CN1562969A - Method for preparing instable substituent N-containing pair of alkali-ethylene substitution pyrrole - Google Patents

Method for preparing instable substituent N-containing pair of alkali-ethylene substitution pyrrole Download PDF

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CN1562969A
CN1562969A CN 200410017547 CN200410017547A CN1562969A CN 1562969 A CN1562969 A CN 1562969A CN 200410017547 CN200410017547 CN 200410017547 CN 200410017547 A CN200410017547 A CN 200410017547A CN 1562969 A CN1562969 A CN 1562969A
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highly basic
pyrroles
substituting group
group
unstable
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CN100358866C (en
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毛振民
杨世琼
刘兰芳
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SHANGHAI JINSE MEDICAL TECHNOLOGY DEVELOPMENT Co Ltd
Shanghai Jiaotong University
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SHANGHAI JINSE MEDICAL TECHNOLOGY DEVELOPMENT Co Ltd
Shanghai Jiaotong University
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Abstract

In this invention prepn., raw material pyrrole contg. strong alkali unstable substituting group and 1,2-dihalo ethane with molar ratio of (1:1) to (20:1), inthe presence of alkali, placed in organic solvent proceeding nitro-ethylenation to obtain compound-N-ethenyl substituted pyrrole with strong alkali unstable substituting group. The reaction temp. is 40-120 deg.C for 2-40 hrs. In this invention process, high temp., high pressure and strong alkali are not needed.

