CN109734682A - A kind of cyclic alkenyl radical imines medicine intermediate, preparation method and its as inhibit growth of cancer cells drug on application - Google Patents
A kind of cyclic alkenyl radical imines medicine intermediate, preparation method and its as inhibit growth of cancer cells drug on application Download PDFInfo
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- CN109734682A CN109734682A CN201910120144.3A CN201910120144A CN109734682A CN 109734682 A CN109734682 A CN 109734682A CN 201910120144 A CN201910120144 A CN 201910120144A CN 109734682 A CN109734682 A CN 109734682A
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Abstract
The present invention provides a kind of cyclic alkenyl radical imines medicine intermediate, preparation method and its inhibitory activity to growth of cancer cells.General formula is as followsR in formula1For normal-butyl, tert-butyl, phenyl, cyclohexyl, benzyl, R2For alkyl such as methyl, ethyl, isopropyl, n-hexyls, the aryl such as phenyl, substituted-phenyl or heteroaryl.R3For alkyl such as methyl, ethyl, isopropyl, n-hexyls, the aryl such as phenyl, substituted-phenyl or heteroaryl.Substituting group position, number are not fixed.Preparation method is by α-phosphinimine substituted acrylic aldehyde derivative, acid and isonitrile, and reaction dissolvent is anhydrous 1,2- dichloroethanes, and reaction sloughs solvent after the reaction was completed under reduced pressure, and residue column chromatographs to obtain the target compound of logical formula (I).The present invention provides efficient new synthetic methods to synthesize a kind of cyclic alkenyl radical imines analog derivative, and because the derivative shows certain inhibitory activity to human hepatoma cell HepG-2 and lung cell A549-1, advantageous as the application of medicine.
Description
Technical field
The present invention relates to a kind of cyclic alkenyl radical imines medicine intermediate, preparation method and its inhibition to growth of cancer cells
Activity.
Background technique
In recent years, cancer has been increasingly becoming the first big enemy of human health, and the treatment of cancer gradually receives people
Attention.In the treatment of cancer, drug therapy is a critically important link, the use of effective anticancer drug, Ke Yibang
It helps patient to obtain longer life span, possesses the hope survived.Currently, the anticancer drug of world community approved listing is only
There are about 150 kinds or so.Various due to cancer species, the type of drug seems very insufficient, and research and development are more, and curative effect is better that ground is new
Type anti-tumor drug molecule seems especially urgent.In this patent, we are prepared for the cyclic alkenyl radical imines of a kind of structure novel
Medicine intermediate.Life of such medicine intermediate to -1 liang of class cancer cell of human hepatoma cell HepG-2 and lung cell A549
With certain inhibiting effect.
Summary of the invention
It is a primary object of the present invention to explore to provide a kind of cyclic alkenyl radical imines medicine intermediate, preparation method and its
Anticancer activity.
The invention proposes cyclic alkenyl radical imines medicine intermediates (I):
Wherein, R in formula1For normal-butyl, tert-butyl, phenyl, cyclohexyl, benzyl, R2For for methyl, ethyl, isopropyl, just
The alkyl such as hexyl, the aryl such as phenyl, substituted-phenyl or heteroaryl.R3For the alkyl such as methyl, ethyl, isopropyl, n-hexyl, benzene
The aryl such as base, substituted-phenyl or heteroaryl.Substituting group position, number are not fixed.
The preparation method of the synthesis cyclic alkenyl radical imines medicine intermediate, the method includes following synthesis roads
Diameter:
The method specifically includes the following steps:
By α-phosphinimine substituted acrylic aldehyde derivative and acid and isonitrile, 1:0.1-3:0.1-3 is sequentially added and is equipped in molar ratio
It in the flask of anhydrous 1,2- dichloroethanes, is reacted at 30 DEG C, reacts 6-48 hours, after the reaction was completed, slough under reduced pressure molten
Agent, residue column chromatograph to obtain the cyclic alkenyl radical imine compound 4 of logical formula (I).
The present invention has the beneficial effect that:
1. the present invention reports a kind of novel cyclic alkenyl radical imines medicine intermediate；
2. the present invention provides the preparation methods of a kind of novel cyclic alkenyl radical imines medicine intermediate.
3. the present invention has synthesized a kind of novel cyclic alkenyl radical imines medicine intermediate, alkenyl imines class formation is because to people
The metal ion of -1 target center of body HepG-2 cell and lung cell A549 has the pi-conjugated effect of certain P- and π-π heap
Product effect is worth so that such compound be caused to show certain inhibiting effect to the routine growth of two class cancer cells
Further research and development.
Specific embodiment
The preparation and application effect of compound in (I) formula of the invention are further illustrated below with reference to embodiment.
