CN106045896B - isatin hydrazide derivative and preparation method thereof - Google Patents
isatin hydrazide derivative and preparation method thereof Download PDFInfo
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- CN106045896B CN106045896B CN201610510449.1A CN201610510449A CN106045896B CN 106045896 B CN106045896 B CN 106045896B CN 201610510449 A CN201610510449 A CN 201610510449A CN 106045896 B CN106045896 B CN 106045896B
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- isatin
- hydrazide derivative
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to organic synthesis fields, and in particular to a kind of isatin hydrazide derivative and preparation method thereof.The isatin hydrazide derivative is 4 chlorine N'((2,3 istains, 1 base) methyl) 1 base of benzoyl hydrazine or N'((2,3 istains) methyl) 2 methoxybenzoyl hydrazines.The preparation method of the isatin hydrazide derivative includes the following steps：Substituted benzoic acid, thionyl chloride are first subjected to back flow reaction, after vacuum distillation, back flow reaction is carried out in methyl alcohol with the concentrated sulfuric acid, through being evaporated under reduced pressure, extracting, drying, being evaporated after reaction, back flow reaction is carried out in ethanol with hydrazine hydrate again, through vacuum distillation after reaction, is finally added in ethyl alcohol together with isatin, formaldehyde, glacial acetic acid are added, stirring at normal temperature obtains isatin hydrazide derivative.The derivative of the present invention not only has obvious inhibiting effect to tumour, but also reaction step is few, and yield is high.
Description
Technical field
The invention belongs to organic synthesis fields, and in particular to a kind of isatin hydrazide derivative and preparation method thereof.
Background technology
In recent years, application of the isatin class compound in organic synthesis and medicine has caused organise educational circles and pharmacy circle
Extensive concern.Isatin and derivative are a kind of important nitrogen heterocyclics, have extensive bioactivity.In organic synthesis
In, as reactive intermediate.The compound of the azacyclo- containing isatin can further synthesize many type organic compounds, these changes
Close object has efficient pharmacological activity mostly, some have been developed into clinical medicine.
Hydrazide derivative has the bioactivity such as antibacterial, antiviral.Therefore, hydrazide derivative is as very promising
The prospect of drug extremely merits attention.With deepening continuously for isatin class and hydrazides drug research, to its antibacterial and anti-
Cancer mechanism of action carries out effectively structure of modification and modification and MOLECULE DESIGN on the basis of constantly understanding, it will have more and more
Efficiently, the less toxic isatin class newtype drug containing hydrazide structure promotes the well-being of mankind for clinic.
Invention content
The object of the present invention is to provide a kind of isatin hydrazide derivatives to tumour with obvious inhibiting effect；The present invention
There is provided its simple and practicable preparation method and purposes simultaneously.
The structural formula of isatin hydrazide derivative of the present invention is：
The preparation method of the isatin hydrazide derivative, includes the following steps：
(1) substituted benzoic acid, thionyl chloride are subjected to back flow reaction, product is obtained through vacuum distillation；
(2) product and the concentrated sulfuric acid that are obtained in step (1) are subjected to back flow reaction in methyl alcohol, through being evaporated under reduced pressure, extracting,
Drying is evaporated to obtain product；
(3) product and hydrazine hydrate that are obtained in step (2) are subjected to back flow reaction in ethanol, are produced through vacuum distillation
Object；
(4) product and isatin obtained step (3) is added in ethyl alcohol, then adds in formaldehyde, glacial acetic acid, and room temperature stirs
It mixes, obtains isatin hydrazide derivative.
Wherein：
In step (1), substituted benzoic acid, thionyl chloride usage ratio be 1g:5mL, substituted benzoic acid are to chlorine
Benzoic acid or o-methoxybenzoic acid.
In step (1), 2~4h of back flow reaction.
In step (2), the usage ratio of the benzoic acid replaced in the concentrated sulfuric acid, methanol and step (1) is 1mL:10mL:2g.
In step (2), 2~4h of back flow reaction.
In step (3), the usage ratio of the benzoic acid replaced in hydrazine hydrate, ethyl alcohol and step (1) is 5mL:10mL:1g.
In step (3), 7~8h of back flow reaction.
In step (4), the usage ratio of the benzoic acid replaced in isatin, ethyl alcohol, formaldehyde, glacial acetic acid and step (1) is
0.2g:20mL:0.06g:0.5mL:2g, 8~9h of stirring at normal temperature.
The isatin hydrazide derivative is used to prepare antitumor drug.
Beneficial effects of the present invention are as follows：
The present invention will introduce hydrazides skeleton with the isatin of good antitumor activity, obtain that there is apparent inhibition to make to tumour
Isatin hydrazide derivative, and it is raw materials used cheap, simple and easy to get, reaction step is few, and yield is high, is suitble to industry metaplasia
Production.
