CN104829608A - Coumarin-thiazole-indolone compounds, and preparation method and application thereof - Google Patents

Coumarin-thiazole-indolone compounds, and preparation method and application thereof Download PDF

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CN104829608A
CN104829608A CN201510252481.XA CN201510252481A CN104829608A CN 104829608 A CN104829608 A CN 104829608A CN 201510252481 A CN201510252481 A CN 201510252481A CN 104829608 A CN104829608 A CN 104829608A
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thiazole
oxo
preparation
chromene
base
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CN104829608B (en
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王广成
彭知云
刘文超
何典雄
余健
蒋杨洋
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Jishou University
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Jishou University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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Abstract

The invention discloses coumarin-thiazole-indolone compounds, and a preparation method and application thereof. The compounds are disclosed as Formula (I). The preparation method comprises the following steps: reacting salicylaldehyde and ethyl acetoacetate to obtain 3-acetyl-2H-benzopyranyl-2-one, carrying out bromination, cyclization and hydrazinolysis reaction to obtain 4-(2-oxo-2H-benzopyranyl-3-yl)thiazolyl-2-formylhydrazine, and finally, reacting with various substituted isatin to obtain the target compounds. The compounds can be used as a raw material of antibacterial drugs. The preparation method has the advantage of simple and accessible raw materials, and is convenient to operate.

Description

A kind of tonka bean camphor-thiazole-indolone type compound and method for making thereof and purposes
Technical field
The present invention relates to a kind of tonka bean camphor-thiazole-indolone type compound and preparation method thereof and the application in preparation antibacterials.
Background technology
Along with the widespread use of antibacterials, especially antibiotic abuse, the drug resistance problems of worldwide bacterium is day by day serious in recent years, and presents the trend risen year by year, brings great difficulty to the treatment of infectious diseases.The particularly appearance of the Multidrug resistant bacteria such as methicillin-resistant staphylococcus aureus (MRSA), penicillin resistance pneumococcus (PRSP), multiple-drug resistance tuberculosis bacillus, the life and health of the serious threat mankind.
Isatin has another name called isatin or 2,3-indolinedione, is present in the endogenous active substance in mammalian tissues and body fluid.In addition isatin structure is also present in various natural products, is a kind of common Structures of Natural Products.According to the literature, isatin and derivative thereof have multiple biological activity, as spasmolytic, tuberculosis, antibacterium, antimycotic, antiviral, antitumor etc.Therefore the research tool carrying out original new drug based on isatin is of great significance.
Coumarin kind compound is the secondary metabolism product of a class plant, in various plants, have distribution.Many plants containing coumarin kind compound have had the history of several thousand as drug use in Asia.Coumarin kind compound has multiple biological activity, such as: anti-oxidant, antitumor, anti-inflammatory, anti-neurodegeneration, anti-malarial, anticoagulation, antibacterial and antimycotic etc.Due to chemical structure and the diversified biological activity of its uniqueness, coumarin kind compound has become design and has found the important lead compound source of new drug, develops it and has certain theory significance and actual value.Based on above analysis, tonka bean camphor structure, according to twin medicine principle, is connected with isatin structure by we, design and synthesis one class tonka bean camphor-thiazole-indolone type compound.
Summary of the invention
Technical scheme of the present invention is as follows:
Technical scheme of the present invention is as follows:
A kind of tonka bean camphor-thiazole-indolone type compound, is characterized in that they have general structure as shown in the formula (I):
（I）
Wherein: R 1for hydrogen, alkyl or benzyl, R 2, R 3, R 4or R 5for hydrogen, halogen, alkyl, amino, alkylamino, alkoxyl group, cyano group, nitro, hydroxyl, trifluoromethyl or sulfydryl.
