CN107857766A - A kind of synthetic method of spiral Benzazole compounds based on phenylalanine and more carbonyl class cyclic ketone compounds and its application - Google Patents
A kind of synthetic method of spiral Benzazole compounds based on phenylalanine and more carbonyl class cyclic ketone compounds and its application Download PDFInfo
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Abstract
The invention discloses a kind of synthetic method of the spiral Benzazole compounds based on phenylalanine and more carbonyl class cyclic ketone compounds, the synthetic method includes pyridine base class benzazolyl compounds and phenylalanine and more carbonyl class cyclic ketone compounds carrying out addition condensation reaction in ethanol water, the spiral Benzazole compounds of high yield are obtained, then filter the product for being recrystallized to give purification again.Compared with prior art, synthetic method of the invention simply, conveniently, original multistep reaction is substituted using single process for one-pot synthesis, and raw material is easy to get, and reaction efficiency is high, is adapted to a variety of reaction substrates；The spiral Benzazole compounds obtained simultaneously have pharmaceutical activity, in the medicine that tumour and cancer can be more effectively treated available for clinic.
Description
Technical field
The invention belongs to organic synthesis field, and in particular to a kind of based on phenylalanine and more carbonyl class cyclic ketone compounds
The synthetic method of spiral Benzazole compounds and its application.
Background technology
Spiral indoles (spirooxindole) compound has been reported that can be as P53-MDM2 inhibitor, and these are small
The compound of molecule can be directly targeted tumour cell and on normal cell without influence as a medicine of oncotherapy.
In past several years, the synthetic method of major progress is achieved, to obtain spiral indole derivatives, while creates a hand
The mode of property quaternary carbon center.Reacted for example, Overman reports an asymmetric intramolecular He Ke, high corresponding selection
Synthesize spiral shell-pyrroles -3,3'- indoles] derivative；(bibliography V.Caprio, B.Guyen, Y.Opoku-Boahen,
J.Mann,S.M.Gowan,L.M.Kelland,M.A.Read and S.Neidle,Bio.Med.Chem.Lett.,2000,
10,2063-2066.)
Xie and Wang reports indoles and amino acid fat and the one pot reaction of isatin.(bibliography J.Liu, H.Sun,
X.Liu,L.Ouyang,T.Kang,Y.Xie and X.Wang,Tetrahedron Lett.,2012,53,2336-2340.)
, it is necessary to be modified in advance on indole ring, reaction site is also limited method reported above, it is impossible to quick
The substantial amounts of transformation performed the derivatization with molecular skeleton, this just greatly limit the multifarious research of product.Currently with multigroup
Division is widely used by pharmaceutical synthesis into the method that condensed ring skeleton is quickly prepared with substep synthetic method, by establishing spiral
The multicomponent synthetic method of Benzazole compounds, its function dough can be quickly realized, existing structure is modified, realized multiple
The structure of miscellaneous system.But existing synthetic technology is typically necessary by complex synthesis step, and reaction raw materials
Price is higher, the problems such as operation acquires a certain degree of difficulty.A kind of therefore it provides new synthesis side of spiral Benzazole compounds
Method is necessary.
The content of the invention
It is an object of the invention to provide a kind of spiral indoles based on phenylalanine and more carbonyl class cyclic ketone compounds
The synthetic method of compound, original multistep reaction is substituted using single process for one-pot synthesis, by pyridine base class benzazolyl compounds and benzene
Alanine and more carbonyl class cyclic ketone compounds carry out addition condensation reaction in ethanol water, obtain the spiral indoles of high yield
Class compound.
Present invention also offers this spiral Benzazole compounds in terms of test lung cancer or proliferation of human gastric cancer cell experiment
With.
