CN104031033A - N,N,N-tri-substituted arcyriarubins derivatives and preparing method thereof - Google Patents

N,N,N-tri-substituted arcyriarubins derivatives and preparing method thereof Download PDF

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CN104031033A
CN104031033A CN201410075228.7A CN201410075228A CN104031033A CN 104031033 A CN104031033 A CN 104031033A CN 201410075228 A CN201410075228 A CN 201410075228A CN 104031033 A CN104031033 A CN 104031033A
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group
tri
net
bacterioruberin
reaction
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黄木华
高永臣
贾瑜珲
李婷婷
罗运军
柴春鹏
黑泽峘
杨凤岭
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Beijing Institute of Technology BIT
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Beijing Institute of Technology BIT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Abstract

The invention provides N,N,N-tri-substituted arcyriarubins derivatives and a preparing method thereof. The method includes: subjecting a suspension comprising a strong alkali and N,N-dimethylformamide to cooling in an ice-water bath; under the protection of nitrogen, adding dropwise a N,N-dimethylformamide solution of bisindolylmaleimide into the suspension, and stirring the mixture at a temperature ranging from -10 DEG C to 100 DEG C; adding an electrophilic reagent R11X into the mixture after stirring; cooling the reacted mixture with an ice-water bath, adding a saturated ammonium chloride solution to quench the reaction, extracting with ethyl acetate, combining the organic phases, and washing the combined organic phase with water and a saturated sodium chloride solution successively; and drying the washed organic phase with anhydrous sodium sulfate, and separating residue obtained after filtering and concentration with column chromatography to obtain the N,N,N-tri-substituted arcyriarubins derivatives.

Description

N, N, N-tri-replaces group's net bacterioruberin derivative and preparation method thereof
Technical field
The present invention relates to medicine and chemical engineering of materials field, particularly relate to a kind of N, N, N-tri-replace roll into a ball net bacterioruberin derivatives and preparation method.
Background technology
Bisindole maleimide compounds (BIMs) refers to 3 of maleimide, 4-position respectively with No. 3 positions of two molecule benzazolyl compounds by the C-C key product obtaining that is connected.In treatment tumour, the disease aspects such as diabetic complication have huge potentiality, know taking effective protein kinase C (PKC) inhibitor as people.Representational BIMs has Rebeccamycin (REB) (butterfly rhzomorph), Arcyriarubins (group's net bacterioruberin) and Arcyriaflavins (group's net bacterium flavine) etc.
Based on N, N, trisubstituted net bacterioruberin derivative of N-has special structure, in photoelectric material, is with a wide range of applications.Owing to generally all containing the π key of conjugation in the structure of organic photoelectrical material, but excessive conjugated system and rigidity, bring difficulty usually can to preparation purification and the device application of organic materials.Introducing the active alkyl chain of high vibration, is an important means of organic materials modification.On the one hand, alkyl chain can improve the solvability of material, improves film forming properties, is convenient to purify and wet processes; Meanwhile, the character of all right controlled material of the alkyl chain of different lengths and accumulation pattern, thereby the performance of raising device.
The method of classical introducing alkyl chain is transition metal-catalyzed C-C linked reaction and the alkene-hydrogenation of aldehyde etc., but has deficiency separately.For example, Taiwan Academia Sinica chemistry Zhou great Xin group prepare N, N by the N-alkylation of a net bacterioruberin, N-tri-replaces group's net bacterioruberin derivative, but productive rate is only 57%, even also needs to realize by two-step reaction, also need to use transition metal, expensive and not environmental protection.
Therefore, need at present the urgent technical problem solving of those skilled in the art to be exactly: a kind of simple, environmental protection and the high N of productive rate are provided, N, N-tri-replaces the preparation mechanism of group's net bacterioruberin derivatives.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of simple, environmental protection and the high N of productive rate, N, and N-tri-replaces group's net bacterioruberin derivatives and preparation method thereof.
