CN107805266A - Preparation method as the methyl deoxyribonucleoside of 2 fluorine 2 of Suo Feibuwei intermediates - Google Patents

Preparation method as the methyl deoxyribonucleoside of 2 fluorine 2 of Suo Feibuwei intermediates Download PDF

Info

Publication number
CN107805266A
CN107805266A CN201610814730.4A CN201610814730A CN107805266A CN 107805266 A CN107805266 A CN 107805266A CN 201610814730 A CN201610814730 A CN 201610814730A CN 107805266 A CN107805266 A CN 107805266A
Authority
CN
China
Prior art keywords
formula
compound
phenyl
phenyls
base
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201610814730.4A
Other languages
Chinese (zh)
Inventor
孔锐
袁哲东
郭猛
胡明通
王笃政
强斌
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Medical Technology Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Original Assignee
Shanghai Medical Technology Co Ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Medical Technology Co Ltd, Chia Tai Tianqing Pharmaceutical Group Co Ltd filed Critical Shanghai Medical Technology Co Ltd
Priority to CN201610814730.4A priority Critical patent/CN107805266A/en
Priority to PCT/CN2017/101078 priority patent/WO2018045997A1/en
Priority to CN201780055402.3A priority patent/CN109641930B/en
Publication of CN107805266A publication Critical patent/CN107805266A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C07H13/06—Fatty acids

Abstract

The application belongs to pharmaceutical synthesis field, is related to the preparation method of the methyl deoxyribose of 2 fluorine 2 as Suo Feibuwei intermediates.Specifically, the application provides a kind of method by the preparation of compounds of formula V compounds of formula II, and intermediate therefor.The preparation method of the application stereo-selectively obtains the Formula V compound as beta isomer in the condensation reaction, available for the yield of the compound synthesis route of Suo Feibuwei intermediates formula 1, low process route cost, amplifies more suitable for industrialization.

