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Preparation method of ritodrine hydrochloride

A technology for ritodrine hydrochloride and propanol hydrochloride, applied in the field of preparation of ritodrine hydrochloride, to achieve the effects of promoting economic and technological development, controlling production costs, and high chemical selectivity

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

[0028] Add 2-amino-1-(4-hydroxyphenyl)propanol hydrochloride (II) (50.2g, 0.25mol), triethylamine (25.0g, 0.25mol) and dichloromethane into a 500mL three-necked flask 250mL, stirred at room temperature until the system was dissolved uniformly. Add 4-hydroxyphenylacetic acid (III) (43.7g, 0.29mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (39.2g, 0.25mol) to the system And N-hydroxybenzotriazole (HOBt) (3.37g, 0.1eq), be warming up to 35 ℃, react for 12 hours, TLC detects that the reaction ends. Cool down to room temperature, and remove insoluble matter by filtration. The filtrate was washed successively with saturated brine and water, dried and concentrated to recover the solvent to obtain 70.2 g of intermediate (IV) as an off-white solid with a yield of 93.3%.

Embodiment 2

[0030] Add 2-amino-1-(4-hydroxyphenyl)propanol hydrochloride (II) (50.2g, 0.25mol) and 250mL of N,N-dimethylformamide (DMF) into a 500mL three-necked flask, Stir at room temperature until the system dissolves uniformly. Add 4-hydroxyphenylacetic acid (III) (43.7g, 0.29mol), dicyclohexylcarbodiimide (DCC) (39.2g, 0.25mol) and 4-N,N-lutidine (DMAP) into the system (3.37g, 0.1eq), react at room temperature for 16 hours, and TLC detects that the reaction is complete. The reaction solution was poured into 500mL of dichloromethane, washed successively with 5% dilute hydrochloric acid, 10% sodium bicarbonate, saturated brine and water, dried and concentrated to recover the solvent to obtain 67.5 g of off-white solid as intermediate (IV), Yield 89.7%.

Embodiment 3

[0032] Add intermediate (IV) (60.2g, 0.2mol), 5% palladium carbon catalyst (6g, 10%w / w), 2mL of concentrated hydrochloric acid and 500mL of methanol into a 1L hydrogenation kettle, and keep the hydrogen pressure according to the hydrogenation reaction procedure 5KG and temperature 50 DEG C, to no longer absorbing hydrogen. The temperature was lowered, the catalyst was recovered by filtration, concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of n-hexane and ethyl acetate to obtain 52.5 g of ritodrine hydrochloride (I) as a white solid with a yield of 81.5%.

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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-hydroxyphenylacetic acid (III) to amidation and condensation reactions under the action of a catalyst to obtain an intermediate N-(2-(4-hydroxyphenyl)-2-hydroxy-1-methylethyl)-4-hydroxy phenylacetamide (IV) and obtaining ritodrine hydrochloride (I) through reduction reaction and salt forming reaction of the intermediate (IV). The preparation method has the advantages that the production cost of ritodrine 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, chemically named as 1-(4-hydroxyphenyl)-2-[2-(4-hydroxyphenyl)ethylamino]propanol hydrochloride, I) is an inhibitor of uterine smooth muscle beta 2 receptor. The drug is the only tocolytic agent approved by the US FDA (US Food and Drug Administration) and recommended by ACOG (American College of Obstetricians and Gynecologists). Threatened premature birth, its strong inhibitory effect on uterine contractions, quick effect, is currently the most ideal anti-tocopheral 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 hydrochloride,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C215/60C07C213/02
Inventor 许学农
Owner SUZHOU LIXIN PHARMA
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