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1,4-dihydropyridines compound containing azulene structure and preparation method thereof

A dihydropyridine and compound technology, applied in the field 1, can solve problems such as difficult derivatization, unfavorable molecular diversity research, cumbersome synthesis methods, etc., and achieve good drug dynamics and kinetic properties, good drug use prospects, and synthetic methods simple effect

Inactive Publication Date: 2013-01-02
BOHAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] After research and analysis, the above-mentioned 1,4-dihydropyridine compounds still have problems such as single reaction site, difficult derivatization, poor selectivity, cumbersome synthesis methods, and unfavorable research on molecular diversity.

Method used

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  • 1,4-dihydropyridines compound containing azulene structure and preparation method thereof
  • 1,4-dihydropyridines compound containing azulene structure and preparation method thereof
  • 1,4-dihydropyridines compound containing azulene structure and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Synthesis of Methyl 2,6-Dimethyl-4-(3-carboxymethylazulene-1-yl)-1,4-dihydropyridine-3,5-dicarboxylate

[0040] Methyl 1-formyl azulene-3-carboxylate (2.14 grams, 0.01 moles), methyl acetoacetate (3.48 grams, 0.03 moles), ammonium acetate (2.13 grams, 0.03 moles), p-toluenesulfonic acid (0.17 g) was dissolved in absolute ethanol (120 ml) and heated to reflux for 8 hours. The solvent was evaporated, and the obtained residue was separated through a silica gel column (silica gel: 160~200 mesh; benzene-ethyl acetate (V / V=95:5) was used as the eluent) to obtain 3.11 g of the target product (purple crystals). rate of 76%.

[0041] The structural analysis is as follows:

[0042] 1 H NMR (400MHz, CDCl 3 )δ: 2.37(s, 6H, 2xCH 3 ), 3.51(s, 6H, 2xCH 3 ), 3.91 (s, 3H, CH 3), 5.58 (s, 1H, CH), 5.81 (br s, 1H, NH), 7.43-7.48 (m, 2H, AzH), 7.73 (dd, J=10.0, 10.0Hz, 1H, AzH), 8.20 ( s, 1H, AzH), 8.90 (d, J=10.0Hz, 1H, ArH), 9.53 (d, J=10.0Hz, 1H, ArH).

[0043] IR(KBr)v: 3332(N...

Embodiment 2

[0046] Synthesis of ethyl 2,6-dimethyl-4-(3-carboxymethylazulene-1-yl)-1,4-dihydropyridine-3,5-dicarboxylate

[0047] Methyl 1-formyl azulene-3-carboxylate (2.14 grams, 0.01 moles), ethyl acetoacetate (3.25 grams, 0.025 moles), ammonium acetate (2.13 grams, 0.03 moles), p-toluenesulfonic acid (0.20 g) was dissolved in methanol (140 mL), heated to reflux for 10 hours. The solvent was distilled off, and the obtained residue was separated through a silica gel column (silica gel: 160-200 mesh; benzene-ethyl acetate (V / V=95:5) was used as the eluent) to obtain 3.19 g of the desired product (purple crystals). The rate is 73%.

[0048] The structural analysis is as follows:

[0049] 1 H NMR (400MHz, CDCl 3 )δ: 1.06(t, J=7.2Hz, 6H, 2xCH 3 ), 2.38(s, 6H, 2xCH 3 ), 3.92(s, 6H, 2xCH 3 ), 3.98 (q, J=7.2Hz, 4H, 2xCH 2 CH 3 ), 5.57 (s, 1H, CH), 5.80 (br s, 1H, NH), 7.42-7.47 (m, 2H, AzH), 7.73 (dd, J=9.6, 9.6Hz, 1H, AzH), 8.23 ​​( s, 1H, AzH), 8.89 (d, J=9.6Hz, 1H, ArH), 9.52 (d, ...

Embodiment 3

[0053] Synthesis of isopropyl 2,6-dimethyl-4-(3-carboxymethylazulene-1-yl)-1,4-dihydropyridine-3,5-dicarboxylate

[0054] Methyl 1-formylazulene-3-carboxylate (2.14 g, 0.01 mol), isopropyl acetoacetate (4.2 g, 0.03 mol), ammonium acetate (2.84 g, 0.04 mol), methanesulfonic acid (0.1 g ) was dissolved in isopropanol (120 mL), and heated to reflux for 10 hours. The solvent was distilled off, and the obtained residue was separated through a silica gel column (silica gel: 160-200 mesh; benzene-ethyl acetate (V / V=95:5) was used as the eluent) to obtain 3.49 g of the desired product (purple crystals). rate of 75%.

[0055] The structural analysis is as follows:

[0056] 1 H NMR (400MHz, CDCl 3 )δ: 1.21(d, J=4.8Hz, 12H, 2xCH(CH 3 ) 2 ), 2.40(s, 6H, 2xCH 3 ), 3.94(s, 6H, 2xCH 3 ), 3.98 (s, 3H, CH 3 ), 4.03-4.06(m, 2H, 2xCH(CH 3 ) 2 ), 5.57 (s, 1H, CH), 5.91 (br s, 1H, NH), 7.43-7.48 (m, 2H, AzH), 7.76 (dd, J=9.6, 9.6Hz, 1H, AzH), 8.25 ( s, 1H, AzH), 8.93 (d, J=9.6Hz, 1H, A...

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Abstract

The invention belongs to the field of 1,4-dihydropyridines compounds, in particular relates to a 1,4-dihydropyridines compound containing an azulene structure and a preparation method thereof. The 1,4-dihydropyridines compound containing an azulene structure has the following structure formula. The preparation method comprises the following steps of: carrying out a condensation reaction by using 1-formyl azulene derivative, acetyl acetate and ammonium acetate or 3-amino-2-butene ester as raw materials under the action of an acid catalyst; and purifying to obtain a target product. The preparation method is simple and rapid, can be used for synthesizing a great amount of compound libraries in a short time, thereby being suitable for researching the molecular diversity of compounds.

Description

technical field [0001] The invention belongs to the field of 1,4-dihydropyridine compounds, in particular to a 1,4-dihydropyridine compound containing an azulene structure and a preparation method thereof. Background technique [0002] 1,4-dihydropyridine compounds have good pharmacokinetic and kinetic properties, and many vasodilation, anti-atherosclerosis, anti-cancer, liver-protecting and anti-diabetic drugs contain 1,4-dihydropyridine skeleton[ a) Saushins, A.; Duburs, G. Heterocycles 1988, 27, 269-289; b) Coburn, R.A.; Solo, A.J.; ; c) Manhold, R.; Jablonka, B.; Voigdt, W.; Schoenfinger, K.F.; [0003] Now known 1,4-dihydropyridine compounds have vasodilation effect, so they can be used as coronary heart disease and antihypertensive agents (British patents 1173061 and 1358951; German patents 269892 and 2752820). In addition, 1,4-dihydropyridine compounds are known to cause inhibition of contractility of smooth muscle and cardiac muscle and are useful in the treatment ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/90
Inventor 王道林林力男曹亮李元峰李少飞李伟李帝
Owner BOHAI UNIV