CN104530065A - 1-N acyl substituent indolone derivative application - Google Patents
1-N acyl substituent indolone derivative application Download PDFInfo
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- CN104530065A CN104530065A CN201410844425.0A CN201410844425A CN104530065A CN 104530065 A CN104530065 A CN 104530065A CN 201410844425 A CN201410844425 A CN 201410844425A CN 104530065 A CN104530065 A CN 104530065A
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- dialdehyde
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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Abstract
The invention belongs to the technical field of pharmaceutical synthesis and relates to novel 1-N acyl substituent indolone derivative application. According to the 1-N acyl substituent indolone derivative application, 4-bromaniline serves as a starting material, and by means of oxime forming, cyclizing, acetal protecting and N-alkylation reacting, a 1-N acyl substituent indolone derivative with potential bioactivity is obtained for the first time and has good prospects in the field of tumor resisting.
Description
Technical field
The invention belongs to compou nd synthesis field, particularly relate to indolone derivatives and synthetic method thereof and application.
Technical background
Isatin (isatin), have another name called istain, istain has various good biological activity, as anti-convulsant activity, antiepileptic activity, antidepressant activity, Antianxiety Activity, activity of fighting against senium, anti-tumor activity, anti-microbial activity etc., be extensively studied in its research at various medicine, improvement and optimization.Be a kind of important natural product, be distributed widely in animals and plants and human body.Isatin and derivative thereof have multiple biological activity, and isatin can synthesize as industrial goods at present in a large number, are relatively cheap raw materials.Its 1, polytype chemical reaction can occur for prosposition and phenyl ring, and the synthesis for its derivative provides wide space, and therefore current is that the synthesis of the organic synthesis of substrate or isatin and derivative thereof and active research are very active with isatin.
Summary of the invention
The invention provides a kind of 1-N acyl substituted indolone derivatives and synthetic method thereof and application.
Concrete technical scheme is as follows:
1-N acyl substituted indolone derivatives, structure is as follows:
x represents any one in acyl group.
X be 4-chlorobenzene formacyl, benzoyl, 4-TRIFLUOROMETHYLBENZOYL, 4-methyl benzoyl, 4-fluoro benzoyl, 2-naphthoyl any one; R is hydrogen or bromine.
Corresponding compound is:
A) 1-(4-chlorobenzene formacyl)-(3,3-contracting dialdehyde)-5 bromo indole ketone
B) 1-benzoyl-(3,3-contracting dialdehyde)-5 bromo indole ketone
C) 1-(4-TRIFLUOROMETHYLBENZOYL)-(3,3-contracting dialdehyde)-5 bromo indole ketone
D) 1-(4-methyl benzoyl)-(3,3-contracting dialdehyde)-5 bromo indole ketone
E) 1-(4-fluoro benzoyl)-(3,3-contracting dialdehyde)-5 bromo indole ketone
F) 1-(2-naphthoyl)-(3,3-contracting dialdehyde)-5 bromo indole ketone
The synthetic method of above-mentioned 1-N acyl substituted indolone derivatives, comprises the following steps: using 4-bromaniline as starting raw material, passes through into oxime, cyclisation, acetal protection, N-alkylation, obtains final product 1-N acyl substituted indolone derivatives.
Concrete synthetic technology route is as follows:
The invention still further relates to aforementioned signature 1-N acyl substituted indolone derivatives and prepare the application in antitumor, antiviral or nerve protection medicine.
The invention provides 1-N acyl substituted indolone derivatives and synthetic method thereof and application, synthetic method is reliable, simple.
Accompanying drawing explanation
Fig. 1 embodiment 1 result figure.
Fig. 2 embodiment 2 result figure.
Fig. 3 embodiment 3 result figure.
Fig. 4 embodiment 4 result figure.
Fig. 5 embodiment 5 result figure.
Fig. 6 embodiment 6 result figure.
Fig. 7 embodiment 7 result figure.
Fig. 8 embodiment 8 result figure.
Embodiment
Embodiment 1
5-bromo indole diketone
Get 4-bromaniline 10g(0.058mol) put into 500mL round-bottomed flask, add 250 mL water, add anhydrous sodium sulphate 63.56g(0.452mol under agitation) and oxammonium hydrochloride 13.24g(0.191mol), then 2mol/L hydrochloric acid soln 10 mL is added, stirred at ambient temperature 5 minutes, finally adds Chloral Hydrate 10.6g(0.116mol).By reaction mixture stirring at room temperature 15 minutes, then react 2h at 90 DEG C, after reaction 2h, TLC detects raw material and disappears, and then cools under room temperature, suction filtration, vacuum-drying, obtains yellow solid 13.4g.
