A kind of Suwo Lexan intermediate and preparation method thereof

A technology of compounds and organic solvents, which is applied in the field of synthesizing important intermediates of Suwolexan, can solve the problems of stimulation, expensive enzymes, death, etc., and achieve the effects of easy industrialization, high ee value, and simple post-processing

Active Publication Date: 2022-07-12
SHANGHAI INST OF TECH
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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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  • A kind of Suwo Lexan intermediate and preparation method thereof
  • A kind of Suwo Lexan intermediate and preparation method thereof
  • A kind of Suwo Lexan intermediate and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

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

[0047]

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

Embodiment 2

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

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

Embodiment 3

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

[0056]

[0057] The Boc protecting group was removed first: 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 completion of the reaction 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 deBoc protected substrate is obtained. The resulting substrate was dissolved in 40 mL of MeOH under N 2 Add 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 The Cl aqueous solution was quenched, and then the reaction system was poured into a solution containing 5 wt% Na 2 CO 3 In a separatory funnel of the aqueous solution, after sufficient shaking, it was extracted thr...

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Abstract

The invention discloses a Suvorexan intermediate and a preparation method thereof. Said Suvorexan intermediate is wherein, R represents methyl or ethyl, and PG1 and PG2 represent amino protecting groups. The preparation method is as follows: carrying out a Michael addition reaction with the compound III to obtain compound III; removing the amino protecting group from compound III to generate compound IV; reducing compound IV to obtain compound V; protecting the secondary amine in compound V with an amino protecting group to obtain compound IV VI. The invention avoids the use of the highly toxic compound methyl vinyl ketone, obtains the intermediate of Suvorexan in the desired configuration by using the chiral starting material, and avoids the use of a chiral resolving agent or separation by chiral HPLC , as well as avoiding the use of transition metals and biological enzyme preparations for chiral catalysis. The reaction conditions have the advantages of simple post-processing, easy separation and purification, high yield, high ee value, and easy industrialization.

Description

technical field [0001] The invention relates to an important intermediate for synthesizing Suvorexan, new compound formulas III, IV, V, VI or salts thereof and a preparation method, belonging to the technical field of organic chemistry and pharmaceutical synthesis. Background technique [0002] With the development and progress of society, people's life rhythm has become faster and faster, followed by various pressures. Excessive mental pressure will lead to the phenomenon of insomnia, which has become a A very common social health problem that has a great impact on people's quality of life. Relevant statistics show that nearly one-third of people have sleep disorders at night, and nearly one-fifth of people have sleep disorders. Perfect phenomenon, nearly 1 in 6 people suffer from poor daytime mentality and sluggishness, and 6 percent are insomniacs in the strict sense. There are also data showing that adults in society are now facing increasing pressure, and more and more...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/14C07D403/10C07D243/08C07C271/20C07C269/06
CPCC07D413/14C07D403/10C07D243/08C07C271/20Y02P20/55
Inventor 袁洪顺潘仙华
Owner SHANGHAI INST OF TECH
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