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Preparation method for 1, 2-dihydropyridine derivative

A technology of dihydropyridine and derivatives, applied in organic chemistry and other directions, can solve problems such as harsh reaction conditions, and achieve the effect of simple reaction operation and high atom economy.

Inactive Publication Date: 2014-05-21
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The most common method for the synthesis of dihydropyridines is the nucleophilic addition of nucleophiles to N-acetyl or N-alkyl pyridinium salts, the main disadvantage of these methods is the harsh reaction conditions, because nucleophilic species can be added to pyridinium salts 2-, 4- or 6-position and often get a variety of mixtures (Document 4: Bull, J.A.; Mousseau, J.J.; Pelletier, G.; Charette, A.B. Chem. Rev. 2012, 112, 2642)

Method used

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  • Preparation method for 1, 2-dihydropyridine derivative
  • Preparation method for 1, 2-dihydropyridine derivative
  • Preparation method for 1, 2-dihydropyridine derivative

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Experimental program
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Embodiment 1

[0025] Step one (preparation raw material Ia):

[0026]

[0027] The reaction was carried out in the reactor, and after the reactor was evacuated and replaced with argon three times, 5 mmol of N-sulfonyl-allylamine IIIa was added, and 40 mL of freshly distilled CH 2 Cl 2 , then add 5.5mmol of alkyne IVa, and finally add 10mol% of Cs 2 CO 3 , stirred at 0°C for 12 hours. After the reaction, part of the solvent was evaporated until the volume of the solution was one-fifth of the volume of the solution before evaporation, and the sample was loaded for silica gel column chromatography. The eluent was a mixed solvent of petroleum ether:ethyl acetate=10:1, 3-Aza-1,5-enyne Ia is obtained.

[0028] The characterization data for Ia are as follows:

[0029] 1 H NMR (400MHz, CDCl 3 )δ7.92(d,J=8.3Hz,2H),7.64(d,J=7.7Hz,2H),7.40–7.27(m,8H),7.16(dd,J=8.1,1.4Hz,2H), 6.54(s,1H),6.10(s,1H),3.76(s,3H),3.60(s,3H),2.31(s,3H); 13 C NMR (100MHz, CDCl 3 )δ164.9, 164.2, 144.9, 139.7, 135....

Embodiment 2

[0040]

[0041] The reaction was carried out in the reactor, and the reactor was evacuated and replaced with argon, and 0.2mmol (100.7mg) of 3-aza-1,5-enyne Ia was added, 1mL of THF was added, and then 0.02mmol of Hydroquinone (terephthalene Phenol, 10mol%), reacted at 60°C for 2 days. After removing the solvent with a rotary evaporator, the solid was dissolved in dichloromethane and loaded for silica gel column chromatography. The column was washed with an eluent of petroleum ether: ethyl acetate = 10:1 to obtain 95.7 mg of 1,2-bis Hydropyridine IIa, the isolated yield is 95%.

Embodiment 3

[0043]

[0044] Carry out the reaction in the reactor, vacuumize the reactor and replace it with argon, add 0.2mmol (104.3mg) 3-aza-1,5-enyne Ib, then add 2mL methanol, and react at 60°C under the protection of argon 2 days. After removing the solvent with a rotary evaporator, the solid was dissolved in dichloromethane and loaded for silica gel column chromatography. The column was washed with an eluent of petroleum ether: ethyl acetate = 10:1 to obtain 91.9 mg of 1,2-bis Hydropyridine IIb, the isolated yield was 88%.

[0045] The characterization data of Ib are as follows:

[0046] 1 H NMR (400MHz, CDCl 3 )δ7.91(d,J=7.8Hz,2H),7.63(m,2H),7.32(m,5H),7.15(d,J=7.4Hz,2H),7.06(t,J=8.2Hz, 2H),6.50(s,1H),6.12(s,1H),3.77(s,3H),3.63(s,3H),2.32(s,3H);

[0047] 13 C NMR (100MHz, CDCl 3 )δ164.8,164.2,162.9(d,J=244.7Hz),145.0,139.5,135.2,131.7,130.0,129.9,129.8,129.2,128.5,128.4,121.5,118.1,115.7(d,J=21.9Hz),89.8 ,82.7,54.4,53.1,52.2,21.7;

[0048] HRMS Calculated for C 28 h ...

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Abstract

The invention relates to a preparation method for a 1, 2-dihydropyridine derivative, particularly a new method for preparation of the 1, 2-dihydropyridine derivative from a 3-aza-1, 5-eneyne derivative under the promotion (catalysis) of protonic acid through cyclization reaction. The method takes the 3-aza-1, 5-eneyne derivative as the raw material to generate the 1, 2-dihydropyridine derivative under two conditions. According to the condition A, alcohol is adopted as a solvent (also serving as a catalyst), other catalysts or additives are unnecessary, and reaction is carried out at a temperature ranging from room temperature to 140DEG C; or according to the condition B, alcohol, phenol or protonic acid is added into another organic solvent to serve as a catalyst. The yield of 1, 2-dihydropyridine derivative can reach up to 97%.

Description

technical field [0001] The present invention relates to a protonic acid-promoted method for preparing 1,2-dihydropyridine derivatives, in particular to promote (catalyze) 3-aza-1,5-enynes by alcohols, phenols or protonic acids Derivatives A new method for generating 1,2-dihydropyridine derivatives. Background technique [0002] Dihydropyridine, one of the most important heterocycles, is not only a key structural unit of many natural products, organic materials and medicines, but also a very useful building block in organic synthesis. Because 1,4-dihydropyridine is the main structural unit of many drugs (Document 1: (a) Kappe, C.O.Eur.J.Med.Chem.2000, 35, 1043; (b) Rampe, D.; Kane, J.M. Drug Dev.Res.1994,33,344;(c)Triggle,D.J.Cell.Mol.Neurobiol.2003,23,293;(d)Goldmann,S.;Stoltefuss,J.Angew.Chem.,Int.Ed.1991,30, 1559), so that this type of compound has been extensively studied (article 2: (a) Lavilla, R.J.Chem.Soc., PerkinsTrans.1.2002, 1141; (b) Gaudio, A.C.; Korolskovas, A...

Claims

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Application Information

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IPC IPC(8): C07D211/96
CPCC07D211/02C07D211/96
Inventor 万伯顺信晓义吴凡
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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