CN101979631B - Method for synthesizing nitrogen heterocyclic derivative with double-indolyl structure by lipase catalysis - Google Patents
Method for synthesizing nitrogen heterocyclic derivative with double-indolyl structure by lipase catalysis Download PDFInfo
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Abstract
The invention discloses a method for synthesizing a nitrogen heterocyclic derivative with a double-indolyl structure by lipase catalysis, which comprises the following steps of: forming a reaction system by using indole or indole derivative, aldehyde and solvent, adding lipase into the reaction system, and reacting the mixture for 4 to 72 hours at the temperature of between 10 and 70 DEG C to obtain the nitrogen heterocyclic derivative with the double-indolyl structure, wherein the using amount of the lipase in each liter of reaction system is 15,000 to 1,500,000 units, and the solvent is one solvent or a mixed solvent of multiple solvents. Compared with the conventional chemical synthesis method, the method for synthesizing the nitrogen heterocyclic derivative by using the lipase as a catalyst has the advantages of simple operation, mild reaction condition, environment friendliness and the like.
Description
Technical field
The present invention relates to the compound method of nitrogen heterocyclic verivate, relate in particular to a kind of lipase-catalyzed synthetic method with nitrogen heterocyclic verivate of two indyl structures.
Background technology
Cascade reaction is one type of very important reaction in organic synthesis.Cascade reaction is owing to can save the time and efforts that is used on the isolation of intermediate products, and its efficient is than progressively synthesis efficiency is high, and cascade reaction can reduce the generation of refuse simultaneously, avoids the accumulation of unstable midbody.The method that has had a lot of seminars to report now to utilize cascade reaction to synthesize the compound of more complicated, general using homogeneous phase and dephasign catalyzer etc. in these methods.Multienzyme catalysis cascade reaction has shown very superior condition at present, such as catalytic synthesis of C hydrate (" J.Am.Chem.Soc " 2000,122,5678), and catalysis synthesizing amino acid derivative (" Adv.Synth.Catal " 2008,350,1729) etc.But because the uncompatibility of conditions such as multiple enzyme-to-substrate, solvent, pH value and temperature tends to hinder the application of multienzyme in one kettle way catalysis cascade reaction.
In organic reaction, enzyme is one type of important catalyst.Along with the reach of science, scientist finds that enzyme not only can the catalysis natural response, and can also the reaction of catalysis non-natural under the suitable situation of condition; The ability of this catalysis non-natural reaction is exactly the multifunctionality of enzyme, and for example: lytic enzyme can react (" J.Am.Chem.Soc " 2003 by catalysis aldol; 125; 874) and Mannich reaction (" GreenChem " 2009,6,777); Acylase can catalysis Michael addition reaction (" Chem.Commun " 2004,1724), Markovnikov addition reaction (" Chem.Commun " 2005,2348) etc.Enzymatic multifunctionality has been expanded the application of enzyme in organic synthesis.Single enzyme one kettle way catalysis cascade reaction can well solve the defective of multienzyme one kettle way catalysis cascade reaction.Novi's letter lypase 435 one kettle way catalysis deprotections, acylations and epoxidation reaction (" J.Mol.Catal.B:Enzym " 1999 have been reported such as Klaas etc.; 7; 283), our seminar has also reported the method (" Chem.Commun " 2004,2006) of the substituted imdazole derivatives of proteolytic enzyme one kettle way two step synthetic nitrogens and method (" Adv.Synth.Catal " 2009 that D-amino acid acylated enzyme catalysis synthesizes the verivate of monose; 351,1833).
