CN105705508B

CN105705508B - Acyclonucleosides phosphoric acid ester derivant and preparation method thereof and application medically

Info

Publication number: CN105705508B
Application number: CN201480061359.8A
Authority: CN
Inventors: 魏用刚; 邱关鹏; 罗新峰; 祝国智; 余彦
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Sichuan Haisco Pharmaceutical Co Ltd
Priority date: 2013-12-23
Filing date: 2014-12-23
Publication date: 2017-09-01
Anticipated expiration: 2034-12-23
Also published as: CN105705508A; WO2015096697A1

Abstract

The invention provides a kind of acyclonucleosides phosphoric acid ester derivant and preparation method thereof and application medically, the acyclonucleosides phosphoric acid ester derivant is compound, its stereoisomer or pharmaceutically acceptable salt shown in logical formula (I)：R¹For H or methyl；R²For H, C₁‑₁₀For alkyl, (CH₂‑CH₂‑O)_nH or (CH₂‑CH₂‑O)_n‑C₁‑₁₀Alkyl, the alkyl is optionally further by 0 to 5 R^2aSubstitution；R³For C₁‑₁₀Alkyl, (CH₂‑CH₂‑O)_nH or (CH₂‑CH₂‑O)_n‑C₁‑₁₀Alkyl, the alkyl is optionally further by 0 to 5 R^3aSubstitution；R^2aAnd R^3aEach stand alone as H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carboxyl, C_1‑4Alkyl or C_3‑6Cycloalkyl；N is 1~10.

Description

Acyclonucleosides phosphoric acid ester derivant and preparation method thereof and application medically

Technical field

The present invention relates to the acyclonucleosides phosphate compounds shown in a kind of logical formula (I), its stereoisomer or pharmacy Upper acceptable salt, its preparation method and pharmaceutical composition containing them and treat disease of viral infection preparing In medicine in purposes.

Background technology

Hepatitis B is one of global disease, and it is caused by hepatitis B.There is 1/3rd population in the world at certain Hepatitis B is infected in the degree of kind, including 300,000,000 5 thousand ten thousand chronic carriers.In some Asia and African country, hepatitis B is Through becoming epidemic disease, especially in China.Hepatitis B can cause acute and chronic infection, acute infection generally along with Liver inflammation, vomiting, jaundice, extremely it is individual it is other can also cause death, and chronic infection is possible to induce hepatic sclerosis and liver cancer.At present Although can be by vaccine prevention hepatitis B virus infection, but still chronic hepatitis B disease be treated without effective method.

Hepatitis B is a kind of DNA of addicted to liver property (DNA) virus, the dsdna segment gene with ring-type Group.A shorter chain has 1700 to 2800 nucleotides, and a longer chain has 3020 to 3320 nucleotides, and this is long Chain then encodes the archaeal dna polymerase of virus.The genome encoding of hepatitis B four knowns --- C, X, P and S.Gene C Encoding nuclear proteins (HBcAg), gene S coded surfaces antigen (HBsAg), gene P then encoding DNA polymerases, and gene X codings Protein function is unclear, but the generation that it is considered as with liver cancer is relevant, because it have activated the value-added gene of inducing cell, And allow growth regulator to inactivate.

The life cycle of hepatitis B is complicated, is to enter cell by unknown acceptor and endocytosis, its genome is by place Main albumen cha petroleum ethers rones is transferred to nucleus.In nucleus, hepatitis B will by the archaeal dna polymerase of host cell Dsdna segment is converted into complete double-stranded DNA, and is the cyclic DNA by Covalent bonding together by morphologic change (cccDNA).CccDNA transcribes four virus mRNA as template.This four transcriptons are transported into cytoplasm as template, It is translated into the memebrane protein of virus, nucleoprotein and archaeal dna polymerase.Most long mRNA (3.5kb is longer than viral genome) is as mould Plate replicates new genome copies, transcription nucleocapsid protein and viral dna polymerase.Meanwhile, the RNA of this 3.5kb length will be inverse The antisense strand of hepatitis B virus DNA is transcribed out, viral plus chain is subsequently completed.Double-stranded DNA can as new son virus output or Come back to nucleus and form new cccDNA.

Hepatitis B RNA and DNA synthesis depend on hepatitis B virus DNA polymerase, and hepatitis B virus DNA polymerase is for disease The duplication of poison is necessary.The polymerase has four domains：The assembling of beginning and nucleocapsid for hepatitis B virus duplication is very Important terminal protein, interval albumen, reverse transcriptase and the RNaseH domains for pregenome RNA template of degrading.Although In this way, lacking the high mutation rate that proofreading function result in hepatitis B virus DNA polymerase.

Using archaeal dna polymerase inhibitor a selection for having much attraction is already known to as anti-hepatic-B virus medicine. Special viral polymerase inhibitors belong to nucleoside analog family.For chronic hepatitis B patient treatment due to oral anti-hepatitis B Antiviral nucleoside analog medicine and be improved.In serum, hepatitis B virus DNA can be down to rapidly by nucleoside analog can not The level of survey, and the mechanism that works is clear and definite：The nucleoside analog Reverse transcriptase activity of viral dna polymerase.Meanwhile, with doing Disturb plain IFN-α to compare, nucleoside analog shows good tolerance and smaller adverse reaction.Up to the present, there are five kinds Nucleoside analog hepatitis B virus DNA AG14361, in the U.S. and Europe listing, is wrapped as the medicine for the treatment of chronic hepatitis B Include：lamivudine、adefovir dipivoxil、entecavir、telbivudine、tenofovir disoproxil Fumarate, famciclovir and Clevudine, also have other several medicines to be in the stage of grinding.Meanwhile, because virus exists (Substitution for including varial polymerases amino acid) is mutated caused by residual and varial polymerases in liver, it is long-term antiviral Treatment may cause the resistance to the action of a drug and selectivity of virus.This proposes requirement for exploitation novel antiviral medicine.

The Antiviral Mechanism and ring-type nucleoside analog of acyclonucleosides phosphine compound are basically identical.The difference is that ring-type ucleosides Three step phosphorylation reactions are had to pass through like thing, and acyclonucleosides phosphine compound contains phosphoryl in itself, eliminates first step speed limit Phosphorylation reaction, thus activity is higher, and also its P-C structure is good to the stability of enzyme.But the phosphorus of acyclonucleosides phosphine compound Acid ester moiety has two negative electrical charges, not easily passs through the cell membrane of lipid, reduces bioavilability.To solve this problem, greatly The derivative of amount phosphate is synthesized and studied, and is included in phosphonate moiety and connects different lipophilic groups, such as substitution acetyl group, Amino acid and aromatic ring etc..

European patent EP 206459 describes 9- (phosphate methoxy alkyl) adenine comprising tenofovir structure and derived Thing, and its purposes for antiviral agent, its structural formula are as follows：

Wherein R¹Select hydrogen, methyl, methylol, R²Selected from substituted or unsubstituted ethylidene, methylene, propylidene etc..No Think that it is a part of the invention to be specifically described in this patent.

EP481214 describes the new oral phosphate nucleoside analog prodrug comprising Aldoforwe ester, and its antiviral Medical usage, particularly anti-RNA, DNA virus can be used for treatment tumour etc., its structure is as follows：

Wherein B is selected from purine, cytimidine, uracil, thymidine, bird pyrimidine etc., R³Selected from substituted or unsubstituted C₁- C₂₀Alkyl, R¹、R²Independent is selected from substituted or unsubstituted amino, OR⁴, R⁴Selected from CH₂C(O)N(R⁵)₂, CH₂C(O)OR⁵、 CH2OC(O)R⁵、CH(R⁵)OC(O)R⁵、CH₂C(R⁵)₂C water H or CH₂OR⁵, R⁵Selected from unsubstituted or by hydroxyl, oxygen, nitro, halogen Substituted C₄-C₂₀Alkyl, aryl or aryl-alkyl, R¹、R²Can cyclization.It is not considered as that it is of the invention to be specifically described in this patent A part.

WO02057288 describes acyclonucleosides phosphate compounds and its purposes for antiviral agent, its structural formula It is as follows：

Wherein Q is selected from purine or pyrimidine, R⁴、R⁵Independent is selected from hydrogen, alkyl, aryl etc., R¹、R²、R³、R⁷、R⁸Independent Selected from hydroxyl, halogen, hydrogen, amino, alkyl, alkoxy, alkyl amino etc..It is not considered as that it is of the invention to be specifically described in this patent A part.

CN1583769A describes 9- ((phosphate) methoxyalkyl) adenine derivatives and its for antiviral agent Purposes, its structural formula is as follows：

Wherein R¹、R²Independent is selected from hydrogen or substituted Biphenylmethyl.It is not considered as that it is of the invention to be specifically described in this patent A part.

CN101066981A describes acyclonucleosides phosphate compounds and its purposes for antiviral agent, its structure Formula is as follows；

Wherein R¹Selected from hydrogen, halogen, amino, cyclopropylamino, methoxyl group, ethyoxyl etc., R²Selected from hydrogen or amino, R⁵Choosing From methyl or hydrogen, R³、R⁴Independent is selected from (substituted amino carbonyl epoxide) alkyl.It is not considered as that it is this to be specifically described in this patent A part for invention.

CN1634943A describes acyclonucleosides phosphate compounds and its purposes for antiviral agent, its structural formula It is as follows：

Wherein R is hydrogen or methyl, R²Selected from hydrogen or camphoryl, R¹Selected from the cycloalkyl containing 3-8 carbon, 3-8 carbon it is non- The aromatic hydrocarbons of saturated chain alkyl, the unsaturation cycloalkyl of 3-8 carbon or 6-10 carbon.It is not considered as that it is this hair to be specifically described in this patent A bright part.

WO2011069322 describes acyclonucleosides phosphoric acid ester derivant and its for treating and preventing and virus infection The medical usage of relevant disease, its structural formula is as follows：

Wherein R¹Selected from hydrogen or methyl, R²Selected from-R³Or-OR³, R³Selected from C_1-8Alkyl, C_3-8Cycloalkyl.It is not considered as this patent Middle specific descriptions are the parts of the present invention.

The content of the invention

The present invention is that design is with the compound shown in logical formula (I) on the basis of tenofovir disoproxil, to provide a kind of structure Novel acyclonucleosides phosphoric acid ester derivant, its stereoisomer or pharmaceutically acceptable salt, available for treatment virus Infectious diseases, wherein disease of viral infection include infectious diseases caused by hepatitis type B virus and inhibition of HIV.

