Preparation method of esmolol hydrochloride intermediate

A technology for esmolol hydrochloride and intermediates, which is applied in the field of preparation of esmolol hydrochloride intermediate 4-hydroxyphenylpropionate methyl ester, which can solve the problem of high operation requirements, long reaction steps, and poor atom economy and other problems, to achieve the effects of short preparation steps, mild reaction conditions, and high atom economy

Pending Publication Date: 2020-09-04
HARVEST PHARMA HUNAN CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] In summary, the existing method for synthesizing methyl p-4-hydroxyphenylpropionate also has long reaction steps, difficult starting materials, which are unfavorable for cost reduction, or need heating reaction, use stoichiometric metal reagents, post-treatment Difficult, high operation requirements, not conducive to industrialization
In addition, most reactions still have problems such as poor atom economy.

Method used

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  • Preparation method of esmolol hydrochloride intermediate
  • Preparation method of esmolol hydrochloride intermediate
  • Preparation method of esmolol hydrochloride intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Synthesis of step (a) 3-(4-hydroxyphenyl) methyl acrylate

[0043] Dissolve 17.3g (100mmol) p-bromophenol in 258g dioxane, add 0.224g palladium acetate (1mmol), 0.787g triphenylphosphine (3mmol), 11.865g pyridine (150mmol), and finally add 10.33g methyl acrylate (120mmol), heated to 80°C under the protection of nitrogen, cooled to room temperature after 10h of reaction, distilled off the solvent under reduced pressure, then added 100ml of a mixed solvent of ethyl acetate and n-hexane, washed with water and brine and dried, added activated carbon, filtered and evaporated to dryness The solvent obtained 18.1 g of an oily product, the HPLC purity of the addition of cis and trans olefin products was 91%, and it was directly put into the next step without purification.

[0044] The preparation of step (b) methyl 4-hydroxyphenylpropionate (3)

[0045] Add the crude 3-(4-hydroxyphenyl)methyl acrylate obtained in the previous step to 450 g of ethanol, add 2% target carbon (bas...

Embodiment 2

[0047] Synthesis of step (a) 3-(4-hydroxyphenyl) methyl acrylate

[0048] Dissolve 17.3g (100mmol) p-bromophenol in 258g DMF, add 0.177g palladium chloride (1mmol), 0.787g triphenylphosphine (3mmol), 15.2g triethylamine (150mmol), and finally add 10.33g methyl acrylate (120mmol), heated to 70°C under the protection of nitrogen, cooled to room temperature after 15h of reaction, distilled off the solvent under reduced pressure, then added 100ml of a mixed solvent of ethyl acetate and n-hexane, washed with water and brine and dried, added activated carbon, filtered and evaporated to dryness The solvent obtained 17.5 g of an oily substance, the HPLC purity of the addition of cis and trans olefins was 89%, and it was directly put into the next step without purification.

[0049] Step (b) Preparation of 4-(2-methoxyethyl)phenol (3)

[0050] The 3-(4-hydroxyphenyl) methyl acrylate crude product obtained by the previous step reaction is added to 375g of dioxane, 2% target carbon (based...

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Abstract

The invention belongs to the field of organic synthesis of medicines, and particularly relates to a preparation method of a medicine esmolol hydrochloride intermediate for treating hypertension. The synthesis route provided by the invention comprises the following steps: reacting p-bromophenol with methyl acrylate in the presence of a palladium catalyst and a phosphine ligand to generate 3-(4-hydroxyphenyl) methyl acrylate; and hydrogenating the generated 3-(4-hydroxyphenyl) methyl acrylate in the presence of a palladium-carbon catalyst to obtain a target product methyl 4-hydroxyphenylpropionate. The method has the advantages of short reaction steps, cheap and accessible raw materials, simple technique and convenience of operation, and does not need special reaction conditions, thereby being more suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of organic synthesis of medicines, and in particular relates to a preparation method of medicine-esmolol hydrochloride intermediate 4-hydroxyphenylpropionate methyl ester. Background technique [0002] Esmolol hydrochloride is a fast-acting, short-acting, selective β1-adrenoceptor blocker. It mainly acts on the β1 adrenergic receptors of the myocardium, and in large doses, it can also block the β2 adrenergic receptors of the trachea and vascular smooth muscle. Esmolol hydrochloride preparations listed in China are injections, which are used to control ventricular rate during atrial fibrillation and atrial flutter, and treat perioperative hypertension and sinus tachycardia. [0003] The chemical name of esmolol hydrochloride is 4-(3-isopropylamino-2-hydroxypropoxy) methyl phenylpropionate hydrochloride, CAS No. 81161-17-3, and its structural formula is as 1. [0004] [0005] Patent WO 8201869 and document J Med C...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/732C07C67/303
CPCC07C67/303C07C67/343C07C2523/44C07C2531/24C07C69/732
Inventor 张勇平周雄陈舟刘芳洁
Owner HARVEST PHARMA HUNAN CO LTD
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