In order to address the above problem, the invention discloses a kind of N, N, N-tri-replaces a preparation method for group's net bacterioruberin derivatives, the DMF suspension of highly basic is carried out to ice-water bath cooling, and the pka value of described highly basic is 15～55;
Under the protection of nitrogen, to the N that dropwise adds bisindole maleimide in described suspension, dinethylformamide solution, at the temperature of-10 DEG C～100 DEG C, the mixed solution obtaining is stirred, shown in the following formula I of structure expression of described bisindole maleimide;
Stir in backward described mixed solution and add electrophilic reagent R 11x, there is N-alkylated reaction in the bisindole maleimide in described miscible fluid and described electrophilic reagent, wherein, the mole number ratio of described electrophilic reagent and described bisindole maleimide is (3:1)～(10:1), X is chlorine, bromine, iodine, methanesulfonate ester, p-methylphenyl sulphonate or trifluoromethane sulfonic acid ester, R 11for alkyl, the temperature of reaction of described cationoid reaction is-10 DEG C～100 DEG C;
With the cooling reacted mixed solution of ice-water bath, and add saturated ammonium chloride solution to carry out cancellation reaction, then add ethyl acetate to extract, merge organic phase, successively water and saturated nacl aqueous solution washing;
By the organic phase anhydrous sodium sulfate drying after washing, the residue obtaining after filtering and concentrating separates by column chromatography, obtains having the N of structure expression shown in following formula II, N, and N-tri-replaces group's net bacterioruberin derivative;
Preferably, highly basic and N described in described suspension, the mol ratio of dinethylformamide is (1:10)～(1:100), the N of described bisindole maleimide, N in dinethylformamide solution, the mol ratio of dinethylformamide and bisindole maleimide is (40:1)～(400:1), and the mol ratio of described highly basic and described bisindole maleimide is (3:1)～(10:1).
Preferably, described highly basic is NaH, KH, LiBu n, NaOMe, NaOEt, LiOMe, LiOEt, LiOBu t, LiHMDS, NaHMDS or KHMDS.
The reaction times of preferably, reacting between described bisindole maleimide and described electrophilic reagent is 5 minutes～14 days.
Preferably, described R 11for methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, 3-(dimethylamino) propyl group or 4-(dimethylamino) butyl.
Preferably, R 1and R 6for hydrogen, alkyl or heteroatoms, R 2, R 3, R 4, R 5, R 7, R 8, R 9, R 10for hydrogen, chlorine, bromine, iodine, alkyl, alkoxyl group, alkenyl, aromatic base or substituted aryl.
The present invention also provides a kind of N preparing by aforesaid method, N, N-tri-replaces group's net bacterioruberin derivative, it is characterized in that, the bisindole maleimide preparation with structure expression shown in following formula I has the N of structure expression shown in following formula II, N, N-tri-replaces group's net bacterioruberin derivative;
Compared with prior art, the present invention includes following advantage:
The present invention is set out by bisindole maleimide compounds group net bacterioruberin, by reacting with a series of electrophilic reagents under alkaline condition, one step can be prepared N, N, trisubstituted net bacterioruberin derivative of N-, realize the succinct of this compounds, efficiently, productive rate high (productive rate >96%), and mild condition, post-processing operation is simple and easy, be easy to realize a large amount of synthetic, thereby synthetic a large amount of N at short notice, N, N-tri-replaces group's net bacterioruberin derivative, for having pharmaceutical use and the compound with peculiar photoelectric properties, screening establishes solid basis, and do not use expensive transition metal, because of but the green technology of preparing of low cost.
Brief description of the drawings
Fig. 1 is a kind of N of the present invention, N, and N-tri-replaces the schema of the preparation method embodiment of group's net bacterioruberin derivative;
Fig. 2 is a kind of N of the present invention, N, and N-tri-replaces the preparation method's of group's net bacterioruberin derivative schematic diagram;
Fig. 3, Fig. 4 and Fig. 5 are respectively in the embodiment of the present invention 13,4-bis-(1-dodecyl-1H-indoles-3-)-1-dodecyl-pyrroles-2, infrared spectrum, hydrogen nuclear magnetic resonance spectrogram and the carbon-13 nmr spectra figure of 5-diketone;
Fig. 6 and Fig. 7 are respectively in the embodiment of the present invention 23,4-bis-(1-benzyl-1H-indoles-3-)-1-benzyl-pyrroles-2, the infrared spectrum of 5-diketone and hydrogen nuclear magnetic resonance spectrogram;
Fig. 8, Fig. 9 and Figure 10 are respectively in the embodiment of the present invention 33,4-bis-(1-allyl group-1H-indoles-3-)-1-allyl group-pyrroles-2, infrared spectrum, hydrogen nuclear magnetic resonance spectrogram and the carbon-13 nmr spectra figure of 5-diketone.
Embodiment
For above-mentioned purpose of the present invention, feature and advantage can be become apparent more, below in conjunction with the drawings and specific embodiments, the present invention is further detailed explanation.
