CN106188007B - A kind of 3- piperidyls -4- indolylmaleimides class compounds and its preparation and application - Google Patents
A kind of 3- piperidyls -4- indolylmaleimides class compounds and its preparation and application Download PDFInfo
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
The present invention relates to a kind of 3 piperidyl, 4 indolylmaleimides class compounds and its preparation and application, structural formula of compound to be：R is ester group.It prepares：3 indolylmaleimides, piperidines, catalyst are added in solvent, at 110 120 DEG C heating reaction 10 for 24 hours, purification to get.Compound is preparing the application in preventing or treating the drug of tumour.The compound of the present invention is a kind of novel protein kinase C inhibitor, can be applied to prepare the drug for preventing or treating tumour, preparation method of the present invention is simple, and high income is produced on a large scale.
Description
Technical field
The invention belongs to indolylmaleimides class compound and its preparation and application field, more particularly to a kind of 3- piperidines
Base -4- indolylmaleimides class compounds and its preparation and application.
Background technology
In recent years, with the increasingly raising of people's living standard, modernization of industry process accelerates, and chemicals is in food, change
The fields such as cosmetic and material be widely used and the aggravation of environmental pollution, gastric cancer, lung cancer, leukaemia and breast cancer etc. are pernicious
The incidence of tumour is in ascendant trend year by year.Currently, the antitumor drug used in clinic such as cyclophosphamide
(Cyclophosphamide), cis-platinum (Cisplatin), doxifluridine (Doxifluridine) and methotrexate (MTX)
(methotrexate) etc. all there is toxicity greatly and the shortcomings of lack broad-spectrum anti-tumor effect.
In recent years, with the rapid development of oncobiology and related discipline, it was recognized that the essence of cell carcinogenesis is
Cell infinite multiplication caused by the imbalance of intracellular signal transduction pathway, the thing followed be antitumor drug research and development and focus just
It is transferred to the specificity antitumor drug of new generation for abnormal signal system target site in tumour cell from conventional cell poison.Such as
Drug Imatinib (Imatinib), the Ji Fei for acting on epidermal growth factor tyrosine kinase (tyrosine kinase) are replaced
Buddhist nun (Gefitinib), Tarceva (Erlotinib) and Ursula are for Buddhist nun (Sorafenib) etc..Act on serine/threonine
Protein kinase C (protein kinaseC, PKC) be another kind of protein kinase family, be a kind of Ca2+, phosphatide dependence egg
White kinases plays critically important effect during cell transmembrane signaling.Have now found that PKC have 12 hypotypes (Newton,
A.C.J.Biol.Chem.1995,270,28495.), under normal circumstances, PKC is in inactivated state, when by environmental stimuli,
PKC is activated.A series of evidences show that the generation of the diseases such as cancer is all related with the unconventionality expression of PKC.
With staurosporine (Staurosporine) in microorganism Streptomyces sp. metabolins for lead compound
It is a kind of novel inhibitors of protein kinase C to carry out the indolylmaleimides class compound that structural modification obtains.Bioactivity
Studies have shown that such compound can inhibit PKC active, there are the multiple biological activities such as antitumor.Such as compound Enzastaurin
The III phases clinical research for being currently under treatment B cell leukemia and non-Hodgkin lymphoma etc. (such as sees following documents
Jirousek,M.R.；Giling,J.R.；Gonzalea,C.M.；et.al.,J.Med.Chem.,1996,39,2664；
Robertson,M.J.；Kahl,B.S.；Vose,J.M.；et.al.,J.Clin.Oncol.,2007,25,1741；Tanaka,
M.；Sagawa,S.；Hoshi,J.；et.al.,Bioorg.Med.Chem.Lett.,2006,16,5781).
