CN104829608B - A kind of cumarin thiazole indolone type compound and its preparation method and purposes - Google Patents
A kind of cumarin thiazole indolone type compound and its preparation method and purposes Download PDFInfo
- Publication number
- CN104829608B CN104829608B CN201510252481.XA CN201510252481A CN104829608B CN 104829608 B CN104829608 B CN 104829608B CN 201510252481 A CN201510252481 A CN 201510252481A CN 104829608 B CN104829608 B CN 104829608B
- Authority
- CN
- China
- Prior art keywords
- thiazole
- oxo
- bases
- preparation
- isatin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 0 CCN(C(*1)=O)C2=C[C@@]1C=CC(C)CC(C)C2 Chemical compound CCN(C(*1)=O)C2=C[C@@]1C=CC(C)CC(C)C2 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of cumarin thiazole indolone type compound and its preparation method and purposes.The compound has such as formula（I）Shown structure; preparation method is with salicylide and ethyl acetoacetate as raw material obtains the ketone of 3 acetyl group 2H chromenes 2; 4 (base of 2 oxo 2H chromenes 3) formylhydrazines of thiazole 2 are obtained through bromo, cyclization, hydrazinolysis reaction again, finally target compound is obtained with various substitution isatin reactions.The compound can be as the raw material of antibacterials, and preparation method raw material is simple and easy to get, easy to operate.（I）.
Description
Technical field
The present invention relates to a kind of cumarin-thiazole-indolone type compound and preparation method thereof and in preparation antibacterials
In application.
Background technology
With the abuse of the extensive use of antibacterials, especially antibiotic, worldwide bacterium is resistance in recent years
Property of medicine problem is increasingly serious, and the trend for rising year by year is presented, and great difficulty is brought to the treatment of infectious diseases.Especially
It is methicillin-resistant staphylococcus aureus（MRSA）, penicillin resistance pneumococcus（PRSP）, multiple-drug resistance tuberculosis bacillus etc.
The appearance of Multidrug resistant bacteria, the life and health of the serious threat mankind.
Isatin also known as isatin or 2,3-indolinedione, are present in the endogeneous activity in mammalian tissues and body fluid
Material.In addition isatin structure is also present in various natural products, is a kind of common Structures of Natural Products.According to document report
Road, isatin and its derivative have a multiple biological activities, such as anti-spasm, treating tuberculosis, antibacterium, antimycotic, antiviral, antitumor
Deng.Therefore the research tool that original new drug is carried out based on isatin is of great significance.
Coumarin kind compound is the secondary metabolism product of a class plant, is all distributed in various plants.Many contains
The plant of coumarin kind compound uses the history of thousands of years as medicine in Asia.Coumarin kind compound has many
Bioactivity is planted, for example：Anti-oxidant, antitumor, anti-inflammatory, anti-neurodegeneration, anti-malarial, anticoagulation, antibacterial and antimycotic etc..By
In its unique chemical constitution and diversified bioactivity, coumarin kind compound has become design and finds new drug
Important lead compound source, developing it has the value of certain theory significance and reality.Based on more than analyze, we according to
Twin medicine principle, tonka bean camphor structure is connected with isatin structure, and design has synthesized a class cumarin-thiazole-indolone type compound.
The content of the invention
Technical scheme is as follows：
Technical scheme is as follows：
A kind of cumarin-thiazole-indolone type compound, it is characterized in that they have such as formula（I）Shown general structure：
（I）
Wherein：R1It is hydrogen, alkyl or benzyl, R2、R3、R4Or R5For hydrogen, halogen, alkyl, amino, alkyl amino, alkoxy,
Cyano group, nitro, hydroxyl, trifluoromethyl or sulfydryl.
