CN108892693A - A kind of pharmaceutical composition of nucleoside compound and preparation method thereof and treatment flaviviridae infections - Google Patents
A kind of pharmaceutical composition of nucleoside compound and preparation method thereof and treatment flaviviridae infections Download PDFInfo
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Abstract
The present invention provides a kind of nucleoside compounds with structure shown in Formulas I, have preferable anti-flavivirus activity.Using vero cell as zika virus carrier in embodiment, the nucleoside compound is measured to the inhibitory activity and cytotoxicity of zika virus, the experimental results showed that, nucleoside compound provided by the invention has preferable anti-zika virus activity, and further exploitation is worth to be prepared into the drug for the treatment of flaviviridae infections.
Description
Technical field
The present invention relates to the raw technical fields of medical chemistry, and in particular to a kind of nucleoside compound and preparation method thereof and one
The pharmaceutical composition of kind treatment flaviviridae infections.
Background technique
Flavivirus is the arboviruse that one kind relies primarily on the propagation of the media such as mosquito, tick, wherein common are zika virus, stepping on
Remove from office fever virus 1-4 (DENV 1-4), yellow fever virus (YFV), Xi Luoni viral (WNV) and tick-brone encephalitis virus (TBEV), day
More than 70 kinds of this encephalitis viruses (JEV) etc..These viruses seriously threaten human health, can cause a variety of diseases include fever, hepatitis,
Hemorrhagic fever, it is even fatal when serious.Wherein zika virus is initially found and names in nineteen forty-seven, zika virus since 2013
Cause repeatedly in Central-south America extensive popular;Extensive stockaded village's card epidemic situation is broken out in Brazil within 2015;On 2 1st, 2016, generation
Boundary's health organization announces the outburst of zika virus and propagates to have constituted global public health emergency.Therefore exploring exploitation has
The drug of the treatment flaviviridae infections of effect is significant, extremely urgent.
Nucleoside compound has multiple biological activities, such as antitumor, treating tuberculosis, antiviral, wherein ucleosides chemical combination
The anti-flavivirus activity of object obtains extensive concern in recent years, and existing drug enters clinical research (BCX4430) at present.Further grind
The problem of studying carefully the active compound of outstanding anti-flavivirus, being still current urgent need to resolve.
Summary of the invention
The purpose of the present invention is to provide a kind of nucleoside compounds and preparation method thereof to treat flaviviridae infections with a kind of
Pharmaceutical composition, the nucleoside compound provided by the invention with structure shown in Formulas I has outstanding anti-flavivirus activity.
In order to achieve the above-mentioned object of the invention, the present invention provides following technical scheme:
The present invention provides a kind of nucleoside compounds, have structure shown in Formulas I:
In Formulas I, Ar is R phenyl substituted or unsubstituted, R pyridyl group substituted or unsubstituted, R naphthalene substituted or unsubstituted, R take
Generation or unsubstituted quinolyl, R pyrazinyl substituted or unsubstituted, R pyrimidine radicals substituted or unsubstituted, R pyrazolyl substituted or unsubstituted,
R imidazole radicals substituted or unsubstituted, R furyl substituted or unsubstituted or R thienyl substituted or unsubstituted;
R1And R2It independently is hydrogen, the alkyl of C1~C6, the naphthenic base of C4~C6, hydroxybenzyl, R ' benzyl substituted or unsubstituted
Base, R ' phenylcarbonyl group substituted or unsubstituted, R ' pyridinylmethylene substituted or unsubstituted, R ' naphthalene methylene substituted or unsubstituted
Base, R ' quinolinylmethylidene substituted or unsubstituted, R ' pyrazine methylene substituted or unsubstituted, R ' pyrimidine radicals substituted or unsubstituted
Methylene, R ' pyrazolylmethylene substituted or unsubstituted, R ' imidazoles methylene substituted or unsubstituted, R ' furan substituted or unsubstituted
Mutter methylene or R ' thienyl methene substituted or unsubstituted, and R1And R2It is not simultaneously R ' phenylcarbonyl group substituted or unsubstituted,
And R1And R2It is not simultaneously hydrogen;
The R and R ' independently is the alkyl of C1~C4, the alkoxy of C1~C3, halogen group ,-CF3、-OCF3、-NO2
Or-CN.
Preferably, the alkyl of the C1~C6 includes methyl, ethyl, isopropyl, normal-butyl or tert-butyl.
Preferably, the naphthenic base of the C4~C6 includes cyclohexyl, cyclopenta or cyclobutyl.
Preferably, the halogen group is-F ,-Cl or-Br.
Preferably, the nucleoside compound includes
The present invention provides the preparation methods of nucleoside compound described in above-mentioned technical proposal, include the following steps:
(1) by compound 2, ethyl alcohol, triethylamine and Ar-CH2NH2Mixing carries out nucleophilic substitution, obtains compound 3;
The compound 2 has structure shown in Formula II:
(2) by the compound 3, tetrahydrofuran, triphenyl phosphorus, diisopropyl azodiformate and phthalimide
Mixing carries out light and prolongs reaction, obtains compound 4;
(3) compound 4, ethyl alcohol and hydrazine hydrate are mixed, carries out hydrazinolysis reaction, obtains compound 5;
(41) as R in Formulas I1For hydrogen, R2For the alkyl of C1~C6, the naphthenic base of C4~C6, R ' benzyl substituted or unsubstituted,
R ' pyridinylmethylene substituted or unsubstituted, R ' naphthalenyhnethylene substituted or unsubstituted, R ' quinolyl methylene substituted or unsubstituted
Base, R ' pyrazine methylene substituted or unsubstituted, R ' pyrimidinylmethylene substituted or unsubstituted, R ' pyrazolyl substituted or unsubstituted
Methylene, R ' imidazoles methylene substituted or unsubstituted, R ' furanylmethylenyl substituted or unsubstituted or R ' are substituted or unsubstituted
When thienyl methene, by the compound 5, ethyl alcohol, sodium cyanoborohydride and R3-CO-R4Mixing adjusts the pH of gained system
Value carries out reductive amination process after being 6.5~7.5, obtains compound 6-1;
The R3And R4It independently is hydrogen, the alkyl of C1~C5, R ' phenyl substituted or unsubstituted, R ' pyrrole substituted or unsubstituted
Piperidinyl, R ' naphthalene substituted or unsubstituted, R ' quinolyl substituted or unsubstituted, R ' pyrazinyl substituted or unsubstituted, R ' substitution or not
Substituted pyrimidyl, R ' pyrazolyl substituted or unsubstituted, R ' imidazole radicals substituted or unsubstituted, R ' furyl substituted or unsubstituted or R '
Thienyl substituted or unsubstituted, and R3And R4It is not simultaneously hydrogen;Or R3And R4Form the naphthenic base of C4~C6;
(42) as R in Formulas I1And R2It independently is the alkyl of C1~C6, the naphthenic base of C4~C6, R ' benzyl substituted or unsubstituted
Base, R ' pyridinylmethylene substituted or unsubstituted, R ' naphthalenyhnethylene substituted or unsubstituted, R ' quinolyl substituted or unsubstituted are sub-
Methyl, R ' pyrazine methylene substituted or unsubstituted, R ' pyrimidinylmethylene substituted or unsubstituted, R ' pyrazoles substituted or unsubstituted
Methylene, R ' imidazoles methylene substituted or unsubstituted, R ' furanylmethylenyl substituted or unsubstituted or R ' substitution do not take
When for thienyl methene, by compound 6-1 and methanol, sodium cyanoborohydride and R3-CO-R4Mixing adjusts the pH of gained system
Value carries out reductive amination process after being 6.5~7.5, obtains compound 6-2;
(43) as R in Formulas I1For hydroxybenzyl or hydrogen, R2When for hydroxybenzyl, by the compound 5, ethyl alcohol, cyano boron hydrogen
Change sodium and the mixing of 4- acetoxyl group benzaldehyde, the pH value for adjusting gained system carries out reductive amination process after being 6.5~7.5, obtains
To compound 6-3;
(44) as R in Formulas I1For hydrogen, R2When phenylcarbonyl group substituted or unsubstituted for R ', by the compound 5, methylene chloride,
1- (3- dimethylamino-propyl) -3- ethyl carbodiimide, I-hydroxybenzotriazole, triethylamine and R ' substituted benzoic acid or benzoic acid
Mixing carries out condensation reaction, obtains compound 6-4;
(5) compound 6 is mixed with methylene chloride, trifluoroacetic acid and water, carries out deprotection reaction, obtains with Formulas I
The nucleoside compound of shown structure;The compound 6 includes the compound 6-1, compound 6-2, compound 6-3 or chemical combination
Object 6-4.
Preferably, reagent used by pH value is adjusted in the step (41), step (42) and step (43) is acetic acid.
The present invention provides a kind of pharmaceutical compositions for treating flaviviridae infections, including ucleosides described in above-mentioned technical proposal
Compound and pharmaceutically acceptable carrier.
Preferably, mass content of the nucleoside compound in described pharmaceutical composition is 0.1~99.9%.
Preferably, the flavivirus includes zika virus, dengue fever virus or Xi Luoni virus.
The present invention provides a kind of nucleoside compounds with structure shown in Formulas I, have preferable anti-flavivirus activity.
Using vero cell as zika virus carrier in embodiment, the nucleoside compound is measured to the inhibitory activity of zika virus and thin
Cellular toxicity, the experimental results showed that, nucleoside compound provided by the invention has preferable anti-zika virus activity, is worth into one
Step exploitation is prepared into the drug for the treatment of flaviviridae infections.