Prepare a method for above-mentioned tonka bean camphor-thiazole-indolone type compound, it comprises the following steps:
Step 1: salicylic aldehyde, methyl aceto acetate, piperidines are placed in round-bottomed flask, add ethanol, back flow reaction 5 ~ 24 hours, stopped reaction, cool to room temperature, adds water, extraction into ethyl acetate, merge organic phase, anhydrous sodium sulfate drying, filters, is spin-dried for, cross silicagel column separation and purification, obtain yellow solid powder 3-ethanoyl-2H-chromen-2-one; The mol ratio of described salicylic aldehyde, methyl aceto acetate, piperidines is 1:(1 ~ 5): (0.1 ~ 4);
Step 2: 3-ethanoyl-2H-chromen-2-one, tosic acid, N-bromo-succinimide are placed in round-bottomed flask, add DMF, 50 ~ 160 DEG C are reacted 2 ~ 5 hours, stopped reaction, add saturated sodium thiosulfate solution, extraction into ethyl acetate, merge organic phase, cross silica gel chromatography, obtain white solid powder 3-(2-acetyl bromide)-2H-chromen-2-one; The mol ratio of described 3-ethanoyl-2H-chromen-2-one, tosic acid, N-bromo-succinimide is 1:(1 ~ 5): (1 ~ 10);
Step 3: 3-(2-acetyl bromide)-2H-chromen-2-one, thio-oxamide ethyl ester are placed in round-bottomed flask, add methyl alcohol, stirring at room temperature 5 ~ 24 hours, stopped reaction, add water, extraction into ethyl acetate, merge organic phase, cross silica gel chromatography, obtain Tan solid powder 4-(2-oxo-2H-chromene-3-base) thiazole-2-ethyl formate; Described 3-(2-acetyl bromide)-2H-chromen-2-one, the mol ratio of thio-oxamide ethyl ester are 1:(1 ~ 10);
Step 4: 4-(2-oxo-2H-chromene-3-base) thiazole-2-ethyl formate, hydrazine hydrate are placed in round-bottomed flask, add ethanol, back flow reaction 2 ~ 10, stopped reaction, cool to room temperature, filter, obtain white solid powder 4-(2-oxo-2H-chromene-3-base) thiazole-2-formyl hydrazine; Described 4-(2-oxo-2H-chromene-3-base) thiazole-2-ethyl formate, the mol ratio of hydrazine hydrate are 1:(1 ~ 20);
Step 5: 4-(2-oxo-2H-chromene-3-base) thiazole-2-formyl hydrazine, replacement isatin are placed in round-bottomed flask, add methyl alcohol, back flow reaction 0.5 ~ 4 hour, cool to room temperature, there is solid to separate out, filter to obtain tonka bean camphor-thiazole-indolone type compound (I); The mol ratio of described 4-(2-oxo-2H-chromene-3-base) thiazole-2-formyl hydrazine, replacement isatin is 1:(1 ~ 5).
Tonka bean camphor-thiazole of the present invention-indolone type compound all has various bacteria and suppresses preferably and kill activity, and the development and application for antibacterials provides new selection.
Accompanying drawing explanation
Fig. 1 is the syntheti c route figure of tonka bean camphor-thiazole-indolone type compound.
Embodiment
Following embodiment is to describe the present invention in detail, and unrestricted the present invention.
The preparation of embodiment one: 3-ethanoyl-2H-chromen-2-one
Salicylic aldehyde (1.22g, 10 mmol), methyl aceto acetate (2.6g, 20 mmol), piperidines (0.5 mL) are placed in round-bottomed flask, add ethanol 100 mL, back flow reaction 12 hours, TLC display reaction is complete, stopped reaction, cool to room temperature, adds water 300 mL, extraction into ethyl acetate (200 mL × 3), merges organic phase, anhydrous sodium sulfate drying, filter, be spin-dried for, cross silicagel column separation and purification, obtain yellow solid powder 1.5 g, yield 79 %. 1H NMR (CDCl 3, 400 MHz) δ: 2.73 (s, 3H), 7.33-7.35 (m, 2H), 7.64-7.69 (m, 2H), 8.51 (s, 1H)。
The preparation of embodiment two: 3-(2-acetyl bromide)-2H-chromen-2-one
