Preparation method of chiral homopiperazine ring

A kind of ring-closure reaction, compound technology, applied in the intermediate compound shown in formula Int, in the field of preparation of chiral homopiperazine ring, can solve problems such as being unsuitable for industrialized production

Active Publication Date: 2021-02-05
CHINA RESOURCES DOUBLE CRANE PHARMA COMPANY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] In this synthetic method, the synthetic route of compound (R)-T has seven steps, and the acquisition of chirality is separated by chiral preparative column, which is not suitable for industrial production

Method used

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  • Preparation method of chiral homopiperazine ring
  • Preparation method of chiral homopiperazine ring
  • Preparation method of chiral homopiperazine ring

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0122] route one

[0123]

Embodiment 1-1

[0124] Example 1-1: Synthesis of N-benzyl-N-(3-(R)-tert-butoxycarbonylaminobutanyl)-2-chloroacetamide (compound 2)

[0125]

[0126] Chloroacetyl chloride (12.5 g, 0.11 mol) was slowly added to 80 mL of dichloromethane solution to obtain a dichloromethane solution of chloroacetyl chloride. 3-(R)-tert-butoxycarbonylamino-1-N-benzylbutylamine (27.8g, 0.1mol) represented by formula SM-1 was dissolved in 200mL of dichloromethane, triethylamine (12.2 g, 0.12mol), cooled to -5~0°C, slowly added dropwise the dichloromethane solution of chloroacetyl chloride, the temperature in the system was controlled not to exceed 10°C during the dropwise addition, after the dropwise addition was completed, the temperature was raised to room temperature, and stirred for another 2 hours , TLC monitors the reaction, after the reaction finishes, 50 milliliters of ice water is added in the reaction solution, separates the organic phase, extracts the aqueous phase with 100 milliliters of dichlorometh...

Embodiment 1-2

[0127] Example 1-2: Synthesis of 1-benzyl-4-tert-butoxycarbonyl-5-(R)-methyl-1,4-diazepan-2-one (compound 3)

[0128]

[0129] Compound 2 (32g, 0.09mol) was dissolved in anhydrous N,N-dimethylformamide (DMF, 350mL). After it was completely dissolved, anhydrous cesium carbonate (58.5g, 0.18mol) was added, and the temperature was slowly raised to 75°C, maintain the reaction for 16 hours. After the reaction, add 500 ml of water to the reaction solution, extract with ethyl acetate, combine the extracts, wash with saturated sodium chloride solution, dry the organic phase with anhydrous sodium sulfate, and concentrate , recrystallized from a mixture of ethyl acetate and n-heptane (volume ratio 1:10) to obtain compound 3 as a waxy off-white low-melting solid weighing 26.6 g with a yield of 93%. 1 H NMR (400MHz, CD3OD): δ=7.31(m,5H),4.04(s,2H),3.90(m,1H),3.70(s,2H),2.95(m,1H),2.82(m,1H ), 1.97(m, 1H), 1.63(m, 1H), 1.42(s, 9H), 1.12(d, J=7Hz, 3H).LC-MS(ESI) m / z 319.31([M+H] + ). ...

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Abstract

The present invention relates to a preparation method of a chiral homopiperazine ring compound represented by (R)-I, the method comprising reducing the compound represented by the formula Int to obtain the compound represented by the formula (R)-I. The present invention also relates to novel intermediate compounds represented by formula Int. The chiral homopiperazine ring compound shown in (R)‑I is an important intermediate for the synthesis of the drug Suvorexant for the treatment of sleep disorders. The preparation method of the present invention introduces the chiral center from the starting material, and does not use reactions and reagents that will affect the chiral center during the entire reaction process, avoiding the high cost of chiral resolution or chiral catalysts, and the low yield. The lower method, no chiral participation in the process, ensures the chiral purity of the product, only uses conventional methods and equipment, simple operation, mild conditions, short route, high yield, suitable for industrial production,

Description

technical field [0001] The invention belongs to the field of organic chemistry and medicinal chemistry, and in particular relates to a preparation method of a chiral homopiperazine ring, which is an important intermediate for the synthesis of Suvorexant. The invention also relates to a new intermediate represented by the formula Int body compound. Background technique [0002] Suvorexant is a drug developed by Merck for the treatment of sleep disorders, also known as MK-4305, its trade name is Belsomra, and its chemical name is: 5-chloro-2-[(5R)-5-methyl-4-[ 5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl]-1,3-benzo Oxazole. Suvorexant is the first approved orexin receptor antagonist with unique pharmacological properties. It inhibits neuronal activation of the arousal system by blocking the binding of neuropeptides orexin A and B to orexin receptors. Compared with benzodiazepines, it has obvious advantages and is the sedative-hypnotics with the longest follo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D243/08C07D413/14
CPCC07D243/08C07D413/14Y02P20/55
Inventor 刘开湘马红敏李凯
Owner CHINA RESOURCES DOUBLE CRANE PHARMA COMPANY
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