Specific embodiment
The present invention provides a kind of nucleoside compounds, have structure shown in Formulas I:
In Formulas I, Ar is R phenyl substituted or unsubstituted, R pyridyl group substituted or unsubstituted, R naphthalene substituted or unsubstituted, R take
Generation or unsubstituted quinolyl, R pyrazinyl substituted or unsubstituted, R pyrimidine radicals substituted or unsubstituted, R pyrazolyl substituted or unsubstituted,
R imidazole radicals substituted or unsubstituted, R furyl substituted or unsubstituted or R thienyl substituted or unsubstituted;
R1And R2It independently is hydrogen, the alkyl of C1~C6, the naphthenic base of C4~C6, hydroxybenzyl, R ' benzyl substituted or unsubstituted
Base, R ' phenylcarbonyl group substituted or unsubstituted, R ' pyridinylmethylene substituted or unsubstituted, R ' naphthalene methylene substituted or unsubstituted
Base, R ' quinolinylmethylidene substituted or unsubstituted, R ' pyrazine methylene substituted or unsubstituted, R ' pyrimidine radicals substituted or unsubstituted
Methylene, R ' pyrazolylmethylene substituted or unsubstituted, R ' imidazoles methylene substituted or unsubstituted, R ' furan substituted or unsubstituted
Mutter methylene or R ' thienyl methene substituted or unsubstituted, and R1And R2It is not simultaneously R ' phenylcarbonyl group substituted or unsubstituted,
And R1And R2It is not simultaneously hydrogen;
The R and R ' independently is the alkyl of C1~C4, the alkoxy of C1~C3, halogen group ,-CF3、-OCF3、-NO2
Or-CN.
The present invention does not have a special restriction for the position replaced R in the Ar, phenyl, pyridyl group, naphthalene, quinolyl,
Arbitrarily the position containing hydrogen atom can be taken by R in pyrazinyl, pyrimidine radicals, pyrazolyl, imidazole radicals, furyl or thienyl
Generation.
In the present invention, the R is the alkyl of C1~C4, the alkoxy of C1~C3, halogen group ,-CF3、-OCF3、-NO2
Or-CN, preferably halogen group, more preferably-F ,-Cl or-Br, most preferably-Cl.
In the present invention, the Ar is preferably halogen substituted phenyl, more preferably chlorine substituted-phenyl, most preferably 3- chlorobenzene
Base.
In the present invention, the alkyl of the C1~C6 preferably includes methyl, ethyl, isopropyl, normal-butyl or tert-butyl.
In the present invention, the naphthenic base of the C4~C6 preferably includes cyclohexyl, cyclopenta or cyclobutyl.
The present invention is for the R1And R2Middle R ' substituted position does not have special restriction, phenyl, pyridyl group, naphthalene, quinoline
Arbitrarily the position containing hydrogen atom can be by R ' in base, pyrazinyl, pyrimidine radicals, pyrazolyl, imidazole radicals, furyl or thienyl
Replace.
In the present invention, the R1And R2Independently be hydrogen, the alkyl of C1~C6, the naphthenic base of C4~C6, hydroxybenzyl,
R ' benzyl substituted or unsubstituted, R ' phenylcarbonyl group substituted or unsubstituted, R ' pyridinylmethylene substituted or unsubstituted, R ' substitution or
Unsubstituting naphthyl methylene, R ' quinolinylmethylidene substituted or unsubstituted, R ' pyrazine methylene substituted or unsubstituted, R ' substitution
Or unsubstituted pyrimidinylmethylene, R ' pyrazolylmethylene substituted or unsubstituted, R ' imidazoles methylene substituted or unsubstituted, R '
Furanylmethylenyl or R ' thienyl methene substituted or unsubstituted substituted or unsubstituted, and R1And R2It is not simultaneously hydrogen;It is preferred that solely
It on the spot include hydrogen, methyl, ethyl, isopropyl, cyclohexyl, cyclopenta, cyclobutyl, benzyl, halogen substituted benzyl, trifluoromethyl benzyl
Base, nitrobenzyl, methoxy-benzyl, trifluoro-methoxybenzyl, hydroxybenzyl, naphthalenyhnethylene, pyridinylmethylene, thienyl
Methylene or halogen substituted phenyl carbonyl.
In the present invention, the nucleoside compound preferably includes
The present invention provides the preparation methods of nucleoside compound described in above-mentioned technical proposal, include the following steps:
(1) by compound 2, ethyl alcohol, triethylamine and Ar-CH2NH2Mixing carries out nucleophilic substitution, obtains compound 3;
The compound 2 has structure shown in Formula II:
(2) by the compound 3, tetrahydrofuran, triphenyl phosphorus, diisopropyl azodiformate and phthalimide
Mixing carries out light and prolongs reaction, obtains compound 4;
(3) compound 4, ethyl alcohol and hydrazine hydrate are mixed, carries out hydrazinolysis reaction, obtains compound 5;
(41) as R in Formulas I1For hydrogen, R2For the alkyl of C1~C6, the naphthenic base of C4~C6, R ' benzyl substituted or unsubstituted,
R ' pyridinylmethylene substituted or unsubstituted, R ' naphthalenyhnethylene substituted or unsubstituted, R ' quinolyl methylene substituted or unsubstituted
Base, R ' pyrazine methylene substituted or unsubstituted, R ' pyrimidinylmethylene substituted or unsubstituted, R ' pyrazolyl substituted or unsubstituted
Methylene, R ' imidazoles methylene substituted or unsubstituted, R ' furanylmethylenyl substituted or unsubstituted or R ' are substituted or unsubstituted
When thienyl methene, by the compound 5, ethyl alcohol, sodium cyanoborohydride and R3-CO-R4Mixing adjusts the pH of gained system
Value carries out reductive amination process after being 6.5~7.5, obtains compound 6-1;
The R3And R4It independently is hydrogen, the alkyl of C1~C5, R ' phenyl substituted or unsubstituted, R ' pyrrole substituted or unsubstituted
Piperidinyl, R ' naphthalene substituted or unsubstituted, R ' quinolyl substituted or unsubstituted, R ' pyrazinyl substituted or unsubstituted, R ' substitution or not
Substituted pyrimidyl, R ' pyrazolyl substituted or unsubstituted, R ' imidazole radicals substituted or unsubstituted, R ' furyl substituted or unsubstituted or R '
Thienyl substituted or unsubstituted, and R3And R4It is not simultaneously hydrogen;Or R3And R4Form the cycloalkane of C4~C6;
(42) as R in Formulas I1And R2It independently is the alkyl of C1~C6, the naphthenic base of C4~C6, R ' benzyl substituted or unsubstituted
Base, R ' pyridinylmethylene substituted or unsubstituted, R ' naphthalenyhnethylene substituted or unsubstituted, R ' quinolyl substituted or unsubstituted are sub-
Methyl, R ' pyrazine methylene substituted or unsubstituted, R ' pyrimidinylmethylene substituted or unsubstituted, R ' pyrazoles substituted or unsubstituted
Methylene, R ' imidazoles methylene substituted or unsubstituted, R ' furanylmethylenyl substituted or unsubstituted or R ' substitution do not take
When for thienyl methene, by compound 6-1 and methanol, sodium cyanoborohydride and R3-CO-R4Mixing adjusts the pH of gained system
Value carries out reductive amination process after being 6.5~7.5, obtains compound 6-2;
(43) as R in Formulas I1For hydroxybenzyl or hydrogen, R2When for hydroxybenzyl, by the compound 5, ethyl alcohol, cyano boron hydrogen
Change sodium and the mixing of 4- acetoxyl group benzaldehyde, the pH value for adjusting gained system carries out reductive amination process after being 6.5~7.5, obtains
To compound 6-3;
(44) as R in Formulas I1For hydrogen, R2When phenylcarbonyl group substituted or unsubstituted for R ', by the compound 5, methylene chloride,
1- (3- dimethylamino-propyl) -3- ethyl carbodiimide, I-hydroxybenzotriazole, triethylamine and R ' substituted benzoic acid or benzoic acid
Mixing carries out condensation reaction, obtains compound 6-4;
(5) compound 6 is mixed with methylene chloride, trifluoroacetic acid and water, carries out deprotection reaction, obtains with Formulas I
The nucleoside compound of shown structure;The compound 6 includes the compound 6-1, compound 6-2, compound 6-3 or chemical combination
Object 6-4.
The present invention is by compound 2, ethyl alcohol, triethylamine and Ar-CH2NH2Mixing carries out nucleophilic substitution, obtains compound
3;The compound 2 has structure shown in Formula II:
In the present invention, the compound 2, triethylamine and Ar-CH2NH2The amount of substance and the volume ratio of ethyl alcohol be preferably
1mmol:(1.8~2.2) mmol:(1.8~2.2) mmol:(4~6) mL, more preferably 1mmol:2mmol:2mmol:(5~
5.5)mL。
In the present invention, the compound 2 and Ar-CH2NH2For reactant, the ethyl alcohol is reaction dissolvent, three second
Amine is acid binding agent.
In the present invention, the temperature of the nucleophilic substitution is preferably 35~45 DEG C, and more preferably 40 DEG C;Time is preferred
For 4.5~5.5h, more preferably 4h.In the present invention, the nucleophilic substitution preferably carries out under agitation;The present invention
There is no special restriction for the rate of the stirring, using stirring rate well known to those skilled in the art.
After completing the nucleophilic substitution, preferably gained system is concentrated by the present invention, and residue is pure through silica gel post separation
Change, obtains compound 3.In the present invention, eluant, eluent used by the silica gel column separating purification is preferably methylene chloride
(DCM), methanol (MeOH) and ammonium hydroxide (NH3·H2O), the volume ratio of the methylene chloride, methanol and ammonium hydroxide is preferably 200:10:
0.1;The mass concentration of the ammonium hydroxide is preferably 25~28%.
