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New preparation technique of urapidil hydrochloride

A technology of urapidil hydrochloride and preparation process, applied in the field of pharmaceutical synthesis, can solve problems such as water environment pollution, and achieve the effects of easy post-processing, less side reactions and high yield

Active Publication Date: 2015-01-07
HEBEI YIPIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the route process requires the use of a large amount of phase transfer catalysts, especially the use of a large amount of non-ionic surfactants will cause serious pollution to the water environment

Method used

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  • New preparation technique of urapidil hydrochloride
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  • New preparation technique of urapidil hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1 The new preparation technology of urapidil hydrochloride of the present invention

[0037] A. Under nitrogen protection, in a 50L reactor, add 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (8.50g, 0.02mol), Pd(OAc) in sequence 2 (2.25g, 0.01mol), degassing solvent dioxane (20L) and potassium carbonate (691.1g, 5.0mol) stirred at room temperature and reacted for 0.5h (stirring speed 120r / min), after adding 1-(2-formazan Oxyphenyl)piperazine hydrochloride (571.8g, 2.5mol), 6-(3-chloropropyl)-1,3-dimethyluracil (634.4g, 2.75mol), heated for 6h (stirring speed 120r / min, heating temperature 80°C), after cooling to room temperature, a solid precipitated, filtered under reduced pressure (vacuum degree -0.08MPa~0.1MPa) to obtain the crude product, the crude product was dissolved in 20L of hot ethanol (temperature 70°C) Afterwards, filter while it is hot, and the filtrate stands overnight for 12 hours to obtain white crystals. The filter cake is filtered under...

Embodiment 2

[0043] Embodiment 2 The new preparation technology of urapidil hydrochloride of the present invention

[0044] The difference between this embodiment and embodiment 1 is that the A step uses PdCl 2 (1.77g, 0.01mol) instead of Pd(OAc) 2 (2.25g, 0.01mol), degassing solvent tetrahydrofuran (20L) instead of degassing solvent dioxane (20L), to obtain urapidil 783.6g, yield 81.1%, melting range 157-158 ℃; B step with methanol / isopropanol mixed solvent (20L, V 甲醇 :V 异丙醇 =1:1) instead of methanol / ethanol mixed solvent (20L, V 甲醇 :V 乙醇 =1:1); The present embodiment obtains 304.5 g of urapidil hydrochloride, and the crystallization yield is 72.0%. The total yield is 58.4%, the content of related substances is 0.0041%, and the spectral data are the same as in Example 1.

Embodiment 3

[0045] Embodiment 3 The new preparation technology of urapidil hydrochloride of the present invention

[0046] The difference between this embodiment and embodiment 1 is that the A step uses PdCl 2 (1.77g, 0.01mol) instead of Pd(OAc) 2 (2.25g, 0.01mol), with sodium carbonate (530.0g, .5.0mol) instead of potassium carbonate (691.1g, 5.0mol), degassed tetrahydrofuran (20L) instead of degassed dioxane (20L), to uradi Mole 795.2g, yield 82.3%, melting range 157-158 ℃; B step uses methanol / acetone mixed solvent (20L, V 甲醇 :V 丙酮 =1:1) instead of methanol / ethanol mixed solvent (20L, V 甲醇 :V 乙醇 =1:1); The present embodiment obtains 313.4 g of urapidil hydrochloride, and the crystallization yield is 74.1%. The total yield is 61.0%, the content of related substances is 0.0040%, and the spectral data are the same as in Example 1.

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Abstract

The invention relates to a new preparation technique of urapidil hydrochloride, belonging to the technical field of drug synthesis. According to the new preparation technique, a Pd / NHC catalytic system is directly utilized to catalyze 6-(3-chloropropyl)-1,3-dimethyluracil and 1-(2-methoxyphenyl)piperazino hydrochloride to prepare urapidil, and the urapidil is further acidified to prepare the urapidil hydrochloride. The new preparation technique of urapidil hydrochloride has the advantages of simple structure of raw materials, no need of abundant phase-transfer catalysts, fewer side reactions, easy after-treatment, favorable product selectivity and higher yield, and is suitable for industrial production; and the related substance content is less than 0.0047%, and the total yield is greater than 58%.

Description

technical field [0001] The invention relates to a preparation process, in particular to a new preparation process of urapidil hydrochloride, which belongs to the technical field of drug synthesis. Background technique [0002] Hypertension is one of the diseases that seriously threaten human health at present. It is the main cause of coronary heart disease, congestive heart failure and stroke. Among the causes of renal failure, hypertension is second only to diabetes. At present, the clinically used antihypertensive drugs mainly include: adrenoceptor blockers, calcium antagonists, angiotensin converting enzyme (ACE) inhibitors, diuretics, etc. according to their mechanism of action. Among them, the new generation of α-receptor blockers represented by urapidil hydrochloride and prazosin have been clinically recommended as first-line antihypertensive drugs due to their definite antihypertensive effect, less adverse reactions, and certain blood lipid-lowering effects. The rese...

Claims

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Application Information

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IPC IPC(8): C07D239/545
CPCC07D239/545
Inventor 韩婷于宏伟陈芳芳程瑶李培鸿赵翠然邱玉敏
Owner HEBEI YIPIN PHARMA
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