To achieve these goals, the technical solution adopted by the present invention is：One kind is based on phenylalanine and more carbonyl class rings
The synthetic method of the spiral Benzazole compounds of assimilation compound, the synthetic method comprise the following steps：
(1) that pyridine base class benzazolyl compounds, phenylalanine and more carbonyl class cyclic ketone compounds are placed in into ethanol water is anti-
Answer in solvent, heating stirring back flow reaction；Wherein, pyridine base class benzazolyl compounds, phenylalanine and more carbonyl class cyclic ketones chemical combination
The mol ratio of thing is 1:(0.8-1):(1-1.2)；
(2) after reaction terminates, it is cooled to room temperature, product obtains spiral indoles through filtering and recrystallization isolates and purifies
Compound.
In the step (1), the volume ratio of absolute ethyl alcohol and distilled water in ethanol water is 2:(1-1.2).
The reaction condition of the step (1) is：Under air ambient, reaction 2-4h is stirred at reflux under heating condition.
In the step (1), the amount ratio of pyridine base class benzazolyl compounds and reaction dissolvent is 1mmol:(45-50)mL.
The step (2) concretely comprises the following steps：After reaction terminates, treat that temperature is cooled to room temperature, reaction product filtered,
Solid crude product is obtained, then solid crude product CH3OH/DMF mixed solvents are recrystallized, and spiral shell is obtained after recrystallizing 1-2 times
Revolve Benzazole compounds；Wherein, CH3OH/DMF in the mixed solvents CH3OH and DMF dosage volume ratio is 7:3.
In step (1), the structural formula of the pyridine base class benzazolyl compounds isWherein R for-
H ,-CH3,-CH2CH3,-CHO ,-COOCH2CH3,-OCH3,-CF3,-NO2,-NH2,-Ph ,-Cl, any one in Br or-I.
In step (1), more carbonyl class cyclic ketone compounds are selected from In it is any
It is a kind of；Wherein, R1For-H ,-CH3,-CH2CH3,-CHO ,-COOCH2CH3,-OCH3,-CF3,-NO2,-NH2,-Ph ,-Cl, Br or-
Any one in I.
A kind of spiral Benzazole compounds provided by the invention, are prepared using the above method.
Present invention also offers this spiral Benzazole compounds in terms of test lung cancer or proliferation of human gastric cancer cell experiment
Using will reacting the product of gained, to be configured to concentration be 0,1.5625,3.125,6.25,12.5,25,50,100 micrograms/milli
The solution risen, then carry out cell proliferation experiment test respectively to lung cancer and stomach cancer cell with the solution of this concentration gradient and divide
Analysis.
The reaction mechanism of the present invention：Pyridine radicals indoles first with more carbonyl ketone occur Michael addition reaction, then with phenylpropyl alcohol
Into loop coil after propylhomoserin condensation.
Beneficial effects of the present invention：Compared with prior art, the present invention substitutes original multistep using single process for one-pot synthesis
Reaction, pyridine base class benzazolyl compounds and phenylalanine and more carbonyl class cyclic ketone compounds are subjected to addition in ethanol water
Condensation reaction is that can obtain the spiral Benzazole compounds of high yield, and method simple operations are convenient, and raw material is cheap and easy to get, and reaction is molten
Agent is environment friendly and pollution-free, and the spiral Benzazole compounds synthesized can suppress to the propagation of lung cancer or stomach cancer cell.
Brief description of the drawings
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of embodiment 1；
Fig. 2 is the carbon-13 nmr spectra figure of embodiment 1；
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of embodiment 2；
Fig. 4 is the carbon-13 nmr spectra figure of embodiment 2；
Fig. 5 is the hydrogen nuclear magnetic resonance spectrogram of embodiment 3；
Fig. 6 is the carbon-13 nmr spectra figure of embodiment 3；
Fig. 7 is the hydrogen nuclear magnetic resonance spectrogram of embodiment 4；
Fig. 8 is the carbon-13 nmr spectra figure of embodiment 4；
Fig. 9 is the number that the concentration gradient after the product obtained by embodiment 1-4 is prepared is tested to lung cancer or proliferation of human gastric cancer cell
According to figure；
Wherein, IC50 (BGC-823) is that proliferation of human gastric cancer cell tests the data obtained, and IC50 (A549) proliferation of lung cancer cells is real
Test the data obtained；
Figure 10 is the song that the concentration gradient after the product obtained by embodiment 1-4 is prepared influences on lung cancer or gastric cancer cell activity
Line chart；
Wherein, tumor chemotherapeutic drug cis-platinum (Cis-DDP) controls thing with reference to control thing, DMSO for the positive for negative reference,
P1-P4 corresponds to the concentration gradient after embodiment 1-4 products therefroms are prepared respectively；
Figure 11 is the reaction equation of the present invention.