After obtaining compound 3, the present invention is by the compound 3, tetrahydrofuran, triphenyl phosphorus, azoformic acid diisopropyl
Ester and phthalimide mixing, carry out light and prolong reaction, obtain compound 4.In the present invention, the compound 3, benzene neighbour two
The amount of the substance of carboximide, triphenyl phosphorus and diisopropyl azodiformate and the volume ratio of tetrahydrofuran are preferably
1.2mmol:(1.6~2.0) mmol:(2.2~2.6) mmol:(2.2~2.6) mmol:(8~12) mL, more preferably
1.2mmol:1.8mmol:2.4mmol:2.4mmol:10mL.
In the present invention, the compound 3 and phthalimide are reactant, and the tetrahydrofuran is to react molten
Agent, the triphenyl phosphorus and diisopropyl azodiformate are reagent needed for light prolongs reaction.
In the present invention, it is preferably 15~40 DEG C that the light, which prolongs the temperature of reaction, and more preferably 20~30 DEG C;In the present invention
Embodiment in, specifically carry out the light at room temperature and prolong reaction, that is, be not necessarily to additional heating or cooling.In the present invention,
The time that the light prolongs reaction is preferably 2.5~3.5h, more preferably 3h.In the present invention, the light prolongs reaction and is preferably stirring
It is carried out under the conditions of mixing;The present invention does not have the rate of the stirring special restriction, and use is well known to those skilled in the art
Stirring rate.
It completes after the light prolongs reaction, preferably gained system is concentrated by the present invention, and residue is obtained through silica gel column separating purification
To compound 4.In the present invention, eluant, eluent used by the silica gel column separating purification is preferably methylene chloride, methanol and ammonia
Water, the volume ratio of the methylene chloride, methanol and ammonium hydroxide are preferably 200:10:0.1;The mass concentration of the ammonium hydroxide is preferably 25
~28%.
After obtaining compound 4, the present invention mixes the compound 4, ethyl alcohol and hydrazine hydrate, carries out hydrazinolysis reaction, obtains
Compound 5.In the present invention, the mass content of hydrazine is preferably 65% in the hydrazine hydrate.
In the present invention, the compound 4 and hydrazine hydrate are reactant, and the ethyl alcohol is reaction dissolvent.
In the present invention, the temperature of the hydrazinolysis reaction is preferably the temperature of alcohol reflux;The time of the hydrazinolysis reaction
Preferably 1.5~2.5h, more preferably 2h.
After completing the hydrazinolysis reaction, the present invention filters after gained system is preferably cooled to room temperature, and gained filtrate is dense
Contracting, residue obtain compound 5 through silica gel column separating purification.In the present invention, it is washed used by the silica gel column separating purification
De- agent is preferably methylene chloride, methanol and ammonium hydroxide, and the volume ratio of the methylene chloride, methanol and ammonium hydroxide is preferably 100:10:
0.2;The mass concentration of the ammonium hydroxide is preferably 25~28%.
After obtaining compound 5, the present invention according to the specific structure of the nucleoside compound with structure shown in Formulas I,
Select different reaction raw materials and preparation method.
As R in Formulas I1For hydrogen, R2It is taken for the alkyl of C1~C6, the naphthenic base of C4~C6, R ' benzyl substituted or unsubstituted, R '
Generation or unsubstituting biocides methylene, R ' naphthalenyhnethylene substituted or unsubstituted, R ' quinolinylmethylidene substituted or unsubstituted, R '
Pyrazine methylene substituted or unsubstituted, R ' pyrimidinylmethylene substituted or unsubstituted, R ' pyrazolyl methylene substituted or unsubstituted
Base, R ' imidazoles methylene substituted or unsubstituted, R ' furanylmethylenyl substituted or unsubstituted or R ' thiophene substituted or unsubstituted
When methylene, the present invention is by the compound 5, ethyl alcohol, sodium cyanoborohydride and R3-CO-R4Mixing adjusts gained system
PH value carries out reductive amination process after being 6.5~7.5, obtains compound 6-1;
The R3And R4It independently is hydrogen, the alkyl of C1~C5, R ' phenyl substituted or unsubstituted, R ' pyrrole substituted or unsubstituted
Piperidinyl, R ' naphthalene substituted or unsubstituted, R ' quinolyl substituted or unsubstituted, R ' pyrazinyl substituted or unsubstituted, R ' substitution or not
Substituted pyrimidyl, R ' pyrazolyl substituted or unsubstituted, R ' imidazole radicals substituted or unsubstituted, R ' furyl substituted or unsubstituted or R '
Thienyl substituted or unsubstituted, and R3And R4It is not simultaneously hydrogen;Or R3And R4Form the cycloalkane of C4~C6.
In the present invention, the R3-CO-R4Preferably formaldehyde, acetone, acetaldehyde, cyclobutanone, cyclopentanone, cyclohexanone, benzene first
Aldehyde, 4- fluorobenzaldehyde, 4- chlorobenzaldehyde, 4- bromobenzaldehyde, 4- trifluoromethylated benzaldehyde, 4- nitrobenzaldehyde, 4- methoxybenzene
Formaldehyde, 4- trifluoro-methoxybenzaldehyde, 1- naphthaldehyde, 2- naphthaldehyde, 4- pyridine carboxaldehyde, thiophene -2-formaldehyde or 3- fluorobenzaldehyde.
For ease of operation, in an embodiment of the present invention, paraformaldehyde is specifically used.
In the present invention, the amount of the substance of the compound 5 and sodium cyanoborohydride and ethyl alcohol and R3-CO-R4Volume ratio
Preferably 2.4mmol:(9~10) mmol:(28~32) mL:(0.4~0.6) mL, more preferably 2.4mmol:9.6mmol:
30mL:0.5mL.In the present invention, the compound 5 and R3-CO-R4For reactant, the ethyl alcohol is reaction dissolvent, the cyanogen
Base sodium borohydride is go back original reagent.
In the present invention, adjusting reagent used by pH value is preferably acetic acid;Usage amount of the present invention for the acetic acid
There is no special restriction, the pH of reaction system can be adjusted to 6.5~7.5.In the present invention, the reaction system
PH value is preferably 7.
In the present invention, the temperature of the reductive amination process is preferably 15~40 DEG C, and more preferably 20~30 DEG C;At this
In the embodiment of invention, the reductive amination process is specifically carried out at room temperature, that is, is not necessarily to additional heating or cooling.At this
In invention, the time of the reductive amination process is preferably 3.5~4.5h, more preferably 4h;The present invention is preferably examined by thin layer
Reaction process is surveyed, to guarantee fully reacting.In the present invention, the reductive amination process preferably carries out under agitation;This
Invention does not have the rate of the stirring special restriction, using stirring rate well known to those skilled in the art.
After completing the reductive amination process, gained system is preferably used the NaOH solution of 1mol/L at 0 DEG C by the present invention
It is quenched, H is added2O dilution, DCM extraction, washs gained organic phase using saturated salt solution, and anhydrous magnesium sulfate is dry, mistake
Filter, gained filtrate is concentrated, residue obtains compound 6-1 through silica gel column separating purification.In the present invention, the silicon
Eluant, eluent used by rubber column gel column isolates and purifies is preferably methylene chloride, methanol and ammonium hydroxide, the methylene chloride, methanol and ammonium hydroxide
Volume ratio is preferably 100:10:1;The mass concentration of the ammonium hydroxide is preferably 25~28%.
As R in Formulas I1And R2It independently is the alkyl of C1~C6, the naphthenic base of C4~C6, R ' benzyl substituted or unsubstituted, R '
Pyridinylmethylene substituted or unsubstituted, R ' naphthalenyhnethylene substituted or unsubstituted, R ' quinolinylmethylidene substituted or unsubstituted,
R ' pyrazine methylene substituted or unsubstituted, R ' pyrimidinylmethylene substituted or unsubstituted, R ' pyrazolyl substituted or unsubstituted are sub-
Methyl, R ' imidazoles methylene substituted or unsubstituted, R ' furanylmethylenyl substituted or unsubstituted or R ' thiophene substituted or unsubstituted
When pheno methylene, the present invention is by compound 6-1 and methanol, sodium cyanoborohydride and R3-CO-R4Mixing adjusts gained system
PH value carries out reductive amination process after being 6.5~7.5, obtains compound 6-2.In the present invention, when preparing the compound 6-2
The proportion and response parameter of reaction raw materials are preferably consistent with when preparing the compound 6-1, are no longer repeated herein.
As R in Formulas I1For hydroxybenzyl or hydrogen, R2When for hydroxybenzyl, the present invention is by the compound 5, ethyl alcohol, cyano boron
Sodium hydride and the mixing of 4- acetoxyl group benzaldehyde, the pH value for adjusting gained system carry out reductive amination process after being 6.5~7.5,
Obtain compound 6-3.In the present invention, when preparing the compound 6-3 proportion and response parameter of reaction raw materials preferably with
It prepares consistent when the compound 6-1, is no longer repeated herein.
As R in Formulas I1For hydrogen, R2When phenylcarbonyl group substituted or unsubstituted for R ', the present invention is by the compound 5, dichloromethane
Alkane, 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide, I-hydroxybenzotriazole, triethylamine and R ' substituted benzoic acid or benzene
Formic acid mixing, carries out condensation reaction, obtains compound 6-4.In the present invention, the compound 5,1- (3- dimethylamino third
Base) -3- ethyl carbodiimide, I-hydroxybenzotriazole and R ' substituted benzoic acid or benzoic acid substance amount and methylene chloride and
The volume ratio of triethylamine is preferably 0.46mmol:(0.55~0.65) mmol:(0.55~0.65) mmol:(0.55~0.65)
mmol:(4.8~5.2) mL:(0.08~0.12) mL, more preferably 0.46mmol:0.6mmol:0.6mmol:0.6mmol:
5mL:0.1mL.