Getting the 40mL vitriol oil joins in 100mL round-bottomed flask, is slowly joined in the vitriol oil by the yellow solid of 13.4g at 50 DEG C, reacts 30min at adding latter 65 DEG C completely.Be cooled to room temperature after reaction terminates, be then poured in mixture of ice and water by reaction mixture, stir 30min, suction filtration obtains red solid, dry under vacuum drying oven, obtains 5-bromo indole diketone 11.4g 84%.For red solid.
1H NMR(DMSO 400 MHz)δ：11.137（1H,s）,7.757-7.730(1H,t),7.666-7.661(1H,d),6.891-6.870(1H,d).
Fig. 1 is shown in by concrete collection of illustrative plates.
Embodiment 2
(3,3-contracting dialdehyde)-5-bromo indole ketone
Get 5-bromo indole diketone 10.0g(0.044mol) put in 250mL round-bottomed flask, add 125mL toluene, then add ethylene glycol 13.36g(0.221mol) and p-methyl benzenesulfonic acid 1.26g(0.07mol).Water trap is used to react 6h at 130 DEG C, after reaction 6h, TLC detects raw material disappearance, be cooled to room temperature, add 50mL water, then extraction into ethyl acetate (100mL × 3), merges organic phase, anhydrous sodium sulfate drying, decompression revolves desolventizing, sherwood oil: ethyl acetate=10:1 200-300 order silica column purification.Obtain (3,3-contracting dialdehyde)-5-bromo indole ketone 11.0g 91.6%.
1H-NMR(CDCl
3400 MHz)δ : 8.126(1H,s),7.190-7.125(2H,t),6.776-6.754(1H,t),4.587-4.554(2H,t),4.460-4.27(2H, t)。
Fig. 2 is shown in by concrete collection of illustrative plates.
Embodiment 3
1-(4-chlorobenzene formacyl)-(3,3-contracting dialdehyde)-5 bromo indole ketone
By (3, 3-contracting dialdehyde)-5-bromo indole ketone 0.50 g (1.85 mmol) is dissolved in dry methylene dichloride, triethylamine 0.37 g (7.40 mmol) is added under ice bath, parachlorobenzoyl chloride 0.38 g (2.20 mmol) is dropwise added after stirring 5 min, room temperature reaction 4 h, after TLC detection reaction is complete, the water of 15 mL is added in reaction mixture, with dichloromethane extraction 3 times, merge organic relevant dry, with sherwood oil: ethyl acetate=10:1, 200 order purification by silica gel column chromatography, obtain 1-(4-chlorobenzene formacyl)-(3, 3-contracting dialdehyde)-5 bromo indole ketone, for white solid, yield 54%.
1H NMR (CDCl
3400 MHz): δ/ppm 4.390-4.356(m, 2H), 4.534-4.501 (m, 2H), 7.490-7.468 (d, 2H), 7.683-7.632 (m, 4H), 7.837-7.814 (d, 1H).
Fig. 3 is shown in by concrete collection of illustrative plates.
Embodiment 4
1-benzoyl-(3,3-contracting dialdehyde)-5 bromo indole ketone
By (3, 3-contracting dialdehyde)-5-bromo indole ketone 0.50 g (1.85 mmol) is dissolved in dry methylene dichloride, triethylamine 0.37 g (7.40 mmol) is added under ice bath, Benzoyl chloride 0.31 g (2.20 mmol) is dropwise added after stirring 5 min, room temperature reaction 4 h, after TLC detection reaction is complete, the water of 15 mL is added in reaction mixture, with dichloromethane extraction 3 times, merge organic relevant dry, with sherwood oil: ethyl acetate=10:1, 200 order purification by silica gel column chromatography, obtain 1-benzoyl-(3, 3-contracting dialdehyde)-5 bromo indole ketone, for white solid, yield 60%.
1H NMR (CDCl
3400 MHz): δ/ppm 4.387-4.365 (m, 2H), 4.539-4.517 (m, 2H), 7.528-7.502 (t, 2H), 7.655-7.632 (m, 3H), 7.749-7.735 (t, 2H),7.850-7.835 (d, 1H).
Fig. 4 is shown in by concrete collection of illustrative plates.
