CN107382811A - N alkyl substituted benzoic acid derivatives and its production and use - Google Patents

N alkyl substituted benzoic acid derivatives and its production and use Download PDF

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Publication number
CN107382811A
CN107382811A CN201710529927.8A CN201710529927A CN107382811A CN 107382811 A CN107382811 A CN 107382811A CN 201710529927 A CN201710529927 A CN 201710529927A CN 107382811 A CN107382811 A CN 107382811A
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benzoic acid
derivative
influenza
alkyl substituted
compound
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CN107382811B (en
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李雁武
王敬
胡叶敏
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Chongqing Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides a kind of N alkyl substituted benzoic acids derivative, and such compound proves through experiment in vitro, and to A, Type B influenza neuraminidase shows stronger activity；Compared with the reactive compound listed now, reactive compound of the invention does not have chiral centre, synthesizes simpler；Raw material is simple and easy to get simultaneously, and market supply is more, cheap.Preparation method of the present invention is simple, is adapted to industrialized production.

Description

N- alkyl substituted benzoic acid derivatives and its production and use
Technical field
The present invention relates to field of medicaments, and in particular to a kind of N- alkyl substituted benzoic acids derivative and preparation method thereof and use On the way.
Background technology
Influenza is a kind of global infectious diseases as caused by influenza virus, and a kind of infectiousness it is strong, The fast disease of spread speed.Its spittle main through the air, interpersonal contact or the contact with contaminated article Propagate；Typically clinical symptoms are：It is anxious to play high fever, significantly overall pain, weak and slight respiratory symptom.General autumn and winter It it is its high-incidence season, caused complication and the phenomena of mortality are very serious.The disease is caused by influenza virus, can be divided into first (A), Second (B), third (C) three type.According to the protein classes of virus surface and the difference of combination, influenza A virus is further divided into Asia Type, including H1N1, H3N2 etc..H is referred to as red blood cell condensation element, and N is referred to as neuraminidase, and they are all sugared eggs In vain, it is distributed in virus surface.H has 1-15 hypotype, and N has 1-9 hypotype (in the case of Alphavirus).Alphavirus is frequent Generation antigenic variation, infectiousness is big, propagates rapidly, easily occurs a wide range of popular.H1N1 has self limiting, but in baby children Youngster, the elderly and the severe complications such as the easy Complicating Pneumonia In Patients of patient of cardiopulmonary underlying diseases be present and cause death.
It is to prevent and treat the major measure of influenza for target group's vaccine inoculation and drug therapy.Due to more than influenza virus sub-strain and The forecasting accuracy for often breaking out the mankind's convection current sense the characteristics of variation substantially reduces, when new highly pathogenic virus subtype occurs When, the task that corresponding vaccine is hardly possible completion is produced before its propagation.So effective resisiting influenza virus Medicine can control flu outbreak and be tried to gain time precious to one for the development of vaccine.At present, influenza virus prevention and treatment Main Means are to use neuraminidase inhibitor medicine, and the medicine is for target with the neuraminidase of influenza surface (NA) Point.It is in mushroom tetramer glycoprotein that NA is one as one kind of virus surface, has the activity of hydrolysis sialic acid, treats as After mode of the ripe influenza virus through budding departs from host cell, the hemagglutinin of virus surface can be via sialic acid receptor and place Mainly cell membrane is kept in touch, it is necessary to be hydrolyzed sialic acid by neuraminidase, and cut-out virus contacts with the last of host cell, makes Virus smoothly can discharge from host cell, then infect next host cell.Therefore, suppressing NA can protect host from disease Poison infection and the propagation of delay virus, neuraminidase also turn into a potent action target spot for the treatment of of influenza medicine.
Due to the easy variability of influenza virus, its trend and to research and develop corresponding vaccine difficult of causing a disease, therefore medicine are predicted Thing treatment is still to answer the Main Means of infected by influenza now；Clinical practice is wider at present, influenza virus evident in efficacy god Through propylhomoserin enzyme inhibitor zanamivir and Oseltamivir, although its infected by influenza specificity is higher, discovered in recent years is got over Carry out more drug resistant cases.Because it contains multiple chiral centers, synthesis cost is higher, and price is high, intangibly adds The financial burden of patient, and expensive basic medical unit can not be equipped with, be unfavorable for country to the prevention of flu outbreak and Control.Therefore, develop new, efficiently, inexpensive resisiting influenza virus neuraminidase inhibitor has important reality meaning Justice.
