CN102433363B - Method for normal-temperature catalytic synthesis of 1,4-dihydropyridine compounds - Google Patents

Method for normal-temperature catalytic synthesis of 1,4-dihydropyridine compounds Download PDF

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CN102433363B
CN102433363B CN2011103348840A CN201110334884A CN102433363B CN 102433363 B CN102433363 B CN 102433363B CN 2011103348840 A CN2011103348840 A CN 2011103348840A CN 201110334884 A CN201110334884 A CN 201110334884A CN 102433363 B CN102433363 B CN 102433363B
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dihydropyridine compounds
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方东
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Yancheng Teachers University
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Abstract

The invention discloses a method for normal-temperature catalytic synthesis of 1,4-dihydropyridine compounds, which takes bread active dried yeast as a catalyst, aromatic aldehyde, ethyl acetoacetate and ammonium carbonate as raw materials and 2-methyltetrahydrofuran as a solvent and performs reaction in an open or closed system at normal temperature and under normal pressure with stirring. In the invention, filtration is carried out after reaction, filtrate is used as a catalyst, and the solvent in the filtrate can be recovered and used by distillation. Compared with the prior art, the method has the advantages that: (1) the raw material resource is wide, the preparation is convenient, the byproduct which is carbon dioxide is convenient to treat afterwards, and organic ammonium salts including ammonium formate, ammonium acetate and the like are difficult to be treated afterwards; (2) the raw material of the catalyst is widely available and safe and nontoxic; (3) the raw material for preparing the solvent is furfuraldehyde prepared by processing by products such as corncobs and bagasse, is a pure green product and is environment-friendly; and (4) the reaction conditions are mild, and a condenser tube blockage problem caused by decomposition and condensation under a heating condition is solved.