By 3-ethanoyl-2H-chromen-2-one (188 mg, 1 mmol), tosic acid (380 mg, 2 mmol), N-bromo-succinimide (354 mg; 2 mmol) be placed in round-bottomed flask, add DMF 10 mL, 100 DEG C are reacted 2 hours; TLC display reaction is complete; stopped reaction, adds saturated sodium thiosulfate solution, extraction into ethyl acetate; merge organic phase; cross silica gel chromatography, obtain white solid powder 127 mg, yield 44 %. 1H NMR (CDCl 3, 400 MHz) δ: 4.76 (s, 2H), 7.37-7.42 (m, 2H), 7.69-7.73 (m, 2H), 8.65 (s, 1H)。
The preparation of embodiment three: 4-(2-oxo-2H-chromene-3-base) thiazole-2-ethyl formate
3-(2-acetyl bromide)-2H-chromen-2-one (133 mg, 1 mmol), thio-oxamide ethyl ester (399 mg, 3 mmol) are placed in round-bottomed flask; add 10 mL methyl alcohol; stirring at room temperature 24 hours, TLC display reaction is complete, stopped reaction; add 20 mL water; extraction into ethyl acetate, merges organic phase, crosses silica gel chromatography; obtain Tan solid powder 190 mg, yield 63 %. 1H NMR (CDCl 3, 400 MHz) δ: 1.49 (t, 3H), 4.51 (q, 2H), 7.32 (t, 1H), 7.38 (d, 1H), 7.58 (t, 1H), 7.66 (d, 1H), 8.74 (s, 1H), 8.92 (s, 1H)。
Embodiment four: 4-(2-oxo-2H-chromene-3-base) thiazole-2-formyl hydrazine
By 4-(2-oxo-2H-chromene-3-base) thiazole-2-ethyl formate (301mg, 1 mmol), hydrazine hydrate (100 mg, 2 mmol) be placed in round-bottomed flask, add 10 mL ethanol, back flow reaction, TLC display reaction is complete, stopped reaction, cool to room temperature, filters, obtain white solid powder 208 mg, yield 72%. 1H NMR (d 6-DMSO, 400 MHz) δ: 4.76 (s, 2H), 7.46 (t, 1H), 7.50 (d, 1H), 7.69 (t, 1H), 7.76 (d, 1H), 8.59 (s, 1H), 9.07 (s, 1H), 10.23 (s, 1H)。
Embodiment five: the preparation of (Z)-4-(2-oxo-2H-chromene-3-base)-N'-(2-oxindole-3-subunit) thiazole-2-hydrazides (1)
By 4-(2-oxo-2H-chromene-3-base) thiazole-2-formyl hydrazine (301mg, 1 mmol), isatin (147mg, 1 mmol) be placed in round-bottomed flask, add 10 mL methyl alcohol, back flow reaction 2 hours, stopped reaction, cool to room temperature, filter, obtain pressed powder 347 mg, yield 83 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 7.46 (t, 1H), 7.38-7.41 (m, 1H), 7.44 (d, 1H), 7.50-7.53 (m, 1H), 7.56-7.60 (m, 2H), 7.71 (t, 1H), 7.85 (d, 1H), 8.62 (s, 1H), 9.06 (s, 1H), 10.22 (s, 1H), 10.29 (s, 1H); EIMS m/z = 417 [M +]。
Embodiment six: the preparation of (Z)-N'-(the bromo-2-oxindole of 6--3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (2)
Preparation method is with embodiment five, and just isatin replaces with 6-bromo-isatin, yield 86 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 7.41 (t, 1H), 7.42-7.44 (m, 2H), 7.50-7.54 (m, 2H), 7.70 (t, 1H), 7.84 (d, 1H), 8.66 (s, 1H), 9.11 (s, 1H), 10.17 (s, 1H), 10.25 (s, 1H); EIMS m/z = 496 [M +]。
Embodiment seven: the preparation of (Z)-N'-(7-chloro-2-oxo indoles-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (3)
Preparation method is with embodiment five, and just isatin replaces with 7-chlorisatide, yield 73 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 7.38 (t, 1H), 7.41-7.43 (m, 1H), 7.47 (d, 1H), 7.62 (d, 1H), 7.69 (t, 1H), 7.82 (d, 1H), 7.80 (d, 1H), 8.62 (s, 1H), 9.06 (s, 1H), 10.22 (s, 1H), 10.29 (s, 1H); EIMS m/z = 451 [M +]。
Embodiment eight: the preparation of (Z)-N'-(5-nitro-2-oxindole-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (4)
Preparation method is with embodiment five, and just isatin replaces with 5-Nitroisatoic, yield 78 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 7.47 (t, 1H), 7.50 (d, 1H), 7.71 (t, 1H), 7.80 (d, 1H), 7.85 (d, 1H), 8.15 (d, 1H), 8.61 (d, 1H), 8.65 (s, 1H), 9.14 (s, 1H), 10.24 (s, 1H), 10.31 (s, 1H); EIMS m/z = 462 [M +]。