Description

The preparation method of the fluoro- 2- methyl deoxyribonucleosides of 2- as Suo Feibuwei intermediates
Technical field
The application belongs to pharmaceutical synthesis field, is taken off in particular to the fluoro- 2- methyl of 2- as Suo Feibuwei intermediates The preparation method of oxygen nucleosides.
Background technology
Suo Feibuwei (Sofosbuvir), entitled (S) -2- { (S)-{ { (2R, 3R, 4R, 5R) -5- [2, the 4- dioxies of chemistry (the 2H)-yl of generation -3,4- dihydro-pyrimidins -1] the fluoro- 3- hydroxy-4-methyls tetrahydrofuran -2- bases of -4- } methoxyl group } (phenoxy group) phosphinylidyne Base amino } isopropyl propionate, CAS registration numbers：1190307-88-0, trade name Sovaldi, it is to be developed to use by lucky Leadd B.V In the new drug for the treatment of chronic hepatitis C, in food and medicine Surveillance Authority of the Nikkei U.S. (FDA) approval December 6 in 2013 in the U.S. City.January 16 in 2014, Nikkei Europe drug administration (EMEA) approval listed in EU countries.Clinical test proves, Suo Feibu Wei is directed to the overall continued viral response rate difference height of 1~4 type hepatitis, medicine joint Peg-IFN alpha-2b or Ribavirin Up to 90%, 89-95%, 61-63% and 90%.In addition to the patient of some hepatitis and hepatic sclerosis, curative effect also highly significant.
WO2012012465、US20140219958、J.Org.Chem,2011,76(20):The document reports such as 8311-8319 Suo Feibuwei synthesis is usually by the fluoro- 2'- MUs glycosides (formula 1) of (2'R) -2'- deoxidations -2'- and phenoxy group phosphinylidyne amido third The phosphoryl chloride phosphorus oxychloride or phosphate of isopropyl propionate occur phosphorus acylation reaction and obtained, as follows：
For the synthetic method of the compound of formula 1, the report of existing literature can be classified as two synthetic routes：
Document J.Med.Chem., 2005,48 (17):5504-5508 is reported using cytidine as raw material, by function It is prepared by the steps such as group's protection, oxidation, addition, diethylin sulfur trifluoride (DAST) fluorination, deprotection：
Addition reaction needs to use lithium methide to be reacted at -78 DEG C in the route, and condition is harsh, and side reaction is more, while DAST This step yield of fluorination reaction is low, and only 15%.
WO2006031725、WO2008045419、WO2013178571、J.Org.Chem.,2009,74(17):6819- The document reports such as 6824：With (2R) -2- deoxidations -2- fluoro- 2- methyl Ds-erythro form pentonic acid-gamma lactone -3,5- dibenzoates For raw material, by carbonyl reduction into alcohol, then it is transformed into halogen or carboxylic ester derivative, is spread out with Vorbr ü ggen synthetic methods with cytimidine Biological respinse generates nucleosides, finally takes off protection group and obtains the compound of formula 1：
The synthetic route is easy to operate, wherein pentose ring parent nucleus and beta isomer and α in the coupled product of cytimidine side chain Isomer proportion significantly affects the route yield.
Document Organic Process Research＆Development 2008,12,888-891 report a kind of Ji Xi The synthetic method of his shore, in this method, formula 10a/b ribose derivative compounds occur condensation reaction with cytosine derivative and obtain β Isomers and αisomer ratio are 1:1 formula 13a/b compounds, beta isomer are not presented enrichment phenomenon, significantly reduce whole piece The yield of route.
Therefore need exploitation one cause the beta isomer of coupled product obtain enrichment synthetic route, always received with improving route Rate, process route cost is reduced, amplified more suitable for industrialization.
The content of the invention
The application provides a kind of method as follows by the preparation of compounds of formula V compounds of formula II, comprises the following steps：
A) compound of formula II is changed into the compound of formula III in the presence of reducing agent,
B) compound of formula III is changed into the compound of formula IV in the presence of acetylation reagent and alkali,
C) compound of formula IV is changed into compound shown in formula V under lewis acid effect with the coupling of the compound of formula VII,
Wherein, the R1Or R2It is each independently selected from H, C1-6Alkyl, five~hexa-atomic aryl or five~six membered heteroaryl, institute State C1-6Alkyl, five~hexa-atomic aryl or five~six membered heteroaryl optionally by 1,2 or 3 selected from hydroxyl, amino, nitro, Cyano group, halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy or C1-6The substituent substitution of acylamino-.
On the other hand the application provides the preparation method of compound shown in formula 1 a kind of, including foregoing described changed by formula II The method of compound formula V compounds.
In some embodiments of the application, the preparation method of compound shown in a kind of formula 1 is alternatively included such as Lower step：
D) compound of formula V is the compound of formula VI by the role transformation of acid,
E) compound of formula VI is changed into the compound of formula 1 in the presence of ammonia,
The R1Or R2As defined above.
On the other hand the application provides a kind of preparation method of the compound of formula II, comprise the following steps：
F) fluorination reaction first occurs for the compound of formula 2, then sloughs sulfonic group in the presence of acid and 2,2-dimethoxypropane and turn It is changed into the compound of formula 3,
G) compound of formula 3 is changed into the compound of formula 5 with the compound of formula 4 in the presence of alkali and catalyst,
H) compound of formula 5 and sour role transformation are the compound of formula 6,
I) compound of formula 6 is changed into the compound of formula II with the compound of formula 7 under alkali and catalyst action,
The R1And R2As defined above, R3Selected from methyl, ethyl or propyl group.
On the other hand the application provides compound as follows：
The R1、R2And R3As defined above.
On the other hand the application provides purposes of the compound as follows in the compound of formula 1：
The R1、R2And R3As defined above.
In some embodiments of the application, it is preferable that the R1Or R2It is each independently selected from H, methyl, ethyl, third Base, butyl, amyl group, hexyl, phenyl, 4- hydroxy phenyls, 4- aminophenyls, 4- dimethylaminophenyls, 4- fluorophenyls, 4- chlorobenzenes Base, 4- bromophenyls, 4- aminomethyl phenyls, 4- ethylphenyls, 4- methoxyphenyls, 4- ethoxyl phenenyls, 4- methylaminos phenyl, 4- Ethylamino phenyl, 4- Fonnylphenyls, 4- acetylphenyls, 4- formyloxies phenyl, 4- acetoxyl groups phenyl, 4- formyl ammonia Base phenyl, 4- acetylamino phenyls, 2- hydroxy phenyls, 2- aminophenyls, 2- dimethylaminophenyls, 2- fluorophenyls, 2- chlorobenzenes Base, 2- bromophenyls, 2- aminomethyl phenyls, 2- ethylphenyls, 2- methoxyphenyls, 2- ethoxyl phenenyls, 2- methylaminos phenyl, 2- Ethylamino phenyl, 2- Fonnylphenyls, 2- acetylphenyls, 2- formyloxies phenyl, 2- acetoxyl groups phenyl, 2- formyl ammonia Base phenyl, 2- acetylamino phenyls, 2,4- 3,5-dimethylphenyls, 2,4 difluorobenzene base, 2,4 dichloro benzene base, 2,4- dibromo phenyls, Pyrroles -2- bases, pyrroles -3- bases, pyridine -2- bases, pyridin-3-yl or pyridin-4-yl, it is preferred that the R1Or R2Independently of one another Selected from H, methyl or phenyl.
In some embodiments of the application, it is changed into the compound of formula III in the presence of reducing agent by the compound of formula II In, the reducing agent is selected from double (2- methoxyethoxies) sodium aluminates (red aluminum) of three tertiary butyoxy aluminium lithiums, dihydro, and preferably three Tertiary butyoxy aluminium lithium.
In some embodiments of the application, it is changed into formula in the presence of acetylation reagent and alkali by the compound of formula III In IV compound, the acetylation reagent is selected from acetic anhydride, chloroacetic chloride or glacial acetic acid, preferably acetic anhydride.