Description

A kind of method of normal-temperature catalytic synthesis of 1,4-dihydropyridine compounds
One technical field
The present invention relates to a kind of novel method of normal-temperature catalytic synthesis of 1,4-dihydropyridine compounds, belong to technical field of biochemical industry.Present method is applicable to bread with the active dry yeast catalyzer of distinguishing the flavor of, and aromatic aldehyde, acetylacetic ester, volatile salt are raw material, and the 2-methyltetrahydrofuran is solvent, opening wide or the occasion of the synthetic Isosorbide-5-Nitrae-dihydropyridine compounds of closed system at normal temperatures and pressures.
Two background technologies
Isosorbide-5-Nitrae-dihydropyridine compounds is widely used at the aspect such as biological, medical.Its representative compound nifedipine is first-generation calcium antagonist, be specially adapted to the treatment of the diseases such as stenocardia due to coronary spasm, irregular pulse, hypertension, treatment fatty liver, toxic hepatitis, anti-ageing, the anti-effect such as precocious are arranged, also have as new purposes such as treatment gastroenteropathy, Raynaud disease, primary pulmonary hypertension and migraine.
The prior synthesizing method of this compounds is that dry ammonia is passed in the mixing solutions of methyl aceto acetate and aldehyde, perhaps with strong aqua or ammonium acetate as nitrogenous source, adopt backflow or microwave radiation to complete, but the utilization ratio deficiency of ammonia, the aftertreatment of product bothers.Find a kind of convenience, effectively, the method for the synthetic Isosorbide-5-Nitrae dihydropyridine of environmental protection become the focus of organic synthesis.Reported successively in recent years solventless method (Cai Xiaohua, Zhang Guolin. organic chemistry .2005,25 (8): 930-933.), the solvent method (Wang Jianping of nitrogen ball sealed reaction system, the Dumet chrysanthemum, Fu Yongju, Deng .1, the synthetic method of 4-dihydrogen pyridine derivative is improved. synthetic chemistry .2007,15 (1): 42-45.), solvent-free solid-phase synthesis method (Liu Zhulan, Wang Cuiling, make inferior duckweed, etc. solvent-free polishing synthesizes Isosorbide-5-Nitrae-dihydrogen pyridine derivative. chemistry circular .2008.9:718.) etc.
In recent years, the application of bread yeast in organic synthesis is very active, (the A.Kumar such as Kumar, R.A.Maurya.Tetrahedron Letters.2007,48:3887-3890) reported that bread yeast catalyzes and synthesizes many hydrogen quinoline compounds, adopt ammonium acetate as nitrogenous source, reaction is carried out in glucose-phosphate buffered saline buffer, after finishing, use ethyl acetate extraction, the organic phase dried over sodium sulfate, remove after siccative concentrates and obtain thick product, recrystallizing methanol obtains target compound.The post-processing step of this extraction-drying-filtration-concentrated-recrystallization is many, complex process, organic solvent consumption are large, and environmental pollution is larger.
A kind of constant temperature catalyzing the present invention relates to synthetic 1, the method of 4-dihydropyridine compounds is different from above-mentioned disclosed synthetic method, to take the bread active dry yeast to be catalyzer, volatile salt is nitrogenous source, the 2-methyltetrahydrofuran is solvent, under normal temperature and pressure, stirring and react in unlimited or closed system.
Three summary of the invention
The object of the present invention is to provide a kind of method of normal-temperature catalytic synthesis of 1,4-dihydropyridine compounds.
The technical solution that realizes the object of the invention is: the bread active dry yeast of take is catalyzer, aromatic aldehyde, methyl aceto acetate, volatile salt are raw material, the 2-methyltetrahydrofuran is solvent, realizes the synthetic of this target compound under normal temperature and pressure, stirring to react in unlimited or closed system.Filter after completion of the reaction, filter residue is catalyzer, and the solvent that filtrate goes out by fractionation by distillation can recycling use, and the residue crude product obtains straight product with ethyl alcohol recrystallization.
Product of the present invention has following structure:
Figure BSA00000602927300021
R wherein 1For nitro, halogen, alkyl, alkoxyl group etc.; R 2For ethyl.
The raw materials used mol ratio of the present invention is aromatic aldehyde: acetylacetic ester: volatile salt=1: 2: 1, catalyst levels is 4～10% of material total mass, the consumption of solvent is 80～90% of material total mass, by the materials such as raw material, catalyzer, the solvent mix and blend that proportionally feeds intake.
The time of reaction of the present invention is 24～48 hours.
The chemical principle of institute of the present invention foundation is as follows:
According to a kind of constant temperature catalyzing provided by the invention synthetic 1, the method of 4-dihydropyridine compounds, its key problem in technology is that employing bread active dry yeast is catalyzer, aromatic aldehyde, methyl aceto acetate, volatile salt are raw material, the 2-methyltetrahydrofuran is solvent, stirs and reacts in unlimited or closed system at normal temperatures and pressures.Filter after completion of the reaction, filter residue is catalyzer, and the solvent that filtrate goes out by fractionation by distillation can recycling use, and the residue crude product obtains straight product with ethyl alcohol recrystallization.Compared with prior art, its advantage is in the present invention: (1) raw material sources are extensive, easy to prepare, and especially the reacted by product of volatile salt as the nitrogen-atoms source is carbonic acid gas, convenient post-treatment; The organic ammonium salt such as ammonium formiate, ammonium acetate by product is the organic acids such as formic acid, acetic acid, purifies and brings difficulty to aftertreatment.Therefore, volatile salt has more economy, environmental protection double dominant; (2) the bread active dry yeast is catalyzer, and raw material sources are extensive, safety non-toxic; (3) solvent 2-methyltetrahydrofuran cost is lower, and toxicity is less, and its raw material is the furfural obtained by agricultural byproducts processings such as corn cob, bagasse, belongs to and belongs to green chemical industry product, environmental friendliness; (4) reaction is carried out at normal temperatures and pressures, and mild condition has been avoided the problem that under the heating condition, ammonium salt decomposition-condensation causes prolong to block.It is a kind of method of efficient, eco-friendly synthetic Isosorbide-5-Nitrae-dihydropyridine compounds.
