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Synthetic preparation method for key intermediate of ramelteon

A technology for ramelteon and its intermediates, applied in the field of drug synthesis, can solve the problems of unavailable starting materials, heavy environmental pollution, and high production costs

Active Publication Date: 2015-09-23
CHANGZHOU YABANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The object of the present invention is to provide a synthetic preparation method for the key intermediate of ramelteon 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one, aiming at Overcome the side reactions that exist in the above synthetic method of ramelteon and more impurities, large environmental pollution, starting raw materials are not easy to get, higher production costs, etc. Some shortcomings

Method used

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  • Synthetic preparation method for key intermediate of ramelteon
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  • Synthetic preparation method for key intermediate of ramelteon

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1: Synthesis and preparation of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-ol (Ⅲ)

[0064] The reaction formula is as follows:

[0065]

[0066] Add 1050mL (1.05mol) of 1.0M tetrahydrofuran solution of vinylmagnesium bromide into the reaction flask, start stirring, cool the reaction solution to -10~-5°C, add dropwise 2,3-dihydrobenzofuran-4 -formaldehyde (148.2g, 1.00mol) in tetrahydrofuran (500mL) solution, and control the temperature of the reaction solution not to exceed -5°C. After the dropwise addition, keep the temperature at -10~-5°C and react for half an hour, then slowly raise the temperature to room temperature to continue the reaction. After 6 hours, 300 mL of saturated aqueous ammonium chloride solution was added, stirred for 30 minutes, and extracted three times with ethyl acetate (800 mL×3). The organic phase was washed once each with saturated sodium chloride solution (300 mL) and water (300 mL), dried over anhydrous sodium sulfate, filtered, ...

Embodiment 2

[0067] Example 2: Synthesis and preparation of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one (IV)

[0068] The reaction formula is as follows:

[0069]

[0070]At room temperature, add 750 mL of dimethyl sulfoxide solvent into the reaction flask, and then add 150.0 g of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-ol described in formula III (0.85mol), stirring and dissolving, adding 360g (1.29mol) of 2-iodobenzoic acid (IBX) in batches at room temperature, and the addition was completed in about 10 minutes. After continuing to react at room temperature for 2 hours, TLC detected that the raw material point disappeared. Add 2.5L of ethyl acetate, stir for 15 minutes, filter, wash the filtrate twice with water (850mL×2), dry over anhydrous sodium sulfate, filter, and distill the filtrate to remove the solvent under reduced pressure to obtain 139.2g of a yellow oil. The rate is 94.1%.

Embodiment 3

[0071] Example 3: Synthesis and preparation of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-one (IV)

[0072] The reaction formula is as follows:

[0073]

[0074] Add 1500 mL of dichloromethane and 130.0 g (0.74 mol) of 1-(2,3-dihydrobenzofuran-4-yl)-2-propen-1-ol described in formula III to the reaction flask, stir to dissolve 410 g (0.97 mol) of (1,1,1-triacetoxy)-1,1-dihydro-1,2-phenyliodide-3(1H)-one (DMP) was added at room temperature. After continuing to react at room temperature for 2 hours, TLC detected that the raw material point disappeared. Add ethyl acetate 1000mL, 10% Na 2 S 2 o 3 Solution 150mL and saturated NaHCO 3 200 mL of the solution, stirred vigorously for 1 hour, separated the organic phase, washed once with saturated brine (800 mL) and water (800 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled off the solvent under reduced pressure to obtain a yellow oil The product was 124.8g, and the yield was 97.3%.

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Abstract

The invention discloses a synthetic preparation method for a key intermediate of ramelteon 1,2,6,7-tretrahydro-8H-indeno[5,4-b]furan-8-one. According to the preparation method, by taking 2,3-dihydrobenzofuran-4-formaldehyde as an initial raw material, the key intermediate of ramelteon 1,2,6,7-tretrahydro-8H-indeno[5,4-b]furan-8-one is synthesized through Grignard reaction, oxidizing reaction and Nazarov cyclization reaction. The preparation method has the advantages of being high in reaction selectivity, few in side effects, high in total yield and quality, environmental-friendly, simple and convenient in process operation, high in stability and controllability and the like, and is suitable for industrial large-scaled production.

Description

technical field [0001] The invention relates to a method for synthesizing and preparing a key intermediate of ramelteon, belonging to the field of drug synthesis. Background technique [0002] At present, the drugs used clinically at home and abroad to treat insomnia mainly include: barbiturates, benzodiazepines Agonists, nonbenzodiazepines Receptor agonists and natural medicines with sedative and hypnotic effects. Long-term use of barbiturate sedative-hypnotics may lead to drug tolerance, dependence, severe withdrawal symptoms, low therapeutic index, and even severe liver and kidney toxicity. Therefore, such drugs are not suitable for long-term use. Benzodiazepines Agonists and nonbenzodiazepines Hypnotics can shorten the sleep latency and improve the sleep efficiency of patients with insomnia. Long-term or high-dose use does not help patients with insomnia to improve their sleep, but will cause side effects such as withdrawal, rebound insomnia, tolerance, and depen...

Claims

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Application Information

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IPC IPC(8): C07D307/77
Inventor 陈再新吉小龙夏正君臧路杰夏令先郝金星王璠
Owner CHANGZHOU YABANG PHARMA
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