% hydrogen peroxide. The mixture was stirred at a temperature of 60 ° C to 70 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 5-tnfluoromethyl-2 ', 3', 5'-tri-0-acetyluridine was confirmed by means of 19F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 45% ). The 5-trifluoromethyl-2 ', 3', 5'-tri-O-acetyluridine was obtained as a white solid by column chromatography (0.17 g, yield: 40%). H-NMR (deuterated chloroform): d 2.1 1 (s, 3 H), 2.13 (s, 3 H), 2.14 (s, 3 H), 4.34 (d, J = 13.6 Hz, 1 H), 4.43 (m, 1 H) ), 4.43 (dd, J = 3.2 Hz, 13.6 Hz, 1 H), 5.34 (t, J = 5.4 Hz, 1 H), 5.37 (t, J = 5.4 Hz, 1 H), 6.07 (d, J = 5.4Hz, 1 H), 8.01 (s, 1 H), 9.48 (s, 1 H). 13C-NMR (deuterated chloroform): d 20.3, 20.4, 62.7, 69.9, 73.2, 80.5, 87.7, 106.2 (q, JCF = 33.3Hz), 121.6 (q, JCF = 270.3Hz), 140.2 (q, JCF = 6.0) HZ), 149.3, 158.0, 169.6, 169.7, 170.2. 9F-NMR (deuterated chloroform): d -64.0.

EXAMPLE 23 0.23 g (1.0 mmol) of 2'-deoxyuridine were weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 2.1 mol / l, 0.2 ml of an aqueous solution of hydrogen peroxide to 30%, and 0.3 ml of an aqueous solution of ferric sulfate 1.0 mol / l. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 5-trifluoromethyl-2'-deoxyuridine was confirmed by means of 19 F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 85%). The 5-trifluoromethyl-2'-deoxyuridine was obtained as a white solid by column chromatography (0.17 g, yield: 58%). H-NMR (deuterated chloroform): d 2.35 (ddd, J = 6.10Hz, 6.25Hz, 13.53Hz, 1H), 2.39 (ddd, J = 3.61Hz, 6.25Hz, 13.53Hz, 1H), 3.86 (dd) , J = 1 1 .7Hz, 15.3 Hz, 2H), 4.02 (dd, J = 3.61 Hz, 6.10Hz, 1 H), 4.46 (brs, 2H), 4.53 (brs, 1 H), 6.27 (t, J) = 6.25Hz, 1 H), 8.84 (s, 1 H), 10.45 (s, 1 H). 13 C-NMR (deuterated chloroform): d 42.0, 62.0, 71.4, 86.9, 89.0, 104.5 (q, JCF = 32.4Hz), 123.7 (q, JCF = 268.6Hz) 143.1 (q, JCF = 5.66HZ), 150.5, 159.4. 9F-NMR (deuterated chloroform): d -63.7.

EXAMPLE 24 0.32 g (1.0 mmol) of 3 ', 5'-di-0-acetyl-2'-deoxyuridine and 0.058 g (0.3 mmol) of ferrocene were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere of the flask was replaced with argon. The following materials were added: 1.8 ml of dimethyl sulfoxide, 2.0 ml of a sulfuric acid sulfoxide solution. 1 N dimethyl, 1.0 mi of a solution of trifluoromethyl iodide in dimethyl sulfoxide 2.1 mol / l, and 0.2 ml of a 30% aqueous solution of hydrogen peroxide. The mixture was stirred at a temperature of 60 ° C to 70 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of S-trifluoromethyl-S'-S'-di-O-acetyl-deoxyuridine was confirmed by means of 9F-NMR with trifluoroethanol as internal standard (yield according to 19F-NMR: 75%). 5-Trifluoromethyl-3 \ 5'-d¡-0-acetyl-2'-deoxyuridine was obtained as a white solid by column chromatography (0.19 g, yield: 50%). 1 H-NMR (deuterated chloroform): d 2.10 (s, 3H), 2.13 (s, 3H), 2.19 (ddd, J = 6.63Hz, 8.00Hz, 14.34Hz, 1H), 2.63 (ddd, J = 1.96Hz , 5.72 Hz, 14.34Hz, 1 H), 4.28-4.37 (m, 2H), 4.44 (dd, J = 2.66Hz, 1 1 .77Hz, 1 H), 5.23 (td, J = 1.96Hz, 6.63Hz , 1 H), 6.28 (dd, J = 5.72Hz, 8.00Hz, 1 H), 8.09 (s, 1 H), 9.27 (s, 1 H). 3C-NMR (deuterated chloroform): d 20.5, 20.9, 38.7, 63.7, 74.0, 83.1, 86.1, 105.7 (q, JCF = 33.3HZ), 121.7 (q, JCF = 270.2HZ), 140.0 (q, JCF) = 5.91 Hz), 149.2, 158.1, 170.2, 170.4. 9F-NMR (deuterated chloroform): d -63.7.

