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Preparation method of benzodiazepine derivatives

A kind of compound, the technology of bromophenyl, applied in the field of preparation of benzodiazepine derivatives, can solve the problems of low product purity and the like

Active Publication Date: 2018-07-10
福建盛迪医药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The starting reactant that this method uses when preparing the compound shown in formula (D) is t Boc-Glu(OMe)-OH reacts under the action of coupling agent DCC to obtain the compound shown in formula (B), then add hydrochloric acid to remove the Boc protecting group to obtain the compound shown in formula (C), add sodium bicarbonate cyclization reaction to obtain the formula The compound shown in (D) reacts with dimorpholino phosphinyl chloride under the action of deprotonating reagent to obtain the compound shown in formula (E), and reacts with the R-isopropanolamine of single configuration to obtain the compound shown in formula (F) Shown compound, react with 1,1,1-triacetoxy-1,1-dihydro-1,2-phenyliodide-3 (1H) ketone (Dess-Martin oxidizer, Dess-MartinPeriodinane) to obtain the formula ( The compound shown in G) is cyclized after adding hydrochloric acid to obtain the compound shown in formula (Ia); wherein, the isopropanolamine used in the reaction of the compound shown in the preparation formula (F) is a single R configuration, and the yield is 56%. The chemical purity of the compound reaction shown in the formula (Ia) is 93.91%, and the purity of the product obtained by the reaction of a single configuration R-isopropanolamine is relatively low, therefore, it is necessary to improve the existing preparation method

Method used

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  • Preparation method of benzodiazepine derivatives
  • Preparation method of benzodiazepine derivatives
  • Preparation method of benzodiazepine derivatives

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specific Embodiment approach

[0068] The following examples are used to further describe the present invention, but these examples do not limit the scope of the present invention.

[0069] The experimental methods not indicating specific conditions in the examples of the present invention are generally in accordance with conventional conditions, or in accordance with the conditions suggested by raw material or commodity manufacturers. Reagents without specific sources indicated are conventional reagents purchased in the market.

Embodiment 1

[0074] Example 1, (S)-3-(7-bromo-2-oxo-5-(pyridin-2-yl)-2,3-dihydro-1H-benzo[e][1,4]di Aza Preparation of -3-yl) methyl propionate

[0075]

[0076] first step

[0077] (2-Amino-5-bromophenyl)(pyridin-2-yl)methanone

[0078] Add tetrahydrofuran (44mL) into the reaction flask, under nitrogen protection, add n-butyllithium (51mL) at -40°C, control the internal temperature not to exceed -20°C, lower the temperature to -40°C, and slowly add 2-bromopyridine ( 15.8g), after dropping, keep it warm for 1 hour, control the temperature below -40°C, add dropwise a solution of 2-amino-5-bromo-benzoic acid (6.7g) dissolved in (44mL) tetrahydrofuran, and naturally heat up to 0°C after dropping React for about 3 hours. Control the internal temperature below 10°C, slowly add saturated ammonium chloride solution (11mL) dropwise to terminate the reaction, then add water (50mL), let stand to separate the layers, separate the organic layer, and extract the aqueous layer with ethyl acetate...

Embodiment 2

[0086] Example 2, (S)-3-(8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4 ] diazepine Preparation of -4-yl) methyl propionate

[0087]

[0088] first step

[0089] 3-((3S)-7-bromo-2-((2-hydroxypropyl)amino)-5-(pyridin-2-yl)-3H-benzo[e][1,4]diazepine -3-yl)methyl propionate

[0090] Under the protection of argon, add phosphorus oxychloride (1.2kg) into toluene (6.4kg) in the reaction bottle, stir to dissolve, cool to 5°C, drop morpholine (2.68kg) into it within 2h, and control the temperature Not exceeding 20°C. After dropping, react at room temperature for 3h. Filter the insoluble matter, wash it three times with toluene (1kg×3), combine the filtrate, concentrate under reduced pressure to an oily matter, add about (1.92kg) of toluene, heat to dissolve evenly, add petroleum ether (860g) under stirring (if there is insoluble matter , need to filter while it is hot), then add petroleum ether (3.48kg), cool to room temperature, filter, the filter cake is ...

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Abstract

The invention relates to a preparation method of benzodiazepine derivatives. The preparation method comprises preparing a compound shown in the formula (III) from a compound shown in the formula (V),preparing a compound shown in the formula (II) through a reaction and finally preparing benzodiazepine derivatives shown in the formula (I) and their pharmaceutically acceptable salts. The invention also discloses an intermediate in the preparation process and a preparation method thereof. The preparation method shortens the reaction processes, improves the reaction yield, is simple, is easy to operate and control and is conducive to expanded production.

Description

technical field [0001] The present invention relates to a kind of benzodiazepine Methods for the preparation of derivatives. Background technique [0002] The chemical name of the compound of formula (Ia) is (S)-3-(8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a ][1,4]diazepine -4-yl) methyl propionate, [0003] [0004] Patent WO0069836A1 reported containing carboxylate and benzodiazepine The compound of the structure is a short-acting central nervous system (CNS, Central Nervous System) inhibitor, and has effects including sedative hypnosis, anxiolytic, muscle relaxation and anticonvulsant. They can be used for intravenous administration in clinical regimens such as preoperative sedation, anxiolytic and amnestic use during surgery; conscious sedation during short-term diagnostic, surgical or endoscopic procedures; administration of other anesthetics and analgesics Before and / or concurrently, as a component for induction and maintenance of general anes...

Claims

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Application Information

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IPC IPC(8): C07D401/06C07D487/04
CPCC07D401/06C07D487/04Y02P20/55
Inventor 徐洪玉高晓晖边林
Owner 福建盛迪医药有限公司
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