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

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

Info

Publication number
CN104926902A
CN104926902A CN201410097942.6A CN201410097942A CN104926902A CN 104926902 A CN104926902 A CN 104926902A CN 201410097942 A CN201410097942 A CN 201410097942A CN 104926902 A CN104926902 A CN 104926902A
Authority
CN
China
Prior art keywords
compound
reaction
mixture
definition
group
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
CN201410097942.6A
Other languages
Chinese (zh)
Inventor
张容霞
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.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Priority to CN201410097942.6A priority Critical patent/CN104926902A/en
Priority to CN201580008269.7A priority patent/CN106068271B/en
Priority to PCT/CN2015/074363 priority patent/WO2015139602A1/en
Publication of CN104926902A publication Critical patent/CN104926902A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
    • 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
    • C07H19/09—Pyrimidine radicals with arabinosyl as the saccharide radical

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

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

Description

2`-replaces-2,2`-anhydro uridines or 2`-replaces-2,2`-dehydration cytidine compounds and its production and use
Technical field
The present invention relates to medicinal chemistry art, more specifically, relate to 2'-and replace-2,2'-anhydro uridines or 2'-replacement-2,2'-dehydration cytidine compounds and preparation method thereof and the intermediate in preparation process.The invention still further relates to and use described 2'-to replace-2,2'-anhydro uridine or 2'-replacement-2,2'-dehydration cytidine compounds prepare the method that the fluoro-2'-of 2'-deoxidation-2'-replaces uridine or the fluoro-2'-replacement cytidine of 2'-deoxidation-2'-or 2'-deoxidation-2'-itrile group-2'-replacement uridine or 2'-deoxidation-2'-itrile group-2'-replacement cytidine compounds.
Background technology
The fluoro-2'-methyluridine (IIIa) of 2'-deoxidation-2'-is the key intermediate of the anti-third liver medicine Sofosbuvir of preparation.
Sofosbuvir by Gilead Science company develop, FDA on December 6th, 2013 official approval Sofosbuvir be used for the treatment of chronic hepatitis C viral (HCV) infect.Sofosbuvir be first be used for the treatment of some type HCV infection and without the need to use simultaneously Interferon, rabbit effectively and safe drugs.Multinomial clinical trial all shows, and sofosbuvir can realize continued viral response (clinical cure) of very high percentage.More revolutionary breakthrough is, sofosbuvir is curative effect still highly significant when not combining Peg-IFN alpha-2b α, and such as sofosbuvir combines the continued viral response rate controlling patient at the beginning of ribavirin therapy genotype 2 and genotype 3 chronic hepatitis C can reach 100%.Sofosbuvir is a kind of prodrug, is metabolised to the fluoro-2'-methyluridine of 2'-deoxidation-2'--5'-phosplate in vivo.
The synthetic method of the 2'-deoxidation-2'-fluoro-2'-methyluridine of current report is as follows:
In document (Journal of Medicinal Chemistry, 2005,48; 5504), in, take cytidine(C as raw material, first selective protection 3'; 5' position hydroxyl, being then oxidized 2' position hydroxyl is carbonyl, and lithium methide is obtained by reacting 2' position oxy-compound; then blocking group is sloughed; use benzoyl protection 3', 5' position hydroxyl instead, then be obtained by reacting fluoro thing with DAST; be hydrolyzed subsequently and ammonolysis reaction obtain product, as shown in reaction scheme I below.The method route is long, needs to use expensive silicon ether protecting group, and molecular economy is poor; The diastereomer that methyl is beta position can be generated when carrying out methylated.
At patent (WO2005003147; WO2006031725A2; US20040158059) in; 2'-fluoro-2'-methyl-ribo derivative is used to carry out docking with N-benzoylcytosine and react; then final product is obtained, as shown in reaction scheme II below through hydrolysis, ammonolysis reaction.The raw material of the method is not easy to obtain, and synthesis step is loaded down with trivial details, and price is more expensive; Dock containing the isomer that base is alpha position in the product be obtained by reacting, need purifying to remove, formation is wasted.
summary of the invention
The compound of the present inventor's design and synthesis shown in general formula I, this compound can carry out fluoro or itrile group under suitable condition and be obtained by reacting the fluoro-2'-of 2'-deoxidation-2'-and replace uridine or the fluoro-2'-of 2'-deoxidation-2'-replaces cytidine or 2'-deoxidation-2'-itrile group-2'-replaces uridine or 2'-deoxidation-2'-itrile group-2'-replaces cytidine compounds; Or compound of Formula I is through fluoro or nitrile glycosylation reaction, then carries out deprotection reaction and obtain the fluoro-2'-of 2'-deoxidation-2'-and replace uridine or the fluoro-2'-of 2'-deoxidation-2'-replaces cytidine or 2'-deoxidation-2'-itrile group-2'-replaces uridine or 2'-deoxidation-2'-itrile group-2'-replaces cytidine compounds; Or compound of Formula I is through ring-opening reaction, again through fluoro or itrile group, finally carry out deprotection reaction and obtain the fluoro-2'-of 2'-deoxidation-2'-and replace uridine or the fluoro-2'-of 2'-deoxidation-2'-replaces cytidine or 2' deoxidation-2'-itrile group-2'-replaces uridine or 2'-deoxidation-2'-itrile group-2'-replaces cytidine compounds; Or compound of Formula I is through ring-opening reaction; then 2'-hydroxyl forms leavings group; again through fluoro or nitrile glycosylation reaction, finally carry out deprotection reaction and obtain the fluoro-2'-of 2'-deoxidation-2'-and replace uridine or the fluoro-2'-of 2'-deoxidation-2'-replaces cytidine or 2'-deoxidation-2'-itrile group-2'-replaces uridine or 2'-deoxidation-2'-itrile group-2'-replaces cytidine compounds.
Therefore, the object of the present invention is to provide the compound shown in general formula I.
Another object of the present invention is the preparation method providing compound of Formula I.
Another object of the present invention is to provide a kind of method using compound of Formula I to prepare 2'-deoxidation-2'-fluoro-2'-replacement uridine or the fluoro-2'-replacement cytidine of 2'-deoxidation-2'-or 2'-deoxidation-2'-itrile group-2'-replacement uridine or 2'-deoxidation-2'-itrile group-2'-replacement cytidine compounds.
According to the present invention, provide the compound shown in following general formula I:
Wherein,
R and R 1be hydrogen atom or hydroxy-protective group independently of one another, preferably, R and R 1be selected from hydrogen atom, methyl, the acyl group, substituted or unsubstituted benzoyl, substituted or unsubstituted benzyl, trityl, methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, the tetrahydropyrans-2-base that are replaced by C1-C6 straight or branched alkyl independently of one another, three (C1-C6 straight or branched alkyl) are silica-based, the tertiary butyl two (C1-C6 straight or branched alkyl) is silica-based, tert-butyl diphenyl is silica-based, first thiomethyl, methoxymethyl and 2-methoxvethoxvmethvl; Most preferred, R and R 1be selected from hydrogen atom, methyl, formyl radical, ethanoyl, valeryl, substituted or unsubstituted benzoyl, substituted or unsubstituted benzyl, trityl, methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, tetrahydropyrans-2-base independently of one another, trimethyl silicon based, t-Butyldimethylsilyl, tert-butyl diphenyl are silica-based, first thiomethyl, methoxymethyl and 2-methoxvethoxvmethvl; Substituting group on the benzoyl of described replacement and the benzyl of replacement is selected from nitro, C1-C6 straight or branched alkoxyl group, halogen, C1-C6 straight or branched alkyl and phenyl, is preferably selected from nitro, methoxyl group, chlorine, methyl and phenyl; Or
R and R 1merge the hydroxy-protective group forming ring-type, preferably, R and R 1couple together to merge and form-SiR'-O-SiR'-or-SiR'-, wherein R' is C1-C6 straight or branched alkyl, and preferred R' is sec.-propyl;
R 2for C1-C6 straight or branched alkyl, by the C1-C6 straight or branched alkyl of one or more halogen or hydroxyl replacement, itrile group or halogen, preferably, R 2for C1-C4 straight or branched alkyl, trifluoromethyl, methylol, itrile group, difluoromethyl, fluorine or chlorine, most preferred, R 2for methyl, ethyl, trifluoromethyl or itrile group;
R 3for Sauerstoffatom or NR 4, wherein R 4for acyl group, substituted or unsubstituted benzoyl that hydrogen atom, C1-C6 straight or branched alkyl replace, preferably, R 4for hydrogen atom, formyl radical, ethanoyl, substituted or unsubstituted benzoyl, most preferred, R 4for hydrogen atom, formyl radical, acetyl or benzoyl base, the substituting group on the benzoyl of described replacement is selected from nitro, C1-C6 straight or branched alkoxyl group, halogen and C1-C6 straight or branched alkyl, is preferably selected from nitro, methoxyl group, chlorine and methyl.