The content of the invention
In order to solve the problems of the prior art, according to the first aspect of the invention, it is an object of the invention to provide one Class N- alkyl substituted benzoic acid derivatives.
The object of the present invention is achieved like this：
A kind of N- alkyl substituted benzoic acids derivative, there is following structure：
Inventors be surprised to learn that above-mentioned N- alkyl substituted benzoic acids derivative, with relatively strong anti-H1N1 Influenza Activities Meanwhile also there is stronger anti-H3N2 Influenza Activities, or even also have preferable therapeutic effect to Type B influenza.
According to the second aspect of the invention, it is an object of the invention to provide a kind of N- alkyl substituted benzoic acids derivative, It can be used as raw material or pharmaceutical intermediate that above-mentioned benzoic acid derivative I-IV is prepared.
A kind of benzoic acid derivative, there is following structure：
According to the third aspect of the invention we, it is an object of the invention to provide the preparation method of above-claimed cpd.The present invention Using the compound L of amino-contained as initiation material, intermediate compound I a is prepared, then hydrolyzes to obtain compound I.According to similar reason By the compound L of amino-contained of the present invention is initiation material, and intermediate II a is prepared, then hydrolyzes to obtain compound II；This hair The compound L of bright amino-contained is initiation material, and intermediate III a is prepared, then hydrolyzes to obtain compound III；The present invention contains amine The compound L of base is initiation material, and intermediate compound IV a is prepared, then hydrolyzes to obtain compound IV.
Specific syntheti c route is as follows：
According to the fourth aspect of the invention, it is an object of the invention to provide above-mentioned N- alkyl substituted benzoic acids derivative to exist Prepare the application in Tamiflu；Especially in anti-highly pathogenic H1N1 influenzas, H3N2 influenzas and Type B flu pharmaceutical Application.
According to the fifth aspect of the invention, it is an object of the invention to provide benzoic acid derivative (Ia-IVa) as system The purposes of standby N- alkyl substituted benzoic acids derivative (I-IV) raw material or intermediate.
According to the sixth aspect of the invention, it is an object of the invention to provide benzoic acid derivative (Ia-IVa) as N- Purposes in alkyl substituted benzoic acid derivative (I-IV) impurity reference substance.
Beneficial effect：
The present invention provides a kind of N- alkyl substituted benzoic acids derivative I-IV, and to A, Type B influenza neuraminidase is equal Show stronger activity；Compared with the reactive compound listed now, reactive compound of the invention is without in chirality The heart, synthesis are simpler；Raw material is simple and easy to get simultaneously, and market supply is more, cheap.The compounds of this invention I-IV is to A types H1N1 influenzas, H3N2 influenzas and Type B influenza virus have stronger selectivity, and (A influenza viruses have stronger cause to the mankind Characteristic of disease), and have the activity (note of nM levels to two class A type neuraminidase subtypes：Whether cavity is had according to enzyme active center, N1, N4, N5, N8 are one group of hypotype, and N2, N3, N6, N7, N9 is another group of hypotype, and same hypotype enzyme active center structure is similar). The present invention can develop efficiently, cheap anti-influenza virus medicament, be people's health service；To Type B influenza virus nerve Propylhomoserin enzyme also has stronger activity.The compounds of this invention infected by influenza broad covered area, is applicable not only to the treatment of influenza, Prevention available for influenza.Preparation method of the present invention is simple, is adapted to industrialized production.
Embodiment
The present invention is specifically described below by specific embodiment, it is pointed out here that following examples are served only for this hair It is bright to be further described, it is impossible to be interpreted as limiting the scope of the invention, the person skilled in the art of this area can root Some nonessential modifications and adaptations are made to the present invention according to foregoing invention content.All raw materials of the present invention and reagent are commercially available Product.