The invention provides a kind of acyclonucleosides phosphoric acid ester derivant, it is compound, its solid shown in logical formula (I) Isomers or pharmaceutically acceptable salt, wherein：

R¹Selected from H or methyl；

R²Selected from H, C_1-10Alkyl ,-(CH₂-CH₂-O)_n- H or-(CH₂-CH₂-O)_n-C_1-10Alkyl, described alkyl is optional Further by 0 to 5 R^2aSubstitution；

R³Selected from C_1-10Alkyl ,-(CH₂-CH₂-O)_n- H or-(CH₂-CH₂-O)_n-C_1-10Alkyl, wherein described alkyl is appointed Choosing is further by 0 to 5 R^3aSubstitution；

R^2aAnd R^3aIt is independently selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carboxyl, C_1-4Alkyl or C_3-6Cycloalkyl；

N is selected from 1,2,3,4,5,6,7,8,9 or 10.

It is preferred that the present invention relates to the compound shown in a kind of logical formula (I), its stereoisomer or can pharmaceutically receive Salt, wherein：

R¹Selected from H or methyl；

R³Selected from C_1-10Alkyl, wherein described alkyl is optionally further by 0 to 5 R^3aSubstitution；

N is selected from 1,2,3,4 or 5.

Preferred scheme of the present invention, R²Selected from H, C_1-6Alkyl ,-(CH₂-CH₂-O)_n- H or-(CH₂-CH₂-O)_n-C_1-6Alkyl, It is preferred that H, C_1-4Alkyl ,-(CH₂-CH₂-O)_n- H or-(CH₂-CH₂-O)_n-C_1-4Alkyl, described alkyl, cycloalkyl or heterocyclic radical Optionally further by 0 to 5 R^2aSubstitution.

Preferred scheme of the present invention, R²Selected from substituted or unsubstituted H, methyl, ethyl, propyl group, isopropyl, butyl, different Butyl, the tert-butyl group, isopentyl, neopentyl, pentane -3- bases,-(CH₂-CH₂-O)_n- H or-(CH₂-CH₂-O)_n- methyl, preferably Substituted or unsubstituted H, methyl, ethyl, propyl group, isopropyl ,-(CH₂-CH₂-O)_n- H or-(CH₂-CH₂-O)_n- methyl, Further preferred H, methyl or-(CH₂-CH₂-O)_n- methyl, when substituted, optionally by 1 to 5 R^2aSubstitution.

Preferred scheme of the present invention, R³Selected from C_1-6Alkyl ,-(CH₂-CH₂-O)_n- H or-(CH₂-CH₂-O)_n-C_1-6Alkyl, it is excellent Select C_1-4Alkyl ,-(CH₂-CH₂-O)_n-H、-(CH₂-CH₂-O)_n-C_1-4Alkyl, described alkyl is optionally further by 0 to 5 R^3a Substitution.

Preferred scheme of the present invention, R³Selected from substituted or unsubstituted methyl, ethyl, propyl group, isopropyl, butyl, isobutyl Base, the tert-butyl group, isopentyl, neopentyl, pentane -3- bases,-CH₂-CH₂- OH or-(CH₂-CH₂-O)₂- H is preferably replacing or not Substituted propyl group, isopropyl, isobutyl group or the tert-butyl group；Further preferred isopropyl, when substituted, optionally by 1 to 5 R^3aTake Generation.

Preferred scheme of the present invention, the present invention provides the compound shown in a kind of logical formula (I), wherein：

R¹Selected from H or methyl；

R²Selected from substituted or unsubstituted H, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, isoamyl Base, neopentyl, pentane -3- bases,-(CH₂-CH₂-O)_n- H or-(CH₂-CH₂-O)_n- methyl, it is preferably substituted or unsubstituted H, methyl, ethyl, propyl group, isopropyl ,-(CH₂-CH₂-O)_n- H or-(CH₂-CH₂-O)_n- methyl, further preferred H, methyl Or-(CH₂-CH₂-O)_n- methyl, when substituted, optionally by 1 to 5 R^2aSubstitution；

R³Selected from substituted or unsubstituted methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, isoamyl Base, neopentyl, pentane -3- bases,-CH₂-CH₂- OH or-(CH₂-CH₂-O)₂- H, it is preferably substituted or unsubstituted propyl group, different Propyl group, isobutyl group or the tert-butyl group, further preferred isopropyl, when substituted, optionally by 1 to 5 R^3aSubstitution；

R^2aAnd R^3aIt is independently selected from H, F, Cl, hydroxyl, amino, methyl or ethyl；

N is selected from 1,2,3,4 or 5.

Preferred scheme of the present invention, R^2aAnd R^3aBe independently selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, Carboxyl or C_1-4Alkyl, preferably H, F, Cl, hydroxyl, amino, methyl or ethyl.

Preferred scheme of the present invention, n is selected from 1,2 or 3.

Preferred scheme of the present invention, the present invention provides compound shown in a kind of logical formula (I), and the wherein compound is selected from formula (II) compound, its stereoisomer shown in or pharmaceutically acceptable salt, wherein：

R¹Selected from H or methyl, preferably methyl；

R²Selected from H, methyl, ethyl, propyl group, isopropyl ,-CH₂-CH₂-OH、-CH₂-CH₂-O-CH₃、-(CH₂-CH₂-O)₂- H、-(CH₂-CH₂-O)₂-CH₃、-(CH₂-CH₂-O)₃-H、-(CH₂-CH₂-O)₃-CH₃、-(CH₂-CH₂-O)₄- H or-(CH₂- CH₂-O)₄-CH₃, preferably H, methyl, ethyl, propyl group, isopropyl ,-CH₂-CH₂-OH、-CH₂-CH₂-O-CH₃、-(CH₂-CH₂-O)₂- H or-(CH₂-CH₂-O)₂-CH₃。

Preferred scheme of the present invention, a kind of compound selected from shown in logical formula (III), its stereoisomer or pharmaceutically can be with The salt of receiving, wherein：

R²Selected from H, methyl, ethyl, propyl group, isopropyl ,-CH₂-CH₂-O-H、-CH₂-CH₂-O-CH₃、-(CH₂-CH₂-O)₂- H or-(CH₂-CH₂-O)₂-CH₃。

Preferred scheme of the present invention, compound of the present invention is selected from, but is not limited to：

The present invention also provides compound shown in logical formula (I), its stereoisomer or its pharmaceutically acceptable salt, wherein Described salt is hydrochloride, hydrobromate, sulfate, nitrate, phosphate, acetate, maleate, succinate, almond Hydrochlorate, fumarate, malonate, malate, 2 hydroxy propanoic acid salt, oxalates, oxyacetate, salicylate, glucose Aldehydic acid salt, galacturonic hydrochlorate, citrate, tartrate, lysine salt, arginine salt, aspartate, glutamate, Benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate, sylvite, Sodium salt or combinations thereof, preferably hydrochloride, sulfate, phosphate, acetate, maleate, succinate, fumarate, Malate, oxalates, tartrate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, three Fluorine mesylate or combinations thereof, further preferred fumarate, tosilate, fluoroform sulphonate or methanesulfonic acid Salt, more preferably fumarate.

The invention further relates to a kind of pharmaceutical composition, described pharmaceutical composition contains at least one for the treatment of effective dose originally Compound described in the logical formula (I) of invention, or its stereoisomer or pharmaceutically acceptable salt, and pharmaceutically acceptable load Body or excipient.

According to pharmaceutical composition of the present invention, it is preferably used to treat disease of viral infection.Wherein, the virus Infectious diseases can be specifically to include hepatitis type B virus, hepatitis C virus or infectious diseases caused by AIDS virus.

Further, the present invention relates to compound shown in logical formula (I), its stereoisomer or its pharmaceutically acceptable Salt, the application in treatment disease of viral infection related drugs are prepared.

Present invention also offers the method for the treatment of disease of viral infection, this method includes giving this hair of patient effective amounts Compound described in bright logical formula (I), or its stereoisomer or pharmaceutically acceptable salt, or medicine group of the present invention Compound.

The present invention preferred scheme, wherein the disease of viral infection include hepatitis type B virus, hepatitis C virus or Infectious diseases caused by AIDS virus.

The preferred scheme of the present invention, wherein the disease of viral infection includes infectious disease caused by hepatitis type B virus Disease, such as chronic hepatitis B disease.

The compounds of this invention is compared with marketed drug tenofovir dipivoxil, with higher human plasma stability；This The salt of invention compound possesses suitable pharmacokinetics in rats compared with marketed drug tenofovir dipivoxil fumarate Effect.The compounds of this invention is less susceptible to by esterase hydrolyzed in blood plasma, possesses more preferable curative effect, the more potentiality such as low toxicity side effect, has Fine DEVELOPMENT PROSPECT.

Unless there are opposite statement, the term used in the specification and in the claims has following implications.

During the present invention relates to being replaced by multiple substituents, each substituent can be with identical or differ.

During the present invention relates to containing multiple hetero atoms, each hetero atom can be with identical or differ.

Involved elemental carbon, hydrogen, oxygen, sulphur, nitrogen or halogen include theirs in group of the present invention and compound Involved elemental carbon, hydrogen, oxygen, sulphur or nitrogen are optionally further by 1 in isotope situation, and group of the present invention and compound To 5, their corresponding isotopes are substituted, and the isotope of wherein carbon includes¹²C、¹³C and¹⁴C, the isotope of hydrogen include protium (H), Deuterium (D is called heavy hydrogen), tritium (T is called superheavy hydrogen), the isotope of oxygen includes¹⁶O、¹⁷O and¹⁸O, the isotope of sulphur includes³²S、³³S、³⁴S and³⁶S, the isotope of nitrogen includes¹⁴N and¹⁵N, the isotope of fluorine¹⁹F, the isotope of chlorine includes³⁵Cl and³⁷Cl, bromine it is same Position element includes⁷⁹Br and⁸¹Br。

Term " alkyl " refers to the aliphatic hydrocarbon groups of saturation, includes the straight chain and branched group of 1 to 20 carbon atom.It is excellent Select the alkyl containing 1 to 10 carbon atom, non-limiting example includes, methyl, ethyl, n-propyl, isopropyl, normal-butyl, Isobutyl group, the tert-butyl group, n-pentyl, n-nonyl, and its various branched chain isomers etc.；More preferably containing 1 to 4 carbon atom Low alkyl group, non-limiting example includes methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group or tert-butyl group etc..Alkyl Can be substituted or unsubstituted, when substituted, substituent is preferably 1 to 5.The non-limiting example of substituent, Including H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, C_1-10Alkyl, C_1-10Alkoxy, C_1-4Alkoxy- C_1-4Alkoxy, C_2-8Alkenyl, C_1-4Amide groups ,-C (=O)-O-C_1-10Alkyl ,-OC (=O)-C_1-10Alkyl, C_3-10Carbocyclic ring or C_3-10Heterocycle.Preferably, the non-limiting example of substituent includes H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl It is base, carboxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group, ethyoxyl, propoxyl group, different Propoxyl group, butoxy, primary butoxy, sec-butoxy, tert-butoxy, cyclopropane base, cyclobutane base, cyclohexyl, pentamethylene base, It is cycloheptyl alkyl, methoxy ethoxy, methoxyethoxyethoxy, vinyl, formamido, acetylamino, propionamido-, different Propionamido-, amide-based small, phenyl, substituted-phenyl, naphthyl, substituted naphthyl.

