CN102433363A - 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 PDFInfo
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- CN102433363A CN102433363A CN2011103348840A CN201110334884A CN102433363A CN 102433363 A CN102433363 A CN 102433363A CN 2011103348840 A CN2011103348840 A CN 2011103348840A CN 201110334884 A CN201110334884 A CN 201110334884A CN 102433363 A CN102433363 A CN 102433363A
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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
One technical field
The present invention relates to a kind of constant temperature catalyzing and synthesize 1, the novel method of 4-dihydropyridine compounds belongs to technical field of biochemical industry.Present method is applicable to that with bread with the active dry yeast catalyzer of distinguishing the flavor of, aromatic aldehyde, acetylacetic ester, volatile salt are raw material, and the 2-methyltetrahydrofuran is a solvent, at normal temperatures and pressures open wide or closed system synthetic 1, the occasion of 4-dihydropyridine compounds.
Two background technologies
1, the 4-dihydropyridine compounds is widely used at aspects such as biology, medicine.Its representative compound nifedipine is a first-generation calcium antagonist; Be specially adapted to treatment of diseases such as stenocardia due to the coronary spasm, irregular pulse, hypertension; Effects such as treatment fatty liver, toxic hepatitis, anti-ageing, anti-precocity 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 fed in the mixing solutions of methyl aceto acetate and aldehyde; Perhaps with strong aqua or ammonium acetate as nitrogenous source; Adopt and reflux or the microwave radiation completion, but the utilization ratio of ammonia is not enough, the aftertreatment of product is trouble.Seek a kind of convenience, effectively, the method for synthetic 1,4 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 waits .1; The compound method of 4-dihydrogen pyridine derivative is improved. synthetic chemistry .2007,15 (1): 42-45.), solvent-free solid-phase synthesis (Liu Zhulan, Wang Cuiling; Make inferior duckweed, etc. solvent-free polishing synthesizes 1, the 4-dihydrogen pyridine derivative. chemistry circular .2008.9:718.) etc.
In recent years, the application of bread yeast in organic synthesis is very active, (A.Kumar such as Kumar; R.A.Maurya.Tetrahedron Letters.2007 48:3887-3890) has reported that bread yeast catalysis synthesizes many hydrogen quinoline compounds, adopts ammonium acetate as nitrogenous source; Be reflected in glucose-phosphate buffered saline buffer and carry out, finish the back and use ethyl acetate extraction, organic phase is used dried over sodium sulfate; Remove and obtain thick product after siccative concentrates, recrystallizing methanol obtains target compound.The post-processing step of this extraction-drying-filtration-concentrate-recrystallization is many, complex process, organic solvent consumption are big, and environmental pollution is bigger.
A kind of constant temperature catalyzing that the present invention relates to synthetic 1; The method of 4-dihydropyridine compounds is different from above-mentioned disclosed compound method; Be to use active dry yeast to be catalyzer with bread; Volatile salt is a nitrogenous source, and the 2-methyltetrahydrofuran is a solvent, reacts in unlimited or closed system, stirring under the normal temperature and pressure.
Three summary of the invention
The object of the present invention is to provide a kind of constant temperature catalyzing to synthesize 1, the method for 4-dihydropyridine compounds.
The technical solution that realizes the object of the invention is: use active dry yeast to be catalyzer with bread; Aromatic aldehyde, methyl aceto acetate, volatile salt are raw material; The 2-methyltetrahydrofuran is a solvent, realizes the synthetic of this target compound in unlimited or closed system, stirring under the normal temperature and pressure to react.The reaction after-filtration that finishes, filter residue is a catalyzer, and the solvent that filtrating goes out through 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:
R wherein
1Be nitro, halogen, alkyl, alkoxyl group etc.; R
2Be ethyl.
The raw materials used mol ratio of the present invention is an aromatic aldehyde: acetylacetic ester: volatile salt=1: 2: 1; Catalyst levels is 4～10% of a material total mass; The consumption of solvent is 80～90% of a material total mass, materials such as raw material, catalyzer, solvent is proportionally fed intake to mix stir.
The time of reaction according to the invention is 24～48 hours.
The chemical principle of institute of the present invention foundation is following:
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 to adopt bread to use active dry yeast to be catalyzer; Aromatic aldehyde, methyl aceto acetate, volatile salt are raw material, and the 2-methyltetrahydrofuran is a solvent, stir in the unlimited or closed system at normal temperatures and pressures and react.The reaction after-filtration that finishes, filter residue is a catalyzer, and the solvent that filtrating goes out through fractionation by distillation can recycling use, and the residue crude product obtains straight product with ethyl alcohol recrystallization.The present invention compared with prior art, its advantage is: (1) raw material sources are extensive, preparation is convenient, especially the reacted by product of volatile salt as the nitrogen-atoms source is a carbonic acid gas, convenient post-treatment; Organic ammonium salt such as ammonium formiate, ammonium acetate by product then is organic acids such as formic acid, acetate, purifies to aftertreatment and brings difficulty.Therefore, volatile salt has more economy, environmental protection double dominant; (2) bread uses active dry yeast to be 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 that is obtained by agricultural byproducts processings such as corn cob, bagasse, belongs to belong 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 ammonium salt decomposition-condensation causes prolong to block under the heating condition.Be a kind of efficient, eco-friendly synthetic 1, the method for 4-dihydropyridine compounds.
Four description of drawings
Accompanying drawing is that a kind of constant temperature catalyzing of the present invention synthesizes 1, the schema of the method for 4-dihydropyridine compounds.