Description

Contain preparation method to the unstable substituting group N-of highly basic vinyl substituted pyrroles
Technical field
The present invention relates to a kind of preparation method who contains the unstable substituting group N-of highly basic vinyl substituted pyrroles, belong to the heterocycle technical field of organic chemistry.
Background technology
The replacement of the nitrogen on the 5-member heterocyclic ring containing nitrogen pyrrole ring is the emphasis of heterocycle organic chemistry research always.Especially the poly pyrroles be found have good electroconductibility after, pyrroles and derivative thereof have obtained further attention, this derivative can be used to the research that the poly pyroles extremely has the conducting polymer composite of application prospect, also can be used as the research that important intermediate is used for new chemical medicine and organic dye etc.N-vinyl substituted pyrroles is the requisite basis of research poly pyrroles.
At present, the pyrroles of synthetic N-vinyl substituted needs High Temperature High Pressure and carries out under highly basic and strong solvent condition.In the eighties in last century, USSR (Union of Soviet Socialist Republics) scientist Trofimov (Trofimov BA, Atavin AS, Mikhaleva AI, Kalabin GA, Chebotareva EG.Zh.Org.Khim.1973; 9,2205; Trofimov BA.Vinylpyrroles, Pyrroles, part two, The Chemistry of Heterocyclic Compounds., Vol 48, Jones RA Ed., p131, Wiley, New York, 1992) found that the super alkaline condition of application (KOH/DMSO) prepares N-vinyl substituted pyrroles's method (Trofimov reaction).The Trofimov reaction needs with acetylene at 100 to 200 ℃.Under superpower alkalescence and condition of high voltage, generate corresponding N-vinyl substituted pyrroles with ketoxime (Ketoxine) step.
In the formula: R 1, R 2Be hydrogen, alkyl or fragrant cyclic group, wherein R 1, R 2Have at least one to be alkyl or fragrant cyclic group.
Because of being subjected to the limitation that Trofimov reacts superpower reaction conditions, the N-vinyl substituted pyrroles that can prepare and use at present substantially all be alkyl, the replacement of fragrant cyclic group and under the highly basic condition stable pyrrole derivative.Therefore, the deficiency of Trofimov method is a severe reaction conditions, and can not be used for the synthetic N-vinyl substituted azole compounds that contains unstable substituted radical under strong alkaline condition such as ester group, ketone group, aldehyde radical.
1971, W.J.Irwin (W.J.Irwin and D.L.Wheeler, Tetrahedron.Vol.28, pp.1113 to 1121.Pergamon press 1972.) report carries out the reaction of nitrogen vinylation with potassium hydroxide and oxyethane to 2-methyl acetate base pyrroles, but methoxycarbonyl is broken to acid as a result, this method has been used highly basic potassium hydroxide, does not obtain containing the N-vinyl substituted pyrroles of methoxycarbonyl, and methoxycarbonyl is a kind of to the unsettled substituting group of highly basic.
1998, Paola Ciapetti (Paola Ciapetti and Maurizio Taddei, Tetrahedron54 (1998) 11305-11310.) for example guanine, VITAMIN B4, cytosine(Cyt) are raw material to report with nitrogen heterocyclic ring, be dissolved in the dimethyl formamide, with Anhydrous potassium carbonate and 1,70 ℃ of about 72h of reaction in the 2-ethylene dibromide, get the vinylated purine compound of nitrogen, this method is not mentioned carries out synthesizing of pyrroles's nitrogen vinyl compound, and the nitrogen that only relates to nitrogenous purine or pyrimidine is vinylated.
2000, Dariusz Bogdal (Dariusz Bogdal and Krzysztof Jaskot, SyntheticCommunications, 30 (2000), 3341-3352) be reported under the solid-liquid phase transfer catalysis condition with nitrogen heterocyclic ring for example the pyrroles be raw material, join 1 of vigorous stirring, 2-ethylene dichloride, Tetrabutyl amonium bromide, potassium hydroxide, in the mixture of salt of wormwood, 45～50 ℃ of reaction 3.5～5.5h have synthesized without any the nitrogen vinyl substituted pyrroles who replaces.This method has been used highly basic potassium hydroxide equally, can not be used for the synthetic N-vinyl substituted azole compounds that contains unstable substituted radical under strong alkaline condition such as ester group, ketone group, aldehyde radical.
Summary of the invention
The objective of the invention is at the deficiencies in the prior art, a kind of pyrroles N-vinylation method of novel mild condition is provided, research is synthetic to be contained to the unstable substituting group N-of highly basic vinyl substituted pyrroles, as replenishing the Trofimov reaction.
A kind of preparation method who contains the unstable substituting group N-of highly basic vinyl substituted pyrroles of the present invention, it is characterized in that to contain the unstable substituting group pyrroles of highly basic be raw material, utilize 1,2-dihalo ethane is in the presence of alkali, place organic solvent to carry out the reaction of nitrogen vinylation, synthesising target compound.
Wherein, organic solvent is a dimethyl formamide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), tetramethylene sulfone, N-Methyl pyrrolidone or 1,3-dimethyl-2-pyrazolone; Contain the unstable substituting group pyrroles and 1 of highly basic, the mol ratio of 2-dihalo ethane and alkali is 1: 1～20: 1～20, preferred 1: 5～15: 5～15;
