CN113512083A - Method for synthesizing nucleotide or nucleotide analogue - Google Patents

Abstract

The invention provides a method for synthesizing nucleotide or nucleotide analogue. The method comprises the following steps of carrying out nucleophilic substitution reaction on nucleoside and phosphate, pyrophosphate or tripolyphosphate under the catalysis of a phase transfer catalyst so as to obtain the nucleotide or nucleotide analogue, wherein the phosphate, pyrophosphate or tripolyphosphate is non-ammonium phosphate salt, the nucleoside has a structure shown in a formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a prodrug thereof of the structure shown in the formula (I),

Description

Method for synthesizing nucleotide or nucleotide analogue

Technical Field

The present invention relates to the field of biosynthesis, in particular, the present invention relates to methods for synthesizing nucleotides or nucleotide analogs.

Background

Nucleotide compounds have an important position in chemistry, biology and chemical biology. Nucleotide is the basic component of all biological cells, and plays a leading role in growth, development, reproduction, heredity and the like of organisms. Therefore, nucleotides are widely applied to national economic construction, for example, deoxynucleoside triphosphate and deoxynucleoside hexaphosphate are widely applied to DNA sequencing as DNA sequencing reagents, and nucleoside monophosphate can be used as an important additive in infant milk powder.

The synthesis of various nucleotides and nucleotide analogs has important economic significance and scientific research significance. At present, enzymatic synthesis and chemical synthesis are the main methods for synthesizing various kinds of nucleotides, and the chemical methods have been greatly developed after decades of development. Although various types of nucleotides can be synthesized by chemical synthesis, there are still many problems to be solved in the chemical synthesis of nucleotides. For example, the synthesis method is complex, the steps are long, the synthesis cost is high, the reaction yield is low, and the like.

In the prior art, nucleophilic substitution reactions are most widely applied to the synthesis of various nucleotides, wherein ammonium salts of various phosphates as nucleophilic reagents are one of key raw materials for preparing various nucleotides. However, the preparation of various ammonium phosphates is subject to acid-base neutralization, cation exchange and other steps, and the preparation is complicated, so that the preparation complexity causes various ammonium phosphates to have higher prices. And various ammonium phosphates are easy to absorb moisture in the air and need to be stored at low temperature. The decomposition of the reagent is often accompanied in the course of use. On the other hand, there are various commercially available sodium phosphates, potassium phosphates, sodium pyrophosphates, and potassium pyrophosphates, which are not suitable for direct use in nucleotide synthesis, although their prices are not high.

Disclosure of Invention

The present invention is directed to solving, at least to some extent, one of the technical problems in the related art.

To this end, in a first aspect of the invention, the invention provides a method of synthesizing a nucleotide or nucleotide analogue. According to an embodiment of the invention, the method comprises nucleophilic substitution reaction of nucleoside with phosphate, pyrophosphate or tripolyphosphate under catalysis of phase transfer catalyst so as to obtain the nucleotide or nucleotide analogue, the phosphate, pyrophosphate or tripolyphosphate is non-ammonium phosphate salt, wherein the nucleoside has a structure shown in formula (I) or a stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug thereof of the structure shown in formula (I),

wherein X, Y are each independently selected from H, D, F, Cl, Br, CN, NO₂、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、-OR^b、-NR^cR^d、R^bO-C_1-4Alkylene radical, R^dR^cN-C_1-4Alkylene radical, C_1-6Alkyl radical, C_2-6Alkenyl or C_2-6Alkynyl radicals, or X, Y together with the carbon atom to which they are attached, form C_3-6Carbocycle, heterocycle of 5-6 atoms, C_6-10An aromatic ring or a heteroaromatic ring of 5 to 6 atoms, wherein C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Carbocycle, heterocycle of 5-6 atoms, C_6-10The aromatic ring and the 5-6 atom heteroaromatic ring are each independently unsubstituted OR substituted with 1,2,3 OR 4 substituents independently selected from D, F, Cl, Br, CN, -OR^b、-NR^cR^d、C_1-6Alkyl radical, C_1-6Haloalkyl, R^bO-C_1-4Alkylene or R^dR^cN-C_1-4Alkylene radical OR^a _,H、D、F、Cl、Br、CN、NO₂、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、-OR^b、-NR^cR^d、R^bO-C_1-4Alkylene radical, R^dR^cN-C_1-4Alkylene radical, C_1-6Alkyl radical, C_2-6Alkenyl or C_2-6An alkynyl group;

r is H or

R₁、R₂Each is independentThe three sites are selected from H, D, F, Cl, Br, CN, NO₂、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、-OR^b、-NR^cR^d、R^bO-C_1-4Alkylene radical, R^dR^cN-C_1-4Alkylene radical, C_1-6Alkyl radical, C_2-6Alkenyl or C_2-6An alkynyl group;