Schultz in 1991 etc. reports 4- (3- indoles) maleimide compound with antiallergic action and is immunized
Therapeutic effect (Schultz, M.；Tsaklakidis,R.；Haag,R.；Et.al.DE4005970,1991), report in that patent
Road 3- acetylaminohydroxyphenylarsonic acid 4- indoles-N- methyl maleimide compounds.In recent years, document also reported that some 3- amino take
The indolylmaleimides class compound in generation, which has, inhibits H2O2The necrotic cell death of induction and the activity for inhibiting GSK-3
(Tanaka,M.；Sagawa,S.；Hoshi,J.；et.al.Bioorg.Med.Chem.Lett.,2004,14,5171；
Tanaka,M.；Sagawa.S.；Hoshi,J.；et.al.Bioorg.Med.Chem.Lett.,2006,16,5781).3- amino
Substituted indolylmaleimides class compound also has stronger antitumor activity (Ilovich, O.；Billauer,H.；
Dotan,S.；et.al..Bioorg.Med.Chem.,2010,18,612-620；Zhao,S.Y.；Yang,Y.W.；Zhang,
H.Q.；Yue,Y.；Fan,M.Arch.Pharm.Res.,2011,34,519-526).But Malaysia acyl in the compound of document report
3- majorities of imide ring be the aromatic ring structures such as aromatic rings such as indoles, phenyl ring or 3- be directly amino substitution compound, and 3-
Position is connected with the Indolylmaleimide compound of piperidine structure there is not yet document report.It is furtherd investigate to find to live
The good antitumor drug of property is of great significance to the prevention and treatment of tumor disease.
Invention content
Technical problem to be solved by the invention is to provide a kind of 3- piperidyls -4- indolylmaleimides class compounds and
It is prepared and application, and preparation method of the present invention is simple, and high income is produced on a large scale.
A kind of 3- piperidyls -4- indolylmaleimides class compounds of the present invention, the structural formula of compound are：
R is ester group.
The R is-COOC2H5, entitled：3- [3- (ethoxycarbonyl) piperidin-1-yl] -4- (1H- indol-3-yls) -
1H- pyrrole-2,5-diones；The structural formula of compound is：
Or, entitled：3- [4- (ethoxycarbonyl) piperidin-1-yl] -4- (1H- indol-3-yls) -1H- pyrroles -2,5- two
Ketone；The structural formula of compound is：
Selected objective target compound is 3- [3- (ethoxycarbonyl) piperidin-1-yl] -4- (1H- indol-3-yls) -1H- pyrroles -
2,5- diketone and 3- [4- (ethoxycarbonyl) piperidin-1-yl] -4- (1H- indol-3-yls) -1H- pyrrole-2,5-diones.
A kind of preparation method of 3- piperidyls -4- indolylmaleimides class compounds of the present invention, including：
(1) indoles and maleimide are dissolved in solvent, boron trifluoride ether BF is added3.Et2O is stirred back at 90 DEG C
Stream reaction 3-5h, purification obtain 3- indoles succinimides；Wherein mole of indoles, maleimide and boron trifluoride ether
Than being 1:1.0~1.5:0.2~1.0；
(2) 3- indoles succinimide, 2,3-, bis- chloro- 4,5- dicyano benzoquinones DDQ are dissolved in solvent respectively, are mixed,
12-24h is stirred at room temperature, purifies, obtains 3- indolylmaleimides；Wherein 3- indoles succinimide, DDQ, solvent ratios are closed
System is 1mol:1.0~1.5mol:3~20mL；
(3) 3- indolylmaleimides, piperidines, catalyst are added in solvent, are heated at 110-120 DEG C anti-
10-24h is answered, is purified to get 3- piperidyl -4- indolylmaleimides class compounds；Wherein 3- indolylmaleimides, piperidines
Class compound, catalyst total amount molar ratio be 1:1~2:0.2~1:0.2~1.
Solvent is 1,2- dichloroethanes in the step (1).
The ratio of indoles and solvent is 1.0g in the step (1):3~20mL.
It is purified in the step (1) and is：H is added2O stirs 5~20min, and ethyl acetate extracts, then molten through being saturated NaCl
Liquid washing, anhydrous Na2SO4Dry, concentration, recrystallization, recrystallization solvent are 95% ethyl alcohol.
The ratio of water, ethyl acetate and indoles is 3-10mL in purification in step (1):5-10mL:1g.