Embodiment nine: the preparation of (Z)-N'-(5-chloro-2-oxo indoles-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (5)
Preparation method is with embodiment five, and just isatin replaces with 5-chlorisatide, yield 80 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 7.47 (t, 1H), 7.52 (d, 1H), 7.60 (d, 1H), 7.65 (d, 1H), 7.72 (t, 1H), 7.85 (d, 1H), 8.05 (d, 1H), 8.62 (s, 1H), 9.06 (s, 1H), 10.22 (s, 1H), 10.29 (s, 1H); EIMS m/z = 451 [M +]。
Embodiment ten: the preparation of (Z)-N'-(5-methyl-2-oxindole-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (6)
Preparation method is with embodiment five, and just isatin replaces with 5-methylisatin, yield 83 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 2.15 (s, 3H), 6.60 (d, 1H), 6.65 (d, 1H),7.45 (t, 1H), 7.49 (d, 1H), 7.70 (t, 1H), 7.81 (d, 1H), 8.17 (d, 1H), 8.66 (s, 1H), 9.09 (s, 1H), 10.17 (s, 1H), 10.28 (s, 1H); EIMS m/z = 431 [M +]。
Embodiment 11: the preparation of (Z)-N'-(the fluoro-2-oxindole of 5--3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (7)
Preparation method is with embodiment five, and just isatin replaces with 5-fluoro indigo red, yield 69 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 7.44-7.46 (m, 2H), 7.53 (d, 1H), 7.71-7.74 (m, 2H), 7.81 (d, 1H), 7.95-7.98 (m, 1H), 8.55 (s, 1H), 9.17 (s, 1H), 10.18 (s, 1H), 10.32 (s, 1H); EIMS m/z = 435 [M +]。
Embodiment 12: the preparation of (Z)-N'-(5-methoxyl group-2-oxindole-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (8)
Preparation method is with embodiment five, and just isatin replaces with 5-methoxyl group isatin, yield 72 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 3.83 (s, 3H), 7.09 (d, 1H), 7.45 (t, 1H), 7.49 (d, 1H),7.51 (d, 1H), 7.70 (t, 1H), 7.81 (d, 1H), 7.88 (d, 1H), 8.17 (d, 1H), 8.69 (s, 1H), 9.09 (s, 1H), 10.23 (s, 1H), 10.29 (s, 1H); EIMS m/z = 447 [M +]。
Embodiment 13: the preparation of (Z)-N'-(7-trifluoromethyl-2-oxindole-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (9)
Preparation method is with embodiment five, and just isatin replaces with 7-trifluoromethyl isatin, yield 71 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 7.17-7.20 (m, 1H), 7.49 (t, 1H), 7.55 (d, 1H), 7.72-7.73 (m, 2H), 7.82 (d, 1H), 7.97-7.99 (m, 1H), 8.69 (s, 1H), 9.14 (s, 1H), 10.19 (s, 1H), 10.23 (s, 1H); EIMS m/z = 486 [M +]。
Embodiment 14: the preparation of (Z)-N'-(1-methyl-2-oxindole-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (10)
Preparation method is with embodiment five, and just isatin replaces with 1-methylisatin, yield 72 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 3.49 (s, 3H), 7.36-7.39 (m, 1H), 7.44 (d, 1H), 7.47 (t, 1H), 7.51-7.53 (m, 1H), 7.58-7.61 (m, 2H), 7.72 (t, 1H), 7.83 (d, 1H), 8.57 (s, 1H), 9.11 (s, 1H), 10.22 (s, 1H); EIMS m/z = 431 [M +]。
Embodiment 15: the preparation of (Z)-N'-(the bromo-1-methyl of 6--2-oxindole-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (11)
Preparation method is with embodiment five, and just isatin replaces with the bromo-1-methylisatin of 6-, yield 80 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 3.41 (s, 3H), 7.39 (t, 1H), 7.41-7.43 (m, 2H), 7.52-7.54 (m, 2H), 7.69 (t, 1H), 7.85 (d, 1H), 8.68 (s, 1H), 9.12 (s, 1H), 10.19 (s, 1H); EIMS m/z = 510 [M +]。
Embodiment 16: the preparation of (Z)-N'-(the chloro-1-methyl of 7--2-oxindole-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (12)
Preparation method is with embodiment five, and just isatin replaces with the chloro-1-methylisatin of 7-, yield 88 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 3.42 (s, 3H), 7.46 (t, 1H), 7.47-7.49 (m, 1H), 7.51 (d, 1H), 7.72 (d, 1H), 7.74 (t, 1H), 7.83 (d, 1H), 7.85 (d, 1H), 8.61 (s, 1H), 9.11 (s, 1H), 10.23 (s, 1H); EIMS m/z = 465 [M +]。
