CN105985332B - 2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzal thiazolinones and the preparation method and application thereof - Google Patents

2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzal thiazolinones and the preparation method and application thereof Download PDF

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CN105985332B
CN105985332B CN201510069095.7A CN201510069095A CN105985332B CN 105985332 B CN105985332 B CN 105985332B CN 201510069095 A CN201510069095 A CN 201510069095A CN 105985332 B CN105985332 B CN 105985332B
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benzal
thiazolin
yls
triazol
thiazol
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CN105985332A (en
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叶姣
颜晓维
肖梦武
胡艾希
刘艾林
连雯雯
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Hunan University
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Abstract

The present invention relates to or mixtures thereof 4 ketone of [5 (1 base of nitrogen azoles) thiazole, 2 imino group] 5 benzal thiazoline 2 shown in chemical structural formula I, II, III or IV： Wherein, R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Linear or branched alkyl group, halogenated C1~C2Alkyl；X, Y or Z are selected from：CH or N；X1~X5It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Linear or branched alkyl group, fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR, wherein R are selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl；Application of 2 [5 (1 base of nitrogen azoles) thiazole, 2 imino group] 5 benzal thiazoline, 4 ketone in preparing influenza virus neuraminidase inhibitor.

Description

2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzals thiazolinones and its Preparation method and application
Technical field
The present invention relates to the preparation and application of a kind of noval chemical compound, specifically 2- [5- (nitrogen azoles -1- bases) thiazole -2- imido Base] -5- benzal thiazolin 4 ones preparation and its in the application as influenza virus neuraminidase inhibitor.
Background technology
Avian influenza virus can cause the respiratory apparatus or systemic infection of birds, highly pathogenic avian influenza virus that can directly feel Birds are contaminated, the mankind also can be directly or indirectly infected.Highly pathogenic avian influenza virus is that one of the initiation influenza in crowd is potential Risk factor, and can seriously threaten human health.20th century, 4 flu outbreaks once occurred for the mankind：1918 to 1919 " the spanish influenza " (H in year1N1Hypotype), nineteen fifty-seven to " Asia influenza " (H in 19582N2Hypotype), nineteen sixty-eight to 1969 " Mao flu " (H3N2Hypotype) and " Russian influenza " (H in 19771N1Hypotype).Avian influenza virus is containing there are two surfaces Albumen：Avian influenza virus can be divided by hemagglutinin (HA) and neuraminidase (NA) according to the difference of the two protein antigenicities 16 HA hypotypes (H1~H16) and 9 NA hypotypes (N1~N9).So far find that the avian influenza virus subtype of energy direct infection people has： H5N1、H7N1、H7N2、H7N3、H7N7、H9N2、H7N9And H10N8Hypotype.Wherein, highly pathogenic H5N1Hypotype is in 1997 in Hong Kong head The secondary discovery energy direct infection mankind, after in July, 2003, H5N1Bird flu epidemic situation present it is unprecedented breaks out, involve Asia, 17 North America, Europe And Africa countries and regions cause hundreds of people infection and death, direct economic loss to be up to 10,000,000,000 U.S.s Member.H occurs in March, 2003, Holland7N7Type bird flu simultaneously involves entire Europe, and human infection person not only causes people up to 83 The injures and deaths of class, while having inflicted heavy losses on poultry farming.In by the end of March, 2009, and Mexico breaks out people and infects H1N1Type swine flu epidemic situation simultaneously expands It is scattered to all over the world, according to the World Health Organization in the A type H of publication on 2 26th, 20101N1The report of influenza global picture, at least There are 16226 patients of 213 countries and regions to die of this big influenza [Zeng Xiangxing, Li Kangsheng.Medicine and society, 2010, 11,4-6.].By gene sequencing, H1N1Type virus includes human influenza virus, North America avian influenza virus and North America, Europe, Asia Swine influenza virus genetic fragment is the mixing strain of several different plant species influenza viruses, and a kind of swine flu of non-individual or fowl stream Influenza Virus.In March, 2013, finder infects H for the first time in China7N9Bird flu case ends on January 25th, 2015, world health group Knit the H of announcement7N9494 people, dead 221 people are made a definite diagnosis in bird flu.Therefore the research and development to Anti-avian influenza virus drugs, it has also become the world National governments and health and epidemic prevention department's growing interest and one of the significant problem actively addressed.
Avian influenza virus is a kind of virus containing envelope protein, and genome is the sub-thread minus strand for including 8 segments RNA, a variety of virus proteins of codified：Virus surface proteins (hemagglutinin HA, neuraminidase NA), stromatin (M1, M2) core Albumen (NP), non-structural protein (NS1, NS2), RNA polymerase P protein complexes PA, PB1, PB2) [CN101990534A].HA It is the agglutinin that a kind of mediate retroviral enters the combination of target cell and viral genome target cell.NA can catalytic pyrolysis host it is thin The N- acetylaminos of cellular surface glycoprotein end discharge progeny virus from infection cell.NA can also be by changing surface glycoprotein The carbohydrate portions of HA enhance toxicity, promote virus to be discharged from infected host cell, cause or aggravate influenza disease Shape [CN103755697A].In addition, NA has opposite conservative in the mutation process of influenza virus, becomes design, closes At the extraordinary target of Tamiflu.Therefore, using NA as action target, influenza virus is inhibited to replicate by inhibiting NA activity NA inhibitor with toxicity is the First Line drug of anti-avian influenza virus, represent drug have Zanamivir, Oseltamivir and Peramivir and its derivative, wherein Oseltamivir are widely used.But studies have found that some Strain pair Oseltamivir produces drug resistance.
2010, Mohan etc. designed and synthesized a kind of Oseltamivir analogs containing triazole structure, in vitro Inhibitor activity test screen goes out an inhibitor A [Mohan S.et to NAs (Nl) with greater activity and selectivity Al, J.Med.Chem.2010,53 (20), 7377-7391].Xie Yuanchao with the pyrrolidines of L- hydroxyprolines be basic parent nucleus, if Meter synthesizes compound B of the one kind containing triazole and shows preferable NA inhibitory activity [Xie Yuanchao.Shandong University, 2014.].