Solvent is 1,4- dioxane in the step (2)；Purification is：Filtering filters off residue, and concentration filtrate removes solvent,
Ethyl acetate extracts, then through saturated common salt water washing, anhydrous Na2SO4Dry, concentration, recrystallization, recrystallization solvent are 95% second
Alcohol.
The ratio of water, ethyl acetate and 3- indoles succinimides is 3-10mL in purification in step (2):5-
10mL:1g。
Catalyst is copper acetate and/or silver carbonate in the step (3)；Piperidines are piperidines -3- Ethyl formates
Or piperidine-4-ethyl formate；Solvent is chlorobenzene.
The ratio of solvent and 3- indolylmaleimides is 3-10mL in step (3):5-10mL:1g.
3- indolylmaleimides in step (3), piperidines, copper acetate and silver carbonate molar ratio be 1:1
~2:0.2~1:0.2~1.
The step (3) purifies：Water is added to stir, ethyl acetate extraction, organic phase anhydrous Na2SO4Drying boils off molten
Agent then recrystallizes, and recrystallization solvent is 95% ethyl alcohol.
The ratio of water, ethyl acetate and 3- indolylmaleimides in step (3) is 3-10mL:5-10mL:1g.
A kind of 3- piperidyls -4- indolylmaleimides class compounds of the present invention are preparing the medicine for preventing or treating tumour
Application in object.
Using indoles and maleimide as raw material, 3- indoles ambers are obtained by the reaction at 90 DEG C under boron trifluoride ether effect
Amber acid imide, and after through DDQ aoxidize prepare 3- indolylmaleimides, finally copper acetate and silver carbonate catalysis system with piperidines first
The anti-raw aminating reaction of acetoacetic ester prepares kind of a 3- piperidyl -4- indolylmaleimides class compounds, and total recovery is closed up to 30% or more
It is as follows at route：
The compound 3- piperidyl -4- Indolylmaleimide compounds that the present invention obtains are a kind of novel protein kinase C
Inhibitor, research find that the compound has antitumor activity to cervical cancer Hela cells and liver cancer SMMC7721 etc. in vitro,
10-6Inhibiting rate is up to 60% or more under M.
Advantageous effect
(1) the compound of the present invention 3- piperidyls -4- Indolylmaleimide compounds are a kind of novel protein kinase C suppressions
Preparation can be applied to prepare prevention or tumor；
(2) preparation method of the invention is simple, and high income is produced on a large scale.
Description of the drawings
Fig. 1 is compound 3- [3- (ethoxycarbonyl) piperidin-1-yl] -4- (1H- indol-3-yls) -1H- pyrroles -2,5-
The nuclear magnetic resonance spectroscopy of diketone；
Fig. 2 is compound 3- [3- (ethoxycarbonyl) piperidin-1-yl] -4- (1H- indol-3-yls) -1H- pyrroles -2,5-
The carbon-13 nmr spectra of diketone.
Specific implementation mode
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In addition, it should also be understood that, after reading the content taught by the present invention, people in the art
Member can make various changes or modifications the present invention, and such equivalent forms equally fall within the application the appended claims and limited
Range.
Embodiment 1
The preparation of 3- (1H- indol-3-yls) -1H- pyrrolidine-2,5-diones
Indoles 11.7g (0.1mol), maleimide 10.7g (0.11mol) are sequentially added in 250mL round-bottomed flasks,
1,2- dichloroethanes 100mL, boron trifluoride ether 2.8g (0.02mol), back flow reaction 3h at 90 DEG C of oil bath.Reaction finishes, cold
But to room temperature, adding water 100mL, stir 10min, ethyl acetate extracts (200mL × 1), is washed with water organic layer (50mL × 3),
Saturated common salt water washing (50mL × 1), organic layer anhydrous Na2SO4It is dried overnight, after being spin-dried for solvent, 95% ethyl alcohol recrystallization,
Obtain white solid 20.3g, yield 95%, m.p.:192~194 DEG C.