Embodiment 17: the preparation of (Z)-N'-(1-methyl-5-nitro-2-oxindole-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (13)
Preparation method is with embodiment five, and just isatin replaces with 5-nitro-1-methylisatin, yield 77 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 3.46 (s, 3H), 7.46 (t, 1H), 7.51 (d, 1H), 7.71 (t, 1H), 7.84 (d, 1H), 7.87 (d, 1H), 8.16 (d, 1H), 8.62 (d, 1H), 8.67 (s, 1H), 9.15 (s, 1H), 10.24 (s, 1H); EIMS m/z = 475 [M +]。
Embodiment 18: the preparation of (Z)-N'-(the chloro-1-methyl of 5--2-oxindole-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (14)
Preparation method is with embodiment five, and just isatin replaces with the chloro-1-methylisatin of 5-, yield 73 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 3.39 (s, 3H), 7.49 (t, 1H), 7.54 (d, 1H), 7.62 (d, 1H), 7.65 (d, 1H), 7.77 (t, 1H), 7.86 (d, 1H), 8.06 (d, 1H), 8.63 (s, 1H), 9.11 (s, 1H), 10.22 (s, 1H); EIMS m/z = 465 [M +]。
Embodiment 19: the preparation of (Z)-N'-(1,5-dimethyl-2-oxindole-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (15)
Preparation method is with embodiment five, and just isatin replaces with 1,5-dimethylisatin, yield 76 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 2.15 (s, 3H), 3.45 (s, 3H), 6.64 (d, 1H), 6.66 (d, 1H),7.48 (t, 1H), 7.55 (d, 1H), 7.72 (t, 1H), 7.83 (d, 1H), 8.18 (d, 1H), 8.67 (s, 1H), 9.12 (s, 1H), 10.22 (s, 1H); EIMS m/z = 445 [M +]。
Embodiment 20: the preparation of (Z)-N'-(the fluoro-1-methyl of 5--2-oxindole-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (16)
Preparation method is with embodiment five, and just isatin replaces with the fluoro-1-methylisatin of 5-, yield 75 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 3.49 (s, 3H), 7.45-7.47 (m, 2H), 7.54 (d, 1H), 7.71-7.73 (m, 2H), 7.82 (d, 1H), 7.94-7.97 (m, 1H), 8.54 (s, 1H), 9.24 (s, 1H), 10.28 (s, 1H); EIMS m/z = 449 [M +]。
Embodiment 21: the preparation of (Z)-N'-(5-methoxyl group-1-methyl-2-oxindole-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (17)
Preparation method is with embodiment five, and just isatin replaces with 5-methoxyl group-1-methylisatin, yield 79 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 3.44 (s, 3H), 3.83 (s, 3H), 7.11 (d, 1H), 7.46 (t, 1H), 7.52 (d, 1H),7.55 (d, 1H), 7.72 (t, 1H), 7.76 (d, 1H), 7.81 (d, 1H), 8.19 (d, 1H), 8.70 (s, 1H), 9.12 (s, 1H), 10.22 (s, 1H); EIMS m/z = 461 [M +]。
Embodiment 22: the preparation of (Z)-N'-(7-Trifluoromethyl-1-methyl-2-oxindole-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (18)
Preparation method is with embodiment five, and just isatin replaces with 7-Trifluoromethyl-1-methylisatin, yield 85 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 3.41 (s, 3H), 7.18-7.20 (m, 1H), 7.51 (t, 1H), 7.56 (d, 1H), 7.72-7.74 (m, 2H), 7.83 (d, 1H), 7.98-8.00 (m, 1H), 8.72 (s, 1H), 9.15 (s, 1H), 10.24 (s, 1H); EIMS m/z = 499 [M +]。
Embodiment 23: the preparation of (Z)-N'-(1-ethyl-2-oxo indoles-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (19)
Preparation method is with embodiment five, and just isatin replaces with 1-ethyl isatin, yield 68 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 1.25 (t, 3H), 3.42 (q, 2H), 7.49 (t, 1H), 7.38-7.39 (m, 1H), 7.46 (d, 1H), 7.52-7.53 (m, 1H), 7.59-7.61 (m, 2H), 7.74 (t, 1H), 7.81 (d, 1H), 8.63 (s, 1H), 9.25 (s, 1H), 10.17 (s, 1H); EIMS m/z = 445 [M +]。
Embodiment 24: the preparation of (Z)-N'-(6-bromo-1-ethyl-2-oxo indoles-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (20)
Preparation method is with embodiment five, and just isatin replaces with 6-bromo-1-ethyl isatin, yield 72 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 1.28 (t, 3H), 3.46 (q, 2H), 7.45 (t, 1H), 7.46-7.47 (m, 2H), 7.53-7.56 (m, 2H), 7.72 (t, 1H), 7.89 (d, 1H), 8.79 (s, 1H), 9.09 (s, 1H), 10.15 (s, 1H); EIMS m/z = 523 [M +]。
