CN104926902A

CN104926902A - 2'-substituted-2,2'-dehydrated uridine or 2'-substituted-2,2'-dehydrated cytidine compound and preparation method and use thereof

Info

Publication number: CN104926902A
Application number: CN201410097942.6A
Authority: CN
Inventors: 张容霞
Original assignee: Individual
Current assignee: Individual
Priority date: 2014-03-17
Filing date: 2014-03-17
Publication date: 2015-09-23
Also published as: CN106068271B; CN106068271A; WO2015139602A1

Abstract

The invention discloses a 2'-substituted-2,2'-dehydrated uridine or 2'-substituted-2,2'-dehydrated cytidine compound represented by the following general formula I and a preparation method thereof. The invention also relates to a method for preparing 2'-deoxy-2'-fluoro-2'-substituted uridine or 2'-deoxy-2'-fluoro-2'-substituted cytidine or 2'-deoxy-2'-cyano-2'-substituted uridine or 2'-deoxy-2'-cyano-2'-substituted cytidine compound by using the 2'-substituted-2,2'-dehydrated uridine or 2'-substituted-2,2'-dehydrated cytidine compound.

Description

2 '-substituted-2, 2' -dehydrated uridine or 2 '-substituted-2, 2' -dehydrated cytidine compound and preparation method and application thereof

Technical Field

The invention relates to the field of medicinal chemistry, in particular to a2 '-substituted-2, 2' -dehydrated uridine or 2 '-substituted-2, 2' -dehydrated cytidine compound, a preparation method thereof and an intermediate in the preparation process. The present invention also relates to a method for preparing a2 '-deoxy-2' -fluoro-2 '-substituted uridine or 2' -deoxy-2 '-fluoro-2' -substituted cytidine or 2 '-deoxy-2' -cyano-2 '-substituted uridine or 2' -deoxy-2 '-cyano-2' -substituted cytidine compound using the 2 '-substituted-2, 2' -dehydrated uridine or 2 '-substituted-2, 2' -dehydrated cytidine compound.

Background

2' -deoxy-2 ' -fluoro-2 ' -methyluridine (IIIa) is a key intermediate for preparing the anti-hepatitis C drug Sofosbuvir.

Sofosbuvir was developed by Gilead Science, and was formally approved by the FDA for use in the treatment of chronic Hepatitis C Virus (HCV) infection at 12/6 of 2013. Sofosbuvir is the first effective and safe drug for the treatment of certain types of HCV infection without the concomitant use of interferon. Several clinical trials have shown that sofosbuvir is able to achieve a very high proportion of sustained virological responses (clinical cures). A more revolutionary breakthrough is that the therapeutic effect of sofosbuvir is still very significant without combination with peginterferon alfa, for example, the sustained virological response rate of sofosbuvir combined with ribavirin for treating genotype 2 and genotype 3 chronic hepatitis c initial treatment patients can reach 100%. Sofosbuvir is a prodrug that is metabolized in vivo to 2 '-deoxy-2' -fluoro-2 '-methyluridine-5' -monophosphate.

The synthesis method of 2' -deoxy-2 ' -fluoro-2 ' -methyluridine reported so far is as follows:

in the literature (Journal of Medicinal Chemistry,2005,48,5504), cytosine nucleosides are used as starting materials, and the 3',5' -hydroxyl group is selectively protected first, then the 2 '-hydroxyl group is oxidized to carbonyl, and reacted with methyllithium to obtain a 2' -hydroxyl compound, then the protecting group is removed, the 3',5' -hydroxyl group is protected with benzoyl, and then reacted with DAST to obtain fluoro, followed by hydrolysis and aminolysis to obtain the product, as shown in reaction scheme I below. The method has long route, needs expensive silyl ether protecting groups, and has poor molecular economy; methylation can produce diastereomers with the methyl group in the beta position.

In the patents (WO2005003147, WO2006031725a2, US20040158059) a2 '-fluoro-2' -methyl-ribose derivative is used to perform a docking reaction with N-benzoylcytosine followed by hydrolysis and ammonolysis to obtain the final product, as shown in scheme II below. The method has the advantages of difficult obtainment of raw materials, complex synthesis steps and high price; the product obtained by the docking reaction contains an isomer with a base position alpha, and the isomer needs to be purified and removed, thereby causing waste.

Disclosure of Invention

The invention designs and synthesizes a compound shown in a general formula I, and the compound can perform fluoro reaction or nitrile reaction under proper conditions to obtain a2 '-deoxy-2' -fluoro-2 '-substituted uridine or 2' -deoxy-2 '-fluoro-2' -substituted cytidine or 2 '-deoxy-2' -nitrile-2 '-substituted uridine or 2' -deoxy-2 '-nitrile-2' -substituted cytidine compound; or the compound in the general formula I is subjected to a fluoro-reaction or a nitrile-reaction, and then subjected to a deprotection reaction to obtain a2 '-deoxy-2' -fluoro-2 '-substituted uridine or 2' -deoxy-2 '-fluoro-2' -substituted cytidine or 2 '-deoxy-2' -nitrile-2 '-substituted uridine or 2' -deoxy-2 '-nitrile-2' -substituted cytidine compound; or the compound in the general formula I is subjected to ring-opening reaction, fluorination or nitrile alkylation and deprotection reaction to obtain a2 '-deoxy-2' -fluoro-2 '-substituted uridine or 2' -deoxy-2 '-fluoro-2' -substituted cytidine or 2 '-deoxy-2' -nitrile-2 '-substituted uridine or 2' -deoxy-2 '-nitrile-2' -substituted cytidine compound; or the compound in the general formula I is subjected to ring opening reaction, then 2' -hydroxyl forms a leaving group, and then is subjected to fluorination or cyanation reaction, and finally is subjected to deprotection reaction to obtain the compound of 2' -deoxy-2 ' -fluoro-2 ' -substituted uridine or 2' -deoxy-2 ' -fluoro-2 ' -substituted cytidine or 2' -deoxy-2 ' -nitrile-2 ' -substituted uridine or 2' -deoxy-2 ' -nitrile-2 ' -substituted cytidine.

Accordingly, it is an object of the present invention to provide compounds of formula I.

It is a further object of the present invention to provide a process for the preparation of compounds of formula I.

Another object of the present invention is to provide a method for preparing a2 '-deoxy-2' -fluoro-2 '-substituted uridine or 2' -deoxy-2 '-fluoro-2' -substituted cytidine or 2 '-deoxy-2' -cyano-2 '-substituted uridine or 2' -deoxy-2 '-cyano-2' -substituted cytidine compound using the compound of formula I.

According to the present invention, there is provided a compound represented by the following general formula I:

wherein,

r and R₁Each independently is a hydrogen atom or a hydroxyl protecting group, preferably, R and R₁Each independently selected from the group consisting of a hydrogen atom, a methyl group, an acyl group substituted with a C1-C6 linear or branched alkyl group, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, a methanesulfonyl group, a benzenesulfonyl group, a p-toluenesulfonyl group, a tetrahydropyran-2-yl group, a tris (C1-C6 linear or branched alkyl) silyl group, a t-butyl bis (C1-C6 linear or branched alkyl) silyl group, a t-butyl diphenylsilyl group, a methylthiomethyl group, a methoxymethyl group, and a 2-methoxyethoxymethyl group; most preferably, R and R₁Each independently selected from the group consisting of a hydrogen atom, a methyl group, a formyl group, an acetyl group, a pivaloyl group, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, a methanesulfonyl group, a benzenesulfonyl group, a p-toluenesulfonyl group, a tetrahydropyran-2-yl group, a trimethylsilyl group, a tert-butyldimethylsilyl group, a,Tert-butyldiphenylsilyl, methylthiomethyl, methoxymethyl and 2-methoxyethoxymethyl; the substituent on the substituted benzoyl and the substituted benzyl is selected from nitro, C1-C6 linear or branched alkoxy, halogen, C1-C6 linear or branched alkyl and phenyl, preferably selected from nitro, methoxy, chlorine, methyl and phenyl; or

