Preparation process for gout suppressant Lesinaurad intermediates

A preparation process and neutral technology are applied in the field of preparation technology of an intermediate of anti-gout drug Lesinaurad, which can solve the problems of difficult industrial production and high raw material prices, and achieve the effects of low cost, high total yield, and cheap and easy-to-obtain raw materials.

Inactive Publication Date: 2015-10-21
ASTATECH CHENGDU BIOPHARM CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The technical problem to be solved by the present invention is to overcome the deficiencies in the prior art, aiming at the shortcomings of the existing methods or processes, such as the high price of raw materials or the use of precious metal catalysis and difficulty in industrial production, to provide a chemical process for preparing cyclopropylnaphthalene. The method has the characteristics of economy, high efficiency, and easy industrial production

Method used

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  • Preparation process for gout suppressant Lesinaurad intermediates
  • Preparation process for gout suppressant Lesinaurad intermediates
  • Preparation process for gout suppressant Lesinaurad intermediates

Examples

Experimental program
Comparison scheme
Effect test

experiment example 1

[0034] Experimental example 1: the screening of alkali in step (1):

[0035] Add 240G of ethanol into a 500mL three-necked flask, then start stirring, then add 100G of 3-(dimethylamino)-1-(naphthalene-1-yl)-1-acetone hydrochloride, after the addition is complete, heat up to 45- At 50°C, 0.05KG of hydrazine hydrate and the corresponding base (3.5 equivalents) were added dropwise. After the feeding is completed, the temperature is raised to 65-70°C. After the reaction reaches the end point, the temperature of the reaction solution is cooled to 30-40°C, the liquid is separated, the upper organic phase is collected, concentrated to dryness, and compound III is obtained. The reaction data is as follows:

[0036]

[0037] As can be seen from the data in the table above: the reaction effect of NaOH and KOH is better, but the reaction yield is slightly higher with NaOH as alkali, and the price of NaOH is cheaper than KOH, therefore, alkali is preferably NaOH in the step (1).

experiment example 2

[0038] Experimental example 2: the screening of catalyst in the step (2):

[0039] Add 240G of ethanol into a 500mL three-necked flask, then start stirring, then add 100G of 3-(dimethylamino)-1-(naphthalene-1-yl)-1-acetone hydrochloride, after the addition is complete, heat up to 45- At 50°C, 0.05KG of hydrazine hydrate and the corresponding base (3.5 equivalents) were added dropwise. After the feeding is completed, the temperature is raised to 65-70°C. After the reaction reaches the end point, the temperature of the reaction solution is cooled to 30-40°C, the liquid is separated, the upper organic phase is collected, concentrated to dryness, and compound III is obtained.

[0040] Put the above oil into a 2L single-necked bottle, add the corresponding catalyst, and heat to 150-210°C for cracking reaction. After the reaction is complete for a certain period of time, distill under reduced pressure to obtain cyclopropylnaphthalene. The experimental data are as follows:

[0041]...

Embodiment 1

[0044] Add 15KG of ethanol into the 50L reaction kettle, then start stirring, then add 10KG of 3-(dimethylamino)-1-(naphthalene-1-yl)-1-acetone hydrochloride, after the addition is complete, heat up to 45- At 50°C, add dropwise a mixture of 3.8KG hydrazine hydrate and (1.75KG sodium hydroxide / 1.75KG water / 6.5KG methanol). After the feeding is completed, the temperature is raised to 65-70°C. After the reaction reaches the end point, the ethanol is concentrated under reduced pressure, 13KG of MTBE is added, stirred and cooled to 20-25°C, filtered, the filter cake is rinsed with MTBE (5KG), and the filtrates are combined. Separate the layers, wash the organic phase with 2KG saturated brine, distill the organic phase under normal pressure until no liquid flows out, stop the concentration, and put the obtained oil directly into the next reaction.

[0045] Add the above-mentioned oil to a 20L high-temperature kettle, and heat it to 150-190°C for cracking reaction. After 5 hours, the...

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Abstract

The invention discloses a preparation process for gout suppressant Lesinaurad intermediates, and particularly relates to the preparation process of cyclopropyl-naphthalene. The preparation process includes the steps of conducting cyclization on 3-(Dimethylamino)-1-(naphthalen-1-yl)propan-1-one hydrochloride and hydrazine hydrate under the alkaline condition to generate 1-(4,5)-pyrazoline-naphthalene, and conducting high-temperature pyrolysis on the 1-(4,5)-pyrazoline-naphthalene under the neutral condition or the alkali condition to generate the cyclopropyl-naphthalene. The preparation process is few in reaction step, raw materials are cheap and can be easily obtained, the production efficiency is high, the process is green and environmentally friendly, no precious metal is used, no heavy metal residuals are generated, and the industrial production is easy.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry, relates to a preparation process of a pharmaceutical intermediate, in particular to a preparation process of an anti-gout drug Lesinaurad intermediate. Background technique [0002] Gout rates are on the rise, with 8.3 million people living with gout in the US in 2011 and a 64% increase in the UK between 1997 and 2012. According to a study, more than 17.7 million people worldwide are expected to suffer from gout by 2021. Meanwhile, current treatments are limited to the 50-year-old allopurinol and febuxostat from Takeda and Ipsen Pharmaceuticals. Febuxostat was approved in 2009, but the drug is not suitable for every patient. [0003] Lesinurad is a selective uric acid reabsorption inhibitor (SURI), which can inhibit URAT1 transporter to increase uric acid excretion, thereby reducing blood uric acid (sUA) and relieving pain symptoms. Currently, AstraZeneca is developing lesinurad in c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C13/47C07C1/32
Inventor 陈兴王灿辉杨佑喆庄明晨郭鹏
Owner ASTATECH CHENGDU BIOPHARM CORP
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