" alkoxy " refers to-O- alkyl, and wherein alkyl is as herein above defined.Alkoxy can be substitution or not take Generation, its non-limiting example includes, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, tert-butoxy, penta oxygen Base or hexyloxy, preferably with 1 to 12 yuan of alkoxy.When substituted, substituent is preferably 1 to 5.Substituent it is unrestricted Property embodiment, including H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, C_1-10Alkyl, C_1-10Alkoxy, C_1-4Alkoxy -C_1-4Alkoxy, C_2-8Alkenyl, C_1-4Amide groups ,-C (=O)-O-C_1-10Alkyl ,-OC (=O)-C_1-10Alkyl, C_3-10Carbocyclic ring or C_3-10Heterocycle.Preferably, the non-limiting example of substituent includes H, F, Cl, Br, I, hydroxyl, sulfydryl, ammonia Base, cyano group, carbonyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group, ethyoxyl, Propoxyl group, isopropoxy, butoxy, primary butoxy, sec-butoxy, tert-butoxy, cyclopropane base, cyclobutane base, cyclohexyl, Pentamethylene base, cycloheptyl alkyl, methoxy ethoxy, methoxyethoxyethoxy, vinyl, formamido, acetylamino, third Amide groups, Isopropamide base, amide-based small, phenyl, substituted-phenyl, naphthyl, substituted naphthyl.

During " alkenyl " is the alkyl that defines of the present invention, comprising at least one carbon-to-carbon double bond, the alkenyl contains 2 to 20 Carbon atom, preferably 2 to 12 carbon atoms, further preferred 2 to 8 carbon atoms.The non-limiting examples of alkenyl include substitution or Unsubstituted vinyl, 2- acrylic, 3- cyclobutenyls, 2- cyclobutenyls, 4- pentenyls, 3- pentenyls, 2- hexenyls, 3- hexenes Base, 2- heptenyls, 3- heptenyls, 4- heptenyls, 3- octenyls, 3- nonenyls or 4- decene bases etc., when substituted, substituent Preferably 1 to 5, independently selected from F, Cl, Br, I ,=O, alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, mercapto Base, hydroxyl, nitro, cyano group, amino, alkyl acylamino, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, ring Alkyl thiol, hydroxy alkyl, carboxylic acid group, carboxylate or Heterocyclylalkyl sulfydryl.

During " alkynyl " is the alkyl that defines of the present invention, comprising at least one carbon-to-carbon triple bond, the alkynyl contains 2 to 20 Carbon atom, preferably 2 to 12 carbon atoms, further preferred 2 to 8 carbon atoms.The non-limiting examples of alkynyl include substitution or Unsubstituted acetenyl, 1- propinyls, 2-propynyl, 1- butynyls, 2- butynyls, 3- butynyls, 4- pentynyls, 3- pentynes Base, 2- hexin bases, 3- hexin bases, 3- butynyls, 2- heptynyls, 3- heptynyls, 4- heptynyls, 3- octynyls, 3- n-heptylacetylenes base or 4- decynyls etc., when substituted, substituent are preferably 1 to 5, independently selected from F, Cl, Br, I ,=O, alkyl, alkenyl, alkynes Base, alkoxy, alkylthio group, alkyl amino, sulfydryl, hydroxyl, nitro, cyano group, amino, alkyl acylamino, cycloalkyl, aryl, Heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkyl sulfydryl, hydroxy alkyl, carboxylic acid, carboxylate or Heterocyclylalkyl sulfydryl.

" cycloalkyl " refers to substituted or unsubstituted 3 to 8 yuan full carbon monocyclic groups, can be connected with bridged ring or loop coil, its In 1 to 5 can be containing 1 to 5 double bond, but neither one ring has the pi-electron system being completely conjugated.The non-limit of cycloalkyl Property embodiment processed includes, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, two rings [3.2.1] octyl, two rings [5.2.0] nonane Base, three rings [5.31.1] dodecyl, adamantyl, spiral shell [3.3] heptane base, spiral shell [2.4] heptane base, spiral shell [2.5] octyl or Spiral shell [2.3] hexyl etc..When substituted, substituent is preferably 1 to 5.The non-limiting example of substituent, including H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, C_1-10Alkyl, C_1-10Alkoxy, C_1-4Alkoxy -C_1-4Alcoxyl Base, C_2-8Alkenyl, C_1-4Amide groups ,-C (=O)-O-C_1-10Alkyl ,-OC (=O)-C_1-10Alkyl, C_3-10Carbocyclic ring or C_3-10Heterocycle. Preferably, the non-limiting example of substituent includes H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, first Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, fourth oxygen Base, primary butoxy, sec-butoxy, tert-butoxy, cyclopropane base, cyclobutane base, cyclohexyl, pentamethylene base, cycloheptyl alkyl, first Epoxide ethyoxyl, methoxyethoxyethoxy, vinyl, formamido, acetylamino, propionamido-, Isopropamide base, fourth Amide groups, phenyl, substituted-phenyl, naphthyl, substituted naphthyl.

" carbocyclic ring " refers to substituted or unsubstituted saturation or undersaturated aromatic rings or non-aromatic ring, aromatic rings or It can be 3 to 8 yuan monocyclic that person is non-aromatic, and 4 to 12 membered bicyclics or 10 to 15 membered tricyclic systems, carbocyclic ring can be connected with bridged ring Or loop coil, non-limiting example include cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclohexenyl group, suberyl, ring penta Alkene, cyclohexadiene, cycloheptatriene, phenyl, naphthyl, benzo cyclopenta, two rings [3.2.1] octyl, two rings [5.2.0] nonane Base, three rings [5.3.1.1] dodecyl, adamantyl or spiral shell [3.3] heptane base etc..When substituted, substituent be preferably 1 to 5.The non-limiting example of substituent, including H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, C_1-10 Alkyl, C_1-10Alkoxy, C_1-4Alkoxy -C_1-4Alkoxy, C_2-8Alkenyl, C_1-4Amide groups ,-C (=O)-O-C_1-10Alkyl ,-OC (=O)-C_1-10Alkyl, C_3-10Carbocyclic ring or C_3-10Heterocycle.Preferably, the non-limiting example of substituent include H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, Methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, primary butoxy, sec-butoxy, tert-butoxy, cyclopropane base, ring fourth Alkyl, cyclohexyl, pentamethylene base, cycloheptyl alkyl, methoxy ethoxy, methoxyethoxyethoxy, vinyl, formamide Base, acetylamino, propionamido-, Isopropamide base, amide-based small, phenyl, substituted-phenyl, naphthyl, substituted naphthyl.

" heterocyclic radical " refers to substituted or unsubstituted saturation or undersaturated aromatic rings, non-aromatic ring, aromatic rings, non- Aromatic rings can be 3 to 8 yuan of monocyclic, 4 to 12 membered bicyclics or 10 to 15 membered tricyclic systems, and be selected from N, O by least one Or S hetero atom composition, preferably 3 to 10 circle heterocycles, N, S selectively replaced in the ring of heterocycle can be oxidized to various oxidations State.Heterocycle can be connected on hetero atom or carbon atom, and heterocycle can be connected with bridged ring or loop coil.Heterocyclic radical it is unrestricted Property embodiment include Oxyranyle, aziridinyl, oxetanyl, azetidinyl, azepine base, sulphur Heterocycle pentyl, oxinane base, thia cyclohexyl, DOX base, Isosorbide-5-Nitrae-dioxolanyl, 1,2- diazas Pentamethylene base, 1,2- oxazas pentyl, 1,2- oxathiolanes base, 1,3- oxazas pentyl, 1,3- oxygen thias Pentamethylene base, 1,2- diaza-cyclohexanes base, 1,2- morpholines base, 1,2- thioxane base, 1,3- oxygen azepines Cyclohexyl, 1,3- sulfur nitrogen heterocycles hexyl, 1,3- diaza-cyclohexanes base, 1,3- dioxane base, Isosorbide-5-Nitrae-dioxane base, 1,3- thioxane base, Isosorbide-5-Nitrae-diaza-cyclohexane base, Isosorbide-5-Nitrae-thioxane base, Isosorbide-5-Nitrae-dithian base, Spiral shell [3.3] heptane base, spiral shell [2.3] hexyl, azepine spiroheptane base, oxa- spiroheptane base, azaspiro [2.3] oneself Alkyl, oxaspiro [2.3] hexyl, spiral shell [2.4] heptane base, azaspiro [2.4] heptane base, oxaspiro [2.4] heptane base, spiral shell [2.5] octyl, azaspiro [2.5] octyl, oxaspiro [2.5] octyl, azabicyclic [3.2.1] octyl, azepine two Ring [5.2.0] nonyl, oxatricyclo [5.3.1.1] dodecyl, azaadamantane base, pyridine radicals, furyl, thienyl, Pyridine radicals, pyranose, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, piperidyl, piperazine sting base, morpholine, sulphur For morpholine, 1,3- dithiane dihydrofuran, dihydropyran, the ring of two thiophene penta, tetrahydrofuran, nafoxidine, imidazolidine, tetrahydrochysene thiophene Azoles, hexahydro pyrans, benzimidazole, benzo pyridine, pyrrolopyridine, coumaran etc..When substituted, substituent is preferred For 1 to 5.The non-limiting example of substituent, including H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxylic Base, C_1-10Alkyl, C_1-10Alkoxy, C_2-8Alkenyl, C_1-4Amide groups ,-C (=O)-O-C_1-10Alkyl ,-OC (=O)-C_1-10Alkane Base, C_3-10Carbocyclic ring or C_3-10Heterocycle.Preferably, the non-limiting example of substituent include H, F, Cl, Br, I, hydroxyl, sulfydryl, Amino, cyano group, carbonyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group, ethoxy Base, propoxyl group, isopropoxy, butoxy, primary butoxy, sec-butoxy, tert-butoxy, cyclopropane base, cyclobutane base, hexamethylene Base, pentamethylene base, cycloheptyl alkyl, methoxy ethoxy, methoxyethoxyethoxy, vinyl, formamido, acetyl ammonia Base, propionamido-, Isopropamide base, amide-based small, phenyl, substituted-phenyl, naphthyl, substituted naphthyl.

" aryl " refers to that substituted or unsubstituted 6 to 15 yuan full carbon are monocyclic or fused polycycle group, the π electricity with conjugation The polycyclic moiety of subsystem, preferably 6 to 10 yuan aromatic rings, its non-limiting example includes, phenyl and naphthyl；The aryl can be with Condensed heteroaryl, heterocyclic radical or cycloalkyl, and the part being connected with precursor structure is aryl, its non-limiting example includes benzo Furans, benzocyclopentane base, benzothiazole etc..When substituted, substituent is preferably 1 to 5.The non-limiting reality of substituent Apply example, including H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, C_1-10Alkyl, C_1-10Alkoxy, C_2-8Alkene Base, C_1-4Amide groups ,-C (=O)-O-C_1-10Alkyl ,-OC (=O)-C_1-10Alkyl, C_3-10Carbocyclic ring or C_3-10Heterocycle.Preferably, take Dai Ji non-limiting example include H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, methyl, ethyl, N-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, primary fourth Epoxide, sec-butoxy, tert-butoxy, cyclopropane base, cyclobutane base, cyclohexyl, pentamethylene base, cycloheptyl alkyl, methoxyl group second Epoxide, methoxyethoxyethoxy, vinyl, formamido, acetylamino, propionamido-, Isopropamide base, butyramide Base, phenyl, substituted-phenyl, naphthyl, substituted naphthyl.

