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Method for preparing solithromycin

A technology for solithromycin and intermediates, which is applied in the field of preparing solithromycin and can solve the problems of difficulty in producing solithromycin, poor solubility, low conversion rate and the like

Inactive Publication Date: 2016-02-24
ZHEJIANG JINGXIN PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the poorer solubility of compound intermediate II after desugaring and oxidation than intermediate CL-1, the reaction is difficult and the conversion rate is low; moreover, when the exposed amino group is deprotected, acyl group migration impurities will be generated, making it difficult to industrially produce Soli Mycin

Method used

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  • Method for preparing solithromycin
  • Method for preparing solithromycin
  • Method for preparing solithromycin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0094] Preparation of Intermediate II:

[0095]

[0096] Add clarithromycin (50 g, 0.067 mol), triethylamine (18.75 mL, 0.135 mol, 2 equivalents), and ethyl acetate (350 mL) into a 500 mL reaction flask and stir to mix. Benzoic anhydride (22.5 g, 0.1 mol, 1.5 equiv) was added in portions. After the addition, stir at room temperature (20-25°C) for 24h. After detecting that the clarithromycin reaction was complete, the solvent was distilled off under reduced pressure (temperature<45° C.). Add 500 mL ice methanol to the residue, stir in ice bath (0-5° C.) for 0.5 h, and filter with suction. The filter cake was rinsed with ice methanol (100 mL×2) and dried in vacuo to obtain 56 g of white solid.

[0097] ESI[M+1]:852

[0098]

[0099] Add intermediate A (56 g, 0.0657 mol), ethanol (300 mL) and water (300 mL) obtained in the previous step reaction into a 1000 mL reaction flask and mix and stir. Concentrated hydrochloric acid (56 mL, 0.672 mol, 10 equivalents) was slowly ...

Embodiment 2

[0124] Preparation of Oxazole Ring Intermediate IIIa

[0125]

[0126] Add compound II (5.7g, 0.0075mol), azidobutylamine (1.2g, 0.0105mol, 2 equivalents), acetonitrile (40mL), 1,8-diazabicycloundecane-7 in a 250mL reaction flask -ene DBU (0.5 mL), react overnight at 55-65°C. After the reaction of Compound II was detected by sampling, the solvent was evaporated under reduced pressure (suspension evaporation, less than 0.01MPa, 40-45°C), the residue was diluted with water (50mL), extracted with ethyl acetate (50mL×2), and the organic phases were combined. Wash with saturated brine (30mL), dry over anhydrous sodium sulfate, filter with suction, spin dry (suspension evaporation, less than 0.01MPa, 40-45°C), and purify by column chromatography (25×500mm silica gel column, silica gel 200-300 The eluent was dichloromethane:methanol=10:1), and 4g of white solid was obtained, which was Intermediate IIIa.

[0127] ESI[M+1]:814.

Embodiment 3

[0129] Preparation of intermediate IV by fluorination reaction

[0130]

[0131] Add intermediate IIIa (1.63 g, 0.002 mol) and tetrahydrofuran (20 mL) into a 100 mL three-neck reaction flask, replace with nitrogen, and stir to dissolve. The reaction solution was cooled to -30°C, and potassium tert-butoxide (0.45 g, 0.005 mol, 2.5 equivalents) was added in portions. After the addition, keep stirring at -20~-25°C for 1h. N-fluorobisbenzenesulfonamide NFSI (1 g, 0.003 mol, 1.5 equiv) was added in portions. After the addition, keep stirring at -20~-25°C for 1.5h. After the reaction of intermediate IIIa was detected by sampling HPLC, 5% aqueous sodium bicarbonate (50 mL) was added to quench the reaction, extracted with ethyl acetate (100 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, suction filtered, and spun After drying, 1.36 g of light yellow solid was obtained, which was Intermediate IV, which could be directly used in the next reaction wi...

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Abstract

The invention discloses a novel method for preparing solithromycin. Compared with the conventional solithromycin preparation process, a designed synthesis process adopted by the novel method has the advantages that the occurrences of side reactions are effectively reduced, the dangerous and toxic operating steps are avoided, and the reaction conversion rate is improved, so that the production cost is reduced, and the novel method is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and in particular relates to a new method for preparing solithromycin. Background technique [0002] Solithromycin (English name Solithromycin) is a next-generation macrolide antibiotic drug developed by Cempra Pharmaceuticals for the treatment of community-acquired bacterial pneumonia (CABP). It is used in the treatment of chronic obstructive pulmonary disease (COPD), bacterial pneumonia and some infections. Solithromycin is the first fluorine-substituted macrolide drug to enter the clinic. The U.S. Chemical Abstracts Number is (CAS: 760981-83-7), which has a chemical structure shown in the following formula I: [0003] [0004] International patent application WO2009055557 discloses a synthetic route for preparing solithromycin I using clarithromycin as a starting material. A hydroxyl activator with steric hindrance, carbonyldiimidazole (CDI), reacts to generate intermediate CL-1; ...

Claims

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Application Information

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IPC IPC(8): C07H17/08C07H1/00
CPCC07H1/00C07H17/08
Inventor 徐辉郑飞张涛黄悦
Owner ZHEJIANG JINGXIN PHARMA
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