R and R₁Combined to form a cyclic hydroxy-protecting group, preferably, R and R₁Joined together to form-SiR ' -O-SiR ' -or-SiR ' -, wherein R ' is a C1-C6 linear or branched alkyl group, preferably R ' is isopropyl;

R₂is C1-C6 straight or branched chain alkyl, C1-C6 straight or branched chain alkyl substituted by one or more halogens or hydroxyl, nitrile group or halogen, preferably, R₂Is C1-C4 straight or branched chain alkyl, trifluoromethyl, hydroxymethyl, nitrile, difluoromethyl, fluoro or chloro, most preferably, R₂Is methyl, ethyl, trifluoromethyl or nitrile group;

R₃is an oxygen atom or NR₄Wherein R is₄Is a hydrogen atom, an acyl group substituted with a C1-C6 linear or branched alkyl group, a substituted or unsubstituted benzoyl group, preferably, R₄Is hydrogen atom, formyl group, acetyl group, substituted or unsubstituted benzoyl group, most preferably, R₄Is hydrogen atom, formyl, acetyl or benzoyl, and the substituent on the substituted benzoyl is selected from nitro, C1-C6 straight-chain or branched alkoxy, halogen and C1-C6 straight-chain or branched alkyl, preferably selected from nitro, methoxy, chlorine and methyl.

In the definitions herein, halogen means fluorine, chlorine, bromine or iodine, unless otherwise specified.

In one embodiment, the compound of formula I is a compound of formula I-A as follows:

wherein R and R₁Each independently is a hydrogen atom or a hydroxyl protecting group, preferably, R and R₁Each independently selected from the group consisting of a hydrogen atom, a methyl group, a C1-C6 straight or branched chain alkyl substituted acyl group, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, a methanesulfonyl group, a benzenesulfonyl group, a p-toluenesulfonyl group, a tetrahydropyran-2-yl group, a tris (C1-C6 straight or branched chain alkyl) silyl group, a t-butyl bis (C1-C6 straight or branched chain alkyl) silyl group, a t-butyl diphenylsilyl group, a methylthiomethyl group, a methoxymethyl group, and a 2-methoxyethoxymethyl group; or, R and R₁Combined to form a cyclic hydroxy-protecting group, preferably, R and R₁Are connected and combined to form-SiR '-O-SiR' -or-SiR '-, wherein R' is C1-C6 straight chain or branched chain alkyl.

R₃Is an oxygen atom or NR₄Wherein R is₄Is hydrogen atom, acyl, benzoyl or substituted benzoyl which is substituted by C1-C6 straight chain or branched chain alkyl.

The substituents on the substituted benzoyl and benzyl groups are preferably selected from nitro, C1-C6 linear or branched alkoxy, halogen and C1-C6 linear or branched alkyl, more preferably from nitro, methoxy, chloro and methyl.

In the formula I-A, R may preferably be selected from the group consisting of a hydrogen atom, a methyl group, a formyl group, an acetyl group, a pivaloyl group, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, a methanesulfonyl group, a benzenesulfonyl group, a p-toluenesulfonyl group, a tetrahydropyran-2-yl group, a trimethylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a methylthiomethyl group, a methoxymethyl group and a 2-methoxyethoxymethyl group.

In the general formula I-A, R₁Preferably selected from the group consisting of a hydrogen atom, a methyl group, a formyl group, an acetyl group, a pivaloyl group, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, a methanesulfonyl group, a benzenesulfonyl group, a p-toluenesulfonyl group, a tetrahydropyran-2-yl group, a trimethylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a methylthiomethyl group, a,Methoxymethyl and 2-methoxyethoxymethyl.

In the general formula I-A, R and R₁Joined together to form-SiR '-O-SiR' -or-SiR '-, wherein R' is preferably isopropyl; in the general formula I-A, R₃Is an oxygen atom or NR₄Wherein R is₄Preferably, it may be selected from a hydrogen atom, a formyl group, an acetyl group and a benzoyl group.

In another embodiment, the compound of formula I is a compound of formula I-B as follows:

wherein R and R₁Each independently hydrogen or a hydroxy protecting group, preferably selected from the group consisting of hydrogen atoms, C1-C4 alkanoyl, benzoyl, substituted benzoyl, methanesulfonyl, p-toluenesulfonyl and tetrahydropyran-2-yl; r and R₁It is also possible to combine hydroxyl-protecting groups which form a ring, for example cyclic silicon ether or cyclic ether hydroxyl-protecting groups.

The substituent on the substituted benzoyl is preferably selected from halogen, C1-C4 alkyl, etc., and more preferably chlorine.

In the formula I-B, R may preferably be selected from the group consisting of a hydrogen atom, a C1-C2 alkanoyl group, a benzoyl group, a 4-chlorobenzoyl group, a methanesulfonyl group, a p-toluenesulfonyl group and a tetrahydropyran-2-yl group.

In the general formula I-B, R₁Preferably, it may be selected from the group consisting of a hydrogen atom, a C1-C2 alkanoyl group, a benzoyl group, a 4-chlorobenzoyl group, a methanesulfonyl group, a p-toluenesulfonyl group and a tetrahydropyran-2-yl group.

More preferably, the compounds of general formula I according to the invention are selected from the following compounds:

the invention also provides a process for the preparation of compounds of the general formula I, in which R is₃In the case of an oxygen atom, the method is one of the following methods:

the method comprises the following steps:

the compound I-1-1 is obtained by converting the compound II-1 through a closed-loop reaction, and is shown as the following reaction formula:

wherein R is₂Are as defined above for compounds of formula I, I-A or I-B;

or

The second method comprises the following steps:

protecting the 3 'and 5' hydroxyl groups of compound I-1-1 obtained in method one to obtain a compound of general formula I-1-2, as shown in the following reaction scheme:

wherein R and R are other than hydrogen₁Are as defined above for compounds of formula I, I-A or I-B; r₂Are as defined above for compounds of formula I, I-A or I-B;

or,

the third method comprises the following steps:

in the presence of a catalyst, the compound III-1-2 undergoes an intramolecular substitution reaction to be converted into a compound I-1-2, which is shown in the following reaction formula:

wherein, R, R₁And R₂Are as defined above for compounds of formula I, I-A or I-B;

R₅is hydrogen, C1-C4 alkanoyl, benzoyl substituted by C1-C4 alkoxy, benzoyl substituted by halogen, methanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl or p-toluenesulfonyl, more preferably, R is₅Is hydrogen atom, formyl group, acetyl group, benzoyl group, 4-methoxybenzoyl group, 4-chlorobenzoyl group, methylsulfonyl group, trifluoromethanesulfonyl group or p-toluenesulfonyl group; or, R₁And R₅Are combined to formOr

In one embodiment, in the above process for the preparation of a compound of formula I, at R₃In the case of an oxygen atom, R₂Is methyl.

In method one, the ring-closure reaction may be carried out in a suitable solvent in the presence of a base, with or without diphenyl carbonate. The base can be selected from organic base and inorganic base, preferably one or a mixture of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, 4-dimethylaminopyridine and the like; the solvent is one or a mixture of N, N-dimethylformamide, N-dimethylacetamide, DMSO, acetonitrile, acetone, toluene, dioxane, pyridine and the like; the reaction temperature is selected from 20-200 ℃, preferably 60-180 ℃; the ring-closure reaction is preferably carried out in the presence of diphenyl carbonate, and the molar ratio of the compound II-1 to the diphenyl carbonate is 1:1 to 10, preferably 1:1 to 3.