In the present invention, the R ' substituted benzoic acid is preferably parafluorobenzoic acid.
In the present invention, the compound 5 and R ' substituted benzoic acid or benzoic acid are reactant, and the methylene chloride is anti-
Solvent is answered, 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide, I-hydroxybenzotriazole and the triethylamine are condensation reaction
Required reagent.
In the present invention, the temperature of the condensation reaction is preferably 15~40 DEG C, and more preferably 20~30 DEG C;In the present invention
Embodiment in, specifically carry out the condensation reaction at room temperature, that is, be not necessarily to additional heating or cooling.In the present invention,
The time of the condensation reaction is preferably 4.5~5.5h, more preferably 5h.In the present invention, the condensation reaction is preferably being stirred
It is carried out under the conditions of mixing;The present invention does not have the rate of the stirring special restriction, and use is well known to those skilled in the art
Stirring rate.
After completing the condensation reaction, preferably gained system is concentrated by the present invention, and residue is obtained through silica gel column separating purification
To compound 6-4.In the present invention, eluant, eluent used by the silica gel column separating purification be preferably methylene chloride, methanol and
Ammonium hydroxide, the volume ratio of the methylene chloride, methanol and ammonium hydroxide are preferably 100:10:1;The mass concentration of the ammonium hydroxide is preferably 25
~28%.
The present invention mixes compound 6 with methylene chloride, trifluoroacetic acid and water, carries out deprotection reaction, is had
The nucleoside compound of structure shown in Formulas I;The compound 6 include the compound 6-1, compound 6-2, compound 6-3 or
Compound 6-4.In the present invention, the quality of the compound 6 and the volume ratio of methylene chloride, trifluoroacetic acid and water are preferably
50mg:(4.5~5.5) mL:(1.8~2.2) mL:(0.08~0.12) mL, more preferably 50mg:5mL:2mL:0.1mL.
In the present invention, the compound 6 is reactant, and the methylene chloride is reaction dissolvent, and the trifluoroacetic acid mentions
For acidic environment with deprotection base, the water is for hydrolyzing.
In the present invention, the temperature of the deprotection reaction is preferably 15~40 DEG C, and more preferably 20~30 DEG C;At this
In the embodiment of invention, the condensation reaction is specifically carried out at room temperature, that is, is not necessarily to additional heating or cooling.In the present invention
In, the time of the deprotection reaction is preferably 50~70min, more preferably 60min;The present invention is preferably detected by thin layer
Reaction process, to guarantee fully reacting.In the present invention, the deprotection reaction preferably carries out under agitation;This hair
The bright rate for the stirring does not have special restriction, using stirring rate well known to those skilled in the art.
After completing the deprotection reaction, preferably gained system is concentrated by the present invention, and residue is prepared thin layer analysis, is obtained
To the nucleoside compound with structure shown in Formulas I.In the present invention, the used eluant, eluent of thin layer analysis for preparing is preferably
Methylene chloride, methanol and ammonium hydroxide, the volume ratio of the methylene chloride, methanol and ammonium hydroxide are preferably 700:100:1;The ammonium hydroxide
Mass concentration is preferably 25~28%.
The present invention provides a kind of pharmaceutical compositions for treating flaviviridae infections, including ucleosides described in above-mentioned technical proposal
Compound and pharmaceutically acceptable carrier.In the present invention, quality of the nucleoside compound in described pharmaceutical composition
Content is preferably 0.1~99.9%, and more preferably 1~90%, further preferably 10~70%, most preferably 30~50%.
In the present invention, the flavivirus preferably includes zika virus, dengue fever virus or Xi Luoni virus, more preferably
Zika virus.
The present invention does not have special restriction for the type of the pharmaceutically acceptable carrier, using those skilled in the art
Well known carrier, as magnesium carbonate, magnesium stearate, talcum powder, sucrose, lactose, pectin, dextrin, starch, gelatin, methyl are fine
Dimension element, sodium carboxymethylcellulose or cocoa butter.
The present invention does not have special limit for the dosage form for the treatment flaviviridae infections drug that described pharmaceutical composition is prepared into
It is fixed, using dosage form well known to those skilled in the art, such as tablet, sugar coated tablet, film coated tablet, enteric coated tablet, delay
Release tablet formulations, capsule, hard capsule, soft capsule, Duracaps or powder.
The present invention does not have special restriction for the preparation method of the treatment flaviviridae infections drug, not according to dosage form
Together, using preparation method well known to those skilled in the art.
Below in conjunction with the embodiment in the present invention, the technical solution in the present invention is clearly and completely described.It is aobvious
So, described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Based on the reality in the present invention
Example is applied, every other embodiment obtained by those of ordinary skill in the art without making creative efforts all belongs to
In the scope of protection of the invention.
Embodiment 1
Prepare (2R, 3R, 4S, 5R) -2- (6- (3- chlorobenzylamine) -9H- purine -9- base) -5- (isopropyl ammonia) methyl) tetrahydro furan
Mutter -3,4- glycol (1a), and reaction route is as follows:
At room temperature, Et is added into ethyl alcohol (50mL) solution of compound 2 (3g, 9.2mmol)3N(2.6mL,
18.4mmol) with 3- chlorobenzylamine (2.1mL, 18.4mmol), gained mixed liquor is in 40 DEG C of stirring 5h;Concentration, residue is through silica gel
By volume, column separating purification (DCM:MeOH:NH3·H2O=200:10:0.1), obtain colorless oil compound 3 (3.13g,
82%), [α]20 D=-59.03 (c 0.93, MeOH);1H NMR(500MHz,CDCl3)δ8.40(s,1H),7.79(s,1H),
7.39 (s, 1H), 7.30-7.28 (m, 3H), 6.59 (brs, 1H), 5.89 (s, 1H), 5.24 (t, J=5.1Hz, 1H), 5.14
(d, J=5.5Hz, 1H), 4.89 (brs, 2H), 4.58 (s, 1H), 4.00 (d, J=12.6Hz, 1H), 3.84 (d, J=
12.6Hz,1H),1.68(s,3H),1.42(s,3H);LRMS(ESI):M/z=454 [M+Na]+。
At room temperature, into tetrahydrofuran (20mL) solution of compound 3 (1g, 2.4mmol) be added triphenyl phosphorus (1.26g,
4.8mmol), diisopropyl azodiformate (DIAD, 0.94mL, 4.8mmol) and phthalimide (0.53g,
3.6mmol), equality of temperature stirs 3h;Concentration, residue is through silica gel column separating purification (by volume, DCM:MeOH:NH3·H2O=
200:10:0.1) brown oil compound 4, is obtained, is directly used in and reacts in next step.
At room temperature, hydrazine hydrate (1mL) is added into dehydrated alcohol (50mL) solution of compound 4, back flow reaction 2h;By institute
The system of obtaining filters after being cooled to room temperature, gained filtrate is concentrated, residue is through silica gel column separating purification (by volume, DCM:
MeOH:NH3·H2O=100:10:0.2) oily compound 5 (680mg, 68%), [α], are obtained20 D=-23.43 (c 1.05,
MeOH);1HNMR(500MHz,CDCl3)δ8.44(s,1H),7.88(s,1H),7.40(s,1H),7.35-7.30(m,3H),
6.34 (brs, 1H), 6.06 (d, J=2.6Hz, 1H), 5.48-5.46 (m, 1H), 5.16-5.14 (m, 1H), 4.91 (brs,
2H),4.30(brs,1H),3.10-2.99(m,1H),1.64(s,3H),1.43(s,3H);LRMS(ESI):M/z=431 [M+
H]+.
At room temperature, acetone (0.5mL) and cyano boron are added into ethyl alcohol (30mL) solution of compound 5 (1g, 2.4mmol)
Sodium hydride (0.6g, 9.6mmol), use acetic acid adjust gained system pH value be 7, equality of temperature stir 4h, thin layer detect has reacted
Entirely;It is quenched using the NaOH solution (10mL) of 1mol/L at 0 DEG C, H is added2O (50mL) dilution, DCM (30mL × 3) extraction, is adopted
Gained organic phase is washed with saturated salt solution, anhydrous magnesium sulfate dries, filters, and gained filtrate is concentrated, remaining
By volume, object is through silica gel column separating purification (DCM:MeOH:NH3·H2O=100:10:1) oily compound 6a, is obtained
(850mg, 78%).
At room temperature, trifluoroacetic acid (2mL) and water are added into methylene chloride (5mL) solution of compound 6a (50mg)
(0.1mL), equality of temperature stir 1h, and thin layer detects fully reacting;Concentration, residue are prepared thin layer analysis (by volume, DCM:
MeOH:NH3·H2O=700:100:1) oily compound 1a (35mg, 78%), [α], are obtained20 D=-4.13 (c 0.99,
MeOH);1H NMR(500MHz,MeOD)δ8.30(s,1H),8.26(s,1H),7.42(s,1H),7.33-7.26(m,3H),
6.01 (d, J=3.8Hz, 1H), 4.85-4.83 (m, 2H), 4.35 (dd, J=4.2,4.7Hz, 1H), 4.18-4.16 (m, 1H),
3.20-3.04(m,3H),1.19-1.17(m,6H);13C NMR(500MHz,MeOD)δ154.6,152.5,141.5,140.4,
133.9,129.6,129.4,126.9,126.7,125.4,120.0,89.7,82.6,73.1,72.0,49.2,48.2,
20.15,20.10;LRMS(ESI):M/z=433 [M+H]+。
Embodiment 2
Prepare (2R, 3R, 4S, 5R) -2- (6- (3- chlorobenzylamine) -9H- purine -9- base) -5- ((isopropyl (methyl) amino)
Methyl) tetrahydrofuran -3,4- glycol (1b), reaction route is as follows:
Prepare compound 6a according to the method for embodiment 1.