Thiazoles and thiazoline ketone compounds have anti-influenza virus activity：Chinese invention patent [ZL 200810152537.4,2010.12.22 authorize, and ZL 201010223400.0,2012.07.25 are authorized] it reports series and has The thiazole of anti-influenza virus activity and thiazole-substituted mercaptoacetamide derivative；Chinese invention patent [CN 103830233 A, 2014.06.04 are disclosed, CN 103705511 A, and 2014.04.09 is disclosed] describe 5- (1,2,4- triazoles- 1- yls) -2- phenylacetamido-thiazoles and N- [5- (1,2,4- triazol-1-yl) thiazol-2-yl] fatty acid amide anti-influenza activity； Chinese invention patent [CN 103755697 A, 2014.04.30 are disclosed, CN 103739599 A, and 2014.04.23 is disclosed] report 3- [[2- (2- benzyls imino group) thiazole -5- bases] methyl] (1H) -one of quinoline -2 and 3- [[2- (2- benzyls hydrazono-) thiazole -5- Base] methyl] quinoline -2 (1H) -one preparation and anti-influenza activity；In addition, Chinese patent [103648282 A of CN, 2014.03.19 disclose, CN101990534 A, 2008.10.3 is disclosed] it also reported thiazole compound in prevention and treatment disease Purposes in terms of malicious infection.
Invention content
The purpose of the present invention is to provide [5- (nitrogen azoles -1- bases) thiazoles-of 2- shown in chemical structural formula I, II, III or IV Or mixtures thereof 2- imino groups] -5- benzal thiazolin 4 ones：
Wherein, R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Linear or branched alkyl group, fluoro C1~C2Alkyl, chloro C1~C2 Alkyl, bromo C1~C2Alkyl or iodo C1~C2Alkyl；X, Y or Z are selected from：CH or N；X1、X5It is selected from：Hydrogen, C1~C2Alkyl, C3 ~C4Linear or branched alkyl group, fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR； X2、X4It is selected from：Fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；X3It is selected from：Fluorine, Chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；Wherein R is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl.
2- shown in I formula [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzal thiazolin 4 ones are (2E, 5Z) - 2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzal thiazolin 4 ones；[the 5- (nitrogen azoles -1- bases) of 2- shown in II formula Thiazole -2- imino groups] -5- benzal thiazolin 4 ones be (2Z, 5Z) -2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- Benzal thiazolin 4 one；2- shown in III formula [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzal thiazolines -4- Ketone is (2E, 5E) -2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzal thiazolin 4 ones；2- shown in IV formula [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzal thiazolin 4 ones are (2Z, 5E) -2- [5- (nitrogen azoles -1- bases) thiophenes Azoles -2- imino groups] -5- benzal thiazolin 4 ones.
2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzal thiazolin 4 ones provided by the invention are selected from down Row close object：
Wherein, R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Linear or branched alkyl group, fluoro C1~C2Alkyl, chloro C1~C2 Alkyl, bromo C1~C2Alkyl or iodo C1~C2Alkyl；X1、X5It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Linear chain or branched chain alkane Base, fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；X2、X4It is selected from：Fluorine, chlorine, Bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；X3It is selected from：Fluorine, chlorine, bromine, iodine, hydroxyl, two Methylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；Wherein R is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~ C4Branched alkyl.
2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzal thiazolin 4 ones provided by the invention are selected from down Row close object：
Wherein, R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Linear or branched alkyl group, fluoro C1~C2Alkyl, chloro C1~C2 Alkyl, bromo C1~C2Alkyl or iodo C1~C2Alkyl；X1、X5It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Linear chain or branched chain alkane Base, fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；X2、X4It is selected from：Fluorine, chlorine, Bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；X3It is selected from：Fluorine, chlorine, bromine, iodine, hydroxyl, two Methylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；Wherein R is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~ C4Branched alkyl.
2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzal thiazolin 4 ones provided by the invention are selected from down Row close object：
Wherein, R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Linear or branched alkyl group, fluoro C1~C2Alkyl, chloro C1~C2 Alkyl, bromo C1~C2Alkyl or iodo C1~C2Alkyl；X1、X5It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Linear chain or branched chain alkane Base, fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；X2、X4It is selected from：Fluorine, chlorine, Bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；X3It is selected from：Fluorine, chlorine, bromine, iodine, hydroxyl, two Methylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；Wherein R is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~ C4Branched alkyl.
2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzal thiazolin 4 ones provided by the invention are selected from down Row close object：
Wherein, R1 It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Linear or branched alkyl group, fluoro C1~C2Alkyl, chloro C1~C2Alkyl, bromo C1~C2 Alkyl or iodo C1~C2Alkyl；X1、X5It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Linear or branched alkyl group, fluorine, chlorine, bromine, iodine, hydroxyl Base, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；X2、X4It is selected from：Fluorine, chlorine, bromine, iodine, hydroxyl, diformazan ammonia Base, methoxyl group, ethyoxyl, nitro, amino or NHCOR；X3It is selected from：Fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, second Oxygroup, nitro, amino or NHCOR；Wherein R is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl.