Five embodiments
Below through embodiment the present invention is detailed, 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, stirred 48 hours under normal temperature and pressure in unlimited system.The reaction after-filtration that finishes, filter residue is a catalyzer, and the solvent that filtrating goes out through fractionation by distillation can recycling use, and the residue crude product obtains 4-phenyl-1 with the absolute ethyl alcohol recrystallization, 4-dihydropyridine product, productive rate 71%.
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, stirred 24 hours under normal temperature and pressure in unlimited system.The reaction after-filtration that finishes, filter residue is a catalyzer, and the solvent that filtrating goes out through fractionation by distillation can recycling use, and the residue crude product obtains 4-phenyl-1 with 95% ethyl alcohol recrystallization, 4-dihydropyridine product, productive rate 65%.
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.Stirred 30 hours down in normal temperature and pressure.The reaction after-filtration that finishes, filter residue is a catalyzer, and the solvent that filtrating goes out through fractionation by distillation can recycling use, and the residue crude product obtains 4-phenyl-1 with 95% ethyl alcohol recrystallization, 4-dihydropyridine product, productive rate 67%.
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.Stirred 30 hours down in normal temperature and pressure.The reaction after-filtration that finishes, filter residue is a catalyzer, and the solvent that filtrating goes out through fractionation by distillation can recycling use, and the residue crude product obtains 4-(2-nitro) phenyl-1,4-dihydropyridine product (nifedipine), productive rate 68% with the absolute ethyl alcohol recrystallization.
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.The reaction after-filtration that finishes, filter residue is a catalyzer, and the solvent that filtrating goes out through fractionation by distillation can recycling use, and the residue crude product obtains 4-(2-nitro) phenyl-1,4-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.Stirred 30 hours down in normal temperature and pressure.The reaction after-filtration that finishes, filter residue is a catalyzer, and the solvent that filtrating goes out through fractionation by distillation can recycling use, and the residue crude product obtains 4-(4-chlorine) phenyl-1,4-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.Stirred 30 hours down in normal temperature and pressure.The reaction after-filtration that finishes, filter residue is a catalyzer, and the solvent that filtrating goes out through fractionation by distillation can recycling use, and the residue crude product obtains 4-(4-methyl) phenyl-1,4-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.Stirred 30 hours down in normal temperature and pressure.The reaction after-filtration that finishes, filter residue is a catalyzer, and the solvent that filtrating goes out through fractionation by distillation can recycling use, and the residue crude product obtains 4-(3-nitro) phenyl 1,4-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.Stirred 30 hours down in normal temperature and pressure.The reaction after-filtration that finishes, filter residue is a catalyzer, and the solvent that filtrating goes out through fractionation by distillation can recycling use, and the residue crude product obtains 4-(4-methoxyl group) phenyl-1,4-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.Stirred 30 hours down in normal temperature and pressure.The reaction after-filtration that finishes, filter residue is a catalyzer, and the solvent that filtrating goes out through fractionation by distillation can recycling use, and the residue crude product obtains 4-(4-fluorophenyl)-1,4-dihydropyridine product, productive rate 56% with 95% ethyl alcohol recrystallization.
Claims (4)
1. a constant temperature catalyzing synthesizes 1; The method of 4-dihydropyridine compounds; It is characterized in that: use active dry yeast to be catalyzer with bread; Aromatic aldehyde, methyl aceto acetate, volatile salt are raw material, and the 2-methyltetrahydrofuran is a solvent, react in unlimited or closed system, stirring under the normal temperature and pressure.The reaction after-filtration that finishes, filter residue is a catalyzer, and the solvent that filtrating goes out through fractionation by distillation can recycling use, and the residue crude product obtains straight product with ethyl alcohol recrystallization.
2. a kind of constant temperature catalyzing according to claim 1 synthesizes 1, and the method for 4-dihydropyridine compounds is characterized in that product has following structure:
R wherein
1Be nitro, halogen, alkyl, alkoxyl group etc.; R
2Be ethyl.
3. 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 an aromatic aldehyde: acetylacetic ester: volatile salt=1: 2: 1; Catalyst levels is 5～10% of a material total mass, and the consumption of solvent is 80～90% of a material total mass, materials such as raw material, catalyzer, solvent is proportionally fed intake to mix stir.
4. a kind of constant temperature catalyzing according to claim 1 synthesizes 1, and the method for 4-dihydropyridine compounds is characterized in that: the time of reaction is 24～48 hours.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103497147A (en) * | 2013-09-11 | 2014-01-08 | 常州大学 | Synthesis method of 1,4-dihydropyridine compounds by using ytterbium trifluoromethanesulfonate as catalyst |
| CN105130881A (en) * | 2015-09-18 | 2015-12-09 | 苏州顺唐化纤有限公司 | Synthetic method of 1,4-dihydropyridine derivative |
Citations (2)
| 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 |
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Patent Citations (2)
| 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 (2)
| Title |
|---|
| 《Tetrahedron Letters》 20050913 Lee JH. et al. Synthesis of Hantsch 1,4-dihydropyridines by fermenting bakers' yeast 模式图1,2；图1；第7330页第1段 1-4 , 第46期 * |
| LEE JH. ET AL.: "Synthesis of Hantsch 1,4-dihydropyridines by fermenting bakers’ yeast", 《TETRAHEDRON LETTERS》, no. 46, 13 September 2005 (2005-09-13) * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103497147A (en) * | 2013-09-11 | 2014-01-08 | 常州大学 | Synthesis method of 1,4-dihydropyridine compounds by using ytterbium trifluoromethanesulfonate as catalyst |
| CN105130881A (en) * | 2015-09-18 | 2015-12-09 | 苏州顺唐化纤有限公司 | Synthetic method of 1,4-dihydropyridine derivative |
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