R^a、R^b、R^cand R^dEach independently H, D, hydroxy, C_1-6Haloalkyl, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Carbocyclyl, C_3-6carbocyclyl-C_1-4Alkylene, heterocyclic group consisting of 3 to 12 atoms, (heterocyclic group consisting of 3 to 12 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms or (heteroaryl of 5 to 10 atoms) -C_1-4Alkylene, wherein said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Carbocyclyl, C_3-6carbocyclyl-C_1-4Alkylene, heterocyclic group consisting of 3 to 12 atoms, (heterocyclic group consisting of 3 to 12 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms and (heteroaryl of 5 to 10 atoms) -C_1-4Each alkylene is independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, Cl, CN, OH, NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy or C_1-6An alkylamino group;

a is adenine, guanine, cytosine, uracil or thymine.

The inventors of the present application have made the ingenious use of the principle of phase transfer catalysis, i.e. the interaction of ion pairs is used to increase the reactivity and solubility of anions in the reaction. The phase transfer catalyst with the catalytic amount is dissolved in the organic phase, and meanwhile, the phase transfer catalyst and the phosphate which is not dissolved in the organic phase are subjected to anion exchange to generate the amine phosphate in situ. The driving force for ion exchange comes from the fact that the positive ions of the transfer catalyst have a larger structure and can be more tightly bound to the anions to pull the equilibrium towards the formation of amine phosphate. The in-situ generated amine phosphate has better solubility and stronger nucleophilicity in an organic solvent, so that the amine phosphate can react with nucleoside to obtain a nucleotide product, and the phase transfer catalyst is regenerated to complete catalytic cycle. The key of the catalytic cycle is that after the catalyst and phosphate are subjected to ion exchange, phosphate amine salt is generated, and the phosphate amine salt has better solubility and stronger nucleophilicity, so that the completion of the reaction is effectively promoted.

According to an embodiment of the present invention, the method may further include at least one of the following additional technical features:

according to an embodiment of the invention, each of said X, Y is independently selected from H OR-OR^b。

According to an embodiment of the invention, said R₁、R₂Each independently selected from H, D, F, Cl, Br, CN, NO₂、-OR^b。

According to the embodiment of the invention, R is H,

According to embodiments of the invention, there is further included contacting the nucleoside with a proton sponge and POCl₃The contacting is carried out so as to obtain an electrophilic intermediate of the nucleoside. Further improving the success rate of nucleophilic substitution reaction.

According to embodiments of the invention, the nucleoside is conjugated with proton sponge and POCl₃The contact is carried out in PO (OMe)₃Is carried out in (1).

According to an embodiment of the invention, the molar ratio of nucleoside to phosphate, pyrophosphate or tripolyphosphate is 1: 5. further improving the yield of nucleophilic substitution reaction, shortening the reaction time and reducing the waste of raw materials.

According to an embodiment of the invention, the molar ratio of the nucleoside to the phosphate, pyrophosphate or tripolyphosphate and the phase transfer catalyst is 1: 5: (0.5-1.5). Further improving the yield of nucleophilic substitution reaction, shortening the reaction time and reducing the waste of raw materials.

According to an embodiment of the invention, the phase transfer catalyst comprises at least one selected from the group consisting of the following. The reaction according to the embodiment of the invention is catalyzed by the following phase transfer catalyst, so that the utilization rate of raw materials and the yield of target products are further improved.

According to an embodiment of the invention, the phosphate, pyrophosphate or tripolyphosphate comprises at least one selected from:

according to an embodiment of the invention, the nucleotide comprises at least one selected from the group consisting of a nucleoside monophosphate, a nucleoside diphosphate, a nucleoside triphosphate and a nucleoside tetraphosphate.

According to an embodiment of the invention, the nucleoside monophosphate has the structure shown below

According to an embodiment of the present invention, the nucleoside diphosphate has a structure as shown below,

according to an embodiment of the present invention, the nucleoside triphosphate has the structure shown below,

according to an embodiment of the present invention, the nucleoside tetraphosphate has a structure as shown below,

according to the method provided by the embodiment of the invention, the preparation of the nucleotide is realized by promoting the solubility and nucleophilicity of various phosphates and pyrophosphates in an organic solvent by using a phase transfer catalyst. The preparation method of the nucleotide provided by the embodiment of the invention has the advantages of lower cost and simpler, more convenient and faster operation.