Instrument and reagent:
Fusing point is measured with X4 type melting point apparatus (production of Beijing third optical instrument factory), and thermometer is not calibrated；1H NMR and13600 type 600MHz core of C NMR 400 type 400MHz Nuclear Magnetic Resonance of Varian Mercury or Varian Mercury
Magnetic resonance device measurement, deuterated chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-d6) it is solvent, TMS is internal standard；MS is used
The measurement of FinniganTrace mass spectrograph；Elemental analysis is measured using Vario EL III elemental analyser；Agents useful for same is domestic
(or import) chemistry is pure or analysis is pure.Solvent toluene is to be evaporated dry mistake through overweight, and triethylamine is also processed by steaming again.
Embodiment 1
Preparation
Tert-butyl isonitrile 1a (1.2mmol), benzoic acid 2a (1.1mmol) and α-phosphinimine are added into the flask of 50mL
Replace cinnamic acid 3a (1.0mmol), is reacted at 30 DEG C, reaction dissolvent 1,2- dichloroethanes (5mL), after reaction 24 hours,
Solvent 1,2- dichloroethanes are sloughed under reduced pressure, and residue column chromatographs to obtain 0.200g target compound 4a, yield 60%.
1H NMR(CDCl3, 600MHz) and δ (ppm) 8.12 (d, J=7.8Hz, 2H), 7.68 (d, J=7.2 Hz, 2H),
7.64 (t, J=7.2Hz, 1H), 7.51 (t, J=7.8Hz, 2H), 7.42-7.29 (m, 4H), 6.15 (s, 1H), 6.06 (s,
1H),1.42(s,9H)；
13C{1H}NMR(CDCl3,150MHz)δ(ppm)165.1,164.3,135.5,134.2,133.8, 129.8,
129.3,129.0,128.8,128.7,128.1,118.3,78.8,51.9,28.6；
HRMS(ESI-TOF)m/z[M+H]+calcd for C21H23N2O2335.1754；found 335.1757.
Embodiment 2
Tert-butyl isonitrile 1a (0.12mmol), benzoic acid 2a (0.11mmol) and α-phosphinimine are added into the flask of 5mL
Replace cinnamic acid 3a (0.10mmol), reacted at 30 DEG C, reaction dissolvent 1,2- dichloroethanes (0.5mL), is reacted 24 hours
Afterwards, solvent 1,2- dichloroethanes are sloughed under reduced pressure, and residue column chromatographs to obtain 0.022g target compound 4a, yield 67%.
Embodiment 3
Tert-butyl isonitrile 1a (12mmol), benzoic acid 2a (11mmol) and α-phosphinimine are added into the flask of 500mL to take
It for cinnamic acid 3a (10mmol), is reacted at 30 DEG C, reaction dissolvent 1,2- dichloroethanes (50mL), after reaction 24 hours,
Solvent 1,2- dichloroethanes are sloughed under decompression, residue column chromatographs to obtain 1.87g target compound 4a, yield 56%.
Embodiment 4
Tert-butyl isonitrile 1a (1.2mmol), benzoic acid 2a (1.1mmol) and α-phosphinimine are added into the flask of 50mL
Replace cinnamic acid 3a (1.0mmol), reacted at 30 DEG C, reaction dissolvent 1,2- dichloroethanes (10mL), is reacted 12 hours
Afterwards, solvent 1,2- dichloroethanes are sloughed under reduced pressure, and residue column chromatographs to obtain 0.117g target compound 4a, yield 35%.
Embodiment 5
Preparation
Cyclohexyl isonitrile 1b (1.2mmol), benzoic acid 2a (1.1mmol) and α-phosphinimine are added into the flask of 50mL
Replace cinnamic acid 3a (1.0mmol), is reacted at 30 DEG C, reaction dissolvent 1,2- dichloroethanes (5mL), after reaction 24 hours,
Solvent 1,2- dichloroethanes are sloughed under reduced pressure, and residue column chromatographs to obtain 0.198g target compound 4b, yield 55%.
Embodiment 6
Preparation
Tert-butyl isonitrile 1a (1.2mmol), acetic acid 2c (1.1mmol) and α-phosphinimine are added into the flask of 50mL to replace
Crotonaldehyde 3c (1.0mmol), reacts at 30 DEG C, reaction dissolvent 1,2- dichloroethanes (5mL), after reaction 24 hours, is subtracting
Solvent 1,2- dichloroethanes are sloughed in pressure, and residue column chromatographs to obtain 0.101g target compound 4c, yield 48%.
Embodiment 7
Preparation
Benzyl isonitrile 1d (1.2mmol), p-methylbenzoic acid 2d (1.1mmol) and α-phosphine are added into the flask of 50mL
Imines replaces to chlorocinnamaldehyde 3d (1.0mmol), reacts at 30 DEG C, reaction dissolvent 1,2- dichloroethanes (5mL), reaction 24
After hour, solvent 1,2- dichloroethanes are sloughed under reduced pressure, residue column chromatographs to obtain 0.213g target compound 4d, yield
51%.