In some embodiments of the application, it is changed into formula in the presence of acetylation reagent and alkali by the compound of formula III In IV compound, the alkali is selected from triethylamine, pyridine, DIPEA or DMAP, preferably 4- diformazans Aminopyridine.
In some embodiments of the application, it is coupled by the compound of formula IV under lewis acid effect with the compound of formula VII Be changed into compound shown in formula V, the lewis acid be selected from butter of tin, alchlor, ferric trichloride, titanium tetrachloride or BFEE, preferably butter of tin.
In some embodiments of the application, by the compound of formula V pass through acid role transformation be the compound of formula VI in, The acid is selected from glacial acetic acid, formic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid, preferably glacial acetic acid.
In some embodiments of the application, it is changed into by the compound of formula VI in the presence of ammonia in the compound of formula 1, institute The existence form for stating ammonia is selected from methanolic ammonia solution, cholamine solution, ammoniacal liquor or ammonia, preferably methanolic ammonia solution.
In some embodiments of the application, it is changed into by the compound of formula 2 in the compound of formula 3, the fluorination reagent choosing From tetraethyl ammonium fluoride hydrate or triethylamine trihydrofluoride, preferably tetraethyl ammonium fluoride hydrate.
In some embodiments of the application, be changed into by the compound of formula 2 in the compound of formula 3, it is described acid selected from hydrochloric acid, Sulfuric acid or methanesulfonic acid, preferably hydrochloric acid.
In some embodiments of the application, it is changed into formula 5 in the presence of alkali by the compound of formula 3 and the compound of formula 4 In compound, the alkali is selected from triethylamine, pyridine, DIPEA or DMAP, preferably triethylamine；Institute State catalyst and be selected from DMAP.
It is the acid in the compound of formula 6 by the compound of formula 5 and sour role transformation in some embodiments of the application Selected from hydrochloric acid, sulfuric acid, trifluoroacetic acid or acetic acid, preferably trifluoroacetic acid.
In some embodiments of the application, changed by the compound of formula 6 with the compound of formula 7 under alkali and catalyst action For in the compound of formula II, the alkali is selected from triethylamine, pyridine, DIPEA or DMAP, and preferably three Ethamine；The catalyst is selected from DMAP.
The compound of starting materials of formulae 2 used herein can be synthesized to obtain by method well known in the art, for example, by (R)-glyceraldehyde Contracting acetone and 2- (triphenylphosphine alkene) methyl propionate are by Wittig condensation reactions, then through bishydroxy, sulfenylation, oxidation etc. Step can obtain, and specific synthetic route is as follows：
Illustrate and define
Unless otherwise indicated, following term used herein and phrase have following meanings.One specific term or short Language it is especially define in the case of should not be considered as it is uncertain or unclear, and should be common according to this area Implication go to understand.When herein presented trade name, it is intended that refer to its corresponding commodity or its active component.
All stereoisomer forms of term " compound " used herein including compound, geometric isomer form, Tautomeric forms and isotope form.
The event or situation that term " optional " or " optionally " refer to then describes may occur or may not occur, and this is retouched State including the event or situation occurs and the event or situation do not occur.For example, ethyl " optional " is optionally substituted by halogen, refer to second Base can be unsubstituted (CH2CH3), mono-substituted (such as CH2CH2F), polysubstituted (such as CHFCH2F、CH2CHF2Deng) or Substituted (CF completely2CF3).Those skilled in the art it is understood that for any group comprising one or more substituents, Will not introduce any can not possibly spatially be present and/or the substitution that can not be synthesized or substitute mode.
C used hereinm-nReferring to has m~n integer carbon atom in the part.For example, " C1-6Alkyl " refers to alkyl tool There are 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
Term " substituted " refers to that any one or more hydrogen atoms in specific atoms are substituted with a substituent, as long as specific The valence state of atom is normal and the compound after substituting is stable.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.
Term " amino " refers to-NH2Group ,-NH (C1~6Alkyl) group or-N (C1~6Alkyl)2Group.The concrete example of amino Son includes but is not limited to-NH2、-NHCH3、-N(CH3)2、-NHC2H5、-N(C2H5)2、-N(C3H7)2、-N(CH3)C2H5Deng.
Term " alkyl " refers to the aliphatic hydrocarbon group of the saturation for the straight or branched being made up of carbon atom and hydrogen atom, and it is logical The remainder for crossing singly-bound and molecule connects.The non-limiting examples of the term include methyl, ethyl, propyl group, butyl, amyl group, Hexyl, heptyl, octyl group, nonyl, decyl ,-CH (CH3)2、-CH(CH3)(CH2CH3)、-CH(CH2CH3)2、-C(CH3)3、-C (CH2CH3)3、-CH2CH(CH3)2、-CH2CH(CH3)(CH2CH3) etc..
" it is all different with dividing that the group that third, fourth, the word of penta " expression amount of carbon atom and functional group are formed includes its to term Structure body form, such as：1) propyl group includes CH3CH2CH2-、(CH3)2CH-；2) bytyry includes CH3CH2CH2CO-、(CH3)2CHCO-。
Term " alkoxy " refers to-O- alkyl.
Term " acyl group " refers to-CO- alkyl (or H), for example, " C3Acyl group " refers to-CO-C2H5。
Term " acyloxy " refers to-O-CO- alkyl (or H), for example, " C3Acyloxy " refers to-O-CO-C2H5。
Term " acylamino- " refers to-NH-CO- alkyl (or H), for example, " C3Acyloxy " refers to-NH-CO-C2H5。
In this application, in this application, when chemical bond is usedDuring expression, refer to the stereo directional for not limiting the chemical bond, Such as formulaIncludingTwo kinds of isomers.Wherein, oxa- The bit substituent of five-membered ring 1 and 4 bit substituents are beta isomer in homonymy；The bit substituent of oxa- five-membered ring 1 and 4 bit substituents do not exist Homonymy, it is αisomer：
In this application, in certain embodiments, the chipal compounds are enantiomeric excesses, the enantiomeric excess The content (amount of material) for referring to chiral isomer therein is equal to or greater than about 10%, about 20%, about 30%, about 40%, about 50%th, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.1%, About 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9% or about 99.99%.
In this application, the diagram of the compound of raceme, ambiscalemic and scalemic or enantiomer-pure Method comes from Maehr, J.Chem.Ed.1985,62:114-120.Unless otherwise indicated, represent that one is stood with wedge key and dotted line key The absolute configuration at body center.When compound described herein contains olefinic double bond or other geometry asymmetric centers, unless otherwise rule Fixed, they include E, Z geometric isomer.Similarly, all tautomeric forms are included within the scope of the present invention.
In this application, compound may have specific geometry or stereoisomer form.The application contemplates all This kind of compound, including cis and trans isomers, (-)-and (+)-different to enantiomer, (R)-and (S)-enantiomer, diastereomeric Structure body, (D)-isomers, (L)-isomers, and its racemic mixture and other mixtures, such as enantiomter or non-right The excessive mixture of body is reflected, all these mixtures are belonged within scope of the present application.It may be present in the substituents such as alkyl another Outer asymmetric carbon atom.All these isomers and their mixture, are included within the scope of the present invention.
In this application, the reaction is alternatively carried out in a solvent, and all solvents used in this application are commercially available , it can be used without being further purified, reaction is usually what is carried out under inert nitrogen, in anhydrous solvent.