The net bacterioruberin A of group, B, C is as the red pigments of a class physiologically active, from the red sporophore of dark red net bacterium Arcyria denudata, extract and obtain in 1980 by German Steglich group the earliest, they have shown that to protein kinase PKC etc. good inhibition is active, receive much concern owing to there is D-π-A structure in its molecular structure in the research of photoelectric material simultaneously.Research shows, retain maleimide amine moiety NH and there is vital role for the bioactive maintenance of this compounds, and in the research of photoelectric material, people are more prone to replace three NH in molecule simultaneously, this conclusion can be referring to the article of delivering on Chem.Mater. and J.Mater.Chem. (SCI): (a) Chiu, C.W.; Chow, T.J.; Chuen, C.H.; Lin, H.M.; Tao, Y.T.Chem.Mater.2003,15,4527; (b) Lin, Z.; Wen, Y.-S.; Chow, T.J.J.Mater.Chem.2009,19,5141.
Conventionally to based on N, N, trisubstituted net bacterioruberin derivative of N-introduced the active alkyl chain of high vibration to improve the performance of material, and existing scheme comprises multiple.
For example, N prepares by the N-alkylation of a net bacterioruberin in the Zhou great Xin group of chemistry institute of the Taiwan Academia Sinica mentioned in background technology, N, and N-tri-replaces a scheme of rolling into a ball net bacterioruberin derivatives, can be referring to SCI article: (a) Chiu, C.W.; Chow, T.J.; Chuen, C.H.; Lin, H.M.; Tao, Y.T.Chem.Mater.2003,15,4527; (b) Lin, Z.; Wen, Y.-S.; Chow, T.J.J.Mater.Chem.2009,19,5141.].
Again for example, the people such as the Nakazono of Kyushu University have synthesized N, N, N-tri-replaces group's net bacterioruberin derivative, and studied its fluorescence and chemoluminescence phenomenon, and disclose its potentiality as chemical sensor, be alkali but its scheme adopts KOH, acetone is solvent, iodo thing is electrophilic reagent, and productive rate is extremely low, is 4.5-30%, can be referring to the article of delivering on Org.Lett. (SCI): [Nakazono, M.; Nanbu, S.; Uesaki, A.; Kuwano, R.; Kashiwabara, M.; Zaitsu, K.Org.Lett.2007,9,3583.].
Again for example, the Tian He little of East China University of Science has been combined into N, N, N-tri-replaces group's net bacterioruberin derivative, and productive rate is 55-85%, its synthetic can carrying out in two steps, reactivity ratio's indoles of maleimide NH carry out by force and first alkylated reaction, be only afterwards the N-alkylated reaction of indoles NH, can be referring to SCI article: [Ning, Z.; Zhou, Y.; Zhang, Q.; Ma, D.; Zhang, J.; Tian, H.J.Photochem.Photobiol.:Chem.2007,192,8.].
In view of this, one of core idea of the present invention is, a kind of new N is provided, N, and N-tri-replaces the preparation mechanism of group's net bacterioruberin derivative, simplifies preparation process and improves productive rate.
With reference to figure 1, show a kind of N of the present invention, N, N-tri-replaces the schema of the preparation method embodiment of group's net bacterioruberin derivative, specifically can comprise the following steps:
Step 101, that the DMF suspension of highly basic is carried out to ice-water bath is cooling, and the pka value of described highly basic is 15～55.
In the embodiment of the present invention, first prepare the suspension of highly basic, the pka value of highly basic is in 15 to 55 scope.Organic solvent is DMF, can adopt the DMF of new steaming, and organic solvent must newly distill, and highly basic is mixed with the new organic solvent steaming, and obtains the suspension that mixes, carries out ice-water bath cooling in mixing.
In the embodiment of the present invention, described highly basic can be NaH, KH, LiBu n, NaOMe, NaOEt, LiOMe, LiOEt, LiOBu t, LiHMDS, NaHMDS or KHMDS.
In the embodiment of the present invention, the mol ratio of highly basic described in suspension and DMF is (1:10)～(1:100) described in described highly basic.
Step 102, under the protection of nitrogen, to the DMF solution that dropwise adds bisindole maleimide in described suspension, at the temperature of-10 DEG C～100 DEG C, the mixed solution obtaining is stirred.
Shown in the following formula I of structure expression of described bisindole maleimide:
Wherein, R 1and R 6for hydrogen, alkyl or heteroatoms, R 2, R 3, R 4, R 5, R 7, R 8, R 9, R 10for hydrogen, chlorine, bromine, iodine, alkyl, alkoxyl group, alkenyl, aromatic base or substituted aryl.
