CN105732468B - A kind of N '-(2- (1H- indol-3-yls) acetyl group) aromatic hydrazide kind compound and its preparation method and application - Google Patents

A kind of N '-(2- (1H- indol-3-yls) acetyl group) aromatic hydrazide kind compound and its preparation method and application Download PDF

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CN105732468B
CN105732468B CN201610213100.1A CN201610213100A CN105732468B CN 105732468 B CN105732468 B CN 105732468B CN 201610213100 A CN201610213100 A CN 201610213100A CN 105732468 B CN105732468 B CN 105732468B
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reaction
acetyl group
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indol
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CN105732468A (en
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夏雪山
何严萍
冯悦
范孟然
高凤萍
张玉芳
李聪
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Yunnan University YNU
Kunming University of Science and Technology
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Kunming University of Science and Technology
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The present invention provides a kind of N'(2 (3 base of 1H indoles) acetyl group) aromatic hydrazide kind compound and its preparation method and application; N'(2 (3 base of the 1H indoles) acetyl group) aromatic hydrazide kind compound have Formulas I shown in structure; it significantly inhibits HCV virus; HCV-Ab IgG viral therapy index is higher than existing clinical medicine Interferon α1 b (IFN α 1b) and Ribavirin (Ribavirin); it can be used as anti-HCV medicament candidate; and the preparation method of the present invention is simple, yield is high, is suitable for industrial production.

Description

A kind of N '-(2- (1H- indol-3-yls) acetyl group) aromatic hydrazide kind compounds and its system Preparation Method and purposes
Technical field
The invention belongs to field of medicine preparing technology, are related to a kind of N'- (2- (1H- indol-3-yls) acetyl group) virtue Hydrazide kind compound and its preparation method and application.
Background technology
Hepatitis C is that one kind caused by Hepatitis C Virus (hepatitis C virus, HCV) seriously threatens the mankind The liver diseases of health, about 1.7 hundred million people's HCV infections in world wide, wherein nearly 60%-80% would develop into chronic hepatitis, portion Divide and is further development of hepatic sclerosis and liver cancer.HCV still lacks effective prevention vaccine, and therapy in the past 20 years is mainly dry The use in conjunction for disturbing element (IFN)-α or the long-acting IFN and broad-spectrum antiviral medicament Ribavirin of polyethylene glycol (PEG) modification, should Therapy is significant in efficacy but only effective to 40% or so I type patients for II type and III type patient, and fash etc. is serious not Good reaction also affects its use.In recent years a series of HCV protease inhibitors are had developed, as NS3/4A serine proteases inhibit Agent, NS5B RdRp polymerase inhibitors, NS3 unwindases/ribonucleoside triphosphote enzyme inhibitor etc., wherein NS3 serine proteases exist It plays a decisive role in polyprotein transcription and hydrolytic process, inhibits its proteinase activity, growth, the breeding of HCV can be hindered, because This is considered as studying best one of the target spot of anti-hepatitis drug.With using HCV NS3/4A as the inhibitor telavi of target (telarevir) with the use in conjunction of IFN-α and Ribavirin clinically, it is hot that HCV Ns3/4A inhibitor has become research Point.Molecule mainly is designed from substrate structure for the inhibitor of NS3/NS4A serine proteases, these inhibitor are from change It learns and is broadly divided into peptides and non-peptide inhibitor in structure.Now report the compound of some non-peptide albuminoid enzyme inhibitors, such as thiophene Oxazolidine analog derivative, luxuriant and rich with fragrance quinones, benzimidazoles derivative etc., they have the inhibition of 3 protease of good NS in vitro Activity, we are had found by structural analysis, general in their molecules all to contain virtue although these inhibitor structures are different Fragrant female ring is rich in amido bond, and more calm linear structure is presented in these inhibitor molecules mostly, to NS3 protease with Substrate binding site is adapted compared with shallow trench.
There are Benzazole compounds a series of bioactivity, many derivatives to have significant pharmacological activity.In clinic Pharmaceutically, some indole derivatives have been used for treating a variety of diseases, such as cancer, tumour, anti-inflammatory analgesic and viral disease and Communicable disease.
CN1752085A discloses a kind of aromatic hydrazide kind compound, has the following structure：
In this configuration, R1 is hydrogen atom or C1-C6 alkyl；Ar1 and Ar2 are each independently selected from：3- indyls, 5- indoles Base, 2- quinolyls, 4- quinolyls, 2- pyridyl groups, 3- pyridyl groups, 2- pyrrole radicals, 3- pyrrole radicals, 2- thienyls, 3- thienyls, pyrrole Oxazolyl, 2- furyls, 3- furyls；Above-mentioned group is unsubstituted or is replaced selected from following substituent group by 1 or 2：Halogen, Nitro, hydroxyl, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxies, C1-C6 alkoxy acyls, amino, carboxyl, phenyl, benzyl, benzene Sulfonyl.The compound can be used for preventing and/or treat certain autoimmune diseases.
In the art, it is expected that the bioactivity in conjunction with Benzazole compounds is a kind of with anti-hepatitis c virus to prepare The drug of effect.
Invention content
In view of the deficiencies of the prior art, the purpose of the present invention is to provide a kind of N'- (2- (1H- indol-3-yls) acetyl Base) aromatic hydrazide kind compound and its preparation method and application.
For this purpose, the present invention uses following technical scheme：
On the one hand, the present invention provides a kind of N'- (2- (1H- indol-3-yls) acetyl group) aromatic hydrazide kind compound, has Structure shown in Formulas I：
In Formulas I, n=0,1 or 2, R are substituted or unsubstituted phenyl ring, substituted or unsubstituted Naphthalene nucleus, substituted or unsubstituted anthracene nucleus, substituted or unsubstituted furan nucleus, substituted or unsubstituted xenyl,In any one, it is described Phenyl ring, naphthalene nucleus, anthracene nucleus, furan nucleus and xenyl substituent group independently selected from halogen, hydroxyl, nitro, trifluoromethyl, C1-C10 In alkyl or C1-C10 alkoxies any one or at least two combination.