At room temperature, into methanol (10mL) solution of compound 6a (200mg, 0.42mmol) be added paraformaldehyde (15mg,
0.5mmol) with sodium cyanoborohydride (131mg, 2.1mmol), using the pH value of acetic acid adjusting gained system to 7, equality of temperature is stirred
4h, thin layer detect fully reacting;It is quenched using the NaOH solution (2mL) of 1mol/L at 0 DEG C, H is added2O (10mL) dilution, DCM
(10mL × 3) extraction, washs gained organic phase using saturated salt solution, anhydrous magnesium sulfate dries, filters, and gained is filtered
Liquid is concentrated, and residue is through silica gel column separating purification (by volume, DCM:MeOH:NH3·H2O=100:10:1) oil, is obtained
Shape compound 6b.
At room temperature, trifluoroacetic acid (2mL) and water are added into methylene chloride (5mL) solution of compound 6b (50mg)
(0.1mL), equality of temperature stir 1h, and thin layer detects fully reacting;Concentration, residue are prepared thin layer analysis (by volume, DCM:
MeOH:NH3·H2O=700:100:1) oily compound 1b (40mg, 89%), [α], are obtained20 D=-2.90 (c 1.07,
MeOH);1H NMR(500MHz,CDCl3)δ8.27(s,1H),7.94(s,1H),7.40(s,1H),7.33-7.26(m,3H),
5.91 (d, J=3.8Hz, 1H), 4.89 (brs, 2H), 4.70-4.68 (m, 1H), 4.54-4.50 (m, 1H), 4.34-4.32 (m,
1H),3.04-3.01(m,2H),2.49-2.46(m,1H),1.92-1.62(m,6H),1.15-1.01(m,3H);LRMS
(ESI):M/z=447 [M+H]+。
Embodiment 3
Prepare (2R, 3R, 4S, 5R) -2- (6- (3- chlorobenzylamine) -9H- purine -9- base) -5- (ethylamino) methyl) tetrahydro furan
Mutter -3,4- glycol (1c), and reaction route is as follows:
Prepare compound 5 according to the method for embodiment 1.
At room temperature, acetaldehyde (0.1mL) and cyanogen are added into ethyl alcohol (10mL) solution of compound 5 (200mg, 0.46mmol)
Base sodium borohydride (144mg, 2.3mmol), using the pH value of acetic acid adjusting gained system to 7, equality of temperature stirs 4h, and thin layer detection is anti-
It should be complete;It is quenched using the NaOH solution (3mL) of 1mol/L at 0 DEG C, H is added2O (20mL) dilution, DCM (15mL × 3) extraction,
Gained organic phase is washed using saturated salt solution, anhydrous magnesium sulfate dries, filters, and gained filtrate is concentrated, residual
Excess is through silica gel column separating purification (by volume, DCM:MeOH:NH3·H2O=100:10:1) oily compound 6c, is obtained
(63mg, 30%) and compound 6d (130mg, 58%).
At room temperature, trifluoroacetic acid (2mL) and water are added into methylene chloride (5mL) solution of compound 6c (50mg)
(0.1mL), equality of temperature stir 1h, and thin layer detects fully reacting;Concentration, residue are prepared thin layer analysis (by volume, DCM:
MeOH:NH3·H2O=700:100:1) oily compound 1c (36mg, 80%), [α], are obtained20 D=-10.10 (c 1.03,
MeOH);1H NMR(500MHz,CDCl3)δ8.28(s,1H),7.96(s,1H),7.41(s,1H),6.25(s,1H),5.91(s,
1H),4.90(brs,2H),4.68(s,1H),4.50(s,1H),4.37(s,1H),3.00(brs,2H),2.75-2.71(m,
2H),1.14-1.12(m,3H);LRMS(ESI):M/z=419 [M+H]+。
Embodiment 4
Prepare (2R, 3R, 4S, 5R) -2- (6- (3- chlorobenzylamine) -9H- purine -9- base) -5- (lignocaine) methyl) tetrahydro
Furans -3,4- glycol (1d), reaction route is referring to embodiment 3:
At room temperature, trifluoroacetic acid (2mL) and water are added into methylene chloride (5mL) solution of compound 6d (50mg)
(0.1mL), equality of temperature stir 1 hour, and thin layer detects fully reacting;Concentration, residue are prepared thin layer analysis (by volume, DCM:
MeOH:NH3·H2O=700:100:1) it, obtains compound as white solid 1d (30mg, 65%), 111~113 DEG C of mp;[α]20 D
=2.57 (c 1.01, MeOH);1H NMR(500MHz,CDCl3)δ8.40(s,1H),7.96(s,1H),7.41(s,1H),6.25
(s,1H),5.97(s,1H),4.90(brs,2H),4.62-4.60(m,1H),4.58-4.56(m,1H),4.37-4.35(m,
1H), 2.96 (brs, 2H), 2.81-2.75 (m, 4H), 1.46 (t, J=6.9Hz, 6H);LRMS(ESI):M/z=447 [M+H
]+。
Embodiment 5
Prepare (2R, 3R, 4S, 5R) -2- (6- (3- chlorobenzylamine) -9H- purine -9- base) -5- (ring fourth amino) methyl) tetrahydro
Furans -3,4- glycol (1e), reaction route is as follows:
At room temperature, into ethyl alcohol (10mL) solution of compound 5 (200mg, 0.46mmol) be added cyclobutanone (0.1mL) and
Sodium cyanoborohydride (144mg, 2.3mmol), using the pH value of acetic acid adjusting gained system to 7, equality of temperature stirs 4h, thin layer detection
Fully reacting;It is quenched using the NaOH solution (3mL) of 1mol/L at 0 DEG C, H is added2O (20mL) dilution, DCM (15mL × 3) extraction
It taking, gained organic phase is washed using saturated salt solution, anhydrous magnesium sulfate dries, filters, gained filtrate is concentrated,
By volume, residue is through silica gel column separating purification (DCM:MeOH:NH3·H2O=100:10:1) oily compound 6e, is obtained
(63mg, 30%).
At room temperature, trifluoroacetic acid (2mL) and water are added into methylene chloride (5mL) solution of compound 6e (50mg)
(0.1mL), equality of temperature stir 1h, and thin layer detects fully reacting;Concentration, residue are prepared thin layer analysis (by volume, DCM:
MeOH:NH3·H2O=700:100:1) it, obtains compound as white solid 1e (33mg, 71%), 95~97 DEG C of mp;[α]20 D=-
12.23(c 1.48,MeOH);1H NMR(500MHz,CDCl3)δ8.22(s,1H),7.94(s,1H),7.41(s,1H),6.42
(s, 1H), 5.88 (d, J=5.4Hz, 1H), 4.89 (brs, 2H), 4.74-4.73 (m, 1H), 4.48-4.46 (m, 1H), 4.37-
4.35(m,1H),3.29-3.25(m,1H),2.89(s,2H),2.21-2.17(m,2H),1.73-1.71(m,4H);13C NMR
(500MHz,CDCl3)δ152.48,139.19,134.59,129.97,127.17,127.68,125.72,90.33,84.40,
74.25,72.13,53.94,50.83,48.27,30.27,14.67;LRMS(ESI):M/z=445 [M+H]+。
Embodiment 6
Prepare (2R, 3R, 4S, 5R) -2- (6- (3- chlorobenzylamine) -9H- purine -9- base) -5- (penta amino of ring) methyl) tetrahydro
Furans -3,4- glycol (1f):
Preparation method with embodiment 5, the difference is that, using cyclopentanone substitute cyclobutanone, obtain white solid chemical combination
Object 1f, yield 67%, 88~90 DEG C of mp;[α]20 D=-6.27 (c 1.18, MeOH);1H NMR(500MHz,CDCl3)δ8.15
(s, 1H), 7.89 (s, 1H), 7.40 (s, 1H), 7.32-7.30 (m, 3H), 6.46 (s, 1H), 5.88 (d, J=5.4Hz, 1H),
4.88(brs,2H),4.79-4.77(m,1H),4.54(s,1H),4.36-4.34(m,1H),3.10-2.95(m,3H),1.84-
1.80(m,2H),1.64-1.60(m,2H),1.52-1.50(m,2H),1.30-1.28(m,2H);13C NMR(500MHz,
CDCl3)δ152.65,140.45,139.24,134.58,129.98,127.72,127.69,125.74,90.39,84.09,