In the embodiment of the present invention, adopt bisindole maleimide to prepare N, N, when N-tri-replaces group's net bacterioruberin derivative, first adopt highly basic to process bisindole maleimide, particularly, by bisindole maleimide be dissolved in step 101 in same N, in dinethylformamide, then in the environment of nitrogen, be dissolved in N to dropwise adding in suspension, the bisindole maleimide of dinethylformamide, after dropping, solution is stirred and obtains mixing solutions, in whole treating processes, maintain the temperature in the scope of-10 DEG C～100 DEG C, it is 5 minutes～14 days that the time of processing is preferably.。
Highly basic processing can rapidly and efficiently realize the deprotonation of bisindole maleimide activity-NH, makes electrophilic reagent N-alkylated reaction more fully occur with bisindole maleimide, improves the transformation efficiency of raw material.
Wherein, in the DMF solution of described bisindole maleimide, the mol ratio of DMF and bisindole maleimide is (40:1)～(400:1).The mol ratio of described highly basic and described bisindole maleimide is (3:1)～(10:1).
Step 103, stir in backward described mixed solution and add electrophilic reagent R 11x, there is N-alkylated reaction in the bisindole maleimide in described miscible fluid and described electrophilic reagent, and wherein, the mole number ratio of described electrophilic reagent and described bisindole maleimide is 3:1～10:1; X is chlorine, bromine, iodine, methanesulfonate ester, p-methylphenyl sulphonate or trifluoromethane sulfonic acid ester, R 11for alkyl, the temperature of reaction of described cationoid reaction is-10 DEG C～100 DEG C.
After bisindole maleimide being processed with highly basic, can in mixing solutions, add electrophilic reagent R 11x, R 11can there is N-alkylated reaction with bisindole maleimide in X, wherein, and R 11the mole number ratio of X and bisindole maleimide is 3:1～10:1.
In the embodiment of the present invention, N-alkylated reaction carries out under the temperature condition of-10 DEG C～100 DEG C, and the time of N-alkylated reaction can be 5 minutes～14 days.
Wherein, described R 11can be methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, 3-(dimethylamino) propyl group or 4-(dimethylamino) butyl.
The reaction times of wherein, reacting between described bisindole maleimide and described electrophilic reagent can be 5 minutes～14 days.
Step 104, the cooling reacted mixed solution of use ice-water bath, and add saturated ammonium chloride solution to carry out cancellation reaction, then add ethyl acetate to extract, merge organic phase, successively water and saturated nacl aqueous solution washing.
Step 105, by the organic phase anhydrous sodium sulfate drying after washing, the residue obtaining after filtering and concentrating separates by column chromatography, obtains having the N of structure expression shown in following formula II, N, N-tri-replaces and rolls into a ball net bacterioruberin derivatives.
Bisindole maleimide and electrophilic reagent occur can generate N after N-alkylated reaction, N, and N-tri-replaces group's net bacterioruberin derivative, has some mineral compound in reaction product, therefore also needs further to process to isolate the organism in reaction product.
First, it is cooling that reacted solution carries out ice-water bath, then, carries out cancellation reaction.The principle of cancellation reaction is excessive because of a certain reactant in chemical reaction, and when reaction proceeds to a certain degree, target product obtains, and the words that this excess reactant exists further reaction generate undesirable product, so need cancellation.The principle of cancellation is to react with it with the another kind of compound more easily reacting with this excessive compound, thereby it is removed from system, can, with saturated ammonium chloride cancellation reaction, remove unreacted alkali, is convenient to the separating-purifying of next step product.
Carrying out after cancellation reaction, can further add ethyl acetate to extract, be dissolved in ethyl acetate and extract by organism; The organic phase extracting first washes with water, then with saturated nacl aqueous solution washing, to remove the moisture in organic phase; Then be dried by anhydrous sodium sulphate, further to remove moisture residual in organic phase; Then concentrate and remove ethyl acetate; The organism that carries out obtaining after aftertreatment comprises target product N, N, and N-tri-replaces group's net bacterioruberin derivative, can further adopt column chromatography to separate, and obtains the N as formula II, N, N-tri-replaces group's net bacterioruberin derivative.
In concrete realization, can adopt tlc (Thin layer chromatography, TLC) to follow the tracks of reaction, accurately judge the conversion of raw material and the generation situation of new product according to the difference of Rf value.
