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Method for preparing Eprosartan impurity EP12A

A kind of eprosartan, EP12A technology, applied in the field of medicinal chemistry

Inactive Publication Date: 2015-08-19
ZHEJIANG HUAHAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no literature reporting the structure and preparation method of this impurity, so the directional synthesis of this impurity and the establishment of an analysis method for this impurity are of great significance to the quality control of eprosartan API

Method used

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  • Method for preparing Eprosartan impurity EP12A
  • Method for preparing Eprosartan impurity EP12A
  • Method for preparing Eprosartan impurity EP12A

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Synthesis of (E)-4-[[2-butyl-5-(2-ethoxycarbonylvinyl)imidazol-1-yl]methyl]benzoic acid [impurity EP12A]:

[0020] To a 500 mL three-neck flask, add 28.6g (0.10 mol) 4-[[(2-butyl-5-formyl) imidazol-1-yl] methyl] benzoic acid, 26.4g (0.20 mol) Monoethyl malonate, 150g toluene, 1.74g (0.02 mol) morpholine, started stirring, raised the temperature to reflux, separated water, and reacted for 12h. The reaction solution was concentrated under reduced pressure, and then purified by column chromatography to obtain 30.0 g of white solid, HPLC purity: 98%, yield: 84.3%. 1 H NMR (DMSO- d 6 ) δ 0.80 (t, J=4.0 Hz, 3H), 1.19 (t, J=4.0 Hz, 3H), 1.28 (m, 2H), 1.56 (m, 2H), 2.65 (t, J=4.0 Hz, 2H ), 4.10 (q, J = 4.0 Hz, 2H), 5.49 (s, 2H), 6.31 (d, J = 12.0 Hz, 1H), 7.08 (d, J = 7.0 Hz, 2H), 7.38 (d, J = 12.0 Hz, 1H), 7.70 (s, 1H), 7.94 (d, J = 7.0 Hz, 2H), 13.07 (b, 1H); 13 C NMR (DMSO- d 6 ) δ 14.1, 14.6, 22.1, 26.4, 29.7, 46.3, 60.3, 114.7, 126.3, 128.6, 130.3, 130.5, 130.9, 131...

Embodiment 2

[0022] Synthesis of (E)-4-[[2-butyl-5-(2-ethoxycarbonylvinyl)imidazol-1-yl]methyl]benzoic acid [impurity EP12A]:

[0023] To a 500 mL three-neck flask, add 28.6g (0.10 mol) 4-[[(2-butyl-5-formyl) imidazol-1-yl] methyl] benzoic acid, 26.4g (0.20 mol) Monoethyl malonate, a mixed solvent of 75g toluene and 75g xylene, 1.74g (0.02 mol) morpholine, started stirring, raised the temperature to reflux, separated water, and reacted for 12h. The reaction solution was concentrated under reduced pressure, and then purified by column chromatography to obtain 30.3 g of white solid, HPLC purity: 98%, yield: 85.0%. 1 H NMR (DMSO- d 6 ) δ 0.80 (t, J=4.0 Hz, 3H), 1.19 (t, J=4.0 Hz, 3H), 1.28 (m, 2H), 1.56 (m, 2H), 2.65 (t, J=4.0 Hz, 2H ), 4.10 (q, J = 4.0 Hz, 2H), 5.49 (s, 2H), 6.31 (d, J = 12.0 Hz, 1H), 7.08 (d, J = 7.0 Hz, 2H), 7.38 (d, J = 12.0 Hz, 1H), 7.70 (s, 1H), 7.94 (d, J = 7.0 Hz, 2H), 13.07 (b, 1H); 13 C NMR (DMSO- d 6 ) δ 14.1, 14.6, 22.1, 26.4, 29.7, 46.3, 60.3, 114.7, 126.3...

Embodiment 3

[0025] Synthesis of (E)-4-[[2-butyl-5-(2-ethoxycarbonylvinyl)imidazol-1-yl]methyl]benzoic acid [impurity EP12A]:

[0026] To a 500 mL three-neck flask, add 28.6g (0.10 mol) 4-[[(2-butyl-5-formyl) imidazol-1-yl] methyl] benzoic acid, 26.4g (0.20 mol) Monoethyl malonate, 180g toluene, 1.74g (0.02 mol) morpholine, started stirring, raised the temperature to reflux, separated water, and reacted for 12h. The reaction solution was concentrated under reduced pressure, and then purified by column chromatography to obtain 31.3 g of white solid, HPLC purity: 97%, yield: 88.0%. 1 H NMR (DMSO- d 6 ) δ 0.80 (t, J=4.0 Hz, 3H), 1.19 (t, J=4.0 Hz, 3H), 1.28 (m, 2H), 1.56 (m, 2H), 2.65 (t, J=4.0 Hz, 2H ), 4.10 (q, J = 4.0 Hz, 2H), 5.49 (s, 2H), 6.31 (d, J = 12.0 Hz, 1H), 7.08 (d, J = 7.0 Hz, 2H), 7.38 (d, J = 12.0 Hz, 1H), 7.70 (s, 1H), 7.94 (d, J = 7.0 Hz, 2H), 13.07 (b, 1H); 13 C NMR (DMSO- d 6 ) δ 14.1, 14.6, 22.1, 26.4, 29.7, 46.3, 60.3, 114.7, 126.3, 128.6, 130.3, 130.5, 130.9, 131...

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Abstract

The invention discloses a method for preparing an Eprosartan impurity EP12A. The method comprises the step of condensing 4-[[(2-butyl-5-formyl)imidazol-1-yl]methyl]benzoic acid with monoethyl malonate in the presence of a catalyst, so as to obtain the Eprosartan impurity EP12A. The method has the beneficial effects that the reaction conditions are mild, the process is simple, the reaction time is short, side products are few, the yield is good, and the high-purity Eprosartan impurity EP12A can be obtained.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to (E)-4-[[2-butyl-5-(2-ethoxycarbonylvinyl) imidazol-1-yl] methyl] benzoic acid (eprosartan impurity EP12A) preparation method. Background of the invention [0002] Eprosartan (English name Eprosartan), chemical name (E)-[[2-butyl-1-[(4-hydroxyphenyl)methyl]-1H-imidazol-5-yl]methylene] -2-thienylpropionic acid, its structural formula is as follows: [0003] [0004] Eprosartan is an antihypertensive drug developed by SmithKline Beecham. Clinical studies have shown that it is effective in reducing systolic blood pressure and diastolic blood pressure in patients with mild, moderate and severe hypertension. [0005] Due to the particularity of its structure, there are few reported methods for preparing eprosartan, such as the synthetic method disclosed in the patent EP 970073. Although the condensation reaction needs to be carried out under low pressure, it is not easy to mai...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/64
CPCC07D233/64
Inventor 朱元勋徐志杰周传伟张文灵王鹏
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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