CN102351772A - Method for tandem synthesis of dipyrrole and its derivatives through one-pot process - Google Patents

Method for tandem synthesis of dipyrrole and its derivatives through one-pot process Download PDF

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CN102351772A
CN102351772A CN2011102444268A CN201110244426A CN102351772A CN 102351772 A CN102351772 A CN 102351772A CN 2011102444268 A CN2011102444268 A CN 2011102444268A CN 201110244426 A CN201110244426 A CN 201110244426A CN 102351772 A CN102351772 A CN 102351772A
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pyrroles
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邱方利
蒋华江
黄国波
葛昌华
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Abstract

The invention relates to a method for tandem synthesis of dipyrrole and its derivatives through a one-pot process. Dipyrrole and its derivatives have a structural formula as shown in formula (I). Dipyrrole and its derivatives are prepared in this way: trisubstituted alkene shown in formula (II) and isocyanide shown in formula (III) are taken as the main raw materials which react with the catalyst alkali at a certain temperature in an organic solvent so as to obtain the target product. The preparation method of dipyrrole and its derivatives in the invention has mild reaction conditions, and the products have good antibacterial activity and antitumor activity, wherein, the (I), (II) and (III) have the following structural formulas.

Description

The method of synthetic two pyrroles of a kind of one kettle way series connection and verivate thereof
Technical field
What the present invention relates to is the method for synthetic two pyrroles of a kind of one kettle way series connection and verivate thereof, and specifically relating to three substituted olefines and isonitrile is the method that main raw material prepares two pyrroles and verivate thereof.
Background technology
Pyrrole ring is one of important heterogeneous ring compound, and pyrroles and pyrrole derivative extensively are present among many natural products and the medicine.Particularly two pyrroles have the group of the synthetic precursor of various oceans natural product; The natural product that comprises uncommon 1,3 '-two pyroles groups that has been found that, the cytotoxicity that shows methicillin-resistant golden staphylococci (MRSA) and human cancer has stronger anti-microbial activity.
P-methyl benzenesulfonic acid isonitrile (TosMIC) is a kind of broad-spectrum synthon, in organic chemistry, has been widely used in synthetic various heterogeneous ring compounds, and making up pyrrole ring is its a most important purposes.Yet, begin simply and effectively synthetic 1,3 '-two pyrrole derivative from ready-made starting raw material and also do not appear in the newspapers; Have report to adopt microwave synthesis method and other complicated compound methods, these methods normally reaction scheme are long, and cost is higher, and raw material is difficult to obtain and harsh reaction conditions.Therefore, we have invented a kind of new and simple method, connect with TosMIC reaction one kettle way with polysubstituted alkene and synthesize 1,3 '-two pyrrole derivative.
Summary of the invention
The primary technical problem that the present invention solves is to provide a kind of 1,3 '-two new pyrrole derivative.
Invent described two pyrrole derivative, its structure is suc as formula shown in (I):
Figure BSA00000562029500011
In the formula (I), R 1, R 2=alkoxyl group, alkyl, ester group, cyanic acid, carbonyl etc.
Second technical problem that the present invention solves is to provide a kind of preparation method of above-mentioned two pyrrole derivative.
The preparation method of described two pyrrole derivative comprises following method:
Isonitrile reaction shown in olefin(e) compound shown in the formula (II) and the formula (III) obtains the compound shown in the formula (I);
Figure BSA00000562029500021
In the formula (II), R 1=alkoxyl group, alkyl and substituted aroma hydrocarbon thereof etc.; R 2=ester group, cyanic acid, carbonyl etc.; R 3=ester group, carbonyl etc.
In the formula (III), R=p-toluenesulfonyl, alkyl and aromatic hydrocarbon thereof etc.
Respectively aforesaid method is elaborated below.