Compound manually orSoftware is named, and commercial compound uses supplier's directory name.
In herein described synthetic route, reaction yield height is often walked, it is simple to operate, and compound shown in formula IV and O- tri- In methylsilyl-N4- benzoylcytosine condensation products, beta isomer is up to 5/1 with the ratio of αisomer, compared to text The method for offering report, yield are greatly improved, and have made and significantly improving for the synthesis of Suo Feibuwei and its intermediate.
Embodiment
Following examples are further non-limitingly described in detail to technical solution of the present invention.They should not be considered as Limit the scope of the present invention, and the simply exemplary illustration and Typical Representative of the present invention.The solvent that is used in the present invention, examination Agent and raw material etc. be commercially available chemistry it is pure or analysis net product.
Embodiment 1
Formula 2-1 compounds (6.0g, 19.34mmol) are dissolved in no Shui dioxanes (60mL), add tetraethyl ammonium fluoride water Compound (4.85g, 29mmol), 100 DEG C of stirring reaction 1h are risen to, are cooled to room temperature, add 2,2-dimethoxypropane (60mL), Concentrated hydrochloric acid (4.84mL, 58.03mmol) is added dropwise at room temperature, drips complete holding and reaction 3h is stirred at room temperature, second is added into reaction solution Acetoacetic ester (60mL) dilutes, and is washed with saturated sodium bicarbonate solution (60mL), and revolving removes most of organic solvent, adds second Acetoacetic ester extracts liquid separation, and organic phase is washed twice with saturated aqueous common salt, and aqueous phase merges with ethyl acetate extraction once, organic to be harmonious And and colorless oil 4.3g, crude yield 88.8% are evaporated to obtain with anhydrous sodium sulfate drying, filtering, filtrate.
Embodiment 2
Formula 3-1 compounds (0.5g, 2mmol), DMAP (24mg, 0.2mmol) are dissolved in anhydrous THF (5mL), are down to 0 DEG C, Triethylamine (0.66mL, 4.79mmol) is added, is added dropwise to cinnamoyl chloride (0.67g, 4mmol) THF solution, drips and finishes stirring reaction 3h, reactant mixture filtering, filtrate are evaporated to obtain yellow oil, purified by silicagel column, collects and eluted containing target product Liquid is simultaneously evaporated to obtain pale yellow oil 0.65g, yield 85.5%.
MS：[M+H]+=367.
1H NMR (400MHz, CDCl3)：δ 0.98 (s, 6H), 1.42-1.45 (d, 3H), 2.20 (s, 3H), 3.66-3.92 (m, 4H), 4.96-5.03 (d, 1H), 5.22-5.31 (d, 1H), 7.20-7.43 (m, 5H).
Embodiment 3
Formula 3-1 compounds (0.5g, 2mmol), DMAP (24mg, 0.2mmol) are dissolved in anhydrous THF (5mL), are down to 0 DEG C, Triethylamine (1.11mL, 8mmol) is added, is added dropwise to acryloyl chloride (0.36g, 4mmol) THF solution, drips and finishes stirring reaction 24h, reactant mixture filtering, filtrate are evaporated to obtain yellow oil, purified by silicagel column, collects and eluted containing target product Liquid is simultaneously evaporated to obtain pale yellow oil 0.46g, yield 75.6%.
MS：[M+H]+=291.
1H NMR (400MHz, CDCl3)：δ 0.99 (s, 6H), 1.43-1.46 (d, 3H), 2.12 (s, 3H), 3.61-3.88 (m, 4H), 4.68-4.74 (m, 2H), 5.11-5.16 (m, 1H).
Embodiment 4
Formula 5-1 compounds (100mg, 0.26mmol) are dissolved in anhydrous methylene chloride (5mL), add trifluoroacetic acid (60mg, 0.53mmol), reaction 48h is stirred at room temperature, reaction solution is diluted with DCM, adds saturated sodium bicarbonate solution washing, and liquid separation is organic Mutually it is evaporated to obtain semi-solid thing 50mg, yield 65%.
MS：[M+H]+=295.
1H NMR (400MHz, CDCl3)：δ 1.46-1.51 (d, 3H), 3.61-3.93 (m, 4H), 4.12 (brs, 1H), 4.88-4.93 (d, 1H), 5.19-5.27 (d, 1H), 7.21-7.40 (m, 5H).
Embodiment 5
Formula 5-2 compounds (100mg, 0.33mmol) are dissolved in anhydrous methylene chloride (5mL), add trifluoroacetic acid (75mg, 0.66mmol), reaction 48h is stirred at room temperature, reaction solution is diluted with DCM, adds saturated sodium bicarbonate solution washing, and liquid separation is organic Mutually it is evaporated to obtain semi-solid thing 46mg, yield 64%.
MS：[M+H]+=219.
1H NMR (400MHz, CDCl3)：δ 1.43-1.49 (d, 3H), 3.56-3.90 (m, 4H), 4.08 (brs, 1H), 4.71-4.78 (m, 2H), 5.13-5.18 (m, 1H).
Embodiment 6
Formula 6-1 compounds (50mg, 0.17mmol), DMAP (2mg, 0.017mmol) are dissolved in anhydrous THF (5mL), are down to 0 DEG C, triethylamine (0.094mL, 0.68mmol) is added, is added dropwise to cinnamoyl chloride (56.6mg, 0.34mmol) THF solution, drop Finish stirring reaction 12h, reacting liquid filtering removes solid, and filtrate is evaporated to obtain pale yellow oil, tied again with ethyl acetate/petroleum ether It is brilliant to obtain white powder 52mg, yield 72.1%.
MS：[M+H]+=425.
1H NMR (400MHz, CDCl3)：δ 1.71-1.77 (d, 3H), 4.44-4.48 (d, 2H), 4.84-4.88 (m, 1H), 5.3-5.4 (m, 1H), 6.42-6.53 (m, 2H), 7.34-7.45 (m, 6H), 7.49-7.55 (m, 4H), 7.71-7.83 (m, 2H)。
Embodiment 7
Formula 6-1 compounds (50mg, 0.17mmol), DMAP (2mg, 0.017mmol) are dissolved in anhydrous THF (5mL), are down to 0 DEG C, triethylamine (0.094mL, 0.68mmol) is added, is added dropwise to acryloyl chloride (30.76mg, 0.34mmol) THF solution, drop Finish stirring reaction 12h, reacting liquid filtering removes solid, and filtrate is evaporated to obtain pale yellow oil, tied again with ethyl acetate/petroleum ether It is brilliant to obtain white powder 43mg, yield 72.7%.
MS：[M+H]+=349.
1H NMR (400MHz, CDCl3)：δ 1.66-1.73 (d, 3H), 4.38-4.42 (d, 2H), 4.82-4.86 (m, 1H), 5.26-5.42 (m, 1H), 5.96-6.11 (m, 2H), 6.39-6.50 (m, 2H), 7.46-7.57 (m, 6H).
Embodiment 8
Formula 6-2 compounds (50mg, 0.23mmol), DMAP (2.8mg, 0.023mmol) are dissolved in anhydrous THF (5mL), dropped To 0 DEG C, triethylamine (0.13mL, 0.92mmol) is added, is added dropwise to acryloyl chloride (41.5mg, 0.46mmol) THF solution, drop Finish stirring reaction 12h, reacting liquid filtering removes solid, and filtrate is evaporated to obtain pale yellow oil 48mg, yield 76.9%.
MS：[M+H]+=273.
1H NMR (400MHz, CDCl3)：δ 1.65-1.71 (d, 3H), 4.33-4.45 (d, 2H), 4.79-4.81 (m, 1H), 5.23-5.34 (m, 1H), 5.56-5.78 (m, 4H), 6.22-6.51 (m, 2H).
Embodiment 9
Formula 6-2 compounds (50mg, 0.23mmol), DMAP (2.8mg, 0.023mmol) are dissolved in anhydrous THF (5mL), dropped To 0 DEG C, triethylamine (0.13mL, 0.92mmol) is added, is added dropwise to cinnamoyl chloride (76mg, 0.46mmol) THF (1mL) compositions Solution, drip and finish stirring reaction 12h, reacting liquid filtering removes solid, and filtrate is evaporated to obtain pale yellow oil, with ethyl acetate/ Petroleum ether recrystallizes to obtain white powder 56mg, yield 70.2%.
MS：[M+H]+=349.
1H NMR (400MHz, CDCl3)：δ 1.70-1.75 (d, 3H), 4.43-4.51 (d, 2H), 4.86-4.93 (m, 1H), 5.23-5.44 (m, 1H), 6.05-6.17 (m, 2H), 6.43-6.55 (m, 2H), 7.43-7.66 (m, 6H).
Embodiment 10
The compound (5g, 11.78mmol) of formula II -1 is dissolved in THF (50mL), is cooled to -30 DEG C, three tert-butoxies are added dropwise The THF solution (16.5mL, 16.5mmol) of lithium aluminium hydride reduction, drop, which finishes, is gradually heating to -15 DEG C, stirring reaction 2h.Add EA (50mL), saturated ammonium chloride solution (50mL) is added dropwise, continues to stir 1h, filtered by Disodium sulfate decahydrate, filter cake is washed with EA Three times, filtrate liquid separation, organic phase with watery hydrochloric acid, pure water, merge organic layer, with saturated common salt water washing, anhydrous sulphur successively Sour sodium is dried overnight, and is evaporated to obtain pale yellow oil 4.5g, yield 89.6%.
MS：[M+Na]+=449.
1H NMR (400MHz, CDCl3)：δ 1.51-1.60 (d, 3H), 3.63 (brs, 1H), 4.15-4.34 (d, 2H), 4.75-4.83 (m, 1H), 5.18-5.39 (m, 1H), 5.43 (s, 1H), 6.33-6.50 (m, 2H), 7.25-7.41 (m, 6H), 7.53-7.67 (m, 4H), 7.78-7.89 (m, 2H).
Embodiment 11
The compound (5g, 14.35mmol) of formula II -2 is dissolved in THF (50mL), is cooled to -30 DEG C, three tert-butoxies are added dropwise The THF solution (20.1mL, 20.1mmol) of lithium aluminium hydride reduction, drop, which finishes, is gradually heating to -15 DEG C, stirring reaction 2h.Add EA (50mL), saturated ammonium chloride solution (50mL) is added dropwise, continues to stir 1h, filtered by Disodium sulfate decahydrate, filter cake is washed with EA Three times, filtrate liquid separation, organic phase with watery hydrochloric acid, pure water, merge organic layer, with saturated common salt water washing, anhydrous sulphur successively Sour sodium is dried overnight, and is evaporated to obtain pale yellow oil 4.7g, yield 93.5%.