Indoles and verivate thereof extensively are present in terrestrial organism and the halobiontic active metabolite.Claudio C.Silveira study group reported seven water cerous compoundss synthetic two indyl alkane derivatives of catalysis in glycerine method (" Tetrahedron Letters " 2009,6060-6063).Teck-Peng Loh study group utilize iodine in solvent-free synthetic two indyl alkane derivatives (" Tetrahedr on " 2004,2051-2055).Asit K.Chakraborti study group reported ionic liquid-catalyzed indoles and aldehyde reaction prepare the method for the compound of two indyl alkanes (" Green Chemistry " 2008,10,1111-1118).But aforesaid method has harm to environment, and especially certain methods is used acid or lewis acidic catalyzer, complicated process steps.At present still need develop new environment amenable catalyzer comes catalysis to synthesize two indyl alkane compounds; As can develop a kind of multifunctionality of enzyme of utilizing and come catalytic combination to become the method for two indyl alkane compounds, should be able to have more wide application prospect.
Summary of the invention
The invention provides a kind of easy and simple to handle, reaction conditions is gentle, productive rate is higher lipase-catalyzed synthetic method with nitrogen heterocyclic verivate of two indyl structures.
A kind of lipase-catalyzed synthetic method with nitrogen heterocyclic verivate of two indyl structures comprises:
With indoles or indole derivatives and aldehyde and solvent formation reaction system, 10 ℃～70 ℃ reactions 4 hours～72 hours, make nitrogen heterocyclic verivate behind the adding lypase with two indyl structures; Wherein, the consumption of lypase is 15000units～1500000units in every liter of reaction system, 1units=1 unit of enzyme activity; Solvent is the mixed solvent of a kind of solvent or multiple solvent.
The present invention finds; Indoles or indole derivatives and aldehyde can at first carry out nucleophilic addition through the katalysis of lypase in the presence of solvent, and then cancellation; Carry out the Michael addition reaction at last, thereby generate nitrogen heterocyclic verivate with two indyl structures.
The consumption that increases enzyme can improve catalytic effect, but uses too much enzyme to influence the dispersion of enzyme in reaction system easily, is unfavorable for the turnover of substrate in the enzyme catalysis site, takes place thereby hinder reaction.Therefore, the present invention selects suitable lypase consumption for use, is beneficial to the carrying out that reacts.
Described indoles or indole derivatives are preferably the compound of structure shown in the structural formula II, can adopt the commercially available prod;
Among the formula II, R
1Be H or methyl; R
2Be H, methyl or bromine; R
3Be H, methyl, nitro, bromine or methoxyl group.
Described aldehyde is preferably the compound of structure shown in the structural formula II I, can adopt the commercially available prod;
In the formula III, R
4Be H, methyl, ethyl, propyl group, sec.-propyl, phenyl, hydroxyl, benzyl, p-methoxyphenyl, p-nitrophenyl, m-nitro base, ortho-nitrophenyl base, rubigan, p-hydroxybenzene, pyridyl, N, N-dimethylamino phenyl, 5-bromo-2-hydroxy phenyl or 4-methoxyl group-3-hydroxy phenyl.
The nitrogen heterocyclic verivate with two indyl structures of structure shown in the reaction of the compound of structure shown in compound of structure shown in the described structural formula II and the structural formula II I generating structure formula I, concrete reaction formula is following:
Among the formula I, R
1Be H or methyl; R
2Be H, methyl or bromine; R
3Be H, methyl, nitro, bromine or methoxyl group; R
4Be H, methyl, ethyl, propyl group, sec.-propyl, phenyl, hydroxyl, benzyl, p-methoxyphenyl, p-nitrophenyl, m-nitro base, ortho-nitrophenyl base, rubigan, p-hydroxybenzene, pyridyl, N, N-dimethylamino phenyl, 5-bromo-2-hydroxy phenyl or 4-methoxyl group-3-hydroxy phenyl; And R among the formula I
1, R
2, R
3With R among the formula II
1, R
2, R
3Has identical implication, R among the formula I
4With R in the formula III
4Has identical implication.
Described solvent is preferably DMSO 99.8MIN., N, one or both in dinethylformamide, dioxane, acetonitrile, octane, ethanol, toluene, THF (THF), ETHYLE ACETATE, normal hexane, hexanaphthene, chloroform, methylene dichloride, water, pyridine, the acetone.