A kind of method for preparing above-mentioned cumarin-thiazole-indolone type compound, it comprises the following steps：
Step 1：Salicylide, ethyl acetoacetate, piperidines are placed in round-bottomed flask, ethanol, back flow reaction 5 ~ 24 is added
Hour, stopping reaction being cooled to room temperature, adds water, and ethyl acetate extraction merges organic phase, and anhydrous sodium sulfate drying is filtered,
It is spin-dried for, crosses silica gel column separating purification, obtains yellow solid powder 3- acetyl group -2H- chromen-2-ones；Described salicylide,
Ethyl acetoacetate, the mol ratio of piperidines are 1：（1~5）：（0.1~4）；
Step 2：3- acetyl group -2H- chromen-2-ones, p-methyl benzenesulfonic acid, N- bromo-succinimides are placed in round bottom
In flask, DMF is added, 50 ~ 160 DEG C are reacted 2 ~ 5 hours, stop reaction, add saturated sodium thiosulfate solution, ethyl acetate
Extraction, merges organic phase, crosses silica gel chromatography, obtains white solid powder 3- (2- acetyl bromides) -2H- chromenes -2-
Ketone；Described 3- acetyl group -2H- chromen-2-ones, p-methyl benzenesulfonic acid, the mol ratio of N- bromo-succinimides are 1：（1~
5）：（1~10）；
Step 3：3- (2- acetyl bromides) -2H- chromen-2-ones, thio-oxamide ethyl ester are placed in round-bottomed flask,
Methyl alcohol is added, is stirred at room temperature 5 ~ 24 hours, stop reaction, add water, ethyl acetate extraction merges organic phase, crosses silicagel column color
Spectrum purifying, obtains Tan solid powder 4- (2- oxo -2H- chromene -3- bases) thiazole -2- Ethyl formates；Described 3- (2-
Acetyl bromide) -2H- chromen-2-ones, thio-oxamide ethyl ester mol ratio be 1：（1~10）；
Step 4：4- (2- oxo -2H- chromene -3- bases) thiazole -2- Ethyl formates, hydrazine hydrate are placed in round-bottomed flask
In, ethanol is added, back flow reaction 2 ~ 10 stops reaction, is cooled to room temperature, filters, and obtains white solid powder 4- (2- oxos -2H-
Chromene -3- bases) thiazole -2- formylhydrazines；Described 4- (2- oxo -2H- chromene -3- bases) thiazole -2- Ethyl formates,
The mol ratio of hydrazine hydrate is 1：（1~20）；
Step 5：4- (2- oxo -2H- chromene -3- bases) thiazole -2- formylhydrazines, substitution isatin are placed in round-bottomed flask
In, methyl alcohol is added, back flow reaction 0.5 ~ 4 hour is cooled to room temperature, has solid to separate out, and filters to obtain cumarin-thiazole-indolone
Type compound（I）；Described 4- (2- oxo -2H- chromene -3- bases) thiazole -2- formylhydrazines, the mol ratio of substitution isatin are
1：（1~5）.
Cumarin-thiazole-indolone type compound of the present invention all has to various bacteria and preferably suppresses and kill
Deactivation, for the development and application of antibacterials provides new selection.
Brief description of the drawings
Fig. 1 is the syntheti c route figure of cumarin-thiazole-indolone type compound.
Specific embodiment
Following embodiment is to describe the present invention in detail, is not intended to limit the present invention.
Embodiment one：The preparation of 3- acetyl group -2H- chromen-2-ones
By salicylide（1.22g, 10 mmol）, ethyl acetoacetate（2.6g, 20 mmol）, piperidines（0.5 mL）It is placed in circle
In the flask of bottom, the mL of ethanol 100 is added, back flow reaction 12 hours, TLC display reactions are finished, and stop reaction, are cooled to room temperature, plus
Enter the mL of water 300, ethyl acetate extraction（200 mL×3）, merging organic phase, anhydrous sodium sulfate drying, filtering is spin-dried for, and crosses silica gel
Column separating purification, obtains the g of yellow solid powder 1.5, the % of yield 79.1H NMR (CDCl3, 400 MHz) δ: 2.73 (s,
3H), 7.33-7.35 (m, 2H), 7.64-7.69 (m, 2H), 8.51 (s, 1H)。
Embodiment two：The preparation of 3- (2- acetyl bromides) -2H- chromen-2-ones
By 3- acetyl group -2H- chromen-2-ones（188 mg, 1 mmol）, p-methyl benzenesulfonic acid（380 mg, 2
mmol）, N- bromo-succinimides（354 mg, 2 mmol）It is placed in round-bottomed flask, adds the mL of DMF 10,100 DEG C of reactions