EXAMPLE 25 0.1 1 g (1.0 mmol) of cytosine was weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 2.0 ml of dimethyl sulfoxide, 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l, 0.2 mi of an aqueous solution of 30% hydrogen peroxide, and 0.3 ml of an aqueous solution of ferric sulfate 1.0 mol / l. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 5-trifluoromethyl-cytosine was confirmed by means of 19 F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 27%). The 5-trifluoromethylcytosine was obtained as a white solid by column chromatography (0.010 g, yield: 5.6%). H-NMR (deuterated dimethyl sulfoxide): d 6.95 (brs, 2H), 7.72 (brs, 2H), 7.95 (s, 1 H). 3C-NMR (deuterated dimethyl sulfoxide): d 94.3 (q, JCF = 33.5HZ), 124.2 (q, JCF = 268.7HZ), 145.8, 1 56.0, 1 61.5. 9F-NMR (deuterated dimethyl sulfoxide): d -60.8.

MS (m / z): 181 [M] +.

EXAMPLE 26 0.15 g (1.0 mmol) of N4-acetylcytosine was weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 17 ml of dimethyl sulfoxide, 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l, 0.2 ml of an aqueous solution of 30% hydrogen peroxide, and 0.3 ml of an aqueous solution of ferric sulphate 1.0 mol / l. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of N 4 -acetyl-5-trifluoromethylcytosine was confirmed by means of 19 F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19 F-NMR: 35%). The N 4 -acetyl-5-trifluoromethylcytosine was obtained as a white solid by column chromatography (0.067 g, yield: 30%). 1 H-NMR (deuterated dimethyl sulfoxide): d 2.56 (s, 3H), 8.04 (s, 1 H), 1 1 .58 (brs, 2H). 13C-NMR (deuterated dimethyl sulfoxide): d 23.0, 102.3 (q, JCF = 31.9Hz), 123.4 (q, JCF = 268.8HZ), 144.7 (q, JCF = 5.6Hz), 151.2, 160.5, 172.1 . 9F-NMR (deuterated dimethyl sulfoxide): d-61 .8. MS (m / z): 224 [M + Hf.

EXAMPLE 27 0.24 g (1.0 mmol) of cytidine were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 4.0 ml of dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l, 0.3 ml of an aqueous solution of ferric sulphate 1.0 mol / l, and 0.2 Mi from an aqueous solution of 30% hydrogen peroxide. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 5-trifluoromethylcytidine was confirmed by means of 19 F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 24%). The 5-trifluoromethylcytidine was obtained by column chromatography (0.034 g, yield: 11%). 1 H-NMR (deuterated dimethyl sulfoxide): d 3.52 (m, 1 H), 3.70 (m, 1 H), 3.96 (m, 3 H), 5.00 (d, J = 13.6 Hz, 1 H), 5.28 (t , J = 5.4 Hz, 1 H), 5.48 (d, J = 13.6 Hz, 1 H), 5.76 (m, 1 H), 7.16 (brs, 1 H), 7.72 (brs 2 H), 8.84 (s, 1 HOUR). 19 F-NMR (deuterated dimethyl sulfoxide): d -60.9.

EXAMPLE 28 0.15 g (1.0 mmol) of 2'-deoxycytidine were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 2.0 ml of dimethyl sulfoxide, 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l, 0.2 ml of an aqueous solution of 30% hydrogen peroxide, and 0.3 ml of an aqueous solution of ferric sulfate 1.0 mol / l. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. ambient. The formation of 5-trifluoromethyl-2'-deoxycytidine was confirmed by means of 19 F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 11%). The 5-trifluoromethyl-2'-deoxycytidine was obtained as a white solid by column chromatography (0.01 g, yield: 3.3%). 1 H-NMR (deuterated dimethyl sulfoxide): d 2.16 (m, 2H), 3.62 (m, 2H), 3.82 (m, 1 H), 4.20 (m, 1 H), 5.06 (d, J = 12.5Hz, 1 H), 5.19 (d, J = 12.5 Hz, 1 H), 6.04 (t, J = 5.6 Hz, 1 H), 7.04 (brs, 1 H), 7.64 (brs, 2 H), 8.60 (s, 1 H). 9F-NMR (deuterated dimethyl sulfoxide): d -60.8.