Embodiment
The embodiment of the present invention is described in detail below.It is it should be appreciated that described herein specific
Embodiment is merely to illustrate and explain the present invention, it is not limited to these embodiments.In embodiment, all reaction raw materials and molten
Agent etc. is all An Naiji reagent manufactures.
Embodiment 1
A kind of synthetic method of the spiral Benzazole compounds based on phenylalanine, the synthetic method include following step
Suddenly：
(1) 1mmol 2- vinylpyridine base indolines, 1mmol phenylalanines and 1mmol isatin are weighed respectively, are placed on
In 50mL ethanol water reaction dissolvent, under air ambient, heating stirring back flow reaction 3 hours；
(2) after reaction terminates, treat that temperature is cooled to room temperature, reaction product is filtered, obtain solid crude product, Ran Hougu
Body crude product CH3OH/DMF mixed solvents are recrystallized, and orange/yellow solid i.e. pyridine radicals diindyl is obtained after recrystallizing 2 times
Quinoline compound 1；；Yield is 50%, and fusing point is 120-124 DEG C.
The product structure formula of gained pyridine radicals diindyl quinoline compound 1 is：
The hydrogen nuclear magnetic resonance modal data of product：
1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),10.26(s,1H),8.28-8.15(m,2H),7.91-
7.78 (m, 1H), 7.51 (d, J=7.0Hz, 1H), 7.24 (dd, J=5.1,3.3Hz, 2H), 7.19-7.13 (m, 3H), 7.13-
7.05 (m, 2H), 6.89 (dtd, J=11.5,7.6,1.1Hz, 2H), 6.61-6.47 (m, 4H), 4.97 (s, 1H), 4.03 (q, J
=7.1Hz, 1H), 3.83 (d, J=8.6Hz, 1H), 2.98 (ddd, J=18.9,13.8,6.7Hz, 2H)
The carbon-13 nmr spectra data of product：
13C NMR(101MHz,DMSO-d6)δ180.67,177.27,150.95,147.56,142.55,142.37,
139.15,136.74,134.10,129.48,128.98,128.03,127.19,126.05,125.91,125.41,124.91,
122.83,121.47,120.65,109.11,108.98,75.69,65.07,64.05,59.77,57.96。
Embodiment 2
A kind of synthetic method of the spiral Benzazole compounds based on phenylalanine, the synthetic method include following step
Suddenly：
(1) 1mmol 2- vinylpyridine base indolines, 1mmol phenylalanines and 1mmol 4- nitros-isatin are weighed respectively,
It is placed in 50mL ethanol water reaction dissolvent, under air ambient, heating stirring back flow reaction 3 hours；
(2) after reaction terminates, treat that temperature is cooled to room temperature, reaction product is filtered, obtain solid crude product, Ran Hougu
Body crude product CH3OH/DMF mixed solvents are recrystallized, and white solid i.e. pyridine radicals diindyl is obtained after recrystallizing 2 times
Quinoline compound 2；；Yield is 35%, and fusing point is 80-82 DEG C.