Detailed Description

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs and all patent publications cited throughout the disclosure of the present invention are hereby incorporated by reference in their entirety.

The following definitions shall apply unless otherwise indicated. For the purposes of the present invention, the chemical elements are defined in accordance with the periodic Table of the elements, CAS version and the handbook of Chemicals, 75, thEd, 1994. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltio: 1999, and "March's Advanced Organic Chemistry", by Michael B.Smith Jerry March, John Wiley & Sons, New York:2007, all of which are hereby incorporated by reference.

The stereochemical definitions and conventions used in the present invention are generally in accordance with S.P. Parker, Ed., McGraw-Hill Dictionary of chemical terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers (atropisomers) and mixtures thereof, such as racemic mixtures, are also included within the scope of the present invention. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

Depending on the choice of starting materials and process, the compounds according to the invention may be present as one of the possible isomers or as a mixture thereof, for example as the pure optical isomer, or as a mixture of isomers, for example as a mixture of racemic and non-corresponding isomers, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may be in the cis or trans (cis-or trans-) configuration.

The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers (atropisomers) and geometric (or conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

Unless otherwise indicated, the structures described herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric atropisomer, and geometric (or conformational)) forms of the structure; for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, individual stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) isomeric mixtures of the compounds of the present invention are within the scope of the invention.

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the scientific acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with suitable bases include alkali metal, alkaline earth metal, ammonium and N + (C1-4 alkyl) 4 salts. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8 sulfonates and aromatic sulfonates.

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester, aliphatic (C1-24) ester, acyloxymethyl ester, carbonic ester, carbamate and amino acid ester. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symphosis Series, Edward B.Roche, ed., Bioreversible Carriers in Drug designs, American Pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, Prodrugs in Design and Clinical Applications, Nature Review Delivery, 2008,7,255 and 270, S.J.Herer et al, Prodrugs of pharmaceuticals and pharmaceuticals, Journal of chemical Chemistry,2008,51,2328 and 5.

Any asymmetric atom (e.g., carbon, etc.) of a compound of the invention can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -, (R, R) -, (S, S) -, (S, R) -or (R, S) -configurations. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration. Substituents on atoms having unsaturated double bonds may, if possible, be present in cis- (Z) -or trans- (E) -form.

Thus, as described herein, the compounds of the present invention may exist in one of the possible isomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof.

The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". The terms "optionally," "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. In general, the term "optionally" whether preceded by the term "substituted" or not, indicates that one or more hydrogen atoms in a given structure are unsubstituted or substituted with a particular substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein the substituent can be, but is not limited to, D, F, Cl, Br, CN, N₃、OH、NH₂、NO₂Oxo (═ O), -C (═ O) R^a、-C(＝O)OR_b、-C(＝O)NR^cR^d、-S(＝O)2NR^cR^d、(RbO)₂P (═ O) -C0-2 alkylene, -OR^b、-NR^cR_d、RbO-C_1-4Alkylene radical, R^dR^cN-C_1-4Alkylene radical, C_1-12Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-12Cycloalkyl radical, C_3-12cycloalkyl-C_1-4Alkylene, heterocyclic group consisting of 3 to 12 atoms, (heterocyclic group consisting of 3 to 12 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 16 atoms or (heteroaryl of 5 to 16 atoms) -C_1-4Alkylene, wherein each R is^a、R^b、R^c、R^dHave the definitions as described in the present invention.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-6 alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl, and the term "heteroaryl of 5-10 atoms" specifically refers to independently disclosed heteroaryl of 5 atoms, heteroaryl of 6 atoms, heteroaryl of 7 atoms, heteroaryl of 8 atoms, heteroaryl of 9 atoms, and heteroaryl of 10 atoms.

In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "alkyl" or "alkyl group" as used herein, denotes a saturated straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms; in some of these embodiments, the alkyl group contains 1 to 12 carbon atoms; in some of these embodiments, the alkyl group contains 1 to 10 carbon atoms; in other embodiments, the alkyl group contains 1 to 9 carbon atoms; in other embodiments, the alkyl group contains 1 to 8 carbon atoms; in other embodiments, the alkyl group contains 1 to 6 carbon atoms; in other embodiments, the alkyl group contains 1 to 4 carbon atoms, and in other embodiments, the alkyl group contains 1 to 3 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr,

