CN102491932A - 3-indoline ketone derivative, and preparation method and application thereof - Google Patents
3-indoline ketone derivative, and preparation method and application thereof Download PDFInfo
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- CN102491932A CN102491932A CN201110440699XA CN201110440699A CN102491932A CN 102491932 A CN102491932 A CN 102491932A CN 201110440699X A CN201110440699X A CN 201110440699XA CN 201110440699 A CN201110440699 A CN 201110440699A CN 102491932 A CN102491932 A CN 102491932A
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Abstract
The invention specifically relates to a 3-indoline ketone derivative and a preparation method and application thereof, belonging to the field of preparation methods for novel compounds. The derivative has a structural formula as described in the specification. In the formula, R is any one selected from the group of hydrogen, halogen, nitro groups and alkoxy groups, X is any one selected from the group of halogen, alkene, carboxylic acid and ester, and Y is any one selected from the group of hydrogen, alkyl groups, carboxylic acid and ester. According to the invention, the 3-indoline ketone derivative is synthesized for the first time; the derivative possibly has good biological activity, a synthetic process for the derivative is simple, and product yield is high.
Description
Technical field
The invention belongs to new compound preparation method field, relate in particular to a kind of 3-indolinone analog derivative and preparation method thereof and application thereof.
Technical background
3-indolinone analog derivative is the medicine that directly suppresses vascular endothelial cell; Can block new vessel endotheliocyte dna replication dna; Suppress microvascular hyperplasia, it generates the factor through antagonizing vessel, the biological effect of ability specific inhibition VEGF; It is newborn to suppress intratumoral vasculature, the effect of performance high efficiency anti-tumor.This medicine can suppress the growth and the transfer of human colon carcinoma, mammary cancer and ovarian cancer transplanted tumor, and prostate cancer and schwann's sheath tumour cell are all had the effect that suppresses growth, and to not influence of normal somatic cell.Can also suppress the transfer of a lot of tumours, comprise the treatment of old advanced solid tumor and lymphoma, acute leukemia etc.
3-substituted indole-2-ketone compound is one type of effective protein proteins tyrosine kinase inhibitor; Wherein oxysuccinic acid Sutent (Sunitinibmalate) is 3-substituted indole-2-ketone protein tyrosine kinase inhibitor of being produced by Pfizer; Have antitumor and dual function angiogenesis inhibitor; Be used to treat the invalid pernicious GISTs and the metastatic renal cell cancer that maybe can not tolerate of standard care clinically by the drugs approved by FDA listing in 2006 01 month.Research shows in addition, and 3 introducing indoles methylene radical at the 3-indole-2-ketone compound have better antitumor activity.
3-indolinone analog derivative is as antineoplastic medicine of new generation; Be one type of angiogenesis inhibitor, compare that the treatment pattern that the target new vessel generates possibly mean higher specificity with the traditional treatment mode that suppresses tumor growth; Lower toxicity; And the resistance that helps overcoming tumour, accepted extensively and approve that tempting application prospect is arranged by tumour circle.Part 3-indolinone analog derivative has got into clinical and the experiment of II phase, and obtains curative effect preferably.In a word, along with the further research to the antitumor immunity of organism effect mechanism, the treatment that the indolinone analog derivative is applied to tumour patient will have more wide prospect.
Summary of the invention
The object of the present invention is to provide a kind of 3-indolinone analog derivative and preparation method thereof and application thereof.That the present invention has is simple to operate, reaction conditions is gentle, synthetic route is short, yield is higher, low cost and other advantages.
The object of the invention is realized through following technical scheme:
A kind of 3-indolinone analog derivative, general structure is following:
Wherein R is any of hydrogen, halogen, nitro, alkoxyl group;
X is any of halogen, alkene, carboxylic acid, ester;
Y is any of hydrogen, alkyl, carboxylic acid, ester.
And said R is a hydrogen.
And said X is a vinylformic acid.
And said Y is methyl or propionic acid.
And described R is a hydrogen, and X is a bromine, and Y is a methyl, is 1-methyl-3-Ben Yajiaji-4-bromo indole quinoline ketone.
And described R is a hydrogen, and X is a methyl acrylate, and Y is a methyl, is 1-methyl-3-Ben Yajiaji-4-methyl acrylate indolinone.
