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Preparation method of 5-chloro-2-[5-(r)-methyl-1,4-diazepane-1-]benzoxazole

A technology of dimethylaminopropyl, ethylcarbodiimide hydrochloride, applied in the fields of organic chemistry and medicinal chemistry, can solve the problems of increased production cost, high cost, long route and the like

Active Publication Date: 2019-05-21
CHINA RESOURCES DOUBLE CRANE PHARMA COMPANY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The second synthetic route is not only long and costly, but also easily causes heavy metal pollution due to the introduction of chiral heavy metal catalysts
At the same time, the production process will put forward higher requirements for the equipment, and it is necessary to purchase new special equipment, which greatly increases the production cost.

Method used

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  • Preparation method of 5-chloro-2-[5-(r)-methyl-1,4-diazepane-1-]benzoxazole
  • Preparation method of 5-chloro-2-[5-(r)-methyl-1,4-diazepane-1-]benzoxazole
  • Preparation method of 5-chloro-2-[5-(r)-methyl-1,4-diazepane-1-]benzoxazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102] route one

[0103]

Embodiment 1-1

[0105] Preparation of 4-(N-(5-chloro-benzoxazole-2-)-)amino-2-(R)-tert-butoxycarbonylamino-butane (shown in formula III-1)

[0106]

[0107] Suspend 3-(R)-tert-butoxycarbonylamino-1-butylamine (207g, 1.1mol) shown in formula V-1 in 1L of dichloromethane, cool to 0°C, add triethylamine (122g , 1.2mol), cooled to -5~0°C, slowly added dropwise the solution of 2,5-dichlorobenzoxazole (188g, 1mol) in dichloromethane (800mL) shown in formula VI-1, the inner temperature was constant When the temperature exceeds 10°C, the dropwise addition is completed, let the reaction warm up to room temperature (23°C), stir for 3 hours, and monitor the reaction by TLC. After the reaction is completed, 1L of 15% ammonium chloride ice water is added to the reaction solution, and the organic layer and the water layer are separated. Then extract with 200 mL of dichloromethane, combine the organic layers, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and recrystallize from ethy...

Embodiment 1-2

[0109] N-(2-(5-chlorobenzoxazole)-N-(4-(2-(R)-tert-butoxycarbonylaminobutane))-2-chloroacetamide (shown in formula II-1) Synthesis

[0110]

[0111]The 4-(N-(5-chloro-benzoxazole-2-)-)amino-2-(R)-tert-butoxycarbonylamino-butanol shown in III-1 prepared in Example 1-1 The filtrate of alkanes was transferred to the reaction flask, cooled to -5~0°C again, DBU (182.4g, 1.2mol) was added, and the solution of chloroacetyl chloride (125g, 1.1mol) in 0.8L dichloromethane was slowly added dropwise to control The internal temperature does not exceed 10°C. After the addition is completed, the temperature is raised to room temperature, and stirred for 2 hours. The reaction is monitored by TLC. After the reaction is completed, 500 ml of ice water is added to the reaction solution, the organic phase is separated, and the aqueous phase is extracted with 500 ml of dichloromethane. Combine the organic phases, wash the organic phase with 500 ml of saturated aqueous sodium bicarbonate soluti...

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Abstract

The invention relates to a method for preparing 5-chlorine-2[5-(R)-methyl-1,4-diazacycloheptyl-1-] benzoxazole. The method includes the step of reducing a compound in the formula I (please see the formula in the specification). The invention further relates to a new midbody compound shown in the formula I. 5-chlorine-2[5-(R)-methyl-1,4-diazacycloheptyl-1-] benzoxazole is an important midbody for synthesizing medicine Suvorexant treating sleep disorders. According to the preparation method, initial materials are introduced into a chiral center, in the whole reaction process, reactions and reagents influencing the chiral center are not adopted, the chiral separation or chiral catalystic method which is high in cost and low in yield is avoided, chiral interference reactions do not exist in the technological process, chiral purity of products is guaranteed, only conventional methods and equipment are used, operation is easy, conditions are moderate, lines are short, the yield is high, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of organic chemistry and medicinal chemistry, in particular to the intermediate 5-chloro-2-[5-(R)-methyl-1,4-diazepane-1-]benzoxane of medicine Suvorexant The preparation method of azole also relates to a new intermediate 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 it is the sedative-hypnotic drug that maintains the longest sleep time among the follow-up hypnotics so far...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/04C07D263/58
CPCY02P20/55
Inventor 刘开湘周宜遂李凯
Owner CHINA RESOURCES DOUBLE CRANE PHARMA COMPANY
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