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Suvorexant intermediate and preparation method thereof

A technology of intermediates and compounds, which is applied in the fields of organic chemistry and drug synthesis, can solve problems such as irritation, expensive enzymes, and death, and achieve the effects of easy industrialization, simple post-processing, and high ee value

Active Publication Date: 2020-11-17
SHANGHAI INSTITUTE OF TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The advantage of this route is that it does not use halogenated solvents and heavy metals, and it is relatively environmentally friendly, but it also has shortcomings, and it also does not avoid the use of methyl vinyl ketone, and uses biological Enzyme preparations, enzymes are expensive, which is not conducive to large-scale industrial production
[0017] Through the analysis of the synthesis process of Suvorexan in the above-mentioned literature, it can be seen that the highly toxic substance methyl vinyl ketone is involved in the synthesis route to construct a diazepine ring, which has a strong effect on the eyes, skin, mucous membranes and upper respiratory tract. Irritating effects, which may cause death in severe cases
In addition, it is necessary to use HPLC and resolving agents for separation, or use transition metals and biological enzymes for chiral catalysis, which greatly limits its industrial development

Method used

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  • Suvorexant intermediate and preparation method thereof
  • Suvorexant intermediate and preparation method thereof
  • Suvorexant intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Synthesis of (S)-3-(((2-((tert-butoxycarbonyl)amino)ethyl)((R)-1-phenylethyl)amino)butanoic acid methyl ester:

[0047]

[0048] Under nitrogen protection, (S)-tert-butyl (2-(((1-phenylethyl)amino)ethyl)carbamate (5.8g, 22mmol) was dissolved in 80mL THF and cooled to 0 ℃. Slowly add 1.6M n-butyllithium hexane solution into the system (30.0mL, 44mmol). The resulting solution was stirred for 30 minutes, then cooled to -78℃, then added dropwise in 20mL of anhydrous Methyl crotonate solution (2.0 g, 20 mmol) in THF. The mixture was stirred at -78 ° C for 1 h 30 min. After the reaction was complete, the reaction was quenched, and 20 mL of saturated NH 4 Cl aqueous solution, and the resulting solution was slowly warmed to room temperature. The system was extracted with (2×10 mL) EA. The resulting organic phases were combined and dried with anhydrous MgSO4, then distilled and purified under reduced pressure to obtain 6.5 g of a colorless liquid with a yield of 89%.

[00...

Embodiment 2

[0052] Synthesis of (S)-3-(((2-((tert-butoxycarbonyl)amino)ethyl)((R)-1-phenylethyl)amino)butanoic acid methyl ester:

[0053] Under nitrogen protection, (S)-tert-butyl (2-(((1-phenylethyl)amino)ethyl)carbamate (5.8g, 22mmol) was dissolved in 80mL THF and cooled to 0 ℃. 2.0M tetrahydrofuran solution of lithium diisopropylamide was slowly added to the system (22.0mL, 44mmol), the resulting solution was stirred for 30 minutes, then cooled to -78℃, then added dropwise in 20mL of Methyl crotonate solution (2.0 g, 20 mmol) in water THF. The mixture was stirred at -78 ° C for 1 h 30 min. After the reaction was complete, the reaction was quenched, and 20 mL of saturated NH 4 Cl aqueous solution, and the resulting solution was slowly warmed to room temperature. The system was extracted with (2×10 mL) EA. The obtained organic phases were combined and washed with anhydrous MgSO 4 After drying, it was distilled under reduced pressure and purified to obtain 5.6 g of colorless liquid wi...

Embodiment 3

[0055] Synthesis of (R)-7-methyl-1-((R)-1-phenylethyl)-1,4-diaza-5-lactam:

[0056]

[0057] The Boc protecting group was first removed: the substrate (3.64 g, 10 mmol) was dissolved in 20 mL of DCM, 20 mL of saturated HCl / EA was added, and the reaction was stirred for 6 h. After the reaction was complete, the solvent was removed by rotary evaporation, and the residue was basified with saturated aqueous NaHCO3 and extracted with DCM. Concentrate the organic phase with anhydrous MgSO 4 dry. A de-Boc-protected substrate was obtained. The resulting substrate was dissolved in 40 mL of MeOH under N 2 Join CH under protection 3 ONa (0.65 g, 12 mmol), and stirred at room temperature for 12 h. The reaction was cooled to room temperature and washed with saturated NH 4 Cl aqueous solution was quenched, and then the reaction system was poured into a solution containing 5wt% Na 2 CO 3 In the separatory funnel of the aqueous solution, shake it well and extract it with DCM three ...

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Abstract

The invention discloses a suvorexant intermediate and a preparation method thereof. In the suvorexant intermediate, R represents methyl or ethyl, and PG1 and PG2 represent amino protecting groups. Thepreparation method comprises the following steps: carrying out Michael addition reaction to obtain a compound III; removing an amino protecting group from the compound III to generate a compound IV;reducing the compound IV to obtain a compound V; and protecting secondary amine in the compound V by using an amino protecting group to obtain a compound VI. According to the method disclosed by the invention, the use of a highly toxic compound methyl vinyl ketone is avoided, the suvorexant intermediate with the required configuration is obtained by using chiral starting raw materials, the separation by using a chiral resolving agent or chiral HPLC (High Performance Liquid Chromatography) is avoided, and the use of transition metal and a biological enzyme preparation for chiral catalysis is avoided. The reaction conditions have the advantages of simple post-treatment, easiness in separation and purification, high yield, high ee value, easiness in industrialization and the like.

Description

technical field [0001] The invention relates to an important intermediate for synthesizing Suvoraxan, a new compound with formulas III, IV, V, VI or salts thereof and a preparation method, belonging to the technical fields of organic chemistry and drug synthesis. Background technique [0002] With the development and progress of society, people's pace of life has also become faster and faster, followed by all kinds of pressure, excessive mental pressure will lead to the phenomenon of insomnia, which has become a It is a very common social health problem that has a great impact on people's quality of life. According to relevant statistics, nearly one-third of people have sleep disorders at night, and nearly one-fifth of people have sleep disorders. It is a perfect phenomenon that nearly one-sixth of the people suffer from poor spirits and listlessness during the day, and six percent of the people are strictly insomniacs. There are also data showing that the pressure faced by...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07D403/10C07D243/08C07C271/20C07C269/06
CPCC07D413/14C07D403/10C07D243/08C07C271/20Y02P20/55
Inventor 袁洪顺潘仙华
Owner SHANGHAI INSTITUTE OF TECHNOLOGY
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