The product structure formula of gained pyridine radicals diindyl quinoline compound 2 is：
The hydrogen nuclear magnetic resonance modal data of product：
1H NMR(400MHz,DMSO-d6) δ 10.89 (s, 1H), 10.56 (s, 1H), 8.42 (dd, J=6.0,2.3Hz,
1H), 8.31-8.20 (m, 2H), 8.11 (ddd, J=8.6,4.2,1.8Hz, 1H), 7.78 (d, J=7.6Hz, 1H), 7.27 (d,
J=7.0Hz, 2H), 7.24-7.14 (m, 3H), 7.10 (dd, J=8.6,4.8Hz, 1H), 6.97-6.83 (m, 1H), 6.81-
6.68 (m, 1H), 6.60 (t, J=6.2Hz, 1H), 6.57-6.42 (m, 2H), 4.98 (d, J=2.6Hz, 1H), 3.93 (dd, J
=35.4,8.6Hz, 2H), 2.99 (ddd, J=18.0,13.5,6.4Hz, 2H)
The carbon-13 nmr spectra data of product：
13C NMR(101MHz,DMSO-d6)δ179.82,178.38,150.73,148.98,147.76,142.36,
141.97,139.21,136.63,133.52,129.05,128.34,128.06,127.56,127.38,126.72,125.96,
124.42,122.99,121.93,120.78,109.31,109.12,74.95,65.10,63.75,57.12。
Embodiment 3
A kind of synthetic method of the spiral Benzazole compounds based on phenylalanine, the synthetic method include following step
Suddenly：
(1) 1mmol 2- vinylpyridine base indolines, 1mmol phenylalanines and 1mmol acenaphthenequinones are weighed respectively, are placed on
In 50mL ethanol water reaction dissolvent, under air ambient, heating stirring back flow reaction 2 hours；
(2) after reaction terminates, treat that temperature is cooled to room temperature, reaction product is filtered, obtain solid crude product, Ran Hougu
Body crude product CH3OH/DMF mixed solvents are recrystallized, and orange/yellow solid i.e. pyridine radicals diindyl is obtained after recrystallizing 2 times
Quinoline compound 3；Yield is 63%, and fusing point is 86-87 DEG C.
The product structure formula of gained pyridine radicals diindyl quinoline compound 3 is：
The hydrogen nuclear magnetic resonance modal data of product：
1H NMR(400MHz,DMSO-d6) δ 10.23 (s, 1H), 8.18 (d, J=2.8Hz, 2H), 8.11-8.02 (m,
1H), 7.87 (d, J=8.3Hz, 1H), 7.80 (d, J=7.0Hz, 1H), 7.73 (d, J=8.0Hz, 1H), 7.69-7.51 (m,
3H), 7.23 (d, J=7.1Hz, 2H), 7.20-7.08 (m, 3H), 7.05 (t, J=7.3Hz, 1H), 6.69 (td, J=7.7,
1.1Hz, 1H), 6.54 (d, J=7.6Hz, 1H), 6.47-6.35 (m, 1H), 6.30 (d, J=7.5Hz, 1H), 5.00 (d, J=
1.2Hz, 1H), 3.98 (d, J=9.1Hz, 1H), 3.81 (d, J=8.1Hz, 1H), 3.01 (ddd, J=18.9,13.7,
6.5Hz,2H).
The carbon-13 nmr spectra data of product：
13C NMR(101MHz,DMSO-d6)δ203.36,179.59,150.65,147.70,142.15,140.84,
139.02,136.57,133.40,131.71,130.80,129.70,129.15,128.64,128.19,128.03,127.97,
127.87,125.93,125.25,124.66,122.92,122.54,121.06,120.32,108.94,78.58,65.97,
63.42,57.43。
Embodiment 4
A kind of synthetic method of the spiral Benzazole compounds based on phenylalanine, the synthetic method include following step
Suddenly：
(1) 1mmol 2- vinylpyridine base indolines, 1mmol phenylalanines and the bromo- isatin of 1mmol 4- are weighed respectively, are put
Put in 48mL ethanol water reaction dissolvent, under air ambient, heating stirring back flow reaction 3 hours；
(2) after reaction terminates, treat that temperature is cooled to room temperature, reaction product is filtered, obtain solid crude product, Ran Hougu
Body crude product CH3OH/DMF mixed solvents are recrystallized, and white solid i.e. pyridine radicals diindyl quinoline is obtained after recrystallizing 2 times
Compound 4；Yield is 26%, and fusing point is 87-89 DEG C.