Temperature of reaction is 40～120 ℃, and is preferred: 50～100 ℃; Reaction times is 2～40 hours, and is preferred: 5～20 hours; It is new compound that target compound contains the unstable substituting group N-of highly basic vinyl substituted pyrroles.
Its reaction equation is as follows:
R in the formula 1, R 2, R 3, R 4Can be hydrogen, alkyl, halogen, fragrant cyclic group, ester group, ethanoyl, nitro, aldehyde radical or itrile group, but R 1, R 2, R 3, R 4In have ester group, ethanoyl, nitro, aldehyde radical or an itrile group at least.
Also can have simultaneously alkyl, the replacement of fragrant cyclic group or halogenated pyrroles to the unstable substituting group pyrroles of highly basic for containing single or multiple ester groups, ethanoyl, nitro, aldehyde radical, itrile group of the present invention containing.
As shown from the above technical solution, because reaction of the present invention does not need High Temperature High Pressure and highly basic, so reaction conditions is comparatively gentle, can synthesize simultaneously to contain the N-vinyl pyrrole of highly basic instability to Dai Ji.
Embodiment
The present invention will be further described below by embodiment, so that better understand the present invention, but it does not limit protection scope of the present invention, and the experimental technique of unreceipted actual conditions in the following example is usually according to normal condition.
Embodiment 1
3,4-diethyl-ester group pyrroles 200mg (0.95mmol) is dissolved in the 1ml dimethyl formamide (DMF), add Anhydrous potassium carbonate 1.31g (9.5mmol), add glycol dibromide 1.78g (9.5mmol), earlier 50 ℃ of stirring reactions 4 hours, again 80 ℃ of stirring reactions 10 hours.Reacting liquid filtering, filter cake washs with dimethyl formamide 4ml, and the filtrate rotary evaporation removes and desolvates, (eluent is a hexanaphthene to the gained residuum: ethyl acetate=2: 1) get white solid 1-vinyl-3 through silica gel column chromatography, 4-diethyl-ester group pyrroles, yield 55%, 53～58 ℃ of fusing points.Its analyzing test data is as follows:
IR (KBr compressing tablet, cm -1): 3142,1716 (s), 1508 (s), 1485 (s)
1HNMR(500MHz，CDCl 3)δ1.27(t，J＝6.95Hz，6H)，4.27(m，J＝7.2Hz，4H)，4.92(dd，Ja＝8.8Hz，Jb＝2Hz，1H)，5.31(dd，Ja＝15.7Hz，Jb＝2Hz，1H)，6.74(dd，Ja＝15.7Hz，Jb＝8.7Hz，1H)，7.38(s，2H)
13CNMR(MHz，CDCl 3)δ14.5，60.6，102.4，117.7，125.0，131.9，163.4
MS：237.1(m/z)
Ultimate analysis: C:60.50%, H:6.99%, N:5.84%
Calculate: C:60.18%, H:6.27%, N:5.85%
Embodiment 2
3-acetyl pyrrole 200mg (1.83mmol) is dissolved in the 2ml dimethyl formamide (DMF), adds Anhydrous potassium carbonate 2.53g (18.3mmol), adds the 1-bromine, and 2-monochloroethane 2.62g (18.3mmol) was 75 ℃ of stirring reactions 15 hours.Reacting liquid filtering, filter cake washs with dimethyl formamide 4ml, and the filtrate rotary evaporation removes and desolvates, and (eluent is a hexanaphthene to the gained residuum: ethyl acetate=4: 1) get light yellow viscous material 1-vinyl-3-acetyl pyrrole, yield 50% through silica gel column chromatography.Its analyzing test data is as follows:
λ Ethanol Max=268nm
1HNMR(400MHz，CDCl 3)δ1.25(s，3H)，4.84(dd，Ja＝9.2Hz，Jb＝2Hz，1H)，5.26(dd，Ja＝15.6Hz，Jb＝1.6Hz，1H)，6.66(s，1H)，6.81(dd，Ja＝15.6Hz，Jb＝9.2Hz，1H)，6.89(s，1H)，7.45(s，1H)
13CNMR(100MHz，CDCl 3)δ21.4，100.7，110.7，120.1，123.7，127.3，132.6，193.6
HRMS calculates C 8H 9NO (m/z): 135.0684, analytical results: 135.0688
Embodiment 3
2-ethoxycarbonyl 4-nitro-pyrrole 500mg (2.78mmol) was dissolved in the 4ml dimethyl formamide (DMF), adds Anhydrous potassium carbonate 3.84g (27.8mmol), adds glycol dibromide 5.22g (27.8mmol), 90 ℃ of stirring reactions 40 hours.Reacting liquid filtering, filter cake washs with dimethyl formamide 10ml, the filtrate rotary evaporation removes and desolvates, and (eluent is a hexanaphthene to the gained residuum: ethyl acetate=3: 1) get white solid 1-vinyl 2-ethoxycarbonyl 4-nitro-pyrrole, yield 40% through silica gel column chromatography.Its analyzing test data is as follows:
IR (KBr compressing tablet, cm -1): 3128,1703 (s), 1651 (s), 1539 (s)
1HNMR(400MHz，CDCl 3)δ1.37(s，3H)，4.34(q，2H)，5.13(d，J＝8.4Hz1H)，5.42(d，J＝15.6Hz，1H)，7.46(s，1H)，7.85(dd，Ja＝15.6Hz，Jb＝8.8Hz，1H)，7.94(s，1H)
13CNMR(100MHz，CDCl 3)δ14.2，61.3，106.1，113.2，122.2，132.0，159.8
HRMS calculates C 9H 10N 2O 4(m/z): 210.0641, analytical results: 210.0640
Embodiment 4
3-aldehyde-base pyrroles 250mg (2.63mmol) was dissolved in the 3ml dimethyl formamide (DMF), adds Anhydrous potassium carbonate 4.34g (31.4mmol), adds glycol dibromide 6.32g (33.6mmol), 70 ℃ of stirring reactions 23 hours.Reacting liquid filtering, filter cake washs with ether 10ml, add 5ml water, with ether 30ml extraction three times, collect the ether layer, spend the night with anhydrous sodium sulfate drying, suction filtration, the filtrate rotary evaporation removes and desolvates, and (eluent is a hexanaphthene to the gained residuum: ethyl acetate=2: 1) get light yellow oil 1-vinyl 3-aldehyde-base pyrroles, yield 38% through silica gel column chromatography.Its analyzing test data is as follows:
1HNMR(400MHz，CDCl 3)δ4.90(dd，Ja＝8.8Hz，Jb＝2Hz，1H)，5.30(dd，Ja＝15.6Hz，Jb＝2Hz，1H)，6.70(s，1H)，6.84(dd，Ja＝16Hz，Jb＝8.8Hz，1H)，6.94(s，1H)，7.47(s，1H)
HRMS calculates C 7H 7NO (m/z): 121.0528, analytical results: 121.0526