The purpose of the present invention is to provide 2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzals thiazoline - 4- ketone is selected from following compounds：
Wherein, R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Linear or branched alkyl group, fluoro C1~C2Alkyl, chloro C1~C2 Alkyl, bromo C1~C2Alkyl or iodo C1~C2Alkyl；X, Y or Z are selected from：CH or N；N is selected from：1,2 or 3；(NH2)nIt is selected from：2- NH2、3-NH2、4-NH2、2,4-(NH2)2、2,5-(NH2)2、2,6-(NH2)2、3,4-(NH2)2、3,5-(NH2)2、2,3,4- (NH2)3Or 2,3,5- (NH2)3。
The purpose of the present invention is to provide 2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzals thiazoline - 4- ketone is selected from following compounds：
Wherein, R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Linear or branched alkyl group, fluoro C1~C2Alkyl, chloro C1~C2 Alkyl, bromo C1~C2Alkyl or iodo C1~C2Alkyl；X, Y or Z are selected from：CH or N；N is selected from：1,2 or 3；(NHCOR)nIt is selected from： 2-NHCOR、3-NHCOR、4-NHCOR、2,4-(NHCOR)2、2,5-(NHCOR)2、2,6-(NHCOR)2、3,4-(NHCOR)2、3, 5-(NHCOR)2、2,3,4-(NHCOR)3Or 2,3,5- (NHCOR)3。
The purpose of the present invention is to provide structural formula I shown in 2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- Benzal thiazolin 4 one is selected from：2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (2- fluorine benzal) thiazolin 4 one, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } - 5- (3- fluorine benzal) thiazolin 4 one, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imido Base } -5- (2- chlorine benzal) thiazolin 4 one, { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] is sub- by 2- Amino } -5- (3- chlorine benzal) thiazolin 4 one, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] Imino group } -5- (4- chlorine benzal) thiazolin 4 one, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazole -2- Base] imino group -5- (2- bromines benzal) thiazolin 4 one, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazoles - 2- yls] imino group -5- (3- bromines benzal) thiazolin 4 one, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiophenes Azoles -2- bases] imino group -5- (4- bromines benzal) thiazolin 4 one, 5- benzals -2- [4- tertiary butyls -5- (1H-1,2,4- Triazol-1-yl) thiazol-2-yl] imino group thiazolin 4 one, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiophenes Azoles -2- bases] imino group -5- (2- methylbenzilidenes) thiazolin 4 one, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazole -1- Base) thiazol-2-yl] imino group -5- (3- methylbenzilidenes) thiazolin 4 one, 2- [4- tertiary butyls -5- (1H-1,2,4- tri- Azoles -1- bases) thiazol-2-yl] imino group -5- (4- methylbenzilidenes) thiazolin 4 one, 2- [4- tertiary butyls -5- (1H-1,2, 4- triazol-1-yls) thiazol-2-yl] imino group -5- (2- benzylidenes) thiazolin 4 one, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group -5- (3- benzylidenes) thiazolin 4 one, 2- { [uncles 4- Butyl -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group -5- (3- nitrobenzals) thiazolin 4 one, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (4- nitrobenzals) thiazoline -4- Ketone, 5- (3- amino benzal) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } thiazole Quinoline -4- ketone, 5- (4- amino benzal) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } Thiazolin 4 one, 5- (3- acetylaminos benzal) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazole -2- Base] imino group } thiazolin 4 one or 5- (4- acetylaminos benzal) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazole -1- Base) thiazol-2-yl] imino group } thiazolin 4 one.
The purpose of the present invention is to provide 2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzals thiazoline - The preparation method of 4- ketone, it is characterised in that its preparation reaction is as follows：
In formula, R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Linear or branched alkyl group, fluoro C1~C2Alkyl, chloro C1~C2 Alkyl, bromo C1~C2Alkyl or iodo C1~C2Alkyl；X, Y or Z are selected from：CH or N；X1、X5It is selected from：Hydrogen, C1~C2Alkyl, C3 ~C4Linear or branched alkyl group, fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl or nitro；X2、X4It is selected from：Fluorine, Chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl or nitro；X3It is selected from：Fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, Methoxyl group, ethyoxyl or nitro.
The purpose of the present invention is to provide 5- (amino benzal) -2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] thiazoles The preparation side of quinoline -4- ketone and 5- (acetylamino benzal) -2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] thiazolin 4 one Method, it is characterised in that their preparation reaction is as follows：
In formula, R is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl；R1It is selected from：Hydrogen, C1~C2Alkane Base, C3~C4Linear or branched alkyl group, fluoro C1~C2Alkyl, chloro C1~C2Alkyl, bromo C1~C2Alkyl or iodo C1~C2 Alkyl；X, Y or Z are selected from：CH or N；N is selected from 1,2 or 3；(NO2)nIt is selected from：2-NO2、3-NO2、4-NO2、2,4-(NO2)2、2,5- (NO2)2、2,6-(NO2)2、3,4-(NO2)2、3,5-(NO2)2、2,3,4-(NO2)3Or 2,3,5- (NO2)3；(NH2)nIt is selected from：2- NH2、3-NH2、4-NH2、2,4-(NH2)2、2,5-(NH2)2、2,6-(NH2)2、3,4-(NH2)2、3,5-(NH2)2、2,3,4- (NH2)3Or 2,3,5- (NH2)3；(NHCOR)nIt is selected from：2-NHCOR、3-NHCOR、4-NHCOR、2,4-(NHCOR)2、2,5- (NHCOR)2、2,6-(NHCOR)2、3,4-(NHCOR)2、3,5-(NHCOR)2、2,3,4-(NHCOR)3Or 2,3,5- (NHCOR)3。
The purpose of the present invention is to provide 2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzals thiazoline - 4- ketone has influenza neuraminidase inhibitory activity, the application in preparing influenza virus neuraminidase inhibitor.
The present invention has the following advantages that compared with prior art：
Having invented 2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzal thiazolin 4 ones has influenza virus Neuraminic acid enzyme inhibition activity.
Specific implementation mode
Following embodiment is intended to illustrate invention rather than limitation of the invention further.
The preparation of (2E, 5E) -2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzals thiazolin 4 one (III) Method is as described in embodiment 1~24.
Embodiment 1
2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } thiazolin 4 one (2) It prepares
11.25g (50mmol) 4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazole -2- amine, 100mL dichloromethane, 6.90g (50mmol) Anhydrous potassium carbonate is added in stirring and dissolving, and 4.0ml (50mmol) chloracetyl chloride is added dropwise in stirring at normal temperature 30min, Normal-temperature reaction 2.5h.Reaction solution pours into ice water, dichloromethane extraction, and saturated aqueous sodium carbonate washing merges organic phase, anhydrous Sodium sulphate is dried, and precipitation, ethyl alcohol recrystallization obtains 13.50g white solids 1, yield 93%, m.p.130~133 DEG C.
