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Preparation method of ritodrine hydrochloride

A technology for ritodrine hydrochloride and propanol hydrochloride, which is applied in the field of preparation of ritodrine hydrochloride to achieve the effects of high chemical selectivity, improved quality and control of production costs

Active Publication Date: 2013-05-22
SUZHOU LIXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Investigating this synthetic route, there are at least two weaknesses as follows: first, these synthetic routes all require bromination reactions; second, this route always includes the protection and deprotection process of hydroxyl

Method used

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  • Preparation method of ritodrine hydrochloride
  • Preparation method of ritodrine hydrochloride
  • Preparation method of ritodrine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Add 2-amino-1-(4-hydroxyphenyl)propanol hydrochloride (II) (50.2g, 0.25mol), triethylamine (25.0g, 0.25mol), potassium iodide (0.5 g, 1%eq) and absolute ethanol 125mL, warming up to 50-55°C, stirring until the system dissolves uniformly. 4-(2-Chloroethanol)phenol (III) (46.8 g, 0.3 mol) was slowly added dropwise to the reaction liquid, and the drop was completed in about 1 hour. Be warming up to 85 DEG C, continue to react for 6 hours, TLC detects that the reaction ends. Cool down to room temperature and remove triethylamine hydrochloride by filtration. The filtrate was adjusted to pH 4-5 with hydrochloric acid. Ethanol was recovered under reduced pressure, and the residue was recrystallized from a mixed solvent of n-hexane and ethyl acetate to obtain 66.8 g of ritodrine hydrochloride (I) as a white solid with a yield of 83.0%.

Embodiment 2

[0028] Add 2-amino-1-(4-hydroxyphenyl)propanol hydrochloride (II) (50.2g, 0.25mol), triethylamine (25.0g, 0.25mol), potassium iodide (0.5 g, 1%eq) and absolute ethanol 125mL, warming up to 50-55°C, stirring until the system dissolves uniformly. 4-(2-Chloroethanol)phenol (III) (60.0 g, 0.3 mol) was slowly added dropwise to the reaction solution, and the drop was completed in about 1 hour. Be warming up to 80 DEG C, continue to react for 3 hours, TLC detects that the reaction ends. Cool down to room temperature, and remove triethylamine hydrobromide by filtration. The filtrate was adjusted to pH 4-5 with hydrochloric acid. Ethanol was recovered under reduced pressure, and the residue was recrystallized from a mixed solvent of n-hexane and ethyl acetate to obtain 70.2 g of ritodrine hydrochloride (I) as a white solid with a yield of 87.2%.

Embodiment 3

[0030] Add 2-amino-1-(4-hydroxyphenyl)propanol hydrochloride (II) (50.2g, 0.25mol), potassium carbonate (17.5g, 0.13mol), potassium iodide (0.5g , 1%eq) and tetrahydrofuran 125mL, the temperature was raised to 40-50°C, and stirred until the system was dissolved uniformly. 4-(2-Chloroethanol)phenol (III) (46.8 g, 0.3 mol) was slowly added dropwise to the reaction liquid, and the drop was completed in about 1 hour. The temperature was raised to reflux, and the reaction was continued for 5 hours, and the reaction was detected by TLC. Cool down to room temperature, and remove insoluble matter by filtration. The filtrate was adjusted to pH 4-5 with hydrochloric acid. Tetrahydrofuran was recovered under reduced pressure, and the residue was recrystallized from a mixed solvent of n-hexane and ethyl acetate to obtain 64.5 g of ritodrine hydrochloride (I) as a white solid with a yield of 80.1%.

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Abstract

The invention discloses a preparation method of ritodrine hydrochloride (I). The preparation method comprises the following steps of: subjecting 2-amino-1-(4-hydroxyphenyl) propanol hydrochloride (II) and 4-(2-halogen ethanol) phenol (III) to condensation reaction in the presence of a catalyst to obtain ritodrine and then forming salt with ritodrine and hydrochloric acid to obtain ritodrine hydrochloride (I). The preparation method has the advantages that the production cost of ritodrine hydrochloride can be effectively controlled, the product quality is substantially improved and economic and technical development of the active pharmaceutical ingredient is promoted.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis method design and preparation of raw materials and intermediates, and in particular relates to a preparation method of ritodrine hydrochloride. Background technique [0002] Ritodrine Hydrochloride (Ritodrine Hydrochloride, chemical name is 1-(4-hydroxyphenyl)-2-[2-(4-hydroxyphenyl)ethylamino]propanol hydrochloride, I) is developed by Belgian Solvay company beta of 2 Adrenergic receptor agonist. The drug is the only tocolytic approved by the U.S. Food and Drug Administration (FDA) and recommended by the American College of Obstetricians and Gynecologists (ACOG). For premature birth, it has strong uterine contraction inhibitory effect and quick effect, and is currently the most ideal anti-fetal drug. Its side effects are predictable and controllable, the relapse of premature birth can be repeated, and it is not limited by time and dose. This is the biggest advantage of ritodrine hydroc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/60C07C213/04
Inventor 许学农
Owner SUZHOU LIXIN PHARMA
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