Preparation method and application of high-purity olmesartan medoxomil intermediate ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazolyl-5-carboxylate

A technology of methyl ethyl and propylimidazole, applied in the field of chemical synthesis, can solve problems such as low yield, low product purity, and in-depth research on impurities

Active Publication Date: 2015-02-18
HUANGGANG LUBAN PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] At present, the synthetic method of 4-(1-hydroxyl-1-methylethyl)-2-propylimidazole-5-carboxylate (1) has low product purity, low yield, and impurities in the product Inadequately researched technical flaws

Method used

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  • Preparation method and application of high-purity olmesartan medoxomil intermediate ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazolyl-5-carboxylate
  • Preparation method and application of high-purity olmesartan medoxomil intermediate ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazolyl-5-carboxylate
  • Preparation method and application of high-purity olmesartan medoxomil intermediate ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazolyl-5-carboxylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Preparation of 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester (1)

[0072] Add 100g (4.16mol) of magnesium powder to tetrahydrofuran (2L), pass in methyl chloride gas at 60℃ until the magnesium powder disappears (about 3 hours), then reflux for 30 minutes, cool to room temperature, and obtain gray methyl magnesium chloride Tetrahydrofuran solution. A 2.1L tetrahydrofuran solution of ethyl 2-propylimidazole-4,5-dicarboxylate (2) (211.9g, 0.83mol) was added dropwise at 30°C. After 2 hours, continue to stir for 30 minutes. The solvent was removed under reduced pressure, and saturated ammonium chloride solution was added dropwise to the residue until the solid was dissolved. 2.5L of ethyl acetate was added, the organic layer was separated, the aqueous layer was extracted with ethyl acetate 500ml×2, and the organic layers were combined. Wash once with saturated brine. Dry with anhydrous magnesium sulfate. The solvent was evaporated to obtain li...

Embodiment 2

[0077] Preparation of ketone ethyl ester impurity 3 reference substance

[0078] Take 10.0 g of the oily substance prepared in Example 1 and carry out column chromatography separation, eluting with dichloromethane:methanol=25:1 eluent, collect the eluent rich in ketone ethyl impurity 3, and remove the solvent. , Get 0.3 g of ketone ethyl ester impurity 3.

[0079] HPLC conditions: chromatographic column: C184.6*250mm 5um; mobile phase: 0.02M tetrabutylammonium bromide + 1% triethylamine aqueous solution (pH=6.0): acetonitrile=78:22; column temperature: room temperature; detection wavelength : 254nm; flow rate: 1ml / min; sample concentration: 45mg-25ml (acetonitrile: water=1:4), injection volume: 2ul; retention time of ketone ethyl impurity 3: 11.67min.

[0080] MS (Q-TOF micro, ESI + ):247.10[M+Na] + .

[0081] 1 HNMR(CDCl 3 )δ:9.8~10.5(1H,br,N H ,),4.45(2H,q,OC H 2 CH 3 ),2.76(2H,t,CH 3 CH 2 C H 2 ),2.74(3H,s,-C H 3 ),2.02(2H,m,CH 3 C H 2 CH 2 ),1.42(3H,t,OCH 2 C H 3 ),0.98(3H,t,C H ...

Embodiment 3

[0083] Preparation of ketone ethyl ester impurity 3 reference substance

[0084] According to the literature ARKIVOC (2010), (2), 292-302 method to prepare ketone ethyl impurity 3 reference substance 15.2 g.

[0085] MS (Q-TOF micro, ESI + ):247.1[M+Na] + .

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Abstract

The invention provides a preparation method of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazolyl-5-carboxylate (1). The method accurately controls the reaction material ratio, solvent composition, solvent consumption, reaction temperature, reaction time and other technological parameters, and obviously lowers the content of the impurity compound disclosed as Formula 3, thereby obtaining the high-purity olmesartan medoxomil. The invention also provides application of the compound disclosed as Formula 3 as a quality control standard substance in preparing the ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazolyl-5-carboxylate (1).

Description

Technical field [0001] The invention relates to the field of chemical synthesis. Specifically, the present invention relates to a method for preparing a high-purity olmesartan medoxomil intermediate 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid ethyl ester, and Application of the prepared ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate in the further preparation of olmesartan medoxomil. Background technique [0002] Olmesartan Medoxomil (Olmesartan Medoxomil, whose structure is shown below) was developed by Sankyo (Sankyo), Japan, and was launched in the United States under the trade name Benicar in May 2002. Olmesartan medoxomil is an ideal antihypertensive drug. It has good curative effect on all types of hypertension, long half-life, convenient taking, small dosage, quick onset, stronger and lasting antihypertensive effect, and adverse reactions Advantages such as low incidence. Olmesartan medoxomil can also be taken with other antihypert...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/90C07D405/14
CPCC07D233/90C07D405/14
Inventor 杨小龙刘向群李强陈潜杨铁波
Owner HUANGGANG LUBAN PHARM
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