10.25g (34mmol) compound Isosorbide-5-Nitrae .95g (34mmol) potassium rhodanide, the dissolving of 100ml ethyl alcohol are heated to reflux anti- Answer 5.0h.It is cooling, solid is precipitated, filters, dry 9.50g faint yellow solids 2, yield 86%, m.p.182~185 DEG C.1H NMR(CDCl3, 400MHz) and δ:1.19 (s, 9H, 3 × CH3), 3.90 (s, 2H, CH2), 8.11 (s, 1H, C2H2N33-H), 8.28 (s, 1H, C2H2N35-H), 12.01 (s, 1H, NH).
Embodiment 2
(2E, 5E) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (3- nitre Base benzal) thiazolin 4 one preparation
35ml acetic acid 0.65g sodium acetates prepare the buffer solution of pH=4~5, and 2 He of 2.0mmol intermediates is added 4.0mmol 3- nitrobenzaldehydes, heating reflux reaction 10h.It is cooling, wash, filtering, ethyl alcohol recrystallization obtain yellow solid (2E, 5E) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (3- nitrobenzals) thiazole Quinoline -4- ketone, yield 80%, m.p.258~260 DEG C.1H NMR(CDCl3, 400MHz) and δ:1.22,1.29 (s, 9H, 3 × CH3), 7.67~7.74 (m, 1H, C6H4), 7.85~7.92 (m, 2H, C6H4,=CH), 8.13 (s, 1H, C2H2N33-H), 8.30~ 8.32 (m, 2H, C6H4), 8.42,8.55 (s, 1H, C2H2N35-H), 12.07 (s, 1H, NH).
Embodiment 3
(2E, 5E) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (4- nitre Base benzal) thiazolin 4 one preparation
Operating method reacts 10h, obtains yellow solid (2E, 5E)-with embodiment 2, compound 2 and 4- nitrobenzaldehydes 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (4- nitrobenzals) thiazoline - 4- ketone, yield 82%, m.p.272~273 DEG C.1H NMR(CDCl3, 400MHz) and δ:1.22,1.26 (s, 9H, 3 × CH3), 7.70 ~7.76 (m, 2H, C6H4), 7.83,7.91 (s, 1H ,=CH), 8.13 (s, 1H, C2H2N33-H), 8.30 (s, 1H, C2H2N35- H), 8.34~8.38 (m, 2H, C6H4), 12.09 (s, 1H, NH).
Embodiment 4
(2E, 5E) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (2- fluorine Benzal) thiazolin 4 one preparation
Operating method reacts 10h, obtains yellow solid (2E, 5E)-with embodiment 2, compound 2 and the fluorine-based benzaldehydes of 2- 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (2- fluorine benzal) thiazoline -4- Ketone, yield 70%, m.p.254~256 DEG C.1H NMR(CDCl3, 400MHz) and δ:1.19,1.24 (s, 9H, 3 × CH3), 7.17~ 7.22 (m, 1H, C6H4), 7.29 (d, J=7.9Hz, 1H, C6H4), 7.43~7.47 (m, 1H, C6H4), 7.59~7.65 (m, 1H, C6H4), 8.08 (s, 1H ,=CH), 8.14 (s, 1H, C2H2N33-H), 8.33 (s, 1H, C2H2N35-H), 12.01 (s, 1H, NH).
Embodiment 5
(2E, 5E) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (3- fluorine Benzal) thiazolin 4 one preparation
Operating method reacts 10h, obtains yellow solid (2E, 5E)-with embodiment 2, compound 2 and the fluorine-based benzaldehydes of 3- 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (3- fluorine benzal) thiazoline -4- Ketone, yield 81%, m.p.203~205 DEG C.1H NMR(CDCl3, 400MHz) and δ:1.22,1.27 (s, 9H, 3 × CH3), 7.16 (t, J=8.1Hz, 1H, C6H4), 7.30~7.39 (m, 2H, C6H4), 7.45~7.50 (m, 1H, C6H4), 7.78,7.85 (s, 1H ,=CH), 8.13 (s, 1H, C2H2N33-H), 8.31 (s, 1H, C2H2N35-H), 12.01 (s, 1H, NH).
Embodiment 6
(2E, 5E) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (2- chlorine Benzal) thiazolin 4 one preparation
Operating method reacts 10h, obtains yellow solid (2E, 5E)-with embodiment 2, compound 2 and 2- chloro benzaldehydes 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (2- chlorine benzal) thiazoline -4- Ketone, yield 67%, m.p.286~288 DEG C.1H NMR(CDCl3, 400MHz) and δ:1.22 (s, 9H, 3 × CH3), 7.38~7.40 (m, 2H, C6H4), 7.51~7.53 (m, 1H, C6H4), 7.64 (s, 1H, C6H4), 8.14 (s, 1H, C2H2N33-H), 8.21 (s, 1H ,=CH), 8.32 (s, 1H, C2H2N35-H)。
Embodiment 7
(2E, 5E) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (3- chlorine Benzal) thiazolin 4 one preparation
Operating method reacts 10h, obtains yellow solid (2E, 5E)-with embodiment 2, compound 2 and 3- chloro benzaldehydes 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (3- chlorine benzal) thiazoline -4- Ketone, yield 73%, m.p.240~242 DEG C.1H NMR(CDCl3, 400MHz) and δ:1.22,1.27 (s, 9H, 3 × CH3), 7.42~ 7.46 (m, 3H, C6H4), 7.53,7.64 (s, 1H, C6H4), 7.75,7.82 (s, 1H ,=CH), 8.13 (s, 1H, C2H2N33-H), 8.30 (s, 1H, C2H2N35-H), 12.03 (s, 1H, NH).
Embodiment 8
(2E, 5E) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (4- chlorine Benzal) thiazolin 4 one preparation
Operating method reacts 10h, obtains yellow solid (2E, 5E)-with embodiment 2, compound 2 and 4- chloro benzaldehydes 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (4- chlorine benzal) thiazoline -4- Ketone, yield 73%, m.p.260~262 DEG C.1H NMR(CDCl3, 400MHz) and δ:1.25 (s, 9H, 3 × CH3), 7.47~7.52 (m, 4H, C6H4), 7.78,7.84 (s, 1H ,=CH), 8.13 (s, 1H, C2H2N33-H), 8.30 (s, 1H, C2H2N35-H), 12.01 (s, 1H, NH).
