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Compound for preparing suvorexant and preparation method thereof

A compound and mixture technology, applied in the field of drug synthesis, can solve the problems of unfavorable industrial mass production, strong irritation, unfriendly environment, etc., and achieve the effect of high ee value, easy purification, and simple post-treatment

Active Publication Date: 2014-07-16
武汉久安药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The above two routes have the following disadvantages: the highly toxic compound methyl ketene is used as the starting material, and methyl ketene is strongly irritating to the eyes, skin, mucous membranes and upper respiratory tract, and it is not easy to handle during use; finally to the preparation of suvorexant In the process, chiral resolution is required, which is not conducive to large-scale industrial production, and the yield is low
[0014] Disadvantages of this route: the highly toxic compound methyl ketene is used as the starting material, and methyl ketene is strongly irritating to the eyes, skin, mucous membranes and upper respiratory tract, and it is not easy to handle when used; in addition, heavy metal catalysts are used, and the cost is relatively high , and not friendly to the environment
[0017] Disadvantages of this route: the highly toxic compound methyl ketene is used as the starting material, and methyl ketene is strongly irritating to eyes, skin, mucous membranes and upper respiratory tract
[0020] Disadvantages of this route: the highly toxic compound methyl ketene is used as the starting material, and methyl ketene is strongly irritating to eyes, skin, mucous membranes and upper respiratory tract
After inhalation, oral administration or percutaneous absorption, severe poisoning may die, and it is difficult to handle during use; after that, suvorexant can be obtained through chiral resolution or chiral catalysis, which is not conducive to large-scale industrial production, and the yield is low

Method used

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  • Compound for preparing suvorexant and preparation method thereof
  • Compound for preparing suvorexant and preparation method thereof
  • Compound for preparing suvorexant and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Synthesis of (R)-methyl-2-(N-benzyl-3-((tert-butoxycarbonyl)amino)butanamido)acetate

[0065]

[0066] Methyl-2-(benzylamino)acetate (20mmol), (R)-3-((tert-butoxycarbonyl)amino)butanoic acid (21mmol), 1-hydroxybenzotriazole (25mmol), dry Add triethylamine (30mmol) into the flask, add 25ml of anhydrous DMF, add EDC (24mmol) under stirring, and react at 10°C for 5h. Add 10% citric acid solution, extract with ethyl acetate, 5% Na 2 CO 3 The organic layer was washed with solution, washed with saturated brine, MgSO 4 Dry, filter and evaporate to dryness, the obtained product is recrystallized with ethyl acetate and petroleum ether (1:2, volume ratio) to obtain (yield 98%, m.p.: 107 ° C, [α] 26 D=21.97 (103.76mg / 20ml, MeOH)). 1HNMR (600MHz, DMSO-d6) δppm7.38-7.23 (m, 5H), 6.73-6.72 (d, 1H), 4.75-4.4 (m, 2H), 4.31-3.95 (m, 2H), 3.89-3.87 ( t,1H),3.64-3.62(d,3H),2.64-2.50(m,1H),2.37-2.23(m,1H),1.38-1.37(d,9H),1.08-1.06(m,3H); ( figure 1 ) MS (ESI) m / z 365.20 ([M+H]+)....

Embodiment 2

[0068] Synthesis of (R)-methyl-2-(N-benzyl-3-((tert-butoxycarbonyl)amino)butanamido)acetate

[0069] Methyl-2-(benzylamino)acetate (20mmol), (R)-3-((tert-butoxycarbonyl)amino)butanoic acid (21mmol), 1-hydroxybenzotriazole (25mmol), carbonic acid Potassium (60mmol) was added to the flask, 50ml of anhydrous dichloromethane was added, CDI (22mmol) was added under stirring, and the reaction was carried out at 20°C for 6h. Add 10% citric acid solution, extract with ethyl acetate, 5% Na 2 CO 3 The organic layer was washed with solution, washed with saturated brine, MgSO 4 Dry, filter and evaporate to dryness, the obtained product is recrystallized with ethyl acetate and petroleum ether (1:2, volume ratio) to obtain (yield 97.5%, m.p.: 107 ° C, [α] 26 D=21.97 (103.76mg / 20ml, MeOH)).

Embodiment 3

[0071] Synthesis of (R)-methyl-2-(N-benzyl-3-((tert-butoxycarbonyl)amino)butanamido)acetate

[0072] Methyl-2-(benzylamino)acetate (20mmol), (R)-3-((tert-butoxycarbonyl)amino)butanoic acid (21mmol), 1-hydroxybenzotriazole (25mmol), hydrogenation Add sodium (24mmol) into the flask, add 50ml of anhydrous acetone, add HOAt (25mmol) under stirring, and react at 30°C for 4h. Add 10% citric acid solution, extract with ethyl acetate, 5% Na 2 CO 3 The organic layer was washed with solution, washed with saturated brine, MgSO 4 Dry, filter and evaporate to dryness, the obtained product is recrystallized with ethyl acetate and petroleum ether (1:2, volume ratio) to obtain (yield 97%, m.p.: 107 ° C, [α] 26 D=21.97 (103.76mg / 20ml, MeOH)).

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Abstract

The invention relates to three novel compound formulas I, II and III for preparing suvorexant, stereoisomers or salt thereof and a preparation method of the formulas I, II and III. The invention also relates to a method for preparing the suvorexant. The preparation method disclosed by the invention can be used for synthesizing to obtain the chiral compounds I, II and III through a chiral initiator and use the chiral compounds I, II and III for the synthesis of the suvorexant and has the advantages of easiness for operation, moderation in reaction condition, easiness for post processing, easiness for purification, high yield, high ee value and easiness for industrialization.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and provides a suvorexant synthesis process and a preparation method for new compounds formulas I, II, III, stereoisomers or salts thereof, and formulas I, II, III for preparing suvorexant. Background technique [0002] Insomnia is the most common sleep disorder, about 30-50% of adults have shown symptoms of insomnia, of which 10-15% have been diagnosed with insomnia. According to statistics, the loss caused by insomnia reaches tens of billions of dollars every year. Although insomnia is associated with many serious physical and mental diseases, people's attention to it is far from enough. For a long time, insomnia is only defined as a symptom of other diseases, so little progress has been made in its understanding and treatment . [0003] Currently, sedative-hypnotics for the treatment of insomnia include the following categories: antidepressant sedatives, benzodiazepine sedative-hypnot...

Claims

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Application Information

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IPC IPC(8): C07D403/10C07D413/14C07D243/08C07C271/22C07C269/06
CPCY02P20/55C07D403/10C07C271/22C07D243/08C07D413/14
Inventor 张桂森刘笔锋周言
Owner 武汉久安药业有限公司
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