In the second method, the hydroxyl protecting reaction is carried out in a suitable solvent in the presence of an acidic or basic catalyst, wherein the acidic catalyst is one or a mixture of p-toluenesulfonic acid, methanesulfonic acid, acetic acid, zinc chloride, stannic chloride, boron trifluoride and the like, and the basic catalyst is one or a mixture of triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium hydride and the like; the solvent is one or a mixture of toluene, benzene, acetone, methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, dioxane, acetonitrile, dichloromethane, dichloroethane, ethyl acetate, N-dimethylformamide, N-methylpyrrolidone and the like; the reaction temperature is selected from-20 ℃ to 120 ℃;

in the third method, the intramolecular substitution reaction may occur in the presence of an acidic or basic catalyst, the acidic catalyst being one selected from trimethylsilyl trifluoromethanesulfonate, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, zinc chloride, tin chloride, boron trifluoride and the like or a mixture thereof, the basic catalyst being one selected from triethylamine, pyridine, 4-dimethylaminopyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, potassium carbonate, sodium hydride and the like or a mixture thereof; the reaction solvent is one or a mixture of methanol, ethanol, isopropanol, toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane, dichloroethane, N-dimethylformamide, pyridine and the like.

The invention also provides a process for the preparation of compounds of the general formula I, in which R is₃Is NR₄In the case of (2), the method is one of the following methods:

the method comprises the following steps:

the compound I-2-1 is obtained by converting the compound II-2 through a closed-loop reaction, and is shown in the following reaction formula:

wherein R is₂And R₄Are as defined above for compounds of the general formula I or I-A;

or

The second method comprises the following steps:

protecting the 3 'and 5' hydroxyl groups of compound I-2-1 obtained in method one to obtain a compound of general formula I-2-2, as shown in the following reaction scheme:

wherein R and R are other than hydrogen₁Are as defined above for compounds of the general formula I or I-A; r₂And R₄Are as defined above for compounds of the general formula I or I-A;

or,

the third method comprises the following steps:

in the presence of a catalyst, the compound III-2-2 undergoes an intramolecular substitution reaction to be converted into a compound I-2-2, which is shown in the following reaction formula:

wherein, R, R₁、R₂And R₄Are as defined above for compounds of the general formula I or I-A;

In the process for the preparation of the compounds of the general formula I as described above, in R₃Is NR₄In the case of (3), R is preferably₂Is methyl; and/or preferably R₄Is hydrogen atom, formyl, acetyl or benzoyl.

In the preparation of the compounds of the formula I, the above-mentioned pairs are in R₃The description of the reaction conditions in the case of oxygen atoms applies equally to R₃Is NR₄And therefore, will not be described in detail herein.

The invention also provides a method for preparing a2 '-deoxy-2' -fluoro-2 '-substituted uridine or 2' -deoxy-2 '-fluoro-2' -substituted cytidine or 2 '-deoxy-2' -cyano-2 '-substituted uridine or 2' -deoxy-2 '-cyano-2' -substituted cytidine compound using a compound of formula I, at R₃In the case of an oxygen atom, the method is one of the following methods:

the method comprises the following steps:

the compound I-1-1 undergoes fluoro-or nitrile-reaction to obtain a compound IV-1-1, which is shown in the following reaction formula:

wherein R is₆Is fluorine or nitrile group, R₂Are as defined for compounds of formula I, I-A or I-B;

or,

the second method comprises the following steps:

carrying out fluorination or nitrile reaction on the compound I-1-2 to obtain a compound V-1-1; then, the protecting group is removed to obtain a compound IV-1-1, which is shown as the following reaction formula:

wherein R and R are other than hydrogen₁Are as defined above for compounds of formula I, I-A or I-B; r₂Are as defined for compounds of formula I, I-A or I-B; r₆Is fluorine or nitrile group;

or,

the third method comprises the following steps:

the compound I-1-1 is subjected to ring-opening reaction to obtain a compound XI-1, the hydroxyl groups at the 3 'position and the 5' position are protected to obtain a compound VI-1-1, and the compound VI-1-1 can also be obtained by the ring-opening reaction of the compound I-1-2; then carrying out fluoro-substitution or nitrile-substitution reaction on the compound VI-1-1 to obtain a compound V-1-1; then, the protecting group is removed to obtain a compound IV-1-1, which is shown as the following reaction formula:

or,

the method four comprises the following steps:

carrying out acylation reaction or sulfonylation reaction on the 2' -hydroxyl of the compound VI-1-1 obtained in the third method to obtain a compound VII-1-1; carrying out fluoro-reaction or nitrile-reaction on the compound VII-1-1 to obtain a compound V-1-1; finally, the protecting group is removed to obtain a compound IV-1-1, which is shown as the following reaction formula:

wherein R and R are other than hydrogen₁Are as defined above for compounds of formula I, I-A or I-B; r₂Are as defined for compounds of formula I, I-A or I-B; r₆Is fluorine or nitrile group, R₇Selected from the group consisting of formyl, acetyl, benzoyl, 4-methoxybenzoyl, 4-chlorobenzoyl, methylsulfonyl, phenylsulfonyl, p-toluenesulfonyl and trifluoromethylsulfonyl.

In the above process, in R₃In the case of an oxygen atom, R is preferably₂Is methyl.

In the above reaction, the fluorination reaction or the cyanation reaction is carried out in the presence of a fluorinating agent or a cyanation agent. The fluorinating agent is selected from F₂One or a mixture of HF, HF/Py, NaF, KF, tetrabutylammonium fluoride, triethylamine trihydrofluoride, diethylaminosulfur trifluoride and bis- (2-methoxyethyl) aminesulfluoride; the nitrile-based reagent is one or a mixture of sodium cyanide, potassium cyanide, trimethyl cyano silane, hydrogen cyanide, cyanogen gas, tetrabutyl ammonium cyanide and the like; the solvent for the fluoro-or nitrile-reaction is one or a mixture of methanol, ethanol, isopropanol, water, toluene, benzene, acetone, methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, dioxane, acetonitrile, dichloromethane, dichloroethane, ethyl acetate, N-dimethylformamide, N-methylpyrrolidone and the like; the fluorination reaction or the nitrile reaction can be carried out in the presence of acid or alkali, and the alkali is selected from inorganic alkali and organic alkali, preferably one or a mixture of potassium carbonate, triethylamine, pyridine and the like; the acid may be selected from hydrogen fluoride and the like; the reaction temperature of the fluorination reaction or the nitrile reaction is-80 ℃ to 150 ℃;

the acylation reaction is carried out in a suitable solvent in the presence of a base, wherein the base is one or a mixture of triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hexamethyldisilazide, lithium hexamethyldisilazide and the like; the acylating agent is selected from methyl formate, ethyl formate, formic acid, acetyl chloride, acetic anhydride, benzoyl chloride, benzoic anhydride, 4-methoxybenzoyl chloride, 4-methoxybenzoyl anhydride, 4-chlorobenzoyl chloride, 4-chlorobenzoic anhydride and the like; the reaction solvent is one or a mixture of toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane, N-dimethylformamide, pyridine and the like; the reaction temperature is-80 ℃ to 150 ℃;

the sulfonylation reaction is carried out in a suitable solvent in the presence of a base, wherein the base is one or a mixture of triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hexamethyldisilazide, lithium hexamethyldisilazide and the like; the sulfonylation reagent is selected from methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride and trifluoromethanesulfonic anhydride; the reaction solvent is one or a mixture of toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane, N-dimethylformamide, pyridine and the like; the reaction temperature is-80 ℃ to 150 ℃;

the hydroxyl protection reaction is carried out in a proper solvent in the presence of an acidic or basic catalyst, wherein the acidic catalyst is one or a mixture of p-toluenesulfonic acid, methanesulfonic acid, acetic acid, zinc chloride, stannic chloride, boron trifluoride and the like, and the basic catalyst is one or a mixture of triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium hydride and the like; the solvent is one or a mixture of toluene, benzene, acetone, methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, dioxane, acetonitrile, dichloromethane, dichloroethane, ethyl acetate, N-dimethylformamide, N-methylpyrrolidone and the like; the reaction temperature is selected from-20 ℃ to 120 ℃;

the dehydroxylation protecting group reaction can be carried out in the presence of acid or alkali, or in the presence of neutral reagent, wherein the acid is one or a mixture of p-toluenesulfonic acid, methanesulfonic acid, acetic acid, hydrochloric acid, sulfuric acid, zinc chloride, tin chloride, boron trifluoride and the like, and the alkali is one or a mixture of ammonia gas, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium fluoride, sodium fluoride, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium hydride, potassium tert-butoxide and the like; the neutral reagent is selected from tetrabutylammonium fluoride, palladium carbon and active nickel; the reaction solvent is one or a mixture of methanol, ethanol, isopropanol, toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane, N-dimethylformamide, pyridine, water and the like; the reaction temperature is-20 ℃ to 120 ℃;

the ring-opening reaction is carried out under the alkaline condition, and the alkali is one or a mixture of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; the reaction solvent is one or a mixture of methanol, ethanol, isopropanol, toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane, N-dimethylformamide, pyridine, water and the like; the reaction temperature is-20 ℃ to 120 ℃.

