Preparation method of solithromycin

A technology of solithromycin and its compound, which is applied in the field of preparation of macrolide drug solithromycin, and can solve the problems that it is not suitable for industrial production

Inactive Publication Date: 2017-09-29
ZHEJIANG JINGXIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] Therefore, there are many defects in the above-mentioned method, are not suitable for suitability for suitability for suitability for industrialized production, need to be improved urgently

Method used

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  • Preparation method of solithromycin
  • Preparation method of solithromycin
  • Preparation method of solithromycin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Preparation of Intermediate II:

[0074] ⑴Preparation of Compound A

[0075]

[0076] 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 Compound A as a white solid.

[0077] ESI[M+1]:852

[0078]

[0079] Add compound A (56 g, 0.0657 mol), ethanol (300 mL), and water (300 mL) obtained in the previous step into a 1000 mL reaction flask and mix and stir. Concentrated hydrochloric acid (56 m...

Embodiment 2

[0107] Preparation of compound Ⅲ by fluorination reaction

[0108]

[0109] Dissolve 2.05 g of acetyl-protected intermediate II (2.90 mmol) in a mixed solution of 20 ml of DMF / THF (tetrahydrofuran) (9:1), and add 0.39 g of potassium tert-butoxide (3.48 mmol), the addition was completed, the mixture was stirred at -20°C for 0.5 hours, then 1.01 g of NFSI (N-fluorobisbenzenesulfonamide) (3.19 mmol) was added, the addition was completed, and the reaction was continued at -20°C for two hours. Sampling HPLC detects that the reaction is complete, adding a small amount of water to quench the reaction, diluting the reaction solution with 50 milliliters of ethyl acetate, then washing (6*50 milliliters) with saturated brine several times, drying over anhydrous sodium sulfate, filtering and spinning to obtain the crude product ( can be used directly in the next step). The crude product was purified by column chromatography (silica gel 200-300 mesh, Qingdao Huanghai), using 4 L of eth...

Embodiment 8

[0119] Preparation of compound III

[0120]

[0121] Compound VII (6.74 g, 0.01 mol) was dissolved in DMF:THF=9:1 mixed solvent (40 ml) and replaced with nitrogen. The reaction solution was cooled to -25°C. Sodium hydrogen (1 g, 0.025 mol, 2.5 eq) was added. After the addition is complete, react at -20°C to -25°C for 1h. NFSI (5 g, 0.015 mol, 1.5 eq) was added in portions. After the addition is complete, react at -20°C to -25°C for 1h. After the reaction of the raw materials was detected by sampling, 90ml of ice water was added dropwise, and the temperature was controlled not to exceed 10°C, and solids were precipitated. After dropping, stir for 15 minutes, filter with suction, rinse with ice water. The filter cake was dissolved in 50 ml of ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. Suction filtration and spin-drying gave 6.67 g of a light yellow solid crude product, MS=692. The crude product was directly reacted in the next ...

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Abstract

The invention provides a preparation method of solithromycin. The method comprises the following steps: performing fluorination reaction on a compound II to generate a compound III; forming a butt joint on the compound III and 4-azidobutylamine to form an oxazole ring compound VI; and performing ring-closing reaction on the compound VI and 3-aminophenylacetylene to obtain the solithromycin I. The method abandons the explosive and hazardous azido intermediate oxidization in the prior art, so the reaction operation is safer. Especially, it is pleasantly surprising that in the process of preparing oxazole-ring and five-membered ring triazoles, since the reactant solubility is higher, the reactant conversion rate is high, and the side reactions are fewer; and thus, the method lowers the production cost, is beneficial to environmental protection and suitable for industrial production, and has great application value.

Description

technical field [0001] The present invention relates to medicinal chemistry, in particular to a preparation method of medicine, in particular to a preparation method of macrolide drug solithromycin. Background technique [0002] Solithromycin (English name Solithromycin) is a new generation of macrolide antibiotics developed by Cempra Pharmaceuticals for the treatment of community-acquired bacterial pneumonia (CABP) and can also be applied to chronic obstructive pulmonary disease (COPD) , bacterial pneumonia and some infections, the drug is now in phase III clinical trials. Solithromycin is the first fluorine-substituted macrolide drug entering clinical practice. U.S. Chemical Abstracts Number CAS: 760981-83-7, has the chemical structure shown in the following formula I: [0003] [0004] WO2009055557 discloses a method for preparing solithromycin I using clarithromycin as a starting material. As shown in Reaction Formula 1, clarithromycin protects the sugar hydroxyl gr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/00C07H17/08C07H1/00
CPCC07H1/00C07H17/00C07H17/08
Inventor 徐辉郑飞黄悦雷平生赵哲辉
Owner ZHEJIANG JINGXIN PHARMA
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