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Preparation method of tasimelteon key intermediate

A technology of tasimelteon and intermediates, which is applied in the field of preparation of key intermediates of tasimelteon, can solve problems such as being unsuitable for large-scale production, high toxicity, etc., and achieves safe and controllable production process, low cost and high yield high effect

Inactive Publication Date: 2020-08-11
杭州拜善晟生物科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The diethyl cyanomethyl phosphate used in the cyclization reaction is highly toxic and not suitable for large-scale production

Method used

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  • Preparation method of tasimelteon key intermediate
  • Preparation method of tasimelteon key intermediate
  • Preparation method of tasimelteon key intermediate

Examples

Experimental program
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Embodiment 1

[0035] Embodiment 1. metal catalyst: the preparation of the Ru catalyst of salen ligand

[0036] At 25-30°C, 80g RuCl 3 The hydrate was dissolved in 4L of ethanol and stirred to dissolve. Subsequently, 342.8 g of 4-isopropyltoluene was added to the reaction mass. The reaction mass was heated to 83-85°C for about 12h. Stop heating, cool to 0-5 ° C and stir for 2-3h. After filtering and eluting with 80 ml of ethanol, the eluate was collected and dried in vacuo to obtain 61 g of solid. Detected as RuCl by H NMR 2 (p-cymene) dimer.

[0037] In inert gas N 2 Under the protection of , the temperature is 0°C, add 260ml of tetrahydrofuran solution (3mmol) of lithium diisopropylamide to 2L salen ligand tetrahydrofuran solution (1.5mmol), after the addition is completed, stir at 25-30°C for 1h, then, Add RuCl dropwise at 0°C 2 (p-cymene) dimer (61 g, 0.75 mmol) and 132 ml of pyridine, the reaction mass was stirred overnight at 25-30° C. to obtain a dark red solution. The dark r...

Embodiment 2

[0038] Example 2. Preparation of ethyl (1R, 2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropane-1-carboxylate

[0039] Dissolve 106g of 4-vinyl-2,3-dihydrobenzofuran in 1060ml of ethyl acetate, add 11.9g of the Ru catalyst with salen ligand prepared in Example 1 under stirring conditions, and heat to 50°C , at N 2Under protection, a solution of ethyl diazoacetate in ethyl acetate (126.4 g of ethyl diazoacetate dissolved in 1060 ml of ethyl acetate) was added dropwise within 30 min, and stirred for another 16 h. Qualitatively detected by HPLC, the reaction has been completed. Wash twice with 1 L of water at 10-20 °C, combine the aqueous layers, and extract with 500 ml of ethyl acetate. After extraction, the organic layers were combined and concentrated. The concentrated organic layer was purified by silica gel chromatography, and gradient elution was performed with 2 L of petroleum ether and 5 L of a mixture of ethyl acetate and petroleum ether at a volume ratio of 1:9. The elua...

Embodiment 3

[0040] Example 3. Preparation of (1R,2R)-2-(2,3-dihydro-4-benzofuryl)cyclopropanecarboxylic acid

[0041] Dissolve 148g of (1R, 2R)-2-(2,3-dihydrobenzofuran-4-yl)cyclopropane-1-carboxylic acid ethyl ester prepared in Example 2 in 268ml of tetrahydrofuran and 134ml of ethanol mixed solution At a temperature of 10-20° C., NaOH solution (46.21 g NaOH dissolved in 402 ml water) was added thereto. The reaction mass was heated to 40 °C for 16 h. Concentrate without residues of tetrahydrofuran and ethanol solvents. The mixture was dissolved in 300 ml of water and washed twice with 500 ml of dichloromethane. At 10-20°C, add 85% H 3 PO 4 Aqueous solution The aqueous layer was acidified to pH=3. The acidified aqueous layer was extracted twice with 500 ml of ethyl acetate and concentrated to obtain 119 g of crude solid. As detected by HPLC, the chiral purity is 92.2%, the enantiomer is 3.3%, and the diastereomer is 4.5%.

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Abstract

The invention discloses a preparation method of a tasimelteon key intermediate. According to the method, 4-vinyl-2, 3-dihydrobenzofuran is used as an initial raw material, (1R, 2R)-2-(2, 3-dihydrobenzofuran-4-yl) cyclopropane-1-ethyl formate is generated through a one-step catalytic reaction, and then (1R, 2R)-2-(2, 3-dihydro-4-benzofuranyl) cyclopropanecarboxylic acid is obtained through hydrolysis and resolution. The key step of asymmetric catalysis of chiral cyclopropane is developed, an adopted salen ligand Ru catalyst can catalyze chiral cyclopropane in one step, the process is simplified, and meanwhile the catalyst is non-toxic, environmentally friendly and high in utilization rate; then hydrolyzing into acid is realized, and chiral resolution is carried out; not only is the opticalpurity improved, but also a reagent for resolution can be recycled. The method is simple in overall process, high in operability, safe and controllable in production process, environment-friendly, energy-saving, low in cost, high in yield and suitable for large-scale production.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis, in particular to a method for preparing a key intermediate of tasimelteon. Background technique [0002] Non-24-hour sleep-wake cycle disorder (Non-24) is a serious circadian rhythm disorder. Many blind people suffer from this disease. Patients cannot adapt to the inherent 24-hour circadian cycle because they cannot receive or synchronize with external environmental stimuli. Pattern, its own rhythm may appear shorter or longer than 24h, eventually leading to sleep and wake cycle disturbance, which seriously affects daily work and life. [0003] Tasimetron was first discovered by Bristol-Myers Squibb Company, and then continued to be developed by Vanda Pharmaceutical Company, and was developed as a drug for the treatment of non-24-hour sleep-wake cycle disorder (Non-24). In 2014, Tasimelon was approved by the FDA (trade name: Hetlioz), which is the first drug for the treatment of...

Claims

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Application Information

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IPC IPC(8): C07D307/79B01J31/18
CPCC07D307/79B01J31/1805C07B2200/07B01J2531/821B01J2531/0252B01J2231/52
Inventor 王喆明谭昊
Owner 杭州拜善晟生物科技有限公司
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