The invention also provides a method for preparing a2 '-deoxy-2' -fluoro-2 '-substituted uridine or 2' -deoxy-2 '-fluoro-2' -substituted cytidine or 2 '-deoxy-2' -cyano-2 '-substituted uridine or 2' -deoxy-2 '-cyano-2' -substituted cytidine compound using a compound of formula I, at R₃Is NR₄In the case of (2), the method is one of the following methods:

the method comprises the following steps:

the compound I-2-1 undergoes fluoro-or nitrile-reaction to obtain a compound IV-2-1, when R is required₄When the compound is a hydrogen atom, the compound IV-2-1 is a2 '-deoxy-2' -fluoro-2 '-substituted cytidine or a 2' -deoxy-2 '-cyano-2' -substituted cytidine compound; when R is₄When not hydrogen atom, 2' -deprotection is obtained by deprotection reactionAn oxy-2 ' -fluoro-2 ' -substituted cytidine or 2' -deoxy-2 ' -cyano-2 ' -substituted cytidine compound X; or, the compound IV-2-1 is further hydrolyzed to obtain 2 '-deoxy-2' -fluoro-2 '-substituted uridine or 2' -deoxy-2 '-cyano-2' -substituted uridine compound IV-1-1, which is shown in the following reaction formula:

wherein R is₆Is fluorine or nitrile group, R₂And R₄Are as defined for compounds of formula I or I-A;

or,

the second method comprises the following steps:

carrying out fluorination reaction or nitrile reaction on the compound I-2-2 to obtain a compound V-2-1, removing a hydroxyl protecting group from the compound V-2-1 to obtain a compound IV-2-1 as required, carrying out hydrolysis reaction on the compound IV-2-1 to obtain a compound IV-1-1, and obtaining a compound X from the compound IV-2-1 by removing a amino protecting group; or, the compound V-2-1 is hydrolyzed and subjected to hydroxyl protecting group removal simultaneously to obtain a compound IV-1-1, or, the compound V-2-1 is hydrolyzed firstly to obtain a compound V-1-1, then the hydroxyl protecting group is removed to obtain a compound IV-1-1, or, the compound V-2-1 is subjected to hydroxyl protecting group removal and amino protecting group removal to obtain a compound X, as shown in the following reaction formula:

wherein R and R are other than hydrogen₁Are as defined above for compounds of the general formula I or I-A; r₂And R₄Are as defined for compounds of formula I or I-A; r₆Is fluorine or nitrile group;

or,

the third method comprises the following steps:

the compound I-2-1 is subjected to ring-opening reaction to obtain a compound XI-2, the hydroxyl groups at the 3 'position and the 5' position are protected to obtain a compound VI-2-1, and the compound VI-2-1 can also be obtained by the ring-opening reaction of the compound I-2-2; carrying out fluorination or nitrile reaction on the compound VI-2-1 to obtain a compound V-2-1; compound V-2-1 Compound IV-1-1 and Compound X were prepared as described in Process II, and are represented by the following reaction scheme:

or,

the method four comprises the following steps:

carrying out acylation reaction or sulfonylation reaction on the 3' -hydroxyl of the compound VI-2-1 obtained in the third method to obtain a compound VII-2-1; the compound VII-2-1 is subjected to fluoro-reaction or nitrile-reaction to obtain a compound V-2-1, and the compound V-2-1 is subjected to the preparation of a compound IV-1-1 and a compound X by the method described in the second method, wherein the reaction formula is as follows:

wherein R and R are other than hydrogen₁Are as defined above for compounds of the general formula I or I-A; r₂And R₄Are as defined for compounds of formula I or I-A; r₆Is fluorine or nitrile group, R₇Selected from the group consisting of formyl, acetyl, benzoyl, 4-methoxybenzoyl, 4-chlorobenzoyl, methylsulfonyl, phenylsulfonyl, p-toluenesulfonyl and trifluoromethylsulfonyl.

At the upper partIn the process, in R₃Is NR₄In the case of (3), R is preferably₂Is methyl.

In the above method, the hydrolysis reaction is carried out in the presence of an acid selected from one or a mixture of acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, zinc chloride, tin chloride, boron trifluoride and the like, or a base selected from one or a mixture of triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide and the like; the reaction solvent is one or a mixture of methanol, ethanol, isopropanol, toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane, N-dimethylformamide, pyridine, water and the like, and the reaction temperature is-20 ℃ to 120 ℃.

In the above method, the deamination protecting group reaction is carried out in the presence of a base, wherein the base is one or a mixture of ammonia gas, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, carbonic acid, sodium methoxide, sodium ethoxide, potassium tert-butoxide, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine and the like; the reaction solvent is one or a mixture of methanol, ethanol, isopropanol, toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane, N-dimethylformamide, pyridine, water and the like, and the reaction temperature is-20 ℃ to 120 ℃.

In the above method, the hydrolysis and the deprotection reaction of hydroxyl groups are carried out in the presence of an acid selected from one or a mixture of acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, zinc chloride, tin chloride, boron trifluoride and the like, or a base selected from one or a mixture of triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide and the like; the reaction solvent is one or a mixture of methanol, ethanol, isopropanol, toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane, N-dimethylformamide, pyridine, water and the like, and the reaction temperature is-20 ℃ to 120 ℃.

In the above method, the dehydroxylation and deamination protecting group reaction is carried out in the presence of a base, wherein the base is one or a mixture of ammonia gas, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, carbonic acid, sodium methoxide, sodium ethoxide, potassium tert-butoxide, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, and N-methylmorpholine; the reaction solvent is one or a mixture of methanol, ethanol, isopropanol, toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane, N-dimethylformamide, pyridine, water and the like, and the reaction temperature is-20 ℃ to 120 ℃.

In the process for producing a2 '-deoxy-2' -fluoro-2 '-substituted cytidine or 2' -deoxy-2 '-cyano-2' -substituted cytidine compound using a compound of formula I, the above pair is represented by R₃The descriptions of the fluorination reaction, the cyanation reaction, the dehydroxylation protecting group reaction, the ring-opening reaction, the hydroxyl group-protecting reaction, the acylation reaction and the sulfonylation reaction in the case of an oxygen atom are also applicable to R₃Is NR₄And therefore, will not be described in detail herein.

The present invention also provides a process for preparing a2 '-deoxy-2' -fluoro-2 '-substituted uridine or a 2' -deoxy-2 '-cyano-2' -substituted uridine compound using a compound of general formula I, said process comprising:

taking 2' -C-methyluridine (II-1-3) as a raw material, carrying out closed-loop reaction to obtain a compound I-1-3, and then directly adding a fluoro reagent or a nitrile reagent into a reaction kettle to generate a compound IV-1-2, wherein the reaction formula is as follows:

wherein R is₆Is fluorine or nitrile group.