Four accompanying drawing explanations
Accompanying drawing is the schema of the method for a kind of normal-temperature catalytic synthesis of 1,4-dihydropyridine compounds of the present invention.
Five embodiments
The present invention is described in detail in detail by the following examples, and these embodiment are only for clear open the present invention, not as limitation of the present invention.
Embodiment 1
In the 50mL round-bottomed flask, add 5mmol (0.53g) phenyl aldehyde, 10mmol (1.30g) methyl aceto acetate, 5mmol (0.48g) volatile salt, 1.0g catalyzer, 20mL solvent, in unlimited system, stirred 48 hours under normal temperature and pressure.Filter after completion of the reaction, filter residue is catalyzer, and the solvent that filtrate goes out by fractionation by distillation can recycling use, and the residue crude product obtains 4-phenyl-Isosorbide-5-Nitrae-dihydropyridine product, productive rate 71% with the dehydrated alcohol recrystallization.
Embodiment 2
In the 50mL round-bottomed flask, add 5mmol (0.53g) phenyl aldehyde, 10mmol (1.30g) methyl aceto acetate, 5mmol (0.48g) volatile salt, 2.0g catalyzer, 20mL solvent, in unlimited system, stirred 24 hours under normal temperature and pressure.Filter after completion of the reaction, filter residue is catalyzer, and the solvent that filtrate goes out by fractionation by distillation can recycling use, and the residue crude product obtains 4-phenyl-Isosorbide-5-Nitrae-dihydropyridine product, productive rate 65% with 95% ethyl alcohol recrystallization.
Embodiment 3
In the 50mL round-bottomed flask, add 5mmol (0.53g) phenyl aldehyde, 10mmol (1.30g) methyl aceto acetate, 5mmol (0.48g) volatile salt, 1.5g catalyzer, 20mL solvent, clog bottleneck confined reaction system.Under normal temperature and pressure, stirred 30 hours.Filter after completion of the reaction, filter residue is catalyzer, and the solvent that filtrate goes out by fractionation by distillation can recycling use, and the residue crude product obtains 4-phenyl-Isosorbide-5-Nitrae-dihydropyridine product, productive rate 67% with 95% ethyl alcohol recrystallization.
Embodiment 4
In the 50mL round-bottomed flask, add 5mmol (0.76g) 2-nitrobenzaldehyde, 10mmol (1.30g) methyl aceto acetate, 5mmol (0.48g) volatile salt, 1.2g catalyzer, 20mL solvent, clog bottleneck confined reaction system.Under normal temperature and pressure, stirred 30 hours.Filter after completion of the reaction, filter residue is catalyzer, and the solvent that filtrate goes out by fractionation by distillation can recycling use, and the residue crude product obtains 4-(2-nitro) phenyl-1 with the dehydrated alcohol recrystallization, 4-dihydropyridine product (nifedipine), productive rate 68%.
Embodiment 5
In the 50mL round-bottomed flask, add 5mmol (0.76g) 2-nitrobenzaldehyde, 10mmol (1.30g) methyl aceto acetate, 5mmol (0.48g) volatile salt, 1.0g catalyzer, 20mL solvent, stirred 30 hours under normal temperature and pressure in unlimited system.Filter after completion of the reaction, filter residue is catalyzer, and the solvent that filtrate goes out by fractionation by distillation can recycling use, and the residue crude product obtains 4-(2-nitro) phenyl-Isosorbide-5-Nitrae-dihydropyridine product, productive rate 59% with 95% ethyl alcohol recrystallization.
Embodiment 6
In the 50mL round-bottomed flask, add 5mmol (0.7g) 4-chlorobenzaldehyde, 10mmol (1.30g) methyl aceto acetate, 5mmol (0.48g) volatile salt, 1.0g catalyzer, 20mL solvent, clog bottleneck confined reaction system.Under normal temperature and pressure, stirred 30 hours.Filter after completion of the reaction, filter residue is catalyzer, and the solvent that filtrate goes out by fractionation by distillation can recycling use, and the residue crude product obtains 4-(4-chlorine) phenyl-Isosorbide-5-Nitrae-dihydropyridine product, productive rate 66% with 95% ethyl alcohol recrystallization.
Embodiment 7
In the 50mL round-bottomed flask, add 5mmol (0.60g) 4-tolyl aldehyde, 10mmol (1.30g) methyl aceto acetate, 5mmol (0.48g) volatile salt, 1.0g catalyzer, 20mL solvent, clog bottleneck confined reaction system.Under normal temperature and pressure, stirred 30 hours.Filter after completion of the reaction, filter residue is catalyzer, and the solvent that filtrate goes out by fractionation by distillation can recycling use, and the residue crude product obtains 4-(4-methyl) phenyl-Isosorbide-5-Nitrae-dihydropyridine product, productive rate 62% with 95% ethyl alcohol recrystallization.
Embodiment 8
In the 50mL round-bottomed flask, add 5mmol (0.76g) 3-nitrobenzaldehyde, 10mmol (1.30g) methyl aceto acetate, 5mmol (0.48g) volatile salt, 1.0g catalyzer, 20mL solvent, clog bottleneck confined reaction system.Under normal temperature and pressure, stirred 30 hours.Filter after completion of the reaction, filter residue is catalyzer, and the solvent that filtrate goes out by fractionation by distillation can recycling use, and the residue crude product obtains 4-(3-nitro) phenyl Isosorbide-5-Nitrae-dihydropyridine product, productive rate 60% with 95% ethyl alcohol recrystallization.
Embodiment 9
In the 50mL round-bottomed flask, add 5mmol (0.68g) 4-methoxybenzaldehyde, 10mmol (1.30g) methyl aceto acetate, 5mmol (0.48g) volatile salt, 1.0g catalyzer, 20mL solvent, clog bottleneck confined reaction system.Under normal temperature and pressure, stirred 30 hours.Filter after completion of the reaction, filter residue is catalyzer, and the solvent that filtrate goes out by fractionation by distillation can recycling use, and the residue crude product obtains 4-(4-methoxyl group) phenyl-Isosorbide-5-Nitrae-dihydropyridine product, productive rate 66% with 95% ethyl alcohol recrystallization.
Embodiment 10
In the 50mL round-bottomed flask, add 5mmol (0.62g) 4-fluorobenzaldehyde, 10mmol (1.30g) methyl aceto acetate, 5mmol (0.48g) volatile salt, 1.0g catalyzer, 20mL solvent, clog bottleneck confined reaction system.Under normal temperature and pressure, stirred 30 hours.Filter after completion of the reaction, filter residue is catalyzer, and the solvent that filtrate goes out by fractionation by distillation can recycling use, and the residue crude product obtains 4-(4-fluorophenyl)-Isosorbide-5-Nitrae-dihydropyridine product, productive rate 56% with 95% ethyl alcohol recrystallization.