The described reaction of the inventive method specifically can be according to carrying out as follows: a certain amount of formula (II) compound alkene and formula (III) compound isonitrile are main raw material, under nitrogen protection, are catalyzer with alkali, in organic solvent, react.Temperature of reaction is 0 ℃～60 ℃, reaction times 0.5～24h; Reaction finishes, and reaction solution is with saturated NH 4It is 7-8 that Cl solution is regulated the pH value, uses dichloromethane extraction then, merges organic layer and uses Na 2CO 3With saturated common salt water washing, anhydrous sodium sulfate drying, vacuum concentration,, obtain formula (I) two pyrrole derivative products with column chromatography or recrystallization purifying.
It is one of following that described solvent is selected from: compounds such as halogenated alkane, ester compound, ether compound, nitrile; One of preferred following: 1,2-ethylene dichloride, methylene dichloride, trichloromethane, tetracol phenixin, methyl acetate, ETHYLE ACETATE, propyl acetate, butylacetate, isopropyl acetate, dioxane, DMF, ether, propyl ether, isopropyl ether, THF, butyl ether, acetone, pimelinketone, acetonitrile, propionitrile; One of more preferably following: THF, DMF, acetonitrile.
Invent described catalyzer and comprise organic bases and mineral alkali, comprise Na 2CO 3, K 2CO 3, Cs 2CO 3, NaH, KOH, NaOH, DBU, TEA etc.
The amount of substance ratio that feeds intake of described formula (II) compound and formula (III) compound is recommended as 1.0: 0.8～and 2.5, preferred 1.0: 1.0～1.3.The volumetric usage of said solvent is recommended as 3～5ml/mmol in the quality of formula (II) compound.
Temperature of reaction is-10 ℃～60 ℃, reaction times 0.5～24h.
After reaction finishes, can adopt separation methods such as crystallization, filtration, column chromatography to separate and obtain formula (I) compound.
Beneficial effect of the present invention is embodied in following several respects: two pyrrole derivative preparing methods of the present invention are new approach, do not see bibliographical information so far.Two pyrrole derivative of the inventive method preparation, simple to operate, reaction conditions is gentle, and product has anti-microbial activity and anti-tumor activity preferably.
Embodiment
Below with specific embodiment technical scheme of the present invention is described, but protection scope of the present invention is not limited thereto:
Embodiment 1
Under nitrogen protection, with raw material ethyl-2-cyanic acid-3-ethoxy propylene ester: TosMIC: NaH (1: 1.2: 1.3) in molar ratio is mixed to join the anhydrous CH of 10mL 3Among the CN, stirring at room reaction 12h, reaction finishes, and reaction solution is with saturated NH 4It is 7-8 that Cl solution is regulated the pH value, uses methylene dichloride 10mL * 3 extractions then, merges organic layer, the Na with 10% 2CO 3Solution and saturated common salt water washing, anhydrous sodium sulfate drying, vacuum concentration is used column chromatography purification, obtains product 4-oxyethyl group-1 ' H-[1,3 '-two pyrroles]-3,4 '-dintrile, and product is a white solid, and yield is 53%.
Embodiment 2
Under nitrogen protection, with raw material ethyl-2-cyanic acid-3-ethoxy propylene ester: TosMIC: Cs 2CO 3(1: 1.2: 1.3) is mixed to join the anhydrous CH of 10mL in molar ratio 3Among the CN, stirring at room reaction 12h, reaction finishes, and reaction solution is with saturated NH 4It is 7-8 that Cl solution is regulated the pH value, uses methylene dichloride 10mL * 3 extractions then, merges organic layer, the Na with 10% 2CO 3Solution and saturated common salt water washing, anhydrous sodium sulfate drying, vacuum concentration is used column chromatography purification, obtains product 4-oxyethyl group-1 ' H-[1,3 '-two pyrroles]-3,4 '-dintrile, and product is a white solid, and yield is 49%.
Embodiment 3
Under nitrogen protection, with raw material ethyl-2-cyanic acid-3-ethoxy propylene ester: TosMIC: K 2CO 3(1: 1.2: 1.3) is mixed to join the anhydrous CH of 10mL in molar ratio 3Among the CN, stirring at room reaction 12h, reaction finishes, and reaction solution is with saturated NH 4It is 7-8 that Cl solution is regulated the pH value, uses methylene dichloride 10mL * 3 extractions then, merges organic layer, the Na with 10% 2CO 3Solution and saturated common salt water washing, anhydrous sodium sulfate drying, vacuum concentration is used column chromatography purification, obtains product 4-oxyethyl group-1 ' H-[1,3 '-two pyrroles]-3,4 '-dintrile, and product is a white solid, and yield is 28%.