Embodiment 25: the preparation of (Z)-N'-(7-chloro-1-ethyl-2-oxo indoles-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (21)
Preparation method is with embodiment five, and just isatin replaces with 7-chloro-1-ethyl isatin, yield 78 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 1.23 (t, 3H), 3.44 (q, 2H), 7.45 (t, 1H), 7.47-7.49 (m, 1H), 7.55 (d, 1H), 7.79 (d, 1H), 7.80 (t, 1H), 7.84 (d, 1H), 7.87 (d, 1H), 8.72 (s, 1H), 9.14 (s, 1H), 10.15 (s, 1H); EIMS m/z = 479 [M +]。
Embodiment 26: the preparation of (Z)-N'-(5-nitro-1-ethyl-2-oxo indoles-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (22)
Preparation method is with embodiment five, and just isatin replaces with 5-nitro-1-ethyl isatin, yield 84 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 1.26 (t, 3H), 3.46 (q, 2H), 7.47 (t, 1H), 7.57 (d, 1H), 7.78 (t, 1H), 7.87 (d, 1H), 7.90 (d, 1H), 8.21 (d, 1H), 8.65 (d, 1H), 8.69 (s, 1H), 9.21 (s, 1H), 10.20 (s, 1H); EIMS m/z = 490 [M +]。
Embodiment 27: the preparation of (Z)-N'-(5-chloro-1-ethyl-2-oxo indoles-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (23)
Preparation method is with embodiment five, and just isatin replaces with 5-chloro-1-ethyl isatin, yield 80 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 1.26 (t, 3H), 3.45 (q, 2H), 7.52 (t, 1H), 7.55 (d, 1H), 7.64 (d, 1H), 7.68 (d, 1H), 7.77 (t, 1H), 7.86 (d, 1H), 8.07 (d, 1H), 8.63 (s, 1H), 9.15 (s, 1H), 10.21 (s, 1H); EIMS m/z = 479 [M +]。
Embodiment 28: the preparation of (Z)-N'-(5-methyl isophthalic acid-ethyl-2-oxo indoles-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (24)
Preparation method is with embodiment five, and just isatin replaces with 5-methyl isophthalic acid-ethyl isatin, yield 81 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 1.25 (t, 3H), 2.17 (s, 3H), 3.45 (q, 2H), 6.64 (d, 1H), 6.69 (d, 1H),7.49 (t, 1H), 7.58 (d, 1H), 7.74 (t, 1H), 7.86 (d, 1H), 8.25 (d, 1H), 8.74 (s, 1H), 9.15 (s, 1H), 10.09 (s, 1H); EIMS m/z = 459 [M +]。
Embodiment 29: the preparation of (Z)-N'-(1-benzyl-2-oxindole-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (25)
Preparation method is with embodiment five, and just isatin replaces with 1-benzyl isatin, yield 84 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 5.19 (s, 2H), 7.38-7.39 (m, 5H), 7.40 (t, 1H), 7.41-7.43 (m, 1H), 7.45 (d, 1H), 7.54-7.56 (m, 1H), 7.58-7.60 (m, 2H), 7.78 (t, 1H), 7.86 (d, 1H), 8.62 (s, 1H), 9.15 (s, 1H), 10.19 (s, 1H); EIMS m/z = 507 [M +]。
Embodiment 30: the preparation of (Z)-N'-(the bromo-1-p-chlorobenzyl of 6--2-oxindole-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (26)
Preparation method is with embodiment five, and just isatin replaces with 6-bromo-1-p-chlorobenzyl isatin, yield 62 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 1H NMR (d 6-DMSO, 400 MHz) δ: 5.02 (s, 2H), 7.30 (d, 2H), 7.41 (d, 2H), 7.46 (t, 1H), 7.47-7.49 (m, 2H), 7.53-7.55 (m, 2H), 7.69 (t, 1H), 7.88 (d, 1H), 8.70 (s, 1H), 9.15 (s, 1H), 10.21 (s, 1H); EIMS m/z = 620 [M +]。
Embodiment 31: the preparation of (Z)-N'-(the chloro-1-p-chlorobenzyl of 7--2-oxindole-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (27)
Preparation method is with embodiment five, and just isatin replaces with 7-chloro-1-p-chlorobenzyl isatin, yield 69 %. 1H NMR (d 6-DMSO, 400 MHz) δ: 3.85 (s, 3H), 4.98 (s, 2H), 6.80 (d, 2H), 7.14 (d, 2H), 7.45 (t, 1H), 7.47-7.48 (m, 1H), 7.52 (d, 1H), 7.78 (d, 1H), 7.79 (t, 1H), 7.85 (d, 1H), 7.88 (d, 1H), 8.61 (s, 1H), 9.11 (s, 1H), 10.02 (s, 1H); EIMS m/z = 572 [M +]。