Present invention combination NS3/NS4A serpin design features are analyzed, and indoles, this structural unit draws Enter into the design of HCV protease inhibitor, and imports and can synthesize serial chain type with the acylamino- group that serine is combined N '-(2- (1H- indol-3-yls) acetyl group) virtue hydrazide compounds, experiment in vitro prove that such compound has apparent HCV-Ab IgG Activity.
In the present invention, the halogen be F, Cl, Br or I in any one or at least two combination.
In the present invention, the C1-C10 alkyl can be C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl, example It such as can be but be not limited to methyl, ethyl, propyl, butyl or amyl.
In the present invention, the C1-C10 alkoxies can be C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alcoxyl Base, such as can be but be not limited to methoxyl group, ethyoxyl, propoxyl group or butoxy.
Preferably, N'- (2- (1H- indol-3-yls) acetyl group) aromatic hydrazide kind compound of the present invention is with 1 institute of table Show in the compound of structure any one or at least two combination.
Table 1
On the other hand, the present invention provides the fragrant acyls of N'- (2- (1H- indol-3-yls) acetyl group) as described in relation to the first aspect The preparation method of hydrazine class compound, the described method comprises the following steps：
(1) heteroauxin obtains ethychlozate ester shown in Formula II with C1-C5 alcohol generation esterification, and reaction equation is as follows：
Wherein R1For C1-C5 alkyl；
(2) indoles acethydrazide shown in formula III is obtained by the reaction with hydrazine hydrate in ethychlozate ester shown in Formula II, and reaction equation is as follows：
(3) aromatic carboxylic acids shown in formula IV is reacted with chlorination reagent is prepared aryl-acyl chlorides shown in Formula V, and reaction equation is such as Under：
(4) (2- (the 1H- Yin of N'- shown in Formulas I are obtained by the reaction with aryl-acyl chlorides shown in Formula V in the indoles acethydrazide shown in formula III Diindyl -3- bases) acetyl group) aromatic hydrazide kind compound, reaction equation is as follows：
In the preparation process in accordance with the present invention, step (1) the C1-C5 alcohol can be C1, C2, C3, C4 or C5 alcohol, preferably Any one in methanol, ethyl alcohol, propyl alcohol, butanol or amylalcohol, further preferably methanol, i.e. R1It can be C1 alkyl (i.e. first Base), C2 alkyl, C3 alkyl, C4 alkyl or C5 alkyl, preferably methyl.
Preferably, the molar ratio of step (1) heteroauxin and C1-C5 alcohol is 1:(5-40), such as 1:6、1:8、1: 10、1:12、1:15、1:18、1:20、1:22、1:24、1:28、1:30、1:32、1:35 or 1:38.In the present invention, alcohol is both made It is also used as reaction dissolvent for reaction raw materials, it is therefore desirable to more alcohol.
Preferably, step (1) is described reacts using strong acid as catalyst, preferably the concentrated sulfuric acid, the concentrated sulfuric acid preferably 98% The concentrated sulfuric acid.
Preferably, the temperature of step (1) described reaction be 50-80 DEG C, such as 50 DEG C, 53 DEG C, 55 DEG C, 58 DEG C, 60 DEG C, 63 DEG C, 65 DEG C, 68 DEG C, 70 DEG C, 73 DEG C, 75 DEG C, 78 DEG C or 80 DEG C.
Preferably, the time of step (1) described reaction is 1-8 hours, for example, 1 hour, 1.5 hours, 2 hours, it is 2.5 small When, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 when or it is 8 small When.
Preferably, the molar ratio of ethychlozate ester and hydrazine hydrate shown in step (2) described Formula II is 1:(1-4), such as 1: 1、1:1.5、1:1.8、1:2、1:2.2、1:2.5、1:2.8、1:3、1:3.3、1:3.5、1:3.8 or 1:4.
Preferably, solvent for use is ethylene glycol monomethyl ether in step (2) described reaction.
Preferably, the temperature of step (2) described reaction be 110-130 DEG C, such as 110 DEG C, 115 DEG C, 120 DEG C, 125 DEG C or 130℃。
Preferably, the time of step (2) described reaction be 5-24 hours, such as 6 hours, 7 hours, 8 hours, 9 hours, 10 Hour, 12 hours, 14 hours, 15 hours, 17 hours, 19 hours, 20 hours, 21 hours, 22 hours or 23 hours.
Preferably, step (3) described chlorination reagent be thionyl chloride, phosphorus trichloride or phosphorus pentachloride in any one or At least two combination, preferably thionyl chloride.
Preferably, the molar ratio of step (3) aromatic carboxylic acids and chlorination reagent is 1:(2-6), such as 1:2、1:2.2、 1:2.5、1:2.8、1:3、1:3.5、1:4、1:4.3、1:4.5、1:4.8、1:5、1:5.5、1:5.8 or 1:6.
Preferably, solvent for use is tetrahydrofuran in step (3) described reaction, and 1-3 is preferably added in tetrahydrofuran Drip DMF.
Preferably, the temperature of step (3) described reaction be 60-90 DEG C, such as 60 DEG C, 65 DEG C, 70 DEG C, 75 DEG C, 80 DEG C, 85 DEG C or 90 DEG C.
Preferably, the time of step (3) described reaction be 5-20 hours, such as 5 hours, 6 hours, 7 hours, 8 hours, 9 Hour, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours or 20 hours.
Preferably, the molar ratio of step (4) the indoles acethydrazide and aryl-acyl chlorides is 1:(1-1.5), such as 1:1、1: 1.1、1:1.2、1:1.3、1:1.4 or 1:1.5.
Preferably, step (4) reaction carries out in the presence of alkaline reagent.
Preferably, the alkaline reagent is triethylamine.
Preferably, the molar ratio of the alkaline reagent and indoles acethydrazide is 1:(1-3), such as 1:1、1:1.3、1:1.5、 1:1.8、1:2、1:2.2、1:2.5、1:2.8 or 1:3.
Preferably, solvent for use is tetrahydrofuran in step (4) described reaction.
Preferably, the temperature of step (4) described reaction be 0-30 DEG C, such as 0 DEG C, 5 DEG C, 10 DEG C, 12 DEG C, 15 DEG C, 18 DEG C, 20 DEG C, 23 DEG C, 25 DEG C, 28 DEG C or 30 DEG C.
