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Preparation method of high-purity and low-chroma gemfibrozil

A technology of gemfibrozil and gemfibrozil isobutyl ester, applied in the field of medicinal chemistry, can solve the problems of gemfibrozil unqualified, easy to deteriorate and easy to change color after long-term storage, and achieve pure white color and high quality Requirements, the effect of low chroma

Active Publication Date: 2018-02-06
浙江精进药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When preparing gemfibrozil, the residual 2,5-xylenol is more likely to change color and remain in gemfibrozil in a small amount through the high-temperature distillation process, resulting in problems such as unqualified gemfibrozil and easy deterioration in long-term storage

Method used

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  • Preparation method of high-purity and low-chroma gemfibrozil
  • Preparation method of high-purity and low-chroma gemfibrozil
  • Preparation method of high-purity and low-chroma gemfibrozil

Examples

Experimental program
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Effect test

Embodiment 1

[0035] Embodiment 1, a kind of preparation method of high-purity, low chroma gemfibrozil, carries out following steps successively:

[0036] 1), in a 1000ml reaction bottle, put 180ml of water, 182 grams of 5-chloro-2,2-dimethylpentanoic acid isobutyl ester (0.82mol, 107 grams of 2,5-xylenol (0.87mol), 130 grams (3.2mol) of sodium hydroxide, 10 grams of tetrabutylammonium bromide, heated and refluxed for 10 hours. After the reaction solution was cooled to room temperature, the static layering was carried out for 30 minutes, and the upper organic layer separated was washed with 10% (mass % ) sodium hydroxide solution (about 30ml * 3 times), the condensation product crude gefibutyl ester was obtained, ready for distillation. Through liquid phase detection, the content of 2,5-xylenol was 0.021%.

[0037] Remarks: Washing with 10% sodium hydroxide solution can remove as much free 2,5-xylenol as possible in the organic layer.

[0038] 2), the above-mentioned gefibutyl ester crude ...

Embodiment 2-1

[0042] Embodiment 2-1, a kind of preparation method of high purity, low chroma gemfibrozil:

[0043] Step 1) is the same as step 1) of the embodiment;

[0044] 2) Add the above-mentioned crude product of gemfibroxan to a 500ml round bottom bottle, then add a small amount of saturated sodium carbonate solution, adjust the pH to 10.0-10.5, raise the temperature to an internal temperature of 190 degrees, and distill under reduced pressure to obtain gemfibrox The distilled product of isobutyl ester has a normalized liquid phase content of 99.87%, and a 2,5-xylenol content of 0.0004%.

[0045] Step 3) and step 4) are equal to step 3) and step 4) of Example 1; 182 grams of gefibrozil are finally obtained, the yield is 89%, the normalized content of the liquid phase is 99.93%, and the xylenol content is 0.0001 %, Chroma 1.6.

Embodiment 2-2～ Embodiment 2-4

[0046] Embodiment 2-2~embodiment 2-4, the saturated sodium carbonate solution in embodiment 2-1 is changed into respectively that mass concentration is 70% sodium hydroxide solution, mass concentration is 70% potassium hydroxide solution, saturated Potassium carbonate solution; the pH was also adjusted to 10.0-10.5, and the rest of the content was equal to that of Example 2-1. The comparison of the obtained results is as described in Table 1 below.

[0047] Table 1

[0048]

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Abstract

The invention discloses a high-purity low-chroma gemfibrozil preparation method. The method comprises 1, preparing a gemfibrozil isobutyl ester crude product and can also comprises 2, adding an alkali liquor II in the gemfibrozil isobutyl ester crude product until the system pH is in a range of 10.0-12 and carrying out reduced pressure rectification to obtain gemfibrozil isobutyl ester, 3, carrying out reflux alkaline hydrolysis on the gemfibrozil isobutyl ester and carrying out acid adjustment to obtain a gemfibrozil crude product, and 4, refining the gemfibrozil crude product through adding an alcohol-water solution into the gemfibrozil crude product, carrying out heating reflux, carrying out heat preservation for 0.5-1h, carrying out cooling to a temperature of 0-5 DEG C, carrying out thermal insulation stirring for 1.5-2.5h, carrying out filtration to obtain filter cake and drying the filter cake to obtain high-purity low-chroma gemfibrozil.

Description

technical field [0001] The invention relates to a preparation method of gemfibrozil with high purity and chromaticity, which belongs to the technical field of medicinal chemistry, and specifically relates to a gemfibrozil with a pure white color, a liquid-phase normalized content of more than 99.9%, and a chromaticity of less than 3.0. The preparation method of gemfibrozil, so that gemfibrozil will not turn red and change color when stored for a long time. Background technique [0002] Gemfibrozil, the chemical name is 2,2-dimethyl-5-(2,5-dimethylphenyloxy)-pentanoic acid, the English name is 5-(2,5-dimethylphenoxy)-2 ,2-dimethylpentanoic acid, the structural formula is as follows: [0003] [0004] Gemfibrozil is a clofibrate blood lipid regulating drug, used for hyperlipidemia, stable drug effect, low adverse reaction rate, high safety, can be taken for a long time, and can prevent arteriosclerosis and help reduce myocardial infarction morbidity. It was launched in t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C27/02C07C59/68C07C67/31C07C69/712
CPCC07C51/09C07C67/31C07C69/712C07C59/68
Inventor 赵金浩王晖
Owner 浙江精进药业有限公司
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