The present invention is set out by bisindole maleimide compounds group net bacterioruberin, by reacting with a series of electrophilic reagents under alkaline condition, one step can be prepared N, N, trisubstituted net bacterioruberin derivative of N-, realize the succinct of this compounds, efficiently, productive rate high (productive rate >96%), and mild condition, post-processing operation is simple and easy, be easy to realize a large amount of synthetic, thereby synthetic a large amount of N at short notice, N, N-tri-replaces group's net bacterioruberin derivative, for having pharmaceutical use and the compound with peculiar photoelectric properties, screening establishes solid basis, and do not use expensive transition metal, because of but the green technology of preparing of low cost.
With reference to figure 2, show a kind of N of the present invention, N, N-tri-replaces the preparation method's of group's net bacterioruberin derivative schematic diagram.
(1) step adopts the DMF suspension of highly basic to process bisindole maleimide; (2) step is by electrophilic reagent R 11mix R with bisindole maleimide after treatment 11be substituted on indyl; (3) step is carried out post-reaction treatment and purifying, obtains target product.
Electrophilic reagent R 11while reaction with bisindole maleimide, with the H on R substituted indole group, as shown in formula II, the H on formula I group is by R 11replace.Wherein, R 11for alkyl, preferably, any one in concrete methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, 3-(dimethylamino) propyl group or 4-(dimethylamino) butyl.R 2, R 3, R 4, R 5, R 7, R 8, R 9, R 10constant identical with formula I, can be hydrogen, chlorine, bromine, iodine, alkyl, alkoxyl group, alkenyl, aromatic base or substituted aryl respectively, R 1and R 6constant identical with formula I, can be hydrogen, alkyl or heteroatoms respectively.
In the embodiment of the present invention, the X in electrophilic reagent RX can be any one of chlorine, bromine, iodine, methanesulfonate ester (OMs), p-methylphenyl sulphonate (OTs) or trifluoromethane sulfonic acid ester (OTf).
By the method for the embodiment of the present invention, set out by bisindole maleimide compounds group net bacterioruberin, by reacting with a series of electrophilic reagents under alkaline condition, one step can be prepared N, N, trisubstituted net bacterioruberin derivative of N-, realize the succinct of this compounds, efficiently, productive rate high (productive rate >96%), and mild condition, post-processing operation is simple and easy, be easy to realize a large amount of synthetic, thereby synthetic a large amount of N at short notice, N, N-tri-replaces group's net bacterioruberin derivative, for having pharmaceutical use and the compound with peculiar photoelectric properties, screening establishes solid basis, and do not use expensive transition metal, because of but the green technology of preparing of low cost.
Accordingly, the present invention also provides a kind of N preparing by aforesaid method, N, N-tri-replaces group's net bacterioruberin derivative, it is characterized in that, the bisindole maleimide preparation with structure expression shown in following formula I has the N of structure expression shown in following formula II, N, and N-tri-replaces group's net bacterioruberin derivative;
For making those skilled in the art understand better the present invention, below by multiple specific embodiments, N in the present invention is described, N, N-tri-replaces a preparation method for group's net bacterioruberin derivatives.
Embodiment 1:
3,4-bis-(1-dodecyl-1H-indoles-3-)-1-dodecyl-pyrroles-2, the preparation of 5-diketone, wherein, R is dodecyl [CH 3(CH 2) 10cH 2-], X is bromine (Br), highly basic is NaOEt, and pka=16, preparation process is:
Under nitrogen protection; to the cooling NaOEt of ice-water bath (1M in THF is housed; 4.8ml, 4.8mmol) DMF (10ml) suspension in dropwise add DMF (10ml) solution of bisindole maleimide (400mg, 1.20mmol).Stir after 30 minutes, positive bromo-dodecane (1.72ml, 7.2mmol) is added to above-mentioned reaction mixture, and be heated to 55 DEG C.After 24 hours, adopt tlc TLC test to show, react completely.
Stopped reaction, with the cooling reaction mixture of ice-water bath, and adds saturated ammonium chloride solution (10ml) cancellation reaction.Add ethyl acetate to extract (3 × 20ml), merge organic layer, successively water and saturated nacl aqueous solution washing.Organic phase anhydrous sodium sulfate drying, after filtering and concentrating, residue separates by column chromatography, elutriant is made up of ethyl acetate (EtOAc) and sherwood oil (Petroleum Ether), and concrete ratio is V (EtOAc)/V (Petroleum Ether)=1/18, obtains red solid and be N after separation, N, N-tri-replaces group's net bacterioruberin derivative, and quality is 959mg, and the yield that can calculate thus target product is 96%.
