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Preparation method of etodolac intermediate

A technology of etodolac and intermediates, applied in the field of drug synthesis, can solve the problems of high production cost, low yield, process safety, complicated operation and the like, and achieves the effect of improving operation safety and simplifying production operation.

Pending Publication Date: 2022-01-14
LUNAN PHARMA GROUP CORPORATION
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] However, the above process is still difficult to avoid the strong acidic conditions of Fischer Indole and the defects of more impurities in the product
[0012] Document Heterocycles, 2003,60(5), 1095-1110 adopts the active precursor 3-ethoxytetrahydrofuran of 2,3-dihydrofuran as the donor of 4-hydroxybutyraldehyde, which cannot avoid the higher production cost question:
[0017] In summary, the current preparation method of 7-ethyltryptol has many deficiencies in terms of safe process, cumbersome operation, low yield, and high production cost. , high purity, low production cost suitable for industrialized production of 7-ethyl tryptophan reaction route is still a problem to be solved at present

Method used

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  • Preparation method of etodolac intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0052] At room temperature, 7-ethylindole (SM-1, 14.52g, 0.1mol), 2-((ethoxycarbonthio)thio) ethyl acetate (SM-2, 33.17g, 0.16mol), Dilauroyl peroxide (DLP, 63.78g, 0.16mol) was added to 1,2-dichloroethane (250ml), and the temperature-controlled reflux reaction was completed. After the reaction solution was cooled to room temperature, purified water (500ml) was added , liquid separation to get the organic phase, extract the aqueous phase with dichloromethane (200ml × 2), combine the organic phases, wash with saturated sodium thiosulfate solution (300ml × 2), wash with saturated brine (300ml × 2), wash with anhydrous sodium sulfate After drying and filtering, the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I, with a yield of 98.6% and a purity of 99.89% by HPLC.

Embodiment 2

[0054] At room temperature, 7-ethylindole (SM-1, 14.52g, 0.1mol), 2-((ethoxycarbonthio)thio) ethyl acetate (SM-2, 24.87g, 0.12mol), Hydrogen peroxide (35%, 15.54g, 0.16mol) was added in 1,2-dichloroethane (250ml), and after the temperature-controlled reflux reaction was completed, the reaction solution was cooled to room temperature, purified water (500ml) was added, and divided The organic phase was taken from the liquid, the aqueous phase was extracted with dichloromethane (200ml×2), the organic phases were combined, washed with saturated sodium thiosulfate solution (300ml×2), washed with saturated brine (300ml×2), dried over anhydrous sodium sulfate, After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain intermediate I with a yield of 95.3% and a purity of 99.78% by HPLC.

Embodiment 3

[0056] At room temperature, 7-ethylindole (SM-1, 14.52g, 0.1mol), 2-((ethoxycarbonthio)thio) ethyl acetate (SM-2, 45.82g, 0.22mol), Dicumyl peroxide (43.26g, 0.16mol) was added into 1,2-dichloroethane (250ml), and after the temperature-controlled reflux reaction was completed, the reaction solution was cooled to room temperature, purified water (500ml) was added, and divided The organic phase was taken from the liquid, the aqueous phase was extracted with dichloromethane (200ml×2), the organic phases were combined, washed with saturated sodium thiosulfate solution (300ml×2), washed with saturated brine (300ml×2), dried over anhydrous sodium sulfate, After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain Intermediate I with a yield of 93.6% and a HPLC purity of 99.72%.

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Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of an etodolac intermediate. According to the invention, 7-ethyl indole is used as a starting material to react with ethyl 2-((ethyoxylcarbothioxo)thioxo) acetate, and then a reducing agent is used for reducing to prepare the important etodolac intermediate 7-ethyl tryptophol, so the problem of high production cost caused by usage of 2,3-dihydrofuran or an active precursor 3-ethoxytetrahydrofuran thereof as a 4-hydroxybutyraldehyde donor can be solved, the problems of considerable impurities, difficult purification and low yield of a target product prepared by using the Fischer Indole synthesis method can be avoided, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of an etodolac intermediate. Background technique [0002] Etodolac (Etodolac) is a powerful non-steroidal anti-inflammatory analgesic, used for the treatment of rheumatoid arthritis, rheumatoid arthritis and osteoarthritis embolism, with good tolerance, mild side effects, Strong analgesic effect and other characteristics, this product has few gastrointestinal adverse reactions, especially suitable for elderly patients. The drug was developed by AHP Wyeth-Ayesrt in the United States and first launched in the UK in 1985. Its chemical structure is as follows: [0003] [0004] There are many synthetic methods of etodolac reported at present, such as U.S. Patent US4585877A and literature "Research on the Synthetic Technology of etodolac". Tianjin Chemical Industry, 2004, 18 (5), 22-23, "The synthetic technology of etodolac ". Acta Chemica...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/12
CPCC07D209/12
Inventor 张贵民张乃华鲍广龙
Owner LUNAN PHARMA GROUP CORPORATION
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