Embodiment 1：
The syntheti c route of compound (I)
Detailed process is：
4- (5- (2,2- diacetyl methylol ester) pyrrolidines -1- ketone) -3- (2- (1- ethyl-propylamines base)-ethyl) benzene first The preparation of sour methyl esters (Ia)：
L (0.34mmol) is dissolved in 1ml 1, in 2- dichloroethanes and 0.5ml acetic acid, is adding propione (2.30mmol) and NaBH3CN (1.2mmol), mixture are stirred at room temperature 6 hours, reactant mixture ethyl acetate 10ml Dilution, then uses saturated sodium bicarbonate (3 × 5mL) respectively, and water (2 × 5mL) and saturated aqueous common salts (2 × 5mL) wash organic layer, Organic layer anhydrous sodium sulfate drying, filter, concentration, residue with silica gel column chromatography separate Ia (colorless oil, 86% Yield)：1H NMR (300MHz, CDCl3) δ 0.87 (m, 6H), 1.52 (m, 4H), 1.82 (s, 3H), 2.17 (s, 3H), 2.36 (m, 2H), 2.75 (m, 2H), 2.90 (m, 1H), 3.00 (m, 1H), 3.18 (m, 2H), 3.39 (m, 1H), 3.95 (d, J=12Hz, 1H), 3.96 (s, 3H), 4.24 (d, J=12.0Hz, 1H), 4.25 (d, J=12.0Hz, 1H), 4.34 (d, J=11.6Hz, 1H), 7.12 (d, J=8.3Hz, 1H), 8.02 (d, J=8.3Hz, 1H), 8.10 (s, 1H)；MS(ES)m/z 476(M+1).
4- (5- (2,2- dihydroxymethyl) pyrrolidines -1- ketone) -3- (2- (1- ethyl-propylamines base)-ethyl) benzoic acid (I) Prepare：
Ia (0.2mmol) is dissolved in 2ml methanol, 2ml 1Mol/L sodium hydroxide is added, then by mixture in room Temperature lower stirring half an hour, then pH value is adjusted to 2 with 1Mol/L hydrochloric acid.Mixture is evaporated, the solid of residual is dissolved in 3ml In methanol, filtering, filtrate is concentrated, the residue of acquisition separates to obtain I (white solid, 74% yield) through post layer chromatography：m.p. 300 DEG C of ＞；1H NMR (400MHz, D2O) δ 0.90 (m, 6H), 1.65 (m, 4H), 2.25 (t, J=8.0Hz, 2H), 2.66 (t, J =8Hz, 2H), 3.13-3.07 (m, 2H), 3.24 (m, 2H), 3.40 (d, J=12.4Hz, 1H), 3.50 (d, J=12.4Hz, 1H), 3.66 (d, J=12.0Hz, 1H), 3.72 (d, J=12.0Hz, 1H), 3.99 (m, 1H), 7.29 (d, J=8.2Hz, 1H), 7.84 (d, J=8.2Hz, 1H), 7.94 (s, 1H)；MS(ES)m/z 379(M+1).
Embodiment 2：
The syntheti c route of compound (II)：
Detailed process is：
4- (5- (2,2- diacetyl methylol ester) pyrrolidines -1- ketone) -3- (2- isopropylamine bases-ethyl) methyl benzoate (IIa) preparation：
L (0.34mmol) is dissolved in 1ml 1, in 2- dichloroethanes and 0.5ml acetic acid, is adding acetone (2.30mmol) and NaBH3CN (1.2mmol), mixture are stirred at room temperature 6 hours, reactant mixture ethyl acetate 10ml Dilution, then uses saturated sodium bicarbonate (3 × 5mL) respectively, and water (2x 5mL) and saturated aqueous common salts (2 × 5mL) wash organic layer, Organic layer anhydrous sodium sulfate drying, filter, concentration, residue with silica gel column chromatography separate IIa (colorless oil, 88% Yield)：1H NMR (400MHz, CDCl3) δ 1.24 (d, J=6.5Hz, 3H), 1.31 (d, J=6.5Hz, 3H), 1.79 (s, 3H), 2.17 (s, 3H), 2.27 (m, 1H), 2.37 (m, 1H), 2.71 (m, 1H), 2.80 (m, 1H), 2.97 (m, 1H), 3.11 (m, 1H), 3.23 (m, 2H), 3.44 (m, 1H), 3.90 (d, J=12Hz, 1H), 3.92 (s, 3H), 4.21 (t, J=11.7Hz, 2H), 4.31 (d, J=12Hz, 1H), 7.09 (d, J=8.2Hz, 1H), 7.97 (d, J=8.2Hz, 1H), 8.05 (s, 1H)；MS(ES) m/z 448(M+1).