IR(KBr):3425,3139,3056,2782,1770,1707,1554,1456,743cm-1。1H NMR(400MHz,
DMSO-d6):δ=2.76 (dd, J=18.0Hz, 5.6Hz, 1H, CH2), 3.18 (dd, J=18.0,9.5Hz, 1H, CH), 4.34
(dd, J=9.5Hz, 4.7Hz, 1H, CH2), 7.00 (t, J=7.2Hz, 1H, Ar-H), 7.10 (t, J=7.0Hz, 1H, Ar-H),
7.32 (s, 1H, Ar-H), 7.37 (d, J=7.8Hz, 1H, Ar-H), 7.42 (d, J=7.7Hz, 1H, Ar-H), 11.01 (s, 1H,
N-H), 11.28 (s, 1H, N-H).MS(EI,m/z):214[M+],162,156,143,115,105,89.
Embodiment 2
The preparation of 3- (1H- indol-3-yls) -1H- pyrrole-2,5-diones
3- (1H- indol-3-yls) -1H- pyrrolidine-2,5-diones prepared by embodiment 1 are added in 250mL round-bottomed flasks
5.35g (0.025mol), dioxane 60mL, stirring make solid all dissolve.5.68g (0.025mol) 2,3- bis- chloro- 4 is taken,
5- dicyano benzoquinones (DDQ) are dissolved in 60mL dioxane, are slowly added dropwise in above-mentioned solution, are stirred to react at room temperature for 24 hours.
Reaction finishes, and filtering filters off insoluble matter, filtrate steaming removal solvent, and solid adds ethyl acetate (200mL) fully to dissolve, and extracts, washing
Organic layer (50mL × 2), saturated common salt water washing (50mL × 1), organic layer pour into conical flask, anhydrous Na2SO4It is dried overnight,
95% ethyl alcohol recrystallization obtains yellow solid 4.6g, yield 87%, m.p.:224~226 DEG C of .IR (KBr):3433,3347,
3240,3057,1751,1702,1601,740cm-1.1H NMR(400MHz,DMSO-d6) δ 6.81 (s, 1H), 7.24 (dt, J=
22.2,7.3Hz, 2H), 7.53 (d, J=7.8Hz, 1H), 7.98 (d, J=7.8Hz, 1H), 8.38 (s, 1H), 10.78 (s,
1H),12.04(s,1H)；13C NMR(101MHz,DMSO-d6):δ105.80,113.01,115.73,120.83,121.85,
123.42,126.05,131.37,137.12,139.92,173.62,173.80；MS(EI):M/z=212 [M]+,184,156,
141,128,122,114。
Embodiment 3
The preparation of 3- (1H- indol-3-yls) -1H- pyrrole-2,5-diones
3- (1H- indol-3-yls) -1H- pyrrolidine-2,5-diones prepared by embodiment 1 are added in 250mL round-bottomed flasks
4.28g (0.02mol), dioxane 50mL, stirring make solid all dissolve.Take bis- chloro- 4,5- of 6.81g (0.03mol) 2,3-
Dicyano benzoquinone (DDQ) is dissolved in 50mL dioxane, is slowly added dropwise in above-mentioned solution, is stirred to react 12h at room temperature.Instead
It should finish, filtering filters off insoluble matter, filtrate steaming removal solvent, and solid adds ethyl acetate (120mL) fully to dissolve, and extraction, washing has
Machine layer (50mL × 2), saturated common salt water washing (50mL × 1), organic layer pour into conical flask, anhydrous Na2SO4It is dried overnight, 95%
Ethyl alcohol recrystallization obtains yellow solid 3.94g, yield 93%, m.p.:224~226 DEG C of
Embodiment 4
The preparation of 3- [3- (ethoxycarbonyl) piperidin-1-yl] -4- (1H- indol-3-yls) -1H- pyrrole-2,5-diones