MS：[M+Na]+=373.
1H NMR (400MHz, CDCl3)：δ 1.44-1.61 (d, 3H), 3.59 (brs, 1H), 4.19-4.32 (d, 2H), 4.68-4.77 (m, 1H), 5.18-5.39 (m, 1H), 5.43 (s, 1H), 5.36-5.47 (m, 1H), 5.89-5.97 (m, 2H), 6.25-6.41 (m, 2H), 7.41-7.66 (m, 6H).
Embodiment 12
The compound (5g, 18.37mmol) of formula II -3 is dissolved in THF (50mL), is cooled to -30 DEG C, three tert-butoxies are added dropwise The THF solution (25.7mL, 25.7mmol) of lithium aluminium hydride reduction, drop, which finishes, is gradually heating to -15 DEG C, stirring reaction 2h.Add EA (50mL), saturated ammonium chloride solution (50mL) is added dropwise, continues to stir 1h, filtered by Disodium sulfate decahydrate, filter cake is washed with EA Three times, filtrate liquid separation, organic phase with watery hydrochloric acid, pure water, merge organic layer, with saturated common salt water washing, anhydrous sulphur successively Sour sodium is dried overnight, and is evaporated to obtain pale yellow oil 4.5g, yield 89.3%.
MS：[M+Na]+=397.
1H NMR (400MHz, CDCl3)：δ 1.53-1.66 (d, 3H), 3.63 (brs, 1H), 4.21-4.29 (d, 2H), 4.55-4.71 (m, 1H), 5.20-5.36 (m, 1H), 5.55 (s, 1H), 5.83-6.01 (m, 4H), 6.15-6.40 (m, 2H).
Embodiment 13
The compound (5g, 14.35mmol) of formula II -4 is dissolved in THF (50mL), is cooled to -30 DEG C, three tert-butoxies are added dropwise The THF solution (20.1mL, 20.1mmol) of lithium aluminium hydride reduction, drop, which finishes, is gradually heating to -15 DEG C, stirring reaction 2h.Add EA (50mL), saturated ammonium chloride solution (50mL) is added dropwise, continues to stir 1h, filtered by Disodium sulfate decahydrate, filter cake is washed with EA Three times, filtrate liquid separation, organic phase with watery hydrochloric acid, pure water, merge organic layer, with saturated common salt water washing, anhydrous sulphur successively Sour sodium is dried overnight, and is evaporated to obtain pale yellow oil 4.3g, yield 85.5%.
MS：[M+Na]+=373.
1H NMR (400MHz, CDCl3)：δ 1.47-1.63 (d, 3H), 3.63 (brs, 1H), 4.22-4.38 (d, 2H), 4.65-4.79 (m, 1H), 5.28-5.44 (m, 1H), 5.56 (s, 1H), 5.62-5.87 (m, 1H), 5.93-6.10 (m, 2H), 6.29-6.45 (m, 2H), 7.40-7.68 (m, 6H).
Embodiment 14
The compound (3.75g, 8.79mmol) of formula III -1 is dissolved in anhydrous THF (20mL), add DMAP (1.07g, 8.79mmol), -20 DEG C are cooled to, acetic anhydride (1.66mL, 17.59mmol) is added dropwise, drips and finishes stirring reaction 2h, is added in reaction solution Enter EA and moisture liquid, organic phase with water and saturated common salt water washing, anhydrous sodium sulfate drying, is evaporated to obtain white solid successively 3.86g, yield 93.7%.
MS：[M+Na]+=491.
1H NMR (400MHz, CDCl3)：δ 1.48-1.53 (d, 3H), 2.11 (s, 3H), 4.11-4.31 (d, 2H), 4.70- 4.82 (m, 1H), 5.20-5.36 (m, 1H), 5.50 (s, 1H), 6.27-6.52 (m, 2H), 7.23-7.46 (m, 6H), 7.58- 7.72 (m, 4H), 7.81-7.97 (m, 2H).
Embodiment 15
The compound (3g, 8.56mmol) of formula III -2 is dissolved in anhydrous THF (20mL), add DMAP (1.04g, 8.56mmol), -20 DEG C are cooled to, acetic anhydride (1.62mL, 17.13mmol) is added dropwise, drips and finishes stirring reaction 2h, is added in reaction solution Enter EA and moisture liquid, organic phase with water and saturated common salt water washing, anhydrous sodium sulfate drying, is evaporated to obtain white solid successively 3.21g, yield 95.5%.
MS：[M+Na]+=415.
1H NMR (400MHz, CDCl3)：δ 1.43-1.50 (d, 3H), 2.13 (s, 3H), 4.16-4.37 (d, 2H), 4.68- 4.80 (m, 1H), 5.23-5.39 (m, 1H), 5.47 (s, 1H), 5.66-5.72 (m, 1H), 5.92-6.10 (m, 2H), 6.29- 6.43 (m, 2H), 7.30-7.49 (m, 6H).
Embodiment 16
The compound (3.5g, 12.76mmol) of formula III -3 is dissolved in anhydrous THF (20mL), add DMAP (1.55g, 12.76mmol), -20 DEG C are cooled to, acetic anhydride (2.41mL, 25.52mmol) is added dropwise, drips and finishes stirring reaction 2h, is added in reaction solution Enter EA (50mL) and water (50mL), liquid separation after stirring extraction, organic phase is successively with water and saturated common salt water washing, anhydrous sodium sulfate Dry, be evaporated to obtain white solid 3.81g, yield 94.4%.
MS：[M+Na]+=339.
1H NMR (400MHz, CDCl3)：δ 1.53-1.59 (d, 3H), 2.14 (s, 3H), 4.20-4.33 (d, 2H), 4.50- 4.67 (m, 1H), 5.20-5.34 (m, 1H), 5.51 (s, 1H), 5.89-6.03 (m, 4H), 6.25-6.40 (m, 2H).
Embodiment 17
The compound (3g, 8.56mmol) of formula III -4 is dissolved in anhydrous THF (20mL), add DMAP (1.04g, 8.56mmol), -20 DEG C are cooled to, keeps being added dropwise to acetic anhydride (1.62mL, 17.13mmol) at t≤- 20 DEG C, drips and finishes stirring instead 2h is answered, EA and moisture liquid are added in reaction solution, organic phase with water and saturated common salt water washing, anhydrous sodium sulfate drying, is steamed successively Do to obtain white solid 3.13g, yield 93.2%.
MS：[M+Na]+=415.
1H NMR (400MHz, CDCl3)：δ 1.52-1.57 (d, 3H), 2.01 (s, 3H), 4.18-4.35 (d, 2H), 4.59- 4.75 (m, 1H), 5.18-5.36 (m, 1H), 5.53 (s, 1H), 5.61-5.68 (m, 1H), 5.90-6.13 (m, 2H), 6.27- 6.40 (m, 2H), 7.28-7.46 (m, 6H).
Embodiment 18
In nitrogen protection and dry environment, N- benzoylcytosines (0.92g, 4.27mmol), ammonium sulfate (11.3mg, 0.085mmol) it is suspended in HMDS (10mL), is warming up to 130 DEG C of return stirring reaction 2h, is down to room temperature, revolving removes HMDS, Pale yellow syrup is obtained, is added into the syrup molten by the chlorobenzene (10mL) of the compound (1g, 2.13mmol) of formula IV -1 Liquid, 0 DEG C is down to, is slowly added dropwise into SnCl4(1.1mL, 9.39mmol), rise to 70 DEG C of stirring reactions 20h, HPLC and measure reaction solution The beta comfiguration and α structure contents of middle product are followed successively by 60.25% and 11.90%, isomer proportion beta/alpha=5.06.It is down to room temperature, Dichloromethane, sodium acid carbonate and diatomite are added, is stirred, is down to 0 DEG C, pure water is added dropwise, drop, which finishes, is warmed to room temperature stirring reaction 2h, a large amount of bubbles are emerged, and gained mixture is filtered, and filtrate is washed twice with saturated aqueous common salt, and anhydrous sodium sulfate drying is overnight, Yellow solid crude product is evaporated to obtain, white powder 0.91g, yield 68.36%, purity 96.81% are recrystallized to obtain with methanol/chlorobenzene (HPLC)。
MS：[M+H]+=624.
1H NMR (400MHz, CDCl3)：δ 1.56-1.66 (d, 3H), 4.40-4.45 (d, 2H), 4.81-4.89 (m, 1H), 5.25-5.36 (m, 1H), 5.40 (s, 1H), 6.41-6.52 (m, 2H), 7.29-7.49 (m, 8H), 7.56-7.69 (m, 8H), 7.73-7.88 (m, 2H), 8.16 (d, 1H), 8.37 (d, 1H).
Embodiment 19
In nitrogen protection and dry environment, N- benzoylcytosines (1.1g, 5.1mmol), ammonium sulfate (13.5mg, 0.10mmol) it is suspended in HMDS (10mL), is warming up to 130 DEG C of return stirring reaction 2h, is down to room temperature, revolving removes HMDS, Pale yellow syrup is obtained, chlorobenzene (10mL) group by the compound (1g, 2.55mmol) of formula IV -2 is added into the syrup Into solution, be down to 0 DEG C, be slowly added dropwise into SnCl4(1.31mL, 11.21mmol), rise to 70 DEG C of stirring reaction 20h, HPLC surveys Obtain the beta comfiguration of product and α structure contents in reaction solution and be followed successively by 62.31% and 12.56%, isomer proportion beta/alpha=4.96.Drop To room temperature, dichloromethane, sodium acid carbonate and diatomite are added, is stirred, be down to 0 DEG C, pure water is added dropwise, drop, which finishes to be warmed to room temperature, to be stirred Reaction 2h is mixed, a large amount of bubbles are emerged, gained mixture is filtered, and filtrate is washed twice with saturated aqueous common salt, and anhydrous sodium sulfate is done It is dry overnight, yellow solid crude product is evaporated to obtain, white powder 1.08g, yield 77.42%, purity are recrystallized to obtain with methanol/chlorobenzene 96.77% (HPLC).