The ring-closure reaction can be carried out in a suitable solvent in the presence of a base and in the presence or absence of diphenyl carbonate, wherein the base can be selected from organic bases and inorganic bases, and is preferably selected from one or a mixture of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, 4-dimethylaminopyridine and the like; the solvent is one or a mixture of N, N-dimethylformamide, N-dimethylacetamide, DMSO, acetonitrile, acetone, toluene, dioxane, pyridine and the like; the reaction temperature is selected from 20-200 ℃, preferably 60-140 ℃; the ring-closure reaction is preferably carried out in the presence of diphenyl carbonate, and the molar ratio of the compound II-1-3 to the diphenyl carbonate is 1: 1-10, preferably 1: 1-3.

The fluorinating agent is selected from F₂One or a mixture of HF, HF/Py, NaF, KF, tetrabutylammonium fluoride, triethylamine trihydrofluoride, diethylaminosulfur trifluoride, bis- (2-methoxyethyl) aminesulfluoride, and the like; the nitrile-based reagent is one or a mixture of sodium cyanide, potassium cyanide, trimethyl cyanide silane, hydrogen cyanide, cyanogen gas, tetrabutylammonium cyanide and the like.

The fluorination or cyanation may be carried out in the presence of an acid or a base selected from inorganic and organic bases, preferably one or a mixture of potassium carbonate, triethylamine, pyridine, etc.; the acid may be selected from hydrogen fluoride and the like; the solvent for the fluoro-or nitrile-reaction is one or a mixture of methanol, ethanol, isopropanol, water, toluene, benzene, acetone, methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, dioxane, acetonitrile, dichloromethane, dichloroethane, ethyl acetate, N-dimethylformamide, N-methylpyrrolidone and the like; the temperature of the fluorination or nitrile reaction is-80 ℃ to 150 ℃.

Advantageous effects

The method for preparing the compound shown in the general formula I and then preparing the 2 '-deoxy-2' -fluoro-2 '-substituted uridine or 2' -deoxy-2 '-fluoro-2' -substituted cytidine or 2 '-deoxy-2' -nitrile-2 '-substituted uridine or 2' -deoxy-2 '-nitrile-2' -substituted cytidine compound has the advantages that: the 2-position configuration is inverted by intramolecular substitution using the existing structural skeleton of uridine or cytidine analog, and then the 2-position configuration is inverted again by fluorination or cyanation reaction to obtain the desired configuration. In this process, the configuration of the uracil base or cytosine base remains unchanged, avoiding the production of isomers. Experiments prove that the method has mild reaction conditions, easy operation, high yield, stable quality of the obtained product and high purity, and can be used for industrial scale production.

Detailed Description

Example 1:

2' -C-methyluridine (0.2g,0.8mmol) was dissolved in N, N-dimethylformamide (4ml), diphenyl carbonate (0.256g,1.2mmol) and sodium hydrogencarbonate (55mg,0.66mmol) were added, heating was carried out to 150 ℃, stirring was carried out for 6 hours, cooling was carried out, the solvent was removed under reduced pressure, ethyl acetate was added to the residue, and the mixture was slurried and filtered to obtain a solid (150mg, yield: 81%).

Ia:¹H NMR(300MHz,CD₃OD):7.80(d,1H,J=7.5Hz),6.05(d,1H,J=7.5Hz),5.91(s,1H),4.34(d,1H,J=4.8Hz),4.07(m,1H),3.56(m,2H),1.63(s,3H);ESI-MS m/z(M+1)241。

Example 2:

compound Ia (0.24g,1mmol)) from example 1 was dissolved in 70% HF pyridine solution, heated to 140-150 deg.C, stirred for 3 hours, cooled, the solvent removed under reduced pressure, acetone was added to the residue, slurried, and filtered to give a solid (0.18g, yield: 70%).

IIIa:¹H NMR(300MHz,DMSO-d₆):11.48(s,1H),7.82(d,1H,J=6.0Hz),6.00(d,1H,J=15.6Hz),5.67(m,2H),5.30(s,1H),3.85(m,3H),3.62(s,1H),1.25(d,3H,J=16.8Hz),ESI-MS m/z(M-1)259。

Example 3:

2' -C-methyluridine (18.4g,0.07mol), carbonyldiimidazole (216.2g,0.10mol), sodium bicarbonate (8.4g,0.10mol) were suspended in N, N-dimethylformamide (50ml), the temperature was raised to 130 ℃ to react for 4 hours, cooling was performed, inorganic salts were removed by filtration, ethyl acetate (200ml) was added to the filtrate, the mixture was separated, cooled to room temperature, and then subjected to suction filtration, ethyl acetate washing and drying to obtain a yellow solid (19.9g, yield: 83%).

Example 4:

compound Ia (0.24g,1mmol) from example 1 was dissolved in dichloromethane (4ml), triethylamine (0.5ml) was added, the mixture was stirred for 24 hours in an ice bath with benzoyl chloride (0.28g) being added slowly and the temperature being raised slowly to ambient temperature, the solvent was removed under reduced pressure to give a residue, and silica gel column chromatography gave the product (0.37g, yield: 82%).

Ib:¹H NMR(300MHz,CDCl₃):7.96-8.10(m,6H),7.41-7.65(m,9H),7.32(d,1H,J=5.4Hz),6.09(d,1H,J=5.4Hz),5.79(m,2H),4.67(m,1H),4.48(m,2H),1.81(s,3H);ESI-MS m/z(M-1)447。

Example 5:

compound Ib (0.45g,1mmol) obtained in example 4 was dissolved in a mixture of dichloromethane and pyridine, DAST (0.32g) was added, stirring was carried out for 24 hours, and it was diluted with dichloromethane (20ml), washed with water (30 ml. times.2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give a residue which was subjected to column chromatography to give a product (0.36g, yield: 78%).

IIa:¹H NMR(400MHz,CDCl₃And DMSO-d₆):7.99(d,J=7.6Hz,2H),7.90(d,J=7.6Hz,2H),7.34～7.61(m,7H),6.10(brs,1H),5.64(brs,1H),5.42(d,J=8.0Hz,1H),4.53-4.68(m,3H),1.40(d,J=22.8Hz,3H);ESI-MS m/z(M+1)469。

Example 6:

compound IIa (0.47g,1mmol) from example 5 was dissolved in 10% ammonia in methanol, stirred overnight, the solvent removed under reduced pressure, the residue slurried in ethyl acetate and filtered to give a white solid (0.2g, yield: 77%).

Example 7:

the compound IVa (0.57g,1mmol) was dissolved in dichloroethane (20ml), trimethylsilyl trifluoromethanesulfonate (1ml) was added, the reaction was heated for 12 hours, cooled, the reaction solution was concentrated to dryness, dichloromethane (100ml) was added to dissolve it, washed with water (50ml) and saturated brine (50ml) in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain an oily substance, which was purified by column chromatography to obtain a white solid (0.3g, yield: 67%).

Example 8:

compound Ia (1.3g,5.4mmol) from example 1 was dissolved in dry N, N-dimethylformamide (10ml), p-toluenesulfonic acid monohydrate (1.12g,5.9mmol) and 3, 4-dihydropyran (1.28ml,14.04mmol) were added, the reaction was stirred at room temperature for 5 hours, water and dichloromethane were added, the layers were separated, the organic layer was concentrated, and the product was purified by silica gel chromatography to give 1.3 g.

Ic:¹H NMR(300MHz,CDCl₃):7.29(m,1H),6.08(m,1H),5.61(m,1H),4.33-4.72(m,4H),3.37-3.90(m,6H),1.43-1.82(m,12H),1.25(s,3H);ESI-MS m/z(M+1)427。

Example 9:

the compound Ic (0.43g,1mmol) of example 8 was dissolved in 70% HF pyridine solution, heated to 100 to 120 ℃ and stirred for 5 hours, cooled, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give a solid (0.18g, yield: 72%).