EXAMPLE 29 0.13 g (1.0 mmol) of adenine were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 2.0 ml of dimethyl sulfoxide, 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l, 0.2 mi of an aqueous solution of 30% hydrogen peroxide, and 0.3 ml of an aqueous sulphate solution Ferric 1.0 mol / l. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 8-trifluoromethyladenine was confirmed by means of 19 F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 26%). The 8-trifluoromethyladenine was obtained as a white solid by preparative thin layer chromatography (0.02 g, yield: 10%). 1 H-NMR (deuterated dimethyl sulfoxide): d 8.31 (s, 1 H), 14.08 (brs, 2H). 13 C-NMR (deuterated dimethyl sulfoxide): d 1 19.9, 121.0 (q, JCF = 270.2HZ), 147.1, 150.9, 156.8. 19 F-NMR (deuterated dimethyl sulfoxide): d -62.9. MS (m / z): 203 [M] +.

EXAMPLE 30 0.27 g (1.0 mmol) of adenosine were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 4.0 ml of dimethyl sulfoxide, 1.0 ml of an iodide solution of trifluoromethyl in dimethyl sulfoxide 3.0 mol / l, 0.3 ml of an aqueous solution of ferric sulfate 1.0 mol / l, and 0.2 ml of an aqueous solution of 30% hydrogen peroxide. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 8-trifluoromethyladenosine was confirmed by means of 9F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 6.7%). The 8-trifluoromethyladenosine was obtained as a white solid by column chromatography (0.01 g, yield: 3.1%). 1 H-NMR (deuterated dimethyl sulfoxide): d 3.62 (m, 2H), 4.04 (m, 1 H), 4.23 (m, 1 H), 5.05 (dd, 1 H), 5.24 (m, 1 H), 5.52 (m, 2H), 5.81 (d, 1 H), 7.92 (brs, 2H) 8.24 (s, 1 H). 19 F-NMR (deuterated dimethyl sulfoxide): d -60.2.

EXAMPLE 31 0.15 g (1.0 mmol) of 2,6-diaminopurine were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 4.0 ml of dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l, 0.3 ml of an aqueous solution of ferric sulfate 1.0 mol / l, and 0.2 ml of an aqueous solution of 30% hydrogen peroxide. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 2,6-diamino-8-trifluoromethylpurine was confirmed by means of 19 F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 45%). The 2,6-diamino-8-trifluoromethylpurine was obtained as a white solid by column chromatography (0.050 g, yield: 23%). 1 H-NMR (deuterated dimethyl sulfoxide): d 6.1 7 (s, 2H), 7.26 (s, 2H), 12.2 (brs, 1 H). 13 C-NMR (deuterated dimethyl sulfoxide): d 1 14.8, 1 16.0 (q, JCF = 269.1 HZ), 144.3, 1 52.7, 157.0, 161 .7. 19 F-NMR (deuterated dimethyl sulfoxide): d -62.6. MS (m / z): 218 [M] +.

EXAMPLE 32 0.1 g (1.0 mmol) of 2,6-diaminopurine were weighed and placed in a 50 ml two-necked flask equipped with a rotor magnetic, and the atmosphere of the flask was replaced with argon. The following materials were added: 3.0 ml of dimethyl sulfoxide, 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.3 ml of tridecafluoro-1-iodohexane, 0.3 ml of an aqueous solution of ferric sulfate 1.0 mol / I, and 0.2 ml of an aqueous solution of 30% hydrogen peroxide. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 2,6-diamino-8-perfluorohexylpurine was confirmed by means of 9F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 10%). The 2,6-diamino-8-perfluorohexylpurine was obtained as a white solid by column chromatography (0.018 g, yield: 4.0%). 1 H-NMR (deuterated dimethyl sulfoxide): d 6.20 (s, 2 H), 7.31 (s, 2 H), 12.2 (brs, 1 H). 9F-NMR (deuterated dimethyl sulfoxide): d -126.2 (q, 2F), -122.9 (brs, 2F), -121.9 (m, 4F), -108.9 (m, 2F), -80.7 (t, JFF = 9.5Hz, 3F). MS (m / z): 469 [M + H] +.