Preferably, the time of step (4) described reaction be 5-24 hours, such as 5 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 21 hours, 22 hours, 23 hours or 24 hours.
As the preferred technical solution of the present invention, the fragrant hydrazides of N'- (2- (1H- indol-3-yls) acetyl group) of the present invention The preparation method of class compound includes the following steps：
(1) heteroauxin obtains heteroauxin methyl esters with methanol generation esterification, and reaction equation is as follows：
(2) indoles acethydrazide is obtained by the reaction with hydrazine hydrate in heteroauxin methyl esters, and reaction equation is as follows：
(3) aromatic carboxylic acids shown in formula IV is reacted with thionyl chloride is prepared aryl-acyl chlorides shown in Formula V, and reaction equation is such as Under：
(4) (2- (the 1H- Yin of N'- shown in Formulas I are obtained by the reaction with aryl-acyl chlorides shown in Formula V in the indoles acethydrazide shown in formula III Diindyl -3- bases) acetyl group) aromatic hydrazide kind compound, reaction equation is as follows：
On the other hand, the present invention provides the fragrant acyls of N'- (2- (1H- indol-3-yls) acetyl group) as described in relation to the first aspect Purposes of the hydrazine class compound in preparing anti hepatitis C virus drug.
N'- (2- (1H- indol-3-yls) acetyl group) aromatic hydrazide kind compound of the present invention can be used as anti-hepatitis C virus The active constituent candidate of cytotoxic drug has apparent anti-HCV activity.
Compared with the existing technology, the invention has the advantages that：
N'- (2- (1H- indol-3-yls) acetyl group) aromatic hydrazide kind compounds prepared by the present invention have HCV virus bright Aobvious inhibiting effect, HCV-Ab IgG viral therapy index are higher than existing clinical medicine interferon α-1b (IFN α -1b) and Ribavirin (Ribavirin), anti-HCV medicament candidate is can be used as, and the preparation method of the present invention is simple, yield is high, is suitable for industry Production.
Specific implementation mode
The technical solution further illustrated the present invention below by specific implementation mode.Those skilled in the art should be bright , the embodiment, which is only to aid in, understands the present invention, should not be regarded as a specific limitation of the invention.
Embodiment 1
In the present embodiment, it is prepared by the following method -1 compound of Formulas I, specifically includes following steps：
(1) heteroauxin 8.8g (50mmol), methanol (60mL), the concentrated sulfuric acid are added in 500 milliliters of round-bottomed flasks (3mL), 70 DEG C are reacted 1-3 hours, and TLC is detected after completion of the reaction, steam methanol, and water (50mL) is added, and detach organic phase, water phase It is extracted with ethyl acetate (3 × 20mL), merges organic phase, use saturated sodium bicarbonate solution and water washing, anhydrous sodium sulfate successively It is dry, heteroauxin methyl esters crude product is obtained after reduced pressure, this product is directly used in without purifying reacts in next step.
(2) the addition heteroauxin methyl esters 9.46g (48mmol) in 500 milliliters of round-bottomed flasks, ethylene glycol monomethyl ether (40mL), Hydrazine hydrate 5mL, 115 DEG C of heating reflux reactions about 20 hours, thin-layer chromatography (TLC) detects raw material point and disappears, and stops reaction, cooling To room temperature, water (50mL) is added, stands and white solid is precipitated, suction filtration obtains crude product, indoles acethydrazide is obtained with ethyl alcohol recrystallization 9.2 grams of white solid.
(3) various aromatic carboxylic acids 1.6mmol, anhydrous tetrahydro furan 10mL are added in 100 milliliters of round-bottomed flasks, is added dropwise one DMF to be dripped, 0.5mL thionyl chlorides, oil bath is added, 70 DEG C of heating are reacted about 10 hours, and TLC is detected after completion of the reaction, steams solvent, It obtains aroyl chloride crude product and is directly used in and react in next step.
(4) 3- indoles acethydrazide (300mg, 1.59mmol), anhydrous tetrahydro furan 10 are added in 100 milliliters of round-bottomed flasks Milliliter, Et3The tetrahydrofuran solution of chlorobenzoyl chloride (1.59mmol) is added dropwise in N (3mL, 1.59mmol), generates precipitation, continues room Temperature (25 DEG C) stir 12 hours, TLC detect after completion of the reaction, solvent is removed under reduced pressure and obtains orange/yellow solid, respectively use ethyl acetate, Water washing, suction filtration obtain faint yellow crude product, white solid sterling, yield are recrystallized to obtain with appropriate solvent：92%.mp： 180.0-181.0℃。
Nucleus magnetic hydrogen spectrum and mass spectral characteristi are carried out to obtained product, it is as a result as follows：
1H-NMR(500MHz,DMSO-d6),δ(ppm):3.78(s,2H,CH2),7.02(s,1H,Ar-H),7.09-7.34 (m,4H,Ar-H),7.43-7.54(m,2H,Ar-H),7.63-7.65(m,1H,Ar-H),7.84-7.86(m,2H,Ar-H), 10.18 (s, 1H, NH), 10.36 (s, 1H, NH), 10.91 (s, 1H, indoles-NH)；m/z 294.1[M++1]。
Embodiment 2
In the present embodiment, formula I-2 to Formulas I -35 compound, preparation method and -1 compound of 1 Formulas I of embodiment Preparation the difference is that only that the aroyl chloride used in step (4) is respectively In addition to this, the Formulas I -1 of preparation method and embodiment 1 is changed The preparation method for closing object is identical.