-CH2CH2CH3), isopropyl (i-Pr, -CH (CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH (CH3)2), sec-butyl (s-Bu, -CH (CH3) CH2CH3, tert-butyl (t-Bu, -C (CH3)3), n-pentyl (-CH2CH2CH2CH 3), 2-pentyl (-CH (CH3) CH2CH3), 3-pentyl (-CH (CH2CH3)2), 2-methyl-2-butyl (-C (CH3)2CH2CH3), 3-methyl-2-butyl (-CH (CH3) CH (CH3)2), 3-methyl-1-butyl (-CH2CH2CH (CH3)2), 2-methyl-1-butyl (-CH CH (CH 585) CH2CH 5732), n-hexyl (-CH2CH 585732), 2-hexyl (-CH (CH3) CH2CH2CH3), 3-hexyl (-CH (CH2CH3) (CH2CH2CH3)), 2-methyl-2-pentyl (-C (CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH (CH3) CH (CH3) CH2CH3), 4-methyl-2-pentyl (-CH (CH3) CH2CH (CH3)2), 3-methyl-3-pentyl (-C (CH3) (CH2CH3)2), 2-methyl-3-pentyl (-CH (CH2CH3) CH (CH3)2), 2, 3-dimethyl-2-butyl (-C (CH3)2CH (CH3)2), 3, 3-dimethyl-2-butyl (-CH (CH3) C (CH3)3), n-heptyl, n-octyl, and the like, wherein the alkyl group can be independently unsubstituted or substituted with one or more substituents described herein.

The term "alkyl" and its prefix "alk", as used herein, are intended to encompass both straight and branched saturated carbon chains. The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a straight or branched chain saturated hydrocarbon radical. Unless otherwise specified, the alkylene group contains 1 to 10 carbon atoms, in other embodiments 1 to 6 carbon atoms, in other embodiments 1 to 4 carbon atoms, and in other embodiments 1 to 2 carbon atoms. Examples of such include methylene (-CH2-), ethylene (-CH2CH2-), isopropylidene (-CH (CH3) CH2-) and the like, wherein the alkylene group may independently be unsubstituted or substituted by one or more substituents described herein.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon group of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein C-C in at least one position is an sp2 double bond, wherein the alkenyl groups may be independently unsubstituted or substituted with one or more substituents described herein, including the positioning of the groups as "cis", "trans" or "Z" "E", wherein specific examples include, but are not limited to, vinyl (-CH ═ CH —)₂) Allyl (-CH)₂CH＝CH₂) And so on.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein the C-C in at least one position is a sp triple bond, wherein the alkynyl radical may independently be unsubstituted or substituted with one or more substituents as described herein, specific examples include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH ≡ CH), and₂C.ident.CH), 1-propynyl (-C.ident.C-CH)₃) And so on.

The terms "carbocycle", "carbocyclyl" or "carbocyclic" are used interchangeably herein and all refer to a non-aromatic carbocyclic ring system that is saturated or contains one or more units of unsaturation, contains 3 to 14 ring carbon atoms, and does not contain any aromatic rings. In some embodiments, the number of carbon atoms is 3 to 12; in other embodiments, the number of carbon atoms is from 3 to 10; in other embodiments, the number of carbon atoms is from 3 to 8; in other embodiments, the number of carbon atoms is from 3 to 6; in other embodiments, the number of carbon atoms is from 5 to 6; in other embodiments, the number of carbon atoms is from 5 to 8. In other embodiments, the number of carbon atoms is from 6 to 8. Such "carbocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged carbocyclic ring systems. Bicyclic carbocyclyl includes bridged bicyclic carbocyclyl, fused bicyclic carbocyclyl and spirobicyclic carbocyclyl, and a "fused" bicyclic ring system contains two rings that share 2 contiguous ring atoms. The bridged bicyclic group includes two rings that share 2,3,4, or 5 adjacent ring atoms. Spiro ring systems share 1 ring atom. Suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of carbocyclic groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. Bridging carbocyclyl groups include, but are not limited to, bicyclo [2.2.2] octyl, bicyclo [2.2.1] heptyl, bicyclo [3.3.1] nonyl, bicyclo [3.2.3] nonyl, and the like.