" heteroaryl " refers to substituted or unsubstituted 5 to 15 yuan of aromatic rings, and is selected from N, O or S hetero atom containing 1 to 3 Composition, preferably 5 to 10 yuan aromatic rings, the non-limiting example of heteroaryl includes pyridine radicals, furyl, thienyl, N- alkyl Pyrrole radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, benzofuran, benzimidazole, benzo pyridine or pyrrolopyridine etc.. When substituted, substituent is preferably 1 to 5.The non-limiting example of substituent, including H, F, Cl, Br, I, hydroxyl, mercapto Base, amino, cyano group, carbonyl, carboxyl, C_1-10Alkyl, C_1-10Alkoxy, C_1-4Alkoxy -C_1-4Alkoxy, C_2-8Alkenyl, C_1-4Acyl Amido ,-C (=O)-O-C_1-10Alkyl ,-OC (=O)-C_1-10Alkyl, C_3-10Carbocyclic ring or C_3-10Heterocycle.Preferably, substituent is non- Restricted embodiment includes H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carbonyl, carboxyl, methyl, ethyl, n-propyl, different Propyl group, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, primary butoxy, Zhong Ding Epoxide, tert-butoxy, cyclopropane base, cyclobutane base, cyclohexyl, pentamethylene base, cycloheptyl alkyl, methoxy ethoxy, methoxy Base oxethyl ethyoxyl, vinyl, formamido, acetylamino, propionamido-, Isopropamide base, amide-based small, phenyl, take For phenyl, naphthyl, substituted naphthyl.

" amino " refers to-NH₂, can be substituted or unsubstituted, when substituted, substituent is preferably 1 to 2, Independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, hydroxyl, amino, alkyl amino, alkyl acylamino, heterocycle alkane Base, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, hydroxy alkyl, carboxylic acid group or carboxylic acid ester groups, substituent Non-limiting example, including hydroxyl, amino, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, first Epoxide, ethyoxyl, propoxyl group, isopropoxy, butoxy, primary butoxy, sec-butoxy, tert-butoxy, cyclopropane, cyclobutane, Hexamethylene, pentamethylene, cycloheptane, formamido, acetylamino, propionamido-, Isopropamide base, amide-based small, phenyl, substitution Phenyl, naphthyl, substituted naphthyl.

The present invention "=O " be this area ordinary practice usage, refer to double bond be connected oxygen atom, for example in carbonyl with The connected double bond oxygen atom of carbon atom.

" stereoisomer " refers to the isomers produced by spatially arrangement mode is different as atom in molecule, including suitable Trans isomer, enantiomter and rotamer.

" pharmaceutical composition " represent one or more compounds described herein or its physiology/pharmaceutically acceptable salt or Pro-drug and the mixture of other chemical constituents, other components such as physiology/pharmaceutically acceptable carrier and excipient. The purpose of pharmaceutical composition is to promote the administration of compound on organism body.

" prodrug " refers to that the present inventionization with bioactivity can be converted into physiological conditions or by solvolysis Compound.The prodrug of the present invention is prepared by modifying the functional group in the compound, the operation that the modification can be routinely Or be removed in vivo, and obtain parent compound.Prodrug includes a hydroxyl, amino or the mercapto in the compounds of this invention Base is connected to the compound formed on any group, preceding when the prodrug of the compounds of this invention is delivered to mammalian subject Medicine is isolated and forms free hydroxyl, free amino or free thin base respectively.The example of prodrug includes but is not limited to, The compound that hydroxyl or amino-functional group in the compounds of this invention are formed with formic acid, acetic acid or benzoic acid.

" optional " or " optionally " mean ground described later event or environment can with but need not occur, including the event Or the occasion that environment occurs or do not occurred.For example, " aryl is optionally replaced by alkyl " mean alkyl can with but necessarily exist, The explanation includes aryl by alkyl-substituted situation and aryl not by alkyl-substituted situation.

" substituted or unsubstituted " refers to the situation that group can be substituted or unsubstituted, if not referring in the present invention Going out group can be substituted, then it represents that the group is unsubstituted situation.

" alternatively " refer to that the scheme after " alternatively " and the scheme before " alternatively " they are coordination, and It is not the further selection situation in the case of front.

" substitution " refers to that one or more hydrogen atoms are by the situation of other substituent groups in group, if described group quilt Hydrogen atom replaces, and the group of formation is identical with the group replaced by hydrogen atom.The substituted situation of group, such as amino, C_1-4Alkane Base, C_1-4Alkoxy, C_3-6Carbocyclic ring, 3 to 6 circle heterocycles are optionally further selected from H, F, Cl, Br, I, hydroxyl, cyano group, ammonia by 0 to 4 Base, C_1-4Alkyl or C_1-4The substituent of alkoxy is replaced, and the group of formation includes but is not limited to methyl, chloromethyl, three chloromethanes Base, hydroxymethyl ,-CH₂OCH₃、-CH₂SH、-CH₂CH₂CN、-CH₂NH₂、-NHOH、-NHCH₃、-OCH₂Cl、-OCH₂OCH₂CH₃、- OCH₂CH₂NH₂、-OCH₂CH₂SH、-OCH₂CH₂OH, 1- hydroxycyclopropyl, 2- hydroxycyclopropyls, 2- amino cyclopropyl, 4- methyl Furyl, 2- hydroxy phenyls, 4- aminophenyls, phenyl.

The synthetic method of the compounds of this invention：

Wherein

X is selected from F, Cl, Br or I, preferably Cl；

R²、R³Definition is consistent with being defined described in compound of Formula I；

R⁴Selected from H or C_1-4Alkyl, preferably methyl；

R⁵H or amino protecting group are independently selected from, wherein the amino protecting group includes but is not limited to tertiary fourth oxygen Base carbonyl, benzyloxycarbonyl, tablet held before the breast by officials methoxycarbonyl group, allyloxy carbonyl, tri-chloroethoxy base carbonyl, trimethyl silicon substrate carbethoxyl group, Methoxycarbonyl group, carbethoxyl group, 2- xenyl -2- propylene carbonyl oxygens, tert-butoxy, phthalyl, p-toluenesulfonyl, adjacent nitre Base benzenesulfonyl, p-nitrophenyl sulfonyl, pivaloyl group, formoxyl, trifluoroacetyl group, benzoyl, benzyl, trityl, To methoxy-benzyl or 2,4- dimethoxy-benzyl, preferably H or tert-butoxycarbonyl；

A-1 obtains A-2 with halohydrocarbons reaction in the presence of a base, and A-2 reacts in the basic conditions obtains A-3, and A-3 turns in phase A-4 is obtained with the reaction of chlorosulfonic acid halo methyl esters in the presence of shifting catalyst, A-4 reacts in the presence of a base with intermediate B obtains A-5, A-5 deprotections obtain logical formula (I) compound (as two R⁵When being H, it is not necessary to carry out deprotection steps)；

Intermediate B can be made by conventional synthesis process；

Described halogenated hydrocarbons includes but is not limited to the bromo- 2- methoxyethoxyethanes of 2- bromo-ethyl-methyl ethers, 1- or 2- chlorine Ethyl-methyl ether；

The chlorosulfonic acid halo methyl esters includes but is not limited to chlorosulfonic acid chloromethyl ester；

The alkali includes but is not limited to sodium hydride, hydrofining, lithium hydride, sodium methoxide, caustic alcohol, potassium tert-butoxide, the tert-butyl alcohol Sodium, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or triethylamine；

The phase transfer catalyst includes but is not limited to tetrabutyl hydrogen sulfate ammonia (TBAB), benzyltriethylammoinium chloride (TEBA), TBAB, tetrabutylammonium chloride, tri-n-octyl methyl ammonium chloride, DTAC or 14 Alkyl trimethyl ammonium chloride；

The deprotection is to use conventional amino protecting group deprotection method, includes but is not limited to remove-insurance in acid condition Base is protected, trifluoroacetic acid is such as used.

Embodiment

The beneficial effect for describing the implementation process of the present invention in detail below by way of specific embodiment and producing, it is intended to which help is read Reader more fully understand the present invention essence and feature, not as to this case can practical range restriction.

The structure of compound by nuclear magnetic resonance (NMR) or (and) mass spectrum (MS) determines.NMR displacements (δ) are with 10^-6 (ppm) unit is provided.NMR measure is to use (Bruker Avance III 400 and Bruker Avance 300) nuclear-magnetism Instrument, measure solvent is deuterated dimethyl sulfoxide (DMSO-d₆), deuterochloroform (CDCl₃), deuterated methanol (CD₃OD), inside it is designated as four Methyl-monosilane (TMS).

MS measure uses (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

HPLC measure uses Agilent 1260DAD high pressure liquid chromatographs (100 × 4.6mm of Zorbax SB-C18).

Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, and thin-layered chromatography (TLC) makes The specification that silica gel plate is used is 0.15mm~0.20mm, the specification that thin-layer chromatography isolates and purifies product use be 0.4mm~ 0.5mm。

Column chromatography is carrier typically using the mesh silica gel of Yantai Huanghai Sea silica gel 200~300.

Oneself initiation material known of the present invention can be used or synthesized according to methods known in the art, or can purchase in The company such as safe smooth science and technology, silent pacify resistance to Jilin Chemical, Shanghai moral, the imperial chemical industry of Chengdu section, splendid remote chemical science and technology, lark prestige science and technology.

Blanket of nitrogen refers to that reaction bulb connects the nitrogen balloon of an about 1L volume.

Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume.

Hydrogenation is generally vacuumized, and is filled with hydrogen, is operated 3 times repeatedly.

Without specified otherwise in embodiment, reaction is carried out under nitrogen atmosphere.

Without specified otherwise in embodiment, solution refers to the aqueous solution.

Without specified otherwise in embodiment, the temperature of reaction is room temperature.

Room temperature is optimum reaction temperature, is 20 DEG C~30 DEG C.

Boc：Tertbutyloxycarbonyl；TMS：Trimethyl silicon substrate.

N：Represent mol/L.