Embodiment 4
Under nitrogen protection, with raw material ethyl-2-cyanic acid-3-ethoxy propylene ester: isonitrile: NaH (1: 1.2: 1.3) in molar ratio is mixed to join in the THF solvent of 10mL, stirring at room reaction 12h, and reaction finishes, and reaction solution is with saturated NH 4It is 7-8 that Cl solution is regulated pH value, uses methylene dichloride 10mL * 3 to extract then, and the merging organic layer is with 10% Na 2CO 3Solution and saturated common salt water washing, anhydrous sodium sulfate drying, vacuum concentration is used column chromatography purification, obtains product 4-oxyethyl group-1 ' H-[1,3 '-two pyrroles]-3,4 '-dintrile, and product is a white solid, and yield is 35%.
Embodiment 5
Under nitrogen protection, with raw material ethyl-2-cyanic acid-3-ethoxy propylene ester: isonitrile: NaH (1: 1.2: 1.3) in molar ratio is mixed to join in the dioxane solvent of 10mL, stirring at room reaction 12h, and reaction finishes, and reaction solution is with saturated NH 4It is 7-8 that Cl solution is regulated pH value, uses methylene dichloride 10mL * 3 to extract then, and the merging organic layer is with 10% Na 2CO 3Solution and saturated common salt water washing, anhydrous sodium sulfate drying, vacuum concentration is used column chromatography purification, obtains product 4-oxyethyl group-1 ' H-[1,3 '-two pyrroles]-3,4 '-dintrile, and product is a white solid, and yield is 28%.
Embodiment 6
Under nitrogen protection, with raw material ethyl-2-cyanic acid-3-ethoxy propylene ester: TosMIC: NaH (1: 1.2: 1.3) in molar ratio is mixed to join the anhydrous CH of 10mL 3Among the CN, stirring at room reaction 24h, reaction finishes, and reaction solution is with saturated NH 4It is 7-8 that Cl solution is regulated the pH value, uses methylene dichloride 10mL * 3 extractions then, merges organic layer, the Na with 10% 2CO 3Solution and saturated common salt water washing, anhydrous sodium sulfate drying, vacuum concentration is used column chromatography purification, obtains product 4-oxyethyl group-1 ' H-[1,3 '-two pyrroles]-3,4 '-dintrile, and product is a white solid, and yield is 55%.
Embodiment 7
Under nitrogen protection, with raw material ethyl-2-cyanic acid-3-ethoxy propylene ester: TosMIC: NaH (1: 1.2: 1.3) in molar ratio is mixed to join the anhydrous CH of 10mL 3Among the CN, stirring at room reaction 2h, reaction finishes, and reaction solution is with saturated NH 4It is 7-8 that Cl solution is regulated the pH value, uses methylene dichloride 10mL * 3 extractions then, merges organic layer, the Na with 10% 2CO 3Solution and saturated common salt water washing, anhydrous sodium sulfate drying, vacuum concentration is used column chromatography purification, obtains product 4-oxyethyl group-1 ' H-[1,3 '-two pyrroles]-3,4 '-dintrile, and product is a white solid, and yield is 25%.
Embodiment 8
Under nitrogen protection, with raw material ethyl-2-cyanic acid-3-ethoxy propylene ester: TosMIC: NaH (1: 1: 1.2) in molar ratio is mixed to join the anhydrous CH of 10mL 3Among the CN, stirring at room reaction 12h, reaction finishes, and reaction solution is with saturated NH 4It is 7-8 that Cl solution is regulated the pH value, uses methylene dichloride 10mL * 3 extractions then, merges organic layer, the Na with 10% 2CO 3Solution and saturated common salt water washing, anhydrous sodium sulfate drying, vacuum concentration is used column chromatography purification, obtains product 4-oxyethyl group-1 ' H-[1,3 '-two pyrroles]-3,4 '-dintrile, and product is a white solid, and yield is 38%.