Lypase has suitable solvent usually when one type of reaction of catalysis.Lypase is better certain reaction of catalysis usually in its suitable solvents, but because the influence of substrate solubleness often can not obtain satisfied result.The present invention discovers, suitable solvents and other solvent of lypase are used, and can quicken the dissolving of substrate, and can not influence the efficient of lipase-catalyzed this reaction, lypase just better such reaction of catalysis in mixed solvent like this.Therefore, the mixed solvent of the preferred multiple solvent of described solvent.
Described lypase can adopt the conventional commercially available lypase in this area, preferred porcine pancreatic lipase (PPL) or people's steapsase (HPL), more preferably free porcine pancreatic lipase, porcine pancreatic lipase or the people's steapsase produced like Sigma company (Sigma company).
According to the temperature of reaction of lypase and the characteristics of reaction system, the present invention is controlled at temperature of reaction and time in the suitable scope.
Described temperature of reaction is preferably 25 ℃～60 ℃, further is preferably 35 ℃～60 ℃, and the reaction times is preferably 12 hours～and 72 hours.
In order to reduce consumption of raw materials, to practice thrift cost, the consumption of indoles or indole derivatives is 1mol～35mol in every liter of reaction system; The mol ratio of described aldehyde and indoles or indole derivatives is 0.25～5.
The nitrogen heterocyclic verivate with two indyl structures that generates in the inventive method can be through existing column chromatography chromatogram method or tlc separation and purification.For example adopt silica gel or aluminum oxide column chromatography as filler; Adopt the tlc of the conventional commercially available silica-gel plate in this area; Eluent or developping agent are mixed with ETHYLE ACETATE by sherwood oil and form, and wherein the volume ratio of sherwood oil and ETHYLE ACETATE general 1: 0.05～30.
The inventive method is employed in and utilizes lipase-catalyzed synthetic nitrogen heterocyclic verivate with two indyl structural units in the mixed solvent of a kind of solvent or multiple solvent; Compare with existing chemical method; The inventive method easy and simple to handle; Reaction conditions is gentle, and separating step is few, has realized having the synthesizing of nitrogen heterocyclic verivate of two indyl structural units effectively.
Embodiment
Embodiment 1
In water lipase-catalyzed synthetic 3,3 '-((4-nitrophenyl) methylene radical)-two-(1H-indoles) (3,3 '-((4-nitrophenyl) methylene) bis (1H-indole))
It is the reaction system of 1.4L that the indoles (6.6mol) of 400 gram paranitrobenzaldehydes (26.4mol) and 75 grams is joined in the 1L water formation volume.Then, add the porcine pancreatic lipase (PPL) of 40 grams (41600units), reacted 50 hours down, make nitrogen heterocyclic verivate with two indyl structures at 40 ℃.
Using the productive rate of the above-mentioned nitrogen heterocyclic verivate of liquid chromatogram measuring is 79.7%.After above-mentioned nitrogen heterocyclic verivate purified through column chromatography chromatogram method (adopt silica gel as filler), characterize the affirmation structure with proton nmr spectra and infrared spectrum, the result is following:
1H-NMR(400MHz，DMSO-d
6)δ10.92(s，2H)，8.15(d，J＝8.8Hz，2H)，7.61(d，J＝8.4，2H)，7.36(d，J＝8.4Hz，2H)，7.28(d，J＝7.6Hz，2H)，7.05(t，J＝7.2，15.6，8.4Hz，2H)，6.88(m，4H)，6.02(s，1H)；
IR：3423cm
-1，1615cm
-1，1592cm
-1，1507cm
-1，1487cm
-1，1456cm
-1，1339cm
-1，1094cm
-1，746cm
-1。
The above results show synthetic product be 3,3 '-((4-nitrophenyl) methylene radical)-two-(1H-indoles), structural formula is following:
Embodiment 2
In water and hexanaphthene mixed solvent lipase-catalyzed synthetic 3,3 '-((3-nitrophenyl) methylene radical)-two-(1H-indoles) (3,3 '-((3-nitrophenyl) methylene) bis (1H-indole))
The indoles (13.2mol) of 200 gram m-nitrobenzaldehydes (13.2mol) and 150 grams joined the formation volume is the reaction system of 5.3L in the mixed solvent that water and the formed TV of hexanaphthene are 5L, the volume ratio of water and hexanaphthene is 3/1.Then, add people's steapsase (HPL) of 60 grams (1440000units), reacted 12 hours down, make nitrogen heterocyclic verivate with two indyl structures at 50 ℃.
