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Preparation method of related substance J of metoprolol

A compound, the technology of methoxyethyl, is applied in the field of preparation of metoprolol related substance J, which can solve the problems such as no synthesis report

Active 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

At present, some metoprolol-related substances have been synthesized, but for metoprolol-related substance J, there has never been a synthesis report

Method used

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  • Preparation method of related substance J of metoprolol
  • Preparation method of related substance J of metoprolol
  • Preparation method of related substance J of metoprolol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1: Synthesis of 1-(2,3-epoxypropoxy)-4-(2-methoxyethyl)benzene (IV)

[0040] Add 20.0g of compound (Ⅲ), 200mL of 3% sodium hydroxide aqueous solution, 2.0g of tetrabutylammonium bromide and 18.0g of epichlorohydrin into the reaction flask, raise the temperature to 70°C, stir for 5h, and the reaction is complete. 200 mL of ethyl acetate was added for extraction, the liquid was separated, and the ethyl acetate was removed under reduced pressure to obtain 27.0 g of a yellow liquid, which was directly carried out to the next reaction.

Embodiment 2

[0041]Example two: Synthesis of 1-allyloxy-3-[4-(2-methoxyethyl)phenoxy]-2-propanol (Ⅴ)

[0042] Add the compound (IV) prepared in Example 1 and 150 mL of allyl alcohol into the reaction flask, control the temperature at 0-10° C., and add 6.5 g of 60% sodium hydrogen in batches. After the addition, the temperature was raised to 25° C. and stirred for 3 h, and the reaction was completed. Add 100mL of 2N hydrochloric acid to quench the reaction, add 100mL of dichloromethane for extraction, and separate the organic layer. The aqueous phase was extracted once more with 100 mL of dichloromethane. The organic layers were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 34.5 g of oil, which was directly put into the next reaction.

Embodiment 3

[0043] Example Three: Synthesis of 1-[4-(2-methoxyethyl)phenoxy]-3-(2,3-epoxypropoxy)-2-propanol (Ⅵ)

[0044] Add the compound (V) prepared in Example 2 and 350 mL of dichloromethane into the reaction flask, add 51.3 g of m-chloroperoxybenzoic acid, and react at room temperature for 20 h, and the reaction is complete. Filter and wash the filter cake once with dichloromethane. Combine the filtrates, add 150mL10% sodium sulfite solution for washing, and separate the organic layer. The organic layer was washed once with 150 mL of saturated sodium bicarbonate and 150 mL of water. The organic phase was dried, and the solvent was concentrated to obtain 35.0 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 J of metoprolol: 1-(2-hydroxyl-3-isopropamide) propoxyl-3-[4-(2-methoxyl ethyl) phenoxyl-2-propyl alcohol (I). The method comprises the steps of: carrying out a reaction on 4-(2-methly ethyl) phenol (III) and epoxy chloropropane to obtain 1-(2,3-epoxy propoxyl)-4-(2-methoxyl ethyl) benzene (IV); carrying out a reaction on a compound (IV) and allyl alcohol to obtain 1-allyloxy-3-[4-(2-methoxyl ethyl) phenoxyl]-2-propyl alcohol (V); forming 1-[4-(2-methoxyl ethyl) phenoxyl]-3-(2,3-epoxy propoxyl)2-propyl alcohol (VI) under the effect of an oxidizer by the compound (V); and carrying out a reaction on the compound (VI) and isopropylamine to the obtain the compound (I).

Description

technical field [0001] The present invention relates to a metoprolol related substance J: 1-(2-hydroxy-3-isopropylamino)propoxy-3-[4-(2-methoxyethyl)phenoxy]-2 - A new method for the synthesis of propanol (I). Its specific structure is as follows: [0002] Background technique [0003] Metoprolol (II), chemical name is 1-isopropylamino-3-[4-(2-methoxyethyl)phenoxy]-2-propanol, molecular formula is C 15 h 25 NO 3 , trade name Toprol-XL. Clinically, metoprolol hydrochloride, tartrate and succinate are mainly used. It is an aminopropanol drug, which is mainly used clinically to treat hypertension, angina pectoris, myocardial infarction, hypertrophic cardiomyopathy, etc. It is a first-line drug among β-receptor blockers, with an average annual sales of 10 billions of dollars or so. At present, China has no legal sources of raw materials, and the research and development are mainly carried out by the United States, Western Europe and Japan abroad. [0004] [0005] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C217/28C07C213/04C07C43/178C07D303/26
Inventor 陈欢生陈宇袁利邹青
Owner SHANGHAI AOBO PHARMTECH INC LTD
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