Embodiment 32: the preparation of (Z)-N'-(5-nitro-1-o-chlorobenzyl-2-oxindole-3-subunit)-4-(2-oxo-2H-chromene-3-base) thiazole-2-hydrazides (28)
Preparation method is with embodiment five, and just isatin replaces with 5-nitro-1-o-chlorobenzyl isatin, yield 74 %. 1H NMR (d 6-DMSO, 400 MHz) δ:
5.02 (s, 2H), 7.21-7.24 (m, 3H), 7.47 (t, 1H), 7.58 (d, 1H), 7.65 (m, 1H), 7.80 (t, 1H), 7.87 (d, 1H), 7.95 (d, 1H), 8.23 (d, 1H), 8.65 (d, 1H), 8.71 (s, 1H), 9.22 (s, 1H), 10.11 (s, 1H); EIMS m/z = 586 [M +]。
Embodiment 33: the compound that embodiment prepares measures the inhibit activities of various bacteria:
Minimal bactericidal concentration method is adopted to carry out Antibacterial Activity to streptococcus aureus, Clostridium perfringens, Candida albicans, intestinal bacteria.The concrete operations of minimal bactericidal concentration method are: be dissolved in by the compound of certain mass in appropriate distilled water, and ultrasonic or heating makes it fully dissolve or disperse, and is made into certain density compound water solution; Then stepwise dilution, obtains the solution to be measured of a series of concentration gradient.The compound water solution of 1mL different concns is added, the fresh bacterium liquid (10 of 1mL in each aseptic small test tube 5cFU/mL), 37 are placed in oshaking culture 24h in shaking table (180 rpm) incubator of C.Take out after terminating, from each small test tube, draw 0.2 ml mixed solution respectively with micropipet and join on plate culture medium, be coated with rod with glass and bacterium liquid is smeared evenly on flat board, then flat board is upside down in 37 oin the constant incubator of C, cultivating 24h, take out and observe whether have colony growth, is the minimal bactericidal concentration of this antiseptic-germicide with the minimum antimicrobial agent concentration lower than 99% initial bacteria concentration growth.
Active height represents with minimal bactericidal concentration MBC, and MBC is less, and the activity of this compound is higher, and anti-microbial activity is better, the results are shown in Table 1.
The bacteriostatic activity test result of table 1. tonka bean camphor-thiazole-indolone type compound.
Tonka bean camphor-thiazole as can be seen from Table 1-indolone type compound has anti-microbial activity in various degree, and wherein compound 2,3,6,8,9,10,12,19,21,23,26,27 pairs of streptococcus aureuses, Clostridium perfringens, Candida albicans, intestinal bacteria all have good inhibit activities.
Above-mentioned just preferred embodiment of the present invention, not does any pro forma restriction to the present invention.Any those of ordinary skill in the art, when not departing from technical solution of the present invention scope, can utilize the technology contents of above-mentioned announcement to make many possible variations and modification to technical solution of the present invention, or being revised as the Equivalent embodiments of equivalent variations.Therefore, every content not departing from technical solution of the present invention, according to the technology of the present invention essence to any simple modification made for any of the above embodiments, equivalent variations and modification, all should drop in the scope of technical solution of the present invention protection.

Claims (3)

1. tonka bean camphor-thiazole-indolone type compound, is characterized in that: this compound has structure as shown in the formula (I):
（I）
Wherein: R 1for hydrogen, alkyl or benzyl, R 2, R 3, R 4or R 5for hydrogen, halogen, alkyl, amino, alkylamino, alkoxyl group, cyano group, nitro, hydroxyl, trifluoromethyl or sulfydryl.