Intermediate：

[(1R) -2- [6- [double (tert-butoxycarbonyl) amino] purine -9- bases] -1- methyl-ethoxies] methyl-(isopropyl Epoxide carbonyl Oxymethoxy) hypophosphorous acid (1d)

[(1R)-2-[6-[bis(tert-butoxycarbonyl)amino]purin-9-yl]-1-methyl- ethoxy]methyl-(isopropoxycarbonyloxymethoxy)phosphinic acid

[(1R) -2- [6- [(tert-butoxycarbonyl) amino] purine -9- bases] -1- methyl-ethoxies] methyl-(isopropyl oxygen Base carbonyl Oxymethoxy) hypophosphorous acid (2b)

[(1R)-2-[6-(tert-butoxycarbonylamino)purin-9-yl]-1-methyl-ethoxy] methyl-(isopropoxycarbonyloxymethoxy)phosphinic acid

The first step：[[(1R) -2- [6- [double (tert-butoxycarbonyl) amino] purine -9- bases] -1- methyl-ethoxies] first Base-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide isopropyl methyl carbonic ester (1b)

[[(1R)-2-[6-[bis(tert-butoxycarbonyl)amino]purin-9-yl]-1-methyl- ethoxy]methyl-(isopropoxycarbonyloxymethoxy)phosphoryl]oxymethyl isopropyl carbonate

By [[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl epoxide methoxy Base) phosphoryl] epoxide isopropyl methyl carbonic ester fumarate (1a) (100g, 0.157mol) is suspended in dichloromethane In (500mL), the sodium hydroxide solution of dropwise addition 10% is to pH value of solution to 9, and point liquid adds tetrahydrofuran into organic phase (350mL), DMAP (2.0g, 0.0157mol) and triethylamine (57mL, 0.322mol), are added dropwise two dimethyl dicarbonates Butyl ester (90g, 0.322mmol), adds rear stirring reaction 30 minutes, is heated to 60 DEG C, continues stirring reaction 2 at such a temperature small When.Reaction solution is concentrated under reduced pressure removing tetrahydrofuran, residue with Ethyl acetate (200mL) dissolving, successively with water (50mL × 4), saturated aqueous common salt (50mL × 3) is washed, and with anhydrous sodium sulfate drying, is concentrated under reduced pressure, and the separation of residue silica gel column chromatography is carried Pure (ethyl acetate/petroleum ether (v/v)=1: 1~7: 10) obtains title compound [[(1R) -2- [6- [double (tert-butoxy carbonyls Base) amino] purine -9- bases] -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl Butylperoxyisopropyl carbonate (1b), light yellow oil (120g, yield 106%).

Second step：[(1R) -2- [6- [double (tert-butoxycarbonyl) amino] purine -9- bases] -1- methyl-ethoxies] first Base-(isopropoxy carbonyl Oxymethoxy) hypophosphorous acid (1d)

By [[(1R) -2- [6- [double (tert-butoxycarbonyl) amino] purine -9- bases] -1- methyl-ethoxies] methyl-(different Propoxycarbonyl Oxymethoxy) phosphoryl] epoxide isopropyl methyl carbonic ester (1b) (30g, 41.7mmol) is dissolved in acetonitrile In (150mL), water (150mL) is added, triethylamine (1mL) is added dropwise and adjusts reaction solution pH to 8~9, is heated to 30 DEG C of reactions and stays overnight. Dichloromethane (200mL) is added into reaction solution, point liquid, water layer is extracted with dichloromethane (100mL × 2), at 35 DEG C~40 DEG C Under the water layer that is concentrated under reduced pressure obtain [(1R) -2- [6- [(tert-butoxycarbonyl) amino] purine -9- bases] -1- methyl-ethoxies] first Base-(isopropoxy carbonyl Oxymethoxy) hypophosphorous acid (2b), white solid (5.0g, yield 20%)；Merge organic phase, it is organic Mutually washed with saturated aqueous common salt (50mL × 2), anhydrous sodium sulfate drying is concentrated under reduced pressure, the separation of residue silica gel column chromatography is carried Pure (ethyl acetate/petroleum ether (v/v)=1: 1~1: 0) obtain [(1R) -2- [6- [double (tert-butoxycarbonyl) amino] purine - 9- yls] -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) hypophosphorous acid (1d), white solid (4.2g, production Rate 17%).

Embodiment 1

[[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl epoxide methoxy Base) phosphoryl] epoxide methyl 3- hydroxyl -2,2- Dimethyl-propionic acid esters (compound 1)

[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl- (isopropoxycarbonyloxymethoxy) phosphoryl] oxymethyl 3-hydroxy-2,2-dimethyl- propanoate

The first step：3- hydroxyls-PA chloromethyl ester (1B)

Chloromethyl 3-hydroxy-2,2-dimethyl-propanoate

Successively by 3- hydroxyls-PA (1A) (5.9g, 50mmol), tetrabutyl hydrogen sulfate ammonia (1.7g, 5mmol), sodium acid carbonate (8.4g, 100mmol) is dissolved in water (30mL) and dichloromethane (40mL) solution, is cooled to 0 DEG C, drop Chlorination sulfonic acid chloromethyl ester (4.95g, 30mmol), is warmed to room temperature reaction 14 hours.Water (30mL) and dichloro are added into reaction solution Methane (40mL), point liquid, aqueous phase is extracted with dichloromethane (80mL × 2), merges organic phase, and organic phase is washed with saturated common salt Wash, anhydrous sodium sulfate drying, concentrate, residue is with silica gel column chromatography separating-purifying (petroleum ether: ethyl acetate (v/v)=3: 1) Obtain title compound 3- hydroxyls-PA chloromethyl ester (1B), colorless oil (700mg, yield 14%).

¹H-NMR：(CDCl₃)：5.74 (s, 2H), 3.62 (s, 2H), 2.40 (s, 1H), 1.23 (s, 6H).

Second step：2,2- dimethyl -3- trimethylsiloxy group propionic acid chloromethyl esters (1C)

Chloromethyl 2,2-dimethyl-3-trimethylsilyloxy-propanoate

3- hydroxyls-PA chloromethyl ester (1B) (700mg, 4.20mmol) is dissolved in dimethylformamide In (4mL), imidazoles (428mg, 6.3mmol) is added, 0 DEG C is cooled to, trim,ethylchlorosilane (547mg, 5.04mmol) is added dropwise, is risen To room temperature reaction 2 hours.Into reaction solution add water (40mL), with ethyl acetate/n-hexane (v/v=1: 1) extract (50mL × 3) organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography point, are merged Title compound 2,2- dimethyl -3- are obtained from purification (n-hexane: dichloromethane: ethyl acetate (v/v/v)=150: 10: 1) Trimethylsiloxy group propionic acid chloromethyl ester (1C), anhydrous grease (600mg, yield 60%).

¹H-NMR：(CDCl₃)：5.71 (s, 2H), 3.57 (s, 2H), 1.18 (s, 6H), 0.08 (s, 9H).

3rd step：[[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl oxygen Ylmethoxy) phosphoryl] epoxide methyl 2,2- dimethyl -3- trimethylsiloxy groups-propionic ester (1D)

[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl- (isopropoxycarbonyloxymethoxy) phosphoryl] oxymethyl 2,2-dimethyl-3- trimethylsilyloxy-propanoate

[(1R) -2- (adenine -9- bases) -1- methyl ethoxies] methyl acid phosphate (902mg, 3.145mmol) is molten In 1-METHYLPYRROLIDONE (4mL), addition 2,2- dimethyl -3- trimethylsiloxy group propionic acid chloromethyl esters (1C) (1.5g, 6.29mmol), be warming up to 60 DEG C, add chloromethyl butylperoxyisopropyl carbonate (959mg, 6.29mmol) and triethylamine (1.27g, 12.58mmol), 60 DEG C are maintained to react 5 hours.Reaction solution is cooled down to room temperature, water (40mL) is added, with ethyl acetate (50mL × 3) extract, merge organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentration, residue silicagel column color Spectrum separating-purifying (dichloromethane: methanol: ammoniacal liquor (v/v/v)=25: 1: 0.2) obtains title compound [[(1R) -2- (6- amino Purine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 2,2- diformazans Base -3- trimethylsiloxy groups-propionic ester (1D), anhydrous grease (600mg, yield 32%).

4th step：[[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl oxygen Ylmethoxy) phosphoryl] epoxide methyl 3- hydroxyl -2,2- Dimethyl-propionic acid esters (compound 1)

By [[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl epoxide methoxy Base) phosphoryl] epoxide methyl 2,2- dimethyl -3- trimethylsiloxy groups-propionic ester (1D) (600mg, 1mol) is dissolved in tetrahydrochysene furan Mutter in (4mL), add acetic acid (2mL), add water (1mL), maintain 15 DEG C to react 30 minutes.Tetrahydrochysene furan is distilled off in reaction solution Mutter, water (10mL) is added into residue, pH value of solution=8 are adjusted with saturated sodium bicarbonate solution, with ethyl acetate (30mL × 2) Extraction, merges organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography Separating-purifying (dichloromethane: methanol: acetone: ammoniacal liquor (v/v/v/v)=20: 1: 1.5: 0.2~16.5: 1: 1.5: 0.15) is obtained Title compound [[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl epoxide methoxy Base) phosphoryl] epoxide methyl 3- hydroxyl -2,2- Dimethyl-propionic acid esters (compound 1), colorless oil (65mg, 12%).

¹H-NMR：(CDCl₃)：8.32 (d, 1H), 8.00 (d, 1H), 6.38 (d, 2H), 5.78-5.55 (m, 4H), 5.36- 5.30 (m, 1H), 4.98-4.82 (m, 1H), 4.43-4.37 (m, 1H), 4.06-3.88 (m, 2H), 3.85-3.64 (m, 2H), 3.56-3.50 (m, 2H), 1.34-1.21 (m, 15H).

MS M/Z(ESI)：534.2(M+1).

Embodiment 2

[[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl epoxide methoxy Base) phosphoryl] epoxide methyl 3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids ester (compound 2)

[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl- (isopropoxycarbonyloxymethoxy) phosphoryl] oxymethyl 3- (methoxyethoxy) -2,2- dimethyl-propanoate

The first step：3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids methyl esters (2B)

Methyl 3- (methoxy-ethoxy) -2,2-dimethyl-propanoate

Sodium hydride (10g, 0.42mol, wt=60%) is added in tetrahydrofuran (800mL), ice-water bath is cooled to 0 DEG C, 3- hydroxyls -2,2 are slowly added to,-dimethylated methyl propionate (2A) (50g, 0.38mol) reacts 1 hour, adds 2- bromoethyls Methyl ether (63.2g, 0.46mol), is warmed to room temperature and is stirred overnight.Saturated aqueous ammonium chloride is added into reaction solution to be quenched instead Should, point liquid, aqueous layer with ethyl acetate (800mL × 2) extraction merges organic phase, and organic phase is with saturated aqueous common salt (1000mL × 2) Washing, anhydrous sodium sulfate drying, concentration, residue composes separating-purifying (petroleum ether: ethyl acetate (v/v)=25: 1) with silicagel column Obtain title compound 3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids methyl esters (2B), colourless liquid (9.8g, yield 14%).