Using the productive rate of the above-mentioned nitrogen heterocyclic verivate of liquid chromatogram measuring is 80%.After above-mentioned nitrogen heterocyclic verivate purified through column chromatography chromatogram method (adopt aluminum oxide as filler), characterize the affirmation structure with proton nmr spectra and infrared spectrum, the result is following:
1H-NMR(400MHz，DMSO-d
6)δ10.91(s，2H)，8.13(s，1H)，8.05(d，J＝8.0Hz，1H)，7.83(d，J＝8.0Hz，1H)，7.56(t，J＝8.4，16.0，7.6Hz，1H)，7.37(d，J＝8.0Hz，2H)，7.30(d，J＝7.6Hz，2H)，7.05(t，J＝7.2，14.8，7.6Hz，2H)，6.87(m，4H)，6.06(s，1H)；
IR：3413cm
-1，1612cm
-1，1525cm
-1，1456cm
-1，1348cm
-1，1095cm
-1，744cm
-1。
The above results show synthetic product be 3,3 '-((3-nitrophenyl) methylene radical)-two-(1H-indoles), structural formula is following:
Embodiment 3
At N, in dinethylformamide and the water mixed solvent lipase-catalyzed synthetic 3,3 '-((2-nitrophenyl) methylene radical)-two-(1H-indoles) (3,3 '-((2-nitrophenyl) methylene) bis (1H-indole))
The indoles (13.2mol) of 50 gram Ortho Nitro Benzaldehydes (3.3mol) and 150 grams is joined N; The formed TV of dinethylformamide and water is that to constitute volume in the mixed solvent of 1L be the reaction system of 1.2L; N, the volume ratio of dinethylformamide and water is 7/3.Then, add the porcine pancreatic lipase (PPL) of 10 grams (20800units), reacted 72 hours down, make nitrogen heterocyclic verivate with two indyl structures at 55 ℃.
Using the productive rate of the above-mentioned nitrogen heterocyclic verivate of liquid chromatogram measuring is 70.8%.After above-mentioned nitrogen heterocyclic verivate purified through column chromatography chromatogram method (adopt silica gel as filler), characterize the affirmation structure with proton nmr spectra and infrared spectrum, the result is following:
1H-NMR(400MHz，DMSO-d
6)δ10.90(s，2H)，7.87(d，J＝8.0Hz，1H)，7.55(t，J＝7.2，15.2，8.0Hz，1H)，7.35-7.46(m，4H)，7.22(d，J＝7.6Hz，2H)，7.05(t，J＝7.2，14.8，7.6Hz，2H)，6.88(t，J＝14.4，7.2Hz，2H)，6.77(s，2H)，6.41(s，1H)；
IR：3412cm
-1，1615cm
-1，1600cm
-1，1522cm
-1，1456cm
-1，1353cm
-1，1346cm
-1，1095cm
-1，743cm
-1.