EXAMPLE 33 0.15 g (1.0 mmol) of guanine were weighed and placed in a 500 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 197 ml of dimethyl sulfoxide, 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l, 0.2 ml of an aqueous solution of 30% hydrogen peroxide, and 0.3 ml of an aqueous solution of ferric sulfate 1.0 mol / l. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 8-trifluoromethylguanine was confirmed by means of 19 F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 46%). The 8-trifluoromethylguanine was obtained as a white solid by column chromatography (0.019 g, yield: 9%). H-NMR (deuterated dimethyl sulfoxide): d 6.60 (brs, 2H), 10.81 (brs, 1 H), 13.73 (brs, 1 H). 13, C-NMR (deuterated dimethyl sulfoxide): d 1 16.3, 1 19.2 (q, 269. 3Hz), 134.9 (q, JCF = 40.7HZ), 152.8, 154.7, 156.6. 19 F-NMR (deuterated dimethyl sulfoxide): d -63.0.

MS (miz): 218 [M-H] \ EXAMPLE 34 0.41 g (1.0 mmol) of 2 ', 3', 5'-tr'-0-acetylguanosine were weighed and placed in a two-necked 50 ml flask equipped with a magnetic rotor, and the atmosphere of the flask was replaced with argon. The following materials were added: 2.0 ml of dimethyl sulfoxide, 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l, 0.3 ml of an aqueous solution of ferric sulfate 1.0 mol / l, and 0.2 ml of an aqueous solution of 30% hydrogen peroxide. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 8-tnfluoromethyl-2 ', 3', 5'-tri-0-acetylguanosine was confirmed by means of 19F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 9F-NMR: 51% ). The 8-trifluoromethyl-2 ', 3', 5'-tri-O-acetylguanosine was obtained as a yellow solid by column chromatography on silica gel (0.22 g, yield: 47%).

H-NMR (deuterated chloroform): d 2.03 (s, 3H), 2.13 (s, 3H), 2.16 (s, 3H), 4.30 (m, 1 H), 4.44 (m, 2H), 5.87 (t, JFF = 5.0HZ, 1H), 5.94 (d, J = 5.0Hz, 1H), 6.47 (brs, 2H), 12.1 (s, 1 H). 13C-NMR (deuterated chloroform): d 20.3, 20.5, 20.6, 62.9, 70.6, 71.6, 77.2, 80.6, 1 16.4, 1 18.3 (q, JCF = 270.5HZ), 152.6, 154.6, 158.9, 169.5, 169.5, 170.8 . 19F-NMR (deuterated chloroform): d -61.5.

EXAMPLE 35 0.39 g (1.0 mmol) of 2 ', 3', 5'-tri-0-acetylinosine was weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor., and the atmosphere of the flask was replaced with argon. The following materials were added: 5.0 ml of dimethyl sulfoxide, 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l, 0.3 ml of an aqueous solution of ferric sulfate 1.0 mol / l, and 0.2 ml of an aqueous solution of 30% hydrogen peroxide. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the solution The resultant was cooled to room temperature. The formation of 8-trifluoromethyl-2 ', 3', 5'-tri-O-acetylosin was confirmed by means of 19F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 7% ). The 8-trifluoromethyl-2 ', 3', 5'-tri-O-acetylosin was obtained by column chromatography (0.08 g, yield: 4.0%). 1 H-NMR (deuterated dimethyl sulfoxide): d 2.08 (s, 6H), 2.16 (s, 3H), 4.35-4.45 (m, 2H), 4.51 (dd, J = 3.6Hz, 11.3Hz, 1 H), 5.73 (dd, J = 5.5Hz, 5.6Hz, 1 H), 6.08 (d, J = 5.5Hz, 1 H), 6.27 (dd, J = 5.6Hz, 1 H), 8.26 (s, 1 H), 12.49 (brs, 1 H). 13 C-NMR (deuterated dimethyl sulfoxide): d 20.2, 20.5, 20.7, 62. 8, 70.3, 72.0, 80.7, 88.0, 118.1 (q, JCF = 271.7Hz), 124.2, 138.2 (q, JCF = 40.7Hz), 147.2, 150.1, 158.6, 169.2, 169.5, 170.5. 19 F-NMR (deuterated dimethyl sulfoxide): d -61.5.