The product structure formula of gained pyridine radicals diindyl quinoline compound 4 is：
The hydrogen nuclear magnetic resonance modal data of product：
1H NMR(400MHz,DMSO-d6) δ 10.57 (s, 1H), 10.36 (s, 1H), 8.23 (dd, J=4.7,1.5Hz,
2H), 7.81 (d, J=8.0Hz, 1H), 7.66 (d, J=2.0Hz, 1H), 7.32 (dd, J=8.3,2.1Hz, 1H), 7.28-
7.22 (m, 2H), 7.22-7.14 (m, 3H), 7.10 (dd, J=8.3,6.2Hz, 1H), 6.90 (td, J=7.6,1.1Hz, 1H),
6.62 (d, J=7.4Hz, 1H), 6.52 (ddd, J=8.5,5.5,2.0Hz, 3H), 4.95 (dd, J=8.7,5.1Hz, 1H),
3.83 (d, J=8.8Hz, 1H), 3.74 (d, J=9.8Hz, 1H), 3.03 (dd, J=13.7,8.3Hz, 1H), 2.90 (dd, J=
13.7,4.8Hz,1H).
The carbon-13 nmr spectra data of product：
13C NMR(101MHz,DMSO-d6)δ180.78,177.76,151.35,148.17,142.95,142.23,
139.75,137.21,134.34,132.64,129.56,129.25,129.18,128.64,128.53,127.88,126.44,
125.21,123.43,121.23,113.69,111.50,109.54,75.98,65.63,64.57,58.16,56.56。
Test example
Product obtained by embodiment 1-4 is separately added into the normal concentration solution that DMSO is dissolved into 100 mcg/mls, then
The solution that concentration is respectively 0,1.5625,3.125,6.25,12.5,25,50 mcg/mls is half-and-half diluted to, then uses this
The solution of concentration gradient carries out cell proliferation experiment test to lung cancer and stomach cancer cell respectively, and cell survival rate cell is by CCK-
8 are reduced into the ability of bluish violet compound to weigh.Lung cancer cell types and stomach cancer cell line BGC-823 are shifted to an earlier date respectively
24h is inoculated in 96 orifice plates, and cell density is 3 × 104.After the solution packet transaction cell 36-48h of above-mentioned concentration gradient, often
Hole adds 10 μ L CCK-8, continues to cultivate 2h, ELIASA detects each hole 450nm wavelength absorbances.By Fig. 9 and 10, can obtain
Go out：Thing is controlled for positive reference with tumor chemotherapeutic drug cis-platinum (Cis-DDP), DMSO is to be negative with reference to control thing, the institute of embodiment 4
The product obtained is most obvious to the inhibitory action of A549 proliferation of lung cancer cells experiment tests, while the product pair of the gained of embodiment 4
The inhibitory action of BGC-823 proliferation of human gastric cancer cell experiment tests is most obvious.
Claims (9)
1. a kind of synthetic method of the spiral Benzazole compounds based on phenylalanine and more carbonyl class cyclic ketone compounds, its feature
It is, the synthetic method comprises the following steps：
(1) pyridine base class benzazolyl compounds, phenylalanine and more carbonyl class cyclic ketone compounds are placed in ethanol water and react molten
In agent, heating stirring back flow reaction；Wherein, pyridine base class benzazolyl compounds, phenylalanine and more carbonyl class cyclic ketone compounds
Mol ratio is 1:(0.8-1):(1-1.2)；
(2) after reaction terminates, it is cooled to room temperature, product obtains spiral Benzazole compounds through filtering and recrystallization isolates and purifies.