The above results show synthetic product be 3,3 '-((2-nitrophenyl) methylene radical)-two-(1H-indoles), structural formula is following:
Embodiment 4
In water and pyridine mixed solvent lipase-catalyzed synthetic 3,3 '-((4-chloro-phenyl-) methylene radical)-two-(1H-indoles) (3,3 '-((4-nitrophenyl) methylene) bis (1H-indole))
The indoles (14.2mol) of 400 gram 4-chloro-benzaldehydes (28.4mol) and 167 grams joined the formation volume is the reaction system of 1.5L in the mixed solvent that water and the formed TV of pyridine are 1L, the volume ratio of water and pyridine is 2/3.Then, add the porcine pancreatic lipase (PPL) of 50 grams (104000units), reacted 48 hours down, make nitrogen heterocyclic verivate with two indyl structures at 60 ℃.
Using the productive rate of the above-mentioned nitrogen heterocyclic verivate of liquid chromatogram measuring is 91.4%.After above-mentioned nitrogen heterocyclic verivate purified through column chromatography chromatogram method (adopt silica gel as filler), characterize the affirmation structure with proton nmr spectra and infrared spectrum, the result is following:
1H-NMR(400MHz，DMSO-d
6)δ10.87(s，2H)，7.37(d，J＝8.0Hz，3H)，7.31(t，J＝7.2，15.2，8.0Hz，4H)，7.05(t，J＝7.6，14.8，7.2Hz，2H)，6.88(m，4H)，5.89(s，1H)；
IR；3411cm
-1，1613cm
-1，1594cm
-1，1474cm
-1，1456cm
-1，1353cm
-1，1095cm
-1，743cm
-1.
The above results show synthetic product be 3,3 '-((4-chloro-phenyl-) methylene radical)-two-(1H-indoles), structural formula is following:
Embodiment 5
In water and dioxane mixed solvent lipase-catalyzed synthetic 3,3 '-((4-hydroxy phenyl) methylene radical)-two-(1H-indoles) (3,3 '-((4-hydroxylphenyl) methylene) bis (1H-indole))
The indoles (32.8mol) of 100 gram PARA HYDROXY BENZALDEHYDEs (8.2mmol) and 384 grams joined the formation volume is the reaction system of 1.4L in the mixed solvent that water and the formed TV of dioxane are 1L, the volume ratio of water and dioxane is 5/1.Then, add people's steapsase (HPL) of 20 grams (480000units), reacted 36 hours down, make nitrogen heterocyclic verivate with two indyl structures at 50 ℃.
Using the productive rate of the above-mentioned nitrogen heterocyclic verivate of liquid chromatogram measuring is 94.2%.After above-mentioned nitrogen heterocyclic verivate purified through column chromatography chromatogram method (adopt silica gel as filler), characterize the affirmation structure with proton nmr spectra and infrared spectrum, the result is following:
1H-NMR(400MHz，DMSO-d
6)δ10.78(s，2H)，9.23(s，1H)，7.34(d，J＝8.0Hz，2H)，7.26(d，J＝8.4Hz，2H)，7.14(d，J＝8.8Hz，2H)，7.02(t，J＝7.2，14.8，7.6Hz，2H)，6.85(t，J＝7.6，.14.8，7.2Hz，2H)，6.78(s，2H)，6.66(d，J＝8.0Hz，2H)，5.71(s，1H)；
IR：3446cm
-1，3426cm
-1，3405cm
-1，1614cm
-1，1597cm
-1，1512cm
-1，1485cm
-1，1456cm
-1，1353cm
-1，1089cm
-1，743cm
-1.
The above results show synthetic product be 3,3 '-((4-hydroxy phenyl) methylene radical)-two-(1H-indoles), structural formula is following:
Embodiment 6
Lipase-catalyzed synthetic 3-in water and acetonitrile mixed solvent (1-(1H-indol-3-yl) ethyl)-1H-indoles (3-(1-(1H-indol-3-yl) ethyl)-1H-indole)
The indoles (20mol) of 44 gram acetaldehyde (10mol) and 234 grams joined the formation volume is the reaction system of 1.6L in the mixed solvent that water and the formed TV of acetonitrile are 1L, the volume ratio of water and acetonitrile is 10/1.Then, add the porcine pancreatic lipase (PPL) of 100 grams (208000units), reacted 24 hours down, make nitrogen heterocyclic verivate with two indyl structures at 37 ℃.