The Formulas I -2 being prepared is as follows to the character of -35 compound of Formulas I, yield and structural characterization result：
N'- (2- (1H- indol-3-yls) acetyl group) -2- iodobenzenes formylhydrazine (Formulas I -2)：White solid, yield：94%, mp:188.1-189.0℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.68(s,2H,CH2),6.92-6.93(s,1H, Ar-H),6.98-7.24(m,4H,Ar-H),7.32-7.35(m,1H,Ar-H),7.43-7.44(m,1H,Ar-H),7.53- 7.55(m,1H,Ar-H),7.80-7.82(m,1H,Ar-H),10.23(s,1H,NH),10.29(s,1H,NH),10.97(s, 1H, indoles-NH)；m/z 418.0[M+-1]。
N'- (2- (1H- indol-3-yls) acetyl group) phenylacetyl hydrazine (Formulas I -3)：White solid, yield：92%, mp: 96.4-197.4℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.58(s,2H,CH2),3.73(s,2H,CH2),7.23 (s,1H,Ar-H),7.31(m,2H,Ar-H),7.32(m,1H,Ph-H),7.33(m,2H,Ar-H),7.35-7.36(m,4H, Ar-H), 10.01 (2H, 2NH), 10.42 (1H, NH- indoles)；m/z 307.1[M+]。
N'- (2- (1H- indol-3-yls) acetyl group) -4- methoxybenzenes acethydrazide (Formulas I -4), faint yellow solid, yield： 88%, mp:181.2-182.2℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.34(s,2H,CH2),3.60(s,3H, OCH3),3.46(s,2H,CH2),7.16(m,2H,Ar-H),7.21(s,1H,Ar-H),7.23(m,2H,Ar-H),7.24-7.25 (m, 4H, Ar-H), 10.03 (2H, 2NH), 10.88 (1H, NH- indoles)；m/z 338.1[M++1]。
N'- (2- (1H- indol-3-yls) acetyl group) -3- (3,4- Dimethoxyphenyls) propionyl hydrazine (Formulas I -5)：It is orange-yellow Solid, yield：95%, 137.2-138.2 DEG C；1H-NMR(500MHz,DMSO-d6),δ(ppm):2.53(t,2H,CH2),2.89 (t,2H,CH2),3.73(s,2H,CH2),3.79(6H,s,2OCH3),6.77(s,1H,Ar-H),6.83(s,1H,Ar-H), 6.85(m,1H,Ar-H),7.03(s,1H,Ar-H),7.11-7.61(m,4H,Ar-H),9.88(s,1H,NH),10.12(s, 1H, NH), 10.93 (s, 1H, indoles-NH)；m/z382.1[M++1]。
N'- (2- (1H- indol-3-yls) acetyl group) -2- hydroxybenzoyl hydrazines (Formulas I -6), white solid, yield：75%, mp:189.2-190.0℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.82(s,2H,C H2),6.92(s,1H,Ar- H),7.04-7.07(m,1H,Ar-H),7.11-7.14(m,1H,Ar-H),7.29-7.42(m,4H,Ar-H),7.66-7.67 (m, 1H, Ar-H), 7.82-7.84 (m, 1H, Ar-H), 10.13 (1H, NH), 10.41 (s, 1H, NH)；10.88 (1H, NH- Yin Diindyl)；m/z 308.1[M+-1]。
N'- (2- (1H- indol-3-yls) acetyl group) -4- methylbenzenes acethydrazide (Formulas I -7), faint yellow solid, yield： 89%, mp:188.2-189.2℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):2.26(s,3H,CH3),3.41(s,2H, CH2),3.62(s,2H,CH2),6.97(s,1H,Ar-H),7.05-7.17(m,4H,Ar-H),7.18-7.60(m,4H,Ar-H), 10.01 (s, 1H, NH), 10.03 (s, 1H, NH), 10.86 (s, 1H, NH- indoles)；m/z 322.1[M++1]。
N'- (2- (1H- indol-3-yls) acetyl group) -1- naphthalenes acethydrazide (Formulas I -8), orange/yellow solid, yield：85%,
mp:197.5-198.5℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.56(s,2H,CH2),
3.96(s,2H,CH2),6.96(s,1H,Ar-H),7.05-7.23(m,1H,Ar-H),7.33-7.51(m,4H, Ar-H),7.51-7.55(m,3H,Ar-H),7.57-7.59(m,1H,Ar-H),7.82-7.83(m,1H,Ar-H),8.12- 8.13 (m, 1H, Ar-H), 10.03 (s, 1H, NH), 10.20 (s, 1H, NH), 10.85 (s, 1H, NH- indoles)；m/z 357.1[M+]。
N'- (2- (1H- indol-3-yls) acetyl group) cyclohexyl acethydrazide (Formulas I -9), white solid, yield：76%, mp: 187.5-188.5；1H-NMR(500MHz,DMSO-d6),δ(ppm):0.87-1.87(m,11H,cyclohexyl),2.04(s, 2H,CH2),3.60(s,2H,CH2),6.90(s,1H,Ar-H),6.92-7.49(m,4H,Ar-H),10.06(2H,2NH), 10.65 (1H, NH- indoles)；m/z 315.3[M++2]。
N'- (2- (1H- indol-3-yls) acetyl group) -3- (3,4,5- trimethoxyphenyls) propylene hydrazides (Formulas I -10), in vain Color solid, yield：93%, mp:99.2-100.2℃；1H-NMR(500MHz,DMSO-d6),δ(pp m):3.37(s,2H, CH2),3.86(s,9H,3OCH3), 6.88 (s, 2H, Ar-H), 6.93 (s, 1H, Ar-H), 7.05-7.02 (d, 1H, CH=CH), 7.59-7.10 (m, 4H, Ar-H), 7.65-7.63 (d, 1H, CH=CH), 10.09 (s, 1H, NH), 10.28 (s, 1H, NH), 10.51 (s, 1H, indoles-NH)；m/z410.1[M++1]。
N'- (2- (1H- indol-3-yls) acetyl group) furans -2- formylhydrazines (6-11), white solid, yield：77%, mp: 89.5-89.9℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.61(s,2H,CH2),6.65(m,1H,Ar-H),6.98 (s,1H,Ar-H),7.07-7.35(m,4H,Ar-H),7.61-7.63(d,1H,Ar-H),7.88(d,1H,Ar-H),10.05 (s, 1H, NH), 10.23 (s, 1H, NH), 10.88 (s, 1H, NH- indoles)；m/z 284.1[M++1]。
N'- (2- (1H- indol-3-yls) acetyl group) -4- nitrobenzoyl hydrazides, yellow solid (Formulas I -12), yield： 91%, mp:196.8-197.8℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.66(s,2H,C H2),7.00(s,1H, Ar-H),7.07-7.66(m,4H,Ar-H),8.09-8.11(m,2H,Ar-H),8.33-8.35(m,2H,Ar-H),10.25(s, 1H, NH), 10.71 (s, 1H, NH), 10.90 (s, 1H, NH- indoles)；m/z 339.1[M++1]。
N'- (2- (1H- indol-3-yls) acetyl group) Chinese cassia tree hydrazides (Formulas I -13), white solid, yield：85%, mp: 226.5-227.5℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.62(s,2H,CH2),6.70(s,1H,Ar-H), 6.94-7.00 (d, 1H, CH=CH), 7.06-7.08 (m, 1H, Ar-H), 7.27-7.43 (m, 4H, Ar-H), 7.52-7.55 (m, 2H, Ar-H), 7.59-7.60 (m, 2H, Ar-H), 7.61-7.63 (d, 1H, CH=CH), 10.16 (s, 1H, NH), 10.24 (s, 1H, NH), 10.89 (s, 1H, NH- indoles)；m/z 320.1[M++1].