And described R is a hydrogen, and X is a bromine, and Y is a hydrogen, is 3-Ben Yajiaji-4-bromo indole quinoline ketone.
And described R is a hydrogen, and X is a methyl acrylate, and Y is a methyl propionate, is 1-methyl propionate-3-Ben Yajiaji-4-methyl acrylate indolinone.
And described R is a hydrogen, and X is a vinylformic acid, and Y is a propionic acid, is 1-propionic acid-3-Ben Yajiaji-4-vinylformic acid indolinone.
A kind of preparation method of 3-indolinone analog derivative, synthetic route is following:
Wherein R is any of hydrogen, halogen, nitro, alkoxyl group;
X is any of halogen, alkene;
Y is any of hydrogen, alkyl.
The application of 3-indolinone analog derivative in antitumor drug.
Advantage of the present invention and beneficial effect:
(1) synthetic first this type of 3-indolinone analog derivative of the present invention, this verivate possibly have good biological activity.
(2) to have technology simple for synthetic route of the present invention, the advantage that product yield is high.
Description of drawings
Fig. 1 is the nmr spectrum of 4-bromo indole diketone;
Fig. 2 is the nmr spectrum of 4-bromo indole quinoline ketone;
Fig. 3 is the nmr spectrum of 1-methyl-4-bromo indole quinoline ketone;
Fig. 4 is the nmr spectrum of 1-methyl-3-Ben Yajiaji-4-bromo indole quinoline ketone;
Fig. 5 is the nmr spectrum of 3-Ben Yajiaji-4-bromo indole quinoline ketone;
Fig. 6 is the nmr spectrum of 1-methyl propionate-3-Ben Yajiaji-4-methyl acrylate indolinone;
Fig. 7 is the nmr spectrum of 1-propionic acid-3-Ben Yajiaji-4-vinylformic acid indolinone.
Embodiment
In order to understand the present invention, the present invention is described further below in conjunction with embodiment; Following embodiment is illustrative, is not determinate, can not limit protection scope of the present invention with following embodiment.
The general structure of 3-indolinone analog derivative of the present invention is following:
Wherein R is any of hydrogen, halogen, nitro, alkoxyl group;
X is any of halogen, alkene, carboxylic acid, ester;
Y is any of hydrogen, alkyl, carboxylic acid, ester.
Synthetic route is following:
Embodiment 1
R is a hydrogen, and X is a methyl acrylate, and Y is a methyl, and promptly the preparation process of 1-methyl-3-Ben Yajiaji-4-methyl acrylate indolinone is following:
(1) synthetic intermediate 4-bromo indole diketone
Get 3-bromaniline 10g (0.058mol) and put into the 500mL round-bottomed flask; Add 250mL water; Under stirring state, add SODIUM SULPHATE ANHYDROUS 99PCT 63.56g (0.452mol) and oxammonium hydrochloride 13.24g (0.191mol); Add 2mol/L hydrochloric acid soln 10mL then, stirred 5 minutes under the room temperature, add Chloral Hydrate 10.6g (0.116mol) at last.With reaction mixture stirring at room 15 minutes, 90 ℃ of reaction 2h down then, TLC detects raw material and disappears behind the reaction 2h, cool off under the room temperature then, suction filtration, vacuum-drying, yellow solid 12.7g.
Get the 40mL vitriol oil and join in the 100mL round-bottomed flask, the yellow solid with 12.7g under 50 ℃ slowly joins in the vitriol oil, adds back 65 ℃ fully and reacts 30min down.Reaction finishes postcooling to room temperature, then reaction mixture is poured in the mixture of ice and water, stirs 30min; Suction filtration gets red solid, and vacuum drying oven is dry down, sherwood oil: ETHYLE ACETATE=5: 1 200-300 order silicagel column purifying; Get 4-bromo indole diketone 5.6g, productive rate 46.7%.
1H-NMR(DMSO)δ：7.962-7.945(1H，m)，7.788-7.785(1H，d)，7.400-7.385(1H，d)，5.574(1H，s).