MS：[M+H]+=547.
1H NMR (400MHz, CDCl3)：δ 1.61-1.70 (d, 3H), 4.39-4.42 (d, 2H), 4.80-4.88 (m, 1H), 5.19-5.33 (m, 1H), 5.35 (s, 1H), 5.55-5.67 (m, 2H), 5.91-6.08 (m, 3H), 7.22-7.71m, 10H), 8.10 (d, 1H), 8.33 (d, 1H).
Embodiment 20
In nitrogen protection and dry environment, N- benzoylcytosines (1.36g, 6.32mmol), ammonium sulfate (16.71mg, 0.126mmol) it is suspended in HMDS (10mL), is warming up to 130 DEG C of return stirring reaction 2h, is down to room temperature, revolving removes HMDS, Pale yellow syrup is obtained, chlorobenzene (10mL) group by the compound (1g, 3.16mmol) of formula IV -3 is added into the syrup Into solution, be down to 0 DEG C, be slowly added dropwise into SnCl4(1.63mL, 13.91mmol), rise to 70 DEG C of stirring reaction 20h, HPLC surveys Obtain the beta comfiguration of product and α structure contents in reaction solution and be followed successively by 58.26% and 12.33%, isomer proportion beta/alpha=4.73.Drop To room temperature, dichloromethane, sodium acid carbonate and diatomite are added, is stirred, be down to 0 DEG C, pure water is added dropwise, drop, which finishes to be warmed to room temperature, to be stirred Reaction 2h is mixed, a large amount of bubbles are emerged, gained mixture is filtered, and filtrate is washed twice with saturated aqueous common salt, and anhydrous sodium sulfate is done It is dry overnight, yellow solid crude product is evaporated to obtain, white powder 1.23g, yield 82.64%, purity are recrystallized to obtain with methanol/chlorobenzene 96.67% (HPLC).
MS：[M+H]+=471.
1H NMR (400MHz, CDCl3)：δ 1.55-1.69 (d, 3H), 4.36-4.40 (d, 2H), 4.76-4.83 (m, 1H), 5.10-5.29 (m, 1H), 5.33 (s, 1H), 5.66-5.78 (m, 4H), 5.99-6.18 (m, 2H), 7.12-7.35 (m, 5H), 8.11 (d, 1H), 8.30 (d, 1H).
Embodiment 21
In nitrogen protection and dry environment, N- benzoylcytosines (1.1g, 5.1mmol), ammonium sulfate (13.5mg, 0.10mmol) it is suspended in HMDS (10mL), is warming up to 130 DEG C of return stirring reaction 2h, is down to room temperature, revolving removes HMDS, Pale yellow syrup is obtained, chlorobenzene (10mL) group by the compound (1g, 2.55mmol) of formula IV -4 is added into the syrup Into solution, be down to 0 DEG C, be slowly added dropwise into SnCl4(1.31mL, 11.21mmol), rise to 70 DEG C of stirring reaction 20h, HPLC surveys Obtain the beta comfiguration of product and α structure contents in reaction solution and be followed successively by 61.98% and 12.84%, isomer proportion beta/alpha=4.82.Drop To room temperature, dichloromethane, sodium acid carbonate and diatomite are added, is stirred, be down to 0 DEG C, pure water is added dropwise, drop, which finishes to be warmed to room temperature, to be stirred Reaction 2h is mixed, a large amount of bubbles are emerged, gained mixture is filtered, and filtrate is washed twice with saturated aqueous common salt, and anhydrous sodium sulfate is done It is dry overnight, yellow solid crude product is evaporated to obtain, white powder 1.01g, yield 72.41%, purity are recrystallized to obtain with methanol/chlorobenzene 96.08% (HPLC).
MS：[M+H]+=547.
1H NMR (400MHz, CDCl3)：δ 1.61-1.70 (d, 3H), 4.39-4.42 (d, 2H), 4.80-4.88 (m, 1H), 5.19-5.33 (m, 1H), 5.35 (s, 1H), 5.55-5.67 (m, 2H), 5.91-6.08 (m, 3H), 7.22-7.71m, 10H), 8.10 (d, 1H), 8.33 (d, 1H).
Embodiment 22
The compound (0.4g, 0.64mmol) of formula V -1 is suspended in 70% aqueous acetic acid (10mL), backflow is risen to and stirs Reaction 6h is mixed, reaction solution is down to room temperature, separates out white solid, adds frozen water, stirs 1h under ice bath, white is obtained after filtration drying Powder 0.29g, yield 86.86%.
MS：[M+H]+=521.
1H NMR (400MHz, CDCl3)：δ 1.44-1.49 (d, 3H), 4.51-4.56 (d, 2H), 4.88-4.92 (m, 1H), 5.26-5.37 (m, 1H), 5.44 (s, 1H), 6.23-6.46 (m, 2H), 7.20-7.41 (m, 6H), 7.52-7.70 (m, 4H), (7.77-7.92 m, 2H), 8.02 (d, 1H), 8.26 (d, 1H), 9.17 (s, 1H).
Embodiment 23
The compound (0.4g, 0.73mmol) of formula V -2 is suspended in 70% aqueous acetic acid (10mL), backflow is risen to and stirs Reaction 6h is mixed, reaction solution is down to room temperature, separates out white solid, adds frozen water, stirs 1h under ice bath, white is obtained after filtration drying Powder 0.26g, yield 80.08%.
MS：[M+H]+=444.
1H NMR (400MHz, CDCl3)：δ 1.46-1.52 (d, 3H), 4.49-4.53 (d, 2H), 4.86-4.90 (m, 1H), 5.22-5.39 (m, 1H), 5.49 (s, 1H), 5.65-5.72 (m, 1H), 5.88-6.05 (m, 2H), 6.26-6.44 (m, 2H), 7.25-7.47 (m, 6H) 8.05 (d, 1H), 8.23 (d, 1H), 9.20 (s, 1H).
Embodiment 24
The compound (0.4g, 0.85mmol) of formula V -3 is suspended in 70% aqueous acetic acid (10mL), backflow is risen to and stirs Reaction 6h is mixed, reaction solution is down to room temperature, separates out white solid, adds frozen water, stirs 1h under ice bath, white is obtained after filtration drying Powder 0.27g, yield 86.23%.
MS：[M+H]+=368.
1H NMR (400MHz, CDCl3)：δ 1.49-1.55 (d, 3H), 4.47-4.56 (d, 2H), 4.80-4.87 (m, 1H), 5.19-5.35 (m, 1H), 5.45 (s, 1H), 5.69-5.80 (m, 4H), 5.96-6.25 (m, 2H), 8.00 (d, 1H), 8.22 (d, 1H), 9.15 (s, 1H).
Embodiment 25
The compound (0.4g, 0.73mmol) of formula V -4 is suspended in 70% aqueous acetic acid (10mL), backflow is risen to and stirs Reaction 6h is mixed, reaction solution is down to room temperature, separates out white solid, adds frozen water, stirs 1h under ice bath, white is obtained after filtration drying Powder 0.28g, yield 86.24%.
MS：[M+H]+=444.
1H NMR (400MHz, CDCl3)：δ 1.41-1.50 (d, 3H), 4.45-4.52 (d, 2H), 4.83-4.92 (m, 1H), 5.26-5.41 (m, 1H), 5.44 (s, 1H), 5.67-5.75 (m, 1H), 5.86-6.09 (m, 2H), 6.27-6.48 (m, 2H), 7.20-7.45 (m, 6H) 8.01 (d, 1H), 8.24 (d, 1H), 9.18 (s, 1H).
Embodiment 26
At 0 DEG C, VI -1 compound (0.2g, 0.384mmol) is added to methanolic ammonia solution (5.5mL, 38.42mmol) In, stirring reaction 3h, after be gradually increased to room temperature and continue stirring reaction 20h, reaction solution be spin-dried for removing solvent obtain yellow oily Thing, isopropyl ether is added, 3h is stirred at room temperature, separate out white solid, filtered, drying, obtain white powder 81mg, yield 81%, purity 98.5%.
MS：[M+H]+=261.
1H NMR (400MHz, CDCl3)：δ 1.24-1.29 (d, 3H), 3.63-3.66 (m, 1H), 3.81-3.90 (m, 3H), 5.29 (s, 1H), 5.66-5.68 (m, 2H), 5.98-6.03 (d, 1H), 7.97-7.99 (d, 1H), 11.47 (s, 1H).
Embodiment 27
At 0 DEG C, VI -2 compound (0.2g, 0.45mmol) is added into methanolic ammonia solution (6.43mL, 45mmol), Stirring reaction 3h, after be gradually increased to room temperature and continue stirring reaction 20h, reaction solution be spin-dried for removing solvent obtain yellow oil, Isopropyl ether is added, 3h is stirred at room temperature, separates out white solid, is filtered, drying, obtains white powder 92mg, yield 78.6%, purity 97.9%.
MS：[M+H]+=261.
1H NMR (400MHz, CDCl3)：δ 1.24-1.29 (d, 3H), 3.63-3.66 (m, 1H), 3.81-3.90 (m, 3H), 5.29 (s, 1H), 5.66-5.68 (m, 2H), 5.98-6.03 (d, 1H), 7.97-7.99 (d, 1H), 11.47 (s, 1H).
Embodiment 28
At 0 DEG C, VI -3 compound (0.2g, 0.543mmol) is added to methanolic ammonia solution (7.8mL, 38.42mmol) In, stirring reaction 3h, after be gradually increased to room temperature and continue stirring reaction 20h, reaction solution be spin-dried for removing solvent obtain yellow oily Thing, isopropyl ether being added, is stirred at room temperature 3h, separate out white solid, filtered, drying obtains white powder 110mg, yield 77.85%, Purity 98.2%.
MS：[M+H]+=261.
1H NMR (400MHz, CDCl3)：δ 1.24-1.29 (d, 3H), 3.63-3.66 (m, 1H), 3.81-3.90 (m, 3H), 5.29 (s, 1H), 5.66-5.68 (m, 2H), 5.98-6.03 (d, 1H), 7.97-7.99 (d, 1H), 11.47 (s, 1H).
Embodiment 29
At 0 DEG C, VI -4 compound (0.2g, 0.45mmol) is added into methanolic ammonia solution (6.43mL, 45mmol), Stirring reaction 3h, after be gradually increased to room temperature and continue stirring reaction 20h, reaction solution be spin-dried for removing solvent obtain yellow oil, Isopropyl ether is added, 3h is stirred at room temperature, separates out white solid, is filtered, drying, obtains white powder 90mg, yield 76.85%, purity 98.6%.
MS：[M+H]+=261.
1H NMR (400MHz, CDCl3)：δ 1.24-1.29 (d, 3H), 3.63-3.66 (m, 1H), 3.81-3.90 (m, 3H), 5.29 (s, 1H), 5.66-5.68 (m, 2H), 5.98-6.03 (d, 1H), 7.97-7.99 (d, 1H), 11.47 (s, 1H).