2 hours, TLC display reactions were finished, and stop reaction, added saturated sodium thiosulfate solution, and ethyl acetate extraction merges organic
Phase, crosses silica gel chromatography, obtains the mg of white solid powder 127, the % of yield 44.1H NMR (CDCl3, 400 MHz) δ:
4.76 (s, 2H), 7.37-7.42 (m, 2H), 7.69-7.73 (m, 2H), 8.65 (s, 1H)。
Embodiment three：The preparation of 4- (2- oxo -2H- chromene -3- bases) thiazole -2- Ethyl formates
By 3- (2- acetyl bromides) -2H- chromen-2-ones（133 mg, 1 mmol）, thio-oxamide ethyl ester（399
Mg, 3 mmol）It is placed in round-bottomed flask, adds 10 mL methyl alcohol, be stirred at room temperature 24 hours, TLC display reactions is finished, and are stopped anti-
Should, 20 mL water are added, ethyl acetate extraction merges organic phase, crosses silica gel chromatography, obtains Tan solid powder 190
Mg, the % of yield 63.1H NMR (CDCl3, 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)。
Example IV：4- (2- oxo -2H- chromene -3- bases) thiazole -2- formylhydrazines
By 4- (2- oxo -2H- chromene -3- bases) thiazole -2- Ethyl formates（301mg, 1 mmol）, hydrazine hydrate（100
Mg, 2 mmol）It is placed in round-bottomed flask, adds 10 mL ethanol, back flow reaction, TLC display reactions is finished, and stop reaction, cold
But room temperature is arrived, is filtered, obtain the mg of white solid powder 208, yield 72%.1H NMR (d6-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：(Z) -4- (2- oxo -2H- chromene -3- bases)-N'- (2- oxindole -3- subunits) thiazole -
2- hydrazides（1）Preparation
By 4- (2- oxo -2H- chromene -3- bases) thiazole -2- formylhydrazines（301mg, 1 mmol）, isatin（147mg,
1 mmol）It is placed in round-bottomed flask, adds 10 mL methyl alcohol, back flow reaction 2 hours stops reaction, is cooled to room temperature, filter, obtains
The mg of solid powder 347, the % of yield 83.1H NMR (d6-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：(Z)-N'- (the bromo- 2- oxindoles -3- subunits of 6-) -4- (2- oxo -2H- chromene -3- bases)
Thiazole -2- hydrazides（2）Preparation
Preparation method replaces with 6- bromo-isatins, the % of yield 86 with embodiment five, simply isatin.1H NMR (d6-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：(Z)-N'- (7- chloro-2-oxo indoles -3- subunits) -4- (2- oxo -2H- chromene -3- bases)
Thiazole -2- hydrazides（3）Preparation
Preparation method replaces with 7- chlorisatides, the % of yield 73 with embodiment five, simply isatin.1H NMR (d6-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：(Z)-N'- (5- nitro -2- oxindole -3- subunits) -4- (2- oxo -2H- chromenes -3-
Base) thiazole -2- hydrazides（4）Preparation
Preparation method replaces with 5- Nitroisatoics, the % of yield 78 with embodiment five, simply isatin.1H NMR (d6-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：(Z)-N'- (5- chloro-2-oxo indoles -3- subunits) -4- (2- oxo -2H- chromene -3- bases)
Thiazole -2- hydrazides（5）Preparation
Preparation method replaces with 5- chlorisatides, the % of yield 80 with embodiment five, simply isatin.1H NMR (d6-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：(Z)-N'- (5- methyl -2- oxindole -3- subunits) -4- (2- oxo -2H- chromenes -3-
Base) thiazole -2- hydrazides（6）Preparation
Preparation method replaces with 5- methylisatins, the % of yield 83 with embodiment five, simply isatin.1H NMR (d6-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：(Z)-N'- (the fluoro- 2- oxindoles -3- subunits of 5-) -4- (2- oxo -2H- chromenes -3-
Base) thiazole -2- hydrazides（7）Preparation
Preparation method replaces with 5- fluoro indigo reds, the % of yield 69 with embodiment five, simply isatin.1H NMR (d6-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：(Z)-N'- (5- methoxyl group -2- oxindole -3- subunits) -4- (2- oxo -2H- chromenes -
3- yls) thiazole -2- hydrazides（8）Preparation
Preparation method replaces with 5- methoxyl group isatin, the % of yield 72 with embodiment five, simply isatin.1H NMR (d6-
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：(Z)-N'- (7- trifluoromethyl -2- oxindole -3- subunits) -4- (2- oxo -2H- benzo pyrroles
Mutter -3- bases) thiazole -2- hydrazides（9）Preparation
