Preparation method of erythromycin 6,9 imino ether

A technology of erythromycin and imine ether, applied in the field of pharmaceutical preparation, can solve the problems of material loss, numerous operation steps and the like

Active Publication Date: 2013-09-25
TOPFOND PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has many steps and is easy to cause material loss

Method used

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  • Preparation method of erythromycin 6,9 imino ether
  • Preparation method of erythromycin 6,9 imino ether

Examples

Experimental program
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Effect test

Embodiment 1

[0019] (1) Add 100g of methanol, 40g of hydroxylamine hydrochloride, 45g of sodium acetate, and 100g of erythromycin thiocyanate into a 500ml reaction bottle, heat up to 40-70°C, and react for 24-72 hours.

[0020] (2) HPLC monitors that the erythromycin content is less than 0.5%. After the reaction is over, add 100ml of deionized water dropwise, add 300ml of dichloromethane, add sodium hydroxide solution, adjust the pH=9 to 12, let stand to separate and discard water layer.

[0021] (3) Add 400ml of water and 20g of sodium bicarbonate to the dichloromethane layer, stir and cool down to 0-10°C, add the dichloromethane solution of p-toluenesulfonyl chloride (dissolve 40g of p-toluenesulfonyl chloride in 50ml of dichloromethane ), temperature control 0-10°C, reaction for 1.5-2.5 hours, acetic acid to adjust pH=5.0-6.0, standing to separate layers, adding sodium hydroxide solution to the water layer to adjust pH=9.0-12.0, filtering, drying at 60-90°C for 2 After ~5 hours, 74 g o...

Embodiment 2

[0023] (1) Add 110g of ethanol, 45g of hydroxylamine hydrochloride, 36g of sodium bicarbonate, and 100g of erythromycin thiocyanate into a 500ml reaction bottle, heat up to 40-70°C, and react for 24-72 hours.

[0024] (2) HPLC monitors that the erythromycin content is lower than 0.5%. After the reaction is over, add 100ml dropwise to drinking water, add 300ml dichloroethane, add sodium hydroxide solution, adjust pH=9~12, let stand for stratification, discard Remove the water layer.

[0025] (3) Add 300ml of water and 23g of sodium bicarbonate to the dichloroethane layer, stir and cool down to 0-10°C, add methanesulfonyl chloride in dichloroethane (32g of methanesulfonyl chloride dissolved in 40ml of dichloroethane middle), temperature control at 0-10°C, reaction for 1.5-2.5 hours, standing for stratification, adding sodium hydroxide solution to the water layer to adjust pH=9.0-12.0, filtering, drying at 60-90°C for 2-5 hours, and obtaining 6 , 9 imine ether 74g, HPLC purity 9...

Embodiment 3

[0027] (1) Add 110g of methanol, 42g of hydroxylamine hydrochloride, 36g of sodium bicarbonate, and 100g of erythromycin thiocyanate into a 500ml reaction flask, heat up to 40-70°C, and react for 24-72 hours.

[0028] (2) HPLC monitors that the content of erythromycin is less than 0.5%. After the reaction is over, add 300ml of chloroform and ammonia solution to adjust the pH to 9-11, let the mixture stand for separation, and discard the water layer.

[0029] (3) Add 400ml of water to the chloroform layer, heat up to 60-70°C, distill at normal pressure until the fraction temperature is 70-75°C, stop distillation, and cool down to room temperature.

[0030] (4) Add 300ml acetone and 15g sodium bicarbonate to the cooled reaction solution, stir and cool down to 0-10°C, add p-toluenesulfonyl chloride acetone solution (40g p-toluenesulfonyl chloride is dissolved in 120ml acetone), temperature control 0-10°C, react for 1.5-2.5 hours, add sodium hydroxide solution to adjust pH = 9.0-1...

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Abstract

The invention discloses a preparation method of erythromycin 6,9 imino ether. The method comprises the following steps: 1) with lower alcohols as reaction solvents, erythromycin thiocyanate reacts with hydroxylamine to generate thiocyanate salts of erythromycin; 2) water and water-immiscible low-polar organic solvents are added dropwise into the reaction mixture when the content of erythromycin detected with HPLC is less than 0.5%, lye is added into the mixture, after the mixture is fully mixed, to achieve a pH between 9 and 12, the mixture is allowed to stand to stratify, and a water layer is removed; 3) mesyl chloride or toluene sulfochloride is added into an organic layer for reactions of the Beckman arrangement to generate erythromycin 6,9 imino ether. The method provided by the invention simplifies operations by removing extraction of erythromycin oxime and salts of erythromycin oxime, and thus the conversion rate of erythromycin is improved and the cost of production equipment and energy is reduced. By means of the technology provided by the invention, the weight yield and the HPLC purity of erythromycin 6,9 imino ether synthesized by erythromycin thiocyanate can achieve more than 72% and more than 92% respectively.

Description

technical field [0001] The invention relates to medicine preparation, in particular to a new method for preparing an antibiotic azithromycin intermediate erythromycin 6,9 imine ether. Background technique [0002] Erythromycin 6,9 imine ether, chemical name: (3R, 4R, 5S, 6R, 9R, 10S, 11S, 12R, 13R, 15R)-10-[2,6-dideoxy-3-C-3 -O-methyl--α-L-nucleo-hexapyranosyl)oxy]-6-ethyl-4,5-dihydroxy-3,5,9,11,13,15-hexamethyl- 12-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xyl-hexapyranosyl]oxy]-7,16-dioxa-2-azacyclo [11,2,1]hexadecan-1-en-8-one, American Chemical Abstracts registration number CAS: 99290-97-8, its structural formula is: [0003] [0004] Erythromycin 6,9 imine ether is the key precursor for the synthesis of azithromycin. At present, the synthesis of erythromycin 6,9 imine ether mainly takes erythromycin thiocyanate (I) or erythromycin as raw material to synthesize and extract erythromycin oxime salt (II) and erythromycin oxime (III), Then carry out Beckmann rearrangemen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/00C07H1/00
Inventor 王俊臣陈彦龙张卫民王媛焦国华孟利沙藏文生任清华王振兵
Owner TOPFOND PHARMA CO LTD
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