Embodiment 5
1-(4-TRIFLUOROMETHYLBENZOYL)-(3,3-contracting dialdehyde)-5 bromo indole ketone
By (3, 3-contracting dialdehyde)-5-bromo indole ketone 0.50 g (1.85 mmol) is dissolved in dry methylene dichloride, triethylamine 0.37 g (7.4 mmol) is added under ice bath, 4-trifluoromethyl benzoyl chloride 0.46 g (2.2 mmol) is dropwise added after stirring 5 min, room temperature reaction 4 h, after TLC detection reaction is complete, the water of 15 mL is added in reaction mixture, with dichloromethane extraction 3 times, merge organic relevant dry, with sherwood oil: ethyl acetate=10:1, 200 order purification by silica gel column chromatography, obtain 1-(4-TRIFLUOROMETHYLBENZOYL)-(3, 3-contracting dialdehyde)-5 bromo indole ketone, for white solid, yield 55%.
1H NMR (CDCl
3400 MHz): δ/ppm 4.385-4.351(m, 2H), 4.512-4.479 (m, 2H), 7.665-7.642 (t, 2H), 7.812-7.748 (m, 4H), 7.926-7.902 (m, 1H).
Fig. 5 is shown in by concrete collection of illustrative plates.
Embodiment 6
1-(4-methyl benzoyl)-(3,3-contracting dialdehyde)-5 bromo indole ketone
By (3, 3-contracting dialdehyde)-5-bromo indole ketone 0.50 g (1.85 mmol) is dissolved in dry methylene dichloride, triethylamine 0.37 g (7.40 mmol) is added under ice bath, dropwise add methyl benzoyl chloride 0.34 g (2.20 mmol) after stirring 5 min, room temperature reaction 4 h, after TLC detection reaction is complete, the water of 15 mL is added in reaction mixture, with dichloromethane extraction 3 times, merge organic relevant dry, with sherwood oil: ethyl acetate=10:1, 200 order purification by silica gel column chromatography, obtain 1-(4-methyl benzoyl)-(3, 3-contracting dialdehyde)-5 bromo indole ketone, for white solid, yield 65%.
1H NMR (CDCl
3400 MHz): δ/ppm 2.482 (s, 2H), 4.382-4.349 (m, 2H), 4.545-4.512 (m, 2H), 7.316-7.295(d, 2H), 7.666-7.609 (m, 4H), 7.787-7.764(d, 1H).
Fig. 6 is shown in by concrete collection of illustrative plates.
Embodiment 7
1-(4-fluoro benzoyl)-(3,3-contracting dialdehyde)-5 bromo indole ketone
By (3, 3-contracting dialdehyde)-5-bromo indole ketone 0.50 g (1.85 mmol) is dissolved in dry methylene dichloride, triethylamine 0.37 g (7.40 mmol) is added under ice bath, 4-fluorobenzoyl chloride 0.35 g (2.2 mmol) is dropwise added after stirring 5 min, room temperature reaction 4 h, after TLC detection reaction is complete, the water of 15 mL is added in reaction mixture, with dichloromethane extraction 3 times, merge organic relevant dry, with sherwood oil: ethyl acetate=10:1, 200 order purification by silica gel column chromatography, obtain 1-(4-fluoro benzoyl)-(3, 3-contracting dialdehyde)-5 bromo indole ketone, for white solid, yield 67%.
1H NMR (CDCl
3400 MHz): δ/ppm 4.330-4.364(m, 2H), 4.458-4.492 (m, 2H), 7.623-7.648 (t, 2H), 7.725-7.788 (m, 4H), 7.886-7.909 (d, 1H).
Fig. 7 is shown in by concrete collection of illustrative plates.
Embodiment 8
1-(2-naphthoyl)-(3,3-contracting dialdehyde)-5 bromo indole ketone
By (3, 3-contracting dialdehyde)-5-bromo indole ketone 0.50 g (1.85 mmol) is dissolved in dry methylene dichloride, triethylamine 0.37 g (7.40 mmol) is added under ice bath, 2-naphthoyl chloride 0.43 g (2.20 mmol) is dropwise added after stirring 5 min, room temperature reaction 4 h, after TLC detection reaction is complete, the water of 15 mL is added in reaction mixture, with dichloromethane extraction 3 times, merge organic relevant dry, with sherwood oil: ethyl acetate=10:1, 200 order purification by silica gel column chromatography, obtain 1-(2-naphthoyl)-(3, 3-contracting dialdehyde)-5 bromo indole ketone, for white solid, yield 51%.