In definition herein, if do not specialize, halogen refers to fluorine, chlorine, bromine or iodine.
In one embodiment, compound of Formula I is the compound shown in following general formula I-A:
Wherein, R and R 1be hydrogen atom or hydroxy-protective group independently of one another, preferably, R and R 1be selected from hydrogen atom independently of one another, acyl group, substituted or unsubstituted benzoyl, substituted or unsubstituted benzyl, trityl, methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, tetrahydropyrans-2-base that methyl, C1-C6 straight or branched alkyl replace, three (C1-C6 straight or branched alkyl) are silica-based, the tertiary butyl two (C1-C6 straight or branched alkyl) is silica-based, tert-butyl diphenyl is silica-based, first thiomethyl, methoxymethyl and 2-methoxvethoxvmethvl; Or, R and R 1merge the hydroxy-protective group forming ring-type, preferably, R and R 1couple together to merge and form-SiR'-O-SiR'-or-SiR'-, wherein R' is C1-C6 straight or branched alkyl.
R 3for Sauerstoffatom or NR 4, wherein R 4for the benzoyl of hydrogen atom, acyl group that C1-C6 straight or branched alkyl replaces, benzoyl or replacement.
Substituting group on the benzoyl of described replacement and benzyl is preferably selected from nitro, C1-C6 straight or branched alkoxyl group, halogen and C1-C6 straight or branched alkyl, is more preferably selected from nitro, methoxyl group, chlorine and methyl.
In general formula I-A, R preferably can be selected from hydrogen atom, methyl, formyl radical, ethanoyl, valeryl, substituted or unsubstituted benzoyl, substituted or unsubstituted benzyl, trityl, methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, tetrahydropyrans-2-base, trimethyl silicon based, t-Butyldimethylsilyl, tert-butyl diphenyl are silica-based, first thiomethyl, methoxymethyl and 2-methoxvethoxvmethvl.
In general formula I-A, R 1preferably can be selected from hydrogen atom, methyl, formyl radical, ethanoyl, valeryl, substituted or unsubstituted benzoyl, substituted or unsubstituted benzyl, trityl, methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, tetrahydropyrans-2-base, trimethyl silicon based, t-Butyldimethylsilyl, tert-butyl diphenyl are silica-based, first thiomethyl, methoxymethyl and 2-methoxvethoxvmethvl.
In general formula I-A, R and R 1couple together to merge and form-SiR'-O-SiR'-or-SiR'-, wherein R' is preferably sec.-propyl; In general formula I-A, R 3for Sauerstoffatom or NR 4, wherein R 4preferably can be selected from hydrogen atom, formyl radical, ethanoyl and benzoyl.
In another embodiment, compound of Formula I is the compound shown in following general formula I-B:
Wherein, R and R 1be hydrogen or hydroxy-protective group independently of one another, be preferably selected from hydrogen atom, C1-C4 alkyloyl, benzoyl, the benzoyl of replacement, methylsulfonyl, p-toluenesulfonyl and tetrahydropyrans-2-base; R and R 1also can merge the hydroxy-protective group forming ring-type, such as, be ring-type silicon ethers or ring-type ethers hydroxy-protective group.
Substituting group on the benzoyl of above-mentioned replacement is preferably selected from halogen, C1-C4 alkyl etc., is more preferably chlorine.
In general formula I-B, R preferably can be selected from hydrogen atom, C1-C2 alkyloyl, benzoyl, 4-chlorobenzene formacyl, methylsulfonyl, p-toluenesulfonyl and tetrahydropyrans-2-base.
In general formula I-B, R 1preferably can be selected from hydrogen atom, C1-C2 alkyloyl, benzoyl, 4-chlorobenzene formacyl, methylsulfonyl, p-toluenesulfonyl and tetrahydropyrans-2-base.
More preferably, compound of Formula I of the present invention is selected from following compounds:
Present invention also offers the preparation method of compound of Formula I, at R 3when for Sauerstoffatom, described method is one of following method:
Method one:
Compound I-1-1 is obtained, shown in following reaction formula through ring-closure reaction conversion by Compound II per-1:
Wherein, R 2definition identical with the definition in aforementioned formula I, I-A or I-B compound;
Or
Method two:
The compound obtaining general formula I-1-2 is protected, shown in following reaction formula to 3' and the 5' hydroxyl of the Compound I-1-1 obtained in method one:
Wherein, except not being except hydrogen atom, R and R 1definition identical with the definition in aforementioned formula I, I-A or I-B compound; R 2definition identical with the definition in aforementioned formula I, I-A or I-B compound;
Or,
Method three:
In the presence of a catalyst, compound III-1-2 generation Intramolecular substitution reaction is converted into Compound I-1-2, shown in following reaction formula:
Wherein, R, R 1and R 2definition with identical with the definition in aforementioned formula I, I-A or I-B compound;
R 5for benzoyl, the benzoyl of halogen substiuted, methylsulfonyl, trifyl, benzenesulfonyl or p-toluenesulfonyl that hydrogen, C1-C4 alkyloyl, benzoyl, C1-C4 alkoxyl group replace, preferred, R 5for hydrogen atom, formyl radical, ethanoyl, benzoyl, 4-anisoyl, 4-chlorobenzene formacyl, methylsulfonyl, trifyl or p-toluenesulfonyl; Or, R 1with R 5merge and formed or
In one embodiment, in the preparation method of above-mentioned compound of Formula I, at R 3when for Sauerstoffatom, R 2for methyl.
In method one, described ring-closure reaction can in the presence of a base, under having or existing without diphenyl carbonate, be carried out in a suitable solvent.Described alkali is optional from organic bases and mineral alkali, is preferably selected from the one in sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, triethylamine, DMAP etc. or its mixture; Described solvent is be selected from one in DMF, N,N-dimethylacetamide, DMSO, acetonitrile, acetone, toluene, dioxane, pyridine etc. or its mixture; Described temperature of reaction is selected from 20 DEG C ~ 200 DEG C, preferably 60 DEG C ~ 180 DEG C; Described ring-closure reaction is preferably carried out under diphenyl carbonate exists, and Compound II per-1 is 1:1 ~ 10 with the molar ratio of diphenyl carbonate, is preferably 1:1 ~ 3.
In method two, described hydroxyl protection reaction in the presence of an acidic or basic catalyst, carry out in a suitable solvent, described an acidic catalyst is be selected from one in tosic acid, methylsulfonic acid, acetic acid, zinc chloride, tin chloride, boron trifluoride etc. or its mixture, and described basic catalyst is be selected from one in triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, salt of wormwood, sodium hydride etc. or its mixture; Described solvent is be selected from one in toluene, benzene, acetone, methyl tertiary butyl ether, isopropyl ether, tetrahydrofuran (THF), dioxane, acetonitrile, methylene dichloride, ethylene dichloride, ethyl acetate, DMF, N-Methyl pyrrolidone etc. or its mixture; Described temperature of reaction is selected from-20 DEG C ~ 120 DEG C;
In method three, described Intramolecular substitution reaction can occur in the presence of an acidic or basic catalyst, described an acidic catalyst is be selected from one in trimethylsilyl triflate, tosic acid, methylsulfonic acid, acetic acid, zinc chloride, tin chloride, boron trifluoride etc. or its mixture, described basic catalyst is for being selected from one in triethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene, salt of wormwood, sodium hydride etc. or its mixture; Described reaction solvent is be selected from one in methyl alcohol, ethanol, Virahol, toluene, benzene, acetone, tetrahydrofuran (THF), acetonitrile, methylene dichloride, ethylene dichloride, DMF, pyridine etc. or its mixture.
Present invention also offers the preparation method of compound of Formula I, at R 3for NR 4when, described method is one of following method:
Method one:
Compound I-2-1 is obtained, shown in following reaction formula through ring-closure reaction conversion by Compound II per-2:
Wherein, R 2and R 4definition identical with the definition in aforementioned formula I or I-A compound;
Or
Method two:
The compound obtaining general formula I-2-2 is protected, shown in following reaction formula to 3' and the 5' hydroxyl of the Compound I-2-1 obtained in method one:
Wherein, except not being except hydrogen atom, R and R 1definition identical with the definition in aforementioned formula I or I-A compound; R 2and R 4definition identical with the definition in aforementioned formula I or I-A compound;
Or,
Method three:
In the presence of a catalyst, compound III-2-2 generation Intramolecular substitution reaction is converted into Compound I-2-2, shown in following reaction formula:
Wherein, R, R 1, R 2and R 4definition identical with the definition in aforementioned formula I or I-A compound;
R 5for benzoyl, the benzoyl of halogen substiuted, methylsulfonyl, trifyl, benzenesulfonyl or p-toluenesulfonyl that hydrogen, C1-C4 alkyloyl, benzoyl, C1-C4 alkoxyl group replace, preferred, R 5for hydrogen atom, formyl radical, ethanoyl, benzoyl, 4-anisoyl, 4-chlorobenzene formacyl, methylsulfonyl, trifyl or p-toluenesulfonyl; Or, R 1with R 5merge and formed or