The term "cycloalkyl" refers to a monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring carbon atoms that is saturated, having one or more points of attachment to the rest of the molecule. In some of these embodiments, cycloalkyl is a ring system containing from 3 to 10 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing from 3 to 8 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing from 5 to 8 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing from 3 to 6 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing 5 to 6 ring carbon atoms; examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and the cycloalkyl groups can independently be unsubstituted or substituted with one or more substituents described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring atoms, at least one ring atom being selected from nitrogen, sulfur, and oxygen atoms, wherein the heterocyclyl is non-aromatic and does not contain any aromatic rings, and wherein the ring system has one or more attachment points to the remainder of the molecule. The term "heterocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems. Bicyclic heterocyclic groups include bridged bicyclic heterocyclic groups, fused bicyclic heterocyclic groups, and spiro bicyclic heterocyclic groups. Unless otherwise specified, heterocyclyl groups may be carbon-or nitrogen-based, and-CH 2-groups may be optionally replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. In some embodiments, heterocyclyl is a ring system of 3-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 3-6 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-7 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 6-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-6 ring atoms; in other embodiments, heterocyclyl is a ring system of 4 ring atoms; in other embodiments, heterocyclyl is a ring system of 5 ring atoms; in other embodiments, heterocyclyl is a ring system of 6 ring atoms; in other embodiments, heterocyclyl is a ring system of 7 ring atoms; in other embodiments, heterocyclyl is a ring system of 8 ring atoms.

Examples of heterocyclyl groups include, but are not limited to: oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaoxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thietanyl, and the like. Examples of substitutions of the-CH 2-group in heterocyclyl by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, pyrimidinedione. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane and 1, 1-dioxothiomorpholinyl. Bridging heterocyclyl groups include, but are not limited to, 2-oxabicyclo [2.2.2] octyl, 1-azabicyclo [2.2.2] octyl, 3-azabicyclo [3.2.1] octyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.

The term "heteroatom" refers to O, S, N, P and Si, including any oxidation state form of N, S and P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).

The term "halogen" refers to F, Cl, Br or I.

The term "D" refers to deuteration, i.e., 2H.

The term "aryl" used alone or as a majority of "aralkyl", "aralkoxy", or "aryloxyalkyl" refers to monocyclic, bicyclic, and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms forming a ring and one or more attachment points are attached to the rest of the molecule. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring", e.g., aryl may include phenyl, 2, 3-dihydro-1H-indenyl, naphthyl and anthracenyl. The aryl group can be independently unsubstituted or substituted with one or more substituents described herein.

The term "heteroaryl" may be used alone or as a majority of "heteroarylalkyl" or "heteroarylalkoxy" and refers to monocyclic, bicyclic, and tricyclic systems containing 5 to 16 ring atoms, or 5 to 14 ring atoms, or 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 8 ring atoms, or 5 to 7 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. When a-CH 2-group is present in the heteroaryl group, the-CH 2-group may optionally be replaced by-C (═ O) -. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is 5-14 atom composed of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is 5-12 atom composed of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is 5-10 atom composed of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is 5-8 atom composed of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is 5-7 atom composed of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is 5-6 atom composed of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 6 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N.

In other embodiments, heteroaryl includes, but is not limited to, the following monocyclic groups: 2-furyl group, 3-furyl group, N-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, N-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, pyridazinyl group (e.g., 3-pyridazinyl group), 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, tetrazolyl group (e.g., 5H-tetrazolyl group, 2H-tetrazolyl group), triazolyl group (e.g., 2-triazolyl group, 5-triazolyl group, 4H-1,2, 4-triazolyl, 1H-1,2, 4-triazolyl, 1,2, 3-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bi-or tricyclic groups are also included, but are in no way limited to these groups: indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), phenoxathiin, dibenzoimidazolyl, dibenzofuranyl, dibenzothienyl. The heteroaryl group is optionally substituted with one or more substituents described herein.

The term "comprising" or "comprises" is open-ended, i.e. comprising what is specified in the present invention, but not excluding other aspects.

The invention will be further explained with reference to specific examples. The experimental procedures used in the following examples are all conventional procedures unless otherwise specified. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

EXAMPLE 1 No addition of phase transfer catalyst

Substrate (1.0eq) and proton sponge (2.0eq) were mixed in a 100mL two-necked flask and magnetons were added. Mixing the above mixtureDissolved in 12mL of PO (OMe)₃And (5) pumping for 5 minutes by using a high vacuum oil pump, exchanging argon until no bubbles are generated, and repeating the operation for 3 times. After stirring at-15 ℃ for 10 minutes, POCl was added to the above mixed solution₃(2.0eq), then stirring for 2-3 hours in an ice bath, taking another dry 100mL two-neck flask, adding a magnetic stirrer K₄PPi(5.0eq)，Bu₃N (5.0eq), dry DMF (12mL) was injected and pumped on a high vacuum oil pump for 5 min, 3 times with three changes of argon. Dropwise adding the first-step reaction solution into K under the protection of ice bath and nitrogen₄The PPi flask was rinsed with 10mL DMF and stirring continued for 12 hours in an ice bath. HPLC showed no product formation and the starting material decomposed.

