CN116284183A - Antiviral compound and preparation method and application thereof - Google Patents
Antiviral compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN116284183A CN116284183A CN202210634317.5A CN202210634317A CN116284183A CN 116284183 A CN116284183 A CN 116284183A CN 202210634317 A CN202210634317 A CN 202210634317A CN 116284183 A CN116284183 A CN 116284183A
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- Prior art keywords
- deuterium
- hydrogen
- compound
- hydroxy
- reaction
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 82
- 230000000840 anti-viral effect Effects 0.000 title abstract description 14
- 238000002360 preparation method Methods 0.000 title abstract description 13
- 239000000203 mixture Substances 0.000 claims abstract description 22
- 241000711573 Coronaviridae Species 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 208000015181 infectious disease Diseases 0.000 claims abstract description 8
- 238000011282 treatment Methods 0.000 claims abstract description 7
- 241000282414 Homo sapiens Species 0.000 claims abstract description 5
- 241000700721 Hepatitis B virus Species 0.000 claims abstract description 3
- 241001465754 Metazoa Species 0.000 claims abstract description 3
- 241000711798 Rabies lyssavirus Species 0.000 claims abstract description 3
- 241000712461 unidentified influenza virus Species 0.000 claims abstract description 3
- 238000009472 formulation Methods 0.000 claims abstract 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 120
- 238000006243 chemical reaction Methods 0.000 claims description 92
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 65
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 51
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 50
- 229910052805 deuterium Inorganic materials 0.000 claims description 50
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- 239000000243 solution Substances 0.000 claims description 48
- 150000002431 hydrogen Chemical class 0.000 claims description 39
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- 125000003118 aryl group Chemical group 0.000 claims description 19
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- 238000006467 substitution reaction Methods 0.000 claims description 13
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 11
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- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 230000003301 hydrolyzing effect Effects 0.000 claims description 6
- DDFHBQSCUXNBSA-UHFFFAOYSA-N 5-(5-carboxythiophen-2-yl)thiophene-2-carboxylic acid Chemical compound S1C(C(=O)O)=CC=C1C1=CC=C(C(O)=O)S1 DDFHBQSCUXNBSA-UHFFFAOYSA-N 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
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- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 4
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- 239000010452 phosphate Substances 0.000 claims description 2
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 claims description 2
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- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 2
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Abstract
The invention discloses a compound for antiviral treatment, a preparation method and application thereof. In particular to a compound shown as a formula I or a pharmacy thereofPharmaceutically acceptable salts thereof, and pharmaceutically acceptable formulations prepared from the compounds or pharmaceutically acceptable salts thereof. The compound has better antiviral effect, and can effectively prevent and treat diseases of human beings or animals caused by infection of coronavirus, calicivirus, influenza virus, rabies virus, hepatitis B virus and the like.
Description
Technical Field
The invention relates to the field of medicines, in particular to a nucleoside analogue compound with a better antiviral effect, a preparation method and application thereof.
Background
Nucleoside analogues refer to modified and engineered nucleoside compounds, commonly used in cancer and antiviral infection treatment. Nucleoside analogs can mimic biological counterparts (endogenous nucleosides) in that they compete with the corresponding nucleosides for binding to viral reverse transcriptase or RNA polymerase during viral DNA or RNA synthesis, thereby inhibiting viral replication.
Coronaviruses are a large class of viruses that are widely available in nature, and have a envelope, RNA virus with a linear single positive strand genome. Human diseases caused by coronaviruses are mainly respiratory infections, including severe acute respiratory syndrome, SARS, 2019 novel coronavirus infections, and the like. Coronaviruses infect only vertebrates, such as humans, pigs, cats, dogs, birds, etc., where cats are also a group of more susceptible coronaviruses. Cats will carry coronavirus throughout their life, and typically, coronavirus will not have an effect on their health. When the constitution of a cat decreases, it may become ill. Feline infectious peritonitis viruses and enterocoronaviruses are largely divided into two classes. Feline enterocoronavirus mortality is generally low, often causing feline enteritis. The cat infectious peritonitis virus can cause cat infectious peritonitis, is a chronic, progressive and mortal infectious disease and has higher mortality rate. Coronaviruses have high infection rate, and when they are mutated, they leave the intestinal tract and invade other organs to cause inflammation, they can develop into feline viral peritonitis. Infectious peritonitis in cats is the most common disease in recent years responsible for the death of cats.
Although the existing nucleic acid analogues show better antiviral effects, few compounds with better coronavirus inhibitory effects and the problem of drug resistance is a big problem faced by nucleoside analogue antiviral drugs. Accordingly, there is a continuing need to develop new antiviral compounds.
Disclosure of Invention
In view of the above problems, an object of the present invention is to provide a compound having a good antiviral effect, and a method for preparing the same and use thereof.
The present invention provides a compound of formula I:
wherein,,
x is CR 1 R 2 Wherein R is 1 、R 2 Each independently selected from hydrogen, deuterium, C1-C3 alkyl;
y is CR 3 Or N, wherein R 3 Independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C1-C3 alkyl, said substituted substituents being deuterium, hydroxy, halogen;
z is CR 4 Or N, wherein R 4 Independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C1-C3 alkyl, wherein the substituted substituent is deuterium, hydroxy, halogen;
R 1 hydrogen, deuterium, monophosphate, diphosphate, triphosphate,
R 5 、R 6 、R 7 each independently selected from hydrogen, deuterium, C1-C10 straight or branched chain alkyl, cycloalkyl, aryl, heterocyclyl, alkenyl, alkynyl, nitro, alkanoyl, carbamoyl, wherein R 5 、R 6 、R 7 Optionally by one or more than one R, which may be the same or different 6 Substitution;
R 2 is hydrogen,Deuterium, hydroxy, halogen, amino, nitro, cyano, C1-C6 linear or branched alkyl, alkenyl, alkynylalkoxy,
Wherein R is 2 Optionally by one or more than one R, which may be the same or different 6 Substitution; r is R 3 Is hydrogen, deuterium, hydroxy, halogen, amino, nitro, cyano, C1-C6 straight-chain or branched alkyl, alkenyl, alkynyl, alkoxy,/->
Wherein R is 3 Optionally by one or more than one R, which may be the same or different 6 Substitution;
R 4 is hydrogen, deuterium, hydroxy, C1-C6 linear or branched alkyl, wherein R 4 Optionally by one or more than one R, which may be the same or different 6 Substitution;
R 5 is hydrogen, deuterium, straight or branched alkyl, cycloalkyl, carbonylalkyl, aryl, heterocyclyl, alkanoyl, carbamoyl, or the like, wherein R is 5 Optionally by one or more than one R, which may be the same or different 6 Substitution;
R 6 is deuterium, hydroxy, amino, mercapto, cyano, alkenyl, alkynyl, straight or branched chain alkyl, cycloalkyl, aryl, heterocyclyl, alkoxy, aryloxy, carbamoyl, azido, alkylamino, alkylsulfonyl, arylsulfonyl, or the like, wherein R is 6 Optionally by one or more than one R, which may be the same or different 7 Substitution;
R 7 is deuterium, hydroxy, amino, mercapto, cyano, alkenyl, alkynyl, straight or branched chain alkyl, cycloalkyl, aryl, heterocyclyl, alkoxy, aryloxy, carbamoyl, azido, alkylamino, alkylsulfonyl, arylsulfonyl.
Further, wherein X is CR 1 R 2 Wherein R is 1 、R 2 Each independently selected from hydrogen, deuterium; y is CR 3 Wherein R is 3 Independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, and extraction ofSubstituted or unsubstituted C1-C3 alkyl, wherein the substituted substituent is deuterium, hydroxy, halogen; z is CR 4 Wherein R is 4 Independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, C1-C3 alkyl; r is R 1 Hydrogen, deuterium, monophosphate, diphosphate, triphosphate,
C1-C6 linear or branched alkanes, cycloalkanes, nitro groups, aryl groups, heterocyclic groups, phosphate esters or phosphoramidates; r is R 2 Is hydrogen, deuterium, hydroxy, fluoro, bromo, chloro, amino, nitro, cyano, alkoxy,/->
R 3 Is hydrogen, deuterium, hydroxy, fluoro, bromo, chloro, amino, nitro, cyano, alkoxy,/->
R 4 Hydrogen, deuterium, hydroxy, methyl; r is R 5 Hydrogen, deuterium, methyl; wherein R is 5 Is hydrogen, deuterium, C1-C6 straight or branched alkyl, cycloalkyl, aryl, nitrogen-containing heterocyclyl, oxygen-containing heterocyclyl, R 6 Is hydrogen, deuterium, C1-C6 straight or branched alkyl, cycloalkyl, benzene ring, nitrogen-containing heterocyclyl, R 7 Is hydrogen, deuterium, C1-C6 straight or branched alkyl, cycloalkyl, benzene ring, nitrogen-containing heterocyclic group.
Further, the X is CH 2 The method comprises the steps of carrying out a first treatment on the surface of the Y is CH; z is CH; r1 is hydrogen,
R 2 Is hydroxy, fluoro, ">
R 3 Is hydroxyRadical, fluorine, < >>
R 4 Is hydrogen; r is R 5 Is hydrogen; wherein R is 5 Is C1-C3 straight-chain or branched alkyl, R 6 Is a benzene ring, R 7 Is a C1-C6 straight or branched alkyl group.