In the preparation method of above-mentioned compound of Formula I, at R 3for NR 4when, preferred R 2for methyl; And/or preferred R 4for hydrogen atom, formyl radical, acetyl or benzoyl base.
In the preparation method of compound of Formula I, above-mentioned at R 3for the description of reaction conditions when Sauerstoffatom is equally applicable to R 3for NR 4situation, therefore, do not repeat them here.
The present invention also provides a kind of method using compound of Formula I to prepare 2'-deoxidation-2'-fluoro-2'-replacement uridine or the fluoro-2'-replacement cytidine of 2'-deoxidation-2'-or 2'-deoxidation-2'-itrile group-2'-replacement uridine or 2'-deoxidation-2'-itrile group-2'-replacement cytidine compounds, at R 3when for Sauerstoffatom, described method is one of following method:
Method one:
There is fluoro in Compound I-1-1 or itrile group is obtained by reacting compound IV-1-1, shown in following reaction formula:
Wherein, R 6for fluorine or itrile group, R 2definition identical with the definition in general formula I, I-A or I-B compound;
Or,
Method two:
There is fluoro in Compound I-1-2 or itrile group is obtained by reacting compound V-1-1; Then, slough blocking group and obtain compound IV-1-1, shown in following reaction formula:
Wherein, except not being except hydrogen atom, R and R 1definition identical with the definition in aforementioned formula I, I-A or I-B compound; R 2definition identical with the definition in general formula I, I-A or I-B compound; R 6for fluorine or itrile group;
Or,
Method three:
There is ring-opening reaction and obtain compounds X I-1 in Compound I-1-1, carries out protection obtain compound VI-1-1 to itself 3' and 5' position hydroxyl, and compound VI-1-1 also by Compound I-1-2, ring-opening reaction can occur and obtain; Then compound VI-1-1 generation fluoro or itrile group substitution reaction obtain compound V-1-1; Then, slough blocking group and obtain compound IV-1-1, shown in following reaction formula:
Wherein, except not being except hydrogen atom, R and R 1definition identical with the definition in aforementioned formula I, I-A or I-B compound; R 2definition identical with the definition in general formula I, I-A or I-B compound; R 6for fluorine or itrile group;
Or,
Method four:
The 2' position hydroxyl generation acylation reaction of the compound VI-1-1 obtained in aforesaid method three or sulfonylation obtain compound VI I-1-1; Compound VI I-1-1 is obtained by reacting compound V-1-1 through fluoro or itrile group; Finally, slough blocking group and obtain compound IV-1-1, shown in following reaction formula:
Wherein, except not being except hydrogen atom, R and R 1definition identical with the definition in aforementioned formula I, I-A or I-B compound; R 2definition identical with the definition in general formula I, I-A or I-B compound; R 6for fluorine or itrile group, R 7be selected from formyl radical, ethanoyl, benzoyl, 4-anisoyl, 4-chlorobenzene formacyl, methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl and trifyl.
In the above-mentioned methods, at R 3when for Sauerstoffatom, preferred R 2for methyl.
In above-mentioned reaction, described fluoro-reaction or nitrile glycosylation reaction carry out under fluoro reagent or itrile group reagent exist.Described fluoro reagent is for being selected from F 2, HF, HF/Py, NaF, KF, tetrabutyl ammonium fluoride, triethylamine trihydrofluoride, one in diethylin sulfur trifluoride or two-(2-methoxy ethyl) amine sulfur trifluoride etc. or its mixture; Described itrile group reagent is be selected from one in sodium cyanide, potassium cyanide, trimethylsilyl cyanide, prussic acid, dicyanogen, tetrabutyl nitrilation ammonium etc. or its mixture; The solvent of described fluoro or nitrile glycosylation reaction is be selected from one in methyl alcohol, ethanol, Virahol, water, toluene, benzene, acetone, methyl tertiary butyl ether, isopropyl ether, tetrahydrofuran (THF), dioxane, acetonitrile, methylene dichloride, ethylene dichloride, ethyl acetate, DMF, N-Methyl pyrrolidone etc. or its mixture; Described fluoro-reaction or nitrile glycosylation reaction can carry out in the presence of acids or bases, and described alkali is selected from mineral alkali and organic bases, are preferably the one in salt of wormwood, triethylamine, pyridine etc. or its mixture; Described acid can be selected from hydrogen fluoride etc.; The temperature of reaction of described fluoro-reaction or nitrile glycosylation reaction is-80 DEG C ~ 150 DEG C;
Described acylation reaction in the presence of a base, carry out in suitable solvent, described alkali is be selected from one in triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, salt of wormwood, sodium hydride, sodium methylate, sodium ethylate, potassium tert.-butoxide, hexamethl disilamine base sodium, hexamethl disilamine base lithium etc. or its mixture; Acylating reagent is selected from methyl-formiate, ethyl formate, formic acid, Acetyl Chloride 98Min., diacetyl oxide, Benzoyl chloride, benzoyl oxide, 4-methoxy benzoyl chloride, 4-methoxybenzoic acid acid anhydride, 4-chloro-benzoyl chloride, 4-chloro-benzoic acid acid anhydride etc.; Described reaction solvent is be selected from one in toluene, benzene, acetone, tetrahydrofuran (THF), acetonitrile, methylene dichloride, DMF, pyridine etc. or its mixture; Described temperature of reaction is-80 DEG C ~ 150 DEG C;
Described sulfonylation in the presence of a base, carry out in suitable solvent, described alkali is be selected from one in triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, salt of wormwood, sodium hydride, sodium methylate, sodium ethylate, potassium tert.-butoxide, hexamethl disilamine base sodium, hexamethl disilamine base lithium etc. or its mixture; Sulfonylation agent is for being selected from methylsulfonyl chloride, Tosyl chloride, trifluoromethanesulfchloride chloride, trifluoromethanesulfanhydride anhydride; Described reaction solvent is be selected from one in toluene, benzene, acetone, tetrahydrofuran (THF), acetonitrile, methylene dichloride, DMF, pyridine etc. or its mixture; Described temperature of reaction is-80 DEG C ~ 150 DEG C;
Described hydroxyl protection reaction in the presence of an acidic or basic catalyst, carry out in a suitable solvent, described an acidic catalyst is be selected from one in tosic acid, methylsulfonic acid, acetic acid, zinc chloride, tin chloride, boron trifluoride etc. or its mixture, and described basic catalyst is be selected from one in triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, salt of wormwood, sodium hydride etc. or its mixture; Described solvent is be selected from one in toluene, benzene, acetone, methyl tertiary butyl ether, isopropyl ether, tetrahydrofuran (THF), dioxane, acetonitrile, methylene dichloride, ethylene dichloride, ethyl acetate, DMF, N-Methyl pyrrolidone etc. or its mixture; Described temperature of reaction is selected from-20 DEG C ~ 120 DEG C;
Described dehydroxylation protecting group reaction can be carried out in the presence of acids or bases, also can carry out under neutral reagent exists, described acid is for being selected from one in tosic acid, methylsulfonic acid, acetic acid, hydrochloric acid, sulfuric acid, zinc chloride, tin chloride, boron trifluoride etc. or its mixture, and described alkali is be selected from one in ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, Potassium monofluoride, Sodium Fluoride, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, salt of wormwood, sodium hydride, potassium tert.-butoxide etc. or its mixture; Described neutral reagent is selected from tetrabutyl ammonium fluoride, palladium carbon, active nickel; Described reaction solvent is be selected from the medium one of methyl alcohol, ethanol, Virahol, toluene, benzene, acetone, tetrahydrofuran (THF), acetonitrile, methylene dichloride, DMF, pyridine, water or its mixture; Described temperature of reaction is-20 DEG C ~ 120 DEG C;
Described ring-opening reaction is carried out in the basic conditions, and described alkali is be selected from one in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, sodium hydride, sodium methylate, sodium ethylate, potassium tert.-butoxide etc. or its mixture; Described reaction solvent is be selected from one in methyl alcohol, ethanol, Virahol, toluene, benzene, acetone, tetrahydrofuran (THF), acetonitrile, methylene dichloride, DMF, pyridine, water etc. or its mixture; Described temperature of reaction is-20 DEG C ~ 120 DEG C.
The present invention also provides a kind of method using compound of Formula I to prepare 2'-deoxidation-2'-fluoro-2'-replacement uridine or the fluoro-2'-replacement cytidine of 2'-deoxidation-2'-or 2'-deoxidation-2'-itrile group-2'-replacement uridine or 2'-deoxidation-2'-itrile group-2'-replacement cytidine compounds, at R 3for NR 4when, described method is one of following method:
Method one:
There is fluoro in Compound I-2-1 or itrile group is obtained by reacting compound IV-2-1, depending on the circumstances or the needs of the situation, works as R 4during for hydrogen atom, the fluoro-2'-of compound IV-2-1 i.e. 2'-deoxidation-2'-replaces cytidine or 2'-deoxidation-2'-itrile group-2'-replaces cytidine compounds; Work as R 4when not being hydrogen atom, obtaining the fluoro-2'-of 2'-deoxidation-2'-through deprotection reaction and replace cytidine or 2'-deoxidation-2'-itrile group-2'-replacement cytidine compounds X; Or compound IV-2-1 is hydrolyzed further and obtains the fluoro-2'-replacement uridine of 2'-deoxidation-2'-or 2'-deoxidation-2'-itrile group-2'-replacement uridine compound IV-1-1, shown in following reaction formula:
Wherein, R 6for fluorine or itrile group, R 2and R 4definition identical with the definition in general formula I or I-A compound;
Or,
Method two:
There is fluoro-reaction in Compound I-2-2 or itrile group is obtained by reacting compound V-2-1, depending on the circumstances or the needs of the situation, the first dehydroxylation protecting group of compound V-2-1 obtains compound IV-2-1, compound IV-2-1 obtains compound IV-1-1 through hydrolysis reaction, and compound IV-2-1 also deaminizating protecting group can obtain compounds X; Or; there is hydrolysis in compound V-2-1 and dehydroxylation protecting group obtains compound IV-1-1 simultaneously; or; compound V-2-1 is first hydrolyzed and obtains compound V-1-1; dehydroxylation protecting group obtains compound IV-1-1 again; again or, compound V-2-1 dehydroxylation protecting group and amino protecting group obtain compounds X, shown in following reaction formula:
Wherein, except not being except hydrogen atom, R and R 1definition identical with the definition in aforementioned formula I or I-A compound; R 2and R 4definition identical with the definition in general formula I or I-A compound; R 6for fluorine or itrile group;
Or,
Method three:
There is ring-opening reaction and obtain compounds X I-2 in Compound I-2-1, carries out protection obtain compound VI-2-1 to itself 3' and 5' position hydroxyl, and compound VI-2-1 also by Compound I-2-2, ring-opening reaction can occur and obtain; There is fluoro in compound VI-2-1 or itrile group is obtained by reacting compound V-2-1; Compound V-2-1 prepares shown in compound IV-1-1 and the following reaction formula of compounds X with the method described in method two:
Wherein, except not being except hydrogen atom, R and R 1definition identical with the definition in aforementioned formula I or I-A compound; R 2and R 4definition identical with the definition in general formula I or I-A compound; R 6for fluorine or itrile group;
Or,
Method four:
The 3' position hydroxyl generation acylation reaction of the compound VI-2-1 obtained in aforesaid method three or sulfonylation obtain compound VI I-2-1; Compound VI I-2-1 is obtained by reacting compound V-2-1 through fluoro or itrile group, and compound V-2-1 prepares compound IV-1-1 and compounds X with the method described in method two, shown in following reaction formula:
Wherein, except not being except hydrogen atom, R and R 1definition identical with the definition in aforementioned formula I or I-A compound; R 2and R 4definition identical with the definition in general formula I or I-A compound; R 6for fluorine or itrile group, R 7be selected from formyl radical, ethanoyl, benzoyl, 4-anisoyl, 4-chlorobenzene formacyl, methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl and trifyl.
In the above-mentioned methods, at R 3for NR 4when, preferred R 2for methyl.
In the above-mentioned methods, described hydrolysis reaction carries out in the presence of acids or bases, described acid is for being selected from one in acetic acid, trifluoracetic acid, tosic acid, methylsulfonic acid, zinc chloride, tin chloride, boron trifluoride etc. or its mixture, and described alkali is be selected from one in triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, salt of wormwood, sodium hydride, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydroxide etc. or its mixture; Described reaction solvent is be selected from one in methyl alcohol, ethanol, Virahol, toluene, benzene, acetone, tetrahydrofuran (THF), acetonitrile, methylene dichloride, DMF, pyridine, water etc. or its mixture, and described temperature of reaction is-20 DEG C ~ 120 DEG C.
In the above-mentioned methods, the reaction of described deaminizating protecting group is carried out in the presence of a base, and described alkali is be selected from one in ammonia, sodium hydroxide, potassium hydroxide, hydrated barta, sodium carbonate, carbonic acid, sodium methylate, sodium ethylate, potassium tert.-butoxide, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine etc. or its mixture; Described reaction solvent is be selected from one in methyl alcohol, ethanol, Virahol, toluene, benzene, acetone, tetrahydrofuran (THF), acetonitrile, methylene dichloride, DMF, pyridine, water etc. or its mixture, and described temperature of reaction is-20 DEG C ~ 120 DEG C.
In the above-mentioned methods, described hydrolysis and the reaction of dehydroxylation protecting group are carried out in the presence of acids or bases, described acid is for being selected from one in acetic acid, trifluoracetic acid, tosic acid, methylsulfonic acid, zinc chloride, tin chloride, boron trifluoride etc. or its mixture, and described alkali is be selected from one in triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, salt of wormwood, sodium hydride, sodium methylate, sodium ethylate, potassium tert.-butoxide, sodium hydroxide etc. or its mixture; Described reaction solvent is be selected from one in methyl alcohol, ethanol, Virahol, toluene, benzene, acetone, tetrahydrofuran (THF), acetonitrile, methylene dichloride, DMF, pyridine, water etc. or its mixture, and described temperature of reaction is-20 DEG C ~ 120 DEG C.
In the above-mentioned methods, described dehydroxylation and the reaction of deaminizating protecting group are carried out in the presence of a base, and described alkali is be selected from one in ammonia, sodium hydroxide, potassium hydroxide, hydrated barta, sodium carbonate, carbonic acid, sodium methylate, sodium ethylate, potassium tert.-butoxide, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine etc. or its mixture; Described reaction solvent is be selected from one in methyl alcohol, ethanol, Virahol, toluene, benzene, acetone, tetrahydrofuran (THF), acetonitrile, methylene dichloride, DMF, pyridine, water etc. or its mixture, and described temperature of reaction is-20 DEG C ~ 120 DEG C.
Prepare the fluoro-2'-of 2'-deoxidation-2'-using compound of Formula I and replace cytidine or 2'-deoxidation-2'-itrile group-2'-replaces in the method for cytidine compounds, above-mentioned at R 3for the description of fluoro-reaction when Sauerstoffatom, nitrile glycosylation reaction, the reaction of dehydroxylation protecting group, ring-opening reaction, hydroxyl protection reaction, acylation reaction and sulfonylation is equally applicable to R 3for NR 4situation, therefore, do not repeat them here.
The present invention also provides a kind of method using compound of Formula I to prepare the fluoro-2'-replacement uridine of 2'-deoxidation-2'-or 2'-deoxidation-2'-itrile group-2'-replacement uridine compound, and described method comprises:
With 2'-C-methyluridine (II-1-3) for raw material, obtain Compound I-1-3 through ring-closure reaction, in reactor, then directly add fluoro reagent or itrile group reagent generation compound IV-1-2, shown in following reaction formula:
Wherein, R 6for fluorine or itrile group.
Described ring-closure reaction can be in the presence of a base, under having or existing without diphenyl carbonate, carry out in a suitable solvent, described alkali is optional from organic bases and mineral alkali, is preferably selected from the one in sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, triethylamine, DMAP etc. or its mixture; Described solvent is be selected from one in DMF, N,N-dimethylacetamide, DMSO, acetonitrile, acetone, toluene, dioxane, pyridine etc. or its mixture; Described temperature of reaction is selected from 20 DEG C ~ 200 DEG C, preferably 60 DEG C ~ 140 DEG C; Described ring-closure reaction is preferably carried out under diphenyl carbonate exists, and Compound II per-1-3 is 1:1 ~ 10 with the molar ratio of diphenyl carbonate, is preferably 1:1 ~ 3.
Described fluoro reagent is for being selected from F 2, HF, HF/Py, NaF, KF, tetrabutyl ammonium fluoride, triethylamine trihydrofluoride, diethylin sulfur trifluoride, one in two-(2-methoxy ethyl) amine sulfur trifluoride etc. or its mixture; Described itrile group reagent is be selected from one in sodium cyanide, potassium cyanide, trimethylsilyl cyanide, prussic acid, dicyanogen, tetrabutyl ammonium cyanide etc. or its mixture.