MS M/Z(ESI)：191.1(M+1).

Second step：3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids (2C)

3- (methoxy-ethoxy) -2,2-dimethyl-propionic acid

3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids methyl esters (2B) (4.7g, 24.7mmol) is dissolved in methanol/water (v/v=1: Isosorbide-5-Nitrae 0mL) in the mixed solvent, adds potassium hydroxide (5.5g, 98.8mmol), stirring reaction is stayed overnight at 35 DEG C.To Hydrochloric acid (4N) aqueous solution is added in reaction solution and adjusts solution to acidity, vacuum distillation removes methanol, add water (10mL) dilution, uses second Acetoacetic ester (30mL × 3) is extracted, and merges organic phase, and organic phase is washed with saturated aqueous common salt (100mL × 2), and anhydrous sodium sulfate is done Dry, concentration, residue obtains title compound 3- with silica gel column chromatography separating-purifying (dichloromethane: methanol (v/v)=50: 1) (methoxy ethoxy) -2,2- Dimethyl-propionic acids (2C), colourless liquid (0.9g, yield 21%)；

¹H-NMR：(CDCl₃)：9.17 (s, 1H), 3.65-3.63 (m, 2H), 3.56-3.53 (m, 2H), 3.51 (s, 2H), 3.38 (s, 3H), 1.22 (s, 6H).

MS M/Z(ESI)：177.2(M+1).

3rd step：3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids chloromethyl ester (2D)

Chloromethyl 3- (methoxy-ethoxy) -2,2-dimethyl-propanoate

3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids (2C) (2.6g, 14.8mmol) are dissolved in methylene chloride/water (v/v=1: 1,10mL) in the mixed solvent, ice-water bath is cooled to 0 DEG C, adds tetrabutyl hydrogen sulfate ammonia (1.0g, 2.96mmol), Sodium acid carbonate (5.0g, 59.2mmol), stirring reaction 10 minutes adds chlorosulfonic acid chloromethyl ester (2.42g, 14.8mmol), risen to It is stirred overnight at room temperature.By reaction solution point liquid, water layer is extracted with dichloromethane (10mL), merges organic phase, and organic phase is eaten with saturation Salt water washing (20mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (ethyl acetate: first Alcohol (v/v)=10: 1) obtain title compound 3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids chloromethyl ester (2D), colourless liquid Body (0.91g, yield 27%).

¹H-NMR：(CDCl₃)：5.65 (s, 2H), 3.54-3.51 (m, 2H), 3.45-3.43 (m, 4H), 3.29 (s, 3H), 1.16 (s, 6H).

4th step：[[(1R) -2- (6- [double (tert-butoxycarbonyl) amino] purine -9- bases) -1- methyl-ethoxies] first Base-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- (methoxy ethoxy) -2,2- Dimethyl-propionic acid esters (2E)

[[(1R)-2-(bis(tert-butoxycarbonyl)amino]purin-9-yl)-1-methyl-ethoxy] methyl-(isopropoxy carbonyloxymethoxy)phosphoryl]oxymethyl 3-(methoxy- Ethoxy) -2,2-dimethyl-propanoate

By [(1R) -2- [6- [double (tert-butoxycarbonyl) amino] purine -9- bases] -1- methyl-ethoxies] methyl-(different Propoxycarbonyl Oxymethoxy) hypophosphorous acid (1d) (0.448g, 0.743mmol) is dissolved in DMF (1mL), Triethylamine (0.226g, 2.23mmol) is added, 70 DEG C of stirring reactions are risen to 10 minutes, 3- (methoxy ethoxy) -2,2- is added DMF (1mL) solution of Dimethyl-propionic acid chloromethyl ester (2D) (0.5g, 2.23mmol), 70 DEG C of stirrings 2 are small When.Dichloromethane (10mL) and water (1mL) are added into reaction solution, point liquid, water layer is extracted with dichloromethane (10mL), is associated with Machine phase, organic phase is washed with saturated aqueous common salt (20mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography point Title compound [[(1R) -2- (6- [double (tert-butoxycarbonyls) are obtained from purification (petroleum ether: ethyl acetate (v/v)=3: 1) Amino] purine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids ester (2E), colourless liquid (0.143g, 24%).

¹H-NMR：(CDCl₃)：8.85 (s, 1H), 8.27 (s, 1H), 5.70-5.52 (m, 4H), 4.95-4.91 (m, 1H), 4.45 (d, 1H), 4.26 (dd, 1H), 4.00-3.92 (m, 2H), 3.77-3.71 (m, 1H), 3.59-3.57 (m, 2H), 3.50 (m, 4H), 3.34 (s, 3H), 1.45 (s, 18H), 1.32 (d, 6H), 1.21 (m, 9H).

MS M/Z(ESI)：792.3(M+1).

5th step：[[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl oxygen Ylmethoxy) phosphoryl] epoxide methyl 3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids ester (compound 2)

By [[(1R) -2- (6- [double (tert-butoxycarbonyl) amino] purine -9- bases) -1- methyl-ethoxies] methyl-(different Propoxycarbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids ester (2E) (0.143g, 0.18mmol) is dissolved in dichloromethane (2mL), and ice-water bath is cooled to 0 DEG C, and stirring reaction 5 minutes adds trifluoro second Sour (2mL), stirring reaction 5 minutes is warmed to room temperature reaction 1 hour.By reaction solution with saturated sodium bicarbonate aqueous solution adjust pH to Neutrality, point liquid, water layer is extracted with dichloromethane (10mL × 2), merges organic phase, and organic phase is molten with saturated sodium bicarbonate water successively Liquid (20mL × 2), saturated aqueous common salt (20mL × 2) washing, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography point From purification (ethyl acetate) obtain title compound [[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl - (isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids ester (changes Compound 2), colourless liquid (0.09g, yield 85%).

¹H-NMR：(CDCl₃)：8.33 (s, 1H), 7.99 (s, 1H), 6.01 (s, 2H), 5.70-5.62 (m, 4H), 4.95- 4.88 (m, 1H), 4.36 (d, 1H), 4.18-4.12 (m, 1H), 3.97-3.90 (m, 2H), 3.73-3.67 (m, 1H), 3.59- 3.56 (m, 2H), 3.50-3.48 (m, 4H), 3.34 (s, 3H), 1.32-1.29 (m, 6H), 1.23-1.20 (m, 9H).

MS M/Z(ESI)：592.3(M+1).

The fractionation of compound 2

Take [[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl epoxide methoxy Base) phosphoryl] epoxide methyl 3- (methoxy ethoxy) -2,2- Dimethyl-propionic acids ester (compound 2) (4.5g) be used for split, Method for separating and analyzing：Instrument：Thar analytical SFC；Post：ChiraPak AD-3,150 × 4.6mm；Mobile phase：A For CO2 and B for ETOH (0.05%DEA)；Gradient：B 20%；Flow：2.4mL/min；Back pressure：100bar；Post Temperature：35℃；Wavelength：220nm；Preparative separation method：Instrument：MG II preparative SFC, post：ChiralPak AD-H, 250 × 30mmI.D., mobile phase：A for CO2 and B for ETOH, gradient：B 20%, flow：60mL/min, back pressure： 100bar, column temperature：38 DEG C, wavelength：220nm, cycle：~4.0min；Sample preparation：Compound 2 dissolves in ethanol, and sample is made Product concentration 160mg/ml solution, sample introduction：0.5mL is per pin.

Two optical isomer compound 2-1 (retention times are obtained after separation：2.85min, 2.18g, colorless viscous thing, Ee%=100%), compound 2-2 (retention times：3.28min, 2.04g, colorless viscous thing, ee%=98.3%).

Compound 2-1

1H NMR (400MHz, CDCl3) δ 8.33 (s, 1H), 8.05 (s, 1H), 6.42 (s, 2H), 5.69-5.54 (m, 4H), 4.96-4.86 (m, 1H), 4.38 (dd, 1H), 4.16 (dd, 1H), 3.99-3.90 (m, 2H), 3.69 (dd, 1H), 3.58 (m, 2H), 3.49 (m, 4H), 3.34 (s, 3H), 1.31 (s, 3H), 1.30 (s, 3H), 1.24-1.20 (m, 9H).

31P NMR (162MHz, CDCl3) δ 22.47.

LC-MS M/Z(ESI)：592.3(M+1).

Compound 2-2

1H NMR (400MHz, CDCl3) δ 8.33 (s, 1H), 8.02 (s, 1H), 6.19 (s, 2H), 5.68-5.57 (m, 4H), 4.92 (m, 1H), 4.37 (dd, 1H), 4.15 (dd, 1H), 3.99-3.90 (m, 2H), 3.70 (m, 1H), 3.57 (m, 2H), 3.52-3.47 (m, 4H), 3.34 (s, 3H), 1.32 (s, 3H), 1.30 (s, 3H), 1.24-1.19 (m, 9H).

31P NMR (162MHz, CDCl3) δ 22.47.

LC-MS M/Z(ESI)：592.4(M+1).

Embodiment 3

[[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl epoxide methoxy Base) phosphoryl] epoxide methyl 3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acids ester (compound 3)

[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl- (isopropoxycarbonyloxymethoxy)phosphoryl]oxymethyl 3-(methoxy-ethoxy-ethoxy)- 2,2-dimethyl-propanoate

The first step：3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acids methyl esters (3B)

Methyl 3- (methoxy-ethoxy-ethoxy) -2,2-dimethyl-propanoate

Weigh sodium hydride (8.2g, 0.204mol, wt=60%) to be added in tetrahydrofuran (200mL), ice-water bath cooling To 0 DEG C, 3- hydroxyls-PA methyl esters (3A) (22.44g, 0.170mol) is slowly added to, stirring reaction 0.5 hour, The bromo- 2- methoxyethoxyethanes (62g, 0.339mol) of 1- are added, stirring reaction is warmed to room temperature and stays overnight.By reaction solution saturation Reaction is quenched in aqueous ammonium chloride solution (300mL), point liquid, aqueous layer with ethyl acetate (500mL × 2) extraction, merges organic phase, organic Mutually washed with saturated aqueous common salt (1000mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petroleum ether: ethyl acetate (v/v)=25: 1) obtain title compound 3- (methoxyethoxyethoxy) -2,2- dimethyl - Methyl propionate (3B), colourless liquid (9.73g, yield 25%).

¹H-NMR：(CDCl₃)：3.65 (s, 3H), 3.62-3.56 (m, 6H), 3.52-3.50 (m, 2H), 3.45 (s, 2H), 3.36 (s, 3H), 1.16 (s, 6H).

MS M/Z(ESI)：235.2(M+1).