N'- (2- (1H- indol-3-yls) acetyl group) -4- hydroxybenzoyl hydrazines (Formulas I -14), white solid, yield： 68%, mp:220.1-221.1℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.61(s,2H,CH2),6.85(s,1H, Ar-H),7.07-7.10(m,2H,Ar-H),7.26-7.79(m,4H,Ar-H),7.82-7.84(m,2H,Ar-H),10.02(s, 2H,NH),10.90(s,1H,Ar-H)；m/z 310.1[M++1]。
N'- (2- (1H- indol-3-yls) acetyl group) -3,5- dinitro benzoyls hydrazine (6-15), faint yellow solid, yield： 93%, mp:215.5-216.5℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.69(s,2H,CH2),7.00(s,1H, Ar-H),7.07-7.65(m,4H,Ar-H),8.95(s,1H,Ar-H),9.06(s,2H,Ar-H),10.43(s,1H,NH), 10.90 (s, 1H, NH), 11.17 (s, 1H, NH- indoles)；m/z 384.1[M++1]。
N'- (2- (1H- indol-3-yls) acetyl group) -2,4,5- trimethoxybenzoyl hydrazines (Formulas I -16), white solid, Yield：79%, mp:224.5-225.5℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.66(s,2H,CH2),3.75- 3.93(s,9H,3OCH3),6.77(s,1H,Ar-H),7.01(s,1H,Ar-H),7.08-7.65(m,4H,Ar-H),7.66(s, 1H, Ar-H), 9.90 (s, 1H, NH), 10.53 (s, 1H, NH), 10.92 (s, 1H, NH- indoles)；m/z 384.1[M++1]。
N'- (2- (1H- indol-3-yls) acetyl group) -4- iodobenzenes formylhydrazine (Formulas I -17), white solid, yield：86%,
mp:224.0-245.0℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.65(s,2H,CH2),
7.01(s,1H,Ar-H),7.08-7.65(m,4H,Ar-H),7.66-7.67(m,2H,Ph-H),7.88-7.90 (m, 2H, Ar-H), 10.17 (s, 1H, NH), 10.45 (s, 1H, NH), 10.91 (s, 1H, NH- indoles)；m/z 420.0[M++ 1]。
N'- (2- (1H- indol-3-yls) acetyl group) -4- bromobenzoylhydrazines (Formulas I -18), white solid, yield：84%, mp:221.2-222.2℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.64(s,2H,CH2),7.00-7.02(d,1H, Ar-H),7.07-7.10(d,1H,Ar-H),7.24(s,1H,Ar-H),7.34-7.36(d,2H,Ar-H),7.59-7.64(d, 2H, Ar-H), 7.68-7.70 (d, 2H, Ar-H), 10.13 (s, 1H, NH), 10.41 (s, 1H, NH), 10.59 (s, 1H, NH- Yin Diindyl)；m/z 374.3[M++2]。
N'- (2- (1H- indol-3-yls) acetyl group) -2- nitrobenzoyl hydrazides, faint yellow solid (Formulas I -19), yield： 86%, mp:189.5-199.5℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.67(s,2H,CH2),6.88(s,1H, Ar-H),7.00-7.68(m,4H,Ar-H),7.70-7.73(m,1H,Ar-H),7.75-7.78(m,1H,Ar-H),7.82- 7.85(m,1H,Ar-H),8.08-8.10(m,1H,Ar-H),10.43(s,1H,NH),10.62(s,1H,NH),10.93(s, 1H, NH- indoles)；m/z 339.1[M++1]。
N'- (2- (1H- indol-3-yls) acetyl group) -3- phenylpropyl alcohols hydrazides (Formulas I -20), white solid, yield：81%, mp: 200.0-201.0℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):2.44-2.47(t,2H,C H2),2.84-2.87(t, 2H,CH2),3.60(s,2H,CH2),7.01(s,1H,Ar-H),7.07-7.10(m,1H,Ar-H),7.18-7.28(m,4H,Ar- ), H 7.29-7.63 (m, 4H, Ar-H), 9.86 (s, 1H, NH), 10.89 (s, 1H, indoles-NH), 10.02 (s, 1H, NH)；m/z 322.3[M+1]。
N'- (2- (1H- indol-3-yls) acetyl group) chloro- 4- nitrobenzoyls hydrazides (Formulas I -21) of -2-, yellow solid, production Rate：92%, mp:187.0-188.0℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.64(s,2H,CH2),6.89- 6.94(m,1H,Ar-H),6.97-7.00(m,1H,Ar-H),7.26(s,1H,Ar-H),7.35-7.43(m,1H,Ar-H), 7.61-7.62(d,1H,Ar-H),7.72-7.75(d,1H,Ar-H),8.23-8.24(d,1H,Ar-H),8.33(s,1H,Ar- ), H 10.30 (s, 1H, NH), 10.62 (s, 1H, NH), 10.85 (s, 1H, indoles-NH)；m/z 374.1[M++2]。
N'- (2- (1H- indol-3-yls) acetyl group) -4- methoxybenzoyls hydrazine (Formulas I -22), white solid, yield： 93%, mp:165.2-166.2℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.66(s,2H,CH2),3.81(s,3H, OCH3),7.09-7.12(s,1H,Ar-H),7.04-7.12(d,2H,Ar-H),7.32-7.69(m,4H,Ar-H),7.89- 7.90(d,2H,Ar-H),10.11(s,1H,NH),10.25(s,1H,
), NH 10.93 (s, 1H, indoles-NH)；m/z 324.1[M++1]。
N'- (2- (1H- indol-3-yls) acetyl group) -3- iodobenzenes formylhydrazine (Formulas I -23), white solid, yield：90%, mp:193.5-194.5℃；1H-NMR(MHz,DMSO-d6),δ(ppm):3.64(s,2H,CH2),7.0(s,1H,Ar-H), 7.09-7.37(m,4H,Ar-H),7.64-7.65(d,1H,Ar-H),7.88-7.89(d,1H,Ar-H),7.92-7.94(d, 1H, Ar-H), 8.22 (s, 1H, Ar-H), 10.20 (s, 1H, NH), 10.48 (s, 1H, NH), 10.91 (s, 1H, indoles-NH)；m/ z 420.0[M++1]。