(2) synthetic intermediate 4-bromo indole quinoline ketone
Getting 4-bromo indole diketone 5.0g (0.022mol) puts in the round-bottomed flask of 100mL; The absolute ethyl alcohol that adds 30mL; Stir under the room temperature and make its dissolving, slowly add 50% Hydrazine Hydrate 80 2.2g (0.022mol) then, reaction mixture is placed 75 ℃ of backflow 2h; After the TLC detection reaction is complete, reaction mixture is cooled to room temperature; In reaction mixture, add 1.0g sodium hydroxide again, reaction mixture refluxed is reacted 8h, after the TLC detection reaction is complete; Be cooled to room temperature, reaction mixture is poured in the mixture of ice and water, ethyl acetate extraction three times; Merge organic phase, anhydrous sodium sulfate drying, decompression is revolved and is desolvated; Sherwood oil: ETHYLE ACETATE=6: 1 200-300 order silicagel column purifying gets 4-bromo indole quinoline ketone 3.9g, productive rate 82.9%.
1H?NMR(DMSO)δ：10.606(1H，s)，7.160-7.103(2H，m)，6.827-6.806(1H，m)，3.442(2H，s).
(3) synthetic intermediate 1-methyl-4-bromo indole quinoline ketone
Get 4-bromo indole quinoline ketone 1.0g (0.0047mol) and put in the round-bottomed flask of 50mL, add 10mL N, dinethylformamide stirs under the room temperature, slowly adds Anhydrous potassium carbonate 1.95g (0.014mol) again, adds methyl iodide 1.33g (0.0094mol) again.React 4h under the room temperature, after the TLC detection reaction is complete, in reaction mixture, add the water of 10mL, ethyl acetate extraction three times merges organic phase, anhydrous sodium sulfate drying, and decompression is revolved and is desolvated; Sherwood oil: ETHYLE ACETATE=10: 1 200-300 order silicagel column purifying gets 1-methyl-4-bromo indole quinoline ketone 0.87g, productive rate 87%.
1H?NMR(CDCl
3)δ：7.183-7.174(2H，d)，6.773-6.752(1H，t)，3.470(2H，s)，3.208(3H，s).
(4) synthetic intermediate 1-methyl-3-Ben Yajiaji-4-bromo indole quinoline ketone
Get 1-methyl-4-bromo indole quinoline ketone 0.6g (0.0027mol) and put in the round-bottomed flask of 50mL, add the absolute ethyl alcohol of 15mL, add the anhydrous pyridine of 1mL again, add phenyl aldehyde 0.34g (0.0032mol) subsequently.Reaction mixture refluxed is reacted 6h, after the TLC detection reaction is complete, be cooled to room temperature, reaction mixture is poured in the mixture of ice and water, dichloromethane extraction three times merges organic phase, anhydrous sodium sulfate drying, and decompression is revolved and is desolvated; Sherwood oil: ETHYLE ACETATE=12: 1 200-300 order silicagel column purifying gets 1-methyl-3-Ben Yajiaji-4-bromo indole quinoline ketone 0.57g, productive rate 67.1%.
1H-NMR(CDCl
3)δ：8.795(1H，s)，8.104-8.081(2H，t)，7.466-7.397(3H，m)，7.262-7.241(1H，d)，7.156-7.136(1H，d)，6.808-6.788(1H，d)，3.273(3H，s).
(5) synthetic product 1-methyl-3-Ben Yajiaji-4-methyl acrylate indolinone
Get 1-methyl-3-Ben Yajiaji-4-bromo indole quinoline ketone 0.5g (0.0016mol), methyl acrylate 0.16g (0.0019mol), Pd (OAC) 2 18mg (0.8mmol); K3PO4 0.43g (0.0022mol); Join in the microwave reaction bottle, in the microwave reaction bottle, add 5mL1, the 4-dioxane.The applying argon gas protection, 120 ℃ of reaction 2h in microwave reactor.The TLC detection reaction fully after, add a spot of water, with dichloromethane extraction three times; Merge organic phase, organic phase is given a baby a bath on the third day after its birth inferior with saturated aqueous common salt, and organic phase is used anhydrous sodium sulfate drying; Decompression is revolved and is desolvated; Sherwood oil: ETHYLE ACETATE=10: 1 200-300 order silicagel column purifying gets 1-methyl-3-Ben Yajiaji-4-methyl acrylate indolinone 0.34g, productive rate 66.7%.