Example 10:

the compound Ic (50mg,0.122mmol) of example 8 was dissolved in methanol (1ml), and 1N sodium hydroxide solution (0.2ml) was added thereto, stirred at room temperature overnight, water and dichloromethane were added, the layers were separated, the organic layer was concentrated, and the product was purified by column chromatography to give a product (45mg, yield: 87%).

Va:¹H NMR(300MHz,CDCl₃):7.89(d,1H,J=4.5Hz),6.01(s,1H),5.95(d,1H,J=4.5Hz),5.65(m,2H),4.73(m,3H),4.59(m,1H),3.52-4.30(m,4H),1.56-1.80(m,12H),1.32(s,3H);ESI-MS m/z(M+35)461。

Example 11:

compound Va (0.43g,1mmol) from example 10 was dissolved in a mixture of dichloromethane and pyridine, DAST (0.32g) was added, stirred for 24 hours, diluted with dichloromethane (20ml), washed with water (30 ml. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound IIb. Compound IIb was dissolved in methanol (10ml), p-toluenesulfonic acid (200mg) was added thereto, the mixture was stirred at room temperature for 6 hours, the methanol was removed under reduced pressure, and column chromatography on silica gel was carried out to give product IIIa (180mg, yield: 75%).

Example 12:

2' -C-methyluridine (0.2g,0.8mmol) was dissolved in N, N-dimethylformamide (4ml), diphenyl carbonate (0.256g,1.2mmol) and sodium bicarbonate (55mg,0.66mmol) were added, heating was carried out to 150 ℃, stirring was carried out for 6 hours, cooling was carried out, the solvent was removed under reduced pressure, the residue was dissolved in 70% HF pyridine solution, heating was carried out to 140 to 150 ℃, stirring was carried out for 3 hours, cooling was carried out, the solvent was removed under reduced pressure, the residue was added to acetone, and filtration was carried out to obtain solid IIIa (0.13g, yield: 65%).

Example 13:

compound Va (4.26g,10mmol) of example 10 was dissolved in dry tetrahydrofuran (100ml) under nitrogen protection, triethylamine (6g,60mmol) was added, cooling was carried out to-78 ℃ and trifluoromethanesulfonic anhydride (4.23g,15mmol) was added, and after stirring for 1 hour, a saturated ammonium chloride solution was added to the reaction system, extraction was carried out three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography to give product Vb (4g, yield: 72%). ESI-MS M/z (M-1) 557.

The compound Vb (4g) was dissolved in dry tetrahydrofuran, tetrabutylammonium fluoride (1.87g,7.1mmol) was added, the mixture was heated to reflux, after heating for 1 hour, the temperature was lowered to room temperature, water was added to the reaction system, extraction was carried out three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography to give the product IIb (2.7g, yield: 88%). ESI-MS M/z (M-1) 427.

Compound IIb (2.7g) was dissolved in methanol (20ml), 3M hydrochloric acid (10ml) was added, stirring was carried out at 50 ℃ for 8 hours, concentration was carried out to give a solid, acetonitrile was added, and the mixture was slurried and filtered to give product IIIa (1g, yield: 61%).

Claims

1. A compound of the following formula I:

r and R₁Each independently is a hydrogen atom or a hydroxyl protecting group, or R and R₁Combining to form a cyclic hydroxy protecting group;

R₂is C1-C6 straight chain or branched alkyl, C1-C6 straight chain or branched alkyl substituted by one or more halogens or hydroxylA nitrile group or a halogen;

R₃is an oxygen atom or NR₄Wherein R is₄Is hydrogen atom, acyl substituted by C1-C6 straight chain or branched chain alkyl, and substituted or unsubstituted benzoyl.

2. The compound of claim 1, wherein,

r and R₁Each independently selected from the group consisting of a hydrogen atom, a methyl group, a C1-C6 straight or branched chain alkyl substituted acyl group, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, a methanesulfonyl group, a benzenesulfonyl group, a p-toluenesulfonyl group, a tetrahydropyran-2-yl group, a tris (C1-C6 straight or branched chain alkyl) silyl group, a t-butyl bis (C1-C6 straight or branched chain alkyl) silyl group, a t-butyl diphenylsilyl group, a methylthiomethyl group, a methoxymethyl group, and a 2-methoxyethoxymethyl group; most preferably, R and R₁Each independently selected from the group consisting of a hydrogen atom, a methyl group, a formyl group, an acetyl group, a pivaloyl group, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, a methanesulfonyl group, a benzenesulfonyl group, a p-toluenesulfonyl group, a tetrahydropyran-2-yl group, a trimethylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a methylthiomethyl group, a methoxymethyl group and a 2-methoxyethoxymethyl group; the substituents on the substituted benzoyl and substituted benzyl groups are selected from nitro, C1-C6 linear or branched alkoxy, halogen, C1-C6 linear or branched alkyl and phenyl, preferably from nitro, methoxy, chloro, methyl and phenyl; or,

r and R₁Joined together to form-SiR ' -O-SiR ' -or-SiR ' -, wherein R ' is a C1-C6 linear or branched alkyl group, preferably R ' is isopropyl;

R₂is C1-C4 straight or branched chain alkyl, trifluoromethyl, hydroxymethyl, nitrile, difluoromethyl, fluoro or chloro, most preferably, R₂Is methyl, ethyl, trifluoromethyl or nitrile group;

R₃is an oxygen atom or NR₄Wherein R is₄Is hydrogen atom, formyl group, acetyl group, substituted or unsubstituted benzoyl group, most preferably, R₄Is hydrogen atom, formyl, or BAcyl or benzoyl, wherein the substituents on the substituted benzoyl are selected from nitro, C1-C6 linear or branched alkoxy, halogen and C1-C6 linear or branched alkyl, preferably from nitro, methoxy, chlorine and methyl.

3. The compound of claim 1, the compound of formula I is a compound of formula I-a as follows:

wherein,

r and R₁Each independently is a hydrogen atom or a hydroxyl protecting group, preferably, R and R₁Each independently selected from the group consisting of a hydrogen atom, a methyl group, a C1-C6 straight or branched chain alkyl substituted acyl group, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, a methanesulfonyl group, a benzenesulfonyl group, a p-toluenesulfonyl group, a tetrahydropyran-2-yl group, a tris (C1-C6 straight or branched chain alkyl) silyl group, a t-butyl bis (C1-C6 straight or branched chain alkyl) silyl group, a t-butyl diphenylsilyl group, a methylthiomethyl group, a methoxymethyl group, and a 2-methoxyethoxymethyl group, with R and R being most preferred₁Each independently selected from the group consisting of a hydrogen atom, a methyl group, a formyl group, an acetyl group, a pivaloyl group, a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzyl group, a trityl group, a methanesulfonyl group, a benzenesulfonyl group, a p-toluenesulfonyl group, a tetrahydropyran-2-yl group, a trimethylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a methylthiomethyl group, a methoxymethyl group and a 2-methoxyethoxymethyl group; or,

r and R₁Combined to form a cyclic hydroxy-protecting group, preferably, R and R₁Joined together to form-SiR ' -O-SiR ' -or-SiR ' -, wherein R ' is a C1-C6 linear or branched alkyl group, most preferably, R ' is isopropyl;

R₃is an oxygen atom or NR₄Wherein R is₄Is hydrogen atom, acyl, benzoyl or substituted benzoyl substituted by C1-C6 straight chain or branched chain alkyl, most preferably, R₄Selected from hydrogen atomsFormyl, acetyl and benzoyl;

the substituents on the substituted benzoyl and benzyl groups are preferably selected from nitro, C1-C6 linear or branched alkoxy, halogen and C1-C6 linear or branched alkyl, more preferably nitro, methoxy, chloro and methyl.

