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A kind of method preparing etodolac methyl ester

A technology of methyl etodolac and methyl oxopentanoate, which is applied in the field of preparing methyl etodolac, can solve the problems of affecting product appearance, harming concentrated sulfuric acid, and low yield, so as to achieve easy recycling, improve Product yield and effect of reducing workload

Active Publication Date: 2021-04-02
ZHEJIANG INT STUDIES UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition to the extremely harmful concentrated sulfuric acid, this process also uses extremely toxic acetonitrile. Acetonitrile is easily poisoned due to inhalation, ingestion, and skin absorption, which is not conducive to the health of workers and is not suitable for industrial production.
2. China Journal of Pharmaceutical Industry, 2005, 32(2), 730-731, using 7-ethyltryptol and methyl 3-oxopentanoate as raw materials, using concentrated sulfuric acid as a catalyst and dehydrating agent, in a mixed solvent of methanol and toluene Preparation of etodolac methyl ester in the middle, the yield is 82.7%, the yield of this process is not high, and also adopted the highly harmful concentrated sulfuric acid
[0007] Above-mentioned with 7-ethyltryptol and methyl 3-oxopentanoate as raw material, concentrated sulfuric acid is dehydrating agent, is the main method of industrially preparing methyl etodolac, but there is the big problem of waste acid pollution in this method, and concentrated Sulfuric acid is easy to cause the oxidation of nitrogen-containing products such as methyl etodolac to produce impurities and affect the appearance of the product

Method used

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  • A kind of method preparing etodolac methyl ester
  • A kind of method preparing etodolac methyl ester
  • A kind of method preparing etodolac methyl ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Trimethylchlorosilane as catalyst and dehydrating agent

[0052] At 18°C, in a four-necked flask equipped with a thermometer, a mechanically stirred drying tube and a constant pressure dropping funnel, 283.5 grams of methanol, 96.4 grams of 7-ethyltryptol (98.0% content, 0.5 mol of pure), 3- 71.5 grams (0.55 mol) of methyl oxopentanoate, add 59.7 grams (0.55 mol) of trimethylchlorosilane into the constant pressure dropping funnel, and slowly add it dropwise to the above reaction system, and control the temperature not to exceed 20°C , about 4 hours for the dropwise addition time, and reacted overnight (about 18 hours) at 22°C until the HPLC content of 7-ethyltryptol was less than 0.1%, cooled to 12°C, and incubated for 1 hour, filtered, 25 grams of cold methanol ( 10°C) for rinsing, and the mother liquor is to be treated.

[0053] The filtrate was washed with 150 g of 5% sodium bicarbonate solution and 50 g of water respectively, and dried to obtain a white solid produ...

Embodiment 2

[0059] Trimethylchlorosilane is a catalyst and dehydrating agent, and the mother liquor is applied mechanically

[0060] (1) The first batch of materials

[0061] At 18°C, in a four-necked flask equipped with a thermometer, a mechanically stirred drying tube and a constant pressure dropping funnel, 283.5 grams of methanol, 96.4 grams of 7-ethyltryptol (98.0% content, 0.5 mol of pure), 3- 71.5 grams (0.55 mol) of methyl oxopentanoate, add 59.7 grams (0.55 mol) of trimethylchlorosilane into the constant pressure dropping funnel, and slowly add it dropwise to the above reaction system, and control the temperature not to exceed 20°C , about 4 hours for the dropwise addition time, and reacted overnight (about 18 hours) at 22°C until the HPLC content of 7-ethyltryptol was less than 0.1%, cooled to 12°C, and incubated for 1 hour, filtered, 25 grams of cold methanol ( 10°C) for rinsing, and the mother liquor is to be treated.

[0062] The filtrate was washed with 150 g of 5% sodium ...

Embodiment 3

[0070] Bromotrimethylsilane as catalyst and dehydrating agent

[0071] At 18°C, in a four-necked flask equipped with a thermometer, a mechanically stirred drying tube and a constant pressure dropping funnel, 283.5 grams of methanol, 96.4 grams of 7-ethyltryptol (98.0% content, 0.5 mol of pure), 3- 71.5 grams (0.55 mol) of methyl oxopentanoate, add 82.5 grams (0.55 mol) of bromotrimethylsilane into the constant pressure dropping funnel, and slowly add it dropwise to the above reaction system, and control the temperature not to exceed 20°C , dropwise for about 4 hours, dropwise react overnight at 22°C (about 18 hours) until the HPLC content of 7-ethyltryptol is less than 0.1%, cool to 12°C, and keep warm for 1 hour, filter, and rinse with 25 grams of cold methanol Wash, the mother liquor is to be processed.

[0072] The filtrate was rinsed with 150 g of 5% sodium bicarbonate solution and dried to obtain 138.6 g of a white solid product, HPLC purity: 99.59%, yield: 92.1%, meltin...

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Abstract

The invention provides a method for preparing etodolac methyl ester, which relates to the technical field of organic synthesis. The method provided by the invention comprises the following steps: (1) after the reaction raw materials are mixed, a ring closure reaction is carried out at 20-25° C. to obtain a reaction liquid; the reaction raw materials include 7-ethyltryptol, 3-oxopentanoic acid Methyl ester, trimethylhalosilane and methanol, excluding concentrated sulfuric acid; the trimethylhalosilane is trimethylchlorosilane or trimethylbromosilane; (2) cooling the reaction solution to 10-15°C , and filtered to obtain etodolac methyl ester and mother liquor. The method provided by the invention has high yield and does not use concentrated sulfuric acid which is extremely harmful and easily causes product oxidation. Further, the present invention further improves the product yield through the continuous application of the mother liquor, can obtain almost quantitative products, reduces the workload of solvent treatment, and is easy to operate; and the trimethylhalosilane is easy to recover and recycle.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for preparing methyl etodolac. Background technique [0002] Methyl etodolac (compound 1) is the key intermediate of etodolac (compound 2). Etodolac is a pyrancarboxylic acid non-steroidal anti-inflammatory drug, clinically used for antipyretic and analgesic. The production of etodolac is to take etodolac methyl ester as raw material, and it is prepared by adjusting acid after alkaline hydrolysis, see formula 1 [references: 1, US4585877 (1986), 2, Chinese Journal of Pharmaceutical Industry, 32 (2 ), 730-731, 2005]: [0003] [0004] The industrial preparation of methyl etodolac is generally obtained by dehydration of 7-ethyl tryptophan (compound 3) and methyl 3-oxopentanoate (compound 4) under catalysis, see formula 2: [0005] [0006] Existing literature has: 1, the embodiment 1 of patent JP2009120599 uses 7-ethyl tryptophan and 3-oxopentanoic acid m...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/052C07F7/12
CPCC07D491/052C07F7/123
Inventor 游金宗李迎菲齐德强吴成杰
Owner ZHEJIANG INT STUDIES UNIV
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