Further, the compound has a structure represented by formula II:
further, the compound has a structure represented by formula III:
further, the compound has a structure represented by the following structural formula:
the invention also provides a method for preparing the compound, which comprises the following steps:
wherein R1 is hydrogen,
R2 is OR 'wherein R' is Bn OR
Or R1 andr' connection formation->
(TIPDS)；
1) Step 1, reacting a compound A with 1,2, 4-triazole under the condition of a catalyst to obtain a compound B;
2) And 2, hydrolyzing the compound B under alkaline conditions to obtain the formula II.
Further, the catalyst in the step 1) is phosphorus oxychloride, the reaction solvent is acetonitrile, the reaction temperature is 0 ℃, and the reaction time is 30-60min; the alkali used in the step 2) is hydroxylamine water, the reaction solvent is isopropanol, the reaction temperature is room temperature, and the reaction time is 20min.
Further, when R "is Bn, the step 1 further includes a step of performing benzyl deprotection under DDQ conditions, and the specific reaction conditions are: reacting in dichloromethane solution at 58 ℃ for 43h; when R1 is linked with R' to form
When the method is used, the step 2 further comprises a step of deprotection of a silyl ether protecting group, and the specific reaction conditions are as follows: refluxing in methanol solvent in the presence of ammonium fluoride for 2h.
The invention also provides a method for preparing the compound, which comprises the following steps:
wherein R1 is hydrogen,
R2 is hydroxy;
1) Step 1, hydrolyzing a compound C under alkaline conditions to obtain a compound D;
2) And 2, reacting the compound D with 1,2, 4-triazole under the condition of a catalyst to obtain an intermediate product, and hydrolyzing the intermediate product under the alkaline condition to obtain the compound shown in the formula III.
In the step 2, the catalyst is phosphorus oxychloride, the reaction solvent is acetonitrile, the reaction temperature is 0 ℃, and the reaction time is 30-60min.
The invention also provides a pharmaceutical composition which is a preparation prepared from the active ingredient and pharmaceutically acceptable excipients or carriers; the active ingredient is a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt or solvate thereof.
Further, the above preparation is selected from the group consisting of tablets, dispersions, capsules, granules, powders, suppositories, ointments, pastes, gels, injections, drops, solutions, emulsions or suspensions.
The invention also provides application of the compound or pharmaceutically acceptable salt or solvate thereof in preparing medicaments for treating and/or preventing human or animal virus infection diseases.
Further, the above-mentioned drugs are drugs for treating and/or preventing diseases caused by infection of coronavirus, influenza virus, rabies virus, hepatitis B virus, calicivirus, and herpes virus.
Further, the medicament is a medicament for treating and/or preventing novel human coronavirus infection, feline infectious peritonitis virus infection, feline enterocoronavirus infection and feline stomatitis disease.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Definition and description
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
Pharmaceutically acceptable salts of the present invention refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art.
Alkyl refers to a saturated aliphatic hydrocarbon group, comprising straight and branched chain groups. C1-C6 alkyl means an alkyl group having 1 to 6 carbon atoms. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment.
Cycloalkyl refers to a saturated hydrocarbon group containing one or more rings in the structure. Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment.
Alkenyl is meant to include a compound having at least one unsaturated site, i.e., carbon-carbon sp 2 Hydrocarbon of double bond.
Alkynyl refers to a hydrocarbon containing at least one unsaturated site, i.e., a carbon-carbon sp triple bond.
By heterocyclyl is meant that the atoms constituting the ring contain at least one heteroatom in addition to carbon atoms. The hetero atom may be a nitrogen atom, a sulfur atom, an oxygen atom, or the like. The heterocyclic ring may have one heteroatom or two or more heteroatoms, and the heteroatom may be one atom or two different atoms. The heterocyclic group may be alicyclic or aromatic.
Aryl refers to any functional group or substituent derived from a simple aromatic ring. Aryl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment.
The lipid is C 11 -C 12 Higher alkyl, C 11 -C 12 Higher alkoxy, polyethylene glycol or aryl substituted by alkyl. DDQ refers to 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone, a highly active oxidant.
Bn refers to benzyl.
DMAP refers to 4-dimethylaminopyridine.
DIEA refers to N, N' -diisopropylethylamine.
TPSCl refers to 2,4, 6-triisopropylbenzenesulfonyl chloride.
The invention aims to provide a novel and efficient nucleoside antiviral drug.
Drawings
FIG. 1 is a graph showing in vitro antiviral effects of each compound of examples.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
Synthesis of intermediates:
1) Intermediate a
The synthetic route is as follows:
according to the literature 1 The compound 1 is synthesized by using D-glucose as a raw material. Compound 1 (97.2 g,405.0 mmol) was placed in a dry three-necked flask (2L). Dichloromethane (1L), pyridine (98.2 ml,2.5 equiv) was added. After the mixture was cooled at-10℃and stirred for 15 minutes, bzCl (56.4 mL,1.2 equiv) was slowly added to the reaction solution. After about two hours the starting materials were completely reacted. At this time, an aqueous hydrochloric acid solution (2N, 500 mL) was added to the reaction solution. The mixture was extracted three times with dichloromethane (1 L×3). The combined organic phases were washed once with saturated brine (2L ×1) and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and then purified by flash column chromatography on silica gel with a gradient of ethyl acetate/petroleum ether (20% -50%) to give compound 2 as a colorless oil in 80% (111.5 g). TLC (Petroleum ether/ethyl acetate=1:1, v/v), R f ＝0.50； 1 H NMR (400MHz,CDCl 3 )δ8.04–7.95(m,2H),7.64–7.53(m,1H),7.46(dt,J＝13.7,7.7 Hz,2H),7.34–7.23(m,5H),4.75–4.60(m,2H),4.59–4.53(m,1H),4.50–4.45(m, 1H),4.38(dd,J＝11.2,6.5Hz,1H),4.01(t,J＝3.3Hz,1H),3.75(ddd,J＝7.8,6.5, 3.1Hz,1H),3.22(dd,J＝11.5,4.5Hz,1H),2.91(dd,J＝11.4,3.8Hz,1H). 13 C NMR (101MHz,CDCl 3 )δ166.4,137.7,133.3,129.9,129.8,128.7,128.6,128.1,127.8,86.8, 77.7,72.1,66.5,49.1,36.8.[α] D ＝32.6(c＝5.3,CHCl 3 ),IR(neat):ν max ＝3450,3031, 2937,1715,1583,1269,1110,1096,1069,1025,710,699cm -1 .
Compound 2 (108.6 g,315.7 mmol) was placed in a dry three-necked flask (2L). Toluene (1000 mL) and DBN (61.4 mL,1.6 equiv) were added to the flask at room temperature. PBSF (85.2 mL,1.5 equiv) was slowly added to the three-necked flask at the same temperature. The starting material was reacted completely approximately 2 hours after the end of the addition of PBSF. To the reaction mixture was added saturated sodium bicarbonate (1000 mL, aq) and the reaction was quenched, and the mixture was extracted with dichloromethane (1L X3). The combined organic phases were washed with saturated brine (2 L×1), and dried over anhydrous magnesium sulfate. The volatile solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography. The gradient eluent was ethyl acetate/petroleum ether (1.6% -2%) to afford compound 3 as a colourless oil in 53% yield (57.9 g). TLC (Petroleum ether/ethyl acetate=30:1, v/v), R f ＝0.50； 1 H NMR(400MHz,CDCl 3 )δ8.07–7.86 (m,2H),7.69–7.51(m,1H),7.44(t,J＝7.7Hz,2H),7.29(d,J＝3.8Hz,5H),5.59– 5.02(m,1H),4.64(s,2H),4.45–4.34(m,2H),4.29(dt,J＝10.6,2.9Hz,1H),3.79 (td,J＝8.0,2.9Hz,1H),3.35–2.94(m,2H). 13 C NMR(151MHz,CDCl 3 )δ166.2, 137.2,133.3,129.8,128.7,128.6,128.2,128.0,97.4(d,J＝182.4Hz),84.2(d,J＝ 24.7Hz),72.1,65.8(d,J＝4.9Hz),48.6,34.7,34.5.[α] D ＝31.5,(c＝1.3,CHCl 3 )；IR (neat):ν max ＝2923,1718,1451,1268,1108,1095,1026,749,710,698cm -1 .
Compound 3 (50.0 g,144.5 mmol) was placed in a three-necked flask (1L), dichloromethane (600 mL) was added, and stirred and cooled at-78deg.C for 30 min. And then the reaction solution is communicated with an ozone generator and is blown with ozone until the reaction solution turns blue and does not fade, and then nitrogen is led into the reaction solution to discharge the ozone. The reaction solution was warmed to room temperature and distilled under reduced pressureThe solvent was removed and the compound was used in the next reaction without purification. The above sulfoxide crude product was dissolved in acetic anhydride (300 mL) and heated to 100deg.C, after which the reaction was complete by TLC for about 1.5 hours. To the mixture was added dropwise saturated sodium hydrogencarbonate solution until the pH of the reaction solution became neutral, followed by extraction with ethyl acetate (1L. Times.3). The organic phases were combined, washed with saturated brine (1 L×1), and dried over anhydrous magnesium sulfate. The volatile solvent was distilled off under reduced pressure and purified by silica gel column chromatography. Gradient elution was performed with ethyl acetate/petroleum ether (5% -7%) to give compound 4 as a yellow oil in 67% yield (39.1 g). TLC (Petroleum ether/ethyl acetate=20:1, v/v), R f ＝0.50； 1 H NMR(400MHz,CDCl 3 )δ8.18–7.77(m, 2H),7.50(tt,J＝7.0,1.4Hz,1H),7.38(d,J＝8.0Hz,2H),7.31–7.02(m,5H),6.08 –5.69(m,1H),5.19–4.99(m,1H),4.84–4.53(m,2H),4.50–4.21(m,2H),3.49 (dt,J＝7.2,5.6Hz,1H),3.22–2.93(m,1H),2.24–1.71(m,3H). 13 C NMR(101 MHz,CDCl 3 )δ169.8,169.6,166.2,165.6,137.3,137.0(d,J＝9.8Hz),133.4,133.3, 129.9,129.7,128.7,128.6,128.6,128.3,128.2,128.1,128.1,95.6(d,J＝204.0Hz), 94.3(d,J＝188.0Hz),86.6(d,J＝22.7Hz),81.5(d,J＝20.7Hz),74.8(d,J＝16.8 Hz),74.2,73.4(d,J＝2.0Hz),65.6,64.0,43.2(d,J＝9.4Hz),33.3(d,J＝22.2Hz), 21.8,21.2.[α] D ＝-11.2,(c＝7.8,CHCl 3 )；IR(neat):ν max ＝2946,2879,1746,1720, 1370,1267,1220,1095,1069,1042,1015,709cm -1 .