Claims (6)

1, a kind of preparation method who contains the unstable substituting group N-of highly basic vinyl substituted pyrroles, it is characterized in that to contain the unstable substituting group pyrroles of highly basic be raw material, utilize 1,2-dihalo ethane is in the presence of alkali, place organic solvent to carry out the reaction of nitrogen vinylation, synthetic new compound, promptly contain the unstable substituting group N-of highly basic vinyl substituted pyrroles, contain the unstable substituting group pyrroles and 1 of highly basic, the mol ratio of 2-dihalo ethane and alkali is 1: 1～20: 1～20, temperature of reaction is 40～120 ℃, and the reaction times is 2～40 hours.
2, the preparation method who contains the unstable substituting group N-of highly basic vinyl substituted pyrroles as claimed in claim 1 is characterized in that describedly containing the unstable substituting group pyrroles of highly basic and for containing single or multiple ester groups, ethanoyl, nitro, aldehyde radical, itrile group alkyl replacement or halogenated pyrroles also can being arranged simultaneously.
3, the preparation method who contains the unstable substituting group N-of highly basic vinyl substituted pyrroles as claimed in claim 1 is characterized in that describedly 1, and 2-dihalo ethane is glycol dibromide, 1, and 2-ethylene dichloride or 1-bromine or 2-monochloroethane.
4, the preparation method who contains the unstable substituting group N-of highly basic vinyl substituted pyrroles as claimed in claim 1 is characterized in that described organic solvent is a dimethyl formamide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), tetramethylene sulfone, N-Methyl pyrrolidone or 1,3-dimethyl-2-pyrazolone.
5, the preparation method who contains the unstable substituting group N-of highly basic vinyl substituted pyrroles as claimed in claim 1 is characterized in that described alkali is salt of wormwood, saleratus, yellow soda ash or sodium bicarbonate.
6, a kind of preparation method's synthetic of claim 1 that adopts contains the unstable substituting group N-of highly basic vinyl substituted pyrroles, it is characterized in that structure is:
R in the formula 1, R 2, R 3, R 4Be hydrogen, alkyl, halogen, fragrant cyclic group, ester group, ethanoyl, nitro, aldehyde radical or itrile group, but R 1, R 2, R 3, R 4In have at least one to be ester group, ethanoyl, nitro, aldehyde radical or itrile group.
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CN102516149A (en) * 2011-11-09 2012-06-27 上海交通大学 1,3,4 - Trisubstituted pyrrole compound and preparation method and application thereof

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SU1728239A1 (en) * 1989-11-10 1992-04-23 Иркутский институт органической химии СО АН СССР Method of n-vinylpyrrols synthesis
DE4039559A1 (en) * 1990-12-07 1992-06-11 Schering Ag FUNCTIONALIZED VINYLAZOLES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS CONTAINING THIS VINYLAZOLES AND THE USE THEREOF FOR THE PRODUCTION OF MEDICINAL PRODUCTS
EP0599036B1 (en) * 1992-11-25 1996-12-18 American Cyanamid Company Method for the preparation of 2-aryl-5-trifluoromethyl pyrrole compounds

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102516149A (en) * 2011-11-09 2012-06-27 上海交通大学 1,3,4 - Trisubstituted pyrrole compound and preparation method and application thereof
CN102516149B (en) * 2011-11-09 2014-08-20 上海交通大学 1,3,4 - Trisubstituted pyrrole compound and preparation method and application thereof

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