Embodiment 9
(2E, 5E) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (2- bromines Benzal) thiazolin 4 one preparation
Operating method reacts 10h, obtains yellow solid (2E, 5E)-with embodiment 2, compound 2 and 2- bromobenzaldehydes 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (2- bromines benzal) thiazoline -4- Ketone, yield 81%, m.p.285~287 DEG C.1H NMR(CDCl3, 400MHz) and δ:1.19,1.21 (s, 9H, 3 × CH3), 7.28~ 7.32 (m, 1H, C6H4), 7.42~7.47 (m, 1H, C6H4), 7.65~7.67 (m, 1H, C6H4), 7.72 (dd, J=8.0, 1.0Hz, 1H, C6H4), 8.12 (s, 1H ,=CH), 8.13 (s, 1H, C2H2N33-H), 8.31 (s, 1H, C2H2N35-H)。
Embodiment 10
(2E, 5E) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (3- bromines Benzal) thiazolin 4 one preparation
Operating method reacts 10h, obtains yellow solid (2E, 5E)-with embodiment 2, compound 2 and 3- bromobenzaldehydes 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (3- bromines benzal) thiazoline -4- Ketone, yield 82%, m.p.251~253 DEG C.1H NMR(CDCl3, 400MHz) and δ:1.22,1.27 (s, 9H, 3 × CH3), 7.37 (t, J=7.7Hz, 1H, C6H4), 7.50 (d, J=7.7Hz, 1H, C6H4), 7.58 (d, J=7.9Hz, 1H, C6H4), 7.69~ 7.74 (s, 1H, C6H4), 7.81 (s, 1H ,=CH), 8.13 (s, 1H, C2H2N33-H), 8.30 (s, 1H, C2H2N35-H), 12.03 (s, 1H, NH).
Embodiment 11
(2E, 5E) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (4- bromines Benzal) thiazolin 4 one preparation
Operating method reacts 10h, obtains yellow solid (2E, 5E)-with embodiment 2, compound 2 and 4- bromobenzaldehydes 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (4- bromines benzal) thiazoline -4- Ketone, yield 81%, m.p.268~270 DEG C.1H NMR(CDCl3, 400MHz) and δ:1.22,1.25 (s, 9H, 3 × CH3), 7.44 (dd, J=17.8,8.0Hz, 2H, C6H4), 7.67 (dd, J=21.4,8.4Hz, 2H, C6H4), 7.75,7.82 (m, 1H ,= CH), 8.13 (s, 1H, C2H2N33-H), 8.30 (s, 1H, C2H2N35-H), 12.05 (s, 1H, NH).
Embodiment 12
(2E, 5E) -5- benzals -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } The preparation of thiazolin 4 one
Operating method reacts 10h, obtains yellow solid (2E, 5E) -5- benzal with embodiment 2, compound 2 and benzaldehyde Base -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } thiazolin 4 one, yield 75%, M.p.225~227 DEG C.1H NMR(CDCl3, 400MHz) and δ:1.24 (s, 9H, 3 × CH3), 7.44~7.53 (m, 3H, C6H4), 7.59 (d, J=7.2Hz, 2H, C6H4), 7.87 (s, 1H ,=CH), 8.14 (s, 1H, C2H2N33-H), 8.32 (s, 1H, C2H2N35- H)。
Embodiment 13
(2E, 5E) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (2- first Base benzal) thiazolin 4 one preparation
Operating method reacts 10h, obtains yellow solid (2E, 5E)-with embodiment 2, compound 2 and 2- tolyl aldehydes 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (2- methylbenzilidenes) thiazoline - 4- ketone, yield 60%, m.p.260~262 DEG C.1H NMR(CDCl3, 400MHz) and δ:1.22 (s, 9H, 3 × CH3), 2.48 (s, 3H, CH3), 7.29~7.37 (m, 3H, C6H4), 7.52~7.60 (m, 1H, C6H4), 8.07 (s, 1H ,=CH), 8.12 (s, 1H, C2H2N33-H), 8.30 (s, 1H, C2H2N35-H)。
Embodiment 14
(2E, 5E) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (3- first Base benzal) thiazolin 4 one preparation
Operating method reacts 10h, obtains yellow solid (2E, 5E)-with embodiment 2, compound 2 and 3- tolyl aldehydes 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (3- methylbenzilidenes) thiazoline - 4- ketone, yield 66%, m.p.241~243 DEG C.1H NMR(CDCl3, 400MHz) and δ:1.26 (s, 9H, 3 × CH3), 2.42 (s, 3H, CH3), 7.28~7.39 (m, 3H, C6H4), 7.44~7.70 (m, 1H, C6H4), 7.82 (s, 1H ,=CH), 8.13 (s, 1H, C2H2N33-H), 8.31 (s, 1H, C2H2N35-H)。
Embodiment 15
(2E, 5E) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (4- first Base benzal) thiazolin 4 one preparation
Operating method reacts 10h, obtains yellow solid (2E, 5E)-with embodiment 2, compound 2 and 4- tolyl aldehydes 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (4- methylbenzilidenes) thiazoline - 4- ketone, yield 62%, m.p.245~247 DEG C.1H NMR(CDCl3, 400MHz) and δ:1.25 (s, 9H, 3 × CH3), 2.43 (s, 3H, CH3), 7.31 (d, J=7.9Hz, 2H, C6H4), 7.49 (d, J=7.9Hz, 2H, C6H4), 7.84 (s, 1H ,=CH), 8.14 (s, 1H, C2H2N33-H), 8.32 (s, 1H, C2H2N35-H)。
Embodiment 16
(2E, 5E) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (2- first Oxygroup benzal) thiazolin 4 one preparation
Operating method reacts 10h with embodiment 2, compound 2 and Benzaldehyde,2-methoxy, obtain yellow solid (2E, 5E) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (2- benzylidenes) thiophene Oxazoline -4- ketone, yield 77%, m.p.251~253 DEG C.1H NMR(CDCl3, 400MHz) and δ:1.23 (s, 9H, 3 × CH3), 3.93 (s, 3H, OCH3), 6.97 (d, J=8.3Hz, 1H, C6H4), 7.07 (t, J=7.5Hz, 1H, C6H4), 7.42~7.46 (m, 1H, C6H4), 7.55 (s, 1H, C6H4), 8.13 (s, 1H ,=CH), 8.24 (s, 1H, C2H2N33-H), 8.31 (s, 1H, C2H2N35-H)。
Embodiment 17
(2E, 5E) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (3- first Oxygroup benzal) thiazolin 4 one preparation
Operating method reacts 10h with embodiment 2, compound 2 and m-methoxybenzaldehyde, obtain yellow solid (2E, 5E) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (3- benzylidenes) thiophene Oxazoline -4- ketone, yield 74%, m.p.220~222 DEG C.1H NMR(CDCl3, 400MHz) and δ:1.24 (s, 9H, 3 × CH3), 3.87 (s, 3H, OCH3), 7.01 (dd, J=8.2,2.1Hz, 1H, C6H4), 7.07~7.20 (m, 2H, C6H4), 7.41 (t, J= 7.8Hz, 1H, C6H4), 7.83 (s, 1H ,=CH), 8.13 (s, 1H, C2H2N33-H), 8.30 (s, 1H, C2H2N35-H), 11.99 (s, 1H, NH).