4. The compound of claim 1, wherein the compound of formula I is selected from the group consisting of:

5. a process for the preparation of a compound as claimed in claim 1, in which R₃In the case of an oxygen atom, the method is one of the following methods:

the method comprises the following steps:

wherein R is₂Is as defined in claim 1;

or

The second method comprises the following steps:

wherein R and R are other than hydrogen₁Is as defined in claim 1; r₂Is as defined in claim 1;

or,

the third method comprises the following steps:

wherein, R, R₁And R₂Is as defined in claim 1;

R₅is hydrogen, C1-C4 alkanoyl, benzoyl substituted by C1-C4 alkoxy, benzoyl substituted by halogen, methanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl or p-toluenesulfonyl, preferably, R is₅Is hydrogen atom, formyl group, acetyl group, benzoyl group, 4-methoxybenzoyl group, 4-chlorobenzoyl group, methylsulfonyl group, trifluoromethanesulfonyl group or p-toluenesulfonyl group; or,

R₁and R₅Are combined to formOr

6. The method of claim 5, wherein R₂Is methyl.

7. A process for the preparation of a compound as claimed in claim 1, at R₃Is NR₄In the case of (2), the method is one of the following methods:

the method comprises the following steps:

wherein R is₂And R₄Is as defined in claim 1;

or

The second method comprises the following steps:

wherein R and R are other than hydrogen₁Is as defined in claim 1; r₂And R₄Is as defined in claim 1;

or,

the third method comprises the following steps:

wherein, R, R₁、R₂And R₄Is as defined in claim 1;

R₁and R₅Are combined to formOr

8. The process according to claim 7, wherein R is₂Is methyl, and/or R₄Is hydrogen atom, formyl, acetyl or benzoyl.

9. The production method according to any one of claims 5 to 8,

in the first method, the ring closure reaction is carried out in a suitable solvent in the presence of a base selected from organic bases and inorganic bases, preferably one or a mixture of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, triethylamine and 4-dimethylaminopyridine, with or without diphenyl carbonate; the solvent is one or a mixture of N, N-dimethylformamide, N-dimethylacetamide, DMSO, acetonitrile, acetone, toluene, dioxane and pyridine; the ring-closing reaction is preferably carried out in the presence of diphenyl carbonate, and the molar ratio of the compound II-1 to the diphenyl carbonate is 1: 1-10, preferably 1: 1-3;

in the second method, the hydroxyl protection reaction is carried out in a suitable solvent in the presence of an acidic or basic catalyst, wherein the acidic catalyst is one or a mixture of p-toluenesulfonic acid, methanesulfonic acid, acetic acid, zinc chloride, tin chloride and boron trifluoride, and the basic catalyst is one or a mixture of triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, potassium carbonate and sodium hydride; the solvent is one or a mixture of toluene, benzene, acetone, methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, dioxane, acetonitrile, dichloromethane, dichloroethane, ethyl acetate, N-dimethylformamide and N-methylpyrrolidone;

in the third method, the intramolecular substitution reaction is carried out in the presence of an acidic or basic catalyst, the acidic catalyst is one or a mixture of trimethylsilyl trifluoromethanesulfonate, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, zinc chloride, tin chloride and boron trifluoride, and the basic catalyst is one or a mixture of triethylamine, pyridine, 4-dimethylaminopyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, potassium carbonate and sodium hydride; the reaction solvent is one or a mixture of methanol, ethanol, isopropanol, toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane, dichloroethane, N-dimethylformamide and pyridine.

10. A process for preparing a2 '-deoxy-2' -fluoro-2 '-substituted uridine or 2' -deoxy-2 '-fluoro-2' -substituted cytidine or 2 '-deoxy-2' -cyano-2 '-substituted uridine or 2' -deoxy-2 '-cyano-2' -substituted cytidine compound using the compound of claim 1, at R₃In the case of an oxygen atom, the method is one of the following methods:

the method comprises the following steps:

wherein R is₆Is fluorine or nitrile group, R₂Is as defined in claim 1;

or,

the second method comprises the following steps:

wherein R and R are other than hydrogen₁Is as defined in claim 1; r₂Is as defined in claim 1; r₆Is fluorine or nitrile group;

or,

the third method comprises the following steps:

the compound I-1-1 is subjected to ring-opening reaction to obtain a compound XI-1, the hydroxyl groups at the 3 'position and the 5' position are protected to obtain a compound VI-1-1, and the compound VI-1-1 can also be obtained by the ring-opening reaction of the compound I-1-2; then carrying out fluorination or nitrile reaction on the compound VI-1-1 to obtain a compound V-1-1; then, the protecting group is removed to obtain a compound IV-1-1, which is shown as the following reaction formula:

or,

the method four comprises the following steps:

wherein R and R are other than hydrogen₁Is as defined in claim 1; r₂Is as defined in claim 1; r₆Is fluorine or nitrile group, R₇Selected from the group consisting of formyl, acetyl, benzoyl, 4-methoxybenzoyl, 4-chlorobenzoyl, methylsulfonyl, phenylsulfonyl, p-toluenesulfonyl and trifluoromethylsulfonyl.

11. The process according to claim 10, wherein R is₂Is methyl.

12. A process for preparing a2 '-deoxy-2' -fluoro-2 '-substituted uridine or 2' -deoxy-2 '-fluoro-2' -substituted cytidine or 2 '-deoxy-2' -cyano-2 '-substituted uridine or 2' -deoxy-2 '-cyano-2' -substituted cytidine compound using a compound according to claim 1, at R₃Is NR₄In the case of (2), the method is one of the following methods:

the method comprises the following steps:

the compound I-2-1 undergoes fluoro-or nitrile-reaction to obtain a compound IV-2-1, when R is required₄When the compound is a hydrogen atom, the compound IV-2-1 is a2 '-deoxy-2' -fluoro-2 '-substituted cytidine or a 2' -deoxy-2 '-cyano-2' -substituted cytidine compound; when R is₄When the hydrogen atom is not contained, obtaining a2 '-deoxy-2' -fluoro-2 '-substituted cytidine or a 2' -deoxy-2 '-cyano-2' -substituted cytidine compound X through deprotection reaction; or, the compound IV-2-1 is further hydrolyzed to obtain 2 '-deoxy-2' -fluoro-2 '-substituted uridine or 2' -deoxy-2 '-cyano-2' -substituted uridine compound IV-1-1, which is shown in the following reaction formula:

wherein R is₆Is fluorine or nitrile group, R₂And R₄Is as defined in claim 1;

or,

the second method comprises the following steps:

the compound I-2-2 is subjected to fluorination or nitrile reaction to obtain a compound V-2-1, and according to the requirements, the compound V-2-1 is subjected to hydroxyl protecting group removal to obtain a compound IV-2-1, the compound IV-2-1 is subjected to hydrolysis reaction to obtain a compound IV-1-1, and the compound IV-2-1 can also be subjected to deamination protecting group removal to obtain a compound X; or, the compound V-2-1 is hydrolyzed and subjected to hydroxyl protecting group removal simultaneously to obtain a compound IV-1-1, or, the compound V-2-1 is hydrolyzed firstly to obtain a compound V-1-1, then the hydroxyl protecting group is removed to obtain a compound IV-1-1, or, the compound V-2-1 is subjected to hydroxyl protecting group removal and amino protecting group removal to obtain a compound X, as shown in the following reaction formula:

wherein R and R are other than hydrogen₁Is as defined in claim 1; r₂And R₄Is as defined in claim 1; r₆Is fluorine or nitrile group;

or,

the third method comprises the following steps:

the compound I-2-1 is subjected to ring-opening reaction to obtain a compound XI-2, the hydroxyl groups at the 3 'position and the 5' position are protected to obtain a compound VI-2-1, and the compound VI-2-1 can also be obtained by the ring-opening reaction of the compound I-2-2; carrying out fluorination or nitrile reaction on the compound VI-2-1 to obtain a compound V-2-1; compound V-2-1 Compound IV-1-1 and Compound X were prepared as described in Process two, and are represented by the following reaction scheme:

or,

the method four comprises the following steps:

carrying out acylation reaction or sulfonylation reaction on 3' -hydroxyl of the compound VI-2-1 obtained in the third method to obtain a compound VII-2-1; the compound VII-2-1 is subjected to fluoro-reaction or nitrile-reaction to obtain a compound V-2-1, and the compound V-2-1 is subjected to the preparation of a compound IV-1-1 and a compound X by the method described in the second method, wherein the reaction formula is as follows:

wherein R and R are other than hydrogen₁Is as defined in claim 1; r₂And R₄Is as defined in claim 1; r₆Is fluorine or nitrile group, R₇Selected from formyl, acetyl, benzoyl, 4-methylOxybenzoyl, 4-chlorobenzoyl, methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, and trifluoromethanesulfonyl.