Example 2 addition of trimethylamine hydrochloride (tert-ammonium salt) as phase transfer catalyst

Substrate (1.0eq) and proton sponge (2.0eq) were mixed in a 100mL two-necked flask and magnetons were added. The above mixture was dissolved in 12mL of PO (OMe)₃And (5) pumping for 5 minutes by using a high vacuum oil pump, exchanging argon until no bubbles are generated, and repeating the operation for 3 times. After stirring at-15 ℃ for 10 minutes, POCl was added to the above mixed solution₃(2.0eq), then stirring for 2-3 hours in an ice bath, taking another dry 100mL two-neck flask, adding a magnetic stirrer K₄PPi (5.0eq), trimethylamine hydrochloride (0.5eq) and Bu₃N (5.0eq), dry DMF (12mL) was injected and pumped on a high vacuum oil pump for 5 min, 3 times with three changes of argon. Dropwise adding the first-step reaction solution into K under the protection of ice bath and nitrogen₄The PPi flask was rinsed with 10mL of DMF and stirring was continued at room temperature for 24 hours. The reaction was quenched with 10mL TEAB (1.0M, pH 7.7) and the product was isolated directly by preparative HPLC (H)₂O/CH₃CN 10:90-90:10) to give the triphosphorylated product in 6% yield.

Example 3 tetrabutylammonium bromide (0.2eq) was added as a phase transfer catalyst

Substrate (1.0eq) and proton sponge (2.0eq) were mixed in a 100mL two-necked flask and magnetons were added. The above mixture was dissolved in 12mL of PO (OMe)₃And (5) pumping for 5 minutes by using a high vacuum oil pump, exchanging argon until no bubbles are generated, and repeating the operation for 3 times. After stirring at-15 ℃ for 10 minutes, POCl was added to the above mixed solution₃(2.0eq), then stirring for 2-3 hours in an ice bath, taking another dry 100mL two-neck flask, adding a magnetic stirrer K₄PPi (5.0eq), tetrabutylammonium bromide (0.2eq) and Bu₃N (5.0eq), dry DMF (12mL) was injected and pumped on a high vacuum oil pump for 5 min, 3 times with three changes of argon. Dropwise adding the first-step reaction solution into K under the protection of ice bath and nitrogen₄The PPi flask was rinsed with 10mL of DMF and stirring was continued at room temperature for 24 hours. The reaction was quenched with 10mL TEAB (1.0M, pH 7.7) and the product was isolated directly by preparative HPLC (H)₂O/CH₃CN 10:90-90:10) to give the triphosphorylated product in 21% yield.

EXAMPLE 4 tetrabutylammonium bromide (0.5eq) was added as phase transfer catalyst

Substrate (1.0eq) and proton sponge (2.0eq) were mixed in a 100mL two-necked flask and magnetons were added. The above mixture was dissolved in 12mL of PO (OMe)₃And (5) pumping for 5 minutes by using a high vacuum oil pump, exchanging argon until no bubbles are generated, and repeating the operation for 3 times. After stirring at-15 ℃ for 10 minutes, POCl was added to the above mixed solution₃(2.0eq), then stirring for 2-3 hours in an ice bath, taking another dry 100mL two-neck flask, adding a magnetic stirrer K₄PPi (5.0eq), tetrabutylammonium bromide (0.5eq) and Bu₃N (5.0eq), dry DMF (12mL) was injected and pumped on a high vacuum oil pump for 5 minutes, using a three-way argon purge, and repeated3 times. Dropwise adding the first-step reaction solution into K under the protection of ice bath and nitrogen₄The PPi flask was rinsed with 10mL of DMF and stirring was continued at room temperature for 12 hours. The reaction was quenched with 10mL TEAB (1.0M, pH 7.7) and the product was isolated directly by preparative HPLC (H)₂O/CH₃CN 10:90-90:10) to give the triphosphorylated product in 43% yield.

EXAMPLE 5 tetrabutylammonium bromide (1.5eq) was added as a phase transfer catalyst

Substrate (1.0eq) and proton sponge (2.0eq) were mixed in a 100mL two-necked flask and magnetons were added. The above mixture was dissolved in 12mL of PO (OMe)₃And (5) pumping for 5 minutes by using a high vacuum oil pump, exchanging argon until no bubbles are generated, and repeating the operation for 3 times. After stirring at-15 ℃ for 10 minutes, POCl was added to the above mixed solution₃(2.0eq), then stirring for 2-3 hours in an ice bath, taking another dry 100mL two-neck flask, adding a magnetic stirrer K₄PPi (5.0eq), tetrabutylammonium bromide (1.5eq) and Bu₃N (5.0eq), dry DMF (12mL) was injected and pumped on a high vacuum oil pump for 5 min, 3 times with three changes of argon. Dropwise adding the first-step reaction solution into K under the protection of ice bath and nitrogen₄The PPi flask was rinsed with 10mL of DMF and stirring was continued at room temperature for 12 hours. The reaction was quenched with 10mL TEAB (1.0M, pH 7.7) and the product was isolated directly by preparative HPLC (H)₂O/CH₃CN 10:90-90:10) to give the triphosphorylated product in 42% yield.