Compound 4 (4.0 g,9.9 mmol) and trimethylsilyl protected uracil (7.60 g,29.7 mmol) were dispersed in dry acetonitrile (100 mL). Tin tetrachloride (19.8 mL,1M in CH 2 Cl 2 ) Slowly adding the mixture into the reaction solution. The mixture was quenched with saturated aqueous sodium bicarbonate (100 mL) after 4 hours at room temperature. After adding sodium bicarbonate, the reaction solution produced a large amount of precipitate, the precipitate was removed by filtration under reduced pressure, and the cake was washed three times with methylene chloride and then separated. The aqueous phase was extracted with dichloromethane (100 mL. Times.3). The organic phases were combined, washed with saturated brine (500 mL. Times.1), and dried over anhydrous magnesium sulfate. Removing solvent by vacuum distillation, separating by silica gel column chromatography, and gradient elutingEthyl acetate/petroleum ether (20% -50%) as colorless, foamy solid, 50% yield (2.26 g) of intermediate a (β).
aβ TLC (Petroleum ether/ethyl acetate=1:1, v/v), R f ＝0.30； 1 H NMR(400MHz,CDCl 3 )δ10.04(d,J＝5.8Hz,1H),8.43–7.80(m,2H),7.60–7.52(m,1H),7.41(t,J＝7.7 Hz,2H),7.37–7.28(m,4H),7.27–7.21(m,1H),7.13(dd,J＝7.7,5.7Hz,1H), 6.56(dd,J＝25.3,4.5Hz,1H),5.87(ddd,J＝54.9,6.7,4.5Hz,1H),5.74(dd,J＝ 7.7,1.6Hz,1H),4.82(dd,J＝11.5,1.5Hz,1H),4.71(dd,J＝11.5,3.4Hz,1H),4.64 (d,J＝11.6Hz,1H),4.44(td,J＝6.8,3.5Hz,1H),4.32(dd,J＝11.6,6.7Hz,1H), 4.23(ddd,J＝19.4,10.2,6.7Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ166.3,162.7, 152.5,139.2,137.2,133.4,129.8,129.6,128.6,128.5,128.4,128.3,102.4,100.5(d,J ＝187.2Hz),84.4(d,J＝23.1Hz),73.0,63.8,56.6(d,J＝31.7Hz),47.7(d,J＝8.6 Hz).[α] D ＝133.4,(c＝10.9,CHCl 3 )；IR(neat):ν max ＝3246,3184,3089,2946,2874, 1717,1643,1266,1096,1069,733,709,698cm -1 .
aαTLC (Petroleum ether/ethyl acetate=1:1, v/v), R f ＝0.35； 1 H NMR(600MHz,CDCl 3 )δ 8.78(s,1H),7.97(d,J＝7.7Hz,1H),7.85(d,J＝8.3Hz,1H),7.60(t,J＝7.4Hz, 1H),7.46(t,J＝7.7Hz,1H),7.35–7.26(m,2H),7.24–7.18(m,1H),6.36(dd,J＝ 16.2,2.5Hz,1H),5.66(dd,J＝8.4,2.2Hz,1H),5.16(dt,J＝47.6,2.8Hz,1H),4.60 (d,J＝2.1Hz,1H),4.48–4.40(m,1H),4.36(dt,J＝10.7,3.0Hz,1H),4.15(dt,J＝ 8.0,3.9Hz,1H).
2) Synthesis of intermediate b
The synthetic route is as follows:
2.0g of intermediate a, 4.4mmol of intermediate a are weighed in dry condition under argon atmosphereTo a three-necked flask (250 mL) was added dry methanol (100 mL). Sodium methoxide (1.32 mL,5mol/L in MeOH) was then added slowly to the reaction. After about 30 minutes, the reaction was completed, and a saturated aqueous ammonium chloride solution (100 mL) was added to the reaction mixture to quench the reaction. Extraction was performed with ethyl acetate (100 mL. Times.3). The organic phases were combined, washed with saturated brine (200 mL) and dried over anhydrous magnesium sulfate. The volatile solvent was distilled off under reduced pressure and used in the next reaction without purification. The crude product was dissolved in dry dichloromethane (100 mL) and titanium tetrachloride (0.72 mL,1.5 equiv) was added slowly at room temperature. After about 3 hours the starting materials were completely reacted. To the reaction mixture was added a saturated aqueous sodium hydrogencarbonate solution (4 mL) to quench the reaction, and the reaction mixture was dried over anhydrous magnesium sulfate. Volatile solvents were removed by distillation under the reduced pressure. Purifying the mixture by silica gel column chromatography, gradient eluting with MeOH/CH 2 Cl 2 (2% -5%) of intermediate b was obtained as yellow foam in 80% yield (922.2 mg). TLC (CH) 2 Cl 2 /MeOH＝20:1,v/v),R f ＝0.30； 1 H NMR(400MHz, MeOD)δ7.38(d,J＝7.6Hz,1H),6.46(dd,J＝24.5,5.1Hz,1H),5.69(d,J＝7.6 Hz,1H),5.55(dd,J＝7.2,5.1Hz,1H),4.14–4.05(m,1H),4.03–3.96(m,2H), 3.62(dd,J＝12.2,8.4Hz,1H). 13 C NMR(151MHz,MeOD)δ163.9,151.2,140.6, 100.0,99.4(d,J＝187.4),77.4,62.2,55.2(d,J＝30.2)51.3(d,J＝7.6)；[α] D ＝73.4,(c ＝8.2,MeOH)；IR(neat):ν max ＝3269,3118,3112,2967,2893,2112,1719,1655, 1411,764,732cm -1 .
3) Synthesis of intermediate c
The synthesis of intermediate c is performed by reference to step 2.
4) Synthesis of intermediate d
The synthetic route is as follows:
intermediate c (573.6 mg,0.86 mmol) was dissolved in methanol (10 mL) and ammonium fluoride (29.6 mg,10 equiv) was added to the reaction flask. The reaction solution was refluxed for two hours. After the raw materials disappear, the crude product is obtained by reduced pressure distillation and is directly used for the next reaction without purification. The above crude product was dissolved in an amine methanol solution (10 mL,7 mol/L) and refluxed overnight. After the raw materials disappear, the volatile solvents are removed by reduced pressure distillation, and then the silica gel column chromatography separation is directly carried out. Gradient elution polarity MeOH/CH2Cl2 (2% -10%) afforded compound d as a white, foamy solid.
EXAMPLE 1 Synthesis of Compound S-1
The synthetic route is as follows:
1,2, 4-triazole (2.74 g,39.6 mmol) was dispersed in dry acetonitrile (100 mL) under argon and cooled to 0deg.C. Dried triethylamine (9.17 mL,66.0 mmol) and phosphorus oxychloride (0.82 mL,8.8 mmol) were added sequentially to a solution of 1,2, 4-triazole in acetonitrile. The reaction solution was kept at 0℃for 30 minutes. Intermediate c (573.6 mg,0.86 mmol) was dissolved in dry acetonitrile (20 mL) and the reaction was added via a dropping funnel. Immediately after the completion of the dropwise addition, the ice bath was removed, and the reaction mixture was slowly returned to room temperature, after about 8 hours, the reaction was completed. The reaction was quenched with saturated ammonium chloride (50 mL) and extracted with ethyl acetate (100 mL X3). The organic phases were combined, washed once with saturated brine (100 mL. Times.1), and dried over anhydrous magnesium sulfate. The volatile solvent was distilled off under reduced pressure, followed by separation by silica gel column chromatography. The gradient eluent is ethyl acetate/petroleum ether (20% -40%)Compound 6 was obtained as white foam in 81% (500 mg). TLC (Petroleum ether/ethyl acetate=1:1, v/v), R f ＝0.50； 1 H NMR(400MHz,CDCl 3 )δ 7.84(d,J＝8.4Hz,1H),7.38(d,J＝8.3Hz,1H),6.48(d,J＝8.5Hz,2H),6.00(d,J ＝1.2Hz,1H),5.83–5.53(m,2H),4.47(dd,J＝9.4,4.0Hz,1H),4.14(dd,J＝12.7, 3.1Hz,1H),4.04(dd,J＝12.7,1.8Hz,1H),3.86(d,J＝7.7Hz,6H),3.69(ddd,J＝ 9.4,3.0,1.7Hz,1H),1.69–0.44(m,28H). 13 C NMR(151MHz,CDCl 3 )δ164.7, 163.6,162.5,161.8,150.0,141.0,134.1,111.9,104.8,102.4,99.1,77.8,71.6,62.9, 58.2,56.1,55.7,51.1,17.6,17.5,17.5,17.4,17.2,17.1,17.0,17.0,13.5,13.3,12.7； [α] D ＝10.6,(c＝6.0,CHCl 3 )；IR(neat):ν max ＝2941,2871,1672,1607,1463,1264, 1244,1211,1029,990,976,945,734,697,583cm -1 .