N'- (2- (1H- indol-3-yls) acetyl group) -3- (3- chlorphenyls) propylene hydrazides (Formulas I -24), white solid, production Rate：91%, mp:232.5-233.5℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.65(s,
2H,CH2), 6.74-6.77 (d, 1H, Ar-H), 6.99-7.00 (d, 1H, CH=CH), 7.02-7.38 (m, 4H, Ar-H),7.43-7.44(d,1H,Ar-H),7.52(s,1H,Ar-H),7.56-7.57(m,1H,Ar-H),7.57-7.64(m, 1H, Ar-H), 7.65-7.67 (d, 1H, CH=CH), 10.24 (s, 1H, NH), 10.32 (s, 1H, NH), 10.91 (s, 1H, Yin Diindyl-NH)；m/z 354.5[M++1]。
N'- (2- (1H- indol-3-yls) acetyl group) -3,5- dimethylbenzohydrazides (Formulas I -25), white solid, yield： 92%, mp:193.5-194.5℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):2.31(s,6H,2CH3),3.64(s,2H, CH2),7.00-7.02(d,1H,Ar-H),7.19(s,1H,Ar-H),7.30(s,1H,Ar-H),7.36-7.38(d,1H,Ar- H),7.08-7.09(d,1H,Ar-H),7.50(s,2H,Ar-H),7.65-7.66(d,1H,Ar-H),10.12(s,1H,NH), 10.25 (s, 1H, NH), 10.90 (s, 1H, indoles-NH)；m/z 322.3[M++1]。
N'- (2- (1H- indol-3-yls) acetyl group) -4- chlorobenzoyls hydrazine (Formulas I -26), white solid, yield：86%, mp:207.0-208.0℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):4.02(s,2H,CH2),6.98-7.01(t,1H, Ar-H),7.07-7.10(t,1H,Ar-H),7.29(s,1H,Ar-H),7.35-7.37(d,1H,Ar-H),7.55-7.57(d, 1H,Ar-H),7.63-7.65(d,2H,Ar-H),7.87-7.89(d,2H,Ar-H),10.17(s,1H,NH),10.45(s,1H, ), NH 10.88 (s, 1H, indoles-NH)；m/z329.1[M++2]。
N'- (2- (1H- indol-3-yls) acetyl group) anthracene -10- formylhydrazines (Formulas I -27), faint yellow solid, yield：88%, mp:258.0-259.0℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.82(s,2H,CH2),7.07(s,1H,), 7.51-7.58(m,4H,Ar-H),7.59-7.62(m,2H,Ar-H),7.75-7.77(d,2H,Ar-H),8.13-8.15(d, 2H,Ar-H),8.39-8.40(d,1H,Ar-H),8.69(s,2H,Ar-H),10.39(s,1H,NH),10.61(s,1H,NH), 11.01 (s, 1H, indoles-NH)；m/z 391.2[M+-2]。
N'- (2- (1H- indol-3-yls) acetyl group) -4- ethoxybenzenes formylhydrazine (Formulas I -28), white solid, yield： 93%, mp:170.1-171.1℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):1.32-1.34(t,3H,CH3),3.67 (s,2H,CH2),4.04-4.08(q,2H,CH2),6.99(s,1H,Ar-H),7.01-7.33(d,1H,Ar-H),7.38-7.69 (m, 4H, Ar-H), 7.87-7.89 (d, 2H, Ar-H), 10.10 (s, 1H, NH), 10.24 (s, 1H, NH), 10.92 (s, 1H, Yin Diindyl-NH)；m/z 338.1[M++1]。
N'- (2- (1H- indol-3-yls) acetyl group) benzo [d] [1,3] dioxa amylene -5- carbohydrazides (Formulas I -29), in vain Color solid, yield：92%, mp:106.5-107.5℃；1H-NMR(500MHz,DMSO-d6),δ(p pm):3.67(s,2H, CH2),6.10(s,2H,OCH2O),7.01(s,1H,Ar-H),7.02(d,1H,A r-H),7.11-7.44(m,4H,Ar-H), 7.52-7.53(d,1H,Ar-H),7.67-7.69(d,1H,Ar-H),10.13(s,1H,NH),10.25(s,1H,NH),10.92 (s, 1H, indoles-NH)；m/z 338.1[M++1]。
N'- (2- (1H- indol-3-yls) acetyl group) -3-6- bromobenzenes simultaneously [d] [1,3] dioxa amylene -5- bases) acryloyl Hydrazine (Formulas I -30), white solid, yield：89%, mp:242.7-243.7℃；1H-NMR(500MHz,DMS O-d6),δ(ppm): 3.66(s,2H,CH2),6.12(s,2H,OCH2), O 6.57 (s, 1H, Ar-H), 6.60 (s, 1H, CH=CH), 7.01 (s, 1H, ), Ar-H 7.11 (s, 1H, Ar-H), 7.25-7.66 (d, 4H, Ar-H), 7.73-7.76 (d, 1H, CH=CH), 10.21 (s, 1H, ), NH 10.30 (s, 1H, NH), 10.97 (s, 1H, indoles-NH)；m/z 443.0[M++2]。
N'- (2- (1H- indol-3-yls) acetyl group) -2- fluorobenzoyl hydrazines (Formulas I -31), white solid, yield：91%, mp:153.0-154.0℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.66(s,2H,CH2),7.00-7.02(s,1H, Ar-H),7.09-7.12(m,1H,Ar-H),7.29-7.32(m,1H,Ar-H),7.38-7.39(d,4H,Ar-H),7.54- 7.63(m,1H,Ar-H),7.64-7.68(m,2H,Ar-H),10.26(s,1H,NH),10.27(s,1H,NH),10.92(s, 1H, indoles-NH)；m/z 312.1[M++1]。
N'- (2- (1H- indol-3-yls) acetyl group) -2,3- dichloro-benzoyls hydrazine (Formulas I -32), white solid, yield： 89%, mp:214.5-215.5℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.67(s,2H,CH2),7.00-7.03 (s,1H,Ar-H),7.09-7.46(m,4H,Ar-H),7.46(d,1H,Ar-H),7.73-7.75(d,1H,Ar-H),7.66- 7.67 (d, 1H, Ar-H), 10.35 (s, 1H, NH), 10.44 (s, 1H, NH), 10.93 (s, 1H, indoles-NH)；m/z 363.0(M++2)。