Wherein, N-alkylated reaction equation is:
With reference to figure 3, Fig. 4 and Fig. 5, show respectively in the embodiment of the present invention 13,4-bis-(1-dodecyl-1H-indoles-3-)-1-dodecyl-pyrroles-2, infrared spectrum, hydrogen nuclear magnetic resonance spectrogram and the carbon-13 nmr spectra figure of 5-diketone.
Retention value Rf=0.77[V (the EtOAc)/V (Petroleum Ether)=1/8 of thin-layer chromatography].
Fusing point m.p.:65 DEG C.
Infrared spectrum IR (KBr, cm-1): 3050 (w), 2924 (s), 2853 (s), 1756 (m), 1697 (s), 1629 (m), 1611 (m), 1533 (s), 1466 (s), 1437 (m), 1392 (s), 1372 (s), 1282 (w), 1226 (w), 1161 (m), 1139 (w), 1116 (w), 1118 (w), 814 (w), 739 (s).
Hydrogen nuclear magnetic resonance spectrogram 1h NMR (400MHz, CDCl 3) δ (ppm): 7.67 (s, 2H), 7.46 (s, 1H), 7.29 (d, J=8.0Hz, 2H), 7.08 (t, J=6.0Hz, 2H), 6.94 (d, J=8.0Hz, 2H), 6.72 (t, J=6.0Hz, 2H), 4.15 (t, J=6.0Hz, 4H), 1.79-1.86 (m, 4H), 1.31-1.37 (m, 4H), 0.95 (t, J=8.0Hz, 6H).
Carbon-13 nmr spectra figure 13c NMR (100MHz, CDCl 3) δ (ppm): 172.7,136.2,131.6,126.6,126.3,122.4,121.9,119.8,109.5,106.0,46.8,38.3,32.0,29.6,29.5,29.4,29.3,22.7,14.2.
High resolution mass spec HR-MS (EI): m/z831.6656[M] +(C 56h 85n 3o 2 +, required831.6642).
Wherein, the qualification that Rf value is compound and the separation of compound provide important reference, providing of fusing point can be understood this compound physical property, some important functional groups that can analysis of compounds have by infrared spectrum, the H chemical shift that nucleus magnetic hydrogen spectrum data provide, integration and coupling constant are the important foundations that judges this compound, can have a clear understanding of the type of carbon and relative number by carbon-13 nmr spectra, the molecular weight that the finally detection by high resolution mass spectrum can unquestionable definite synthesized target product.
Embodiment 2:
3,4-bis-(1-benzyl-1H-indoles-3-)-1-benzyl-pyrroles-2, the preparation of 5-diketone, wherein, R is benzyl (C 6h 5cH 2-), X is bromine (Br), highly basic is mineral alkali sodium hydride, and pka=35, preparation process is:
Under nitrogen protection; to the cooling NaH of ice-water bath (60% is housed; 192mg, 4.8mmol) DMF (10ml) suspension in dropwise add DMF (10ml) solution of bisindole maleimide (400mg, 1.20mmol).Stir after 30 minutes, bromobenzyl (0.86ml, 7.2mmol) is added to above-mentioned reaction mixture, and be heated to 55 DEG C.After 1 hour, adopt tlc TLC test to show, react completely.
Stopped reaction, with the cooling reaction mixture of ice-water bath, and adds saturated ammonium chloride solution (10ml) cancellation reaction.Add ethyl acetate to extract (3 × 20ml), merge organic layer, successively water and saturated nacl aqueous solution washing.Organic phase anhydrous sodium sulfate drying, after filtering and concentrating, residue separates by column chromatography, and elutriant is by methylene dichloride (CH 2cl 2) and sherwood oil (Petroleum Ether) composition, concrete ratio is V (CH 2cl 2)/V (Petroleum Ether)=1/1, obtains red solid and is N after separation, N, and N-tri-replaces group's net bacterioruberin derivative, and quality is 710mg, and the yield that can calculate thus target product is 99%.
Wherein, N-alkylated reaction equation is:
With reference to figure 6 and Fig. 7, show respectively in the embodiment of the present invention 23,4-bis-(1-benzyl-1H-indoles-3-)-1-benzyl-pyrroles-2, the infrared spectrum of 5-diketone and hydrogen nuclear magnetic resonance spectrogram.
Retention value Rf=0.37[V (the EtOAc)/V (Petroleum Ether)=1/4 of thin-layer chromatography].
Fusing point m.p.:195 DEG C of (from Petroleum Ether and CHCl 3).