Example 6 addition of 18-crown-6 (0.5eq) as phase transfer catalyst

Substrate (1.0eq) and proton sponge (2.0eq) were mixed in a 100mL two-necked flask and magnetons were added. The above mixture was dissolved in 12mL of PO (OMe)₃Pumping for 5 min and three min with high vacuum oil pumpThe argon gas was purged until no bubble was generated, and the operation was repeated 3 times. After stirring at-15 ℃ for 10 minutes, POCl was added to the above mixed solution₃(2.0eq), then stirring for 2-3 hours in an ice bath, taking another dry 100mL two-neck flask, adding a magnetic stirrer K₄PPi (5.0eq), 18-crown-6 (0.5eq) and Bu₃N (5.0eq), dry DMF (12mL) was injected and pumped on a high vacuum oil pump for 5 min, 3 times with three changes of argon. Dropwise adding the first-step reaction solution into K under the protection of ice bath and nitrogen₄The PPi flask was rinsed with 10mL of DMF and stirring was continued at room temperature for 12 hours. The reaction was quenched with 10mL TEAB (1.0M, pH 7.7) and the product was isolated directly by preparative HPLC (H)₂O/CH₃CN 10:90-90:10) to give the triphosphorylated product in 35% yield.

Example 7 addition of 18-crown-6 (1.5eq) as phase transfer catalyst

Substrate (1.0eq) and proton sponge (2.0eq) were mixed in a 100mL two-necked flask and magnetons were added. The above mixture was dissolved in 12mL of PO (OMe)₃And (5) pumping for 5 minutes by using a high vacuum oil pump, exchanging argon until no bubbles are generated, and repeating the operation for 3 times. After stirring at-15 ℃ for 10 minutes, POCl was added to the above mixed solution₃(2.0eq), then stirring for 2-3 hours in an ice bath, taking another dry 100mL two-neck flask, adding a magnetic stirrer K₄PPi (5.0eq), 18-crown-6 (1.5eq) and Bu₃N (5.0eq), dry DMF (12mL) was injected and pumped on a high vacuum oil pump for 5 min, 3 times with three changes of argon. Dropwise adding the first-step reaction solution into K under the protection of ice bath and nitrogen₄The PPi flask was rinsed with 10mL of DMF and stirring was continued at room temperature for 12 hours. The reaction was quenched with 10mL TEAB (1.0M, pH 7.7) and the product was isolated directly by preparative HPLC (H)₂O/CH₃CN 10:90-90:10) to give the triphosphorylated product in 30% yield.

Example 8 use of Na₄Nucleotide synthesis by PPi

Substrate (1.0eq) and proton sponge (2.0eq) were mixed in a 100mL two-necked flask and magnetons were added. The above mixture was dissolved in 12mL of PO (OMe)₃And (5) pumping for 5 minutes by using a high vacuum oil pump, exchanging argon until no bubbles are generated, and repeating the operation for 3 times. After stirring at-15 ℃ for 10 minutes, POCl was added to the above mixed solution₃(2.0eq), then stirred for 2-3 hours in an ice bath, and another dry 100mL two-necked flask was taken and added with a magnetic stirrer Na₄PPi (5.0eq), tetrabutylammonium bromide (0.5eq) and Bu₃N (5.0eq), dry DMF (12mL) was injected and pumped on a high vacuum oil pump for 5 min, 3 times with three changes of argon. Adding Na dropwise into the first-step reaction solution under the protection of ice bath and nitrogen₄The PPi flask was rinsed with 10mL of DMF and stirring was continued at room temperature for 12 hours. The reaction was quenched with 10mL TEAB (1.0M, pH 7.7) and the product was isolated directly by preparative HPLC (H)₂O/CH₃CN 10:90-90:10) to give the triphosphorylated product in 43% yield.