ESI-MS：318.4
Embodiment 2
R is a hydrogen, and X is a bromine, and Y is a hydrogen, and promptly the compound method of 3-Ben Yajiaji-4-bromo indole quinoline ketone is following:
Get 4-bromo indole quinoline ketone 1.0g (0.0047mol) and put in the round-bottomed flask of 50mL, add the absolute ethyl alcohol of 15mL, add the anhydrous pyridine of 1.5mL again, add phenyl aldehyde 0.6g (0.0057mol) subsequently.Reaction mixture refluxed is reacted 6h, after the TLC detection reaction is complete, be cooled to room temperature; Reaction mixture is poured in the mixture of ice and water, and dichloromethane extraction three times merges organic phase; Anhydrous sodium sulfate drying; Sherwood oil: ETHYLE ACETATE=10: 1 200-300 order silicagel column purifying gets 3-Ben Yajiaji-4-bromo indole quinoline ketone 1.2g, productive rate 84.5%.
1H-NMR(CDCl
3)δ：8.801(1H，s)，8.112-8.088(2H，m)，7.742(1H，s)，7.480-7.452(3H，m)，7.253-7.233(1H，d)，7.097-7.058(1H，d)，6.822-6.802(1H，d).
Embodiment 3
X is a methyl acrylate, and Y is a methyl propionate, and promptly the compound method of 1-methyl propionate-3-Ben Yajiaji-4-methyl acrylate indolinone is following:
Get 3-Ben Yajiaji-4-bromo indole quinoline ketone 1.0g (0.0033mol), methyl acrylate 0.35g (0.004mol), Pd (OAC) 253mg (1.65mmol); K3PO4 0.9g (0.0046mol); Join in the microwave reaction bottle, in the microwave reaction bottle, add 5mL1, the 4-dioxane.The applying argon gas protection, 120 ℃ of reaction 2h in microwave reactor.The TLC detection reaction fully after, add a spot of water, with dichloromethane extraction three times; Merge organic phase, organic phase is given a baby a bath on the third day after its birth inferior with saturated aqueous common salt, and organic phase is used anhydrous sodium sulfate drying; Decompression is revolved and is desolvated; Sherwood oil: ETHYLE ACETATE=15: 1 200-300 order silicagel column purifying gets 1-methyl propionate-3-Ben Yajiaji-4-methyl acrylate indolinone 0.72g, productive rate 55.4%.
1H-NMR(CDCl
3)δ：7.978-7.970(2H，d)，7.525-7.465(2H，m)，7.333-7.300(4H，m)，7.244-7.230(1H，t)，6.993-6.981(1H，d)，4.869(1H，s)，4.233-4.210(2H，t)，3.675(3H，s)，3.611(3H，s)，3.237-3.224(2H，d)，2.843-2.819(2H，t).
Embodiment 4
R is a hydrogen, and X is a vinylformic acid, and Y is a propionic acid, and promptly the compound method of 1-propionic acid-3-Ben Yajiaji-4-vinylformic acid indolinone is following:
Get 1-methyl propionate-3-Ben Yajiaji-4-methyl acrylate indolinone 0.5g (0.0013mol) and put in the round-bottomed flask of 50mL, add a spot of methyl alcohol it is dissolved fully, add 20mL 5% sodium hydroxide solution then; Place 50 ℃ of reaction 6h down, after the TLC detection reaction was complete, reaction mixture was cooled to room temperature; Reaction mixture with washed with dichloromethane three times, is collected water, slowly drip 2MHCl solution to aqueous phase; Till producing white precipitate, filter collecting precipitation, dry under the vacuum; Get 1-propionic acid-3-Ben Yajiaji-4-vinylformic acid indolinone 0.41g, productive rate 89.1%.
1H-NMR(CD
3OD)δ：8.072(1H，s)，7.972(1H，s)，7.559-7.538(1H，d)，7.492-7.454(1H，t)，7.385-7.367(2H，d)，7.331-7.293(2H，t)，7.221-7.185(1H，t)，7.094-7.077(1H，d)，4.858(1H，s)，4.196-4.161(2H，t)，2.782-2.747(2H，t).
Claims (8)
1. 3-indolinone analog derivative, it is characterized in that: the general structure of verivate is following:
Wherein R is any of hydrogen, halogen, nitro, alkoxyl group;
X is any of halogen, alkene, carboxylic acid, ester;
Y is any of hydrogen, alkyl, carboxylic acid, ester.