Infrared spectrum IR (KBr, cm-1): 3061 (w), 3031 (w), 2926 (w), 1756 (w), 1695 (s), 1627 (w), 1610 (w), 1533 (m), 1496 (w), 1466 (w), 1454 (w), 1431 (w), 1388 (m), 1354 (w), 1282 (w), 1245 (w), 1172 (w), 1088 (w), 1068 (w), 1029 (w), 1016 (w), 909 (w), 819 (w), 738 (m), 696 (w), 635 (w).
Hydrogen nuclear magnetic resonance spectrogram 1h NMR (400MHz, CDCl 3) δ (ppm): 7.72 (s, 2H), 7.47 (d, J=7.2Hz, 2H), 7.25-7.34 (m, 9H), 7.19 (d, J=8.0Hz, 2H), 7.10 (d, J=6.4Hz, 4H), 7.02 (t, J=7.6Hz, 2H), 6.98 (d, J=8.0Hz, 2H), 6.72 (t, J=7.6Hz, 2H), 5.32 (s, 4H), 4.84 (s, 4H).
Embodiment 3:
3,4-bis-(1-allyl group-1H-indoles-3-)-1-allyl group-pyrroles-2, the preparation of 5-diketone, wherein, R is allyl group (CH 2=CHCH 2-), X is bromine (Br), highly basic is mineral alkali sodium hydride, and pka=35, preparation process is:
Under nitrogen protection; to the cooling NaH of ice-water bath (60% is housed; 192mg, 4.8mmol) DMF (10ml) suspension in dropwise add DMF (10ml) solution of bisindole maleimide (400mg, 1.20mmol).Stir after 30 minutes, bromobenzyl (0.61ml, 7.2mmol) is added to above-mentioned reaction mixture, and be heated to 55 DEG C.After 1 hour, adopt tlc TLC test to show, react completely.
Stopped reaction, with the cooling reaction mixture of ice-water bath, and adds saturated ammonium chloride solution (10ml) cancellation reaction.Add ethyl acetate to extract (3 × 20ml), merge organic layer, successively water and saturated nacl aqueous solution washing.Organic phase anhydrous sodium sulfate drying, after filtering and concentrating, residue separates by column chromatography, elutriant is made up of ethyl acetate (EtOAc) and sherwood oil (Petroleum Ether), and concrete ratio is V (EtOAc)/V (Petroleum Ether)=1/4, obtains red solid and be N after separation, N, N-tri-replaces group's net bacterioruberin derivative, and quality is 516mg, and the yield that can calculate thus target product is 96%.
Wherein N-alkylated reaction equation is:
With reference to figure 8, Fig. 9 and Figure 10, show respectively in the embodiment of the present invention 33,4-bis-(1-allyl group-1H-indoles-3-)-1-allyl group-pyrroles-2, infrared spectrum, hydrogen nuclear magnetic resonance spectrogram and the carbon-13 nmr spectra figure of 5-diketone.
Retention value Rf=0.23[V (the EtOAc)/V (Petroleum Ether)=1/4 of thin-layer chromatography].
Fusing point m.p.:151 DEG C (from Petroleum Ether and CHCl3).
Infrared spectrum IR (KBr, cm-1): 3050 (w), 2982 (w), 2922 (w), 2872 (w), 1757 (w), 1698 (s), 1635 (w), 1610 (w), 1532 (m), 1466 (m), 1430 (m), 1387 (s), 1337 (w), 1282 (w), 1248 (w), 1198 (m), 1193 (m), 1135 (w), 1016 (w), 991 (w), 930 (w), 817 (w), 739 (m), 647 (w).
Hydrogen nuclear magnetic resonance spectrogram 1h NMR (400MHz, CDCl 3) δ (ppm): 7.71 (s, 2H), 7.25 (d, J=8.4Hz, 2H), 7.06 (t, J=7.6Hz, 2H), 6.95 (d, J=8.0Hz, 2H), 6.72 (t, J=7.6Hz, 2H), 5.88-6.03 (m, 3H), 5.09-5.33 (m, 6H), 4.75 (d, J=5.6Hz, 4H), 4.29 (t, J=5.6Hz, 2H).
Carbon-13 nmr spectra figure 13c NMR (100MHz, CDCl 3) δ (ppm): 172.1,136.2,132.6,132.4,131.8,126.8,126.4,122.3,122.2,120.1,117.8,117.4,109.8,106.3,49.2,40.4.
High resolution mass spec HR-MS (EI): m/z447.1941[M] +(C 29h 25n 3o 2 +, required447.1947).
For embodiment of the method, for simple description, therefore it is all expressed as to a series of combination of actions, but those skilled in the art should know, the present invention is not subject to the restriction of described sequence of operation, because according to the present invention, some step can adopt other orders or carry out simultaneously.Secondly, those skilled in the art also should know, the embodiment described in specification sheets all belongs to preferred embodiment, and related action and parts might not be that the present invention is necessary.