Described fluoro-reaction or itrile groupization can be carried out in the presence of acids or bases, and described alkali is selected from mineral alkali and organic bases, is preferably selected from the one in salt of wormwood, triethylamine, pyridine etc. or its mixture; Described acid can be selected from hydrogen fluoride etc.; The solvent of described fluoro or nitrile glycosylation reaction is be selected from one in methyl alcohol, ethanol, Virahol, water, toluene, benzene, acetone, methyl tertiary butyl ether, isopropyl ether, tetrahydrofuran (THF), dioxane, acetonitrile, methylene dichloride, ethylene dichloride, ethyl acetate, DMF, N-Methyl pyrrolidone etc. or its mixture; The temperature of described fluoro or nitrile glycosylation reaction is-80 DEG C ~ 150 DEG C.
Beneficial effect
The present invention first prepares compound of Formula I and prepares the fluoro-2'-of 2'-deoxidation-2'-again and replace uridine or the fluoro-2'-of 2'-deoxidation-2'-and replace cytidine or 2'-deoxidation-2'-itrile group-2'-and replace the advantage that uridine or 2'-deoxidation-2'-itrile group-2'-replace the method for cytidine compounds and be: utilize the uridine or cytidine analog structural framework that have existed, carry out intramolecular substitution reaction by 2 configuration inversions, and then carry out fluoro or nitrile glycosylation reaction, reverse 2 configurations configuration again that obtain wishing.In this process, the retention of configuration of uridylic base or cytosine base is constant, avoids the generation of isomer.The experiment proved that, this method, reaction conditions is gentle, easy handling, and yield is high, and the product quality obtained is stablized, and purity is high, can carry out technical scale and amplify production.
Embodiment
Embodiment 1:
2'-C-methyluridine (0.2g, 0.8mmol) is dissolved in DMF (4ml), add diphenyl carbonate (0.256g, 1.2mmol) and sodium bicarbonate (55mg, 0.66mmol), be heated to 150 DEG C, stir 6 hours, cooling, removal of solvent under reduced pressure, ethyl acetate is added in resistates, making beating, filters and obtains solid (150mg, yield: 81%).
Ia: 1H NMR(300MHz,CD 3OD):δ7.80(d,1H,J=7.5Hz),6.05(d,1H,J=7.5Hz),5.91(s,1H),4.34(d,1H,J=4.8Hz),4.07(m,1H),3.56(m,2H),1.63(s,3H);ESI-MS m/z(M+1)241。
Embodiment 2:
By embodiment 1 Compound I a (0.24g, 1mmol)) be dissolved in 70%HF pyridine solution, be heated to 140 ~ 150 DEG C, stir 3 hours, cooling, removal of solvent under reduced pressure, adds acetone in resistates, making beating, filters and obtains solid (0.18g, yield: 70%).
IIIa: 1H NMR(300MHz,DMSO-d 6):δ11.48(s,1H),7.82(d,1H,J=6.0Hz),6.00(d,1H,J=15.6Hz),5.67(m,2H),5.30(s,1H),3.85(m,3H),3.62(s,1H),1.25(d,3H,J=16.8Hz),ESI-MS m/z(M-1)259。
Embodiment 3:
By 2'-C-methyluridine (18.4g, 0.07mol), carbonyl dimidazoles (216.2g, 0.10mol), sodium bicarbonate (8.4g, 0.10mol) suspension N, in dinethylformamide (50ml), be warming up to 130 DEG C, react 4 hours, cooling, cross and filter inorganic salt, add ethyl acetate (200ml) in filtrate, analysis of material, cool to room temperature, suction filtration, ethyl acetate is washed, and dries, obtain yellow solid (19.9g, yield: 83%).
Embodiment 4:
By embodiment 1 Compound I a (0.24g, 1mmol) be dissolved in methylene dichloride (4ml), add triethylamine (0.5ml), ice bath, slowly adds Benzoyl chloride (0.28g), slowly rises to envrionment temperature, stir 24 hours, removal of solvent under reduced pressure obtains resistates, and silica gel column chromatography obtains product (0.37g, yield: 82%).
Ib: 1H NMR(300MHz,CDCl 3):δ7.96-8.10(m,6H),7.41-7.65(m,9H),7.32(d,1H,J=5.4Hz),6.09(d,1H,J=5.4Hz),5.79(m,2H),4.67(m,1H),4.48(m,2H),1.81(s,3H);ESI-MS m/z(M-1)447。
Embodiment 5:
By embodiment 4 compounds ib (0.45g, 1mmol) be dissolved in the mixture of methylene dichloride and pyridine, add DAST (0.32g), stir 24 hours, add methylene chloride (20ml) dilution, washs with water (30ml × 2), anhydrous sodium sulfate drying, filter, removal of solvent under reduced pressure obtains resistates and carries out column chromatography and obtain product (0.36g, yield: 78%).
IIa: 1h NMR (400MHz, CDCl 3and DMSO-d 6): δ 7.99 (d, J=7.6Hz, 2H), 7.90 (d; J=7.6Hz, 2H), 7.34 ~ 7.61 (m, 7H); 6.10 (brs, 1H), 5.64 (brs; 1H), 5.42 (d, J=8.0Hz; 1H), 4.53-4.68 (m, 3H); 1.40 (d, J=22.8Hz, 3H); ESI-MS m/z (M+1) 469.
Embodiment 6:
Embodiment 5 Compound II per a (0.47g, 1mmol) be dissolved in the ammonia methanol solution of 10%, stirring is spent the night, removal of solvent under reduced pressure, and resistates is pulled an oar in ethyl acetate, filters to obtain white solid (0.2g, yield: 77%).
IIIa: 1H NMR(300MHz,DMSO-d 6):δ11.48(s,1H),7.82(d,1H,J=6.0Hz),6.00(d,1H,J=15.6Hz),5.67(m,2H),5.30(s,1H),3.85(m,3H),3.62(s,1H),1.25(d,3H,J=16.8Hz),ESI-MS m/z(M-1)259。
Embodiment 7:
By compound IV a (0.57g, 1mmol) be dissolved in ethylene dichloride (20ml), add Trimethylsilyl trifluoromethanesulfonate (1ml), reacting by heating 12 hours, cooling, by concentrated for reaction solution dry, add methylene dichloride (100ml) to dissolve, use water (50ml) and saturated brine (50ml) washing successively, anhydrous sodium sulfate drying, filters, filtrate is concentrated dry, obtain oily matter, obtain white solid (0.3g, yield: 67%) through column chromatography purification.
Ib: 1H NMR(300MHz,CDCl 3):δ7.96-8.10(m,6H),7.41-7.65(m,9H),7.32(d,1H,J=5.4Hz),6.09(d,1H,J=5.4Hz),5.79(m,2H),4.67(m,1H),4.48(m,2H),1.81(s,3H);ESI-MS m/z(M-1)447。
Embodiment 8:
By embodiment 1 Compound I a (1.3g, 5.4mmol) be dissolved in dry DMF (10ml), add a hydration tosic acid (1.12g, 5.9mmol) and 3,4-dihydropyrane (1.28ml, 14.04mmol), stirring at room temperature reacts 5 hours, add water and methylene dichloride, separatory, organic layer concentrates, and purified on silica obtains product 1.3g.
Ic: 1H NMR(300MHz,CDCl 3):δ7.29(m,1H),6.08(m,1H),5.61(m,1H),4.33-4.72(m,4H),3.37-3.90(m,6H),1.43-1.82(m,12H),1.25(s,3H);ESI-MS m/z(M+1)427。
Embodiment 9:
Embodiment 8 Compound I c (0.43g, 1mmol) is dissolved in 70%HF pyridine solution, is heated to 100 ~ 120 DEG C, stir 5 hours, cooling, removal of solvent under reduced pressure, resistates obtains solid (0.18g, yield: 72%) through purification by silica gel column chromatography.
IIIa: 1H NMR(300MHz,DMSO-d 6):δ11.48(s,1H),7.82(d,1H,J=6.0Hz),6.00(d,1H,J=15.6Hz),5.67(m,2H),5.30(s,1H),3.85(m,3H),3.62(s,1H),1.25(d,3H,J=16.8Hz),ESI-MS m/z(M-1)259。
Embodiment 10:
By embodiment 8 Compound I c (50mg, 0.122mmol) be dissolved in methyl alcohol (1ml), add 1N sodium hydroxide solution (0.2ml), stirred overnight at room temperature, add water and methylene dichloride, separatory, obtains product (45mg, yield: 87%) through column chromatography purification after organic layer is concentrated.
Va: 1H NMR(300MHz,CDCl 3):δ7.89(d,1H,J=4.5Hz),6.01(s,1H),5.95(d,1H,J=4.5Hz),5.65(m,2H),4.73(m,3H),4.59(m,1H),3.52-4.30(m,4H),1.56-1.80(m,12H),1.32(s,3H);ESI-MS m/z(M+35)461。
Embodiment 11:
By embodiment 10 compound Va (0.43g, 1mmol) be dissolved in the mixture of methylene dichloride and pyridine, add DAST (0.32g), stir 24 hours, add methylene chloride (20ml) dilution, with water (30ml × 2) washing, and anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains Compound II per b.Be dissolved in by Compound II per b in methyl alcohol (10ml), add tosic acid (200mg), stirring at room temperature 6 hours, decompression removing methyl alcohol, silica gel column chromatography obtains product IIIa (180mg, yield: 75%).
IIIa: 1H NMR(300MHz,DMSO-d 6):δ11.48(s,1H),7.82(d,1H,J=6.0Hz),6.00(d,1H,J=15.6Hz),5.67(m,2H),5.30(s,1H),3.85(m,3H),3.62(s,1H),1.25(d,3H,J=16.8Hz),ESI-MS m/z(M-1)259。
Embodiment 12:
By 2'-C-methyluridine (0.2g, 0.8mmol) be dissolved in N, in dinethylformamide (4ml), add diphenyl carbonate (0.256g, 1.2mmol) and sodium bicarbonate (55mg, 0.66mmol), be heated to 150 DEG C, stir 6 hours, cooling, removal of solvent under reduced pressure, resistates is dissolved in 70%HF pyridine solution, be heated to 140 ~ 150 DEG C, stir 3 hours, cooling, removal of solvent under reduced pressure, resistates is added in acetone, filters and obtains solid IIIa (0.13g, yield: 65%).
Embodiment 13:
Under nitrogen protection; by embodiment 10 compound Va (4.26g; 10mmol) be dissolved in dry tetrahydrofuran (100ml); add triethylamine (6g; 60mmol); be cooled to-78 DEG C, add trifluoromethanesulfanhydride anhydride (4.23g, 15mmol); stir after 1 hour; in reaction system, add saturated ammonium chloride solution, with dichloromethane extraction three times, merge organic phase; anhydrous sodium sulfate drying; concentrated, resistates obtains product Vb (4g, yield: 72%) through silica gel column chromatography.ESI-MS m/z(M-1)557。
Compound Vb (4g) is dissolved in dry tetrahydrofuran, add tetrabutyl ammonium fluoride (1.87g, 7.1mmol), be warming up to backflow, heat and be down to room temperature after 1 hour, in reaction system, add water, with dichloromethane extraction three times, merge organic phase, anhydrous sodium sulfate drying, concentrated, resistates obtains product IIb (2.7g, yield: 88%) through silica gel column chromatography.ESI-MS m/z(M-1)427。
Compound II per b (2.7g) is dissolved in methyl alcohol (20ml), adds 3M hydrochloric acid (10ml), and 50 DEG C are stirred 8 hours, concentrate and obtain solid, add acetonitrile, and making beating is filtered and obtained product IIIa (1g, yield: 61%).
IIIa: 1H NMR(300MHz,DMSO-d 6):δ11.48(s,1H),7.82(d,1H,J=6.0Hz),6.00(d,1H,J=15.6Hz),5.67(m,2H),5.30(s,1H),3.85(m,3H),3.62(s,1H),1.25(d,3H,J=16.8Hz),ESI-MS m/z(M-1)259。