Using the productive rate of the above-mentioned nitrogen heterocyclic verivate of liquid chromatogram measuring is 90%.After above-mentioned nitrogen heterocyclic verivate purified through column chromatography chromatogram method (adopt silica gel as filler), characterize the affirmation structure with proton nmr spectra and infrared spectrum, the result is following:
1H-NMR(400MHz，CDCl
3)δ7.81(s，2H)，7.48(d，J＝8.0Hz.2H)，7.23(d，J＝8.0Hz，2H)，7.06(t，J＝7.2，14.8，7.6Hz，2H)，6.94(t，J＝7.6，14.8，7.2Hz，2H)，6.79(s，2H)，4.58(m，1H)，1.71(d，J＝7.2Hz，3H)；
IR：3408cm
-1，1617cm
-1，1596cm
-1，1455cm
-1，1352cm
-1，1094cm
-1，743cm
-1。
The above results shows that synthetic product is 3-(1-(1H-indol-3-yl) ethyl)-1H-indoles, and structural formula is following:
Embodiment 7
Lipase-catalyzed synthetic 5-in THF and water mixed solvent (two (1H-indol-3-yl) methyl)-2-methoxyphenol (5-(di (1H-indol-3-yl) methyl)-2-methoxyphenol)
The indoles (13.2mmol) of 100 gram 4-methoxyl group-3-hydroxy benzaldehydes (6.6mmol) and 150 grams joined the formation volume is the reaction system of 3.2L in the mixed solvent that THF and the formed TV of water are 3L, the volume ratio of THF and water is 1/10.Then, add people's steapsase (HPL) of 30 grams (720000units), reacted 20 hours down, make nitrogen heterocyclic verivate with two indyl structures at 40 ℃.
Using the productive rate of the above-mentioned nitrogen heterocyclic verivate of liquid chromatogram measuring is 75.8%.After above-mentioned nitrogen heterocyclic verivate purified through column chromatography chromatogram method (adopt silica gel as filler), characterize the affirmation structure with proton nmr spectra and infrared spectrum, the result is following:
1H-NMR(400MHz，CDCl
3)δ7.74(s，2H)，7.50(d，J＝8.0Hz，2H)，7.30(d，J＝8.0Hz，2H)，7.19(t，J＝7.2，14.8，7.6Hz，2H)，7.05(t，J＝14.4，7.2Hz，2H)，6.75-6.83(m，3H)，6.62(s，2H)，6.34(s，1H)，5.91(s，1H)，3.90(s，3H)；
IR：3502cm
-1，3413cm
-1，1615cm
-1，1592cm
-1，1478cm
-1，1455cm
-1，1350cm
-1，1086cm
-1，741cm
-1.
The above results shows that synthetic product is 5-(two (1H-indol-3-yl) methyl)-2-methoxyphenol, and structural formula is following:
Embodiment 8
Lipase-catalyzed synthetic 4-bromo-2-(two (1H-indol-3-yl)-methyl) phenol (4-bromo-2-(di (1H-indol-3-yl)-methyl) phenol) in water and ETHYLE ACETATE mixed solvent
The indoles (1mol) of 10 gram 5-bromo-2-hydroxy benzaldehydes (5mol) and 11.7 grams joined the formation volume is the reaction system of 1L in the mixed solvent that water and the formed TV of ETHYLE ACETATE are 1L, the volume ratio of water and ETHYLE ACETATE is 8/1.Then, add the porcine pancreatic lipase (PPL) of 25 grams (52000units), reacted 32 hours down, make nitrogen heterocyclic verivate with two indyl structures at 45 ℃.