Compound 6 (430 mg,0.8 mmol) was weighed into a 25mL round bottom flask, dissolved by adding isopropanol (1 mL) and aqueous hydroxylamine (50 wt% in h2o,6.2 μl,1.5 equiv) was added. The reaction is stirred for 20 minutes at room temperature. After the reaction is completed, the solvent is removed by reduced pressure distillation to obtain a crude product, and the crude product is directly used for the next reaction without purification. The hydrolysate from the previous step was dissolved in methanol (10 mL) and ammonium fluoride (29.6 mg,10 equiv) was added to the reaction flask. The reaction solution was refluxed for two hours. After the raw materials disappear, the crude product is obtained by reduced pressure distillation and is directly used for the next reaction without purification. The above crude product was dissolved in an amine methanol solution (10 mL,7 mol/L) and refluxed overnight. After the raw materials disappear, the volatile solvents are removed by reduced pressure distillation, and then the silica gel column chromatography separation is directly carried out. Gradient elution polarity MeOH/CH 2 Cl 2 (2% -10%) of the compound S-1 was obtained as white foam in 85% yield (187.0 mg). TLC (CH) 2 Cl 2 /MeOH＝10:1,v/v),R f ＝ 0.30； 1 H NMR(400MHz,MeOD)δ7.36(dt,J＝13.8,6.3Hz,1H),6.05(dd,J＝ 12.3,6.7Hz,1H),5.65(dd,J＝13.5,7.4Hz,1H),4.18(dt,J＝21.7,7.5Hz,2H), 3.72(dt,J＝18.2,9.3Hz,2H). 13 C NMR(101MHz,MeOD)δ152.1,146.3,132.4, 99.7,78.3,75.3,64.6,64.2,53.9.[α] D ＝-67.2,(c＝2.0,CHCl 3 )；IR(neat):ν max ＝ 3327,2936,2832,1676,1445,1405,1021,641,589,505cm -1 .
EXAMPLE 2 preparation of Compound S-2 of the present invention
The synthetic route is as follows:
compound d (719.7 mg,2.6 mmol) was taken as per the literature 2 And the previously reported procedure gives compound 7 as a white, foamy solid in 85% yield (820.0 mg). TLC (Petroleum ether/ethyl acetate=1:1, v/v), R f ＝ 0.50； 1 H NMR(400MHz,CDCl 3 )δ9.27(s,1H),7.45(d,J＝8.1Hz,1H),5.85(d,J ＝2.4Hz,1H),5.77(dd,J＝8.1,2.1Hz,1H),4.93(dd,J＝5.8,2.4Hz,1H),4.84(dd, J＝5.7,3.2Hz,1H),4.42(dd,J＝11.4,6.8Hz,1H),4.31(dd,J＝11.4,6.8Hz,1H), 3.81(td,J＝6.8,3.2Hz,1H),2.57(hept,J＝7.0Hz,1H),1.57(s,3H),1.31(s,3H), 1.18(dd,J＝7.0,1.1Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ176.6,163.0,150.1, 141.9,112.8,103.2,89.0,85.4,70.5,65.1,53.7,33.9,27.4,25.2,19.0,18.9.[α] D ＝- 9.4,(c＝3.9,CHCl 3 )；IR(neat):ν max ＝3060,2982,2936,2874,1680,1452,1423, 1374,1211,1150,1055,764,748,732,545,426cm -1 .
Compound 7 (97.3 mg,0.26 mmol) was taken as per the literature 3 The procedure was reported to give compound S-2 as a white, foamy solid in 73% yield (68.0 mg). TLC (CH) 2 Cl 2 /MeOH＝20:1,v/v),R f ＝0.3； 1 H NMR (400MHz,MeOD)δ7.40(d,J＝8.3Hz,1H),6.06(d,J＝6.6Hz,1H),5.74(d,J＝ 8.2Hz,1H),4.41–4.24(m,2H),4.23(dd,J＝6.6,3.7Hz,1H),4.11(t,J＝3.7Hz, 1H),3.53(td,J＝6.6,3.7Hz,1H),2.61(p,J＝7.0Hz,1H),1.19(d,J＝7.0Hz, 6H). 13 C NMR(101MHz,MeOD)δ178.2,151.5,147.9,134.3,98.4,77.9,74.9,66.4, 64.6,50.2,35.2,19.3,19.3.[α] D ＝-1.1,(c＝2.7,CHCl 3 )；IR(neat):ν max ＝3355, 3277,2973,2972,1692,1449,1389,1342,1190,1157,956,584cm -1 .
EXAMPLE 3 preparation of Compound S-3 of the present invention
The synthetic route is as follows:
intermediate d (0.5 g,1.9 mmol) was weighed into a round bottom flask (100 mL) and para-toluene sulfonic acid (33.0 mg,0.1 equiv) and acetone (20 mL) were added. 2, 2-dimethoxypropane was slowly added to a round bottom flask (0.35 mL,1.5 equiv). After about 4 hours the reaction was quenched by addition of saturated aqueous sodium bicarbonate (20 mL). Extraction was performed with ethyl acetate (50 mL. Times.3). The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous magnesium sulfate. After the volatile solvent was distilled off under reduced pressure, it was used in the next reaction without purification. The above crude product was weighed into a dry three-necked flask (100 mL) with 2-ethyltelescoping (phenyl) -L-alaninate (1.4 g,1.5 equiv) and argon was purged three times. Dry tetrahydrofuran (20 mL) was added under argon atmosphere. After cooling the reaction to 0deg.C, t-BuMgCl (2.9 mL,1.5 equiv) was slowly added dropwise to the reaction. After the reaction of the starting materials was completed, the reaction was quenched by addition of a saturated aqueous ammonium chloride solution (100 mL). Extraction was performed with ethyl acetate (100 mL. Times.3), washing was performed with saturated brine (200 mL. Times.1), and drying was performed with anhydrous magnesium sulfate. After removal of the volatile solvent by distillation under reduced pressure, the crude product was separated by column chromatography on silica gel with gradient elution of polarity MeOH/CH 2 Cl 2 (2% -8%) of white, foamy solid 8 was obtained in 91% yield (1.05 g). TLC (CH) 2 Cl 2 /MeOH＝20:1,v/v),R f ＝ 0.3； 1 H NMR(400MHz,CDCl 3 )δ8.98(s,1H),7.46(d,J＝8.1Hz,1H),7.32(t,J＝ 7.8Hz,2H),7.21(d,J＝8.0Hz,2H),7.16(t,J＝7.3Hz,1H),5.85(d,J＝2.3Hz, 1H),5.73(d,J＝8.1Hz,1H),4.89(qd,J＝5.6,2.3Hz,2H),4.40(dt,J＝10.6,6.7 Hz,1H),4.30(dt,J＝10.6,6.2Hz,1H),4.17–3.89(m,4H),3.81(td,J＝6.4,2.4Hz, 1H),1.65–1.46(m,4H),1.46–1.22(m,10H),0.88(t,J＝7.5Hz,6H). 13 C NMR (101MHz,CDCl 3 )δ163.0,150.1,142.2,129.9,125.3,120.3,120.2,112.7,103.3, 89.0,85.3,71.1,67.9,67.7,67.7,54.7,54.6,50.4,40.4,27.5,25.3,23.3,23.3,21.3, 21.2,11.1,11.1.[α] D ＝-13.2,(c＝2.2,CHCl 3 )；IR(neat):ν max ＝2964,1685,1591, 1534,1516,1490,1453,1376,1260,1207,154,1064,934,764,750cm -1 .
Compound 8 (76.5 mg,0125 mmol) was taken and the procedure reported was followed 3 White foamy solid S-3 was obtained in 90% yield (66.0 mg). TLC (CH) 2 Cl 2 /MeOH＝10:1,v/v),R f ＝0.4； 1 H NMR (400MHz,MeOD)δ7.38(t,J＝7.8Hz,2H),7.32–7.03(m,4H),6.07(d,J＝6.8 Hz,1H),5.62(d,J＝8.2Hz,1H),4.29(hept,J＝5.6,5.1Hz,2H),4.22–4.11(m, 2H),4.11–3.89(m,3H),3.51(td,J＝5.9,3.2Hz,1H),1.51(h,J＝6.1Hz,1H),1.37 (q,J＝5.1Hz,7H),0.90(t,J＝7.5Hz,6H). 13 C NMR(101MHz,MeOD)δ175.0(d, J＝5.1Hz),152.2,152.1,152.0,146.2,132.2,130.9,126.2,121.3(d,J＝5.0Hz), 100.0,77.8,74.8,68.8(d,J＝5.5Hz),68.2,64.3,51.6,51.2(d,J＝8.7Hz),41.8, 24.3,24.3,20.6,20.6,11.4,11.3.[α] D ＝-32.9,(c＝2.1,MeOH；IR(neat):ν max ＝ 3327,2939,2832,1679,1455,1021,829,751,663,674,590,570,552,547cm -1 .
