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Suvorexant intermediate preparation method

A compound and reaction technology, which is applied in the field of preparation of Suwo Leisheng intermediates, can solve the problems of cumbersome steps, low yield, difficult operation, etc., and achieve the effect of mild reaction conditions, simplified reaction steps, and avoiding operation and treatment

Inactive Publication Date: 2018-04-20
SHANGHAI SYNCORES TECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The above three routes have the following disadvantages: the highly toxic compound methyl vinyl ketone is used as the starting material, and methyl vinyl ketone is strongly irritating to the eyes, skin, mucous membranes and upper respiratory tract, and is not easy to handle during use; the route one is in In the preparation process, chiral resolution is required, which is not suitable for industrialized large-scale production, and the overall yield of the route is low; route 2 requires the use of chiral resolution reagents, and the yield of this process is low, resulting in a large waste of materials and increased costs; Route 3 uses heavy metal ruthenium to catalyze asymmetric reductive amination, which is costly and environmentally unfriendly
[0013] This route constructs a diazepane skeleton through chiral starting materials, and is further applied to the synthesis of chiral compound Suvorexan, avoiding chiral separation and the use of chiral catalysts, with mild reaction conditions and high ee value, but There are shortcomings such as cumbersome steps in the route

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Synthesis of (R)-methyl-2-(N-benzyl-3-((fluorenylmethoxycarbonyl)amino)butanamido)acetate

[0032]

[0033] Methyl-2-(benzylamino)acetate (40mmol), (R)-3-((fluorenylmethoxycarbonyl)amino)butanoic acid (42mmol), 1-hydroxybenzotriazole (50mmol), dry N-methylmorpholine (60 mmol) was added to the flask, 100 ml of DCM was added, EDCI (48 mmol) was added under stirring, and the reaction was carried out at 10-20° C. for 6 h. 10% citric acid solution was added, extracted with ethyl acetate, the organic layer was washed with 5% sodium carbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness, and the obtained product was reconstituted with ethyl acetate and petroleum ether. After crystallization, 17.5 g of the product was obtained, and the yield was 90%. 1 H NMR (400MHz, CDCl 3 )δ7.76(d,J=7.5Hz,2H),7.61(d,J=7.1Hz,2H),7.35(m,7H),7.19(dd,J=22.7,7.1Hz,2H),4.67– 4.59(m, 2H), 4.35(d, J=7.1Hz, 2H), 4.20(dd, J=20.3,...

Embodiment 2

[0035] Synthesis of (R)-4-benzyl-7-methyl-1,4-diazepan-2,5-dione

[0036]

[0037] (R)-Methyl-2-(N-benzyl-3-((fluorenylmethoxycarbonyl)amino)butanamido)acetate (20 mmol) was added to the flask, followed by morpholine (26.13 g), React at 90~100℃ for 6h. Lower the reaction temperature, add 10% citric acid solution, extract with ethyl acetate, wash the organic phase with 10% citric acid solution for several times, then wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to dryness to obtain the product 4.3g, yield 93%. 1 H NMR (400MHz, CDCl 3 )δ7.30–7.15(m, 5H), 5.90(s, 1H), 4.58(d, J=3.6Hz, 2H), 3.95(dd, J=44.5, 17.4Hz, 2H), 3.77(m, 1H) ),2.79(m,2H),1.23(d,J=6.5Hz,3H).MS(ESI)m / z 233.10([M+H] + )

Embodiment 3

[0039] Synthesis of (R)-4-benzyl-7-methyl-1,4-diazepan-2,5-dione

[0040]

[0041] (R)-Methyl-2-(N-benzyl-3-((fluorenylmethoxycarbonyl)amino)butanamido)acetate (20 mmol) was added to the flask, followed by piperidine (25.5 g) , and react at 90~100℃ for 6h. Lower the reaction temperature, add 10% citric acid solution, extract with ethyl acetate, wash the organic phase with 10% citric acid solution for several times, then wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to dryness to obtain the product 4.1 g, yield 88%.

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Abstract

The invention relates to a preparation method of a suvorexant intermediate represented by a formula IV, wherein the preparation route is defined in the specification. According to the present invention, the method has advantages of simple and safe operation, good yield, low environmental pollution and good economic benefits, and is suitable for industrial production. The formulas III and IV are defined in the specification, wherein R represents C1-5 substituted or unsubstituted benzyl and allyl.

Description

technical field [0001] The present invention relates to a method for preparing an intermediate of Suvorexan. technical background [0002] Orexins (orexins) are neuropeptides that are related to the regulation of the sleep-wake cycle and play an important role in keeping people awake. Suvorexant (Suvorexant) is an Orexins (orexin) receptor antagonist, the drug by blocking Orexins (orexin) to transmit the message, and achieve the effect of improving patients' sleep. 2014.08.13, the US Food and Drug Administration (FDA) approved Merck's new insomnia drug suvorexant (trade name Belsomra) for the market. [0003] The following literature reports the synthetic route of this compound: [0004] (1) the synthetic route of US2008 / 132490 report is as follows: [0005] [0006] (2) The synthetic route reported by Org.Process Res.Dev.2011, 15, 367-375 is as follows: [0007] [0008] (3) The synthetic routes reported in WO2012148553 and J.Am.Chem.Soc.2011, 133, 8362-8371 are a...

Claims

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Application Information

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IPC IPC(8): C07D243/08C07C271/22C07C269/06
CPCC07C271/22C07D243/08C07C269/06
Inventor 林建平郭效文苏虎黄超刘东顺陶安平黄鲁宁顾虹
Owner SHANGHAI SYNCORES TECH INC
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