Preparation method replaces with 7- trifluoromethyl isatin, the % of yield 71 with embodiment five, simply isatin.1H NMR (d6-
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：(Z)-N'- (1- methyl -2- oxindole -3- subunits) -4- (2- oxo -2H- chromenes -3-
Base) thiazole -2- hydrazides（10）Preparation
Preparation method replaces with 1- methylisatins, the % of yield 72 with embodiment five, simply isatin.1H NMR (d6-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：(Z)-N'- (the bromo- 1- methyl -2- oxindoles -3- subunits of 6-) -4- (2- oxo -2H- benzo pyrroles
Mutter -3- bases) thiazole -2- hydrazides（11）Preparation
Preparation method replaces with the bromo- 1- methylisatins of 6-, the % of yield 80 with embodiment five, simply isatin.1H NMR (d6-
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：(Z)-N'- (the chloro- 1- methyl -2- oxindoles -3- subunits of 7-) -4- (2- oxo -2H- benzo pyrroles
Mutter -3- bases) thiazole -2- hydrazides（12）Preparation
Preparation method replaces with the chloro- 1- methylisatins of 7-, the % of yield 88 with embodiment five, simply isatin.1H NMR (d6-
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：(Z)-N'- (1- methyl-5-nitro -2- oxindole -3- subunits) -4- (2- oxo -2H- benzos
Pyrans -3- bases) thiazole -2- hydrazides（13）Preparation
Preparation method replaces with 5- nitro -1- methylisatins, the % of yield 77 with embodiment five, simply isatin.1H NMR
(d6-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：(Z)-N'- (the chloro- 1- methyl -2- oxindoles -3- subunits of 5-) -4- (2- oxo -2H- benzo pyrroles
Mutter -3- bases) thiazole -2- hydrazides（14）Preparation
Preparation method replaces with the chloro- 1- methylisatins of 5-, the % of yield 73 with embodiment five, simply isatin.1H NMR (d6-
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：(Z)-N'- (1,5- dimethyl -2- oxindole -3- subunits) -4- (2- oxo -2H- benzo pyrroles
Mutter -3- bases) thiazole -2- hydrazides（15）Preparation
Preparation method replaces with 1,5- dimethylisatins, the % of yield 76 with embodiment five, simply isatin.1H NMR (d6-
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：(Z)-N'- (the fluoro- 1- methyl -2- oxindoles -3- subunits of 5-) -4- (2- oxo -2H- benzo pyrroles
Mutter -3- bases) thiazole -2- hydrazides（16）Preparation
Preparation method replaces with the fluoro- 1- methylisatins of 5-, the % of yield 75 with embodiment five, simply isatin.1H NMR (d6-
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：(Z)-N'- (5- methoxyl group -1- methyl -2- oxindole -3- subunits) -4- (2- oxos -2H-
Chromene -3- bases) thiazole -2- hydrazides（17）Preparation
Preparation method replaces with 5- methoxyl group -1- methylisatins, the % of yield 79 with embodiment five, simply isatin.1H NMR
(d6-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：(Z)-N'- (7- Trifluoromethyl-1s-methyl -2- oxindole -3- subunits) -4- (2- oxos -
2H- chromene -3- bases) thiazole -2- hydrazides（18）Preparation
Preparation method replaces with 7- Trifluoromethyl-1s-methylisatin, the % of yield 85 with embodiment five, simply isatin.1H
NMR (d6-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：(Z)-N'- (1- ethyl-2-oxo indoles -3- subunits) -4- (2- oxo -2H- chromenes -
3- yls) thiazole -2- hydrazides（19）Preparation
Preparation method replaces with 1- ethyl isatin, the % of yield 68 with embodiment five, simply isatin.1H NMR (d6-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：(Z)-N'- (the bromo- 1- ethyl-2-oxos indoles -3- subunits of 6-) -4- (2- oxo -2H- benzos
Pyrans -3- bases) thiazole -2- hydrazides（20）Preparation
Preparation method replaces with the bromo- 1- ethyls isatin of 6-, the % of yield 72 with embodiment five, simply isatin.1H NMR (d6-
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：(Z)-N'- (the chloro- 1- ethyl-2-oxos indoles -3- subunits of 7-) -4- (2- oxo -2H- benzos
Pyrans -3- bases) thiazole -2- hydrazides（21）Preparation
Preparation method replaces with the chloro- 1- ethyls isatin of 7-, the % of yield 78 with embodiment five, simply isatin.1H NMR (d6-
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：(Z)-N'- (5- nitro -1- ethyl-2-oxo indoles -3- subunits) -4- (2- oxo -2H- benzene