13. The method of claim 12, wherein R₂Is methyl.

14. The method of any one of claims 10-13,

the fluorination reaction or the nitrile reaction is carried out in the presence of a fluorination reagent or a nitrile reagent; the fluorinating agent is selected from F₂One or a mixture of HF, HF/Py, NaF, KF, tetrabutylammonium fluoride, triethylamine trihydrofluoride, diethylaminosulfur trifluoride and bis- (2-methoxyethyl) aminesulfluoride; the nitrile-based reagent is one or a mixture of sodium cyanide, potassium cyanide, trimethyl cyano silane, hydrogen cyanide, cyanogen gas and tetrabutyl ammonium cyanide; the fluorination reaction or the nitrile reaction can be carried out in the presence of acid or alkali, and the alkali is selected from inorganic alkali or organic alkali, preferably one or a mixture of potassium carbonate, triethylamine or pyridine; the acid may be selected from hydrogen fluoride and the like; the solvent for the fluoro-or nitrile-reaction is one or a mixture of methanol, ethanol, isopropanol, water, toluene, benzene, acetone, methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, dioxane, acetonitrile, dichloromethane, dichloroethane, ethyl acetate, N-dimethylformamide and N-methylpyrrolidone;

the acylation reaction is carried out in a suitable solvent in the presence of a base, wherein the base is one or a mixture of triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hexamethyldisilazide and lithium hexamethyldisilazide; the acylating agent is selected from the group consisting of methyl formate, ethyl formate, formic acid, acetyl chloride, acetic anhydride, benzoyl chloride, benzoic anhydride, 4-methoxybenzoyl chloride, 4-methoxybenzoic anhydride, 4-chlorobenzoyl chloride and 4-chlorobenzoic anhydride; the reaction solvent is one or a mixture of toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane, N-dimethylformamide and pyridine;

the sulfonylation reaction is carried out in a suitable solvent in the presence of a base, wherein the base is one or a mixture of triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hexamethyldisilazide and lithium hexamethyldisilazide; the sulfonylating agent is selected from methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride and trifluoromethanesulfonic anhydride; the reaction solvent is one or a mixture of toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane, N-dimethylformamide and pyridine;

the hydroxyl protection reaction is carried out in a suitable solvent in the presence of an acidic or basic catalyst, wherein the acidic catalyst is one or a mixture of p-toluenesulfonic acid, methanesulfonic acid, acetic acid, zinc chloride, tin chloride and boron trifluoride, and the basic catalyst is one or a mixture of triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, potassium carbonate and sodium hydride; the solvent is one or a mixture of toluene, benzene, acetone, methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, dioxane, acetonitrile, dichloromethane, dichloroethane, ethyl acetate, N-dimethylformamide and N-methylpyrrolidone;

the dehydroxylation protecting group reaction can be carried out in the presence of acid or alkali, and also in the presence of a neutral reagent, wherein the acid is one or a mixture of p-toluenesulfonic acid, methanesulfonic acid, acetic acid, hydrochloric acid, sulfuric acid, zinc chloride, tin chloride and boron trifluoride, and the alkali is one or a mixture of ammonia gas, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium fluoride, sodium fluoride, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium hydride and potassium tert-butoxide; the neutral reagent is selected from tetrabutylammonium fluoride, palladium carbon and active nickel; the reaction solvent is one or a mixture of methanol, ethanol, isopropanol, toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane, N-dimethylformamide, pyridine and water;

the ring-opening reaction is carried out under the alkaline condition, and the alkali is one or a mixture of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, sodium hydride, sodium methoxide, sodium ethoxide and potassium tert-butoxide; the reaction solvent is one or a mixture of methanol, ethanol, isopropanol, toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane, N-dimethylformamide, pyridine and water;

the hydrolysis reaction is carried out in the presence of acid or alkali, the acid is selected from one or a mixture of acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, zinc chloride, stannic chloride and boron trifluoride, and the alkali is selected from one or a mixture of triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium hydroxide; the reaction solvent is one or a mixture of methanol, ethanol, isopropanol, toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane, N-dimethylformamide, pyridine and water;

the deamination protecting group reaction is carried out in the presence of alkali, wherein the alkali is one or a mixture of ammonia gas, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, carbonic acid, sodium methoxide, sodium ethoxide, potassium tert-butoxide, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine and N-methylmorpholine; the reaction solvent is one or a mixture of methanol, ethanol, isopropanol, toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane, N-dimethylformamide, pyridine and water;

the hydrolysis and the hydroxyl-protecting group removal reaction are carried out in the presence of acid or alkali, wherein the acid is one or a mixture of acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, zinc chloride, tin chloride and boron trifluoride, and the alkali is one or a mixture of triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, potassium carbonate, sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium hydroxide; the reaction solvent is one or a mixture of methanol, ethanol, isopropanol, toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane, N-dimethylformamide, pyridine and water;

the dehydroxylation and deamination protecting group reaction is carried out in the presence of alkali, wherein the alkali is one or a mixture of ammonia gas, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, carbonic acid, sodium methoxide, sodium ethoxide, potassium tert-butoxide, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine and N-methylmorpholine; the reaction solvent is one or a mixture of methanol, ethanol, isopropanol, toluene, benzene, acetone, tetrahydrofuran, acetonitrile, dichloromethane, N-dimethylformamide, pyridine and water.

15. A method of using the compound of claim 1 for preparing a2 '-deoxy-2' -fluoro-2 '-substituted uridine or 2' -deoxy-2 '-cyano-2' -substituted uridine compound, said method comprising:

wherein R is₆Is fluorine or nitrile group.

16. The production method according to claim 15, wherein,

the ring-closure reaction is carried out in a suitable solvent in the presence of a base and in the presence or absence of diphenyl carbonate, wherein the base is selected from organic bases or inorganic bases, and is preferably selected from one or a mixture of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, triethylamine and 4-dimethylaminopyridine; the solvent is one or a mixture of N, N-dimethylformamide, N-dimethylacetamide, DMSO, acetonitrile, acetone, toluene, dioxane and pyridine; the ring-closing reaction is carried out in the presence of diphenyl carbonate, and the molar ratio of the compound II-1-3 to the diphenyl carbonate is 1: 1-10, preferably 1: 1-3;

the fluorinating agent is selected from F₂One or a mixture of HF, HF/Py, NaF, KF, tetrabutylammonium fluoride, triethylamine trihydrofluoride, diethylaminosulfur trifluoride and bis- (2-methoxyethyl) aminesulfluoride; the nitrile-based reagent is one or a mixture of sodium cyanide, potassium cyanide, trimethyl cyanide silane, hydrogen cyanide, cyanogen gas and tetrabutylammonium cyanide.

17. The preparation method according to claim 16, wherein the fluoro-or nitrilation reaction is carried out in the presence of an acid or a base selected from inorganic or organic bases, preferably one or a mixture selected from potassium carbonate, triethylamine and pyridine; the acid is hydrogen fluoride; the solvent for the fluoro-or nitrile-reaction is one or a mixture of methanol, ethanol, isopropanol, water, toluene, benzene, acetone, methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, dioxane, acetonitrile, dichloromethane, dichloroethane, ethyl acetate, N-dimethylformamide and N-methylpyrrolidone.