Furthermore, the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one such feature. In the description of the present invention, "a plurality" means at least two, e.g., two, three, etc., unless specifically limited otherwise.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (9)

1. A method for synthesizing a nucleotide or nucleotide analogue, characterized in that a nucleoside is subjected to a nucleophilic substitution reaction with a phosphate, pyrophosphate or tripolyphosphate, said phosphate, pyrophosphate or tripolyphosphate being a non-ammonium phosphate salt, under catalysis of a phase transfer catalyst, so as to obtain said nucleotide or nucleotide analogue,

wherein the nucleoside has a structure shown in formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a prodrug thereof,

wherein X, Y are each independently selected from H, D, F, Cl, Br, CN, NO₂、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、-OR^b、-NR^cR^d、R^bO-C_1-4Alkylene radical, R^dR^cN-C_1-4Alkylene radical, C_1-6Alkyl radical, C_2-6Alkenyl or C_2-6Alkynyl radicals, or X, Y together with the carbon atom to which they are attached, form C_3-6Carbocycle, heterocycle of 5-6 atoms, C_6-10An aromatic ring or a heteroaromatic ring of 5 to 6 atoms, wherein C is_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl radical、C_3-6Carbocycle, heterocycle of 5-6 atoms, C_6-10The aromatic ring and the 5-6 atom heteroaromatic ring are each independently unsubstituted OR substituted with 1,2,3 OR 4 substituents independently selected from D, F, Cl, Br, CN, -OR^b、-NR^cR^d、C_1-6Alkyl radical, C_1-6Haloalkyl, R^bO-C_1-4Alkylene or R^dR^cN-C_1-4Alkylene radical OR^a _,H、D、F、Cl、Br、CN、NO₂、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、-OR^b、-NR^cR^d、R^bO-C_1-4Alkylene radical, R^dR^cN-C_1-4Alkylene radical, C_1-6Alkyl radical, C_2-6Alkenyl or C_2-6An alkynyl group;

r is H or

R₁、R₂Each independently selected from H, D, F, Cl, Br, CN, NO₂、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、-OR^b、-NR^cR^d、R^bO-C_1-4Alkylene radical, R^dR^cN-C_1-4Alkylene radical, C_1-6Alkyl radical, C_2-6Alkenyl or C_2-6An alkynyl group;

R^a、R^b、R^cand R^dEach independently H, D, hydroxy, C_1-6Haloalkyl, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Carbocyclyl, C_3-6carbocyclyl-C_1-4Alkylene, heterocyclic group consisting of 3 to 12 atoms, (heterocyclic group consisting of 3 to 12 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms or (heteroaryl of 5 to 10 atoms) -C_1-4Alkylene, wherein said C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Carbocyclyl, C_3-6carbocyclyl-C_1-4Alkylene, heterocyclic group consisting of 3 to 12 atoms, (heterocyclic group consisting of 3 to 12 atoms) -C_1-4Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkylene, heteroaryl of 5 to 10 atoms and (heteroaryl of 5 to 10 atoms) -C_1-4Each alkylene is independently unsubstituted or substituted with 1,2,3 or 4 substituents independently selected from D, F, Cl, CN, OH, NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy or C_1-6An alkylamino group;

a is adenine, guanine, cytosine, uracil or thymine.

2. The method of claim 1, wherein each of said X, Y is independently selected from H OR-OR^b。

3. The method of claim 1, wherein R is₁、R₂Each independently selected from H, D, F, Cl, Br, CN, NO₂、-OR^b。

4. The method of claim 1, wherein R is H,

5. The method of claim 1, further comprising contacting the nucleoside with a proton sponge and POCl₃Contacting to obtain an electrophilic intermediate of a nucleoside;

optionally, the nucleoside is conjugated with proton sponge and POCl₃The contact is carried out in PO (OMe)₃Is carried out in (1).

6. The method of claim 1, wherein the molar ratio of nucleoside to phosphate, pyrophosphate or tripolyphosphate is from 1: 5;

preferably, the molar ratio of the nucleoside to the phosphate, pyrophosphate or tripolyphosphate and the phase transfer catalyst is 1: 5: (0.5-1.5).

7. The method of claim 1, wherein the phase transfer catalyst comprises at least one selected from the group consisting of:

8. the method of claim 1, wherein the phosphate, pyrophosphate, or tripolyphosphate includes at least one selected from the group consisting of:

9. the method according to claim 1, wherein the nucleotide comprises at least one selected from the group consisting of a nucleoside monophosphate, a nucleoside diphosphate, a nucleoside triphosphate and a nucleoside tetraphosphate,

optionally, the nucleoside monophosphate has the structure shown below

Optionally, the nucleoside diphosphate has a structure as shown below,

optionally, the nucleoside triphosphate has the structure shown below,

optionally, the nucleoside tetraphosphate has the structure shown below,