Claims (17)

1. following compound shown in general formula I:
R and R 1be hydrogen atom or hydroxy-protective group independently of one another, or R and R 1merge the hydroxy-protective group forming ring-type;
R 2for C1-C6 straight or branched alkyl, by the C1-C6 straight or branched alkyl of one or more halogen or hydroxyl replacement, itrile group or halogen;
R 3for Sauerstoffatom or NR 4, wherein R 4for acyl group, substituted or unsubstituted benzoyl that hydrogen atom, C1-C6 straight or branched alkyl replace.
2. compound according to claim 1, wherein,
R and R 1be selected from hydrogen atom independently of one another, acyl group, substituted or unsubstituted benzoyl, substituted or unsubstituted benzyl, trityl, methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, tetrahydropyrans-2-base that methyl, C1-C6 straight or branched alkyl replace, three (C1-C6 straight or branched alkyl) are silica-based, the tertiary butyl two (C1-C6 straight or branched alkyl) is silica-based, tert-butyl diphenyl is silica-based, first thiomethyl, methoxymethyl and 2-methoxvethoxvmethvl; Most preferred, R and R 1be selected from hydrogen atom, methyl, formyl radical, ethanoyl, valeryl, substituted or unsubstituted benzoyl, substituted or unsubstituted benzyl, trityl, methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, tetrahydropyrans-2-base independently of one another, trimethyl silicon based, t-Butyldimethylsilyl, tert-butyl diphenyl are silica-based, first thiomethyl, methoxymethyl and 2-methoxvethoxvmethvl; Replace benzoyl and replacement benzyl on substituting group be selected from nitro, C1-C6 straight or branched alkoxyl group, halogen, C1-C6 straight or branched alkyl and phenyl, be preferably selected from nitro, methoxyl group, chlorine, methyl and phenyl; Or,
R and R 1couple together to merge and form-SiR'-O-SiR'-or-SiR'-, wherein R' is C1-C6 straight or branched alkyl, and preferred R' is sec.-propyl;
R 2for C1-C4 straight or branched alkyl, trifluoromethyl, methylol, itrile group, difluoromethyl, fluorine or chlorine, most preferred, R 2for methyl, ethyl, trifluoromethyl or itrile group;
R 3for Sauerstoffatom or NR 4, wherein R 4for hydrogen atom, formyl radical, ethanoyl, substituted or unsubstituted benzoyl, most preferred, R 4for hydrogen atom, formyl radical, acetyl or benzoyl base, the substituting group on the benzoyl of replacement is selected from nitro, C1-C6 straight or branched alkoxyl group, halogen and C1-C6 straight or branched alkyl, is preferably selected from nitro, methoxyl group, chlorine and methyl.
3. compound according to claim 1, compound of Formula I is the compound shown in following general formula I-A:
Wherein,
R and R 1be hydrogen atom or hydroxy-protective group independently of one another, preferably, R and R 1be selected from hydrogen atom independently of one another, acyl group, substituted or unsubstituted benzoyl, substituted or unsubstituted benzyl, trityl, methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, tetrahydropyrans-2-base that methyl, C1-C6 straight or branched alkyl replace, three (C1-C6 straight or branched alkyl) are silica-based, the tertiary butyl two (C1-C6 straight or branched alkyl) is silica-based, tert-butyl diphenyl is silica-based, first thiomethyl, methoxymethyl and 2-methoxvethoxvmethvl; most preferred, R and R 1be selected from hydrogen atom, methyl, formyl radical, ethanoyl, valeryl, substituted or unsubstituted benzoyl, substituted or unsubstituted benzyl, trityl, methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl, tetrahydropyrans-2-base independently of one another, trimethyl silicon based, t-Butyldimethylsilyl, tert-butyl diphenyl are silica-based, first thiomethyl, methoxymethyl and 2-methoxvethoxvmethvl; Or,
R and R 1merge the hydroxy-protective group forming ring-type, preferably, R and R 1couple together to merge and form-SiR'-O-SiR'-or-SiR'-, wherein R' is C1-C6 straight or branched alkyl, most preferred, and R' is sec.-propyl;
R 3for Sauerstoffatom or NR 4, wherein R 4for hydrogen atom, C1-C6 straight or branched alkyl replace acyl group, benzoyl, replacement benzoyl, most preferred, R 4be selected from hydrogen atom, formyl radical, ethanoyl and benzoyl;
Replace benzoyl and benzyl on substituting group be preferably selected from nitro, C1-C6 straight or branched alkoxyl group, halogen and C1-C6 straight or branched alkyl, be more preferably nitro, methoxyl group, chlorine and methyl.
4. compound according to claim 1, wherein, compound of Formula I is selected from following compounds:
5. the preparation method of compound described in claim 1, at R 3when for Sauerstoffatom, described method is one of following method:
Method one:
Compound I-1-1 is obtained, shown in following reaction formula through ring-closure reaction conversion by Compound II per-1:
Wherein, R 2definition identical with the definition in claim 1;
Or
Method two:
The compound obtaining general formula I-1-2 is protected, shown in following reaction formula to 3' and the 5' hydroxyl of the Compound I-1-1 obtained in method one:
Wherein, except not being except hydrogen atom, R and R 1definition identical with the definition in claim 1; R 2definition identical with the definition in claim 1;
Or,
Method three:
In the presence of a catalyst, compound III-1-2 generation Intramolecular substitution reaction is converted into Compound I-1-2, shown in following reaction formula:
Wherein, R, R 1and R 2definition identical with the definition in claim 1;
R 5for benzoyl, the benzoyl of halogen substiuted, methylsulfonyl, trifyl, benzenesulfonyl or p-toluenesulfonyl that hydrogen, C1-C4 alkyloyl, benzoyl, C1-C4 alkoxyl group replace, preferably, R 5for hydrogen atom, formyl radical, ethanoyl, benzoyl, 4-anisoyl, 4-chlorobenzene formacyl, methylsulfonyl, trifyl or p-toluenesulfonyl; Or,
R 1with R 5merge and formed or
6. preparation method according to claim 5, wherein, R 2for methyl.
7. the preparation method of compound described in claim 1, at R 3for NR 4when, described method is one of following method:
Method one:
Compound I-2-1 is obtained, shown in following reaction formula through ring-closure reaction conversion by Compound II per-2:
Wherein, R 2and R 4definition identical with the definition in claim 1;
Or
Method two:
The compound obtaining general formula I-2-2 is protected, shown in following reaction formula to 3' and the 5' hydroxyl of the Compound I-2-1 obtained in method one:
Wherein, except not being except hydrogen atom, R and R 1definition identical with the definition in claim 1; R 2and R 4definition identical with the definition in claim 1;
Or,
Method three:
In the presence of a catalyst, compound III-2-2 generation Intramolecular substitution reaction is converted into Compound I-2-2, shown in following reaction formula:
Wherein, R, R 1, R 2and R 4definition identical with the definition in claim 1;
R 5for benzoyl, the benzoyl of halogen substiuted, methylsulfonyl, trifyl, benzenesulfonyl or p-toluenesulfonyl that hydrogen, C1-C4 alkyloyl, benzoyl, C1-C4 alkoxyl group replace, preferably, R 5for hydrogen atom, formyl radical, ethanoyl, benzoyl, 4-anisoyl, 4-chlorobenzene formacyl, methylsulfonyl, trifyl or p-toluenesulfonyl; Or,
R 1with R 5merge and formed or
8. preparation method according to claim 7, R 2for methyl, and/or R 4for hydrogen atom, formyl radical, acetyl or benzoyl base.
9. the preparation method according to any one of claim 5-8, wherein,
In method one, described ring-closure reaction in the presence of a base, under having or existing without diphenyl carbonate, carry out in a suitable solvent, described alkali is selected from organic bases and mineral alkali, is preferably selected from the one in sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, triethylamine and DMAP or its mixture; Described solvent is be selected from one in DMF, N,N-dimethylacetamide, DMSO, acetonitrile, acetone, toluene, dioxane and pyridine or its mixture; Described ring-closure reaction is preferably carried out under diphenyl carbonate exists, and Compound II per-1 is 1:1 ~ 10 with the molar ratio of diphenyl carbonate, is preferably 1:1 ~ 3;
In method two, described hydroxyl protection reaction in the presence of an acidic or basic catalyst, carry out in a suitable solvent, described an acidic catalyst is be selected from one in tosic acid, methylsulfonic acid, acetic acid, zinc chloride, tin chloride and boron trifluoride or its mixture, and described basic catalyst is be selected from one in triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, salt of wormwood and sodium hydride or its mixture; Described solvent is be selected from one in toluene, benzene, acetone, methyl tertiary butyl ether, isopropyl ether, tetrahydrofuran (THF), dioxane, acetonitrile, methylene dichloride, ethylene dichloride, ethyl acetate, DMF and N-Methyl pyrrolidone or its mixture;
In method three, described Intramolecular substitution reaction occurs in the presence of an acidic or basic catalyst, described an acidic catalyst is be selected from one in trimethylsilyl triflate, tosic acid, methylsulfonic acid, acetic acid, zinc chloride, tin chloride and boron trifluoride or its mixture, described basic catalyst is for being selected from one in triethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene, salt of wormwood and sodium hydride or its mixture; Described reaction solvent is be selected from one in methyl alcohol, ethanol, Virahol, toluene, benzene, acetone, tetrahydrofuran (THF), acetonitrile, methylene dichloride, ethylene dichloride, DMF and pyridine or its mixture.
10. use compound described in claim 1 to prepare the method for 2'-deoxidation-2'-fluoro-2'-replacement uridine or the fluoro-2'-replacement cytidine of 2'-deoxidation-2'-or 2'-deoxidation-2'-itrile group-2'-replacement uridine or 2'-deoxidation-2'-itrile group-2'-replacement cytidine compounds compound, at R 3when for Sauerstoffatom, described method is one of following method:
Method one:
There is fluoro in Compound I-1-1 or itrile group is obtained by reacting compound IV-1-1, shown in following reaction formula:
Wherein, R 6for fluorine or itrile group, R 2definition identical with the definition in claim 1;
Or,
Method two:
There is fluoro in Compound I-1-2 or itrile group is obtained by reacting compound V-1-1; Then, slough blocking group and obtain compound IV-1-1, shown in following reaction formula:
Wherein, except not being except hydrogen atom, R and R 1definition identical with the definition in claim 1; R 2definition identical with the definition in claim 1; R 6for fluorine or itrile group;
Or,
Method three:
There is ring-opening reaction and obtain compounds X I-1 in Compound I-1-1, carries out protection obtain compound VI-1-1 to itself 3' and 5' position hydroxyl, and compound VI-1-1 also by Compound I-1-2, ring-opening reaction can occur and obtain; Then compound VI-1-1 generation fluoro or itrile group are obtained by reacting compound V-1-1; Then, slough blocking group and obtain compound IV-1-1, shown in following reaction formula:
Wherein, except not being except hydrogen atom, R and R 1definition identical with the definition in claim 1; R 2definition identical with the definition in claim 1; R 6for fluorine or itrile group;
Or,
Method four:
The 2' position hydroxyl generation acylation reaction of the compound VI-1-1 obtained in method three or sulfonylation obtain compound VI I-1-1; Compound VI I-1-1 is obtained by reacting compound V-1-1 through fluoro or itrile group; Finally, slough blocking group and obtain compound IV-1-1, shown in following reaction formula:
Wherein, except not being except hydrogen atom, R and R 1definition identical with the definition in claim 1; R 2definition identical with the definition in claim 1; R 6for fluorine or itrile group, R 7be selected from formyl radical, ethanoyl, benzoyl, 4-anisoyl, 4-chlorobenzene formacyl, methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl and trifyl.
11. preparation methods according to claim 10, R 2for methyl.
The method that 12. use compound described in claim 1 to prepare the fluoro-2'-of 2'-deoxidation-2'-replaces uridine or the fluoro-2'-replacement cytidine of 2'-deoxidation-2'-or 2'-deoxidation-2'-itrile group-2'-replacement uridine or 2'-deoxidation-2'-itrile group-2'-replacement cytidine compounds, at R 3for NR 4when, described method is one of following method:
Method one:
There is fluoro in Compound I-2-1 or itrile group is obtained by reacting compound IV-2-1, depending on the circumstances or the needs of the situation, works as R 4during for hydrogen atom, the fluoro-2'-of compound IV-2-1 i.e. 2'-deoxidation-2'-replaces cytidine or 2'-deoxidation-2'-itrile group-2'-replaces cytidine compounds; Work as R 4when not being hydrogen atom, obtaining the fluoro-2'-of 2'-deoxidation-2'-through deprotection reaction and replace cytidine or 2'-deoxidation-2'-itrile group-2'-replacement cytidine compounds X; Or compound IV-2-1 is hydrolyzed further and obtains the fluoro-2'-replacement uridine of 2'-deoxidation-2'-or 2'-deoxidation-2'-itrile group-2'-replacement uridine compound IV-1-1, shown in following reaction formula:
Wherein, R 6for fluorine or itrile group, R 2and R 4definition identical with the definition in claim 1;
Or,
Method two:
There is fluoro in Compound I-2-2 or itrile group is obtained by reacting compound V-2-1, depending on the circumstances or the needs of the situation, the first dehydroxylation protecting group of compound V-2-1 obtains compound IV-2-1, compound IV-2-1 obtains compound IV-1-1 through hydrolysis reaction, and compound IV-2-1 also deaminizating protecting group can obtain compounds X; Or; there is hydrolysis in compound V-2-1 and dehydroxylation protecting group obtains compound IV-1-1 simultaneously; or; compound V-2-1 is first hydrolyzed and obtains compound V-1-1; dehydroxylation protecting group obtains compound IV-1-1 again; again or, compound V-2-1 dehydroxylation protecting group and amino protecting group obtain compounds X, shown in following reaction formula:
Wherein except not being except hydrogen atom, R and R 1definition identical with the definition in claim 1; R 2and R 4definition identical with the definition in claim 1; R 6for fluorine or itrile group;
Or,
Method three:
There is ring-opening reaction and obtain compounds X I-2 in Compound I-2-1, carries out protection obtain compound VI-2-1 to itself 3' and 5' position hydroxyl, and compound VI-2-1 also by Compound I-2-2, ring-opening reaction can occur and obtain; There is fluoro in compound VI-2-1 or itrile group is obtained by reacting compound V-2-1; Compound V-2-1 prepares compound IV-1-1 and compounds X with the method described in method two, shown in following reaction formula:
Wherein, except not being except hydrogen atom, R and R 1definition identical with the definition in claim 1; R 2and R 4definition identical with the definition in claim 1; R 6for fluorine or itrile group;
Or,
Method four:
The 3' position hydroxyl generation acylation reaction of the compound VI-2-1 obtained in method three or sulfonylation obtain compound VI I-2-1; Compound VI I-2-1 is obtained by reacting compound V-2-1 through fluoro or itrile group, and compound V-2-1 prepares compound IV-1-1 and compounds X with the method described in method two, shown in following reaction formula:
Wherein, except not being except hydrogen atom, R and R 1definition identical with the definition in claim 1; R 2and R 4definition identical with the definition in claim 1; R 6for fluorine or itrile group, R 7be selected from formyl radical, ethanoyl, benzoyl, 4-anisoyl, 4-chlorobenzene formacyl, methylsulfonyl, benzenesulfonyl, p-toluenesulfonyl and trifyl.
13. preparation method according to claim 12, wherein R 2for methyl.
14. methods according to any one of claim 10-13, wherein,
Described fluoro-reaction or nitrile glycosylation reaction carry out under fluoro reagent or itrile group reagent exist; Described fluoro reagent is for being selected from F 2, HF, HF/Py, NaF, KF, tetrabutyl ammonium fluoride, triethylamine trihydrofluoride, one in diethylin sulfur trifluoride and two-(2-methoxy ethyl) amine sulfur trifluoride or its mixture; Described itrile group reagent is be selected from one in sodium cyanide, potassium cyanide, trimethylsilyl cyanide, prussic acid, dicyanogen and tetrabutyl nitrilation ammonium or its mixture; Described fluoro-reaction or nitrile glycosylation reaction can carry out in the presence of acids or bases, and described alkali is selected from mineral alkali or organic bases, are preferably the one in salt of wormwood, triethylamine or pyridine or its mixture; Described acid can be selected from hydrogen fluoride etc.; The solvent of described fluoro or nitrile glycosylation reaction is be selected from one in methyl alcohol, ethanol, Virahol, water, toluene, benzene, acetone, methyl tertiary butyl ether, isopropyl ether, tetrahydrofuran (THF), dioxane, acetonitrile, methylene dichloride, ethylene dichloride, ethyl acetate, DMF and N-Methyl pyrrolidone or its mixture;
Described acylation reaction in the presence of a base, carry out in suitable solvent, described alkali is be selected from one in triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, salt of wormwood, sodium hydride, sodium methylate, sodium ethylate, potassium tert.-butoxide, hexamethl disilamine base sodium and hexamethl disilamine base lithium or its mixture; Acylating reagent is selected from methyl-formiate, ethyl formate, formic acid, Acetyl Chloride 98Min., diacetyl oxide, Benzoyl chloride, benzoyl oxide, 4-methoxy benzoyl chloride, 4-methoxybenzoic acid acid anhydride, 4-chloro-benzoyl chloride and 4-chloro-benzoic acid acid anhydride; Described reaction solvent is be selected from one in toluene, benzene, acetone, tetrahydrofuran (THF), acetonitrile, methylene dichloride, DMF and pyridine or its mixture;
Described sulfonylation in the presence of a base, carry out in suitable solvent, described alkali is be selected from one in triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, salt of wormwood, sodium hydride, sodium methylate, sodium ethylate, potassium tert.-butoxide, hexamethl disilamine base sodium and hexamethl disilamine base lithium or its mixture; Sulfonylation agent is selected from methylsulfonyl chloride, Tosyl chloride, trifluoromethanesulfchloride chloride and trifluoromethanesulfanhydride anhydride; Described reaction solvent is be selected from one in toluene, benzene, acetone, tetrahydrofuran (THF), acetonitrile, methylene dichloride, DMF and pyridine or its mixture;
Described hydroxyl protection reaction in the presence of an acidic or basic catalyst, carry out in a suitable solvent, described an acidic catalyst is be selected from one in tosic acid, methylsulfonic acid, acetic acid, zinc chloride, tin chloride and boron trifluoride or its mixture, and described basic catalyst is be selected from one in triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, salt of wormwood and sodium hydride or its mixture; Described solvent is be selected from one in toluene, benzene, acetone, methyl tertiary butyl ether, isopropyl ether, tetrahydrofuran (THF), dioxane, acetonitrile, methylene dichloride, ethylene dichloride, ethyl acetate, DMF and N-Methyl pyrrolidone or its mixture;
Described dehydroxylation protecting group reaction can be carried out in the presence of acids or bases, also can carry out under neutral reagent exists, described acid is for being selected from one in tosic acid, methylsulfonic acid, acetic acid, hydrochloric acid, sulfuric acid, zinc chloride, tin chloride and boron trifluoride or its mixture, and described alkali is be selected from one in ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, Potassium monofluoride, Sodium Fluoride, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, salt of wormwood, sodium hydride and potassium tert.-butoxide or its mixture; Described neutral reagent is selected from tetrabutyl ammonium fluoride, palladium carbon and active nickel; Described reaction solvent is be selected from one in methyl alcohol, ethanol, Virahol, toluene, benzene, acetone, tetrahydrofuran (THF), acetonitrile, methylene dichloride, DMF, pyridine and water or its mixture;
Described ring-opening reaction is carried out in the basic conditions, and described alkali is be selected from one in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, sodium hydride, sodium methylate, sodium ethylate and potassium tert.-butoxide or its mixture; Described reaction solvent is be selected from one in methyl alcohol, ethanol, Virahol, toluene, benzene, acetone, tetrahydrofuran (THF), acetonitrile, methylene dichloride, DMF, pyridine and water or its mixture;
Described hydrolysis reaction carries out in the presence of acids or bases, described acid is for being selected from one in acetic acid, trifluoracetic acid, tosic acid, methylsulfonic acid, zinc chloride, tin chloride and boron trifluoride or its mixture, and described alkali is be selected from one in triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, salt of wormwood, sodium hydride, sodium methylate, sodium ethylate, potassium tert.-butoxide and sodium hydroxide or its mixture; Described reaction solvent is be selected from one in methyl alcohol, ethanol, Virahol, toluene, benzene, acetone, tetrahydrofuran (THF), acetonitrile, methylene dichloride, DMF, pyridine and water or its mixture;
The reaction of described deaminizating protecting group is carried out in the presence of a base, and described alkali is be selected from one in ammonia, sodium hydroxide, potassium hydroxide, hydrated barta, sodium carbonate, carbonic acid, sodium methylate, sodium ethylate, potassium tert.-butoxide, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine and N-methylmorpholine or its mixture; Described reaction solvent is be selected from one in methyl alcohol, ethanol, Virahol, toluene, benzene, acetone, tetrahydrofuran (THF), acetonitrile, methylene dichloride, DMF, pyridine and water or its mixture;
Described hydrolysis and the reaction of dehydroxylation protecting group are carried out in the presence of acids or bases, described acid is for being selected from one in acetic acid, trifluoracetic acid, tosic acid, methylsulfonic acid, zinc chloride, tin chloride and boron trifluoride or its mixture, and described alkali is be selected from one in triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, N-methylmorpholine, salt of wormwood, sodium hydride, sodium methylate, sodium ethylate, potassium tert.-butoxide and sodium hydroxide or its mixture; Described reaction solvent is be selected from one in methyl alcohol, ethanol, Virahol, toluene, benzene, acetone, tetrahydrofuran (THF), acetonitrile, methylene dichloride, DMF, pyridine and water or its mixture;
Described dehydroxylation and the reaction of deaminizating protecting group are carried out in the presence of a base, and described alkali is be selected from one in ammonia, sodium hydroxide, potassium hydroxide, hydrated barta, sodium carbonate, carbonic acid, sodium methylate, sodium ethylate, potassium tert.-butoxide, triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine and N-methylmorpholine or its mixture; Described reaction solvent is be selected from one in methyl alcohol, ethanol, Virahol, toluene, benzene, acetone, tetrahydrofuran (THF), acetonitrile, methylene dichloride, DMF, pyridine and water or its mixture.
The method that 15. use compound described in claim 1 to prepare the fluoro-2'-of 2'-deoxidation-2'-replaces uridine or 2'-deoxidation-2'-itrile group-2'-replacement uridine compound, described method comprises:
With 2'-C-methyluridine (II-1-3) for raw material, obtain Compound I-1-3 through ring-closure reaction, in reactor, then directly add fluoro reagent or itrile group reagent generation compound IV-1-2, shown in following reaction formula:
Wherein, R 6for fluorine or itrile group.
16. preparation methods according to claim 15, wherein,
Described ring-closure reaction in the presence of a base, under having or existing without diphenyl carbonate, carry out in a suitable solvent, described alkali, for being selected from organic bases or mineral alkali, is preferably selected from the one in sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood, triethylamine and DMAP or its mixture; Described solvent is be selected from one in DMF, N,N-dimethylacetamide, DMSO, acetonitrile, acetone, toluene, dioxane and pyridine or its mixture; Described ring-closure reaction is carried out under diphenyl carbonate exists, and Compound II per-1-3 is 1:1 ~ 10 with the molar ratio of diphenyl carbonate, is preferably 1:1 ~ 3;
Described fluoro reagent is for being selected from F 2, HF, HF/Py, NaF, KF, tetrabutyl ammonium fluoride, triethylamine trihydrofluoride, one in diethylin sulfur trifluoride and two-(2-methoxy ethyl) amine sulfur trifluoride or its mixture; Described itrile group reagent is be selected from one in sodium cyanide, potassium cyanide, trimethylsilyl cyanide, prussic acid, dicyanogen and tetrabutyl ammonium cyanide or its mixture.
17. preparation methods according to claim 16, wherein, described fluoro or nitrile glycosylation reaction carry out in the presence of acids or bases, and described alkali is selected from mineral alkali or organic bases, are preferably selected from the one in salt of wormwood, triethylamine and pyridine or its mixture; Described acid is hydrogen fluoride; The solvent of described fluoro or nitrile glycosylation reaction is be selected from one in methyl alcohol, ethanol, Virahol, water, toluene, benzene, acetone, methyl tertiary butyl ether, isopropyl ether, tetrahydrofuran (THF), dioxane, acetonitrile, methylene dichloride, ethylene dichloride, ethyl acetate, DMF and N-Methyl pyrrolidone or its mixture.
CN201410097942.6A 2014-03-17 2014-03-17 2'-substituted-2,2'-dehydrated uridine or 2'-substituted-2,2'-dehydrated cytidine compound and preparation method and use thereof Pending CN104926902A (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN201410097942.6A CN104926902A (en) 2014-03-17 2014-03-17 2'-substituted-2,2'-dehydrated uridine or 2'-substituted-2,2'-dehydrated cytidine compound and preparation method and use thereof
CN201580008269.7A CN106068271B (en) 2014-03-17 2015-03-17 2 '-substituted-2, 2' -dehydrated uridine or 2 '-substituted-2, 2' -dehydrated cytidine compound and preparation method and application thereof
PCT/CN2015/074363 WO2015139602A1 (en) 2014-03-17 2015-03-17 2'-substituted-2,2'-dehydrated uridine or 2'-substituted-2,2'-dehydrated cytidine compound and preparation method and use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410097942.6A CN104926902A (en) 2014-03-17 2014-03-17 2'-substituted-2,2'-dehydrated uridine or 2'-substituted-2,2'-dehydrated cytidine compound and preparation method and use thereof

