CN101979631A - 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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- WOJBBIJJRKFKOJ-UHFFFAOYSA-N CC(c1c[nH]c2c1cccc2)c1c[nH]c2ccccc12 Chemical compound CC(c1c[nH]c2c1cccc2)c1c[nH]c2ccccc12 WOJBBIJJRKFKOJ-UHFFFAOYSA-N 0.000 description 1
- JHFRGGQERATAMF-UHFFFAOYSA-N [O-][N+](c1ccccc1C(c1c[nH]c2ccccc12)c1c[nH]c2c1cccc2)=O Chemical compound [O-][N+](c1ccccc1C(c1c[nH]c2ccccc12)c1c[nH]c2c1cccc2)=O JHFRGGQERATAMF-UHFFFAOYSA-N 0.000 description 1
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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 synthetic method of nitrogen heterocyclic derivative, relate in particular to a kind of lipase-catalyzed synthetic method with nitrogen heterocyclic derivative of two indyl structures.
Background technology
Cascade reaction is the very important reaction of a class in organic synthesis.Cascade reaction be owing to can save the time and efforts that is used on the isolation of intermediate products, and its efficient is than synthesis efficiency height progressively, and cascade reaction can reduce the generation of refuse simultaneously, avoids the accumulation of unstable intermediate.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), 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 a class 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 lipase 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 method (" Chem.Commun " 2004 of the imdazole derivatives that two step of proteolytic enzyme one kettle way synthetic nitrogen replaces; 2006) and method (" Adv.Synth.Catal " 2009 of the derivative of the synthetic monose of D-amino acid acylated enzyme catalysis; 351,1833).
Indoles and derivative 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 needing to develop new environment amenable catalyzer comes catalysis to synthesize two indyl alkane compounds, come catalytic combination to become the method for two indyl alkane compounds as developing a kind of multifunctionality of enzyme of utilizing, 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 derivative of two indyl structures.
A kind of lipase-catalyzed synthetic method with nitrogen heterocyclic derivative 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 derivative behind the adding lipase with two indyl structures; Wherein, the consumption of lipase 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 by the katalysis of lipase in the presence of solvent, and then cancellation, carry out the Michael addition reaction at last, thereby generate nitrogen heterocyclic derivative 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 lipase 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 derivative 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 as follows:
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 dimethyl sulfoxide (DMSO), N, one or both in dinethylformamide, dioxane, acetonitrile, octane, ethanol, toluene, tetrahydrofuran (THF) (THF), ethyl acetate, normal hexane, hexanaphthene, chloroform, methylene dichloride, water, pyridine, the acetone.
When lipase reacts in catalysis one class, have suitable solvent usually.Lipase 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 lipase are used, and can quicken the dissolving of substrate, and can not influence the efficient of lipase-catalyzed this reaction, lipase just better such reaction of catalysis in mixed solvent like this.Therefore, the mixed solvent of the preferred multiple solvent of described solvent.
Described lipase can adopt the conventional commercially available lipase 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 as Sigma company (Sigma company).
According to the temperature of reaction of lipase 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 ℃, and more preferably 35 ℃～60 ℃, the reaction times is preferably 12 hours～and 72 hours.
In order to reduce consumption of raw materials, to save 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 derivative with two indyl structures that generates in the inventive method can be by 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 ethyl acetate by sherwood oil and form, and wherein the volume ratio of sherwood oil and ethyl acetate general 1: 0.05～30.
The inventive method adopts and utilize lipase-catalyzed synthetic nitrogen heterocyclic derivative 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, the reaction conditions gentleness, separating step is few, has realized having nitrogen heterocyclic derivative synthetic 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 are 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 derivative with two indyl structures at 40 ℃.
