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O-alkyl macrolide, azalide derivatives and their regioselective preparation process

A regioselective, azalide technology, used in sugar derivatives, organic chemistry, etc.

Inactive Publication Date: 2008-04-16
GLAXOSMITHKLINE ISTRAZIVACKI CENTAR ZAGREB D O O (HR)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Additionally, regioselective O-alkylation of the 11-hydroxyl groups of macrolides and azalides using diazoalkanes in the presence of transition metal halides or boronic acids has not been reported in the prior art.

Method used

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  • O-alkyl macrolide, azalide derivatives and their regioselective preparation process
  • O-alkyl macrolide, azalide derivatives and their regioselective preparation process
  • O-alkyl macrolide, azalide derivatives and their regioselective preparation process

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] 11-O-Methyl-Azithromycin

[0087] Method I

[0088] Azithromycin (75 g, 0.1 mol) and boric acid (3.1 g, 0.05 mol) were dissolved in absolute ethanol (300 mL), and then the yellow condensate of diazomethane (about 0.27 mol) obtained by method A was continuously added dropwise to the reaction in the mixture. The mixture was stirred at room temperature for 6 hours. A few drops of acetic acid were added to remove excess diazomethane. Ether was removed under reduced pressure, then ethanol was evaporated to a volume of 200 mL. The product was precipitated out by adding 400 mL of water. The crude product was dried in a vacuum oven at 40° C. for 12 hours. The yield was 87%. Crystallization of the product using ethanol / water afforded 100% pure (LC-MS analysis) 11-O-methyl-azithromycin in 73% yield.

[0089] ES-MS: m / z 763.2(M+H), 605.3(M+H-cladinose)

[0090] 1 H NMR (500MHz, CDCl 3 ): δ (ppm) 3.59 (s, 3H, 11-OMe), 3.42 (d, 1H, 11-H), 3.25 (dd, 1H, 2′-H), 3.03 (t, 1H...

Embodiment 2

[0098] 11-O-Methyl-2′-O,3′-N-Dibenzyloxycarbonyl-Azithromycin

[0099] 2'-O, 3'-N-dibenzyloxycarbonyl-azithromycin (J. Antibiotics 45 (1992) 527-534) (0.204g, 0.203mmol) and TiCl 4 (0.040g, 0.210mmol) was dissolved in DMF (5mL) and stirred at room temperature for 1 hour. A solution of diazomethane prepared by method B in diethyl ether (about 4 mmol) was added and the resulting mixture was stirred at room temperature for 6 hours. Use NaHCO 3 The mixture was diluted with aqueous solution (50 mL) and extracted with ethyl acetate (3 x 30 mL). Use Na 2 SO 4 The organic layer was dried and concentrated to obtain the title compound.

[0100] ES-MS: m / z 1017.3(M+H), 859.4(M+H-cladinose)

Embodiment 3

[0102] 11-O-Methyl-9-deoxy-9a-aza-9a-homoerythromycin

[0103] 9-deoxy-9a-aza-9a-homoerythromycin (J.Chem.Soc.Perkin Trans.1(1986)1881-1890) (1.00g, 1.36mmol) and H 3 BO 3 (0.084g, 1.36mmol) was dissolved in acetonitrile (20mL) and stirred at room temperature for 1 hour. A solution of diazomethane prepared by method B in diethyl ether (about 6 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours. Use NaHCO 3 The mixture was diluted with aqueous solution (50 mL) and extracted with ethyl acetate (3 x 30 mL). Use Na 2 SO 4 The organic layer was dried and concentrated to obtain the target compound (0.813 g, yield 80%).

[0104] ES-MS: m / z 749.6(M+H), 591.5(M+H-cladinose)

[0105] 1 H NMR (500MHz, CDCl 3 ): δ (ppm) 3.56 (s, 3H, 11-OMe), 3.43 (d, 1H, 11-H), 3.30 (dd, 1H, 2′-H), 3.03 (t, 1H, 4″-H )

[0106] 13 C NMR (125MHz, CDCl 3 ): δ (ppm) 84.3 (11-C), 78.1 (4″-C), 70.9 (2′-C) 62.4 (11-OMe)

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PUM

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Abstract

The present invention relates to novel 11-O-alkyl macrolides and azalides, their pharmaceutically acceptable salts and solvates, and also to pharmaceutical compositions thereof. The disclosure of the present invention also relates to a method for preparing 11-O-alkyl macrolides and azalides by using diazoalkanes containing ortho-diols under the conditions of transition metal halides or boric acids as catalysts. Systemic macrolides and azalides undergo regioselective 11-O-alkylation reactions. In another aspect, the present disclosure also relates to the use of 11-O-alkyl macrolides and azalides as antibacterial agents, or as intermediates in the synthesis of other antibacterial agents.

Description

technical field [0001] In one aspect, the present invention relates to a process enabling the regioselective O-alkylation of macrolides and azalides on a large scale. In particular, the present invention relates to the regioselective 11-O-alkane synthesis of macrocyclic lactones and azalides containing vicinal diol systems using diazoalkanes in the presence of transition metal halides or boronic acids as catalysts. Kylation reaction. In another aspect, the present invention relates to 11-O-alkyl macrolides and azalides prepared according to the above method, their pharmaceutically acceptable salts and solvates, and their use as antibacterial agents or as synthetic other The application of intermediates of antibacterial agents. Background of the invention [0002] O-alkyl derivatives of some macrolide and azalide antibiotics have been disclosed in the literature. Among these compounds, O-methyl derivatives of erythromycin (clarithromycin) (US Patent 4,331,803) and azithrom...

Claims

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Application Information

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IPC IPC(8): C07H17/00C07H17/08
CPCC07H17/00C07H17/08
Inventor 达沃尔·基德梅特戈雅纳·拉扎尔夫斯基马尔科·德里克马里加·勒雅克
Owner GLAXOSMITHKLINE ISTRAZIVACKI CENTAR ZAGREB D O O (HR)
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