The preparation of 4- (5- (2,2- methylol) pyrrolidines -1- ketone) -3- (2- isopropylamine bases-ethyl) benzoic acid (II)：
IIa (0.2mmol) is dissolved in 2ml methanol, 2ml 1Mol/L sodium hydroxide is added, then by mixture in room Temperature lower stirring half an hour, then pH value is adjusted to 2 with 1Mol/L hydrochloric acid.Mixture is evaporated, the solid of residual is dissolved in 3ml In methanol, filtering, filtrate is concentrated, the residue of acquisition separates to obtain II (white solid, 58% yield) through post layer chromatography：m.p. 300 DEG C of ＞；1H NMR (400MHz, D2O) δ 1.27 (d, J=5.8Hz, 3H), 1.29 (d, J=5.8Hz, 3H), 2.28 (t, J= 8.0Hz, 2H), 2.69 (t, J=8.0Hz, 2H), 3.00 (m, 1H), 3.10 (m, 1H), 3.32-3.25 (m, 2H), 3.40 (m, 1H), 3.43 (d, J=12.1Hz, 1H), 3.52 (d, J=12.1Hz, 1H), 3.70 (d, J=12.2Hz, 1H), 3.75 (d, J= 12.2Hz, 1H), 7.30 (d, J=8.3Hz, 1H), 7.85 (d, J=8.3Hz, 1H), 7.95 (s, 1H)；MS(ES)m/z 351(M +1).
Embodiment 3：
The syntheti c route of compound (III)：
Detailed process is：
4- (5- (2,2- diacetyl methylol ester) pyrrolidines -1- ketone) -3- (2- diethyl amido-ethyl) methyl benzoate (IIIa) preparation：
L (0.34mmol) is dissolved in 1ml 1, in 2- dichloroethanes and 0.5ml acetic acid, is adding acetaldehyde (2.30mmol) and NaBH3CN (1.2mmol), mixture is stirred at room temperature 6 hours, then acetaldehyde is added into system (2.30mmol) and NaBH3CN (1.2mmol) continues stirring 15 hours.Reactant mixture is diluted with ethyl acetate 10ml, then Saturated sodium bicarbonate (3 × 5mL) is used respectively, and water (2x 5mL) and saturated aqueous common salts (2 × 5mL) wash organic layer, organic layer nothing Aqueous sodium persulfate is dried, and is filtered, and concentration, residue separates to obtain IIIa (colorless oil, 68% yield) with silica gel column chromatography：1H NMR (400MHz, CDCl3) δ 7.98-7.96 (m, 2H), 7.14 (d, J=7.8Hz, 1H), 4.23 (d, J=12.0Hz, 1H), 4.33 (d, J=12.1Hz, 1H), 4.27 (d, J=12.1Hz, 1H), 4.05 (d, J=12.0Hz, 1H), 3.94 (s, 3H), 3.54-3.47 (m, 2H), 3.21 (m, 2H), 3.12 (m, 2H), 3.02-2.94 (m, 3H), 2.66-2.59 (m, 2H), 2.21 (m, 1H), 2.16 (s, 3H), 1.71 (s, 3H), 1.40 (t, J=7.2Hz, 6H)；MS(ES)m/z 463(M+1).
