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Preparation method of ritodrine

A technology of hydroxyphenyl and propanol hydrochloride, which is applied in the preparation of organic compounds, chemical instruments and methods, and the preparation of amino hydroxyl compounds, to achieve the effects of promoting economic and technological development, controlling production costs, and high chemical selectivity

Active Publication Date: 2014-04-30
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
  • Preparation method of ritodrine
  • Preparation method of ritodrine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Add 2-amino-1-(4-hydroxyphenyl)propanol hydrochloride (II) (50.2g, 0.25mol), triethylamine (25.0g, 0.25mol) and methylene chloride in a 500mL three-necked flask 250mL, heat up to 40-45°C, and stir until the system dissolves uniformly. Lowered to below 10°C, slowly added a dichloromethane solution of 4-hydroxyphenylacetyl chloride (III) (46.8g, 0.28mol) dropwise, and the dropwise was completed in about 1 hour. The reaction was continued at room temperature for 6 hours, and TLC detected that the reaction was complete. The reaction solution was washed with 10% sodium bicarbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was recovered under reduced pressure, and the residue was recrystallized from a mixed solvent of n-hexane and ethyl acetate to obtain an off-white solid N-(2-(4-hydroxyphenyl)-2-hydroxyl-1-methylethyl)-4- Hydroxyphenylacetamide (IV) 68.5g, yield 91.0%.

Embodiment 2

[0029] 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 a temperature of 50°C until no more hydrogen is absorbed. The temperature was lowered, the catalyst was recovered by filtration, concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain 47.2 g of white solid ritodrine (I), with a yield of 82.2%.

Embodiment 3

[0031] Add intermediate (IV) (60.2 g, 0.2 mol) and 250 mL tetrahydrofuran into a 500 mL three-necked flask, and stir until the system is uniformly dissolved. The temperature was lowered to 0°C, and Lithium Aluminum Hydride (11.4 g, 0.3 mol) was added in batches to the reaction solution. After the addition was complete, the temperature was raised to reflux, and the reaction was continued for 4 hours, and the reaction was detected by TLC. After cooling down to room temperature, 30 mL of 10% sodium hydroxide solution was added, and the insoluble matter was removed by filtration. Tetrahydrofuran was recovered from the filtrate under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain 48.5 g of white solid ritodrine (I), with a yield of 84.5%.

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Abstract

The invention discloses a preparation method of ritodrine (I). The preparation method comprises the following steps of: subjecting 2-amino-1-(4-hydroxyphenyl) propanol hydrochloride (II) and 4-hydroxy phenylacetyl chloride (III) to amidation reaction to obtain an intermediate N-(2-(4- hydroxyphenyl)-2-hydroxy-1-methylethyl)-4-hydroxy phenylacetamide (IV) and obtaining ritodrine (I) through reduction 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. Background technique [0002] Ritodrine (Ritodrine, chemically called 1-(4-hydroxyphenyl)-2-[2-(4-hydroxyphenyl)ethylamino]propanol, I) is a β-activator that stimulates uterine smooth muscle. 2 receptor. 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 a strong inhibitory effect on uterine contractions and a rapid effect. Its side effects are predictable and controllable. It is the biggest advantage of ritodrine that it can be used repeatedly for recurrence of premature birth, and it is not limited by time and dose. [0003] [0004] At present, there are many reports on the preparation methods of ritodrine...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C215/60C07C213/08
Inventor 许学农
Owner SUZHOU LIXIN PHARMA
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