74.34,71.87,60.09,49.76,32.33,24.05,24.03;LRMS(ESI):M/z=459 [M+H]+。
Embodiment 7
Prepare (2R, 3R, 4S, 5R) -2- (6- (3- chlorobenzylamine) -9H- purine -9- base) -5- (Cyclohexylamino) methyl) tetrahydro
Furans -3,4- glycol (1g):
Preparation method with embodiment 5, the difference is that, using cyclohexanone substitute cyclobutanone, obtain white solid chemical combination
Object 1g, yield 67%, 102~104 DEG C of mp;[α]20 D=-7.76 (c 0.98, MeOH);1H NMR(500MHz,CDCl3)δ
8.37 (s, 1H), 7.99 (s, 1H), 7.40 (s, 1H), 7.32-7.30 (m, 3H), 6.46 (s, 1H), 5.98 (d, J=5.4Hz,
1H),4.88(brs,2H),4.63-4.61(m,1H),4.46(s,1H),4.36-4.34(m,1H),3.03-3.00(m,1H),
2.84(s,2H),1.29-1.26(m,4H),1.11-1.06(m,6H);13C NMR(500MHz,CDCl3)δ154.63,
152.72,140.45,139.14,134.57,129.97,127.70,127.68,125.71,120.54,90.32,84.27,
74.42,72.03,57.36,50.78,48.17,32.78,32.52,24.91,24.87;LRMS(ESI):M/z=473 [M+H
]+。
Embodiment 8
Prepare (2R, 3S, 4R, 5R) -2- ((benzylamine) methyl) -5- (6- (3- chlorobenzylamine) -9H- purine -9- base) tetrahydro furan
Mutter -3,4- glycol (1h):
Preparation method with embodiment 5, the difference is that, using benzaldehyde substitute cyclobutanone, obtain oily compound 1h,
Yield 67%, [α]20 D=-15.15 (c 0.99, MeOH);1H NMR(500MHz,CDCl3)δ8.15(s,1H),7.87(s,
1H), 7.40 (s, 1H), 7.34-7.27 (m, 8H), 6.42 (s, 1H), 5.86 (d, J=5.4Hz, 1H), 4.85 (brs, 2H),
4.72-4.69(m,1H),4.44-4.41(m,1H),4.37-4.34(m,1H),3.84(s,2H),3.01-2.89(m,2H);13C
NMR(500MHz,CDCl3)δ154.64,152.82,140.50,138.92,138.74,134.48,129.90,128.55,
128.20,127.66,127.59,127.37,125.70,90.17,84.20,74.43,71.92,53.88,50.46,27.21;
LRMS(ESI):M/z=479 [M+H]+。
Embodiment 9
It prepares (2R, 3S, 4R, 5R) -2- (6- (3- chlorobenzylamine) -9H- purine -9- base) -5- ((4- fluorine benzyl amino) methyl)
Tetrahydrofuran -3,4- glycol (1i):
Preparation method with embodiment 5, the difference is that, using 4- fluorobenzaldehyde substitute cyclobutanone, obtain white solid
89~91 DEG C of compound 1i, mp [α]20 D=-12.54 (c 1.22, MeOH),1HNMR(500MHz,MeOD)δ8.05(s,1H),
7.76 (s, 1H), 7.25 (s, 1H), 7.16-1.14 (m, 5H), 6.89 (t, J=8.5Hz, 2H), 6.20 (brs, 1H), 5.73
(d, J=5.8Hz, 1H), 4.73 (brs, 2H), 4.57 (t, J=5.4Hz, 1H), 4.31 (brs, 1H), 4.26 (brs, 1H),
3.68 (s, 2H), 2.85 (dd, J=12.5,3.8Hz, 1H), 2.75 (dd, J=12.5,4.5Hz);13C NMR(500MHz,
CDCl3) δ 162.10 (d, J=242.5Hz), 154.30,152.65,140.37,138.70,134.59,129.98,129.66
(d, J=7.9Hz), 127.75,125.73,125.73,115.38,115.24,90.35,85.43,75.03,72. 66,
53.12,50.53,29.70;LRMS(ESI):M/z=499 [M+H]+。
Embodiment 10
Prepare (2R, 3S, 4R, 5R) -2- (6- (3- chlorobenzylamine) -9H- purine -9- base) -5- ((4- benzyl chloride amino) methyl)
Tetrahydrofuran -3,4- glycol (1j):
Preparation method with embodiment 5, the difference is that, using 4- chlorobenzaldehyde substitute cyclobutanone, obtain oily chemical combination
Object 1j, yield 70%, [α]20 D=-13.62 (c 1.52, MeOH),1H NMR(500MHz,MeOD)δ8.21(s,1H),8.12
(s, 1H), 7.43 (s, 1H), 7.34-7.29 (m, 3H), 7.21 (d, J=7.5Hz, 2H), 7.14 (d, J=7.5Hz, 2H),
4.88(brs,1H),4.34(brs,1H),4.26(brs,1H),3.83(s,2H),3.02(s,2H),2.34(s,2H);13C
NMR(500MHz,CDCl3)δ153.47,151.47,139.41,137.11,135.54,133.52,132.21,131.77,
128.91,126.66,126.61,126.58,125.99,125.06,124.69,89.24,83.50,74.18,72.21,
58.51,54.37,28.75.LRMS(ESI):M/z=515 [M+H]+。
Embodiment 11
Prepare (2R, 3S, 4R, 5R) -2- (6- (3- chlorobenzylamine) -9H- purine -9- base) -5- ((4- bromobenzylamino) methyl)
Tetrahydrofuran -3,4- glycol (1k):
Preparation method with embodiment 5, the difference is that, using 4- bromobenzaldehyde substitute cyclobutanone, obtain white solid
Compound 1k, yield 60%, 84~86 DEG C of mp;[α]20 D=-25.84 (c 0.98, MeOH),1H NMR(500MHz,CDCl3)δ
8.21 (brs, 1H), 7.89 (brs, 1H), 7.45 (d, J=8.0Hz, 2H), 7.39 (s, 1H), 7.28 (brs, 3H), 7.20 (d,
J=7.93Hz, 1H), 6.42 (brs, 1H), 5.87 (d, J=5.8Hz, 1H), 4.87 (brs, 2H), 4.72 (t, J=5.5Hz,
1H), 4.43 (s, 1H), 4.38 (s, 1H), 3.80 (s, 2H), 2.97 (dd, J=12.5,4.0Hz, 1H), 2.87 (dd, J=
12.5,4.8Hz,1H);13C NMR(500MHz,CDCl3)δ154.62,152.71,140.39,138.84,138.42,
134.56,131.57,129.97,129.78,127.73,127.70,125.74,121.01,90.19,85.24,74.69,
72.53,53.15,50.53,29.71.LRMS(ESI):M/z=560 [M+H]+。
Embodiment 12
Prepare (2R, 3S, 4R, 5R) -2- (6- (3- chlorobenzylamine) -9H- purine -9- base) -5- ((4- benzylamino)
Methyl) tetrahydrofuran -3,4- glycol (1l):
Preparation method with embodiment 5, the difference is that, using 4- trifluoromethylated benzaldehyde substitute cyclobutanone, obtain white
Color solid chemical compound 1l, yield 55%, 80~82 DEG C of mp;[α]20 D=-17.73 (c 1.25, MeOH);1H NMR(500MHz,
CDCl3) δ 8.26 (s, 1H), 7.94 (s, 1H), 7.62 (d, J=7.8Hz, 2H), 7.47 (d, J=7.8Hz, 2H), 7.41 (s,
1H), 7.30-7.28 (m, 3H), 6.23 (brs, 1H), 5.90 (d, J=5.8Hz, 1H), 4.90 (brs, 1H), 4.59 (brs,
1H),4.47-4.44(m,2H),3.95(s,2H),3.03-2.93(m,2H);LRMS(ESI):M/z=549 [M+H]+。
Embodiment 13
Prepare (2R, 3S, 4R, 5R) -2- (6- (3- chlorobenzylamine) -9H- purine -9- base) -5- ((4- nitrobenzyl amino) first
Base) tetrahydrofuran -3,4- glycol (1m):
Preparation method with embodiment 5, the difference is that, substitute cyclobutanone using 4- nitrobenzaldehyde, it is solid to obtain white
Body compound 1m, yield 65%, 84~86 DEG C of mp;[α]20 D=-24.08 (c1.07, MeOH),1H NMR(500MHz,MeOD)
δ 8.20 (s, 1H), 8.19 (d, J=8.6Hz, 2H), 7.89 (s, 1H), 7.52 (d, J=8.6Hz, 2H), 7.40 (s, 1H),
7.31-7.29 (m, 3H), 6.42 (brs, 1H), 5.87 (d, J=5.8Hz, 1H), 4.87 (brs, 2H), 4.79-4.76 (m,
1H), 4.47 (brs, 1H), 4.42 (brs, 1H), 3.87 (d, J=7.2Hz, 2H), 3.03 (dd, J=12.6,3.5Hz, 1H),
2.90 (dd, J=12.6,4.7Hz, 1H);13C NMR(500MHz,CDCl3)δ154.65,152.67,147.47,147.14,
138.87,134.57,129.99,128.56,127.76,127.67,125.75,123.68,90.24,85.43,74.61,
72.56,53.08,50.76,29.33.LRMS(ESI):M/z=526 [M+H]+。
Embodiment 14
Prepare (2R, 3S, 4R, 5R) -2- (6- (3- chlorobenzylamine) -9H- purine -9- base) -5- ((4- methoxybenzylamino) first
Base) tetrahydrofuran -3,4- glycol (1n):
Preparation method with embodiment 5, the difference is that, using 4-methoxybenzaldehyde substitute cyclobutanone, obtain oily
Compound 1n, yield 65%, [α]20 D=-15.95 (c 1.11, MeOH),1HNMR(500MHz,CDCl3)δ8.13(s,1H),
7.90 (s, 1H), 7.40 (s, 1H), 7.29-7.25 (m, 5H), 6.87 (d, J=7.8Hz, 2H), 6.42 (brs, 1H), 5.90
(d, J=5.8Hz, 1H), 4.87 (brs, 1H), 4.67 (brs, 1H), 4.50 (brs, 1H), 4.38 (brs, 1H), 3.87-3.80
(m,5H),3.00(br,2H);13C NMR(500MHz,CDCl3)δ159.05,152.71,140.46,138.95,134.54,