3- (1H- indol-3-yls) -1H- pyrrole-2,5-diones are taken (to obtain) 0.32g (1.5mmol), piperazine in embodiment 2
Pyridine -3- Ethyl formates 0.47g (3.0mmol), copper acetate 0.05g (0.3mmol), silver carbonate 0.08g (0.3mmol) are added extremely
In 25mL round-bottomed flasks, chlorobenzene 5mL is then added, is heated to 120 DEG C of stirrings for 24 hours, reaction is finished, and water 10mL is added, and is stirred 5 minutes,
Ethyl acetate 50mL × 3 is extracted, and organic phase is dried with anhydrous sodium sulfate, boils off solvent, Exocarpium Citri Rubrum is obtained with 95% ethyl alcohol recrystallization
Color solid 0.29g, yield 58%, m.p:182-184℃.IR(KBr):3312,3051,2939,2856,1700,1624,
1533,1442,1343,1267,1232,1183,1106,1018,745,659cm-1；1H NMR(400MHz,CDCl3)δ1.20
(t, J=6.9Hz, 3H), 1.50 (dd, J=22.4,10.8Hz, 1H), 1.70-1.59 (m, 2H), 2.00 (d, J=11.4Hz,
1H), 2.59 (s, 1H), 3.08 (t, J=11.6Hz, 1H), 3.30 (t, J=11.4Hz, 1H), 3.84 (d, J=12.7Hz,
1H), 4.09 (q, J=6.7Hz, 2H), 4.28 (d, J=13.1Hz, 1H), 7.24-7.12 (m, 3H), 7.34 (d, J=7.7Hz,
1H), 7.49 (d, J=7.5Hz, 1H), 7.66 (s, 1H), 8.77 (s, 1H)；13C NMR(101MHz,CDCl3)δ14.09,
24.67,26.82,41.68,48.68,49.88,60.64,101.79,105.44,111.55,120.01,120.24,
122.36,125.48,127.74,135.86,143.57,168.52,171.62,173.10；MS(EI):M/z=367 [M]+,
338,322,294,266,238,168,140,127,114。HRMS(EI):m/z[M]+calcd for C20H21N3O4,
367.1532；found,367.1530.
Embodiment 5
The preparation of 3- [4- (ethoxycarbonyl) piperidin-1-yl] -4- (1H- indol-3-yls) -1H- pyrrole-2,5-diones
3- (1H- indol-3-yls) -1H- pyrrole-2,5-diones are taken (to obtain) 0.32g (1.5mmol), piperazine in embodiment 2
Pyridine -4- Ethyl formates 0.47g (3.0mmol), copper acetate 0.05g (0.3mmol), silver carbonate 0.08g (0.3mmol) are added extremely
In 25mL round-bottomed flasks, chlorobenzene 5mL is then added, is heated to 120 DEG C of stirrings for 24 hours, reaction is finished, and water 10mL is added, and is stirred 5 minutes,
Ethyl acetate 50mL × 3 is extracted, and organic phase is dried with anhydrous sodium sulfate, boils off solvent, 95% ethyl alcohol recrystallization obtains Chinese red
Solid 0.26g, yield 46%, m.p.：164-166℃.IR(KBr):3320,3052,2969,2857,1700,1623,1533,
1444,1343,1267,1184,1097,1039,938,895,746,659cm-1；1H NMR(400MHz,CDCl3)δ1.24(t,
J=7.0Hz, 3H), 1.86-1.70 (m, 4H), 2.44 (d, J=8.5Hz, 1H), 3.07 (t, J=12.0Hz, 2H), 4.23-
4.08 (m, 4H), 7.28-7.09 (m, 3H), 7.36 (d, J=7.8Hz, 1H), 7.50 (d, J=7.5Hz, 1H), 7.58 (s,
1H),8.69(s,1H)；13C NMR(101MHz,CDCl3)δ14.18,28.36(2C),40.52,47.58(2C),60.63,
101.32,105.60,111.53,120.07,120.29,122.42,125.40,127.82,135.81,143.48,168.52,
171.49,174.28；HRMS(EI):m/z[M]+calcd for C20H21N3O4,367.1532；found,367.1530.
