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Preparation method of midazolam intermediate

A technology for midazolam and intermediates, which is applied in the field of preparation of midazolam intermediates, can solve the problems of increased side reactions, poor equipment compatibility, poor reaction selectivity and the like

Pending Publication Date: 2022-07-01
CHENGDU EASTON BIOPHARMACEUTICALS CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Therefore, it is of great significance to develop a new synthesis method for the midazolam intermediate M6 that is more suitable for industrial production. This patent adopts a method that is not commonly used in the Raney nickel catalytic reaction system through further research on the above reactions. DMF or DMA is used as a solvent to develop reaction conditions that are more suitable for scale-up. The method described in this patent has the advantages of less reaction solvent consumption, good equipment compatibility and easy scale-up, and can avoid the existing existing reported methods. The problems of increased side reactions, poor reaction selectivity, and poor equipment compatibility during the reaction amplification process

Method used

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  • Preparation method of midazolam intermediate
  • Preparation method of midazolam intermediate
  • Preparation method of midazolam intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Add 15.0g (45.3mmol, 1.0X) M5 and DMF to the hydrogenation reaction kettle, stir and dissolve, add quantitative wet Raney nickel, replace with nitrogen and hydrogen for 3 times respectively, pass in hydrogen, keep the pressure at 1.0MPa, at 20 Stir the reaction at -30°C for 20-25h, and check the reaction process by TLC. After completion, filter the reaction solution through diatomaceous earth to ensure that the Raney nickel is below the liquid level during the filtration process to prevent the Raney nickel from burning and the filter cake. Put into water for storage, and the filtered reaction solution was tested for conversion rate by HPLC. See HPLC chromatogram for details figure 1 .

Embodiment 2

[0031] The reactions of Examples 2 and 3 were repeated according to the method described in Example 1, and the results are shown in Table 1.

Embodiment 1、 Embodiment 2、 Embodiment 3

[0038] Embodiment 1, embodiment 2, embodiment 3, comparative example 1 measure the reaction conversion rate by HPLC;

[0039] Comparative Example 2 A silica gel thin-layer plate was used by TLC, dichloromethane:methanol=10 / 1 mixed solvent was used as a developing agent, and a UV detector with a wavelength of 254 nm was used to detect that the reaction was mixed, and the content of the product was estimated to be less than 10%.

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Abstract

The invention discloses a preparation method of a midazolam intermediate. The preparation method provided by the invention has the advantages of low solvent consumption, good equipment compatibility, easiness in amplification and the like.

Description

Technical field [0001] The invention belongs to the field of drug synthesis, and specifically relates to a preparation method of midazolam intermediates. Background technique [0002] benzodiazepine GABAergic drugs are a class of drugs with high pharmacological activity and broad application prospects. They mainly mediate their effects by agonistically binding to the γ-aminobutyric acid receptor (GABAA) in the central nervous system. Typical pharmacological properties are: : Anti-anxiety, sedative-hypnosis, anti-convulsant, central muscle relaxation and preoperative anesthesia, etc. [0003] Midazolam was developed by Roche and was first approved for marketing in the United States in 1998. Its main dosage forms include tablets, injections, oral solvents, etc., and the corresponding raw materials include free base, maleate, hydrochloride and other different ready-made drugs. Way. In my country, it belongs to the second category of psychotropic drugs controlled by the stat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D243/16C07D487/04
CPCC07D243/16C07D487/04
Inventor 汪永强乔旋申茂昌乔智涛王颖
Owner CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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