Embodiment 8
Anticancer activity experiment
1. compound 4a-4d of table tests the inhibitory activity of two kinds of cancer cells
As can be seen from the above Table 1, compound represented by formula of the invention (I) is to body HepG-2 cell and lung
The growth of two class cancer cell of cancer cell A549-1 has certain inhibiting effect.It is wherein best with compound 4d effect.Its Central Plains
Because may be due to metal ion of the alkenyl imines class formation to two quasi-cancer cell target centers have the pi-conjugated effect of certain P- and
The pi-conjugated pile up effect of π-, so that the normal growth metabolism of above-mentioned two classes cell is affected, thus to above-mentioned two classes cancer cell
Growth shows certain inhibiting effect.
The above embodiments are only the preferred technical solution of the present invention, and are not construed as limitation of the invention, this Shen
Please in embodiment and embodiment in feature in the absence of conflict, can mutual any combination.Protection model of the invention
The technical solution that should be recorded with claim is enclosed, the equivalent replacement side of technical characteristic in the technical solution recorded including claim
Case is protection scope.Equivalent replacement i.e. within this range is improved, also within protection scope of the present invention.
Claims (7)
1. a kind of cyclic alkenyl radical imines medicine intermediate, which is characterized in that have the structure of logical formula (I) expression:
Wherein, R in formula1For any one in normal-butyl, tert-butyl, phenyl, cyclohexyl, benzyl, R2For for methyl, ethyl, different
Any one in propyl, n-hexyl, phenyl, substituted-phenyl or heteroaryl；R3For methyl, ethyl, isopropyl, n-hexyl, benzene
Base, substituted-phenyl or heteroaryl.
2. the preparation method of cyclic alkenyl radical imines medicine intermediate according to claim 1, which is characterized in that synthesis road
Diameter is as follows:
α-phosphinimine substituted acrylic aldehyde derivative and acid and isonitrile are sequentially added in the container equipped with anhydrous 1,2- dichloroethanes,
It is reacted at 28-30 DEG C, reacts 6-48 hours, after the reaction was completed, slough solvent under reduced pressure, residue column chromatographs to obtain general formula
(I) cyclic alkenyl radical imine compound 4.
3. the preparation method of cyclic alkenyl radical imines medicine intermediate according to claim 2, which is characterized in that described
α-phosphinimine substituted acrylic aldehyde derivative is α-phosphinimine cinnamic acid, α-phosphinimine crotonaldehyde, α-phosphinimine substitution to chlorine cortex cinnamomi
Any one in aldehyde.
4. the preparation method of cyclic alkenyl radical imines medicine intermediate according to claim 2, which is characterized in that described
Isonitrile is any one in tert-butyl isonitrile, normal-butyl isonitrile, cyclohexyl isonitrile, phenyl isonitrile or benzyl isonitrile.
5. the preparation method of cyclic alkenyl radical imines medicine intermediate according to claim 2, which is characterized in that described
Acid is benzoic acid, to any one in methyl substituted benzoic acid, formic acid, acetic acid.
6. the preparation method of cyclic alkenyl radical imines medicine intermediate according to claim 2, which is characterized in that the step
Suddenly the molar ratio of (2) α-phosphinimine substituted acrylic aldehyde derivative and acid and isonitrile is 1:0.1-3:0.1-3.
7. cyclic alkenyl radical imines analog derivative according to claim 1 inhibits human hepatoma cell HepG-2 and lung in preparation
Application on the drug of cancer cell A549-1 growth.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2039689A1 (en) * | 2006-05-26 | 2009-03-25 | Kaneka Corporation | Process for production of optically active 3-amino-2 -hydroxypropionic cyclopropylamide derivatives and salts thereof |
| JP2011051896A (en) * | 2007-12-21 | 2011-03-17 | Kaneka Corp | Method for producing n-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2039689A1 (en) * | 2006-05-26 | 2009-03-25 | Kaneka Corporation | Process for production of optically active 3-amino-2 -hydroxypropionic cyclopropylamide derivatives and salts thereof |
| JP2011051896A (en) * | 2007-12-21 | 2011-03-17 | Kaneka Corp | Method for producing n-cyclopropyl-3-amino-2-hydroxyhexanoic acid amide hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| NA LIU 等: "Odorless Isocyanide Chemistry: One-Pot Synthesis of Heterocycles via the Passerini and Postmodi fi cation Tandem Reaction Based on the in Situ Capture of Isocyanides", 《J. ORG. CHEM. 》 * |
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