EXAMPLE 4 preparation of Compound S-4 of the present invention
The synthetic route is as follows:
compound d (174.7 mg,0.67 mmol) was taken and dissolved in dryDry dichloromethane, DMAP was added and isobutyric anhydride was added slowly with stirring at 0 ℃. After the reaction was completed, the reaction was quenched with saturated aqueous sodium bicarbonate, extracted with dichloromethane, and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove volatile components. The separation was performed by flash column chromatography on silica gel with gradient eluent ethyl acetate/petroleum ether (20% -50%) to give 9 as a white foam with a yield of 95% (300.0 mg). TLC (Petroleum ether/ethyl acetate=1:1, v/v), R f ＝0.50； 1 H NMR(400MHz,CDCl 3 )δ 9.11–8.74(m,1H),7.77(d,J＝8.2Hz,1H),6.39(d,J＝7.5Hz,1H),5.85(dd,J＝ 8.2,2.2Hz,1H),5.50(dd,J＝7.5,4.0Hz,1H),5.43(dd,J＝4.0,2.8Hz,1H),4.40 (dd,J＝11.9,5.5Hz,1H),4.24(dd,J＝11.9,6.2Hz,1H),3.66(td,J＝5.9,2.8Hz, 1H),2.64(dp,J＝10.6,7.0Hz,2H),2.51(h,J＝7.0Hz,1H),1.21(dd,J＝7.0,5.4 Hz,12H),1.11(dd,J＝7.0,2.0Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ176.6, 175.9,175.8,162.6,150.7,139.8,104.0,75.2,72.9,64.4,61.5,47.7,34.1,34.0,33.9, 19.1,19.1,19.0,18.9,18.8,18.8.[α] D ＝-8.7,(c＝4.6,CHCl 3 )；IR(neat):ν max ＝2975, 2938,2874,1740,1688,1629,1452,1377,1343,1248,1186,1143,1097,1076,916, 811,732cm -1 .
Compound 9 was dissolved in dichloromethane (10 mL), and the reaction solution was cooled to 0 ℃. DMAP (4.4 mg,0.1 equiv), DIEA (313.5 uL,5.0 equiv) and TPSCl (163.5 mg, 1.5 equiv) were then added to the reaction solution. After the addition was completed, the reaction solution was slowly returned to room temperature and stirred for 2 hours. After TLC detection of disappearance of starting material, the reaction solution was cooled to 0℃and then DIEA (257.0 uL,4.0 equiv) and hydroxylamine hydrochloride (100 mg,4.0 equiv) were slowly added. After the reaction mixture was kept at 0℃and stirred for 1 hour, an ice-water mixture (20 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with dichloromethane (20 mL. Times.3). The organic phases were combined and washed three times with aqueous potassium carbonate (10 mL. Times.3), twice with water (20 mL. Times.2), and once with saturated brine (20 mL. Times.2). Drying was performed with anhydrous magnesium sulfate. The volatile solvent was distilled off under reduced pressure, followed by separation by silica gel column chromatography. Gradient eluent MeOH/CH 2 Cl 2 (1.25％-1.7% to give compound S-4 as a white foam in 85% yield (148.4 mg). TLC (CH) 2 Cl 2 /MeOH＝20:1,v/v),R f ＝0.4； 1 H NMR(400MHz,CDCl 3 )δ8.59(s,1H),8.37–7.90(m,1H),7.06(d,J＝8.2Hz, 1H),6.39(d,J＝7.8Hz,1H),5.76(d,J＝8.1Hz,1H),5.55–5.40(m,2H),4.37(dd, J＝11.8,5.5Hz,1H),4.21(dd,J＝11.8,6.5Hz,1H),3.60(td,J＝6.0,2.4Hz,1H), 2.63(dp,J＝8.4,7.0Hz,2H),2.55(d,J＝7.0Hz,1H),1.32–1.17(m,12H),1.12(d, J＝7.0Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ176.7,176.0,175.9,149.8,144.7, 129.9,100.1,74.,72.8,64.7,61.0,47.3,34.1,34.0,34.0,19.1,19.1,19.1,18.9,18.9, 18.8.[α] D ＝-67.2,(c＝2.0,CHCl 3 )；IR(neat):ν max ＝3327,2926,2832,1676,1445, 1405,1021,641,621,602,579,559,542,505cm -1 .
EXAMPLE 5 preparation of Compound S-5 of the present invention
The synthetic route is as follows:
substrate b (0.3 g,1.14 mmol) was weighed into a 25ml dry round bottom flask. To the flask were added dry pyridine (10 mL) and 1,3 dichloro-1, 3-tetraisopropyl disiloxane (0.44 mL,1.37 mmol). The reaction mixture was heated to 40℃for about 4 hours, and the reaction was completed. The reaction was quenched by the addition of hydrochloric acid solution (2N, 100 mL). Extraction was performed with ethyl acetate (100 mL. Times.3). The organic phases were combined, washed with saturated brine (200 mL ×1), and dried over anhydrous magnesium sulfate. The volatile solvent was distilled off under reduced pressure to give a crude product. The crude product was used in the synthesis of compound 10 without purification. White foamy solid 10 was obtained in 80% yield (459.8 mg) according to the synthetic manner of compound 6. TLC (Petroleum ether/ethyl acetate=1:1, v/v), R f ＝0.50； 1 H NMR(400MHz,CDCl 3 )δ8.83(s,1H),8.21(s,1H),7.83(d,J＝ 6.5Hz,1H),6.52(d,J＝6.5Hz,1H),6.02(dd,J＝24.0,4.5Hz,1H),5.76(ddd,J＝ 55.6,7.6,4.6Hz,1H),4.40(ddd,J＝20.0,9.7,7.6Hz,1H),4.19–4.07(m,2H),3.85 (dt,J＝13.9,2.7Hz,1H),1.05(ddt,J＝16.6,12.4,4.0Hz,28H). 13 C NMR(101MHz, CDCl 3 )δ161.4,153.9,150.9,146.4,146.3,116.6,97.6(d,J＝188.8Hz),75.8(d,J＝ 23.0Hz),63.7(d,J＝30.3Hz),57.7,50.1(d,J＝7.8Hz),17.5,17.4,17.4,17.3,17.2, 17.1,16.9,16.9,13.7,13.4,12.9,12.6.[α] D ＝30.9,(c＝7.1,CHCl 3 )；IR(neat):ν max ＝ 2977,1739,1697,1599,1507,170,1443,1387,1345,1265,1187,1147,992,733,703, 665cm -1 .
Compound 10 (200.0 mg,0.36 mmol) was weighed into a 25ml round bottom flask. Isopropanol (5 mL) was added, aqueous hydroxylamine (50 wt% in H) 2 O, 23.8. Mu.L, 1.5 equiv). The mixture was stirred at room temperature for 20 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and was used directly in the next reaction without purification. The above crude product was dissolved in methanol (5 mL) and ammonium fluoride (134.6 mg,3.6 mmol) was added. The reaction solution was refluxed for about 2 hours, and the starting material disappeared. Volatile solvents were removed by distillation under the reduced pressure. Separating the mixture by silica gel column chromatography, gradient eluting with MeOH/CH 2 Cl 2 (1.2% -1.7%) to give compound S-5 as a white solid in 85% yield (84.8 mg). TLC (CH) 2 Cl 2 /MeOH＝20:1,v/v),R f ＝0.30； 1 H NMR (400MHz,MeOD)δ7.38(d,J＝7.6Hz,1H),6.46(dd,J＝24.5,5.1Hz,1H),5.69(m, 1H),5.62(ddd,J＝55.6,7.2,5.0Hz,1H),4.09(ddd,J＝19.9,9.8,7.2Hz,1H),4.03– 3.81(m,2H),3.62(dd,J＝12.2,8.5Hz,1H). 13 C NMR(101MHz,MeOD)δ165.4, 152.6,142.1,101.5,100.9(d,J＝186.1Hz),78.9(d,J＝23.8Hz),63.7,56.7(d,J＝ 30.1Hz),52.8(d,J＝7.4Hz).[α] D ＝158.8,(c＝8.4,MeOH)；IR(neat):ν max ＝3278, 3188,1719,1642,1421,1381,1227,1175,979,808cm -1 .
EXAMPLE 6 preparation of Compound S-6 of the present invention
The synthetic route is as follows:
compound b (162.4 mg,0.61 mmol) and DMAP (7.5 mg,0.1 equiv) were dispersed in dry dichloromethane (10 mL). Isobutyric anhydride (0.31 mL,1.83 mmol) was slowly added to the reaction mixture with stirring at 0deg.C, and the reaction was completed after about two hours. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (10 mL). Extraction was performed with dichloromethane (20 mL. Times.3). The organic phases were combined and washed with saturated brine (50 mL). Drying over anhydrous magnesium sulfate, and distilling off the volatile solvent under reduced pressure, and then directly using the dried product for synthesizing the compound 11. 1,2, 4-triazole (421.3 mg,6.1 mmol) was dispersed in dry acetonitrile (50 mL) under argon and cooled to 0deg.C. Dried triethylamine (1.41 mL,10.2 mmol) and phosphorus oxychloride (0.125mL,1.35 mmol) were added sequentially to an acetonitrile solution of 1,2, 4-triazole. The reaction solution was kept at 0℃for 30 minutes. The crude product from the previous step was dissolved in dry acetonitrile (10 mL) and the reaction solution was added via a dropping funnel. Immediately after the completion of the dropwise addition, the ice bath was removed, and the reaction mixture was slowly returned to room temperature, after about 8 hours, the reaction was completed. The reaction was quenched with saturated ammonium chloride (30 mL) and extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, washed once with saturated brine (100 mL. Times.1), and dried over anhydrous magnesium sulfate. The volatile solvent was distilled off under reduced pressure, followed by separation by silica gel column chromatography. The gradient eluent was ethyl acetate/petroleum ether (25% -50%) to afford compound 11 as a white, foamy solid in 90% yield (248.8 mg). TLC (Petroleum ether/ethyl acetate=1:1, v/v), R f ＝0.50； 1 H NMR(400MHz,CDCl 3 )δ8.87(s,1H),8.22(s,1H),7.85 (d,J＝6.5Hz,1H),6.54(d,J＝6.5Hz,1H),6.19(dd,J＝24.1,4.1Hz,1H),5.87(ddd, J＝54.7,7.1,4.1Hz,1H),5.55(ddd,J＝20.4,10.5,7.1Hz,1H),4.65–4.43(m,1H), 4.34(dd,J＝11.8,3.7Hz,1H),4.09(dd,J＝11.9,7.6Hz,1H),2.58(dp,J＝22.7,7.0 Hz,2H),1.42–0.98(m,12H). 13 C NMR(101MHz,CDCl 3 )δ176.6,176.0,161.4, 154.0,151.2,146.6,146.0,116.3,96.9(d,J＝190.1Hz),64.4(d,J＝31.2Hz),62.9, 47.0(d,J＝7.1Hz),34.0,34.0,19.0,19.0,19.0,18.9.[α] D ＝24.3,(c＝7.5,MeOH)； IR(neat):ν max ＝3279,3198,3117,2975,2937,2878,1731,1666,1270,1415, 1387,1347,1188,1148,1097,1001,807cm -1 .
