Preparation method of intermediate of metoprolol

A technology of intermediates and phosphine ligands, applied in the field of organic synthesis of drugs, can solve the problems of unfavorable industrialization, high operation requirements, and low selectivity of chemical reactions, and achieve the effect of cheap raw materials and short preparation steps

Active Publication Date: 2019-04-02
HARVEST PHARMA HUNAN CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] In summary, the existing methods for synthesizing p-4-(2-methoxyethyl)phenol still have the use of stoichiometric metal reagents, or the use of highly toxic, high operating requirements, unfavorable for industrialization, and low chemical reaction selectivity Reaction, or the initial raw materials with high price, and some other operation steps are longer, which is not conducive to cost reduction

Method used

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  • Preparation method of intermediate of metoprolol
  • Preparation method of intermediate of metoprolol
  • Preparation method of intermediate of metoprolol

Examples

Experimental program
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Effect test

Embodiment 1

[0039] Step (a) Synthesis of 4-(2-methoxyvinyl)phenol (4)

[0040] Dissolve 17.3g (100mmol) of p-bromophenol (5) in 258g of dioxane, add 0.224g of palladium acetate (1mmol), 0.787g of triphenylphosphine (3mmol), 15.2g of triethylamine (150mmol), and finally add Methyl vinyl ether 7.0g (120mmol), heated to 80°C under the protection of nitrogen, cooled to room temperature after 15h of reaction, concentrated the solvent, added ethyl acetate, washed with water and brine, added activated carbon, filtered and evaporated to dryness to obtain an oil The HPLC purity of the cis- and trans-alkenes was 91%, and it was directly put into the next step without purification.

[0041] Step (b) Preparation of 4-(2-methoxyethyl)phenol (3)

[0042] The crude product of 4-(2-methoxyvinyl)phenol (4) obtained by the previous step reaction is added to 375g ethyl acetate, 2% target carbon (based on 5) is added, and hydrogen is fed and pressurized to 40 atmospheres, heated to 50°C for 16 hours, coole...

Embodiment 2

[0044] Step (a) Synthesis of 4-(2-methoxyvinyl)phenol (4)

[0045]Dissolve 17.3g (100mmol) p-bromophenol (5) in 258gDMF, add 0.177g palladium chloride (1mmol), 0.787g triphenylphosphine (3mmol), 15.2g triethylamine (150mmol), and finally add methylethylene Base ether 7.0g (120mmol), heated to 90°C under nitrogen protection, cooled to room temperature after 15h of reaction, concentrated the solvent, added ethyl acetate, washed with water and brine and dried, added activated carbon, filtered and evaporated to dryness to obtain an oily substance, followed by The HPLC purity of the addition of formula and trans alkenes was 89%, and they were directly put into the next step without purification.

[0046] Step (b) Preparation of 4-(2-methoxyethyl)phenol (3)

[0047] The crude product of 4-(2-methoxyvinyl)phenol (4) obtained by the previous step reaction is added to 375g ethyl acetate, 2% target carbon (based on 5) is added, and hydrogen is fed and pressurized to 30 atmospheres, he...

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Abstract

The invention belongs to the field of organic synthesis of medicines, and particularly relates to a preparation method of an intermediate of a medicine metoprolol for treating hypertension. The synthetic route provided by the invention is as follows: p-bromophenol reacts with methyl vinyl ether in the presence of a palladium catalyst and a phosphine ligand to generate 4-(2-methoxyvinyl)phenol; andhydrogenating the 4-(2-methoxy vinyl)phenol in the presence of a palladium-carbon catalyst to obtain the target product 4-(2-methoxyethyl)phenol. The reaction steps of the method are short, the raw materials are cheap and are easily available, the process is simple, operation is convenient, no special reaction conditions are needed, and therefore, the method is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of organic synthesis of medicines, in particular to a preparation method of p-4-(2-methoxyethyl)phenol, an intermediate of medicine metoprolol. Background technique [0002] Metoprolol is a β-receptor blocker, which has a selective blocking effect on β1 receptors and a weak blocking effect on β2 receptors. It has no intrinsic sympathomimetic activity and membrane stabilizing effect. It exerts antihypertensive effect by antagonizing the excessive activation of the sympathetic nervous system. The main antihypertensive mechanism involves reducing cardiac output, improving the blood pressure regulation function of baroreceptors, and inhibiting the renin-angiotensin-aldosterone system. Metoprolol can be taken orally or intravenously. It is rapidly and completely absorbed after oral administration. The blood concentration reaches its peak in 1.5-2 hours after oral administration. The bioavailability is about 50%. The drug-p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C43/178C07C41/20C07C41/30
CPCC07C41/20C07C41/30C07C43/1787C07C43/1783
Inventor 袁金桥秦敏陈舟傅海燕
Owner HARVEST PHARMA HUNAN CO LTD
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