1H NMR (CDCl
3400 MHz): δ/ppm 4.230-4.258(m, 2H), 4.289-4.347 (m, 2H), 7.239-7.242 (d, 3H), 7.497-7.535 (m, 3H), 7.592-7.677 (m, 1H), 7.894-7.914(m, 2H), 7.985-8.157 (m, 1H).
Fig. 8 is shown in by concrete collection of illustrative plates.
Embodiment 9 growth inhibitory activity to tumor cell tests
IC50 i.e. half inhibiting rate, and typical curve is a S type curve.IC50 is the concentration corresponding to check sample one half for 50% inhibition concentration and cell survival amount, and half suppresses lower, illustrates that the toxicity of medicine to cell is higher.
Take off row compound solution:
A) 1-(4-chlorobenzene formacyl)-(3,3-contracting dialdehyde)-5 bromo indole ketone; B) 1-benzoyl-(3,3-contracting dialdehyde)-5 bromo indole ketone; C) 1-(4-TRIFLUOROMETHYLBENZOYL)-(3,3-contracting dialdehyde)-5 bromo indole ketone; D) 1-(4-methyl benzoyl)-(3,3-contracting dialdehyde)-5 bromo indole ketone; E) 1-(4-fluoro benzoyl)-(3,3-contracting dialdehyde)-5 bromo indole ketone; F) 1-(2-naphthoyl)-(3,3-contracting dialdehyde)-5 bromo indole ketone; , be adjusted to suitable concentration for subsequent use.
Get K562, HePG2 as cell to be measured, add above-claimed cpd solution measures cell IC according to ordinary method
50 value.Obtain result as follows:
Result shows, 1-N acyl substituted indolone derivatives of the present invention has good suppression human liver cancer cell HePG2, K562 cell growth effect.
Embodiment 9
By a) 1-(4-chlorobenzene formacyl)-(3,3-contracting dialdehyde)-5 bromo indole ketone; B) 1-benzoyl-(3,3-contracting dialdehyde)-5 bromo indole ketone; C) 1-(4-TRIFLUOROMETHYLBENZOYL)-(3,3-contracting dialdehyde)-5 bromo indole ketone; D) 1-(4-methyl benzoyl)-(3,3-contracting dialdehyde)-5 bromo indole ketone; E) 1-(4-fluoro benzoyl)-(3,3-contracting dialdehyde)-5 bromo indole ketone; F) 1-(2-naphthoyl)-(3,3-contracting dialdehyde)-5 bromo indole ketone;
Add common drug auxiliary material respectively, make conventional medicine tablet.
Claims (1)
1.1-N acyl substituted indolone derivatives is preparing the application in antitumor drug; Described 1-N acyl substituted indolone derivatives structure is as follows:
, X represents any one in 4-chlorobenzene formacyl, benzoyl, 4-TRIFLUOROMETHYLBENZOYL, 4-methyl benzoyl, 4-fluoro benzoyl or 2-naphthoyl.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1079464A (en) * | 1991-12-18 | 1993-12-15 | 阿斯特拉公司 | Treatment comprises the preparation method of the valuable indolone of illness of cholinergic function reduction and the derivative of indole dione |
| WO1994029272A1 (en) * | 1993-06-16 | 1994-12-22 | Astra Aktiebolag | 1-substituted isatin and oxindole derivatives as inhibitors of acetylcholinesterase |
| CN1350523A (en) * | 1999-05-04 | 2002-05-22 | 美国家庭用品有限公司 | Indoline derivatives as progesterohe antagonists |
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2013
- 2013-05-13 CN CN201410844425.0A patent/CN104530065A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1079464A (en) * | 1991-12-18 | 1993-12-15 | 阿斯特拉公司 | Treatment comprises the preparation method of the valuable indolone of illness of cholinergic function reduction and the derivative of indole dione |
| WO1994029272A1 (en) * | 1993-06-16 | 1994-12-22 | Astra Aktiebolag | 1-substituted isatin and oxindole derivatives as inhibitors of acetylcholinesterase |
| CN1350523A (en) * | 1999-05-04 | 2002-05-22 | 美国家庭用品有限公司 | Indoline derivatives as progesterohe antagonists |
Non-Patent Citations (1)
| Title |
|---|
| BIN ZENG，等: "Design, Synthesis and biological activity evaluation of novel N-Acylation substituted isatin derivatives", 《ADVANCED MATERIALS RESEARCH》 * |
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Application publication date: 20150422 |