And pyrans -3- bases) thiazole -2- hydrazides（22）Preparation
Preparation method replaces with 5- nitro -1- ethyl isatin, the % of yield 84 with embodiment five, simply isatin.1H NMR
(d6-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：(Z)-N'- (the chloro- 1- ethyl-2-oxos indoles -3- subunits of 5-) -4- (2- oxo -2H- benzos
Pyrans -3- bases) thiazole -2- hydrazides（23）Preparation
Preparation method replaces with the chloro- 1- ethyls isatin of 5-, the % of yield 80 with embodiment five, simply isatin.1H NMR (d6-
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：(Z)-N'- (5- methyl isophthalic acids-ethyl-2-oxo indoles -3- subunits) -4- (2- oxo -2H- benzene
And pyrans -3- bases) thiazole -2- hydrazides（24）Preparation
Preparation method replaces with 5- methyl isophthalic acids-ethyl isatin, the % of yield 81 with embodiment five, simply isatin.1H NMR
(d6-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：(Z)-N'- (1- benzyl -2- oxindole -3- subunits) -4- (2- oxo -2H- chromenes -
3- yls) thiazole -2- hydrazides（25）Preparation
Preparation method replaces with 1- benzyl isatin, the % of yield 84 with embodiment five, simply isatin.1H NMR (d6-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：(Z)-N'- (the bromo- 1- p-chlorobenzyls -2- oxindoles -3- subunits of 6-) -4- (2- oxo -2H- benzene
And pyrans -3- bases) thiazole -2- hydrazides（26）Preparation
Preparation method replaces with the bromo- 1- p-chlorobenzyls isatin of 6-, the % of yield 62 with embodiment five, simply isatin.1H NMR
(d6-DMSO, 400 MHz) δ: 1H NMR (d6-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：(Z)-N'- (the chloro- 1- p-chlorobenzyls -2- oxindoles -3- subunits of 7-) -4- (2- oxos -2H-
Chromene -3- bases) thiazole -2- hydrazides（27）Preparation
Preparation method replaces with the chloro- 1- p-chlorobenzyls isatin of 7-, the % of yield 69 with embodiment five, simply isatin.1H NMR
(d6-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：(Z)-N'- (5- nitro -1- o-chlorobenzyl -2- oxindole -3- subunits) -4- (2- oxos -
2H- chromene -3- bases) thiazole -2- hydrazides（28）Preparation
Preparation method replaces with 5- nitro -1- o-chlorobenzyl isatin, the % of yield 74 with embodiment five, simply isatin.1H
NMR (d6-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 is prepared is determined to the inhibitory activity of various bacteria：
Staphylococcus aureus, Bacillus perfringens, Candida albicans, Escherichia coli are entered using MBC method
Row Antibacterial Activity.The concrete operations of MBC method are：The compound of certain mass is dissolved in appropriate distilled water,
Ultrasound or heating make it fully dissolve or disperse, and are made into certain density compound water solution；Then stepwise dilution, obtaining one is
The solution to be measured of row concentration gradient.The compound water solution of 1mL various concentrations is added in each aseptic small test tube, 1mL is new
Fresh bacterium solution（105CFU/mL）, it is placed in 37oThe shaking table of C（180 rpm）Shaken cultivation 24h in incubator.Taken out after end, with micro-
Amount pipettor is drawn 0.2 ml mixed liquors and is added on plating medium respectively from each small test tube, and rod is applied by bacterium solution with glass
Smear uniform on flat board, flat board is then upside down in 37oIn the constant incubator of C, 24h is cultivated, taking-up has seen whether bacterium
It is born length, with the MBC that the minimum antimicrobial agent concentration grown less than 99% initial bacteria concentration is the antiseptic.
The height of activity represents that MBC is smaller with MBC MBC, active higher, the antibacterial activity of this compound
It is better, the results are shown in Table 1.
The bacteriostatic activity test result of 1. cumarins of table-thiazole-indolone type compound.
Cumarin-thiazole-indolone type compound has different degrees of antibacterial activity, wherein chemical combination as can be seen from Table 1
Thing 2,3,6,8,9,10,12,19,21,23,26,27 pairs of staphylococcus aureuses, Bacillus perfringens, Candida albicans, large intestines
Bacillus all has preferable inhibitory activity.