EXAMPLE 36 0.14 g (1.0 mmol) of hypoxanthine and 0.058 g (0.3 mmol) of ferrocene were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 2.0 ml sulfoxide dimethyl, 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l, and 0.2 ml of an aqueous solution of 30% hydrogen peroxide. %. The mixture was stirred at a temperature of 60 ° C to 70 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 8-trifluoromethylhypoxanthine was confirmed by means of 9F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 9F-NMR: 24%). The 8-trifluoromethylhypoxanthine was obtained by column chromatography (0.026 g, yield: 13%). H-NMR (deuterated dimethyl sulfoxide): d 8.13 (s, 1 H), 12.52 (s, 1 H), 14.89 (brs, 1 H). 3C-NMR (deuterated dimethyl sulfoxide): d 1 19.0 (q, JCF = 270.1 HZ), 122.6, 138.0 (q, JCF = 41.2HZ), 147.6, 1 52.3, 156.4. 19 F-NMR (deuterated dimethyl sulfoxide): d -63.2. MS (m / z): 205 [M + H] +.

EXAMPLE 37 0.19 g (1.0 mmol) of xanthine were weighed and placed in a 100 ml two-necked flask equipped with a magnetic rotor, and the The atmosphere of the flask was replaced with argon. The following materials were added: 47 ml of dimethyl sulfoxide, 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l, 0.2 ml of an aqueous solution of 30% hydrogen peroxide, and 0.3 ml of an aqueous solution of ferric sulphate 1.0 mol / l. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 8-trifluoromethylxanthine was confirmed by means of 19 F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 44%). The 8-trifluoromethylxanthine was obtained by column chromatography (0.044 g, yield: 20%). H-NMR (deuterated dimethyl sulfoxide): d 1 1 .16 (s, 1 H), 1 1.83 (s, 1 H), 15.07 (brs, 1 H). 13 C-NMR (deuterated dimethyl sulfoxide): d 1 10.0, 1 18.7 (q, JCF = 269.9Hz), 138.0 (q, JCF = 41.1 Hz), 148.1, 151.7, 156.2. 19 F-NMR (deuterated dimethyl sulfoxide): d -63.1. MS (m / z): 221 [M + H] +.

EXAMPLE 38 0.19 g (1.0 mmol) of caffeine were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 2.0 ml of dimethyl sulfoxide, 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l, 0.3 ml of an aqueous solution of ferric sulfate 1.0 mol / l, and 0.2 ml of an aqueous solution of 30% hydrogen peroxide. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 8-trifluoromethylcaffeine was confirmed by means of 19F-NMR with 2, 2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 17%). The 8-trifluoromethylcaffeine was obtained as a white solid by column chromatography (0.033 g, yield: 13%). 1 H-NMR (deuterated acetone): d 3.33 (s, 3 H), 3.52 (s, 3 H), 4.21 (q, JHF = 1 .25 Hz, 3 H). 13C-NMR (deuterated acetone): d 27.8, 29.7, 33.3 (q, JCF = 1 -98HZ), 1 10.3, 1 19.2 (q, JCF = 270.2HZ), 138.4 (q, JCF = 39.6HZ), 147.0. 9F-NMR (deuterated acetone): d -62.1 (d, JHF = 1 .25Hz).

MS (m / z): 262 [M] +.

EXAMPLE 39 The formation of 8-trifluoromethylcaffeine was confirmed in the same manner as in Example 38 (yield according to 19F-NMR: 48%), except that 0.5 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide was used instead of 2.0 ml of the sulfuric acid solution in 1 N dimethyl sulfoxide.

EXAMPLE 40 1.94 g (10 mmol) of caffeine were weighed and placed in a 100 ml two neck flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 20 ml of dimethyl sulfoxide, 20 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 10 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l, 3.0 ml of an aqueous solution of ferric sulfate 1.0 mol / l, and 2.0 ml of an aqueous solution of 30% hydrogen peroxide. The mixture was stirred at a temperature of 50 ° C to 60 ° C for 60 minutes and then the resulting solution was cooled to room temperature. The formation of 8-trifluoromethylcaffeine was confirmed by means of 19F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 9F-NMR: 20%).

EXAMPLE 41 1.94 g (10 mmol) of caffeine were weighed and placed in a 300 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 50 ml of dimethyl sulfoxide, 0.055 ml of concentrated sulfuric acid, 30 mmol of trifluoromethyl iodide gas, 3.0 ml of an aqueous solution of ferric sulphate 1.0 mol / l, and 2.0 ml of a aqueous solution of 30% hydrogen peroxide. The mixture was stirred at a temperature of 50 ° C to 60 ° C for 60 minutes and then the resulting solution was cooled to room temperature. The formation of 8-trifluoromethylcaffeine was confirmed by means of 9F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 9F-NMR: 23%).

EXAMPLE 42 The formation of 8-trifluoromethylcaffeine was confirmed in the same manner as in Example 41 (yield according to F-NMR: 15%), except that an aqueous solution of ferric ammonium sulfate, 0 mol / l, was used instead of the aqueous solution of ferric sulphate 1.0 mol / l.