129.95,129.61,127.71,127.69,125.74,114.01,90.30,84.44,74.79,72.17,55.29,
53.09,50.10,29.71;LRMS(ESI):M/z=511 [M+H]+。
Embodiment 15
Prepare (2R, 3S, 4R, 5R) -2- (6- (3- chlorobenzylamine) -9H- purine -9- base) -5- ((4- trifluoromethoxy benzyl ammonia
Base) methyl) tetrahydrofuran -3,4- glycol (1o):
Preparation method with embodiment 5, the difference is that, using 4- trifluoro-methoxybenzaldehyde substitute cyclobutanone, obtain
Oily compound 1o, yield 50%, [α]20 D=-14.41 (c 1.45, MeOH),1H NMR(500MHz,MeOD)δ8.24(s,
1H), 8.15 (s, 1H), 7.45 (d, J=8.2Hz, 2H), 7.42 (s, 1H), 7.33-7.23 (m, 5H), 5.99 (d, J=
5.3Hz,1H),4.84(brs,3H),4.38-4.36(m,1H),4.28-4.26(m,1H),3.90(s,2H),3.02(s,2H)
;13C NMR(500MHz,CDCl3)δ154.23,152.67,148.41,140.38,138.88,134.55,129.96,
129.50,127.72,127.69,125.74,121.30,119.60,90.23,84.99,74.70,72.40,52.94,
50.46,29.79;LRMS(ESI):M/z=565 [M+H]+。
Embodiment 16
Prepare (2R, 3S, 4R, 5R) -2- (6- (3- chlorobenzylamine) -9H- purine -9- base) -5- ((4- hydroxyl benzyl amino) first
Base) tetrahydrofuran -3,4- glycol (1p):
Preparation method with embodiment 5, the difference is that, using 4- acetoxyl group benzaldehyde alternate collar butanone, obtain white
Color solid chemical compound 1p, yield 50%, 84~85 DEG C of mp;[α]20 D=-5.71 (c 1.53, MeOH),1H NMR(500MHz,
MeOD) δ 8.21 (s, 1H), 8.13 (s, 1H), 7.41 (s, 1H), 7.34-7.28 (m, 5H), 6.84 (d, J=7.9Hz, 2H),
6.04 (d, J=4.7Hz, 1H), 4.84-4.82 (m, 3H), 4.47-4.43 (m, 1H), 4.40-4.38 (m, 1H), 4.25-4.16
(m,2H),3.64-3.60(m,1H),3.47-3.38(m,1H);13C NMR(500MHz,MeOD)δ158.67,152.54,
140.58,133.96,131.28,129.64,126.97,126.82,125.43,121.09,115.56,90.61,79.98,
73.08,71.90,50.83,48.45,29.42;LRMS(ESI):M/z=497 [M+H]+。
Embodiment 17
Prepare (2R, 3S, 4R, 5R) -2- (6- (3- chlorobenzylamine) -9H- purine -9- base) -5- (((naphthyridines -1- methyl) ammonia
Base) methyl) tetrahydrofuran -3,4- glycol (1q):
Preparation method with embodiment 5, the difference is that, using 1- naphthaldehyde substitute cyclobutanone, obtain white solid
Conjunction object 1q, yield 64%, 94~95 DEG C of mp;[α]20 D=-19.44 (c 1.25, MeOH),1H NMR(500MHz,CDCl3)δ
8.02-7.99 (m, 2H), 7.77 (m, 3H), 7.49 (d, J=6.8Hz, 1H), 4.46-7.37 (m, 4H), 7.28-7.25 (m,
3H), 6.45 (brs, 1H), 5.86 (d, J=5.8Hz, 1H), 4.81 (brs, 1H), 4.63 (s, 1H), 4.46 (brs, 1H),
4.37(s,1H),4.31(s,2H),3.10(s,2H);LRMS(ESI):M/z=531 [M+H]+。
Embodiment 18
Prepare (2R, 3S, 4R, 5R) -2- (6- (3- chlorobenzylamine) -9H- purine -9- base) -5- (((naphthyridines -2- methyl) ammonia
Base) methyl) tetrahydrofuran -3,4- glycol (1r):
Preparation method with embodiment 5, the difference is that, using 2- naphthaldehyde substitute cyclobutanone, obtain white solid
Conjunction object 1r, yield 45%, 77~78 DEG C of mp;[α]20 D=-28.68 (c 1.52, MeOH),1H NMR(500MHz,CDCl3)δ
8.20 (s, 1H), 7.88 (s, 1H), 7.82-7.78 (m, 3H), 7.71 (s, 1H), 7.47-7.45 (m, 2H), 7.42 (d, J=
8.3Hz, 1H), 7.37 (s, 1H), 7.24 (brs, 3H), 6.52 (s, 1H), 5.87 (d, J=5.5Hz, 1H), 4.82 (brs,
1H),4.71-4.69(m,1H),4.42(brs,1H),4.36(brs,1H),3.98(brs,2H),3.00-2.98(m,1H),
2.92-2.89(m,1H);13C NMR(500MHz,CDCl3)δ154.56,152.77,140.45,138.85,137.07,
134.51,133.33,132.67,129.93,128.21,127.66,126.55,126.30,126.12,125.69,120.16,
90.05,85.16,74.64,72.53,53.99,50.67,29.71.LRMS(ESI):M/z=531 [M+H]+。
Embodiment 19
Prepare (2R, 3R, 4S, 5R) -2- (6- (3- chlorobenzylamine) -9H- purine -9- base) -5- ((pyridin-4-yl methyl) ammonia
Base) methyl) tetrahydrofuran -3,4- glycol (1s):
Preparation method with embodiment 5, the difference is that, using 4- pyridine carboxaldehyde substitute cyclobutanone, obtain white solid
Compound 1s, yield 73%, 89~91 DEG C of mp;[α]20 D=-17.00 (c 1.31, MeOH),1HNMR(500MHz,CDCl3)δ
8.47 (d, J=4.8Hz, 2H), 8.15 (s, 1H), 7.90 (s, 1H), 7.39 (s, 1H), 7.30-7.28 (m, 5H), 6.35
(brs, 1H), 5.90 (d, J=6.1Hz, 1H), 4.90-4.87 (m, 3H), 4.51 (brs, 1H), 4.41 (brs, 1H), 3.93-
3.83 (m, 2H), 3.04 (dd, J=12.6,3.0Hz, 1H), 2.89 (dd, J=12.6,4.2Hz, 1H);13C NMR(500MHz,
CDCl3)δ154.60,152.67,149.45,139.28,134.57,129.98,127.73,127.69,125.72,123.04,
90.23,85.27,74.05,72.38,52.47,50.76,29.71;LRMS(ESI):M/z=482 [M+H]+。
Embodiment 20
Prepare (2R, 3R, 4S, 5R) -2- (6- (3- chlorobenzylamine) -9H- purine -9- base) -5- ((thiophene -2- ylmethyl) ammonia
Base) methyl) tetrahydrofuran -3,4- glycol (1t):
Preparation method with embodiment 5, the difference is that, using thiophene -2-formaldehyde substitute cyclobutanone, obtain white solid
Compound 1t, yield 65%, 81~82 DEG C of mp;[α]20 D=-12.47 (c 1.24, MeOH),1H NMR(500MHz,CDCl3)δ
8.14 (s, 1H), 7.88 (s, 1H), 7.39 (s, 1H), 7.27 (s, 2H), 7.21 (d, J=4.5Hz, 1H), 6.95-6.94 (m,
1H), 6.53 (brs, 1H), 5.89 (d, J=5.6Hz, 1H), 4.86 (brs, 1H), 4.75-4.73 (m, 1H), 4.45 (brs,
1H), 4.36 (brs, 1H), 4.04 (s, 2H), 3.03 (dd, J=12.6,3.4Hz, 1H), 2.94 (dd, J=12.6,4.3Hz,
1H);13C NMR(500MHz,CDCl3)δ154.57,152.75,142.80,140.46,138.96,134.52,129.95,
127.68,126.75,125.73,125.47,124.87,120.18,90.06,84.92,74.55,72.36,50.19,
48.36,29.71;LRMS(ESI):M/z=487 [M+H]+。
Embodiment 21
It prepares (2R, 3S, 4R, 5R) -2- (6- (3- chlorobenzylamine) -9H- purine -9- base) -5- ((3- fluorine benzyl amino) methyl)
Tetrahydrofuran -3,4- glycol (1u):
Preparation method with embodiment 5, the difference is that, using 3- fluorobenzaldehyde substitute cyclobutanone, obtain oily chemical combination
Object 1u, yield 52%, [α]20 D=-16.57 (c 2.5, DCM),1H NMR(500MHz,MeoD)δ8.22(s,1H),8.13(s,
1H), 7.42 (s, 1H) 7.30 (brs, 4H) 7.15 (m, 2H) 7.00 (t, J=5.0Hz, 1H) 5.98 (d, 1H) 4.84 (brs, 1H)
4.43(s,1H)4.27(s,1H)3.89(s,2H)3.35(s,2H)3.02(dd,2H).LRMS(ESI):M/z=499 [M+H]+。
Embodiment 22
Prepare N- (((2R, 3S, 4R, 5R) -5- (6- (3- chlorobenzylamine) -9H- purine -9- base) -3,4- dihydro tetrahydrofuran -
2- yl) methyl -4- fluorobenzamide (1v), reaction route is as follows:
At room temperature, 1- (3- diformazan ammonia is added into methylene chloride (5mL) solution of compound 5 (200mg, 0.46mmol)
Base propyl) -3- ethyl carbodiimide (EDC, 93mg, 0.6mmol), I-hydroxybenzotriazole (HOBt, 92mg, 0.6mmol), three
Ethamine (0.1mL) and parafluorobenzoic acid (84mg, 0.6mmol), equality of temperature stir 5h;Concentration, residue (are pressed through silica gel column chromatography
Volume ratio, DCM:MeOH:NH3·H2O=100:10:1) oily compound 6v (130mg, 50%), is obtained.