Above-mentioned simply presently preferred embodiments of the present invention, not makees any formal limitation to the present invention.It is any to be familiar with sheet
The technical staff in field, in the case where technical solution of the present invention scope is not departed from, all using the technology contents of the disclosure above
Many possible variations and modification, or the Equivalent embodiments for being revised as equivalent variations are made to technical solution of the present invention.Therefore, it is all
It is the content without departing from technical solution of the present invention, any is simply repaiied to made for any of the above embodiments according to the technology of the present invention essence
Change, equivalent variations and modification, all should fall in the range of technical solution of the present invention protection.
Claims (1)
1. the preparation method of a kind of cumarin-thiazole-indolone type compound, it is characterised in that including following steps：
Step 1：Salicylide, ethyl acetoacetate, piperidines are placed in round-bottomed flask, addition ethanol, back flow reaction 5 ~ 24 hours,
Stop reaction, be cooled to room temperature, add water, ethyl acetate extraction merges organic phase, and anhydrous sodium sulfate drying, filtering is spin-dried for,
Silica gel column separating purification is crossed, yellow solid powder 3- acetyl group -2H- chromen-2-ones are obtained；Described salicylide, acetyl
Ethyl acetate, the mol ratio of piperidines are 1：（1~5）：（0.1~4）；
Step 2：3- acetyl group -2H- chromen-2-ones, p-methyl benzenesulfonic acid, N- bromo-succinimides are placed in round-bottomed flask
In, DMF is added, 50 ~ 160 DEG C are reacted 2 ~ 5 hours, stop reaction, add saturated sodium thiosulfate solution, ethyl acetate extraction
Take, merge organic phase, cross silica gel chromatography, obtain white solid powder 3- (2- acetyl bromides) -2H- chromen-2-ones；
Described 3- acetyl group -2H- chromen-2-ones, p-methyl benzenesulfonic acid, the mol ratio of N- bromo-succinimides are 1：（1~5）：
（1~10）；
Step 3：3- (2- acetyl bromides) -2H- chromen-2-ones, thio-oxamide ethyl ester are placed in round-bottomed flask, are added
Methyl alcohol, is stirred at room temperature 5 ~ 24 hours, stops reaction, adds water, and ethyl acetate extraction merges organic phase, crosses silica gel column chromatography pure
Change, obtain Tan solid powder 4- (2- oxo -2H- chromene -3- bases) thiazole -2- Ethyl formates；Described 3- (2- bromine second
Acyl group) -2H- chromen-2-ones, thio-oxamide ethyl ester mol ratio be 1：（1~10）；
Step 4：4- (2- oxo -2H- chromene -3- bases) thiazole -2- Ethyl formates, hydrazine hydrate are placed in round-bottomed flask,
Ethanol is added, back flow reaction 2 ~ 10 stops reaction, is cooled to room temperature, filters, and obtains white solid powder 4- (2- oxo -2H- benzene
And pyrans -3- bases) thiazole -2- formylhydrazines；Described 4- (2- oxo -2H- chromene -3- bases) thiazole -2- Ethyl formates, water
The mol ratio for closing hydrazine is 1：（1~20）；
Step 5：4- (2- oxo -2H- chromene -3- bases) thiazole -2- formylhydrazines, substitution isatin are placed in round-bottomed flask,
Methyl alcohol is added, back flow reaction 0.5 ~ 4 hour is cooled to room temperature, has solid to separate out, and filters to obtain cumarin-thiazole-indolone type
Compound；Described 4- (2- oxo -2H- chromene -3- bases) thiazole -2- formylhydrazines, the mol ratio of substitution isatin are 1：（1~
5）；
Wherein：R1It is hydrogen, alkyl or benzyl, R2、R3、R4Or R5It is hydrogen, halogen, alkyl, amino, alkyl amino, alkoxy, cyanogen
Base, nitro, hydroxyl, trifluoromethyl or sulfydryl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510252481.XA CN104829608B (en) | 2015-05-18 | 2015-05-18 | A kind of cumarin thiazole indolone type compound and its preparation method and purposes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510252481.XA CN104829608B (en) | 2015-05-18 | 2015-05-18 | A kind of cumarin thiazole indolone type compound and its preparation method and purposes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104829608A CN104829608A (en) | 2015-08-12 |
| CN104829608B true CN104829608B (en) | 2017-06-30 |
Family
ID=53807848