Embodiment 18
(2E, 5E) -5- (3- amino benzal) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazole -2- Base] imino group thiazolin 4 one preparation
10ml dichloromethane and 10ml acetic acid 1.0mmol raw materials (2E, 5E) -2- [4- tertiary butyls -5- (1H-1,2, 4- triazol-1-yls) thiazol-2-yl] imino group } -5- (3- nitrobenzals) thiazolin 4 one, appropriate iron powder and 1ml is added Water, stirring at normal temperature react 5h.Filtering, washing, dichloromethane extraction, saturated aqueous sodium carbonate wash organic phase, anhydrous slufuric acid Sodium is dried, and precipitation obtains yellow solid (2E, 5E) -5- (3- amino benzal) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazoles - 1- yls) thiazol-2-yl] imino group } thiazolin 4 one, yield 81%, m.p.224~226 DEG C.1H NMR (DMSO, 400MHz) δ:1.18 (s, 9H, 3 × CH3), 5.49 (s, 2H, NH2), 6.69 (d, J=7.7Hz, 1H, C6H4), 6.81 (d, J=6.4Hz, 2H, C6H4), 7.18 (t, J=8.0Hz, 1H, C6H4), 7.57 (s, 1H ,=CH), 8.29 (s, 1H, C2H2N33-H), 9.03 (s, 1H, C2H2N35-H), 12.66 (s, 1H, NH).
Embodiment 19
(2E, 5E) -5- (4- amino benzal) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazole -2- Base] imino group thiazolin 4 one preparation
Operating method is the same as embodiment 18, (2E, 5E) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazole -2- Base] imino group -5- (4- nitrobenzals) thiazolin 4 one be raw material, react 5h, obtain yellow solid (2E, 5E) -5- (4- Amino benzal) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } thiazolin 4 one, Yield 85%, m.p.210~212 DEG C.1H NMR (DMSO, 400MHz) δ:1.20 (s, 9H, 3 × CH3), 6.16 (s, 2H, NH2), 6.67 (d, J=7.9Hz, 2H, C6H4), 7.39 (d, J=7.6Hz, 2H, C6H4), 7.58 (s, 1H ,=CH), 8.29 (s, 1H, C2H2N33-H), 9.03 (s, 1H, C2H2N35-H), 12.59 (s, 1H, NH).
Embodiment 20
(2E, 5E) -5- (3- acetylaminos benzal) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazoles - 2- yls] imino group thiazolin 4 one preparation
10ml acetic acid 0.5mmol raw materials (2E, 5E) -5- (3- amino benzal) -2- [4- tertiary butyls -5- (1H-1, 2,4- triazol-1-yls) thiazol-2-yl] imino group } thiazolin 4 one, 0.5mmol chloroacetic chlorides are added dropwise, stirring at normal temperature reacts 1h. Washing, ethyl acetate extraction, saturated aqueous sodium carbonate wash organic phase, anhydrous sodium sulfate drying, and precipitation obtains yellow solid { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] is sub- by (2E, 5E) -5- (3- acetylaminos benzal) -2- Amino } thiazolin 4 one, yield 64%, m.p.302~304 DEG C.1H NMR (DMSO, 400MHz) δ:1.16 (s, 9H, 3 × CH3), 2.05 (s, 3H, COCH3), 7.33 (d, J=6.1Hz, 1H, C6H4), 7.44 (d, J=6.5Hz, 2H, C6H4), 7.70 (s, 1H ,=CH), 8.20 (s, 1H, C6H4), 8.28 (s, 1H, C2H2N33-H), 9.02 (s, 1H, C2H2N35-H), 10.12 (s, 1H, NHAc), 12.82 (s, 1H, NH).
Embodiment 21
(2E, 5E) -5- (4- acetylaminos benzal) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazoles - 2- yls] imino group thiazolin 4 one preparation
Operating method with embodiment 20, (2E, 5E) -5- (4- amino benzal) -2- [4- tertiary butyls -5- (1H-1,2,4- Triazol-1-yl) thiazol-2-yl] imino group thiazolin 4 one be raw material, react 1h, obtain yellow solid (2E, 5E) -5- (4- Acetylamino benzal) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } thiazoline -4- Ketone, yield 68%, m.p.245~247 DEG C.1H NMR (DMSO, 400MHz) δ:1.19 (s, 9H, 3 × CH3), 2.08 (s, 3H, COCH3), 7.62 (d, J=8.4Hz, 2H, C6H4), 7.69 (s, 1H ,=CH), 7.75 (d, J=7.7Hz, 2H, C6H4), 8.29 (s, 1H, C2H2N33-H), 9.02 (s, 1H, C2H2N35-H), 10.28 (s, 1H, NHAc), 12.79 (s, 1H, NH).