N'- (2- (1H- indol-3-yls) acetyl group) -4- phenylbenzohydrazides (Formulas I -33), white solid, yield： 92%, mp:221.0-222.0℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.74(s,2H,CH2),7.04(s,1H, Ar-H),7.12(s,1H,Ar-H),7.37-7.48(m,4H,Ar-H),7.65-7.67(m,4H,Ar-H),7.72-7.75(t, 3H, Ar-H), 8.00-8.02 (d, 2H, Ar-H), 10.28 (s, 1H, NH), 10.52 (s, 1H, NH), 10.91 (s, 1H, indoles- NH)；m/z 370.2[M++1]。
N'- (2- (1H- indol-3-yls) acetyl group) -1- naphthalenes formylhydrazine (Formulas I -34), white solid, yield：93%, mp: 203.0-204.0℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.67(s,2H,CH2),7.08(s,1H,Ar-H), 7.16-7.19(m,1H,Ar-H),7.44-7.48(m,2H,Ar-H),7.58-7.64(m,4H,Ar-H),7.74-7.80(m, 2H,Ar-H),8.00-8.01(d,1H,Ar-H),8.06-8.07(d,1H,Ar-H),8.48-8.50(d,1H,Ar-H),10.38 (s, 1H, NH), 10.46 (s, 1H, NH), 11.03 (s, 1H, indoles-NH)；m/z 344.1[M++1]。
N'- (2- (1H- indol-3-yls) acetyl group) -2- naphthalenes formylhydrazine (Formulas I -35), white solid, yield：89%, mp: 214.0-215.0℃；1H-NMR(500MHz,DMSO-d6),δ(ppm):3.74(s,2H,CH2),7.04-7.06(s,1H,Ar- H),7.11-7.14(m,1H,Ar-H),7.38-7.42(m,2H,Ar-H),7.59-7.65(m,2H,Ar-H),7.73-7.74 (d,1H,Ar-H),7.98-8.05(m,4H,Ar-H),8.56(s,1H,Ar-H),10.29(s,1H,NH),10.61(s,1H, ), NH 10.97 (s, 1H, indoles-NH)；m/z344.2[M++1]。
Embodiment 3
In the present embodiment, the external anti-HCV activity of Formulas I -1 to -35 compound of Formulas I is evaluated, using human liver cancer Cell strain Huh 7.5.1 carry out the horizontal anti-HCV activity evaluation of cell in vitro, and method is described as follows：
Mtt assay detects drug cytotoxicity：The Huh 7.5.1 cells of logarithmic growth phase, with 9 × 103A cells/well paving After 96 orifice plates, adherent 5 hours, 2 μ L DMSO gradient dilution drugs, 5 times of dilutions are added, 5 dilutions, each gradient is equipped with Three repeating holes, while blank control (containing only culture medium), cell controls, DMSO controls and HCV-Ab IgG positive drug profit bar are set Wei Lin (Ribavirin) is compareed, 200 holes μ L/ of final volume.Culture plate is placed in 37 DEG C, 5%CO2Incubator is cultivated.Third The 5mg/mL MTT solution of 20 μ L, 37 DEG C, 5%CO are added in experimental port for it2It is incubated 4 hours.It discards supernatant, 150 μ L/ is added The DMSO of well, oscillation dissolving after ten minutes, are calculated in the value for measuring OD490 in microplate reader, and with Graphad Prism 5.0 Drug IC50 (IC50：Half-inhibition concentration, by the concentration needed for cell growth inhibition 50%) value.Calculation formula：Cell growth Inhibiting rate (%)=(1-test hole OD values/control wells OD values) × 100%.
HCV inhibition of DNA replication is tested：The Huh 7.5.1 cells of logarithmic growth phase, with 9 × 103Cells/well cells are spread After 96 orifice plates, adherent 5 hours, 2 μ LDMSO gradient dilution drugs are added, 5 times of dilutions, 5 dilutions, each gradient is equipped with three A repeating hole, while virus is added, if cell controls, virus control, HCV-Ab IgG positive control (Ribavirin), DMSO are compareed, eventually 200 holes μ L/ of volume.Culture plate is placed in 37 DEG C, 5%CO2Incubator is cultivated, after 3 days collect supernatant 3000rpm/min from Heart 10min takes clarified supernatant to carry out RNA carrying capacity detections.HCV inhibition of DNA replication rate and EC50 are calculated with Graphad Prism 5.0 (EC50：Half effective concentration causes the individual of study subject 50% to generate a kind of drug dose of specific effect).Calculation formula： HCV inhibition of DNA replication rate (%)=(1- test hole HCV RNA carrying capacity/control wells HCV RNA carrying capacity) × 100%
HCV-Ab IgG evaluating drug effect：Therapeutic index (Therapeutic index, TI) is that drug inhibits dense to the half of cell Spend IC50With the ratio of the half effective concentration to virus, Drug safety is represented, the bigger this numerical value the safer.
