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A kind of preparation method of plazomicin

A compound and selective technology, applied in the preparation of sugar derivatives, chemical instruments and methods, organic chemistry, etc., can solve the problems of incomplete literature reports, few synthesis steps, poor selectivity, etc., achieve simple post-processing steps, improve yield rate, the effect of increasing selectivity

Active Publication Date: 2021-10-08
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Patent WO 2010 132839 reported that sisomicin was used as the starting material, the allylic amino group was protected with ethyl trifluoromercaptoethyl ester, and the amino group was protected with benzyl-N-succinimidyl carbonate, and 4 -benzyloxycarbonyl amino-2-hydroxybutyryl succinimide condensation, take off the trifluoroacetyl group, condensation reduction with 2-benzyloxyacetaldehyde, hydrolysis to take off the protecting group to obtain the target product; this route has few synthetic steps, but The selectivity to multiple amino groups in the structure is poor, and the post-processing of the multi-step reaction requires preparative liquid phase purification, the yield is low, and the literature reports are incomplete

Method used

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1: the preparation of active ester

[0036]

[0037] 1) Preparation of compound 9

[0038] Potassium carbonate (29.0 g, 210 mmol) was dissolved in water (240 mL), compound 8 (10.0 g, 84.0 mmol) was added, and stirred for 30 min. Then a solution of trifluoroacetic anhydride (21.2 g, 100.8 mmol) in dioxane (112 mL) was added dropwise, and reacted overnight at room temperature. Part of the solvent was evaporated, water (300 mL) was added, and washed with methyl tert-butyl ether (50.0 mL×3). The aqueous layer was washed with KHSO under ice bath4 The pH of the solution (2M) was adjusted to 3-4, adding saturated brine (350mL), extracting with DCM (300mL×4), drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate to dryness to obtain an oily substance, that is, compound 9 (14.0 g, 77.2%).

[0039] 2) Preparation of Compound 10

[0040] The above oil (12.0g, 55.8mmol) was dissolved in 100ml of dichloromethane, and N-hy...

Embodiment 2

[0041] Embodiment 2: Preparation of Plazomicin

[0042] 1) Preparation of Compound 2

[0043] Dissolve p-nitrobenzyloxycarbonyl chloride (26.5g, 113mmol) in tetrahydrofuran (THF, 450mL), cool down to 0°C, add N-hydroxy-5-norbornene-2,3-dicarboximide (20.0g, 111.6mmol), then a solution of triethylamine (23.0mL, 167mmol) in THF (250mL) was added dropwise, after the dropwise addition, it was moved to room temperature for 6h. After the reaction, the reaction liquid was lowered to -5~0°C, stirred for 1 h, filtered, and the filtrate was concentrated. The resulting solid was stirred in isopropyl ether (200 mL) for 2 h, and filtered to obtain a white solid (N-hydroxy-5-norbornene-2,3-dicarboximide)-4-nitro-benzyloxymethanol Ester (HONB-PNZ, 37.5 g, 95.1%).

[0044] Dissolve compound 1 (sisomicin, 35.8 g, 80.7 mmol) in methanol (255 mL), add zinc acetate (44.0 g, 239.7 mmol), and stir at 0°C for 24 h. The temperature was lowered to -20°C to -10°C, and the DCM (544mL) solution of th...

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PUM

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Abstract

The invention discloses a preparation method of plazomicin. The method uses sisomicin as the starting material, uses HONB-PNZ to protect the allylic amino group, reacts with hexamethyldisilazane to prepare a fully protected silyl compound, and reacts with active ester for acylation and selective deprotection Based on PNZ, condensed with 2-hydroxyacetaldehyde protected by tert-butyldimethylsilane, reduced, deprotected, and separated by resin column to obtain the target product. Compared with the existing preparation method, the present invention shortens the reaction steps, can be operated in an assembly line, has high yield, simple post-treatment steps, and mild reaction conditions, making the process easier for industrial production.

Description

technical field [0001] The invention relates to a preparation method of plazomicin, which belongs to the technical field of pharmaceutical synthesis. Background technique [0002] Plazomicin is a new type of aminoglycoside antibiotic developed by Ibis Therapeutics, which inhibits protein synthesis by binding to the A site of the 16S rRNA decoding region of the 30S ribosomal subunit, and is used to treat multidrug-resistant intestinal Severe Gram-negative bacterial infections induced by Bacteriaceae can overcome the current clinical resistance to aminoglycoside antibiotics. In 2006, Achaogen obtained the authorization for the joint development of the drug, and on June 25, 2018, the FDA approved Achaogen's antibiotic Plazomicin (trade name: Zemdri) for the treatment of complicated urinary tract infections in adult patients. Submit a listing application to the European EMA in 2019. The structural formula of Plazomicin is as follows: [0003] [0004] Plazomicin is prepare...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H1/00C07H15/236
CPCC07H1/00C07H15/236Y02P20/55
Inventor 范松李法东赵华李东建孟令华张丽
Owner 山东安信制药有限公司
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