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Preparation method of ritodrine

A technology of hydroxyphenyl and intermediates, applied in the field of preparation of ritodrine, to achieve the effect of cost reduction, quality improvement, and promotion of economic and technological development

Active Publication Date: 2013-03-20
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, this synthetic route requires bromination reaction; 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

[0029] 4-Hydroxypropiophenone (150 g, 1 mol) and 400 mL of tetrahydrofuran were added to a 1 L three-necked flask, and dry hydrogen chloride gas was introduced under stirring until the system was saturated. Slowly feed methyl nitrite gas (67.0 g, 1.1 mol) at 40° C. for about 4 hours, and continue the reaction for 1 hour after the passage. TLC detects that the reaction is complete. The solvent was recovered under reduced pressure, and the residue was recrystallized from toluene to obtain 139.6 g of off-white solid 2-oximino-4-hydroxypropiophenone (II), with a yield of 78.2%.

Embodiment 2

[0031] Add intermediate 2-oximino-4-hydroxypropiophenone (II) (89.5g, 0.5mol), 10% palladium carbon catalyst (4.5g, 5%w / w), 36% 80mL of concentrated hydrochloric acid and 400mL of methanol, start stirring, according to the operating procedures of catalytic hydrogenation, feed hydrogen to 0.5MPa, heat up to 60-65°C, until no hydrogen is absorbed, continue stirring for one hour. Cool down to room temperature, discharge, and filter to recover the catalyst. Concentrate under reduced pressure to recover methanol. The residue was recrystallized from isopropanol to obtain 56.5 g of off-white solid 2-amino-1-(4-hydroxyphenyl)propanol hydrochloride (III), with a yield of 75.2%.

Embodiment 3

[0033] Add intermediate 2-amino-1-(4-hydroxyphenyl)propanol hydrochloride (III) (75.5g, 0.5mol), triethylamine (10.0g, 0.1mol) and no Water ethanol 250mL, warm up to 50-55°C, stir until the system dissolves uniformly. P-Hydroxyphenylacetaldehyde (68.0 g, 0.5 mol) was slowly added dropwise to the reaction liquid, and the drop was completed in about 1 hour. Keep this temperature and continue to react for 3 hours, and TLC detects that the reaction is complete. Ethanol was recovered under reduced pressure, and the residue was washed with n-hexane to obtain 121.3 g of yellow solid (1-(4-hydroxyphenyl)-2-[2-(4-hydroxyphenyl)ethylimine]propanol (IV) , yield 85.3%.

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Abstract

The invention discloses a preparation method of ritodrine (1-(4-hydroxyphenyl)-2-[2-(4-hydroxyphenyl)ethylamino]propanol, I), which comprises the following steps: reacting 4-hydroxypropiophenone and alkyl nitrite to obtain an intermediate 2-oximino-4-hydroxypropiophenone (II); performing reduction reaction on the intermediate (II) to obtain 2-amino-1-(4-hydroxyphenyl)propanol hydrochloride (III); then, performing condensation reaction on the intermediate (III) and 4-hydroxyphenylacetaldehyde to generate a Schiff base intermediate (1-(4-hydroxyphenyl)-2-[2-(4-hydroxyphenyl)ethylimido]propanol, IV); and performing reduction reaction on the intermediate (IV) to obtain the ritodrine (I). The preparation method has high chemical selectivity and can be implemented without the protection of any functional group, so that the production cost and quality of the ritodrine (I) are greatly improved.

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-methanol developed by Solvay Company in Belgium. 2 Adrenergic receptor agonist, first listed in Sweden in 1973. This product can stimulate the β of uterine smooth muscle 2 Receptors can inhibit the frequency, intensity and duration of uterine smooth muscle contraction, thereby prolonging the pregnancy period, and increasing the maturity of the fetal heart and lungs, which is beneficial to the health of the baby. It is clinically used for anti-premature treatment of pregnant women over 20 weeks of pregnancy. [0003] [0004] At present, there are many reports on the preparation methods of ritodrine, most of which f...

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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