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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, etc., to achieve high chemical selectivity, promote economic and technological development, and improve quality

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
  • 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 dichloromethane into a 500mL three-necked flask 250mL, warm to 40-45°C, stir until the system is uniformly dissolved. When the temperature drops below 10°C, slowly add 4-hydroxyphenylacetyl chloride (III) (46.8g, 0.28mol) in dichloromethane solution dropwise for 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 with 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-alkoxyphenyl)-2-hydroxy-1-methylethyl)- 4-hydroxyphenylacetamide (IV) was 68.5 g, and the yield was 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 maintain the hydrogen pressure according to the hydrogenation procedure 5KG and temperature 50°C, until no more hydrogen is absorbed. The temperature was lowered, the catalyst was recovered by filtration, and concentrated under reduced pressure. The residue was recrystallized with ethyl acetate to obtain 47.2 g of white solid ritodrine (I) with a yield of 82.2%.

Embodiment 3

[0031] Intermediate (IV) (60.2 g, 0.2 mol) and 250 mL of tetrahydrofuran were added to a 500 mL three-necked flask, and stirred until the system was uniformly dissolved. The temperature was lowered to 0°C, and lithium aluminum tetrahydrogen (11.4 g, 0.3 mol) was added to the reaction solution in batches. After the addition was completed, the temperature was raised to reflux, and the reaction was continued for 4 hours, and the reaction was completed by TLC detection. Reduce to room temperature, add 30 mL of 10% sodium hydroxide solution, and filter to remove insoluble materials. 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 the preparation of raw materials and intermediates, and particularly relates to a preparation method of ritodrine. Background technique [0002] Ritodrine (Ritodrine, chemical name 1-(4-hydroxyphenyl)-2-[2-(4-hydroxyphenyl)ethylamino]propanol, I) is the β that stimulates uterine smooth muscle 2 Receptor. The drug is the only uterine contraction inhibitor approved by the U.S. Food and Drug Administration (FDA) and recommended by the American College of Obstetricians and Gynecologists (ACOG). It has also been included in the "National Essential Drug List" and is mainly used to prevent late abortion and threats. Premature delivery has a strong inhibitory effect on uterine contractions, and the effect is rapid. Its side effects are predictable and controllable. Recurrence of premature birth can be used repeatedly without time and dose limitation, which is the biggest advantage...

Claims

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Application Information

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IPC IPC(8): C07C215/60C07C213/08
Inventor 许学农
Owner SUZHOU LIXIN PHARMA
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