Embodiment 6
The preparation of 3- [4- (ethoxycarbonyl) piperidin-1-yl] -4- (1H- indol-3-yls) -1H- pyrrole-2,5-diones
3- (1H- indol-3-yls) -1H- pyrrole-2,5-diones are taken (to obtain) 0.32g (1.5mmol), piperazine in embodiment 3
Pyridine -4- Ethyl formates 0.47g (3.0mmol), silver carbonate 0.08g (0.3mmol), silver carbonate 0.08g (0.3mmol) are added extremely
In 25mL round-bottomed flasks, chlorobenzene 10mL is then added, is heated to 120 DEG C of stirrings for 24 hours, reaction is finished, and water 10mL is added, and is stirred 5 minutes,
Ethyl acetate 50mL × 3 is extracted, and organic phase is dried with anhydrous sodium sulfate, boils off solvent, 95% ethyl alcohol recrystallization obtains Chinese red
Solid 0.24g, yield 43%, m.p.：164-166℃.
Embodiment 7
Antitumor activity screening is tested
3- piperidyl -4- Indolylmaleimide compounds are detected in vitro culture human cervical carcinoma Hela cell with mtt assay
With the inhibiting effect of liver cancer SMMC7721, assay method and condition are as follows：
Screening technique：Mtt assay
Cell strain：Human cervical carcinoma Hela cell's strain and liver cancer SMMC7721 cell strains
Operating procedure：
It takes and is in one bottle of the good cell of exponential phase of growth growth conditions, 0.25% trypsin digestion is added, makes adherent
Cell detachment is made every milliliter and contains 2 × 104~4 × 104The suspension of cell is inoculated in 96 orifice plates, per 150 μ L of hole, sets 5%
CO272h is cultivated in 37 DEG C in incubator, 5mg/mL MTT [3- (4,5- dimethyl -2- thiazolyls) -2,5- dibromos are added per hole
Benzene bromination tetrazole] solution 100 μ L DMSO Rong Xie Jia Za (formazan) crystallization, after micro oscillator mixing, use microplate reader
It is absorbing wavelength in 492nm, 630nm is that reference wavelength measures optical density, calculates the inhibiting rate of compound on tumor cell growth.
Pharmacological experiments show 1 × 10-5Under mol/L concentration, selected objective target compound 3- (3- group-4 ethyl formate piperazines
Pyridine -1- bases) -4- (1H- indol-3-yls) -1H- pyrrole-2,5-diones and 3- (4- group-4 ethyl formates piperidin-1-yl) -4- (1H-
Indol-3-yl) -1H- pyrrole-2,5-diones have certain inhibition to live cervical cancer Hela cells and liver cancer SMMC7721 cells
Property, inhibiting rate is respectively 68.5% and 52.2%, compound (3- (3- group-4 ethyl formates piperidin-1-yl) -4- (1H- indoles -3-
Base) -1H- pyrrole-2,5-diones and 3- (4- group-4 ethyl formates piperidin-1-yl) -4- (1H- indol-3-yls) -1H- pyrroles -2,5-
Diketone) it is respectively 45.6% and 58.3% to the inhibiting rate of cervical cancer Hela cells and liver cancer SMMC7721 cells.Positive control
Medicine bisindole maleimide is respectively 30.2% He to the inhibiting rate of cervical cancer Hela cells and liver cancer SMMC7721 cells
37.5%.
Claims (9)
1. a kind of 3- piperidyls -4- indolylmaleimides class compounds, it is characterised in that：The structural formula of compound is：
2. a kind of preparation method of 3- piperidyls -4- indolylmaleimides class compounds as described in claim 1, including：
(1) indoles and maleimide are dissolved in solvent, boron trifluoride ether BF is added3.Et2O is stirred at reflux anti-at 90 DEG C
3-5h is answered, purifies, obtains 3- indoles succinimides；The molar ratio of wherein indoles, maleimide and boron trifluoride ether is
1:1.0~1.5:0.2~1.0；
(2) 3- indoles succinimide, 2,3-, bis- chloro- 4,5- dicyano benzoquinones DDQ are dissolved in solvent respectively, are mixed, room temperature
12-24h is stirred, purification obtains 3- indolylmaleimides；Wherein 3- indoles succinimide, DDQ, solvent ratios relationship are
1mol:1.0~1.5mol:0.5~10L；
(3) 3- indolylmaleimides, piperidines, catalyst are added in solvent, reaction is heated at 110-120 DEG C
10-24h purifies to get 3- piperidyl -4- indolylmaleimides class compounds；Wherein 3- indolylmaleimides, piperidines
Compound, catalyst molar ratio be 1:1~2:0.2~1:0.2~1.