EXAMPLE 43 0.19 g (1.0 mmol) of caffeine were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 0.21 ml of an aqueous solution of 42% tetrafluoroboric acid, 4.0 ml of dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l, 0.3 ml of a aqueous solution of ferric tetrafluous robbery 1 .0 mol / l, and 0.2 ml of a 30% aqueous solution of hydrogen peroxide. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 8-trifluoromethylcaffeine was confirmed by means of 19 F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 9F-NMR: 11%).

EXAMPLE 44 0.19 g (1.0 mmol) of caffeine were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 0.016 g (0.3 mmol) of iron powder, 2.0 ml of dimethyl sulfoxide, 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of an iodide solution of trifluoromethyl in dimethyl sulfoxide 3.0 mol / l, and 0.2 ml of an aqueous solution of 30% hydrogen peroxide. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 8-trifluoromethylcaffeine was confirmed by means of 19 F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 9F-NMR: 37%).

EXAMPLE 45 Weighed 0.19 g (1.0 mmol) of caffeine and 0.056 g (0.3 mmol) of ferrocene, and placed in a 50 ml two neck flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 2.0 ml of dimethyl sulfoxide, 2.0 ml of a solution of sulfuric acid in dimethyl sulfoxide N, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l, 0.3 ml of a aqueous solution of ferric sulfate 1.0 mol / l, and 0.2 ml of an aqueous solution of 30% hydrogen peroxide. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 8-trifluoromethylcaffeine was confirmed by means of 19 F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 17%).

EXAMPLE 46 The formation of 8-trifluoromethylcaffeine was confirmed in the same manner as in Example 41 (yield according to 9F-NMR: 13%), except that the reaction was carried out in an air atmosphere without replacement with argon.

EXAMPLE 47 0.18 g (1.0 mmol) of caffeine were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 3.0 ml of dimethyl sulfoxide, 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.3 ml of tridecafluoro-1-iodohexane, 0.3 ml of an aqueous solution of ferric sulfate 1 .0 mol / I, and 0.2 ml of an aqueous solution of 30% hydrogen peroxide. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 8-perfluorohexylcaffeine was confirmed by means of 19 F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 30%). The 8-perfluorohexylcaffeine was obtained as a white solid by column chromatography (0.077 g, yield: 15%). 1 H-NMR (deuterated acetone): d 3.33 (s, 3 H), 3.52 (s, 3 H), 4.21 (s, 3H). 19F-NMR (deuterated acetone): d -125.9 (m, 2F), -22.8 (m, 2F), -122.0 (m, 2F), -1 14.2 (m, 4F), -80.5 (d, JFF = 9.4 Hz, 3F). MS (m / z): 513 [M + H] +.

EXAMPLE 48 0.18 g (1.0 mmol) of theobromine were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 17 ml of dimethyl sulfoxide, 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l, 0.3 ml of an aqueous solution of ferric sulfate 1.0 mol / l, and 0.2 ml of an aqueous solution of 30% hydrogen peroxide. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 8-trifluoromethyltetrabromine was confirmed by 19F-NMR medium with 2,2,2-trifluoroethanol as internal standard (yield according to 19F-NMR: 12%). The 8-trifluoromethyltetrabromine was obtained as a white solid by column chromatography (0.024 g, yield: 10%). 1 H-NMR (deuterated dimethyl sulfoxide): d 3.34 (s, 3 H), 4.04 (s, J = 1 .7 Hz, 3 H), 11 .48 (brs, 1 H). 13 C-NMR (deuterated dimethyl sulfoxide): d 33.1 (q, JCF = 1 .9HZ), 42.1, 109.9 (q, JCF = 1 .9HZ), 1 18.2 (q, JCF = 270.7Hz), 137.0 (q, JCF = 39.2Hz), 147.5, 150.6, 155.2. 19 F-NMR (deuterated dimethyl sulfoxide): d-61 .6. MS (m / z): 248 [M] +.

