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Preparation method of related substance E of metoprolol

A compound, the technology of methoxyethyl, is applied in the field of preparation of metoprolol related substance E, which can solve the problems of low total yield, high price and high cost, and achieve the effect of simple operation, simplified operation and low cost

Inactive Publication Date: 2013-03-13
SHANGHAI AOBO PHARMTECH INC LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are many defects in this route. On the one hand, the 2-hydroxyphenylethanol raw material it adopts is not easy to obtain; on the other hand, when bromoacetonitrile is used to protect the phenolic hydroxyl group, it needs to undergo a deprotection process afterwards
However, deprotection requires the use of expensive catalyst platinum oxide for hydrogenation reduction
Therefore, the total yield of this route is low and the cost is high

Method used

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  • Preparation method of related substance E of metoprolol
  • Preparation method of related substance E of metoprolol
  • Preparation method of related substance E of metoprolol

Examples

Experimental program
Comparison scheme
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Embodiment 1

[0053] The technical scheme of the present invention is further described below with specific examples, but protection scope of the present invention is not limited to this: Embodiment one: the synthesis of 2-hydroxyphenethyl alcohol (IV)

[0054] Add 30.4g of compound (Ⅲ), 300mL of tetrahydrofuran and 24.2g of triethylamine into the reaction flask, control the temperature at 0-10°C, add 20.8g of methyl chloroformate dropwise to the reaction system, and react at room temperature for 1h after the dropwise addition. Filter, cool the filtrate to 0~10°C, add 11.4g of sodium borohydride in 100mL aqueous solution to the filtrate. After the dropwise addition, it was raised to room temperature and reacted for 3 hours, and the reaction was completed. Add 300 mL of ethyl acetate and 300 mL of saturated brine for extraction, and separate the organic layer. The organic layer was dried and concentrated to obtain 30.5 g of oil, which was directly carried out to the next reaction.

Embodiment 2

[0055] Embodiment two: the synthesis of 2-benzyloxyphenethyl alcohol (Ⅴ)

[0056] Add the compound (IV) prepared in Example 1, 56.7g of benzyl bromide, 91.5g of potassium carbonate and 300mL of acetone into the reaction flask, heat up to reflux for 20 hours, and the reaction is complete. Filter and wash the filter cake with acetone. After the filtrate was concentrated, 300 mL of ethyl acetate and 300 mL of water were added for extraction, and the organic layer was separated. The organic layer was dried, and the solvent was removed under reduced pressure to obtain 48.9 g of oil, which was directly put into the next reaction.

Embodiment 3

[0057] Example three: Synthesis of 1-benzyloxy-2-(2-methoxyethyl)benzene (Ⅵ)

[0058] Add 12.3g of 60% sodium hydride and 300mL of N,N-dimethylformamide to the reaction flask, lower the temperature to 0~10°C, and add dropwise 50mL of N,N-dimethylformamide of compound (Ⅴ) prepared in Example 2 solution. After dropping, rise to room temperature and react for 2h. Add 45.6g of methyl iodide dropwise to the system, then react at room temperature for 20h, and the reaction is complete. Add 300 mL of saturated brine dropwise to the system, add 300 mL of ethyl acetate for extraction, and separate the organic layer. The aqueous layer was extracted once more with ethyl acetate, and the organic layers were combined. The organic phase was dried, and the solvent was concentrated to obtain 51.7 g of oil, which was directly put into the next reaction.

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Abstract

The invention discloses a novel method of a related substance E of metoprolol: 1-isopropamide) propoxyl-3-[2-(2-methoxyl ethyl) phenoxyl-2-propyl alcohol (I). The method comprises the steps of: carrying out a reaction on 2-hydroxyphenylacetic acid (III) and chloro-carbonic ester to generate mixed anhydride and reducing to obtain 2-hydroxyl phenethyl alcohol (IV); carrying out a reaction on a compound (IV) and halogenated benzyl to obtain benzyloxy phenethyl alcohol (V); carrying out a reaction to the compound (IV) and a methylating reagent to form 1-benzyloxy-2-(2-methoxyl ethyl) benzene (VI); hydrocarbonizing the compound (IV) by palladium to obtain 2-(2-methoxyl ethyl); carrying out a reaction on the compound (VII) and epoxy chloropropane in presence of a phase transfer catalyst to obtain 2-((2-(2-methoxyl ethyl) phenoxyl)methyl) ethylene oxide (VIII); and carrying out an isopropamide reaction on the compound (VIII) to obtain the compound (I). The line is low in cost, simple to operate, environment-friendly and highly efficient to obtain products.

Description

technical field [0001] The invention relates to a new method for synthesizing metoprolol related substance E: 1-isopropylamino-3-[2-(2-methoxyethyl)phenoxy]-2-propanol (I). Its specific structure is as follows: [0002] Background technique [0003] Cardiovascular and cerebrovascular diseases represented by hypertension, stroke and coronary heart disease seriously endanger human health, especially the incidence of heart disease spreads in all age groups, and its morbidity and mortality rank first among all diseases in most countries in the world Known as "the number one executioner of human health". [0004] Metoprolol (II) is an aminopropanol drug, a selective β-receptor blocker, and is the first choice drug for the treatment of hypertension in the world in recent years. It competes with excitatory epinephrine and norepinephrine, and protects the heart at the receptor's site, inhibits cardiac contractility, prevents hyperexcitability, and blocks nerve impulses. It als...

Claims

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Application Information

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IPC IPC(8): C07C217/32C07C213/04C07C41/16C07C43/205
Inventor 陈欢生陈宇卢玉华邹青
Owner SHANGHAI AOBO PHARMTECH INC LTD
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