Second step：3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acids (3C)

3- (methoxy-ethoxy-ethoxy) -2,2-dimethyl-propionic acid

3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acids methyl esters (3B) (40g, 0.171mol) is dissolved in first Alcohol/water (v/v=1: Isosorbide-5-Nitrae 00mL) in the mixed solvent, adds potassium hydroxide (38.3g, 0.684mol), 35 DEG C of stirring reaction mistakes Night.Reaction solution is adjusted into pH=3 or so with hydrochloric acid (6N) aqueous solution, vacuum distillation removes most of methanol, water layer acetic acid second Ester (200mL × 2) is extracted, and merges organic phase, and organic phase is washed with saturated aqueous common salt (400mL × 2), anhydrous sodium sulfate drying, Concentration, residue obtains title compound 3- (first with silica gel column chromatography separating-purifying (dichloromethane: methanol (v/v)=60: 1) Epoxide ethoxy ethoxy) -2,2- Dimethyl-propionic acids (3C), colourless liquid (24.0g, 64%).

3rd step：3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acids chloromethyl ester (3D)

Chloromethyl 3- (methoxy-ethoxy-ethoxy) -2,2-dimethyl-propanoate

3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acids (3C) (20.0g, 0.091mol) are dissolved in dichloro Methane/water (v/v=1: 1,200mL) in the mixed solvent, ice-water bath is cooled to 0 DEG C, add tetrabutyl hydrogen sulfate ammonia (3.09g, 0.0091mol), sodium acid carbonate (22.9g, 0.273mol), stirring reaction 30 minutes, addition chlorosulfonic acid chloromethyl ester (15g, 0.091mol), stirring reaction is warmed to room temperature to stay overnight.By reaction solution point liquid, water layer is washed with dichloromethane (100mL × 2), is merged Organic phase, organic phase is washed with saturated aqueous common salt (200mL × 2), anhydrous sodium sulfate drying, concentration, residue silicagel column color Spectrum separating-purifying (ethyl acetate: methanol (v/v)=10: 1) obtains title compound 3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acid chloromethyl ester (3D), colourless liquid (14.0g, yield 57%).

¹H-NMR：(CDCl₃)：5.73 (s, 2H), 3.64-3.61 (m, 6H), 3.54-3.52 (m, 2H), 3.50 (s, 2H), 3.38 (s, 3H), 1.24 (s, 6H).

4th step：[[(1R) -2- (6- [double (tert-butoxycarbonyl) amino] purine -9- bases) -1- methyl-ethoxies] first Base-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- (methoxyethoxyethoxy) -2,2- dimethyl - Propionic ester (3E)

[[(1R)-2-(bis(tert-butoxycarbonyl)amino]purin-9-yl)-1-methyl-ethoxy] methyl-(isopropoxycarbonyloxymethoxy)phosphoryl]oxymethyl 3-(methoxy-ethoxy- Ethoxy) -2,2-dimethyl-propanoate

By [(1R) -2- [6- [double (tert-butoxycarbonyl) amino] purine -9- bases] -1- methyl-ethoxies] methyl-(different Propoxycarbonyl Oxymethoxy) hypophosphorous acid (1d) (7.0g, 11.6mmol) is dissolved in DMF (20mL), plus Enter triethylamine (5.3g, 52.2mmol), rise to 70 DEG C of stirring reactions 20 minutes, add 3- (methoxyethoxyethoxy) -2, 2- Dimethyl-propionic acids chloromethyl ester (3D) (14.0g, 52.2mmol), stirring reaction 2 hours at 70 DEG C.Added into reaction solution Dichloromethane (20mL) and water (20mL), point liquid, water layer are extracted with dichloromethane (20mL), merge organic layer, and organic layer is used full With saline solution (50mL × 2) washing, anhydrous sodium sulfate drying, concentration, residue with silica gel column chromatography separating-purifying (petroleum ether: Ethyl acetate (v/v)=3: 1) obtain title compound [[(1R) -2- (6- [double (tert-butoxycarbonyl) amino] purine -9- Base) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- (methoxy ethoxies Ethyoxyl) -2,2- Dimethyl-propionic acids ester (3E), colourless liquid (1.4g, yield 15%).

¹H-NMR：(CDCl₃)：8.80 (s, 1H), 8.23 (s, 1H), 5.63-5.46 (m, 4H), 4.90-4.86 (m, 1H), 4.40 (d, 1H), 4.22 (dd, 1H), 3.96-3.88 (m, 2H), 3.73-3.67 (m, 1H), 3.55 (s, 6H), 3.48-3.45 (m, 4H), 3.32 (s, 3H), 1.40 (m, 18H), 1.26 (d, 6H), 1.17 (d, 9H).

MS M/Z(ESI)：836.2(M+1).

5th step：[[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl oxygen Ylmethoxy) phosphoryl] epoxide methyl 3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acids ester (compound 3)

By [[(1R) -2- (6- [double (tert-butoxycarbonyl) amino] purine -9- bases) -1- methyl-ethoxies] methyl-(different Propoxycarbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acid esters (3E) (1.4g, 1.68mmol) is dissolved in dichloromethane (6mL), and ice-water bath is cooled to 0 DEG C, and stirring reaction 5 minutes adds trifluoro Acetic acid (6mL), stirring reaction 5 minutes is warmed to room temperature reaction 3 hours.Reaction solution is adjusted into pH with saturated sodium bicarbonate aqueous solution To neutral, point liquid, water layer dichloromethane (20mL × 3) extraction merges organic phase, organic phase uses saturated sodium bicarbonate water successively Solution (20mL × 2), the saturated common salt aqueous solution (20mL × 2) washing, anhydrous sodium sulfate drying, concentration, residue silicagel column Chromatographic purification (dichloromethane: methanol (v/v)=30: 1) obtains title compound [[(1R) -2- (adenine -9- Base) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl Oxymethoxy) phosphoryl] epoxide methyl 3- (methoxy ethoxies Ethyoxyl) -2,2- Dimethyl-propionic acids ester (compound 3), colourless liquid (0.37g, yield 35%).

¹H-NMR：(CDCl₃)：8.30 (s, 1H), 7.98 (s, 1H), 6.38 (s, 2H), 5.64-5.53 (m, 4H), 4.91- 4.85 (m, 1H), 4.34 (d, 1H), 4.12 (m 1H), 3.94-3.88 (m, 2H), 3.70-3.65 (m, 1H), 3.62-3.60 (m, 6H), 3.53-3.48 (m, 4H), 3.31 (s, 3H), 1.28-1.27 (m, 6H), 1.23-1.17 (m, 9H).

MS M/Z(ESI)：636.2(M+1).

The fractionation of compound 3

Take [[(1R) -2- (adenine -9- bases) -1- methyl-ethoxies] methyl-(isopropoxy carbonyl epoxide methoxy Base) phosphoryl] epoxide methyl 3- (methoxyethoxyethoxy) -2,2- Dimethyl-propionic acids ester (compound 3) (8.6g) is used for Split, method for separating and analyzing：Instrument：Thar analytical SFC, post：ChiralPak AD-3,150 × 4.6mm, 3um, Mobile phase：A for CO₂And B for Ethanol (0.05%DEA), gradient：B 25%, flow：2.4mL/min, the back of the body Pressure：100bar, column temperature：35 DEG C, wavelength：220nm；Preparative separation method：Instrument：The preparative SFC of Thar 350, post： ChiralPak AD-10u, 300 × 50mmI.D., mobile phase：A for CO₂And B for Ethanol, gradient：B 25%, flow：200mL/min, back pressure：100bar, column temperature：38 DEG C, wavelength：220nm, cycle：~3min, sample preparation：Change Compound 3 dissolves the solution sample introduction that sample concentration 20mg/ml is made in ethanol：2.5mL is per pin.

Two optical isomer compound 3-1 (retention times are obtained after separation：2.67min, 3.2g, colorless viscous thing, Ee%=100%), compound 3-2 (retention times：3.07min, 3g, colorless viscous thing, ee%=98%).

Compound 3-1

¹H NMR (400MHz, CDCl3) δ 8.34 (s, 1H), 7.98 (s, 1H), 5.97 (s, 2H), 5.73-5.53 (m, 4H), 4.91 (m, 1H), 4.36 (dd, 1H), 4.15 (dd, 1H), 4.01-3.88 (m, 2H), 3.70 (m, 1H), 3.64-3.56 (m, 6H), 3.51 (m, 4H), 3.37 (s, 3H), 1.30 (d, 6H), 1.21 (m, 9H).

³¹P NMR (162MHz, CDCl3) δ 22.58.

LC-MS M/Z(ESI)：636.2(M+1).

Compound 3-2

1H NMR (400MHz, CDCl3) δ 8.34 (s, 1H), 7.98 (s, 1H), 5.97 (s, 2H), 5.72-5.53 (m, 4H), 4.91 (m, 1H), 4.36 (dd, 1H), 4.15 (dd, 1H), 4.02-3.87 (m, 2H), 3.70 (dd, 1H), 3.65-3.55 (m, 6H), 3.51 (m, 4H), 3.37 (s, 3H), 1.30 (d, 6H), 1.21 (m, 9H).

³¹P NMR (162MHz, CDCl3) δ 22.55.

LC-MS M/Z(ESI)：636.2(M+1).

The preparation of the compound 2-1 of embodiment 4 fumarate

Compound 2-1 (1.95g, 3.29mmol) is dissolved in ethyl acetate (18mL), addition fumaric acid (0.382g, 3.29mmol) and absolute methanol (2mL), it is heated to being cooled to room temperature again after 50 DEG C of stirrings are clarified completely to solution, adds oil Ether (20mL), stirring and crystallizing 3 hours, filtering collects filter cake and is dried under reduced pressure to obtain title compound (1.5g, yield 65.2%).

¹H NMR (400MHz, DMSO) δ 13.13 (s, 2H), 8.14 (s, 1H), 8.04 (s, 1H), 7.20 (s, 2H), 6.64 (s, 2H), 5.67-5.47 (m, 4H), 4.89-4.76 (m, 1H), 4.27 (d, 1H), 4.18 (dd, 1H), 3.98 (m, 3H), 3.49 (s, 2H), 3.46-3.35 (m, 4H), 3.22 (s, 3H), 1.24 (d, 6H), 1.12 (s, 6H), 1.08 (d, 3H).

³¹P NMR (162MHz, DMSO) δ 23.13.

LC-MS M/Z(ESI)：592.2(M+1).

The preparation of the compound 2-2 of embodiment 5 fumarate

Compound 2-2 (1.61g, 2.73mmol) is dissolved in ethyl acetate (14.5mL), fumaric acid is added (0.316g, 2.73mmol) and absolute methanol (1.5mL), is heated to being cooled to room again after 50 DEG C of stirrings are clarified completely to solution Temperature, adds petroleum ether (16ml), and stirring and crystallizing 3 hours, filtering collects filter cake and is dried under reduced pressure to obtain title compound (1.3g, yield 67.7%).