2. a preparation method for tonka bean camphor-thiazole-indolone type compound, is characterized in that comprising following step:
Step 1: salicylic aldehyde, methyl aceto acetate, piperidines are placed in round-bottomed flask, add ethanol, back flow reaction 5 ~ 24 hours, stopped reaction, cool to room temperature, adds water, extraction into ethyl acetate, merge organic phase, anhydrous sodium sulfate drying, filters, is spin-dried for, cross silicagel column separation and purification, obtain yellow solid powder 3-ethanoyl-2H-chromen-2-one; The mol ratio of described salicylic aldehyde, methyl aceto acetate, piperidines is 1:(1 ~ 5): (0.1 ~ 4);
Step 2: 3-ethanoyl-2H-chromen-2-one, tosic acid, N-bromo-succinimide are placed in round-bottomed flask, add DMF, 50 ~ 160 DEG C are reacted 2 ~ 5 hours, stopped reaction, add saturated sodium thiosulfate solution, extraction into ethyl acetate, merge organic phase, cross silica gel chromatography, obtain white solid powder 3-(2-acetyl bromide)-2H-chromen-2-one; The mol ratio of described 3-ethanoyl-2H-chromen-2-one, tosic acid, N-bromo-succinimide is 1:(1 ~ 5): (1 ~ 10);
Step 3: 3-(2-acetyl bromide)-2H-chromen-2-one, thio-oxamide ethyl ester are placed in round-bottomed flask, add methyl alcohol, stirring at room temperature 5 ~ 24 hours, stopped reaction, add water, extraction into ethyl acetate, merge organic phase, cross silica gel chromatography, obtain Tan solid powder 4-(2-oxo-2H-chromene-3-base) thiazole-2-ethyl formate; Described 3-(2-acetyl bromide)-2H-chromen-2-one, the mol ratio of thio-oxamide ethyl ester are 1:(1 ~ 10);
Step 4: 4-(2-oxo-2H-chromene-3-base) thiazole-2-ethyl formate, hydrazine hydrate are placed in round-bottomed flask, add ethanol, back flow reaction 2 ~ 10, stopped reaction, cool to room temperature, filter, obtain white solid powder 4-(2-oxo-2H-chromene-3-base) thiazole-2-formyl hydrazine; Described 4-(2-oxo-2H-chromene-3-base) thiazole-2-ethyl formate, the mol ratio of hydrazine hydrate are 1:(1 ~ 20);
Step 5: 4-(2-oxo-2H-chromene-3-base) thiazole-2-formyl hydrazine, replacement isatin are placed in round-bottomed flask, add methyl alcohol, back flow reaction 0.5 ~ 4 hour, cool to room temperature, there is solid to separate out, filter to obtain tonka bean camphor-thiazole-indolone type compound (I); The mol ratio of described 4-(2-oxo-2H-chromene-3-base) thiazole-2-formyl hydrazine, replacement isatin is 1:(1 ~ 5).
3. the application of a kind of tonka bean camphor-thiazole-indolone type compound according to claim 1 in preparation antibacterials.
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RU2604063C1 (en) * 2015-09-17 2016-12-10 федеральное государственное автономное образовательное учреждение высшего образования "Южный федеральный университет" 3-[2-[n'-(2-hydroxy-5-chlorobenzylidene)hydrazino]-4-(2,5-dimethylthiophen-3-yl)thiazol-5-yl]chromen-2-one - chromogenic chemosensor on f- anions
CN105237521A (en) * 2015-10-27 2016-01-13 吉首大学 Coumarin-isatin type compounds, and preparation method and purpose thereof
CN105237521B (en) * 2015-10-27 2018-08-24 诸暨市志缇生物科技有限公司 A kind of cumarin-isatin type compound and its preparation method and purposes
CN105541808A (en) * 2016-02-04 2016-05-04 吉首大学 Metronidazole-isatin type compound as well as preparation method and application thereof
CN105601624B (en) * 2016-02-17 2018-05-22 南京双科医药开发有限公司 A kind of 1,2,4- triazines-coumarin type compound and its preparation method and purposes
CN108250087A (en) * 2018-03-15 2018-07-06 常州大学 A kind of synthetic method of 4- isobutoxies benzylamine
CN108250087B (en) * 2018-03-15 2020-06-30 常州大学 Synthesis method of 4-isobutoxy benzylamine
CN108558843A (en) * 2018-05-11 2018-09-21 贵州医科大学 A kind of cumarin-triazole-isatin type compound and its preparation method and application
CN111087392A (en) * 2019-12-30 2020-05-01 西南大学 Vinyl conjugated indolylaminothiazole compound and preparation method and application thereof
CN114621214A (en) * 2022-04-25 2022-06-14 宜春学院 Antibacterial Schiff base N-acylate and preparation method and application thereof
CN114621214B (en) * 2022-04-25 2024-04-26 宜春学院 Antibacterial Schiff base N-acylate, and preparation method and application thereof

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