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Method for preparing solithromycin

A technology of solithromycin and compounds, applied in the field of preparation of macrolide drug solithromycin, capable of solving problems such as unsuitable 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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  • Method for preparing solithromycin
  • Method for preparing solithromycin
  • Method for preparing solithromycin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Preparation of Intermediate II:

[0083] ①Preparation of Compound A

[0084]

[0085]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 under vacuum at 50° C. to obtain 56 g of compound A as a white solid.

[0086] ESI[M+1]:852

[0087] ②Preparation of Compound B

[0088]

[0089] 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 m...

Embodiment 2

[0117] Preparation of compound III by fluorination reaction

[0118] The sugar hydroxyl protecting group is acetyl

[0119]

[0120] 2.05 g of acetyl-protected compound II (2.90 mmol) was dissolved in 20 ml of DMF / THF mixed solution (9:1), and at -20°C, 0.39 g of potassium tert-butoxide (3.48 mmol) was added in batches, After 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, 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 ...

Embodiment 3

[0122] Preparation of compound V by docking reaction

[0123]

[0124] 1.33 g of compound III (1.84 mmol) and 2.44 g of I (7.36 mmol) were dissolved in 20 ml of acetonitrile / water mixture (10:1), and heated to reflux overnight. The next day, the reaction solution was cooled to room temperature, spin-dried directly, and the residue was subjected to column chromatography (silica gel 200-300 mesh, Qingdao Huanghai) (dichloromethane:methanol=30:1) to obtain V crude product (directly used in the following step).

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Abstract

The invention provided a method for preparing solithromycin. The method comprises the following steps: a compound II is subjected to a fluorination reaction, so that a compound III is produced, and the compound III docks with an amino group in a side chain of a compound IV five-member ring triazole (1-(4-aminobutyl)-4-(3-protected aminophenyl)-1H-1,2,3-triazole), so that a compound V containing an oxazole ring is formed; and the compound V is subjected to corresponding de-protection or reduction to form an amino group, so that solithromycin I is obtained. The method for preparing the solithromycin gets rid of easy-explosion dangerous oxidation and fluorination reactions of azido intermediates in the prior art, and reaction operation is more safe; and it is surprised that when the oxazole ring triazole and the five-member ring triazole are prepared, solubility of reactants is high, so that the conversion rate of the reactants is high, side reactions are less, and the production cost is reduced. The method facilitates environmental protection, is suitable for industrialized production, and has a large application value.

Description

technical field [0001] The invention relates to medicinal chemistry, in particular to a method for preparing medicine, in particular to a new method for preparing 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 group th...

Claims

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Application Information

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IPC IPC(8): C07H17/00C07H17/08C07H1/00
CPCY02P20/55C07H17/00C07H1/00C07H17/08
Inventor 徐辉郑飞黄悦雷平生赵哲辉
Owner ZHEJIANG JINGXIN PHARMA
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