Synthesis method of tasimelteon

A synthetic method, the technology of tasimelteon, is applied in the field of new synthesis of the anti-insomnia drug tasimelteon, which can solve the problems of difficult large-scale industrial production, unstable quality of finished products, harsh reaction conditions, etc., and achieve mild reaction conditions, The effect of good product quality and simple route

Active Publication Date: 2016-09-21
ZHEJIANG UNIV OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] The purpose of the present invention is to provide a new synthetic method of tasimelteon, so as to overcome the problems of harsh reaction conditions, cumbersome operation, low yield, unstable finished product quality and difficulty in large-scale industrial production in the prior art

Method used

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  • Synthesis method of tasimelteon
  • Synthesis method of tasimelteon
  • Synthesis method of tasimelteon

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1: the preparation of compound (II)

[0054] Take a 100mL single-necked flask, add 4-vinyl-2,3-dihydrobenzofuran (5.0g, 34.2mmol), acetonitrile (25mL), 30% hydrogen peroxide (20.8mL), sodium bicarbonate (11.5g, 136.8 mL), stirred at room temperature for 10 h, and TLC monitored that the reaction was complete. Add saturated sodium bisulfite solution dropwise under ice-bath conditions to quench, then extract with ethyl acetate (100mL), wash the organic phase with water (50mL), saturated brine (30mL), concentrate under reduced pressure, column chromatography (washing The removal agent was ethyl acetate:petroleum ether=10:1, v:v) Purification gave 5.0 g of yellow liquid compound (II) with a yield of 91%.

[0055] 1 H NMR (500MHz, CDCl 3 ):δ=2.84(dd,J 1 =2.6Hz,J 2 =5.6Hz,1H),3.14(dd,J 1 =4.2Hz,J 2 =5.6Hz,1H),3.27(t,J=8.7Hz,2H),3.84-3.86(m,1H),4.60(t,J=8.8Hz,2H),6.71-6.76(m,2H),7.12 (t,J=7.9Hz,1H).

Embodiment 2

[0056] Embodiment 2: the preparation of compound (II)

[0057] Take a 50mL single-necked flask, add 4-vinyl-2,3-dihydrobenzofuran (3.0g, 20.5mmol), dichloromethane (15mL), potassium carbonate (15.6g, 113.0mmol), add it while stirring at room temperature 60% m-chloroperoxybenzoic acid (10.6 g, 61.5 mmol) was solid, stirred for 10 h, and the reaction was complete by TLC monitoring. Add dropwise saturated sodium bisulfite solution to quench, then extract with ethyl acetate (50mL), wash the organic phase with water (30mL), saturated brine (20mL), concentrate under reduced pressure, column chromatography (eluent: Ethyl acetate:petroleum ether=10:1, v:v) After purification, 2.7g of yellow liquid compound (II) was obtained with a yield of 80%.

[0058] 1 H NMR (500MHz, CDCl 3 ):δ=2.84(dd,J 1 =2.6Hz,J 2 =5.6Hz,1H),3.14(dd,J 1 =4.2Hz,J 2 =5.6Hz,1H),3.27(t,J=8.7Hz,2H),3.84-3.86(m,1H),4.60(t,J=8.8Hz,2H),6.71-6.76(m,2H),7.12 (t,J=7.9Hz,1H).

Embodiment 3

[0059] Embodiment 3: the preparation of compound (III)

[0060] Take a 50mL three-necked flask, completely dissolve compound (II) (2.0g, 12.3mmol) in tetrahydrofuran (15mL), add diethyl cyanomethyl phosphate (2.2g, 12.4mmol), sodium methoxide (5.3g, 98.1mmol) , vacuumed and protected by nitrogen, refluxed at 80° C., reacted for 8 hours, and the reaction was complete as monitored by TLC. The reaction solution was cooled to room temperature, water (10 mL) was added, and then extracted with ethyl acetate (50 mL), and the extracted organic phase was washed with water (30 mL) and saturated brine (30 mL). The collected organic phase was concentrated under reduced pressure to obtain a brown viscous substance, which was purified by column chromatography (eluent: ethyl acetate:petroleum ether=8:1, v:v) to obtain 2.1 g of a white solid with a yield of 92%.

[0061] FT-IR(KBr)υ:773,984,1237,1439,1457,1478,1592,1612,2238,2898,2971cm -1 ; 1 HNMR (500MHz, CDCl 3 ):δ=1.40-1.48(m,1H),1.54...

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Abstract

The invention discloses a synthesis method of tasimelteon. The synthesis method comprises steps as follows: a compound (I) is subjected to an epoxidation reaction, and a compound (II) is obtained; the compound (II) and diethyl cyanomethylphosphonate are subjected to a ring-closure reaction under the protection of inert gas, and a compound (III) is obtained; the compound (III) is subjected to a reduction reaction, and a compound (IV) is obtained; the compound (IV) is subjected to an acylation reaction, and tasimelteon (V) is obtained. The route is simple, 4-vinyl dihydrobenzofuran is taken as a raw material and subjected to four steps of reactions including epoxidation, cyclopropanation, reduction and acylation, and the target product tasimelteon (V) is prepared. The reaction efficiency is greatly improved, the reaction steps are reduced, the operation procedures are simplified, and a new approach for synthesis of tasimelteon is provided. Besides, the method is suitable for industrial production and has great practical application value and social and economic benefits.

Description

(1) Technical field [0001] The present invention relates to a novel synthesis method of the anti-insomnia medicine tasimelteon. (2) Background technology [0002] The present invention particularly relates to the synthesis of tasimelteon, an anti-insomnia drug with significant curative effect. The structural formula of tasimelteon is as follows: [0003] [0004] Non-24-hour sleep-wake disorder in the blind is a chronic circadian (body clock) disorder that causes sleep timing problems in blind people. Non-24 occurs in people with total insomnia, light does not enter their eyes and they cannot synchronize their body clock with the 24-hour dark cycle. People with this disorder may have trouble falling or staying asleep, and may wake up groggy or feeling as though they need more rest. People with non-24 may find their sleep patterns reversed -- needing to sleep during the day and awake at night. [0005] On January 31, 2014, the FDA approved Hetlioz (trade name) of Vanda ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/79
CPCC07D307/79
Inventor 张兴贤宓森阳孙鑫哲
Owner ZHEJIANG UNIV OF TECH
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