Embodiment 22
The preparation of 2- { [4- tertiary butyls -5- (1H- imidazoles -1- bases) thiazol-2-yl] amino } thiazolin 4 one
4.4g (20mmol) 4- tertiary butyls -5- (1H- imidazoles -1- bases) thiazole -2- amine, 50mL dichloromethane, stirring and dissolving, 2.75g (50mmol) Anhydrous potassium carbonate is added, 1.60ml (50mmol) chloracetyl chloride, normal-temperature reaction is added dropwise in stirring at normal temperature 30min 2.5h.Reaction solution pours into ice water, dichloromethane extraction, and saturated aqueous sodium carbonate washing merges organic phase, and anhydrous sodium sulfate is dry Dry, precipitation, ethyl alcohol recrystallization obtains 4.4g white solids 3, yield 82%, m.p.175~177 DEG C.
0.9g (3mmol) compound 7,0.29g (3mmol) potassium rhodanide, the dissolving of 20ml ethyl alcohol, heating reflux reaction 5.0h.It is cooling, solid is precipitated, filters, dry 0.8g pink solids 4, yield 83%, m.p.241~243 DEG C.1H NMR (CDCl3, 400MHz) and δ:1.20 (s, 9H, 3 × CH3), 3.90 (s, 2H, CH2), 7.09 (s, 1H, C2H3N22-H), 7.19 (s, 1H, C2H3N24-H), 7.70 (s, 1H, C2H3N25-H), 12.08 (s, 1H, NH).
Embodiment 23
(2E, 5E) -2- { [4- tertiary butyls -5- (1H- imidazoles -1- bases) thiazol-2-yl] amino } -5- (3- nitrobenzals) The preparation of thiazolin 4 one
35ml acetic acid 0.65g sodium acetates prepare the buffer solution of pH=4~5, and 4 He of 2.0mmol intermediates is added 4.0mmol 3- nitrobenzaldehydes, heating reflux reaction 10h.It is cooling, wash, filtering, ethyl alcohol recrystallization obtain yellow solid (2E, 5E) -2- { [4- tertiary butyls -5- (1H- imidazoles -1- bases) thiazol-2-yl] amino } -5- (3- nitrobenzals) thiazolin 4 one, Yield 75%, m.p.273~275 DEG C.1H NMR(CDCl3, 400MHz) and δ:1.23,1.30 (s, 9H, 3 × CH3), 7.11 (s, 1H, C2H3N22-H), 7.19 (s, 1H, C2H3N24-H), 7.68~7.72 (m, 2H ,=CH, C2H3N25-H), 7.88 (m, 2H, C6H4), 8.31 (d, J=8.5Hz, 1H, C6H4), 8.56 (s, 1H, C6H4), 12.13 (s, 1H, NH).
Embodiment 24
(2E, 5E) -5- (3- amino benzal) -2- { [4- tertiary butyls -5- (1H- imidazoles -1- bases) thiazol-2-yl] amino } The preparation of thiazolin 4 one
10ml dichloromethane and 10ml acetic acid 1.0mmol raw materials (2E, 5E) -2- { [4- tertiary butyls -5- (1H- imidazoles - 1- yls) thiazol-2-yl] amino } -5- (3- nitrobenzals) thiazolin 4 one, appropriate iron powder and 1ml water, stirring at normal temperature is added React 5h.Filtering, washing, dichloromethane extraction, saturated aqueous sodium carbonate wash organic phase, anhydrous sodium sulfate drying, precipitation Obtain reduzate：Yellow solid yellow solid (2E, 5E) -5- (3- amino benzal) -2- { [4- tertiary butyls -5- (1H- imidazoles - 1- yls) thiazol-2-yl] amino } thiazolin 4 one, yield 82%, m.p.223~225 DEG C.1H NMR (DMSO, 400MHz) δ: 1.21 (s, 9H, 3 × CH3), 5.43 (s, 2H, NH2), 6.68 (d, J=7.7Hz, 1H, C6H4), 6.81 (s, 2H, C2H3N22-H, C6H4), 7.15~7.19 (m, 2H, C2H3N24-H, C6H4), 7.44~7.56 (m, 2H, C2H3N25-H, C6H4), 8.00 (s, 1H, =CH), 11.98 (s, 1H, NH).
(2E, 5Z) -2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups]-is prepared according to the method described in Examples 1 to 24 5- benzals thiazolin 4 one (I), (2Z, 5Z) -2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzals thiazoline - 4- ketone (II) and (2Z, 5E) -2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzals thiazolin 4 one (IV).
Wherein, R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Linear or branched alkyl group, fluoro C1~C2Alkyl, chloro C1~C2 Alkyl, bromo C1~C2Alkyl or iodo C1~C2Alkyl；X, Y or Z are selected from：CH or N；X1、X5It is selected from：Hydrogen, C1~C2Alkyl, C3 ~C4Linear or branched alkyl group, fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR； X2、X4It is selected from：Fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；X3It is selected from：Fluorine, Chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；Wherein R is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl.
Embodiment 25
2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzal thiazolin 4 one resisiting influenza virus neuraminic acids Enzymatic activity
1. experimental principle
Compound MUNANA is the specific substrate of neuraminidase, the metabolite generated under neuraminic acid enzyme effect Under 360nm irradiation excitations, 450nm fluorescence can be generated, the variation of fluorescence intensity can delicately reflect neuraminidase activity. Enzyme is all from A/PR/8/34 (H1N1) virus stain.
2. experimental method
In enzyme reaction system, a certain concentration sample is suspended in influenza neuraminidase NA in reaction buffer (pH6.5), fluorogenic substrate MUNANA is added and starts reaction system, 37 DEG C are incubated after forty minutes, and reaction terminating liquid is added to terminate reaction. In the case where excitation wavelength 360nm and launch wavelength are the Parameter Conditions of 450nm, fluorescence intensity level is measured.According to subtracting for fluorescence intensity Compound can be calculated on a small quantity to the active inhibiting rates of NA.
