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Method for preparing remimazolam

A technology of remimazolam and an intermediate, which is applied in the field of preparation of labor pain anesthetic drug remazolam, can solve problems such as waste, and achieve the effects of improving quality, optimizing preparation process and simple operation.

Active Publication Date: 2021-11-30
SHANGHAI ZAIQI BIO TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this method, the racemate is first obtained through a multi-step reaction, and the undesired configuration can be obtained after resolution. Alkaline can be added to carry out racemization and resolution again, which is conducive to the full utilization of raw materials and solves another problem of resolution. Disadvantage of configuration waste

Method used

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  • Method for preparing remimazolam
  • Method for preparing remimazolam
  • Method for preparing remimazolam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] first step:

[0046] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.9g, 4.7mmol) was added to BOC-glycine (0.63g, 3.61mmol) and 2-(2-amino- 5-Bromo-benzoyl)pyridine (compound (1)) (1.0g, 3.61mmol) / tetrahydrofuran (16mL) solution, stirred at room temperature for 6 hours, concentrated under reduced pressure, added ethyl acetate and water to extract the reaction. The organic layer was washed with brine, dried and spin-dried to obtain compound 2 (1.46 g, yield 93.0%).

[0047] Step two:

[0048]Pass hydrogen chloride gas into the compound 2 (1.46g, 3.36mmol) / methanol (15mL) solution, stop the ventilation after 20 minutes, stir the solution at room temperature overnight, wash with aqueous sodium bicarbonate, and spin the organic layer to dryness with aqueous sodium bicarbonate (1N) Adjust pH=8-9, extract with dichloromethane 3 times, spin dry and recrystallize with methanol / water to obtain compound 3 (0.90 g, yield: 84.9%).

[0049] The third step: 7-bromo...

Embodiment 2

[0057] first step:

[0058] 3,5-Dinitrophenylboronic acid (0.153kg, 0.72mol) was added to BOC-glycine (0.69kg, 3.97mol) and 2-(2-amino-5-bromo-benzoyl)pyridine (compound (1) ) (1kg, 3.61mol) / dioxane (13L) / toluene (4L) solution, reflux and water separation for 6 hours, concentrate under reduced pressure and then add ethyl acetate and water to extract the reaction. The organic layer was washed with brine, dried and spin-dried to obtain compound 2 (1.48 kg, yield 94.3%).

[0059] Step two:

[0060] Add trifluoroacetic acid (0.58kg, 5.11mol) into a solution of compound 2 (1.48kg, 3.41mol) in dioxane (7L), stir the solution overnight at room temperature, wash with aqueous potassium carbonate solution, spin the organic layer to dryness, and use Potassium carbonate aqueous solution (1N) was used to adjust the pH to 8-9, extracted three times with dichloromethane, spin-dried and then recrystallized with methanol / water to obtain compound 3 (0.92kg, yield 85.1%).

[0061] The third s...

Embodiment 3

[0069] first step:

[0070] Tris(2,2,2-trifluoroethyl) borate (1.67kg, 5.41mol) was added to BOC-glycine (6.64kg, 37.89mol) and 2-(2-amino-5-bromo-benzoyl) Pyridine (compound (1)) (10kg, 36.09mol) / dioxane (140L) / toluene (30L) solution, refluxed for 6 hours, concentrated under reduced pressure, added ethyl acetate and water to extract the reaction. The organic layer was washed with brine, dried and spin-dried to obtain compound 2 (14.42 kg, yield 92.0%).

[0071] Step two:

[0072] Concentrated hydrochloric acid (4.15L, 49.8mol) was added in the ethyl acetate (75L) solution of compound 2 (14.42kg, 33.20mol), and the solution was stirred overnight at room temperature, washed with an aqueous solution of DBU, and the organic layer was spin-dried with an aqueous solution of DBU ( 1N) adjust the pH to 8-9, extract with dichloromethane three times, spin dry and recrystallize with methanol / water to obtain compound 3 (9.01kg, yield: 85.8%).

[0073] The third step: 7-bromo-2-(2-hydr...

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Abstract

The invention discloses a preparation method of remimazolam, and belongs to the technical field of medical intermediates. The preparation method comprises the following steps: carrying out condensation on 2-(2-amino-5-bromo-benzoyl) pyridine (1) and BOC-glycine to obtain an intermediate (2); removing Boc protection from the intermediate (2), and performing ring closing to obtain an intermediate (3); performing sulfonylation and substitution reaction on the intermediate (3) to obtain an intermediate (4); oxidizing and cyclizing the intermediate (4) to obtain an intermediate (5); and reacting the intermediate (5) with methyl acrylate, and carrying out chiral resolution to obtain remimazolam (6). The production of an impurity II is avoided, and the quality of the product is improved; and after the resolution, the configuration is not required, alkali can be continuously added for racemization, and the resolution is performed again, so that the process reproducibility is good, and the reaction scale can be smoothly enlarged to a kilogram-level reaction scale.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of remimazolam, an anesthetic for labor pain. Background technique [0002] Remimazolam is an ultra-short-acting intravenous benzodiazepine sedative / anesthetic that acts on GABA-α receptors. In humans, Remimazolam is rapidly metabolized by tissue esterases into inactive metabolites and is not metabolized by cytochrome-dependent hepatic pathways. It has the characteristics of fast effect, short duration, fast recovery and good tolerance. Remimazolam is used for anesthesia induction, maintenance of anesthesia and day surgery anesthesia. Compared with other products, it has certain advantages when applied to patients with cardiovascular disease, respiratory system disease, liver disease and elderly patients. [0003] Remimazolam besylate was officially approved for marketing in July 2020. It is used in the fields of painless diagnosis and treatmen...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04C07B2200/07Y02P20/55
Inventor 杨红侠熊峰范涛杨婷时秋燕
Owner SHANGHAI ZAIQI BIO TECH
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