Productive rate with the above-mentioned nitrogen heterocyclic derivative of liquid chromatogram measuring is 79.7%.After above-mentioned nitrogen heterocyclic derivative purified by column chromatography chromatogram method (adopt silica gel as filler), characterize with proton nmr spectra and infrared spectrum and to confirm structure, the result is as follows:
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 as follows:
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 are joined the formation volume is the reaction system of 5.3L in the mixed solvent that water and the formed cumulative volume 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 derivative with two indyl structures at 50 ℃.
Productive rate with the above-mentioned nitrogen heterocyclic derivative of liquid chromatogram measuring is 80%.After above-mentioned nitrogen heterocyclic derivative purified by column chromatography chromatogram method (adopt aluminum oxide as filler), characterize with proton nmr spectra and infrared spectrum and to confirm structure, the result is as follows:
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 as follows:
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 cumulative volume 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 derivative with two indyl structures at 55 ℃.
Productive rate with the above-mentioned nitrogen heterocyclic derivative of liquid chromatogram measuring is 70.8%.After above-mentioned nitrogen heterocyclic derivative purified by column chromatography chromatogram method (adopt silica gel as filler), characterize with proton nmr spectra and infrared spectrum and to confirm structure, the result is as follows:
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 as follows:
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 are joined the formation volume is the reaction system of 1.5L in the mixed solvent that water and the formed cumulative volume 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 derivative with two indyl structures at 60 ℃.
Productive rate with the above-mentioned nitrogen heterocyclic derivative of liquid chromatogram measuring is 91.4%.After above-mentioned nitrogen heterocyclic derivative purified by column chromatography chromatogram method (adopt silica gel as filler), characterize with proton nmr spectra and infrared spectrum and to confirm structure, the result is as follows:
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 as follows:
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 p-Hydroxybenzaldehydes (8.2mmol) and 384 grams are joined the formation volume is the reaction system of 1.4L in the mixed solvent that water and the formed cumulative volume 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 derivative with two indyl structures at 50 ℃.
Productive rate with the above-mentioned nitrogen heterocyclic derivative of liquid chromatogram measuring is 94.2%.After above-mentioned nitrogen heterocyclic derivative purified by column chromatography chromatogram method (adopt silica gel as filler), characterize with proton nmr spectra and infrared spectrum and to confirm structure, the result is as follows:
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 as follows:
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 are joined the formation volume is the reaction system of 1.6L in the mixed solvent that water and the formed cumulative volume 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 derivative with two indyl structures at 37 ℃.
Productive rate with the above-mentioned nitrogen heterocyclic derivative of liquid chromatogram measuring is 90%.After above-mentioned nitrogen heterocyclic derivative purified by column chromatography chromatogram method (adopt silica gel as filler), characterize with proton nmr spectra and infrared spectrum and to confirm structure, the result is as follows:
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 as follows:
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 are joined the formation volume is the reaction system of 3.2L in the mixed solvent that THF and the formed cumulative volume 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 derivative with two indyl structures at 40 ℃.
Productive rate with the above-mentioned nitrogen heterocyclic derivative of liquid chromatogram measuring is 75.8%.After above-mentioned nitrogen heterocyclic derivative purified by column chromatography chromatogram method (adopt silica gel as filler), characterize with proton nmr spectra and infrared spectrum and to confirm structure, the result is as follows:
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 as follows:
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 ethyl acetate mixed solvent
The indoles (1mol) of 10 gram 5-bromo-2-hydroxy benzaldehydes (5mol) and 11.7 grams are joined the formation volume is the reaction system of 1L in the mixed solvent that water and the formed cumulative volume of ethyl acetate are 1L, the volume ratio of water and ethyl acetate is 8/1.Then, add the porcine pancreatic lipase (PPL) of 25 grams (52000units), reacted 32 hours down, make nitrogen heterocyclic derivative with two indyl structures at 45 ℃.