2. synthetic method according to claim 1, it is characterised in that：It is anhydrous in ethanol water in the step (1)
The volume ratio of ethanol and distilled water is 2:(1-1.2).
3. synthetic method according to claim 1, it is characterised in that：The reaction condition of the step (1) is：Air ambient
Under, reaction 2-4h is stirred at reflux under heating condition.
4. synthetic method according to claim 1, it is characterised in that：In the step (1), pyridine base class benzazolyl compounds
Amount ratio with reaction dissolvent is 1mmol:(45-50)mL.
5. synthetic method according to claim 1, it is characterised in that：The step (2) concretely comprises the following steps：Reaction terminates
Afterwards, treat that temperature is cooled to room temperature, reaction product is filtered, obtain solid crude product, then solid crude product CH3OH/DMF
Mixed solvent is recrystallized, and spiral Benzazole compounds are obtained after recrystallizing 1-2 times；Wherein, CH3OH/DMF in the mixed solvents
CH3OH and DMF dosage volume ratio is 7:3.
6. synthetic method according to claim 1, it is characterised in that：In step (1), the pyridine base class benzazolyl compounds
Structural formula beWherein R is-H ,-CH3,-CH2CH3,-CHO ,-COOCH2CH3,-OCH3,-CF3,-
NO2,-NH2,-Ph ,-Cl, any one in Br or-I.
7. synthetic method according to claim 1, it is characterised in that：In step (1), more carbonyl class cyclic ketone compounds
It is selected fromOrIn any one；Wherein, R1For-H ,-CH3,-CH2CH3,-CHO ,-
COOCH2CH3,-OCH3,-CF3,-NO2,-NH2,-Ph ,-Cl, any one in Br or-I.
A kind of 8. spiral Benzazole compounds that method using described in claim 1-7 any one synthesizes.
A kind of 9. the answering in terms of test lung cancer or proliferation of human gastric cancer cell experiment of spiral Benzazole compounds described in claim 8
With.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109134478A (en) * | 2018-08-24 | 2019-01-04 | 贵州大学 | Thio pyrrolones containing continuous three quaternary carbon splices double loop coil Oxoindole compounds and preparation method and application |
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|---|---|---|---|---|
| US6114540A (en) * | 1997-09-08 | 2000-09-05 | Arqule, Inc. | Spiro[pyrrolidine-2,3'-oxindole] compounds and methods of use |
| CN105585570A (en) * | 2015-12-15 | 2016-05-18 | 贵州大学 | Isoxazole and pyrrolidinyl spirooxindole spliced compound and preparation method and application thereof |
| CN106866686A (en) * | 2017-03-30 | 2017-06-20 | 贵州大学 | Isoxazole splices double volution Oxoindole compounds of 3,3 ' pyrroles and preparation method and application |
-
2017
- 2017-12-11 CN CN201711304439.3A patent/CN107857766B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6114540A (en) * | 1997-09-08 | 2000-09-05 | Arqule, Inc. | Spiro[pyrrolidine-2,3'-oxindole] compounds and methods of use |
| CN105585570A (en) * | 2015-12-15 | 2016-05-18 | 贵州大学 | Isoxazole and pyrrolidinyl spirooxindole spliced compound and preparation method and application thereof |
| CN106866686A (en) * | 2017-03-30 | 2017-06-20 | 贵州大学 | Isoxazole splices double volution Oxoindole compounds of 3,3 ' pyrroles and preparation method and application |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109134478A (en) * | 2018-08-24 | 2019-01-04 | 贵州大学 | Thio pyrrolones containing continuous three quaternary carbon splices double loop coil Oxoindole compounds and preparation method and application |
| CN109134478B (en) * | 2018-08-24 | 2021-04-13 | 贵州大学 | Thiopyrrolone splicing double-spiro-oxoindole compound containing continuous three quaternary carbons and preparation method and application thereof |
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