Claims (9)

1. a kind of method by the preparation of compounds of formula V compounds of formula II, comprise the following steps：
A) compound of formula II is changed into the compound of formula III in the presence of reducing agent,
B) compound of formula III is changed into the compound of formula IV in the presence of acetylation reagent and alkali,
C) compound of formula IV is changed into compound shown in formula V under lewis acid effect with the coupling of the compound of formula VII,
Wherein, the R1Or R2It is each independently selected from H, C1-6Alkyl, five~hexa-atomic aryl or five~six membered heteroaryl, it is described C1-6Alkyl, five~hexa-atomic aryl or five~six membered heteroaryl are optionally by 1,2 or 3 selected from hydroxyl, amino, nitro, cyanogen Base, halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy or C1-6The substituent substitution of acylamino-.
2. according to the method for claim 1, it is characterised in that the R1Or R2Be each independently selected from H, methyl, ethyl, Propyl group, butyl, amyl group, hexyl, phenyl, 4- hydroxy phenyls, 4- aminophenyls, 4- dimethylaminophenyls, 4- fluorophenyls, 4- chlorine Phenyl, 4- bromophenyls, 4- aminomethyl phenyls, 4- ethylphenyls, 4- methoxyphenyls, 4- ethoxyl phenenyls, 4- methylaminos phenyl, 4- ethylaminos phenyl, 4- Fonnylphenyls, 4- acetylphenyls, 4- formyloxies phenyl, 4- acetoxyl groups phenyl, 4- formyls Aminophenyl, 4- acetylamino phenyls, 2- hydroxy phenyls, 2- aminophenyls, 2- dimethylaminophenyls, 2- fluorophenyls, 2- chlorine Phenyl, 2- bromophenyls, 2- aminomethyl phenyls, 2- ethylphenyls, 2- methoxyphenyls, 2- ethoxyl phenenyls, 2- methylaminos phenyl, 2- ethylaminos phenyl, 2- Fonnylphenyls, 2- acetylphenyls, 2- formyloxies phenyl, 2- acetoxyl groups phenyl, 2- formyls Aminophenyl, 2- acetylamino phenyls, 2,4- 3,5-dimethylphenyls, 2,4 difluorobenzene base, 2,4 dichloro benzene base, 2,4- dibromobenzenes Base, pyrroles -2- bases, pyrroles -3- bases, pyridine -2- bases, pyridin-3-yl or pyridin-4-yl, it is preferred that the R1Or R2Each solely On the spot selected from H, methyl or phenyl.
3. the preparation method of compound shown in a kind of formula 1, including described in claim 1 by the preparation of compounds of formula V chemical combination of formula II The method of thing,
4. the preparation method of compound shown in formula 1 according to claim 3, it is characterised in that also comprise the following steps：
D) compound of formula V is the compound of formula VI by the role transformation of acid,
E) compound of formula VI is changed into the compound of formula 1 in the presence of ammonia,
Wherein, the R1Or R2It is each independently selected from H, C1-6Alkyl, five~hexa-atomic aryl or five~six membered heteroaryl, it is described C1-6Alkyl, five~hexa-atomic aryl or five~six membered heteroaryl are optionally by 1,2 or 3 selected from hydroxyl, amino, nitro, cyanogen Base, halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy or C1-6The substituent substitution of acylamino-.
5. according to the preparation method described in any one of claim 3 or 4, it is characterised in that the R1Or R2It is each independently selected from H, methyl, ethyl, propyl group, butyl, amyl group, hexyl, phenyl, 4- hydroxy phenyls, 4- aminophenyls, 4- dimethylaminophenyls, 4- fluorophenyls, 4- chlorphenyls, 4- bromophenyls, 4- aminomethyl phenyls, 4- ethylphenyls, 4- methoxyphenyls, 4- ethoxyl phenenyls, 4- Methylamino phenyl, 4- ethylaminos phenyl, 4- Fonnylphenyls, 4- acetylphenyls, 4- formyloxies phenyl, 4- acetyl oxygen Base phenyl, 4- carboxamidophenyls, 4- acetylamino phenyls, 2- hydroxy phenyls, 2- aminophenyls, 2- dimethylaminophenyls, 2- fluorophenyls, 2- chlorphenyls, 2- bromophenyls, 2- aminomethyl phenyls, 2- ethylphenyls, 2- methoxyphenyls, 2- ethoxyl phenenyls, 2- Methylamino phenyl, 2- ethylaminos phenyl, 2- Fonnylphenyls, 2- acetylphenyls, 2- formyloxies phenyl, 2- acetyl oxygen Base phenyl, 2- carboxamidophenyls, 2- acetylamino phenyls, 2,4- 3,5-dimethylphenyls, 2,4 difluorobenzene base, 2,4 dichloro benzene Base, 2,4- dibromo phenyls, pyrroles -2- bases, pyrroles -3- bases, pyridine -2- bases, pyridin-3-yl or pyridin-4-yl, it is preferred that institute State R1Or R2It is each independently selected from H, methyl or phenyl.
6. a kind of preparation method of the compound of formula II, comprises the following steps：
F) fluorination reaction first occurs for the compound of formula 2, then sloughs sulfonic group in the presence of acid and 2,2-dimethoxypropane and be changed into The compound of formula 3,
G) compound of formula 3 is changed into the compound of formula 5 with the compound of formula 4 in the presence of alkali and catalyst,
H) compound of formula 5 and sour role transformation are the compound of formula 6,
I) compound of formula 6 is changed into the compound of formula II with the compound of formula 7 under alkali and catalyst action,
Wherein, the R1Or R2It is each independently selected from H, C1-6Alkyl, five~hexa-atomic aryl or five~six membered heteroaryl, it is described C1-6Alkyl, five~hexa-atomic aryl or five~six membered heteroaryl are optionally by 1,2 or 3 selected from hydroxyl, amino, nitro, cyanogen Base, halogen, C1-6Alkyl, C1-6Alkoxy, C1-6Acyl group, C1-6Acyloxy or C1-6The substituent substitution of acylamino-, R3Selected from first Base, ethyl or propyl group.
7. preparation method according to claim 6, it is characterised in that the R1Or R2It is each independently selected from H, methyl, second Base, propyl group, butyl, amyl group, hexyl, phenyl, 4- hydroxy phenyls, 4- aminophenyls, 4- dimethylaminophenyls, 4- fluorophenyls, 4- chlorphenyls, 4- bromophenyls, 4- aminomethyl phenyls, 4- ethylphenyls, 4- methoxyphenyls, 4- ethoxyl phenenyls, 4- methylaminos Phenyl, 4- ethylaminos phenyl, 4- Fonnylphenyls, 4- acetylphenyls, 4- formyloxies phenyl, 4- acetoxyl groups phenyl, 4- carboxamidophenyls, 4- acetylamino phenyls, 2- hydroxy phenyls, 2- aminophenyls, 2- dimethylaminophenyls, 2- fluorobenzene Base, 2- chlorphenyls, 2- bromophenyls, 2- aminomethyl phenyls, 2- ethylphenyls, 2- methoxyphenyls, 2- ethoxyl phenenyls, 2- methyl ammonia Base phenyl, 2- ethylaminos phenyl, 2- Fonnylphenyls, 2- acetylphenyls, 2- formyloxies phenyl, 2- acetyloxy phenyls Base, 2- carboxamidophenyls, 2- acetylamino phenyls, 2,4- 3,5-dimethylphenyls, 2,4 difluorobenzene base, 2,4 dichloro benzene base, 2, 4- dibromo phenyls, pyrroles -2- bases, pyrroles -3- bases, pyridine -2- bases, pyridin-3-yl or pyridin-4-yl, it is preferred that the R1Or R2It is each independently selected from H, methyl or phenyl.
8. compound as follows：
Wherein, the R1Or R2It is each independently selected from H, methyl or phenyl, R3Selected from methyl, ethyl or propyl group.
9. purposes of the compound as claimed in claim 8 in the compound of formula 1
CN201610814730.4A 2016-09-09 2016-09-09 Preparation method as the methyl deoxyribonucleoside of 2 fluorine 2 of Suo Feibuwei intermediates Pending CN107805266A (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN201610814730.4A CN107805266A (en) 2016-09-09 2016-09-09 Preparation method as the methyl deoxyribonucleoside of 2 fluorine 2 of Suo Feibuwei intermediates
PCT/CN2017/101078 WO2018045997A1 (en) 2016-09-09 2017-09-08 Method for preparing 2-fluoro-2-methyldeoxynucleoside as an intermediate of sofosbuvir
CN201780055402.3A CN109641930B (en) 2016-09-09 2017-09-08 Preparation method of 2-fluoro-2-methyl deoxynucleoside serving as sofosbuvir intermediate