Publications (1)

Publication Number Publication Date
CN104926902A true CN104926902A (en) 2015-09-23

Family

ID=54114346

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201410097942.6A Pending CN104926902A (en) 2014-03-17 2014-03-17 2'-substituted-2,2'-dehydrated uridine or 2'-substituted-2,2'-dehydrated cytidine compound and preparation method and use thereof
CN201580008269.7A Active CN106068271B (en) 2014-03-17 2015-03-17 2 '-substituted-2, 2' -dehydrated uridine or 2 '-substituted-2, 2' -dehydrated cytidine compound and preparation method and application thereof

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN201580008269.7A Active CN106068271B (en) 2014-03-17 2015-03-17 2 '-substituted-2, 2' -dehydrated uridine or 2 '-substituted-2, 2' -dehydrated cytidine compound and preparation method and application thereof

Country Status (2)

Country Link
CN (2) CN104926902A (en)
WO (1) WO2015139602A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105859811A (en) * 2016-05-05 2016-08-17 精华制药集团南通有限公司 Preparation method of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine
CN111892636A (en) * 2020-08-07 2020-11-06 山东大学 Synthesis method of azvudine
CN112500446A (en) * 2020-12-11 2021-03-16 平江县吉成科技有限责任公司 Synthetic method of 2 '-fluoro-2' -deoxyuridine
CN117551155A (en) * 2024-01-08 2024-02-13 苏州诺维康生物科技有限公司 Synthesis method of 5'-O-DMT-2' -O-propynyl-uridine

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10214554B2 (en) 2016-02-08 2019-02-26 Merck Sharp & Dohme Corp. Process for making chloro-substituted nucleoside phosphoramidate compounds
TWI717468B (en) 2016-02-29 2021-02-01 南韓商Ｃｌａｐ股份有限公司 Semiconducting polymer

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5672698A (en) * 1993-11-15 1997-09-30 Bristol-Myers Squibb Co. Preparation of 2',3'-didehydro-3'-deoxythymidine from 5-methyluridine
EP3521297B1 (en) * 2003-05-30 2021-12-22 Gilead Pharmasset LLC Modified fluorinated nucleoside analogues
NZ702744A (en) * 2012-05-22 2016-12-23 Idenix Pharmaceuticals Llc D-amino acid compounds for liver disease
WO2014160484A1 (en) * 2013-03-13 2014-10-02 Idenix Pharmaceuticals, Inc. Amino acid phosphoramidate pronucleotides of 2'-cyano, azido and amino nucleosides for the treatment of hcv

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105859811A (en) * 2016-05-05 2016-08-17 精华制药集团南通有限公司 Preparation method of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine
CN111892636A (en) * 2020-08-07 2020-11-06 山东大学 Synthesis method of azvudine
CN112500446A (en) * 2020-12-11 2021-03-16 平江县吉成科技有限责任公司 Synthetic method of 2 '-fluoro-2' -deoxyuridine
CN117551155A (en) * 2024-01-08 2024-02-13 苏州诺维康生物科技有限公司 Synthesis method of 5'-O-DMT-2' -O-propynyl-uridine
CN117551155B (en) * 2024-01-08 2024-03-29 苏州诺维康生物科技有限公司 Synthesis method of 5'-O-DMT-2' -O-propynyl-uridine

Also Published As

Publication number Publication date
CN106068271B (en) 2020-03-10
CN106068271A (en) 2016-11-02
WO2015139602A1 (en) 2015-09-24

Similar Documents

Publication Publication Date Title
CN104926902A (en) 2'-substituted-2,2'-dehydrated uridine or 2'-substituted-2,2'-dehydrated cytidine compound and preparation method and use thereof
JP6646663B2 (en) Method for producing gemcitabine- [phenyl (benzoxy-L-alaninyl)] phosphate Method for producing phosphoric acid derivative
JP2020523381A (en) Synthesis of 3'-deoxyadenosine-5'-O-[phenyl(benzyloxy-L-alaninyl)]phosphate (NUC-7738)
EP3712130A1 (en) Method for synthesis of roxadustat and intermediate compounds thereof
CN112321589B (en) Synthesis method of antiviral drug Reidesciclovir and intermediate thereof
CN1086519A (en) Stereoselective anion glycosylation process
CN107216313A (en) A kind of antineoplastic AZD9291 preparation method
KR101154361B1 (en) A Novel and Highly Stereoselective Process for Preparing Gemcitabine and Intermediates Thereof
CN107033205B (en) Preparation method of 3' -deoxyuridine
JP7478660B2 (en) Modified Nucleoside Phosphoramidites
US20120083594A1 (en) Process for the Preparation of disaccharides Applied to Heparin Pentasaccharides
JP2009526782A (en) Method for producing gemcitabine and related intermediates
CN109836465B (en) Method for preparing epirubicin hydrochloride
KR100839322B1 (en) Improved process for the preparation of clevudine as anti-hbv agent
EP2053054B1 (en) Method for introducing nucleic-acid-protecting group
CN110615823A (en) Preparation method of (2'R) -2' -deoxy-2 '-fluoro-2' -methyluridine
KR101241321B1 (en) Improved preparation method of Decitabine
Yin et al. Formal total synthesis of α-elvucitabine
CN116082361B (en) Method for preparing Marbalo Sha Wei intermediate and Marbalo Sha Wei
WO2004065403A1 (en) Processes for production of nucleosides
JP4424900B2 (en) Method for purifying 5'-O-substituted thymidine
CN113880901A (en) Synthetic method of (1 beta, 2 alpha, 4 beta) halogenated nucleoside compound
CN103819402B (en) Dust is for drawing Wei intermediate and its preparation method and application
KR20220024461A (en) Crystal of cross-linked nucleoside intermediate, method for preparing same, and method for preparing cross-linked nucleoside amidite
JP2006022009A (en) METHOD FOR PRODUCING 3-FLUORO-2,3-DIDEOXY-beta-D-RIBOFURANOSYL-TYPE NUCLEOSIDE DERIVATIVE

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20150923

WD01 Invention patent application deemed withdrawn after publication