Productive rate with the above-mentioned nitrogen heterocyclic derivative of liquid chromatogram measuring is 99.0%.After above-mentioned nitrogen heterocyclic derivative purified by column chromatography chromatogram method (adopt silica gel as filler), characterize with proton nmr spectra and infrared spectrum and to confirm structure, the result is as follows:
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 as follows:
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 indoles (9.44mol) of 50 gram paranitrobenzaldehydes (4.72mol) and 152.8 grams are 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 derivative with two indyl structures at 40 ℃.
Productive rate with the above-mentioned nitrogen heterocyclic derivative of liquid chromatogram measuring is 89.0%.After above-mentioned nitrogen heterocyclic derivative purified by column chromatography chromatogram method (adopt silica gel as filler), characterize with proton nmr spectra and infrared spectrum and to confirm structure, the result is as follows:
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 as follows:
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-nitroindolines (6.6mol) of 50 gram paranitrobenzaldehydes (4.72mol) and 185 grams are 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 derivative with two indyl structures.
Productive rate with the above-mentioned nitrogen heterocyclic derivative of liquid chromatogram measuring is 92.0%.After above-mentioned nitrogen heterocyclic derivative purified by column chromatography chromatogram method (adopt silica gel as filler), characterize with proton nmr spectra and infrared spectrum and to confirm structure, the result is as follows:
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 as follows:
Claims (9)
1. lipase-catalyzed synthetic method with nitrogen heterocyclic derivative 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 derivative behind the adding lipase with two indyl structures; Wherein, the consumption of lipase is 15000units～1500000units in every liter of reaction system; Solvent is the mixed solvent of a kind of solvent or multiple solvent.
2. lipase-catalyzed synthetic method according to claim 1 with nitrogen heterocyclic derivative of two indyl structures, it is characterized in that: 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.
3. lipase-catalyzed synthetic method according to claim 1 with nitrogen heterocyclic derivative 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.
4. lipase-catalyzed synthetic method according to claim 1 with nitrogen heterocyclic derivative of two indyl structures, it is characterized in that: described solvent is dimethyl sulfoxide (DMSO), N, one or both in dinethylformamide, dioxane, acetonitrile, octane, ethanol, toluene, tetrahydrofuran (THF), ethyl acetate, normal hexane, hexanaphthene, chloroform, methylene dichloride, water, pyridine, the acetone.
5. lipase-catalyzed synthetic method with nitrogen heterocyclic derivative of two indyl structures according to claim 1, it is characterized in that: described lipase is porcine pancreatic lipase or people's steapsase.
6. lipase-catalyzed synthetic method according to claim 1 with nitrogen heterocyclic derivative of two indyl structures, it is characterized in that: described temperature of reaction is 25 ℃～60 ℃, the reaction times is 12 hours～72 hours.
7. lipase-catalyzed synthetic method according to claim 6 with nitrogen heterocyclic derivative of two indyl structures, it is characterized in that: described temperature of reaction is 35 ℃～60 ℃, the reaction times is 12 hours～72 hours.
8. lipase-catalyzed synthetic method with nitrogen heterocyclic derivative 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.
9. lipase-catalyzed synthetic method with nitrogen heterocyclic derivative 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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| CN109456998A (en) * | 2018-12-17 | 2019-03-12 | 南京工业大学 | A kind of method of lipase-catalyzed synthesis Dicoumarin Derivatives |
| CN110408660A (en) * | 2019-07-09 | 2019-11-05 | 南京工业大学 | A kind of method of lipase-catalyzed synthesis bis-indole compounds |
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| CN109456998A (en) * | 2018-12-17 | 2019-03-12 | 南京工业大学 | A kind of method of lipase-catalyzed synthesis Dicoumarin Derivatives |
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| CN110408660B (en) * | 2019-07-09 | 2022-09-16 | 南京工业大学 | Method for synthesizing bisindole compound under catalysis of lipase |
| CN113373187A (en) * | 2021-05-26 | 2021-09-10 | 江苏阿尔法药业股份有限公司 | Nitrogen heterocyclic compound C27H30FNO6Enzyme-catalyzed synthesis method of |
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