The preparation of 4- (5- (2,2- methylol) pyrrolidines -1- ketone) -3- (2- diethyl amido-ethyl) benzoic acid (III)：
IIIa (0.2mmol) is dissolved in 2ml methanol, 2ml 1Mol/L sodium hydroxide is added, then mixture exists Stir half an hour, then adjusted pH value to 2 with 1Mol/L hydrochloric acid at room temperature.Mixture is evaporated, the solid of residual is dissolved in In 3ml methanol, filtering, filtrate is concentrated, the residue of acquisition separates to obtain III (white solid, 61% yield) through post layer chromatography： M.p. 300 DEG C of ＞；1H NMR (400MHz, D2O) δ 0.97 (t, J=7.2Hz, 3H), 0.99 (t, J=7.2Hz, 3H), 2.00 (m, 2H), 2.39 (m, 2H), 3.00-2.70 (m, 8H), 3.10 (d, J=12.1Hz, 1H), 3.21 (d, J=12.1Hz, 1H), 3.25 (d, J=12.1Hz, 1H), 3.44 (d, J=12.1Hz, 1H), 7.04 (d, J=8.4Hz, 1H), 7.60 (d, J=8.4Hz, 1H), 7.68 (s, 1H)；MS(ES)m/z 345(M+1).
Embodiment 4：
The syntheti c route of compound (IV)：
Detailed process is：
4- (5- (2,2- diacetyl methylol ester) pyrrolidines -1- ketone) -3- (2- diη-propyls amido-ethyl) benzoic acid first The preparation of ester (IVa)：
L (0.34mmol) is dissolved in 1ml 1, in 2- dichloroethanes and 0.5ml acetic acid, is adding propionic aldehyde (2.30mmol) and NaBH3CN (1.2mmol), mixture is stirred at room temperature 6 hours, then propionic aldehyde is added into system (2.30mmol) and NaBH3CN (1.2mmol) continues stirring 15 hours.Reactant mixture is diluted with ethyl acetate 10ml, then Saturated sodium bicarbonate (3 × 5mL) is used respectively, and water (2x 5mL) and saturated aqueous common salts (2 × 5mL) wash organic layer, organic layer nothing Aqueous sodium persulfate is dried, and is filtered, and concentration, residue separates to obtain IVa (colorless oil, 61% yield) with silica gel column chromatography：1H NMR (300MHz, CDCl3) δ 1.00 (m, 6H), 1.73 (s, 3H), 1.82 (m, 4H), 2.17 (s, 3H), 2.23 (m, 1H), 2.44 (m, 1H), 2.80-2.60 (m, 3H), 3.20-2.94 (m, 6H), 3.54-3.47 (m, 1H), 3.95 (s, 3H), 4.00 (d, J= 12.1Hz, 1H), 4.36-4.26 (m, 3H), 7.15 (d, J=8.2Hz, 1H), 8.02-7.98 (m, 2H)；MS(ES)m/z 463 (M+1).
The system of 4- (5- (2,2- dihydroxymethyl) pyrrolidines -1- ketone) -3- (2- diη-propyls amido-ethyl) benzoic acid (IV) It is standby：
IVa (0.2mmol) is dissolved in 2ml methanol, 2ml 1Mol/L sodium hydroxide is added, then by mixture in room Temperature lower stirring half an hour, then pH value is adjusted to 2 with 1Mol/L hydrochloric acid.Mixture is evaporated, the solid of residual is dissolved in 3ml In methanol, filtering, filtrate is concentrated, the residue of acquisition separates to obtain IV (white solid, 65% yield) through post layer chromatography：Mp ＞ 300℃；1H NMR (400MHz, CDCl3) δ 0.84 (t, J=7.2Hz, 6H), 1.59 (m, 4H), 2.22-2.16 (m, 2H), 2.60-2.53 (m, 2H), 2.87 (m, 1H), 3.21-2.98 (m, 7H), 3.27 (d, J=12.3Hz, 1H), 3.30 (d, J= 12.3Hz, 1H), 3.54 (d, J=12.3Hz, 1H), 3.59 (d, J=12.3Hz, 1H), 7.21 (d, J=8.3Hz, 1H), 7.74 (d, J=8.3Hz, 1H), 8.81 (s, 1H)；MS(ES)m/z 393(M+1).