EXAMPLE 49 0.18 g (1.0 mmol) of theophylline were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 2.0 ml of dimethyl sulfoxide, 2.0 ml of a solution of sulfuric acid in 1 N dimethyl sulfoxide, 1.0 ml of a solution of trifluoromethyl iodide in dimethyl sulfoxide 3.0 mol / l, 0.2 ml of an aqueous solution of 30% hydrogen peroxide, and 0.3 ml of an aqueous solution of ferric sulfate 1.0 mol / l. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 8-trifluoromethylteophylline was confirmed by means of 19 F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 9F-NMR: 48%). The 8-trifluoromethylteophylline was obtained as a white solid by column chromatography (0.086 g, yield: 35%). 1 H-NMR (deuterated dimethyl sulfoxide): d 3.24 (s, 3 H), 3.42 (s, 3 H), 1 5.2 (brs, 1 H). 13 C-NMR (deuterated dimethyl sulfoxide): d 27.9, 29.9, 1 09.1, 1 18.2 (q, JCF = 270.0HZ), 137.3 (q, JCF = 37.2HZ), 146.8, 1 50.9, 154.6. 19 F-NMR (deuterated dimethyl sulfoxide): d -62.3. MS (m / z): 248 [M] +.

EXAMPLE 50 0.18 g (1.0 mmol) of theophylline were weighed and placed in a 50 ml two-necked flask equipped with a magnetic rotor, and the atmosphere in the flask was replaced with argon. The following materials were added: 3.0 ml of dimethyl sulfoxide, 2.0 ml of an acid solution sulfuric acid in 1 N dimethyl sulfoxide, 1.3 ml of tridecafluoro-1-iodohexane, 0.3 ml of an aqueous solution of ferric sulfate 1.0 mol / l, and 0.2 ml of a 30% aqueous solution of hydrogen peroxide. The mixture was stirred at a temperature of 40 ° C to 50 ° C for 20 minutes and then the resulting solution was cooled to room temperature. The formation of 8-perfluorohexylteophylline was confirmed by means of 9F-NMR with 2,2,2-trifluoroethanol as internal standard (yield according to 9F-NMR: 12%). The 8-perfluorohexylteophylline was obtained as a white solid by column chromatography (0.02 g, yield: 4.0%). 1 H-NMR (deuterated acetone): d 3.34 (s, 3H), 3.57 (s, 3H), 14.2 (brs, 1 H). 19F-NMR (deuterated acetone): d -127.0 (m.2F), -123.6 (brs, 2F), -122.9 (m, 2F), -122.4 (brs, 2F), -112.3 (m, 2F), -81 .9 (t, JFF = 7.1 Hz, 3F). MS (m / z): 499 [M + H] +.

EXAMPLE 51 The formation of 6- (2-chloroethyl) -5-trifluoromethyluracil was confirmed in the same manner as in Example 22 (yield according to 19F-NMR: 55%), except that 0.16 g of 6- (2-chloroethyl) were used. uracil instead of 0.37 g of 2 ', 3', 5'-tr'-0-acetyluridine. Then, 6- (2-chloroethyl) -5-trifluoromethyluracil was obtained as a white solid by preparative thin layer chromatography (0.10 g, yield: 45%).

Industrial Application The nucleobase having a perfluoroalkyl group according to the present invention is useful as a drug, an intermediate for preparing medicinal and agronomic chemical agents, and so on. The full disclosure of Japanese patent application No. 2005-324943, filed on November 9, 2005, including the specification, claims and summary, is hereby incorporated by reference in its entirety.

Claims

NOVELTY OF THE INVENTION CLAIMS

1 .- A procedure to produce a nucleobase that has a perfluoroalkyl group, which comprises: performing a reaction of one nucleobase with a perfluoroalkyl halide represented by the formula general (2): Rf-X (2) wherein Rf is a C1-C6 perfluoroalkyl group and X is a halogen, in the presence of a sulfoxide represented by the general formula (1 ): R1 a-S-R1 b II 0 (1) wherein each of R1a and R1 b is a C1-C12 alkyl group or a group phenyl optionally substituted; a peroxide and an iron compound.

2. - The method according to claim 1, characterized in that the reaction is carried out in the presence of a acid.