Claims (3)

1. a constant temperature catalyzing synthesizes 1, the method of 4-dihydropyridine compounds, it is characterized in that: the bread active dry yeast of take is catalyzer, aromatic aldehyde, methyl aceto acetate, volatile salt are raw material, the 2-methyltetrahydrofuran is solvent, in under normal temperature and pressure, stirring and react in unlimited or closed system, filter after completion of the reaction, filter residue is catalyzer, the solvent that filtrate goes out by fractionation by distillation can recycling use, the residue crude product obtains straight product with ethyl alcohol recrystallization, and reaction is suc as formula shown in (I):
Figure FSB0000112764990000011
R wherein 1For H, 2-NO 2, 3-NO 2, 4-Cl, 4-CH 3, 4-OCH 3, 4-F; R 2For ethyl.
2. a kind of constant temperature catalyzing according to claim 1 synthetic 1, the method of 4-dihydropyridine compounds, it is characterized in that: raw materials used mol ratio is aromatic aldehyde: methyl aceto acetate: volatile salt=1: 2: 1, catalyst levels is 5～10% of material total mass, the consumption of solvent is 80～90% of material total mass, by raw material, catalyzer, the solvent mix and blend that proportionally feeds intake.
3. the method for a kind of normal-temperature catalytic synthesis of 1,4-dihydropyridine compounds according to claim 1, it is characterized in that: the time of reaction is 24～48 hours.
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CN101602710A (en) * 2009-05-20 2009-12-16 中国药科大学 A kind of new preparation method of butyrate clevidipine key intermediate
CN102174010A (en) * 2011-03-14 2011-09-07 盐城师范学院 Water phase clean synthesis method of 1,4-dihydropyridine compounds

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101602710A (en) * 2009-05-20 2009-12-16 中国药科大学 A kind of new preparation method of butyrate clevidipine key intermediate
CN102174010A (en) * 2011-03-14 2011-09-07 盐城师范学院 Water phase clean synthesis method of 1,4-dihydropyridine compounds

Non-Patent Citations (4)

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Title
LeeJH.etal..SynthesisofHantsch1 4-dihydropyridines by fermenting bakers’ yeast.《Tetrahedron Letters》.2005
Synthesis of Hantsch 1,4-dihydropyridines by fermenting bakers’ yeast;Lee JH. et al.;《Tetrahedron Letters》;20050913(第46期);模式图1,2；图1；第7330页第1段 *
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第7330页第1段.

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