Embodiment 9
Under nitrogen protection, with raw material diethylammonium-2-(ethoxy methylene) malonic ester: TosMIC: NaH in molar ratio (1: 1.2: 1.3) be mixed to join the anhydrous CH of 10mL 3In the CN solvent, stirring at room reaction 12h, reaction finishes, and reaction solution is with saturated NH 4It is 7-8 that Cl solution is regulated pH value, uses methylene dichloride 10mL * 3 to extract then, and the merging organic layer is with 10% Na 2CO 3Solution and saturated common salt water washing, anhydrous sodium sulfate drying, vacuum concentration is used column chromatography purification, obtains product diethylammonium-4-oxyethyl group-1 ' H-[1,3 '-two pyrroles]-3,4 '-dicarboxylicacid, and product is a white solid, and yield is 78%.
Embodiment 10
Under nitrogen protection, with raw material ethyl-2-(ethoxy methylene)-3-oxo bridge butyric acid: TosMIC: NaH (1: 1.2: 1.3) in molar ratio is mixed to join the anhydrous CH of 10mL 3In the CN solvent, stirring at room reaction 12h, reaction finishes, and reaction solution is with saturated NH 4It is 7-8 that Cl solution is regulated pH value, uses methylene dichloride 10mL * 3 to extract then, and the merging organic layer is with 10% Na 2CO 3Solution and saturated common salt water washing, anhydrous sodium sulfate drying, vacuum concentration is used column chromatography purification, obtains product diethylammonium-4-oxyethyl group-1 ' H-[1,3 '-two pyrroles]-3,4 '-dicarboxylicacid, and product is a white solid, and yield is 67%.
Embodiment 11
Under nitrogen protection, with raw material ethyl-2-cyanic acid-3-methoxyl group propylene ester: isonitrile: NaH (1: 1.2: 1.3) in molar ratio is mixed to join the anhydrous CH of 10mL 3In the CN solvent, stirring at room reaction 12h, reaction finishes, and reaction solution is with saturated NH 4It is 7-8 that Cl solution is regulated pH value, uses methylene dichloride 10mL * 3 to extract then, and the merging organic layer is with 10% Na 2CO 3Solution and saturated common salt water washing, anhydrous sodium sulfate drying, vacuum concentration is used column chromatography purification, obtains product 4-methoxyl group-1 ' H-[1,3 '-two pyrroles]-3,4 '-dintrile, and product is a white solid, and yield is 63%.
Embodiment 12
Under nitrogen protection, with raw material diethylammonium-2-(isopropoxy methylene radical) malonic ester: isonitrile: NaH (1: 1.2: 1.3) in molar ratio is mixed to join the anhydrous CH of 10mL 3In the CN solvent, stirring at room reaction 12h, reaction finishes, and reaction solution is with saturated NH 4It is 7-8 that Cl solution is regulated pH value, uses methylene dichloride 10mL * 3 to extract then, and the merging organic layer is with 10% Na 2CO 3Solution and saturated common salt water washing, anhydrous sodium sulfate drying, vacuum concentration is used column chromatography purification, obtains product diethylammonium-4-isopropoxy-1 ' H-[1,3 '-two pyrroles]-3,4 '-dicarboxylicacid, and product is a white solid, and yield is 56%.

Claims (6)

1. an one kettle way is connected and is synthesized the method for two pyrroles and verivate thereof, and the structure of two pyrroles and verivate thereof is suc as formula shown in (I):
Figure FSA00000562029400011
In the formula (I), R 1, R 2=alkoxyl group, alkyl, ester group, cyanic acid, carbonyl etc.
2. the method for synthetic two pyrroles according to claim 1 and verivate thereof comprises following method:
Isonitrile reaction shown in three substituted olefines shown in the formula (II) and the formula (III) obtains the compound shown in the formula (I);
Figure FSA00000562029400012
In the formula (II), R 1=alkoxyl group, alkyl and substituted aroma hydrocarbon thereof etc.; R 2=ester group, cyanic acid, carbonyl etc.; R 3=ester group, carbonyl etc.