3. detecting sample：2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzals thiazolin 4 one (I, II, III Or IV)
Wherein, R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Linear or branched alkyl group, fluoro C1~C2Alkyl, chloro C1~C2 Alkyl, bromo C1~C2Alkyl or iodo C1~C2Alkyl；X, Y or Z are selected from：CH or N；X1、X5It is selected from：Hydrogen, C1~C2Alkyl, C3 ~C4Linear or branched alkyl group, fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR； X2、X4It is selected from：Fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；X3It is selected from：Fluorine, Chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；Wherein R is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl.
4. Activity Results
Preferred compound is in reaction system to the inhibiting rate and its IC of neuraminidase when 40.0 μ g/mL of detectable concentration50 It is worth tabulated below 1：
Table 12- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] suppression of -5- benzals thiazolin 4 one to neuraminidase System activity
2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzal thiazolin 4 ones have good anti-current susceptible Malicious neuraminidase activity can be used for preparing influenza virus neuraminidase inhibitor.

Claims (6)

  1. 2- shown in chemical structural formula I 1. [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzal thiazolin 4 ones：
    Wherein, R1It is selected from：Hydrogen, C1~C2Alkyl, C3~C4Linear or branched alkyl group, fluoro C1~C2Alkyl, chloro C1~C2Alkane Base, bromo C1~C2Alkyl or iodo C1~C2Alkyl；X is selected from：CH；Y, Z is selected from：N；X1、X5It is selected from：Hydrogen, C1~C2Alkyl, C3 ~C4Linear or branched alkyl group, fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR； X2、X4It is selected from：Fluorine, chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；X3It is selected from：Fluorine, Chlorine, bromine, iodine, hydroxyl, dimethylamino, methoxyl group, ethyoxyl, nitro, amino or NHCOR；Wherein R is selected from：Hydrogen, C1~C2Alkyl, C3~C4Straight chain or C3~C4Branched alkyl.
  2. 2. 2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzal thiazolin 4 ones described in claim 1 are selected from formula II compound represented：
    Wherein, R1And X1~X5, X, Y and Z are as described in claim 1.
  3. 3. one kind 2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzal thiazolin 4 ones, are selected from：2- { [the tertiary fourths of 4- Base -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group -5- (2- fluorine benzal) thiazolin 4 one, 2- { [uncles 4- Butyl -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group -5- (3- fluorine benzal) thiazolin 4 one, 2- { [4- Tertiary butyl -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group -5- (2- chlorine benzal) thiazolin 4 one, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (3- chlorine benzal) thiazolin 4 one, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (4- chlorine benzal) thiazoline -4- Ketone, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (2- bromines benzal) thiazoline - 4- ketone, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (3- bromines benzal) thiazole Quinoline -4- ketone, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (4- bromines benzal) thiophene Oxazoline -4- ketone, 5- benzals -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } thiazole Quinoline -4- ketone, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (2- methylbenzilidenes) (3- methyl is sub- by thiazolin 4 one, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- Benzyl) thiazolin 4 one, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (4- first Base benzal) thiazolin 4 one, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } -5- (2- benzylidenes) thiazolin 4 one, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imido Base } -5- (3- benzylidenes) thiazolin 4 one, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazole -2- Base] imino group -5- (3- nitrobenzals) thiazolin 4 one, 2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiophenes Azoles -2- bases] imino group -5- (4- nitrobenzals) thiazolin 4 one, 5- (3- amino benzal) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group thiazolin 4 one, 5- (4- amino benzal) -2- { [tertiary fourths of 4- Base -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group thiazolin 4 one, 5- (3- acetylaminos benzal) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } thiazolin 4 one or 5- (4- acetylaminos Benzal) -2- { [4- tertiary butyls -5- (1H-1,2,4- triazol-1-yls) thiazol-2-yl] imino group } thiazolin 4 one.
  4. 4. the preparation of 2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzal thiazolin 4 ones described in claim 1 Method, it is characterised in that its preparation reaction is as follows：
    In formula, R1、X、Y、Z、X1~X5As described in claim 1.
  5. 5.5- (amino benzal) -2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] thiazolin 4 ones and 5- (acylamino- benzal Base) -2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] thiazolin 4 one preparation method, it is characterised in that their preparation Reaction is as follows：
    In formula, R, R1, X, Y and Z it is as described in claim 1；N is selected from 1,2 or 3；(NO2)nIt is selected from：2-NO2、3-NO2、4-NO2、2, 4-(NO2)2、2,5-(NO2)2、2,6-(NO2)2、3,4-(NO2)2、3,5-(NO2)2、2,3,4-(NO2)3Or 2,3,5- (NO2)3； (NH2)nIt is selected from：2-NH2、3-NH2、4-NH2、2,4-(NH2)2、2,5-(NH2)2、2,6-(NH2)2、3,4-(NH2)2、3,5- (NH2)2、2,3,4-(NH2)3Or 2,3,5- (NH2)3；(NHCOR)nIt is selected from：2-NHCOR、3-NHCOR、4-NHCOR、2,4- (NHCOR)2、2,5-(NHCOR)2、2,6-(NHCOR)2、3,4-(NHCOR)2、3,5-(NHCOR)2、2,3,4-(NHCOR)3Or 2, 3,5-(NHCOR)3。
  6. 6. 2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzal thiazoles according to any one of claims 1 to 3 Application of the quinoline -4- ketone in preparing influenza virus neuraminidase inhibitor.
CN201510069095.7A 2015-02-10 2015-02-10 2- [5- (nitrogen azoles -1- bases) thiazole -2- imino groups] -5- benzal thiazolinones and the preparation method and application thereof Expired - Fee Related CN105985332B (en)

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CN102250078A (en) * 2011-04-25 2011-11-23 湖南大学 Use of 4-(benzofuran-5-yl)-2-benzyliminothiazole in preparation of herbicide
CN102964267A (en) * 2011-09-01 2013-03-13 中山大学 Cyclohexene compound having influenza virus neuraminidase inhibition activity, preparation method and application
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