Specific embodiment
The present invention is described further with reference to embodiments.
Embodiment 1
The preparation of the chloro- N'- of 4- ((2,3- istain -1- bases) methyl) benzoyl hydrazine：
(1) 2g parachlorobenzoic-acids, 10mL thionyl chlorides are placed in round-bottomed flask, back flow reaction 2h, vacuum distillation obtains
Product；
(2) product obtained in step (1), the 1mL concentrated sulfuric acids are placed in round-bottomed flask, add in 10mL methanol as reaction
Solvent, back flow reaction 4h.Then it is evaporated under reduced pressure, is extracted with water and ethyl acetate, retain organic layer, anhydrous sodium sulfate is dry, steams
It is dry to obtain product；
(3) product obtained in step (2) and 10mL hydrazine hydrates are placed in round-bottomed flask, add in 20mL ethyl alcohol as reaction
Solvent, back flow reaction 7h, vacuum distillation obtain product；
(4) product obtained in 0.23g steps (3), 0.2g isatin are placed in round-bottomed flask, add in 20mL ethyl alcohol, then
0.06g formaldehyde, 0.5mL glacial acetic acids are added in, stirring at normal temperature 8h obtains final product.
1 product test result of embodiment is as follows：
Yellow powder, yield 55%, Mp:282.7-282.8℃.1H NMR(400MHz,CDCl3):4.6288(s,
2H),7.1919-7.2455(m,2H),7.4715-7.5103(m,1H),7.6762-7.7174(m,3H),7.9201-7.9415
(d, J=8.56Hz, 2H), 13.3418 (s, 1H), 13.7089 (s, 1H).
Embodiment 2
The preparation of N'- ((2,3- istain -1- bases) methyl) -2- methoxybenzoyl hydrazines：
(1) 2g o-methoxybenzoic acids, 10mL thionyl chlorides are placed in round-bottomed flask, back flow reaction 2h, are evaporated under reduced pressure
Obtain product；
(2) product obtained in step (1), the 1mL concentrated sulfuric acids are placed in round-bottomed flask, add in 10mL methanol as reaction
Solvent, back flow reaction 4h.Then it is evaporated under reduced pressure, is extracted with water and ethyl acetate, retain organic layer, anhydrous sodium sulfate is dry, steams
It is dry to obtain product；
(3) product obtained in step (2) and 10mL hydrazine hydrates are placed in round-bottomed flask, add in 20mL ethyl alcohol as reaction
Solvent, back flow reaction 8h, vacuum distillation obtain product；
(4) product obtained in 0.226g steps (3), 0.2g isatin are placed in round-bottomed flask, add in 20mL ethyl alcohol, then
0.06g formaldehyde, 0.5mL glacial acetic acids are added in, stirring at normal temperature 9h obtains final product.
2 product test result of embodiment is as follows：
Yellow powder, yield 80%, Mp:300.9-301.0℃.1H NMR(400MHz,CDCl3):4.0708-
4.1051(d,3H),4.5700-4.6279(m,2H),7.1740-7.2119(m,2H),7.2650-7.3593(m,2H),
7.4482-7.5514(m,1H),7.6504-7.6873(m,1H),7.9427-8.1540(m,2H),11.8072(s,1H),
13.2072(s,1H)。
Following Anticancer Activities are carried out to the product that embodiment 1-2 is obtained：
1st, experiment material
1.1 cell strain
Human breast cancer cell (human breast cancer cells)；MCF
Gastric carcinoma cells (human gastric cancer cells)；SGC
1.2 reagent
1640 culture mediums of RPMI (GIBCO), newborn bovine serum (Hangzhou Chinese holly biological engineering material), trypsase
(Sigma), MTT (Sigma), injection streptomysin (the auspicious positive pharmacy in Shandong, 1,000,000 units of 1g /), benzylpenicillin sodium for injection
(Shandong Shandong medicine, 800,000 units /).Other common chemical reagent are that domestic analysis is pure.
2nd, experimental method
The preparation of 2.1 culture mediums
One liter of one bag of 1640 culture mediums of RPMI (Gibcio USA) plus water, add 2g sodium bicarbonates, 100,000 units of Penicillin
With 100mg streptomysins, pH value is adjusted to 7.4, with 0.22mm degerming membrane filtration degermings.90mL culture mediums add the newborn ox blood of inactivation
Clear 10mL is complete culture solution.Trypsase is made into 0.25% solution with D-hanks buffer solutions, 4 DEG C of preservations after filtration sterilization
It is spare.
The preparation of 2.2 liquids
Sample 1.0mg accurately is weighed, is added in the 1.5mL centrifuge tubes of sterilizing, DMSO 1mL is added in, is made into 1mg/mL
Stoste, -40 DEG C of freezen protectives.After melting before use respective concentration application is diluted to appropriate D-hanks.