3. a kind of preparation method of 3- piperidyls -4- indolylmaleimides class compounds according to claim 2, special
Sign is：Solvent is 1,2- dichloroethanes in the step (1)；The w/v of indoles and solvent is 1.0g:3~20mL.
4. a kind of preparation method of 3- piperidyls -4- indolylmaleimides class compounds according to claim 2, special
Sign is：It is purified in the step (1) and is：H is added2O stirs 5~20min, and ethyl acetate extracts, then through being saturated NaCl solution
Washing, anhydrous Na2SO4Dry, concentration, recrystallization, recrystallization solvent are 95% ethyl alcohol.
5. a kind of preparation method of 3- piperidyls -4- indolylmaleimides class compounds according to claim 2, special
Sign is：Solvent is 1,4- dioxane in the step (2)；Purification is：Filtering filters off residue, and concentration filtrate removes solvent,
Ethyl acetate extracts, then through saturated common salt water washing, anhydrous Na2SO4Dry, concentration, recrystallization, recrystallization solvent are 95% second
Alcohol.
6. a kind of preparation method of 3- piperidyls -4- indolylmaleimides class compounds according to claim 2, special
Sign is：Catalyst is copper acetate and/or silver carbonate in the step (3)；Piperidines be piperidines -3- Ethyl formates or
Piperidine-4-ethyl formate；Solvent is chlorobenzene；Wherein the envelope-bulk to weight ratio of solvent and 3- indolylmaleimides is 3-20mL:1g.
7. a kind of preparation method of 3- piperidyls -4- indolylmaleimides class compounds according to claim 6, special
Sign is：3- indolylmaleimides, piperidines, copper acetate and silver carbonate molar ratio be 1:1~2:0.2~1:
0.2~1.
8. a kind of preparation method of 3- piperidyls -4- indolylmaleimides class compounds according to claim 2, special
Sign is：The step (3) purifies：Water is added to stir, ethyl acetate extraction, organic phase anhydrous Na2SO4Drying boils off solvent,
It then recrystallizes, recrystallization solvent is 95% ethyl alcohol.
9. a kind of 3- piperidyls -4- indolylmaleimides class compounds as described in claim 1 are prevented or are treated preparing
Application in the drug of tumour.
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| CN101475563A (en) * | 2008-11-21 | 2009-07-08 | 东华大学 | 3-amino-4-indole-N-methyl maleimide compound, preparation and use thereof |
| CN101671329A (en) * | 2009-06-17 | 2010-03-17 | 东华大学 | Indolylmaleimide compound substituted with 3-amino alcohol, preparation method and application thereof |
| CN102924437A (en) * | 2012-11-19 | 2013-02-13 | 东华大学 | 3-piperazine-4-indol maleimide compound and preparation and application thereof |
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| CN101475563A (en) * | 2008-11-21 | 2009-07-08 | 东华大学 | 3-amino-4-indole-N-methyl maleimide compound, preparation and use thereof |
| CN101671329A (en) * | 2009-06-17 | 2010-03-17 | 东华大学 | Indolylmaleimide compound substituted with 3-amino alcohol, preparation method and application thereof |
| CN102924437A (en) * | 2012-11-19 | 2013-02-13 | 东华大学 | 3-piperazine-4-indol maleimide compound and preparation and application thereof |
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| Title |
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| Synthesis and Cytotoxicity of Novel 3-Amino-4-indolylmaleimide Derivatives;Sheng-Yin Zhao et al.;《Arch Pharm Res》;20111231;第34卷(第4期);第519-526页 * |
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