Above to a kind of N provided by the present invention, N, the preparation method that N-tri-replaces group's net bacterioruberin derivative is described in detail, applied specific case herein principle of the present invention and embodiment are set forth, the explanation of above embodiment is just for helping to understand method of the present invention and core concept thereof; , for one of ordinary skill in the art, according to thought of the present invention, all will change in specific embodiments and applications, in sum, this description should not be construed as limitation of the present invention meanwhile.

Claims (7)

1. a N, N, N-tri-replaces the preparation method of group's net bacterioruberin derivative, it is characterized in that, comprising:
The DMF suspension of highly basic is carried out to ice-water bath cooling, the pka value of described highly basic is 15～55;
Under the protection of nitrogen, to the N that dropwise adds bisindole maleimide in described suspension, dinethylformamide solution, at the temperature of-10 DEG C～100 DEG C, the mixed solution obtaining is stirred, shown in the following formula I of structure expression of described bisindole maleimide;
Stir in backward described mixed solution and add electrophilic reagent R 11x, there is N-alkylated reaction in the bisindole maleimide in described miscible fluid and described electrophilic reagent, wherein, the mole number ratio of described electrophilic reagent and described bisindole maleimide is (3:1)～(10:1), X is chlorine, bromine, iodine, methanesulfonate ester, p-methylphenyl sulphonate or trifluoromethane sulfonic acid ester, R 11for alkyl, the temperature of reaction of described cationoid reaction is-10 DEG C～100 DEG C;
With the cooling reacted mixed solution of ice-water bath, and add saturated ammonium chloride solution to carry out cancellation reaction, then add ethyl acetate to extract, merge organic phase, successively water and saturated nacl aqueous solution washing;
By the organic phase anhydrous sodium sulfate drying after washing, the residue obtaining after filtering and concentrating separates by column chromatography, obtains having the N of structure expression shown in following formula II, N, and N-tri-replaces group's net bacterioruberin derivative;
2. the method for claim 1, it is characterized in that, highly basic and N described in described suspension, the mol ratio of dinethylformamide is (1:10)～(1:100), the N of described bisindole maleimide, in dinethylformamide solution, the mol ratio of DMF and bisindole maleimide is (40:1)～(400:1), and the mol ratio of described highly basic and described bisindole maleimide is (3:1)～(10:1).
3. the method for claim 1, is characterized in that, described highly basic is NaH, KH, LiBu n, NaOMe, NaOEt, LiOMe, LiOEt, LiOBu t, LiHMDS, NaHMDS or KHMDS.
4. the method for claim 1, is characterized in that, the reaction times of reacting between described bisindole maleimide and described electrophilic reagent is 5 minutes～14 days.
5. the method for claim 1, is characterized in that, described R 11for methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, 3-(dimethylamino) propyl group or 4-(dimethylamino) butyl.
6. the method for claim 1, is characterized in that, R 1and R 6for hydrogen, alkyl or heteroatoms, R 2, R 3, R 4, R 5, R 7, R 8, R 9, R 10for hydrogen, chlorine, bromine, iodine, alkyl, alkoxyl group, alkenyl, aromatic base or substituted aryl.
7. the N preparing by method described in any one in claim 1-6, N, N-tri-replaces group's net bacterioruberin derivative, it is characterized in that, the bisindole maleimide preparation with structure expression shown in following formula I has the N of structure expression shown in following formula II, N, N-tri-replaces group's net bacterioruberin derivative;
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103382199A (en) * 2013-06-28 2013-11-06 北京理工大学 Preparation method of N-alkyl-bismaleimide

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103382199A (en) * 2013-06-28 2013-11-06 北京理工大学 Preparation method of N-alkyl-bismaleimide

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Title
S. A. LAKATOSH ET.AL.: "Synthesis, and Cytotoxic Activity of Nind-Alkoxy Derivatives of Antibiotic Arcyriarubin and Dechloro-rebeccamycin Aglycon", 《THE JOURNAL OF ANTIBIOTICS》 *
S. A. LAKATOSH ET.AL.: "Synthesis, and Cytotoxic Activity of Nind-Alkoxy Derivatives of Antibiotic Arcyriarubin and Dechloro-rebeccamycin Aglycon", 《THE JOURNAL OF ANTIBIOTICS》, vol. 55, no. 8, 31 August 2002 (2002-08-31), XP009020724 *

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