Compound 11 (200 mg,0.44 mmol) and DDQ (1.0 g,4.4 mmol) were taken. The 1,2, 4-triazole was hydrolyzed according to compound 6 to give S-6 as a white foamy solid in 75% yield (137.6 mg). TLC (Petroleum ether/ethyl acetate=1:1, v/v), R f ＝0.30； 1 H NMR(400MHz,CDCl 3 )δ9.64(s,1H), 7.23(dd,J＝7.7,5.7Hz,1H),6.57(dd,J＝24.3,4.8Hz,1H),5.82(dd,J＝7.8,1.6Hz, 1H),5.79(ddd,J＝54.7,7.4,4.8Hz,1H),5.55(ddd,J＝19.0,10.1,7.4Hz,1H),4.53 –4.28(m,2H),4.22–3.55(m,1H),2.59(dp,J＝24.1,7.0Hz,2H),1.55–0.92(m, 12H). 13 C NMR(101MHz,CDCl 3 )δ176.8,176.2,162.6,152.3,139.0,102.7,97.3(d, J＝190.9Hz),63.2,55.9(d,J＝30.5Hz),46.6(d,J＝7.1Hz),34.0,34.0,19.0,19.0. [α] D ＝109.1(c＝3.2,CHCl 3 )；IR(neat):ν max ＝3265,3188,3108,2976,2932,2879, 1728,1649,1470,1414,1386,1346,1186,1143,1097,1076,1008,983,807,733cm -1 .
EXAMPLE 7 preparation of Compound S-7 of the present invention
The synthetic route is as follows:
1.3g of intermediate a (Compound 5β), 2.85mmol, was placed in a dry three-necked flask (150 mL). Methanol (70 mL) was added and sodium methoxide (0.86 mL,5mol/L in MeOH) was slowly added dropwise to a solution of 5β in methanol with stirring. After about 30 minutes, the starting materials were reacted completely. Adding saturated chloridizingThe reaction was quenched with ammonium (50 mL). The mixture was extracted three times with ethyl acetate (100 mL. Times.3), and the combined organic phases were washed once with saturated brine (200 mL). Drying with anhydrous magnesium sulfate, and distilling off volatile solvent under reduced pressure to obtain crude product. The crude product was used in the next reaction without purification. The crude product from the previous reaction was weighed into a 50ml round bottom flask with 2-ethylnutyl (S) - (perfluorophenyl) phosphonyl) -L-alaninate (1.82 g,3.69 mmol) and anhydrous magnesium chloride (324.5 mg,3.4 mmol). And dry acetonitrile (20 mL) was added to the reaction solution. The above mixed reaction solution was heated to 50℃for 10 minutes. DIPEA (1.45 mL,8.30 mmol) was then added to the reaction. After about 4 hours, the reaction was completed, the temperature of the reaction mixture was returned to room temperature, and a saturated aqueous ammonium chloride solution (50 mL) was added to quench the reaction. The mixture was extracted three times with ethyl acetate (100 mL. Times.3). The organic phases were combined, washed once with saturated brine (100 mL) and dried over anhydrous magnesium sulfate. The volatile solvent was removed by distillation under reduced pressure, and the mixture was separated by column chromatography on silica gel with gradient elution of polarity MeOH/CH 2 Cl 2 (1% -3%) of compound 12 was obtained as white foam in 73% yield (1.34 g). TLC (CH) 2 Cl 2 /MeOH＝20:1,v/v),R f ＝0.40； 1 H NMR(400MHz,CDCl 3 )δ10.01(d,J＝ 6.1Hz,1H),7.38–7.27(m,8H),7.23–7.09(m,4H),7.03(dd,J＝7.7,5.7Hz,1H), 5.81(ddd,J＝55.1,6.8,4.5Hz,1H),5.65(dd,J＝7.7,1.6Hz,1H),4.77(dd,J＝11.7, 1.5Hz,1H),4.59(d,J＝11.5Hz,1H),4.47(ddd,J＝14.2,6.0,2.7Hz,1H),4.34(ddd, J＝10.0,6.5,2.8Hz,1H),4.18–3.96(m,6H),3.82(t,J＝10.3Hz,1H),1.52(p,J＝ 6.3Hz,1H),1.44–1.27(m,8H),0.88(t,J＝7.4Hz,7H). 13 C NMR(101MHz,CDCl 3 ) δ162.9,151.7,150.7,150.7,139.5,137.5,129.8,128.6,128.3,128.2,125.2,120.4, 120.4,101.7,100.4(d,J＝187.0Hz),83.3(d,J＝23.3Hz),73.0,67.8,66.1,56.1(d,J ＝31.6Hz),50.4,48.4,40.3,23.3(d,J＝4.1Hz),21.3(d,J＝4.8Hz),11.1(d,J＝4.3 Hz).[α] D ＝58.1,(c＝7.8,CHCl 3 )；IR(neat):ν max ＝3241,3193,3093,2963,1727,1664, 1206,1151,1068,1023,982,936,764,750cm -1 .
1,2, 4-Tri under argon atmosphereAzole (1.25 g,18.1 mmol) was dispersed in dry acetonitrile (50 mL) and cooled to 0deg.C. Dried triethylamine (4.19 mL,30.2 mmol) and phosphorus oxychloride (0.37 mL,4.02 mmol) were added sequentially to a solution of 1,2, 4-triazole in acetonitrile. The reaction solution was kept at 0℃for 30 minutes. Compound 12 (1.2 g,1.8 mmol) was dissolved in dry acetonitrile (10 mL) and the reaction was added via a dropping funnel. Immediately after the completion of the dropwise addition, the ice bath was removed, and the reaction mixture was slowly returned to room temperature, after about 8 hours, the reaction was completed. The reaction was quenched with saturated ammonium chloride (30 mL) and extracted with ethyl acetate (50 mL. Times.3). The organic phases were combined, washed once with saturated brine (100 mL. Times.1), and dried over anhydrous magnesium sulfate. The volatile solvent was distilled off under reduced pressure, followed by separation by silica gel column chromatography. Gradient eluent MeOH/CH 2 Cl 2 (2% -5%) of compound 13 was obtained as white foam in 77% yield (994.6 mg). TLC (CH) 2 Cl 2 /MeOH ＝20:1,v/v),R f ＝0.50； 1 H NMR(400MHz,CDCl 3 )δ8.86(s,1H),8.20(s,1H),7.83 (d,J＝6.5Hz,1H),7.38–7.27(m,7H),7.20(dt,J＝7.6,1.2Hz,2H),7.17–7.09(m, 1H),6.53(d,J＝6.5Hz,1H),6.11(dd,J＝24.9,3.9Hz,1H),5.91(ddd,J＝55.0,6.5, 4.0Hz,1H),4.75(dd,J＝11.6,1.6Hz,1H),4.58(d,J＝11.7Hz,1H),4.48(ddd,J＝ 10.2,6.8,3.1Hz,1H),4.40(ddd,J＝9.8,6.1,3.1Hz,1H),4.21–3.87(m,5H),3.60 (dd,J＝10.9,9.1Hz,1H),1.50(p,J＝6.2Hz,1H),1.38(d,J＝7.0Hz,3H),1.32(td, J＝7.4,3.2Hz,4H),0.86(t,J＝7.5Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ173.7, 173.6,161.1,153.9,151.0,150.8,150.8,146.5,146.0,137.3,129.8,128.6,128.2,128.2, 125.0,120.4,120.3,116.4,99.6(d,J＝186.9Hz),84.1(d,J＝23.6Hz),73.0,67.7, 65.8(d,J＝5.2Hz),64.9(d,J＝31.9Hz),50.4(d,J＝1.9Hz),48.8(t,J＝8.3Hz), 40.3,23.3,23.3,21.4,21.4,11.1,11.1.[α] D ＝36.3,(c＝11.2,CHCl 3 )；IR(neat):ν max ＝ 3231,3127,3031,2960,1737,1696,1529,1441,1260,1206,1162,1135,1068,1025, 983,932cm -1 .