2.3 cell culture and passage
The equal adhere-wall culture of cell is in the Tissue Culture Flask of complete culture solution containing 10mL, in 37 DEG C, 5%CO2, under saturated humidity
Culture.Cell is washed twice after covering with bottom of bottle with sterilizing D-hanks liquid, is added 0.25% trypsin digestion and cell 2min, is outwelled pancreas
After jog cell can be completely fallen off, after adding full nutrient solution 30mL, cell is dispelled with pipette for protease, is sub-packed in 3 newly
Tissue Culture Flask in, continue to cultivate.
2.4 active anticancers are tested
One bottle of cell for just growing up to intact monolayer is taken, cell is collected after trypsin digestion, is blown and beaten uniformly with pipette,
Two drop cell suspension trypan blues (Trypan Blue) is taken to dye, (dead cell number must not for living cell counting number under microscope
More than 5%), cell number is adjusted to 1 × 10 with complete culture solution4A cell/mL.It is added in 96 porocyte culture plates per hole
100 μ L cell suspensions, CO is placed in by culture plate2It is cultivated in incubator for 24 hours, takes out culture plate after every 11 μ L of Kong Zhongjia containing difference
The solution of concentration sample so that drug final concentration is respectively 50,25,12.5,6.25 and 3.125 μ g/mL, and each concentration is set
3 parallel holes separately set 6 hole cells and make normal control hole and positive 5 FU 5 fluorouracil control wells.Culture plate is in micropore after adding medicine
Mixing is vibrated in plate oscillator, is placed in CO2Continue culture in incubator for 24 hours.Culture plate is taken out, 25 μ L 5mg/mL are added in per hole
MTT liquid, vibrate mixing, continue cultivate 4h.10min is cultivated after adding in per 100 μ L DMSO of hole.Microplate reader measures each hole light and inhales
It receives (OD values), measures wavelength 490nm.Suppression of the drug to four kinds of cell Proliferations is calculated by CalcuSyn softwares according to each hole OD values
Rate processed, i.e. IC50Value, experimental result are shown in Table 1.
1 drug inhibiting tumor cell proliferation experiment of table
Parallel laboratory test three times, experimental result are averaged, and error is between 5-10%.
Claims (10)
1. a kind of isatin hydrazide derivative, it is characterised in that its structural formula is：
Or
。
2. a kind of preparation method of isatin hydrazide derivative described in claim 1, it is characterised in that include the following steps：
（1）Substituted benzoic acid, thionyl chloride are subjected to back flow reaction, product is obtained through vacuum distillation, wherein, substituted benzene first
Acid is parachlorobenzoic-acid or o-methoxybenzoic acid；
（2）By step（1）In obtained product and the concentrated sulfuric acid carry out back flow reaction in methyl alcohol, through being evaporated under reduced pressure, extracting, doing
It is dry, be evaporated to obtain product；
（3）By step（2）In obtained product and hydrazine hydrate carry out back flow reaction in ethanol, obtain product through vacuum distillation；
（4）By step（3）Obtained product and isatin is added in ethyl alcohol, then adds in formaldehyde, glacial acetic acid, and stirring at normal temperature obtains
To isatin hydrazide derivative.
3. the preparation method of isatin hydrazide derivative according to claim 2, it is characterised in that：Step（1）In, substitution
Benzoic acid, thionyl chloride usage ratio be 1g:5mL.
4. the preparation method of isatin hydrazide derivative according to claim 2, it is characterised in that：Step（1）In, reflux
React 2~4h.
5. the preparation method of isatin hydrazide derivative according to claim 2, it is characterised in that：Step（2）In, dense sulphur
Acid, methanol and step（1）The usage ratio of middle substituted benzoic acid is 1mL:10mL:2g.
6. the preparation method of isatin hydrazide derivative according to claim 2, it is characterised in that：Step（2）In, reflux
React 2~4h.
7. the preparation method of isatin hydrazide derivative according to claim 2, it is characterised in that：Step（3）In, hydration
Hydrazine, ethyl alcohol and step（1）The usage ratio of middle substituted benzoic acid is 5mL:10mL:1g.
8. the preparation method of isatin hydrazide derivative according to claim 2, it is characterised in that：Step（3）In, reflux
React 7~8h.
9. the preparation method of isatin hydrazide derivative according to claim 2, it is characterised in that：Step（4）In, indigo
Red, ethyl alcohol, formaldehyde, glacial acetic acid and step（1）The usage ratio of middle substituted benzoic acid is 0.2g:20mL:0.06g: 0.5mL:
2g, 8~9h of stirring at normal temperature.
10. a kind of application of isatin hydrazide derivative described in claim 1, it is characterised in that：Isatin hydrazide derivative
It is used to prepare antitumor drug.
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