3. - The method according to claim 1 or 2, characterized further because the nucleobase are uracils represented by the general formula (3): wherein R2 is a hydrogen atom, an optionally substituted C1_6 alkyl group, or a nitrogen protecting group, R3 is a hydrogen atom, an optionally substituted C1_6 alkyl group, a nitrogen protecting group, or a pentose residue or analogue thereof, and R 4 is a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted amino group, a carboxy group, a carbamoyl group optionally substituted, or an optionally substituted C2-C5 alkoxycarbonyl group; cytosines represented by the general formula (4): wherein R5 is a hydrogen atom, an optionally substituted C1-C6 alkyl group, a nitrogen protecting group, or a pentose residue or analog thereof, R6 is a hydrogen atom, a C1-C6 alkyl group optionally substituted , an optionally substituted amino group, a carboxy group, an optionally substituted carbamoyl group, or an optionally substituted C2-C5 alkoxycarbonyl group, and each of R7 and R8 is a hydrogen atom or a nitrogen protecting group; Adenines represented by the general formula (5): wherein R is a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, a nitrogen protecting group, or a pentose residue or analog thereof, R 10 is a hydrogen atom, a substituted C 1 -C 6 alkyl group optionally, an optionally substituted amino group, a carboxy group, an optionally substituted carbamoyl group, or an optionally substituted C2-C5 alkoxycarbonyl group, and each of R11 and R2 is a hydrogen atom or a nitrogen protecting group; guanines represented by the general formula (6): wherein R 13 is a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group or a nitrogen protecting group, R is a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, a nitrogen protecting group, or a pentose residue or analogous thereof, and each one of R15 and R16 is a hydrogen atom or a nitrogen protecting group; hypoxanthines represented by the general formula (7): wherein R 17 is a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, or a nitrogen protecting group, and R 18 is a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, a nitrogen protecting group, or a pentose residue or analogue thereof; or xanthines represented by the general formula (8): wherein R19 is a hydrogen atom, an optionally substituted C1-C6 alkyl group, or a nitrogen protecting group; R20 is a hydrogen atom, a C1-C6 alkyl group optionally substituted, a nitrogen protecting group, or a pentose residue or analogue thereof; and R21 is a hydrogen atom, an optionally substituted C1_6 alkyl group, or a nitrogen protecting group.

4. The method according to claim 3, further characterized in that the nucleobase are uracils represented by the general formula (3): wherein R2, R3 and R4 are the same as defined above.

5. The process acing to any of claims 1 to 4, further characterized in that X is iodine or bromine.

6. The process acing to any of claims 1 to 5, further characterized in that Rf is a trifluoromethyl group or a perfluoroethyl group.

7. The process acing to any of claims 1 to 6, further characterized in that the iron compound is ferric sulfate, ferric ammonium sulfate, ferric tetrafluoroborate, ferric chloride, ferric bromide, ferric iodide, ferric acetate, ferric oxalate, bis (acetylacetonate) iron (II), ferrocene, bis (r) 5-pentamethylcyclopentadienyl) iron, or iron powder.

8. The process acing to claim 7, further characterized in that the iron compound is ferric sulfate, ferric ammonium sulfate, ferric tetrafluoroborate, ferrocene, or iron powder.

9. The process acing to any of claims 1 to 8, further characterized in that the peroxide is hydrogen peroxide, a mixture of hydrogen peroxide and urea, peroxide of ter- Butyl or peroxyacetic acid.

10. The process acing to claim 9, further characterized in that the peroxide is hydrogen peroxide, or a mixture of hydrogen peroxide and urea. 1 - The process acing to any of claims 2 to 10, further characterized in that the acid is sulfuric acid, hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, phosphoric acid, hexafluorophosphoric acid, tetrafluoroboric acid, acid formic acid, acetic acid, propionic acid, oxalic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid or trifluoroacetic acid. 12. The process acing to claim 1, further characterized in that the acid is sulfuric acid, tetrafluoroboric acid, or trifluoromethanesulfonic acid. 13. The process acing to any of claims 1 to 12, further characterized in that each of R1a and R1b is a methyl group, a butyl group or a phenyl group. 14. - The method acing to any of claims 1 to 13, further characterized in that the reaction temperature is from 20 ° C to 100 ° C. 15. The process acing to any of claims 1 to 14, further characterized in that the pressure of the reaction is from atmospheric pressure (0.1 MPa) to 1.0 MPa. 16.- The 5-perfluoroalquiluracilos represented by the formula general (9): wherein Rf is a perfluoroalkyl group of C 1 -C 6, each of R and R is a hydrogen atom or an optionally substituted C 1 -C 6 alkyl group, and R 24 is an optionally substituted C 1 -C 6 alkyl group, an amino group optionally substituted, or optionally substituted C2-C5 alkoxycarbonyl group, provided that when R22 and R23 are a hydrogen atom, R24 is an optionally substituted C2-C5 alkoxycarbonyl group. 17.- The 8-perfluoroalkylxanthines represented by the general formula (10): wherein Rf is a perfluoroalkyl group of C1-C6, and each of R25, R26 and R27 is a hydrogen atom or an optionally substituted C1-C6 alkyl group, provided that R25, R26 and R27 are not all together an atom of hydrogen.