Compound 13 (20 mg,0.028 mmol) and DDQ (63.6 mg,0.42 mmol) were weighed into a 10mL seal bottle. Dichloromethane (2 mL) was added to the bottle. The mixed reaction solution is stirred at 58 DEG CThe reaction was carried out for 43 hours. After the reaction of the starting materials was completed, the reaction was quenched by addition of saturated aqueous sodium thiosulfate (10 mL). Extraction was performed with dichloromethane (20 mL. Times.3). The organic phases were combined, washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. The volatile solvent was distilled off under reduced pressure and used in the next reaction without purification. The crude product was dissolved in isopropanol (1 mL) and aqueous hydroxylamine solution (50 wt% in H) was added 2 O, 4.4. Mu.L, 1.5 equiv). The reaction is stirred for 20 minutes at room temperature. After the volatile solvent was distilled off under reduced pressure, the mixture was subjected to silica gel column chromatography. Gradient eluent MeOH/CH 2 Cl 2 (4% -8%) of the compound S-7 was obtained as white foam in 55% yield (9.1 mg). TLC (CH) 2 Cl 2 /MeOH＝20:1,v/v),R f ＝0.30； 1 H NMR(400MHz,CDCl 3 )δ10.14(d,J＝5.8Hz,1H),7.34–7.27(m,2H),7.18(d,J＝ 8.5Hz,2H),7.13(t,J＝7.4Hz,1H),7.07(dd,J＝7.7,5.7Hz,1H),6.56–6.34(m, 1H),5.72–5.54(m,1H),5.53(d,J＝5.7Hz,1H),4.45(p,J＝5.2,4.5Hz,1H),4.35– 4.17(m,4H),4.17–3.85(m,3H),1.52(dp,J＝12.7,6.4Hz,1H),1.40–1.13(m,7H), 0.88(t,J＝7.4Hz,6H). 13 C NMR(151MHz,CDCl 3 )δ174.1(d,J＝7.1Hz),163.1, 151.7,150.6(d,J＝6.9Hz),139.8,129.9,125.3,120.3(d,J＝4.7Hz),101.54,100.4 (d,J＝186.8Hz),78.8(d,J＝25.4Hz),68.,67.9,66.7,56.6,50.6,50.4,40.4,23.3,23.3, 21.0,21.0,11.1,11.1.[α] D ＝65.5,(c＝3.8,CHCl 3 )；IR(neat):ν max ＝3269,2963,2927, 2874,2177,2150,2018,1728,1654,1490,1383,1208,1153,1069,1024,939,807cm -1 .
EXAMPLE 8 preparation of Compound S-8 of the present invention
The synthetic route is as follows:
intermediate a (2.0 g,4.4 mmol) was placed in a dry three-necked flask (250 mL). Methanol (100 mL) was added and sodium methoxide (1.32 mL,5mol/L in MeOH) was slowly added dropwise to a solution of intermediate a in methanol with stirring. After about 30 minutes, the starting materials were reacted completely. The reaction was quenched by addition of saturated ammonium chloride (50 mL). The mixture was extracted three times with ethyl acetate (100 mL. Times.3), and the combined organic phases were washed once with saturated brine (200 mL). Drying with anhydrous magnesium sulfate, and distilling off volatile solvent under reduced pressure to obtain crude product. The crude product was used in the next reaction without purification. The above crude product was dissolved in dry dichloromethane (50 mL) and DMAP (53.7 mg,0.44 mmol) was added. Isobutyronic anhydride (1.1 mL,6.6 mmol) was added slowly with stirring at 0deg.C. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (50 mL) and extracted with methylene chloride (100 mL. Times.3). The organic phases were combined and washed once with saturated brine (200 mL). Drying over anhydrous magnesium sulfate, and distilling under reduced pressure to remove volatile components. The separation was performed by flash column chromatography on silica gel with gradient eluent ethyl acetate/petroleum ether (20% -50%) to give compound 14 as a white, foamy solid in 90% yield (1.88 g). TLC (Petroleum ether/ethyl acetate=1:1, v/v), R f ＝0.40； 1 H NMR(400MHz,CDCl 3 )δ9.31 (d,J＝5.8Hz,1H),7.45–7.27(m,5H),7.14(dd,J＝7.7,5.7Hz,1H),6.53(dd,J＝ 25.1,4.6Hz,1H),5.80(ddd,J＝55.3,6.8,4.6Hz,1H),5.7(m,1H),4.81(dd,J＝11.6, 1.6Hz,1H),4.62(d,J＝11.6Hz,1H),4.55–4.43(m,1H),4.40–4.24(m,1H),4.11 (ddt,J＝23.6,11.6,6.8Hz,2H),2.51(p,J＝7.0Hz,1H),1.14(dd,J＝7.0,1.4Hz, 6H). 13 C NMR(101MHz,CDCl 3 )δ176.9,162.5,152.1,138.8,137.4,128.7,128.3, 128.3,102.6,100.3(d,J＝187.2Hz),84.4(d,J＝22.9Hz),73.1,63.3,56.5(d,J＝31.3 Hz),47.5(d,J＝8.7Hz),34.0,19.1(d,J＝4.0Hz).[α] D ＝144.5,(c＝4.8,CHCl 3 )；IR (neat):ν max ＝3249,3188,3112,2976,2879,2176,1729,1655,1416,1156,764,750 cm -1 .
1,2, 4-triazole (2.74 g,39.6 mmol) was dispersed in dry acetonitrile (100 mL) under argon and cooled to 0deg.C. Dried triethylamine (9.17 mL,66.0 mmol) and phosphorus oxychloride (0.82 mL,8.8 mmol) were added sequentially to 1,2, 4-triazateAnd (3) acetonitrile solution of the azole. The reaction solution was kept at 0℃for 30 minutes. Compound 14 (1.67 g,3.96 mmol) was dissolved in dry acetonitrile (20 mL) and the reaction was added via a dropping funnel. Immediately after the completion of the dropwise addition, the ice bath was removed, and the reaction mixture was slowly returned to room temperature, after about 8 hours, the reaction was completed. The reaction was quenched with saturated ammonium chloride (50 mL) and extracted with ethyl acetate (100 mL. Times.3). The organic phases were combined, washed once with saturated brine (100 mL. Times.1), and dried over anhydrous magnesium sulfate. The volatile solvent was distilled off under reduced pressure, followed by separation by silica gel column chromatography. The gradient eluent was ethyl acetate/petroleum ether (20% -40%) to afford compound 15 as a white, foamy solid in 77% yield (1.58 g). TLC (Petroleum ether/ethyl acetate=1:1, v/v), R f ＝0.50； 1 H NMR(400MHz,CDCl 3 )δ8.86(s,1H),8.20(s,1H), 7.84(d,J＝6.5Hz,1H),7.41–7.28(m,5H),6.54(d,J＝6.5Hz,1H),6.11(dd,J＝ 25.1,4.0Hz,1H),5.93(ddd,J＝55.0,6.5,4.0Hz,1H),4.93–4.57(m,2H),4.52– 4.35(m,2H),4.26–3.84(m,2H),2.51(p,J＝7.0Hz,1H),1.13(dd,J＝7.0,1.7Hz, 6H). 13 C NMR(101MHz,CDCl 3 )δ176.8,161.2,154.0,151.0,146.5,146.1,137.2, 128.6,128.2,116.5,99.6(d,J＝186.6Hz),84.6(d,J＝23.3Hz),72.9,65.0(d,J＝32.0 Hz),63.3,47.8(d,J＝8.7Hz),34.0,19.0.[α] D ＝87.9,(c＝20.0,CHCl 3 )；IR(neat): ν max ＝3122,3031,2979,2936,2874,1732,1692,1598,1506,1440,1205,1130,1075, 988,917,832,812,733,698,665cm -1 .
Compound 15 (19.9 mg,0.04 mmol) and DDQ (95.4 mg,0.42 mmol) were weighed into 10ml seal bottles. Dichloromethane (3 mL) was added to the bottle. The above mixture was stirred at 58℃for 43 hours. After the reaction of the starting materials was completed, the reaction was quenched by addition of saturated aqueous sodium thiosulfate (10 mL). Extraction was performed with dichloromethane (20 mL ×3). The organic phases were combined, washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. The volatile solvent was distilled off under reduced pressure and used in the next reaction without purification. The crude product was dissolved in isopropanol (1 mL) and aqueous hydroxylamine solution (50 wt% in H) was added 2 O, 6.2. Mu.L, 1.5 equiv). The reaction is stirred for 20 minutes at room temperature. Reduced pressure distillationAfter the volatile solvent, the mixture was subjected to silica gel column chromatography. Gradient eluent MeOH/CH 2 Cl 2 (1.2% -1.7%) of compound S-8 was obtained as white, foamy solid in 50% yield (7.3 mg). TLC (CH) 2 Cl 2 /MeOH＝20:1,v/v),R f ＝0.50； 1 H NMR (400MHz,CDCl 3 )δ7.30–7.16(m,1H),6.56(dd,J＝25.6,3.8Hz,1H),5.81(d,J＝ 7.6Hz,1H),5.61(ddd,J＝53.2,5.6,3.8Hz,1H),5.37–4.72(m,2H),4.54–4.35(m, 1H),4.34–4.21(m,2H),4.15–3.96(m,1H),2.60(p,J＝7.0Hz,1H),1.18(dd,J＝ 7.0,1.5Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ177.7,162.9,152.1,139.4,102.4, 100.64(d,J＝186.7Hz),79.4(d,J＝26.2Hz),63.7,57.7(d,J＝29Hz)50.5,34.1,19.1 (d,J＝4.0Hz).[α] D ＝124.1,(c＝2.4,CHCl 3 )；IR(neat):ν max ＝3250,2977,1720,1641, 1417,1155,808,764,732,702,560,533cm -1 .
The following experiments prove the beneficial effects of the invention.