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201610814730.4A CN107805266A (en) 2016-09-09 2016-09-09 Preparation method as the methyl deoxyribonucleoside of 2 fluorine 2 of Suo Feibuwei intermediates

Publications (1)

Publication Number Publication Date
CN107805266A true CN107805266A (en) 2018-03-16

Family

ID=61561333

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201610814730.4A Pending CN107805266A (en) 2016-09-09 2016-09-09 Preparation method as the methyl deoxyribonucleoside of 2 fluorine 2 of Suo Feibuwei intermediates
CN201780055402.3A Active CN109641930B (en) 2016-09-09 2017-09-08 Preparation method of 2-fluoro-2-methyl deoxynucleoside serving as sofosbuvir intermediate

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN201780055402.3A Active CN109641930B (en) 2016-09-09 2017-09-08 Preparation method of 2-fluoro-2-methyl deoxynucleoside serving as sofosbuvir intermediate

Country Status (2)

Country Link
CN (2) CN107805266A (en)
WO (1) WO2018045997A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110511258A (en) * 2018-05-21 2019-11-29 中国科学院上海药物研究所 A kind of preparation method of cytidine

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011005860A2 (en) * 2009-07-07 2011-01-13 Alnylam Pharmaceuticals, Inc. 5' phosphate mimics
JP2015518017A (en) * 2012-05-29 2015-06-25 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Method for producing 2-deoxy-2-fluoro-2-methyl-D-ribofuranosyl nucleoside compound
CN105646629A (en) * 2014-11-25 2016-06-08 广州市恒诺康医药科技有限公司 L-nucleoside compounds and application thereof
CN106146585B (en) * 2015-04-10 2019-05-28 正大天晴药业集团股份有限公司 The urea glycoside derivates of deuterium modification
WO2017077552A1 (en) * 2015-11-03 2017-05-11 Mylan Laboratories Limited Process for the preparation of sofosbuvir

Also Published As

Publication number Publication date
CN109641930B (en) 2020-12-04
WO2018045997A1 (en) 2018-03-15
CN109641930A (en) 2019-04-16

Similar Documents

Publication Publication Date Title
Kumar et al. Efficient total synthesis of sapinofuranone B
Shamim et al. 5-Acetyl-6-methyl-4-aryl-3, 4-dihydropyrimidin-2 (1H)-ones: As potent urease inhibitors; synthesis, in vitro screening, and molecular modeling study
KR20100132073A (en) Pai-1 inhibitor
WO2008001718A1 (en) Dehydroxylated fluorinating agent
CN111925381B (en) Synthesis method of baroxavir key intermediate
CN101505751A (en) 8-hydroxyquinoline compounds and methods thereof
Wu et al. One-pot synthesis of difluoromethyl-containing dihydropyrimidinones catalyzed by Yb (PFO) 3 under solvent and dehydrating agent free conditions
CN107531657A (en) (2S, 3R, 4R) 3,5 2 substitutes the Preparation Method And Their Intermediate of the methyl D ribose gamma lactones of 2 deoxidation, 2 hydroxyl 2
KR20190137860A (en) Liver X-Receptor (LXR) Modulators
CN107805266A (en) Preparation method as the methyl deoxyribonucleoside of 2 fluorine 2 of Suo Feibuwei intermediates
JP2023527213A (en) triazolone compounds
CN103724301A (en) (2R)-2-desoxy-2,2-disubstituted-1,4-ribonolactones, preparation method and purpose thereof
Yagci et al. Hit-to-lead optimization on aryloxybenzamide derivative virtual screening hit against SIRT
Eilitz et al. Synthesis of 2-C-trifluoromethyl substituted d-ribose
BRPI0820953B1 (en) Methods for preparing a compound and a composition
Fenain et al. Indium-mediated reduction of β-aminovinyl chloro-difluoromethylated ketones in the presence of heteroaryl aldehydes: A mild entry to novel difluoromethylene enaminone derivatives
CN104974065A (en) Method for preparing alpha-trifluoromethylthio-one
JP6245527B2 (en) Method for producing compound having thiolane ring or thiane ring skeleton
CN115353514B (en) Fluoro-pyridopyrimidinone compounds and synthesis method thereof
CN108822058B (en) A kind of preparation method of benzo thiazides compounds
Zhang et al. Structure–activity relationship studies on anti-HCV activity of ring-expanded (‘fat’) nucleobase analogues containing the imidazo [4, 5-e][1, 3] diazepine-4, 8-dione ring system
CN113135940B (en) Benzothiazole pyrimidine ring compound and preparation method and application thereof
CN116283821B (en) Phencyclized propylamine compound, preparation method and application
CN110172062B (en) Synthesis method of monofluoro spiro compound and intermediate thereof
JPS61215373A (en) Pyrimidine derivative

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
WD01 Invention patent application deemed withdrawn after publication
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20180316