Using the productive rate of the above-mentioned nitrogen heterocyclic verivate of liquid chromatogram measuring is 99.0%.After above-mentioned nitrogen heterocyclic verivate purified through column chromatography chromatogram method (adopt silica gel as filler), characterize the affirmation structure with proton nmr spectra and infrared spectrum, the result is following:
1H-NMR(400MHz，CDCl
3)δ7.96(s，2H)，7.42(d，J＝8.0Hz，2H)，7.35(t，J＝8.0，18.4，10.4Hz，3H)，7.21-7.30(m，4H)，7.07(t，J＝7.6，14.8，7.2Hz，2H)，6.75(d，J＝8.4Hz，1H)，6.67(s，2H)，5.99(s，1H)，5.66(s，1H)；
IR：3411cm
-1，1618cm
-1，1593cm
-1，1487cm
-1，1456cm
-1，1338cm
-1，1098cm
-1，743cm
-1.
The above results shows that synthetic product is 4-bromo-2-(two (1H-indol-3-yl)-methyl) phenol, and structural formula is following:
Embodiment 9
In the mixed solvent of water and acetone lipase-catalyzed synthetic 3,3 '-((4-nitrophenyl) methylene radical) two (5-bromo-1H-indoles) (3,3 '-((4-nitrophenyl) methylene) bis (5-bromo-1H-indole))
The 5-bromo indole (9.44mol) of 50 gram paranitrobenzaldehydes (4.72mol) and 152.8 grams is joined the formation volume is the reaction system of 1.6L in the mixed solvent of water that volume is 1.5L and acetone, the volume ratio of water and acetone is 3/1.Then, add people's steapsase (HPL) of 20 grams (48000units), reacted 20 hours down, make nitrogen heterocyclic verivate with two indyl structures at 40 ℃.
Using the productive rate of the above-mentioned nitrogen heterocyclic verivate of liquid chromatogram measuring is 89.0%.After above-mentioned nitrogen heterocyclic verivate purified through column chromatography chromatogram method (adopt silica gel as filler), characterize the affirmation structure with proton nmr spectra and infrared spectrum, the result is following:
1H-NMR(400MHz，CDCl
3)δ7.90(s，1H)，7.82(s，1H)，7.37-7.40(m，4H)，7.06-7.35(m，5H)，7.01(s，1H)，7.0(s，1H)，6.66(s，1H)，6.61(s，2H)，5.87(s1H)；
IR：3420cm
-1，1612cm
-1，1594cm
-1，1501cm
-1，1487cm
-1，1456cm
-1，1338cm
-1，1092cm
-1，744cm
-1.
The above results show synthetic product be 3,3 '-((4-nitrophenyl) methylene radical) two (5-bromo-1H-indoles), structural formula is following:
Embodiment 10
In the mixed solvent of pyridine and acetone lipase-catalyzed synthetic 3,3 '-((4-nitrophenyl) methylene radical) two (5-nitros-1H-indoles) (3,3 '-((4-nitrophenyl) methylene) bis (5-nitro-1H-indole))
The 5-nitroindoline (6.6mol) of 50 gram paranitrobenzaldehydes (4.72mol) and 185 grams is joined the formation volume is the reaction system of 2L in the mixed solvent of pyridine that volume is 1.8L and acetone, the volume ratio of pyridine and acetone is 3/1.Then, add 30 grams (72000units) people's steapsase (HPL), 36 ℃ of reactions 27 hours down, make nitrogen heterocyclic verivate with two indyl structures.
Using the productive rate of the above-mentioned nitrogen heterocyclic verivate of liquid chromatogram measuring is 92.0%.After above-mentioned nitrogen heterocyclic verivate purified through column chromatography chromatogram method (adopt silica gel as filler), characterize the affirmation structure with proton nmr spectra and infrared spectrum, the result is following:
1H-NMR(400MHz，CDCl
3)δ7.98(d，1H，J＝8.4Hz)，7.64(d，2H，J＝8.0Hz)，7.24-7.29(m，8H)，7.20(d，2H，J＝8.4Hz)，7.11(d，2H，J＝6.8Hz)，7.04(s，2H)，6.52(s，2H)，5.71(s，1H)，2.32(s?3H)；
IR：3420cm
-1，1608cm
-1，1589cm
-1，1508cm
-1，1487cm
-1，1456cm
-1，1336cm
-1，1092cm
-1，746cm
-1.