In the formula (III), R=p-toluenesulfonyl, alkyl and aromatic hydrocarbon thereof etc.
3. the method for synthetic two pyrroles of a kind of one kettle way series connection according to claim 2 and verivate thereof is characterized in that following steps:
Synthesizing of formula (I) compound two pyrroles and verivate thereof: a certain amount of formula (II) compound alkene and formula (III) compound isonitrile are main raw material, are catalyzer with alkali, in organic solvent, react.Be reflected under the nitrogen protection, temperature of reaction is 0 ℃～60 ℃, reaction times 0.5～24h; Reaction finishes, and reaction solution is with saturated NH 4It is 7-8 that Cl solution is regulated the pH value, uses dichloromethane extraction then, merges organic layer and uses Na 2CO 3With saturated common salt water washing, anhydrous sodium sulfate drying, vacuum concentration,, obtain formula (I) two pyrroles and derivative products thereof with column chromatography or recrystallization purifying.
4. the compound method of two pyrroles according to claim 2 and verivate thereof is characterized in that the amount of substance ratio that feeds intake of described formula (II) compound and formula (III) compound is 1.0: 0.8～2.5.
5. the preparation method of two pyrroles according to claim 3 and verivate thereof; It is one of following to it is characterized in that described solvent is selected from: 1; 2-ethylene dichloride, methylene dichloride, trichloromethane, tetracol phenixin, methyl acetate, ETHYLE ACETATE, propyl acetate, butylacetate, isopropyl acetate, dioxane, DMF, ether, propyl ether, isopropyl ether, THF, butyl ether, acetone, pimelinketone, acetonitrile, propionitrile; One of more preferably following: THF, DMF, acetonitrile.
6. the preparation method of a kind of pyridine imine according to claim 3 and verivate thereof is characterized in that said catalyzer comprises: Na 2CO 3, K 2CO 3, Cs 2CO 3, NaH, KOH, NaOH, DBU, TEA etc.
CN2011102444268A 2011-08-24 2011-08-24 Method for tandem synthesis of dipyrrole and its derivatives through one-pot process Pending CN102351772A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103288700A (en) * 2012-02-28 2013-09-11 清华大学 Polysubstituted 3, 3'-dipyrrole, its derivative and preparation method
CN107501156A (en) * 2016-06-14 2017-12-22 兰州大学 A kind of three components series connection synthetic method of polysubstituted pyrrole
CN107814757A (en) * 2017-11-10 2018-03-20 南京医科大学康达学院 A kind of method for synthesizing polysubstituted pyrrole derivative
CN110903231A (en) * 2019-11-09 2020-03-24 上海大学 2-cyanopyrrole compounds and synthesis method thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ARGYRIOS A.ET AL: "Total Synthesis of (±)-Marinopyrrole A via Copper-Mediated N-Arylation", 《ORGANIC LETTERS》 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103288700A (en) * 2012-02-28 2013-09-11 清华大学 Polysubstituted 3, 3'-dipyrrole, its derivative and preparation method
CN103288700B (en) * 2012-02-28 2015-04-22 清华大学 Polysubstituted 3, 3'-dipyrrole, its derivative and preparation method
CN107501156A (en) * 2016-06-14 2017-12-22 兰州大学 A kind of three components series connection synthetic method of polysubstituted pyrrole
CN107501156B (en) * 2016-06-14 2020-04-14 兰州大学 Three-component series synthesis method of polysubstituted pyrrole
CN107814757A (en) * 2017-11-10 2018-03-20 南京医科大学康达学院 A kind of method for synthesizing polysubstituted pyrrole derivative
CN110903231A (en) * 2019-11-09 2020-03-24 上海大学 2-cyanopyrrole compounds and synthesis method thereof
CN110903231B (en) * 2019-11-09 2022-11-08 上海大学 2-cyanopyrrole compounds and synthesis method thereof

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