Using HCV-Ab IgG clinical treatment agents Ribavirin (Ribavirin) as positive control.As stated above to synthesis 35 compounds have carried out drug cytotoxicity and the screening of HCV-Ab IgG virus activity, specific test data (IC50、EC50And SI values) Referring to table 2, as seen from the table, there are 10 compound therapeutic indexs to be higher than Ribavirin in 35 compounds surveyed, wherein living 5 best Formula I-4 of property, Formulas I -5, Formulas I -6, Formulas I -9 and -14 therapeutic index ratio Ribavirin of Formulas I are 7-75 times high, can Primer as HCV-Ab IgG is used.
Table 2
Applicant states that the present invention illustrates N'- (2- (1H- indol-3-yls) acetyl of the present invention by above-described embodiment Base) aromatic hydrazide kind compound and its preparation method and application, but the invention is not limited in above-described embodiments, that is, do not mean that this Invention, which has to rely on above-described embodiment, to be implemented.Person of ordinary skill in the field is it will be clearly understood that any of the present invention It improves, the addition of equivalence replacement and auxiliary element to each raw material of product of the present invention, the selection etc. of concrete mode all fall within this hair Within bright protection domain and the open scope.

Claims (28)

1. a kind of N'- (2- (1H- indol-3-yls) acetyl group) aromatic hydrazide kind compound, which is characterized in that it is with shown in Formulas I Structure：
In Formulas I, n=0,1 or 2；R be substituted or unsubstituted phenyl ring, substituted or unsubstituted naphthalene nucleus, Substituted or unsubstituted anthracene nucleus, substituted or unsubstituted furan nucleus, substituted or unsubstituted xenyl,In any one, it is described Phenyl ring, naphthalene nucleus, anthracene nucleus, furan nucleus and xenyl substituent group independently selected from halogen, hydroxyl, nitro, trifluoromethyl, C1-C10 In alkyl or C1-C10 alkoxies any one or at least two combination, and when n=0, R is not following group： When n=1, R is not following group： When n=2, R is not
2. N'- (2- (1H- indol-3-yls) acetyl group) aromatic hydrazide kind compound according to claim 1, feature exist In the halogen is the combination of any one or at least two in F, Cl, Br or I.
3. N'- (2- (1H- indol-3-yls) acetyl group) aromatic hydrazide kind compound according to claim 1, feature exist In N'- (2- (1H- indol-3-yls) acetyl group) aromatic hydrazide kind compound is appointing in the compound having the following structure It anticipates a kind of or at least two combinations：
4. N'- (2- (1H- indol-3-yls) acetyl group) aromatic hydrazide kind compound according to any one of claim 1-3 Preparation method, which is characterized in that the described method comprises the following steps：
(1) heteroauxin obtains ethychlozate ester shown in Formula II with C1-C5 alcohol generation esterification, and reaction equation is as follows：
Wherein R1For C1-C5 alkyl；
(2) indoles acethydrazide shown in formula III is obtained by the reaction with hydrazine hydrate in ethychlozate ester shown in Formula II, and reaction equation is as follows：
(3) aromatic carboxylic acids shown in formula IV is reacted with chlorination reagent is prepared aryl-acyl chlorides shown in Formula V, and reaction equation is as follows：
(4) (2- (1H- indoles -3- of N'- shown in Formulas I are obtained by the reaction with aryl-acyl chlorides shown in Formula V in the indoles acethydrazide shown in formula III Base) acetyl group) aromatic hydrazide kind compound, reaction equation is as follows：
5. preparation method according to claim 4, which is characterized in that step (1) the C1-C5 alcohol is methanol, ethyl alcohol, third Any one in alcohol, butanol or amylalcohol.
6. preparation method according to claim 5, which is characterized in that step (1) the C1-C5 alcohol is methanol.
7. preparation method according to claim 4, which is characterized in that step (1) heteroauxin rubs with C1-C5 alcohol You are than being 1:(5-40).
8. preparation method according to claim 4, which is characterized in that step (1) reaction is using strong acid as catalyst.
9. preparation method according to claim 8, which is characterized in that step (1) reaction is using the concentrated sulfuric acid as catalyst.
10. preparation method according to claim 4, which is characterized in that the temperature of step (1) described reaction is 50-80 DEG C.
11. preparation method according to claim 4, which is characterized in that the time of step (1) described reaction is 1-8 hours.
12. preparation method according to claim 4, which is characterized in that ethychlozate ester shown in step (2) described Formula II with The molar ratio of hydrazine hydrate is 1:(1-4).
13. preparation method according to claim 4, which is characterized in that solvent for use is second two in step (2) described reaction Alcohol methyl ether.
14. preparation method according to claim 4, which is characterized in that the temperature of step (2) described reaction is 110-130 ℃。
15. preparation method according to claim 4, which is characterized in that the time of step (2) described reaction is that 5-24 is small When.
16. preparation method according to claim 4, which is characterized in that step (3) described chlorination reagent be thionyl chloride, In phosphorus trichloride or phosphorus pentachloride any one or at least two combination.
17. preparation method according to claim 16, which is characterized in that step (3) described chlorination reagent is thionyl chloride.
18. preparation method according to claim 4, which is characterized in that step (3) aromatic carboxylic acids and chlorination reagent Molar ratio is 1:(2-6).
19. preparation method according to claim 4, which is characterized in that solvent for use is tetrahydrochysene in step (3) described reaction Furans.
20. preparation method according to claim 4, which is characterized in that the temperature of step (3) described reaction is 60-90 DEG C.
21. preparation method according to claim 4, which is characterized in that the time of step (3) described reaction is that 5-20 is small When.
22. preparation method according to claim 4, which is characterized in that step (4) the indoles acethydrazide and aryl-acyl chlorides Molar ratio be 1:(1-1.5).
23. preparation method according to claim 4, which is characterized in that step (4) reaction is in the presence of alkaline reagent It carries out.
24. preparation method according to claim 23, which is characterized in that the alkaline reagent is triethylamine.
25. preparation method according to claim 4, which is characterized in that mole of the alkaline reagent and indoles acethydrazide Than being 1:(1-3).
26. preparation method according to claim 4, which is characterized in that the temperature of step (4) described reaction is 0-30 DEG C.
27. preparation method according to claim 4, which is characterized in that the time of step (4) described reaction is that 5-24 is small When.
28. N'- (2- (1H- indol-3-yls) acetyl group) aromatic hydrazide kind compound according to any one of claim 1-3 Purposes in preparing anti hepatitis C virus drug.
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