The above results show synthetic product be 3,3 '-((4-nitrophenyl) methylene radical) two (5-nitros-1H-indoles), structural formula is following:
Claims (6)
1. lipase-catalyzed synthetic method with nitrogen heterocyclic verivate of two indyl structures comprises:
With indoles or indole derivatives and aldehyde and solvent formation reaction system, 35 ℃～60 ℃ reactions 12 hours～72 hours, make nitrogen heterocyclic verivate behind the adding lypase with two indyl structures; Wherein, the consumption of lypase is 15000units～1500000units in every liter of reaction system;
Described solvent is that water, volume ratio are water-hexanaphthene mixture of 3: 1, water-N that volume ratio is 3: 7, pyridine-acetone mixture that water-acetonitrile mixture that dinethylformamide, volume ratio are water-pyridine mixtures of 2: 3, water-dioxane mixture that volume ratio is 5: 1, volume ratio is 10: 1, THF-water mixture that volume ratio is 1: 10, water-ethyl acetate mixture that volume ratio is 8: 1, water-acetone mixture that volume ratio is 3: 1 or volume ratio are 3: 1;
Described indoles or indole derivatives are the compound of structure shown in the structural formula II:
Among the formula II, R
1Be H or methyl; R
2Be H, methyl or bromine; R
3Be H, methyl, nitro, bromine or methoxyl group.
2. lipase-catalyzed synthetic method according to claim 1 with nitrogen heterocyclic verivate of two indyl structures, it is characterized in that: described aldehyde is the compound of structure shown in the structural formula II I:
In the formula III, R
4Be H, methyl, ethyl, propyl group, sec.-propyl, phenyl, hydroxyl, benzyl, p-methoxyphenyl, p-nitrophenyl, m-nitro base, ortho-nitrophenyl base, rubigan, p-hydroxybenzene, pyridyl, N, N-dimethylamino phenyl, 5-bromo-2-hydroxy phenyl or 4-methoxyl group-3-hydroxy phenyl.
3. lipase-catalyzed synthetic method with nitrogen heterocyclic verivate of two indyl structures according to claim 1, it is characterized in that: described lypase is porcine pancreatic lipase or people's steapsase.
4. lipase-catalyzed synthetic method according to claim 1 with nitrogen heterocyclic verivate of two indyl structures, it is characterized in that: described temperature of reaction is 35 ℃～60 ℃, the reaction times is 12 hours～72 hours.
5. lipase-catalyzed synthetic method with nitrogen heterocyclic verivate of two indyl structures according to claim 1 is characterized in that: the consumption of indoles or indole derivatives is 1mol～35mol in every liter of reaction system.
6. lipase-catalyzed synthetic method with nitrogen heterocyclic verivate of two indyl structures according to claim 1, it is characterized in that: the mol ratio of described aldehyde and indoles or indole derivatives is 0.25～5.
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| WO2006025889A2 (en) * | 2004-05-21 | 2006-03-09 | The Texas A & M University System | Inhibition of atherosclerosis by diindolylmethane analogs |
| CN101585800A (en) * | 2009-06-19 | 2009-11-25 | 中国科学院上海有机化学研究所 | Bis(indolyl)methane compound with bioactivity |
| CN101585799A (en) * | 2009-06-19 | 2009-11-25 | 中国科学院上海有机化学研究所 | Method for preparing unsymmetrical bis(indolyl)methane compound |
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| CN101585800A (en) * | 2009-06-19 | 2009-11-25 | 中国科学院上海有机化学研究所 | Bis(indolyl)methane compound with bioactivity |
| CN101585799A (en) * | 2009-06-19 | 2009-11-25 | 中国科学院上海有机化学研究所 | Method for preparing unsymmetrical bis(indolyl)methane compound |
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