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510252481.XA Expired - Fee Related CN104829608B (en) | 2015-05-18 | 2015-05-18 | A kind of cumarin thiazole indolone type compound and its preparation method and purposes |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104829608B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CN108250087B (en) * | 2018-03-15 | 2020-06-30 | 常州大学 | Synthesis method of 4-isobutoxy benzylamine |
| CN108558843B (en) * | 2018-05-11 | 2020-12-15 | 贵州医科大学 | Coumarin-triazole-isatin type compound and preparation method and application thereof |
| CN111087392B (en) * | 2019-12-30 | 2022-06-03 | 西南大学 | Vinyl conjugated indolylaminothiazole compound 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 |
-
2015
- 2015-05-18 CN CN201510252481.XA patent/CN104829608B/en not_active Expired - Fee Related
Non-Patent Citations (3)
| Title |
|---|
| 《Design, synthesis, characterization, antioxidant and in vitro cytotoxic activities of novel coumarin thiazole derivatives》;Sreekanth Thota;《Med Chem Res》;20140807;第24卷;scheme 3 * |
| 《One Pot，Multi·component Synthesis of 3—1(4-Aryl—thiazol-2一y1)一hydrazono]·1，3·dihydro-indole-2-one》;AYCHILUHIM Tewodros Birhanu;《Chem．Res．Chin．Univ．》;20140430;第30卷(第4期);scheme 1 * |
| 《微波辐射下N-[4-(香豆素-3-基)噻唑-2-基]芳醛腙类化合物的合成及生物活性研究》;袁明月;《有机化学》;20131231;第33卷;1.1部分 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104829608A (en) | 2015-08-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104829608B (en) | A kind of cumarin thiazole indolone type compound and its preparation method and purposes | |
| CN104829598B (en) | Quinazolinone compound containing 1, 2, 4-triazole thioether and synthesizing method and application of quinazolinone compound | |
| CN109942546B (en) | Quinolone pyrimidine compound and preparation method and application thereof | |
| CN103819413A (en) | Pentadienone compound containing quinazolinone aryloxy as well as preparation method and application thereof | |
| CN103059006B (en) | Chrysin-1,2,3-triazole compound with anti-microbial activity and preparation method thereof | |
| CN108558756A (en) | - 4 (1H)-quinolinone semicarbazone class compound of 2- aryl -2,3- dihydros and its application | |
| CN110330487A (en) | Quinazolone thiazolium compounds and its preparation method and application | |
| CN101062926A (en) | Preparation and usage of unnatural 3,4-dihydro isocoumarin derivatives | |
| CN104817552B (en) | (E) (base of cumarin 3) the hydrazide kind compound preparation method of thiazole 2 of N ' aryl methylenes 4 and purposes | |
| CN107445935B (en) | Hesperetin analog derivative and its preparation that a kind of amide groups replaces and as the application in anti-inflammatory drug | |
| CN105153143A (en) | Thiouracil derivatives containing oxadiazole/thiadiazole and preparation method and application of thiouracil derivatives | |
| CN110526910B (en) | Thiazole orange benzyl quaternary ammonium salt derivative and preparation method and application thereof | |
| CN105130981B (en) | The application of berberine benzimidazoles compound | |
| CN110372588A (en) | A kind of 4- amido quinoline compound and its preparation method and application | |
| CN105541808A (en) | Metronidazole-isatin type compound as well as preparation method and application thereof | |
| CN102260253A (en) | Benzo[5,6]cycloheptyl[1,2-b]pyridine derivatives and preparation method thereof, and pharmaceutical composition and application thereof in anaphylactic disease resistance | |
| CN105294661B (en) | 5 fluorouracil benzimidazoles compounds and its preparation method and application | |
| CN102079724B (en) | Ethylene sulfonyl chloride azole compounds with anti-microbial activity as well as preparation method and medical use thereof | |
| CN107488148A (en) | A kind of hydrocinnamamide insecticides and preparation method thereof | |
| CN109851611B (en) | Sulfadiazine compound and preparation method and application thereof | |
| CN108558910B (en) | Schiff base type imidazobenzothiazole compound and preparation method and application thereof | |
| CN106588871A (en) | 2-substituted pyridyl quinazolinone derivative and synthesis method and application thereof | |
| CN105541853A (en) | Polysubstituted type gamma-pyranopyrrolidone compound as well as preparation method and application thereof | |
| CN103450177A (en) | Synthesis and preparation method of metronidazole grafted thiazole hydrazone derivatives | |
| CN107602507A (en) | Substitute formyl（Morpholine ethyl）Piperazine compounds and its application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20170630 Termination date: 20180518 |