Embodiment 5：
The syntheti c route of 1- (4- carbonyl -2- guanidine radicals) -5,5- dihydroxymethyls pyrrolidin-2-one (V)：
Detailed process is：
Compound Va (350mg, 0.57mmol) is dissolved in 1mL methanol, then adds 2.5mL 1Mol/L NaOH, will be mixed Liquid is closed to be stirred at room temperature 16 hours.Reaction solution with 1Mol/L HCl adjust PH to 3, be evaporated solution, by the residue of acquisition pass through from Sub- exchange chromatography separates (ion exchange resin；1.4N NH4OH) obtain V (110mg, 59.0% yield)：MS 323(M+1)；1H NMR (300MHz, D2O) δ 7.95 (d, 1H, J=1.8Hz), 7.93 (dd, 1H, J=1.9＆8.2Hz), 7.45 (d, 1H, J= 8.2Hz), 3.7 (dd, 2H, J=8.1＆12.0Hz), 3.55 (d, 1H, J=12.0Hz), 3.29 (d, 1H, J=12Hz), 2.7 (m, 2H), 2.35 (m, 2H)
Embodiment 6：
Viral experiment method：
Strains of influenza viruses is grown in the egg containing embryo.By -4- methyl the umbrellas of neuraminidase specific fluorescence substrate 2 ' Shape ketone-a-N- n acetylneuraminic acid ns (2 '-(4-methylumbelliferyl) a-D-N-acetylneuraminic acid) add IC is determined in entering to 96 fluorescence ELISA Plates50Numerical value.Reaction is being added using the complete virion after purification of neuraminidase Before 100uM fluorogenic substrates, first the inhibitor by twice of dilution is put in 50mM sodium acetates, 100uM calcium chloride, 320uM magnesium chlorides With (pH value 6.0) in 60uM sodium chloride；Preculture 30 minutes at room temperature.Reactant mixture 37 degree culture 15 minutes after, The 0.2M Glycine-NaOHs mixed liquor (pH value 11) accumulated with pentaploid stops reaction.IC50Numerical value is passed through by prism software The response of the corresponding standardization of the logarithm of inhibitor concentration selectively determines；The dense of inhibitor is corresponded to using the part inhibitory activity of enzyme Degree, which is drawn, comes logarithm value progress cross-check, IC50Determined by the dose-response curve of the range of linearity.IC50Numerical value such as following table It is shown：
a：Activity data is the influenza virus (N1 be same group of hypotype with N9) for N9 hypotypes
Being tested by external activity, compound I-IV of the invention shows resisiting influenza virus neuraminidase N1, N2, B activity.Wherein I, II have a strong anti-neuraminidase activity, and to two kinds of different classes of hypotypes (H1N1, H3N2 influenza neuraminidase) all has significant activity, also has to Type B influenza neuraminidase stronger Activity；Compound I, II, III, IV significantly strengthen into hundreds times activity of the activity of influenza A than compound V； Compound I, II, III, IV are strong than compound V to the activity of Type B influenza virus.Compound I, II, III, IV are sub- to N1 classifications Type also has stronger inhibitory activity, and compound V is to N1 classifications hypotype without activity；This explanation the compounds of this invention infected by influenza Broad covered area, it is not only suitable for the treatment of various influenza, it can also be used to the prevention of influenza.To sum up, the present invention has important practicality Meaning.

Claims (9)

1.N- alkyl substituted benzoic acid derivatives, there is following structure：
2. a kind of benzoic acid derivative, there is following structure：
3. the preparation method of derivative as claimed in claim 1, using following route：
4. application of the derivative as claimed in claim 1 in prevention or treatment Tamiflu is prepared.
5. application of the derivative as claimed in claim 1 in preparing prevention or treating anti-H1N1 flu pharmaceuticals.
6. application of the derivative as claimed in claim 1 in preparing prevention or treating anti-H3N2 flu pharmaceuticals.
7. application of the derivative as claimed in claim 1 in preparing prevention or treating anti-Type B flu pharmaceutical.
8. benzoic acid derivative Ia-IVa as claimed in claim 2 is as preparing benzoic acid derivative I-IV raw materials or intermediate Purposes.
9. use of the benzoic acid derivative Ia-IVa as claimed in claim 2 in as benzoic acid derivative I-IV impurity reference substances On the way.
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WO1999014191A1 (en) * 1997-09-17 1999-03-25 Biocryst Pharmaceuticals, Inc. Pyrrolidin-2-one compounds and their use as neuraminidase inhibitors
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