2. 3-indolinone analog derivative according to claim 1 is characterized in that: said R is a hydrogen.
3. 3-indolinone analog derivative according to claim 1 is characterized in that: said X is a vinylformic acid.
4. 3-indolinone analog derivative according to claim 1 is characterized in that: said Y is methyl or propionic acid.
5. 3-indolinone analog derivative according to claim 1 is characterized in that: described R is a hydrogen, and X is a bromine, and Y is a methyl.
6. 3-indolinone analog derivative according to claim 1 is characterized in that: described R is a hydrogen, and X is a methyl acrylate, and Y is a methyl; Or described R is hydrogen, and X is a bromine, and Y is a hydrogen; Or described R is hydrogen, and X is a vinylformic acid, and Y is a propionic acid; Or described R is hydrogen, and X is a methyl acrylate, and Y is a methyl propionate.
7. the preparation method of a 3-indolinone analog derivative, it is characterized in that: synthetic route is following:
Wherein R is any of hydrogen, halogen, nitro, alkoxyl group;
X is any of halogen, alkene;
Y is any of hydrogen, alkyl.
8.3-the application of indolinone analog derivative in preparing antitumor, antiviral, antibiotic or cardiovascular and cerebrovascular control medicine.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106795141A (en) * | 2014-07-08 | 2017-05-31 | Viiv保健英国有限公司 | Isoindoline derivative for treating virus infection |
| CN107151225A (en) * | 2017-06-30 | 2017-09-12 | 贵州大学 | 2 oxyindole analog derivatives, preparation method and use |
| CN114057625A (en) * | 2021-11-03 | 2022-02-18 | 五邑大学 | C2-acyloxy-3-indolinone derivative and preparation method and application thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1115640A (en) * | 1994-07-26 | 1996-01-31 | 中国医学科学院血液学研究所 | Application of 3-substituted aryl oxidized indole compounds |
| CN1155838A (en) * | 1995-06-07 | 1997-07-30 | 苏根公司 | Indolinone compounds for the treatment of disease |
| CN1439005A (en) * | 2000-02-15 | 2003-08-27 | 苏根公司 | Pyrrole substituted 2-indolinone protein kinase inhibitors |
| WO2006064044A1 (en) * | 2004-12-17 | 2006-06-22 | Boehringer Ingelheim International Gmbh | Indolinones and their use as antiproliferative agents |
-
2011
- 2011-12-26 CN CN201110440699XA patent/CN102491932A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1115640A (en) * | 1994-07-26 | 1996-01-31 | 中国医学科学院血液学研究所 | Application of 3-substituted aryl oxidized indole compounds |
| CN1155838A (en) * | 1995-06-07 | 1997-07-30 | 苏根公司 | Indolinone compounds for the treatment of disease |
| CN1439005A (en) * | 2000-02-15 | 2003-08-27 | 苏根公司 | Pyrrole substituted 2-indolinone protein kinase inhibitors |
| WO2006064044A1 (en) * | 2004-12-17 | 2006-06-22 | Boehringer Ingelheim International Gmbh | Indolinones and their use as antiproliferative agents |
Non-Patent Citations (1)
| Title |
|---|
| FUSHENG ZHOU, 等: "Synthesis and Antitumor Activities of 3-Substituted 1-(5-formylfurfuryl)indolin-2-one Derivatives", 《LETTERS IN ORGANIC CHEMISTRY》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106795141A (en) * | 2014-07-08 | 2017-05-31 | Viiv保健英国有限公司 | Isoindoline derivative for treating virus infection |
| CN107151225A (en) * | 2017-06-30 | 2017-09-12 | 贵州大学 | 2 oxyindole analog derivatives, preparation method and use |
| CN107151225B (en) * | 2017-06-30 | 2020-05-08 | 贵州大学 | 2-hydroxyindole derivatives, preparation method and application thereof |
| CN114057625A (en) * | 2021-11-03 | 2022-02-18 | 五邑大学 | C2-acyloxy-3-indolinone derivative and preparation method and application thereof |
| CN114057625B (en) * | 2021-11-03 | 2023-11-24 | 五邑大学 | C2-acyloxy-3-indolinone derivative and preparation method and application thereof |
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Application publication date: 20120613 |