1H NMR (400MHz, DMSO) δ 13.12 (s, 2H), 8.14 (s, 1H), 8.04 (s, 1H), 7.19 (s, 2H), 6.63 (s, 2H), 5.61-5.49 (m, 4H), 4.83 (m, 1H), 4.26 (m, 1H), 4.17 (m, 1H), 4.00-3.89 (m, 3H), 3.49 (m, 2H), 3.45-3.37 (m, 4H), 3.22 (s, 3H), 1.24 (m, 6H), 1.11 (s, 6H), 1.08 (d, 3H).

³¹P NMR (162MHz, DMSO) δ 23.14.

LC-MS M/Z(ESI)：592.2(M+1).

The preparation of the compound 3-1 of embodiment 6 fumarate

Compound 3-1 (1.8g, 2.83mmol) is dissolved in ethyl acetate (16mL), addition fumaric acid (0.328g, 2.83mmol) and absolute methanol (2mL), it is heated to being down to room temperature again after 50 DEG C of stirrings are clarified completely to solution, adds petroleum ether (18mL), stirring and crystallizing 3 hours, filtering collects filter cake and is dried under reduced pressure to obtain title compound (1.3g, yield 61.9%).

¹H NMR (400MHz, DMSO) δ 13.11 (s, 2H), 8.14 (s, 1H), 8.03 (s, 1H), 7.19 (s, 2H), 6.63 (s, 2H), 5.67-5.46 (m, 4H), 4.82 (m, 1H), 4.26 (dd, 1H), 4.17 (dd, 1H), 4.05-3.88 (m, 3H), 3.48 (s, 6H), 3.41 (m, 4H), 3.23 (s, 3H), 1.24 (d, 6H), 1.12 (s, 6H), 1.07 (d, 3H).

³¹P NMR (162MHz, DMSO) δ 23.12.

LC-MS M/Z(ESI)：636.2(M+1).

The preparation of the compound 3-2 of embodiment 7 fumarate

Compound 3-2 (1.8g, 2.83mmol) is dissolved in ethyl acetate (16mL), addition fumaric acid (0.328g, 2.83mmol) and absolute methanol (2mL), it is heated to being down to room temperature again after 50 DEG C of stirrings are clarified completely to solution, adds petroleum ether (18mL), stirring and crystallizing 3 hours, filtering collects filter cake and is dried under reduced pressure to obtain title compound (1.2g, yield 57.1%).

¹H NMR (400MHz, DMSO) δ 13.09 (s, 2H), 8.14 (s, 1H), 8.04 (s, 1H), 6.63 (s, 2H), 4.88-4.77 (m, 1H), 4.26 (dd, 1H), 4.17 (dd, 1H), 4.04-3.87 (m, 3H), 3.53-3.44 (m, 6H), 3.44- 3.35 (m, 4H), 3.27-3.19 (m, 3H), 1.23 (m, 6H), 1.15-1.03 (m, 9H).

³¹P NMR (162MHz, DMSO) δ 23.14.

LC-MS M/Z(ESI)：636.2(M+1).

Study on the stability in test case 1, human plasma

Take people's whole blood to mix anti-freezing by 9: 1 with 3.8% sodium citrate anticoagulant, in 4 DEG C, 15 points are centrifuged under the conditions of 2000g Clock, takes supernatant to be placed in constant incubator or water-bath and is incubated 5 minutes, take tenofovir dipivoxil, compound 2, compound 2-1, compound 2-2 and compound 3 each 250 μ l of DMSO/TBS mixed liquors (0.2mg/mL) and the μ l of pre-temperature human plasma 1000 are mixed Close, fully mix, labeled as mixture 1,2,3, mixture 1,2,3 is placed in constant incubator or water-bath and is incubated, is existed respectively The μ l of reaction mixture 200 are taken when the 0th, 5 seconds, 10 seconds, 15 seconds, 25 seconds, 45 seconds, 1 minute, 2 minutes, 5 minutes and 10 minutes and with 600 μ l methanol solutions are mixed, after fully mixing, and are centrifuged 5 minutes under the conditions of 15000g, are taken supernatant, with being used after 0.22 μm of membrane filtration HPLC is analyzed, and analysis result is as shown in table 1.

Table 1：Human plasma internal stability experimental result

Numbering	Human plasma stability (t_1/2)
		Tenofovir dipivoxil	77.5s
Compound 2	189s
		Compound 2-1	189s
Compound 2-2	189s
		Compound 3	140.8s

Conclusion：Compared with tenofovir dipivoxil, the compounds of this invention has higher human plasma stability.

Test case 2, anti-hepatitis B virus activity screening

With the anti-hepatitis B activity of HepG2.2.15 raji cell assay Raji compounds.The material used and instrument are as follows： HepG2.2.15 cells, RPMI 1640 culture mediums, hyclone, 96 orifice plates, DMSO, the DNA Blood Kit of QIAamp 96, Cell-titer blue, ELIASA, the real-time PCR system of Applied Biosystems 7900.

Each compound is dissolved to 20mM with DMSO, the 20mM of each compound is stored 3 times of DMSO of liquid by -20 DEG C of storages Gradient dilution, totally 9 concentration.Again 200 times are diluted with the RPMI 1640 culture mediums containing 2.0%FBS.The highest test of compound Final concentration of 100 μM.Experimental procedure is with reference to QIAamp 96 DNA Blood Kit (QIAGEN 51161) specification.

QPCR methods determine compound anti-hepatitis B activity and calculate EC₅₀(half effective inhibition concentration).Analyze data and Calculate suppression percentage：Suppression percentage is calculated using equation below：%Inh.=【(HBV quantity of DMSO control-HBV quantity of sample)/HBV quantity of DMSO control】×100.Finally use GraphPad Prism softwares calculate the EC of compound₅₀Value.

Cell-titer blue methods determine the cytotoxicity of compound and calculate CC₅₀(causing 50% cytotoxic concentration).Point Analyse data and calculate versus cell vigor：Cytoactive percentage is calculated using equation below：%cell viability= (fluorescence of sample-fluorescence of medium control)/(fluorescence of DMSO control-fluorescence of medium control)×100.Finally use GraphPad Prism software calculatingization The CC of compound₅₀Value.As a result it is as shown in table 2.

Table 2：Each compound EC₅₀Value and CC₅₀Value

Sequence number	Compound number	EC₅₀(μM)	CC₅₀(μM)
				Control	Tenofovir dipivoxil	0.00182	＞ 100
1	2	＜ 0.0152	50.50
				2	2-1	0.00065	＞ 100
3	2-2	0.00079	＞ 100
				4	3	＜ 0.0152	82.75
5	3-1	0.01068	＞ 100
				6	3-2	0.01592	＞ 100

Conclusion：Test compound shows preferable anti-hepatitis B activity, in the concentration range of test (0.0152-100 μM) does not show cytotoxicity.

Test case 3, Pharmacokinetic Evaluation

Male SD rat (is purchased from Vital River Laboratory Animal Technology Co.LTD, licensing Number：11400700005540) 200-240g, overnight fasting.3 SD rats difference gavage 15mgkg-1 of experimental day are (by original Medicine PMPA is counted), 5,15,30min, 1,2,4,8,12 and 24h before being administered and after administration, by jugular vein blood collection 0.20mL, It is placed in EDTA test tubes.2 times of volumes of acetonitrile, whirlpool mixing 1min, 13000rpm centrifugation 8min are added after blood sample collection.Take The μ L of supernatant 100, add 50 μ L acetonitriles and internal standard (Verapamil, 5.00ngmL-1and glibenclamides, 50.0ngmL-1), After whirlpool mixing 1min, N2 dryings.Residue adds 100 μ L deionized water dissolvings, takes 5 μ L to carry out LC-MS/MS detections.Using Non- compartment model in Pharsight Phoenix 6.3 calculates pharmacokinetic parameter, and evaluate prodrug compound relative to Active compound PMPA oral administration biaavailability.Experimental result is as shown in table 3.

Table 3：Pharmacokinetics in rats evaluation result

Conclusion：Compound 2-1 fumarate and compound 2-2 fumarate and the pyrrole furan of control drug tenofovir two Ester fumarate is compared, with suitable effect.

Claims

1. compound, its stereoisomer shown in a kind of logical formula (I) or pharmaceutically acceptable salt,

Wherein：

R¹Selected from H or methyl；

R²Selected from H, C_1-10Alkyl ,-(CH₂-CH₂-O)_n- H or-(CH₂-CH₂-O)_n-C_1-10Alkyl, described alkyl optionally enters one Step is by 0 to 5 R^2aSubstitution；

R³Selected from C_1-10Alkyl ,-(CH₂-CH₂-O)_n- H or-(CH₂-CH₂-O)_n-C_1-10Alkyl, wherein described alkyl optionally enters One step is by 0 to 5 R^3aSubstitution；

R^2aAnd R^3aIt is independently selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, carboxyl, C_1-4Alkyl or C_3-6Cycloalkanes Base；

N is selected from 1,2,3,4,5,6,7,8,9 or 10.

2. compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt, wherein：

R¹Selected from H or methyl；

R²Selected from substituted or unsubstituted H, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, isopentyl, new Amyl group, pentane -3- bases,-(CH₂-CH₂-O)_n- H or-(CH₂-CH₂-O)_n- methyl, when substituted, optionally by 1 to 5 R^2a Substitution；

R³Selected from substituted or unsubstituted methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, isopentyl, new penta Base, pentane -3- bases,-CH₂-CH₂- OH or-(CH₂-CH₂-O)₂- H, when substituted, optionally by 1 to 5 R^3aSubstitution；

N is selected from 1,2,3,4 or 5.

3. compound according to claim 2, its stereoisomer or pharmaceutically acceptable salt, the wherein compound Selected from the compound shown in logical formula (II), its stereoisomer or pharmaceutically acceptable salt, wherein：

R¹Selected from H or methyl；

R²Selected from H, methyl, ethyl, propyl group, isopropyl ,-CH₂-CH₂-O-CH₃、-CH₂-CH₂-OH、-(CH₂-CH₂-O)₂- H or Person-(CH₂-CH₂-O)₂-CH₃。

4. compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt, wherein compound are selected From one of following structure：

5. according to compound according to any one of claims 1 to 4, its stereoisomer or pharmaceutically acceptable salt, Wherein described salt is tosilate, fluoroform sulphonate, mesylate or fumarate.

6. a kind of pharmaceutical composition, described pharmaceutical composition contains：Treatment effective dose according to profit requires any one of 1~5 Described compound, its stereoisomer or pharmaceutically acceptable salt, and pharmaceutically acceptable carrier or figuration Agent.

7. pharmaceutical composition according to claim 6, the pharmaceutical composition is to be used to treat disease of viral infection.

8. pharmaceutical composition according to claim 7, wherein, the disease of viral infection include hepatitis type B virus, Infectious diseases caused by hepatitis C virus or AIDS virus.

9. compound according to any one of claims 1 to 5, its stereoisomer or pharmaceutically acceptable salt prepare The application in related drugs for treating disease of viral infection.

10. application according to claim 9, wherein the disease of viral infection includes hepatitis type B virus, hepatitis disease Infectious diseases caused by poison or AIDS virus.