The compounds of the present invention are found to have inhibitory effects on various viruses, such as coronaviruses, caliciviruses, etc., in preliminary experiments;
the antiviral action of the novel coronavirus will be described below as typified by a novel coronavirus.
Experimental example 1 in vitro antiviral test
Preparing a solution: the compounds of examples 1-8 were dissolved in an appropriate amount of DMSO and formulated into stock solutions at a concentration of 20 mM. An appropriate amount of the above stock solutions were each taken and diluted with DMEM medium to give a 5 μm dosing solution.
The experimental method comprises the following steps: vero cells were seeded in 96-well plates at 37℃with 5% CO 2 Culturing in DMEM medium under the condition, and performing experiment when the cell density reaches 80%. After infection of Vero cells with coronavirus with moi=0.01 for 2h, the medium was removed. Fresh medium containing 5. Mu.M of the compound was added separately and the culture was continued for 72 hours. As a negative control, 0.1% dmso solution was used. After 72h, the cells were observed under a microscope for lesions. Viral RNA was extracted from 100. Mu.l supernatant of infected cells using the Tianlong automatic nucleic acid extraction system using qRT-PCR measures the replication of the virus. Data analysis was performed using GraphPad Prism 9.0 software and the viral inhibition of each compound was calculated. The experimental results are shown in FIG. 1.
The experimental results show that the compound has a certain antiviral potential, wherein the compounds S-3, S-5, S-6 and S-7 have better antiviral effects.
Reference is made to:
1.Yuichi Yoshimura,K.K.,Kohei Yamada,ANovel Synthesis of 2′-Modified 2′- Deoxy-4′-thiocytidines from D-Glucose.J.Org.Chem.1997,62,13.
2.Takashi Naka,N.M.,Hiroshi Abe,Daisuke Kaga,and Akira Matsuda,The Stereoselective Synthesis of 4′-T-Thioribonucleosides via the Pummerer Reaction.J. Am.Chem.Soc.2000,122,11.
3.Qin,Z.；Dong,B.；Wang,R.；Huang,D.；Wang,J.；Feng,X.；Bian,J.；Li,Z., Preparing anti-SARS-CoV-2 agent EIDD-2801 by a practical and scalable approach, and quick evaluation via machine learning.Acta Pharm Sin B 2021,11,3678-3682。
Claims (15)
1. a compound or a pharmaceutically acceptable salt or solvate thereof, characterized in that the compound has the structure of formula I:
wherein,,
x is CR 1 R 2 Wherein R is 1 、R 2 Each independently selected from hydrogen, deuterium, C1-C3 alkyl;
y is CR 3 Or N, wherein R 3 Independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C1-C3 alkyl, said substituted substituents being deuterium, hydroxy, halogen;
z is CR 4 Or N, wherein R 4 Independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C1-C3 alkyl, said substituted substituent being deuterium,Hydroxy, halogen;
R 1 hydrogen, deuterium, monophosphate, diphosphate, triphosphate,
Linear or branched alkyl, cycloalkyl, nitro, aryl, heterocyclyl, phosphoramidate, or phosphate;
R 5 、R 6 、R 7 each independently selected from hydrogen, deuterium, C1-C10 straight or branched chain alkyl, cycloalkyl, aryl, heterocyclyl, alkenyl, alkynyl, nitro, alkanoyl, carbamoyl, wherein R 5 、R 6 、R 7 Optionally by one or more than one R, which may be the same or different 6 Substitution;
R 2 is hydrogen, deuterium, hydroxy, halogen, amino, nitro, cyano, C1-C6 straight or branched alkyl, alkenyl, alkynylalkoxy,
Wherein R is 2 Optionally by one or more than one R, which may be the same or different 6 Substitution;
R 3 is hydrogen, deuterium, hydroxy, halogen, amino, nitro, cyano, C1-C6 straight or branched alkyl, alkenyl, alkynyl, alkoxy,
Wherein R is 3 Optionally by one or more than one R, which may be the same or different 6 Substitution;
R 4 is hydrogen, deuterium, hydroxy, C1-C6 linear or branched alkyl, wherein R 4 Optionally by one or more than one R, which may be the same or different 6 Substitution;
R 5 is hydrogen, deuterium, straight or branched alkyl, cycloalkyl, carbonylalkyl, aryl, heterocyclyl, alkanoyl, carbamoyl, or the like, wherein R is 5 Optionally by one or more than one R, which may be the same or different 6 Substitution;
R 6 deuterium, hydroxy,Amino, mercapto, cyano, alkenyl, alkynyl, straight or branched alkyl, cycloalkyl, aryl, heterocyclyl, alkoxy, aryloxy, carbamoyl, azido, alkylamino, alkylsulfonyl, arylsulfonyl and the like, wherein R is 6 Optionally by one or more than one R, which may be the same or different 7 Substitution;
R 7 is deuterium, hydroxy, amino, mercapto, cyano, alkenyl, alkynyl, straight or branched chain alkyl, cycloalkyl, aryl, heterocyclyl, alkoxy, aryloxy, carbamoyl, azido, alkylamino, alkylsulfonyl, arylsulfonyl.
2. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X is CR 1 R 2 Wherein R is 1 、R 2 Each independently selected from hydrogen, deuterium; y is CR 3 Wherein R is 3 Independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, substituted or unsubstituted C1-C3 alkyl, said substituted substituent being deuterium, hydroxy, halogen; z is CR 4 Wherein R is 4 Independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, C1-C3 alkyl; r is R 1 Hydrogen, deuterium, monophosphate, diphosphate, triphosphate,
C1-C6 linear or branched alkanes, cycloalkanes, nitro groups, aryl groups, heterocyclic groups, phosphate esters or phosphoramidates; r is R 2 Is hydrogen, deuterium, hydroxy, fluoro, bromo, chloro, amino, nitro, cyano, alkoxy,/->
R 3 Is hydrogen, deuterium, hydroxy, fluoro, bromo, chloro, amino, nitro, cyano, alkoxy,/->
R 4 Hydrogen, deuterium, hydroxy, methyl; r is R 5 Hydrogen, deuterium, methyl; wherein R is 5 Is hydrogen,Deuterium, C1-C6 straight or branched alkyl, cycloalkyl, aryl, nitrogen-containing heterocyclyl, oxygen-containing heterocyclyl, R 6 Is hydrogen, deuterium, C1-C6 straight or branched alkyl, cycloalkyl, benzene ring, nitrogen-containing heterocyclyl, R 7 Is hydrogen, deuterium, C1-C6 straight or branched alkyl, cycloalkyl, benzene ring, nitrogen-containing heterocyclic group.
3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, characterized in that X is CH 2 The method comprises the steps of carrying out a first treatment on the surface of the Y is CH; z is CH; r1 is hydrogen,
R 2 Is hydroxy, fluoro, ">
R 3 Is hydroxy, fluoro, ">
R 4 Is hydrogen; r is R 5 Is hydrogen; wherein R is 5 Is C1-C3 straight-chain or branched alkyl, R 6 Is a benzene ring, R 7 Is a C1-C6 straight or branched alkyl group.
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula ii:
5. a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has the structure of formula iii:
6. a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound has a structure according to the formula:
7. a process for preparing a compound according to claim 4, comprising the steps of:
wherein R1 is hydrogen,
R2 is OR ", wherein R" is Bn OR +.>
Or R1 is linked with R' to form->
1) Step 1, reacting a compound A with 1,2, 4-triazole under the condition of a catalyst to obtain a compound B;
2) And 2, hydrolyzing the compound B under alkaline conditions to obtain the formula II.
8. The method for preparing a compound according to claim 7, wherein the catalyst in the step 1) is phosphorus oxychloride, the reaction solvent is acetonitrile, the reaction temperature is 0 ℃, and the reaction time is 30-60min; the alkali used in the step 2) is hydroxylamine water, the reaction solvent is isopropanol, the reaction temperature is room temperature, and the reaction time is 20min.
9. The method according to claim 7 or 8, wherein when R "is Bn, the step 1 further comprises a step of benzyl deprotection under DDQ conditions, the specific reaction conditions being: reacting in dichloromethane solution at 58 ℃ for 43h; when R1 is linked with R' to form
When the method is used, the step 2 further comprises a step of deprotection of a silyl ether protecting group, and the specific reaction conditions are as follows: refluxing in methanol solvent in the presence of ammonium fluoride for 2h.
10. A process for preparing a compound according to claim 5, comprising the steps of:
wherein R is 1 Is hydrogen,
R 2 Is hydroxyl;
1) Step 1, hydrolyzing a compound C under alkaline conditions to obtain a compound D;
2) And 2, reacting the compound D with 1,2, 4-triazole under the condition of a catalyst to obtain an intermediate product, and hydrolyzing the intermediate product under the alkaline condition to obtain the compound shown in the formula III.
11. A pharmaceutical composition, characterized in that it is a formulation made of an active ingredient and a pharmaceutically acceptable excipient or carrier; the active ingredient is a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt or solvate thereof.
12. The pharmaceutical composition according to claim 11, wherein the formulation is selected from the group consisting of tablets, dispersions, capsules, granules, powders, suppositories, ointments, pastes, gels, injections, drops, solutions, emulsions or suspensions.
13. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of a viral infection disorder in a human or animal.
14. Use according to claim 13, characterized in that the medicament is a medicament for the treatment and/or prophylaxis of coronavirus, influenza virus, rabies virus, hepatitis b virus, calicivirus, herpes virus infection diseases.
15. The use according to claim 13 or 14, characterized in that the medicament is a medicament for the treatment and/or prophylaxis of human novel coronavirus infections, feline infectious peritonitis virus infections, feline enterocoronavirus infections, feline stomatitis diseases.
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