At room temperature, trifluoroacetic acid (2mL) and water are added into methylene chloride (5mL) solution of compound 6v (50mg)
(0.1mL), equality of temperature stir 1h, and thin layer detects fully reacting;Concentration, residue are prepared thin layer analysis (by volume, DCM:
MeOH:NH3·H2O=700:100:1) it, obtains compound as white solid 1v (23mg, 50%), 118~119 DEG C of mp;[α]20 D
=-51.43 (c0.56, DMF),1H NMR(500MHz,CDCl3)δ8.26(s,1H),8.00(s,1H),7.90-7.87(m,
2H), 7.42 (s, 1H), 7.34-7.20 (m, 3H), 7.22-7.18 (m, 2H), 5.98 (d, J=5.3Hz, 1H), 4.83 (brs,
3H), 4.42 (brs, 1H), 4.33-4.31 (m, 1H), 3.87 (dd, J=14.2,4.6Hz, 1H), 3.70 (dd, J=14.2,
3.7Hz,1H).LRMS(ESI):M/z=513 [M+H]+。
Embodiment 23
It prepares (2R, 3S, 4R, 5R) -2- (6- (3- chlorobenzylamine) -9H- purine -9- base) -5- ((4- fluorine benzyl amino) methyl)
Tetrahydrofuran -3,4- glycol (1w), reaction route is as follows:
Midbody compound 6i is prepared according to the method for embodiment 9.
Then preparation method is with embodiment 2, the difference is that, compound 6a is replaced using compound 6i, obtains white
Solid chemical compound 1w, yield 65%, 79~81 DEG C of mp;[α]20 D=-20.74 (c 1.26, MeOH),1H NMR(500MHz,
MeOD)δ8.24(s,1H),8.16(s,1H),7.41(s,1H),7.34-7.30(m,4H),7.27-7.25(m,1H),6.98
(t, J=8.8Hz, 2H), 4.69 (brs, 2H), 4.28-4.24 (m, 2H), 3.60W (s, 2H), 2.82-2.78 (m, 2H), 2.30
(s,3H);LRMS(ESI):M/z=513 [M+H]+。
Embodiment 24
External anti-zika virus activity test is carried out to target compound 1a~1w prepared by Examples 1 to 23, specifically
Using vero cell as zika virus carrier, measurement target compound to the inhibitory activity and cytotoxicity of zika virus, and with west
Nai Fen is net and NITD008 is compared, and the results are shown in Table 1.
Activity test in vitro data of the 1 target compound 1a~1w of table to zika virus
As shown in Table 1, compound provided by the invention has preferable anti-zika virus activity, is worth further exploitation system
The standby drug at treatment flaviviridae infections.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of nucleoside compound has structure shown in Formulas I:
In Formulas I, Ar be R phenyl substituted or unsubstituted, R pyridyl group substituted or unsubstituted, R naphthalene substituted or unsubstituted, R replace or
Unsubstituted quinolyl, R pyrazinyl substituted or unsubstituted, R pyrimidine radicals substituted or unsubstituted, R pyrazolyl substituted or unsubstituted, R take
Generation or unsubstituted imidazole radicals, R furyl substituted or unsubstituted or R thienyl substituted or unsubstituted;
R1And R2Independently be hydrogen, the alkyl of C1~C6, the naphthenic base of C4~C6, hydroxybenzyl, R ' benzyl substituted or unsubstituted,
R ' phenylcarbonyl group substituted or unsubstituted, R ' pyridinylmethylene substituted or unsubstituted, R ' naphthalenyhnethylene substituted or unsubstituted, R '
Quinolinylmethylidene substituted or unsubstituted, R ' pyrazine methylene substituted or unsubstituted, R ' pyrimidine radicals methylene substituted or unsubstituted
Base, R ' pyrazolylmethylene substituted or unsubstituted, R ' imidazoles methylene substituted or unsubstituted, R ' furyl substituted or unsubstituted
Methylene or R ' thienyl methene substituted or unsubstituted, and R1And R2It is not simultaneously R ' phenylcarbonyl group substituted or unsubstituted, and R1
And R2It is not simultaneously hydrogen;
The R and R ' independently is the alkyl of C1~C4, the alkoxy of C1~C3, halogen group ,-CF3、-OCF3、-NO2Or-
CN。
2. nucleoside compound according to claim 1, which is characterized in that the alkyl of the C1~C6 includes methyl, second
Base, isopropyl, normal-butyl or tert-butyl.
3. nucleoside compound according to claim 1, which is characterized in that the naphthenic base of the C4~C6 includes hexamethylene
Base, cyclopenta or cyclobutyl.
4. nucleoside compound according to claim 1, which is characterized in that the halogen group is-F ,-Cl or-Br.
5. nucleoside compound according to any one of claims 1 to 4, which is characterized in that the nucleoside compound packet
It includes
6. the preparation method of any one of Claims 1 to 5 nucleoside compound, includes the following steps:
(1) by compound 2, ethyl alcohol, triethylamine and Ar-CH2NH2Mixing carries out nucleophilic substitution, obtains compound 3;It is described
Compound 2 has structure shown in Formula II:
(2) compound 3, tetrahydrofuran, triphenyl phosphorus, diisopropyl azodiformate and phthalimide are mixed
It closes, carries out light and prolong reaction, obtain compound 4;
(3) compound 4, ethyl alcohol and hydrazine hydrate are mixed, carries out hydrazinolysis reaction, obtains compound 5;
(41) as R in Formulas I1For hydrogen, R2It is taken for the alkyl of C1~C6, the naphthenic base of C4~C6, R ' benzyl substituted or unsubstituted, R '
Generation or unsubstituting biocides methylene, R ' naphthalenyhnethylene substituted or unsubstituted, R ' quinolinylmethylidene substituted or unsubstituted, R '
Pyrazine methylene substituted or unsubstituted, R ' pyrimidinylmethylene substituted or unsubstituted, R ' pyrazolyl methylene substituted or unsubstituted
Base, R ' imidazoles methylene substituted or unsubstituted, R ' furanylmethylenyl substituted or unsubstituted or R ' thiophene substituted or unsubstituted
When methylene, by the compound 5, ethyl alcohol, sodium cyanoborohydride and R3-CO-R4Mixing, the pH value for adjusting gained system are
Reductive amination process is carried out after 6.5~7.5, obtains compound 6-1;
The R3And R4Independently be hydrogen, the alkyl of C1~C5, R ' phenyl substituted or unsubstituted, R ' pyridyl group substituted or unsubstituted,
R ' naphthalene substituted or unsubstituted, R ' quinolyl substituted or unsubstituted, R ' pyrazinyl substituted or unsubstituted, R ' are substituted or unsubstituted phonetic
Piperidinyl, R ' pyrazolyl substituted or unsubstituted, R ' imidazole radicals substituted or unsubstituted, R ' furyl substituted or unsubstituted or R ' substitution or
Unsubstituted thienyl, and R3And R4It is not simultaneously hydrogen;Or R3And R4Form the naphthenic base of C4~C6;
(42) as R in Formulas I1And R2It independently is the alkyl of C1~C6, the naphthenic base of C4~C6, R ' benzyl substituted or unsubstituted, R '
Pyridinylmethylene substituted or unsubstituted, R ' naphthalenyhnethylene substituted or unsubstituted, R ' quinolinylmethylidene substituted or unsubstituted,
R ' pyrazine methylene substituted or unsubstituted, R ' pyrimidinylmethylene substituted or unsubstituted, R ' pyrazolyl substituted or unsubstituted are sub-
Methyl, R ' imidazoles methylene substituted or unsubstituted, R ' furanylmethylenyl substituted or unsubstituted or R ' thiophene substituted or unsubstituted
When pheno methylene, by compound 6-1 and methanol, sodium cyanoborohydride and R3-CO-R4Mixing, the pH value for adjusting gained system are
Reductive amination process is carried out after 6.5~7.5, obtains compound 6-2;
(43) as R in Formulas I1For hydroxybenzyl or hydrogen, R2When for hydroxybenzyl, by the compound 5, ethyl alcohol, sodium cyanoborohydride
It is mixed with 4- acetoxyl group benzaldehyde, the pH value for adjusting gained system carries out reductive amination process after being 6.5~7.5, is changed
Close object 6-3;
(44) as R in Formulas I1For hydrogen, R2When phenylcarbonyl group substituted or unsubstituted for R ', by the compound 5, methylene chloride, 1-
(3- dimethylamino-propyl) -3- ethyl carbodiimide, I-hydroxybenzotriazole, triethylamine and R ' substituted benzoic acid or benzoic acid are mixed
It closes, carries out condensation reaction, obtain compound 6-4;
(5) compound 6 is mixed with methylene chloride, trifluoroacetic acid and water, carries out deprotection reaction, obtains with shown in Formulas I
The nucleoside compound of structure;The compound 6 includes the compound 6-1, compound 6-2, compound 6-3 or compound 6-
4。
7. preparation method according to claim 6, which is characterized in that the step (41), step (42) and step (43)
Reagent used by middle adjusting pH value is acetic acid.
8. a kind of any one of pharmaceutical composition, including Claims 1 to 5 for treating flaviviridae infections nucleoside compound and
Pharmaceutically acceptable carrier.
9. pharmaceutical composition according to claim 8, which is characterized in that the nucleoside compound is in the pharmaceutical composition
Mass content in object is 0.1~99.9%.
10. pharmaceutical composition according to claim 8 or claim 9, which is characterized in that the flavivirus includes zika virus, steps on
Remove from office fever virus or Xi Luoni virus.
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