One-pot processing method for synthesizing rifampicin

A technology of rifampicin and rifamycin, which is applied in the field of preparation of semi-synthetic rifamycin antibacterial drugs, can solve the problems of affecting the quality of intermediates and finished products, affecting the quality of intermediates, and increasing the number of impurities, so as to save The effect of improving the quality of chemical raw materials and finished products and simplifying the process flow

Active Publication Date: 2005-11-02
薛荔 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Because this process is extracted under the strong acid condition of pH 1-2, the practice shows that the obtained rifamycin S undergoes thin-layer chromatography, and the impurity points increase significantly, which seriously affects the quality of the intermediate
In Chinese patent 1045993A, "a preparation method of rifamycin S sodium salt" is introduced. It is also oxidized

Method used

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  • One-pot processing method for synthesizing rifampicin
  • One-pot processing method for synthesizing rifampicin
  • One-pot processing method for synthesizing rifampicin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Get 2520ml of ethyl acetate solution containing rifamycin SV 17.2 million (gained after separation and purification by macroporous resin, 6830u / ml), add dropwise 182 grams of 7.84% sodium hypochlorite aqueous solution under stirring to carry out oxidation reaction, and the reaction solution is passed through thin Layer chromatography, the rifamycin SV point disappears, that is, the ethyl acetate oxidation solution of rifamycin S is generated, first washed with saturated saline, then deionized water, separated to remove the water phase, and the organic phase TLC showed One spot, recovered ethyl acetate, concentrated to dryness under reduced pressure, added 40ml of dimethylformamide to dissolve, added dropwise 8.7g of dimethylol terbutylamine under stirring, and reacted at 50°C for two hours to obtain N-tertbutyl- 1,3-oxazine[5,6-C]rifamycin, one spot on TLC. Recover dimethylformamide under reduced pressure to dryness. After the recovery is complete, add 60ml of n-butanol...

Embodiment 2

[0037] Get 12000ml (3584u / ml) of fermentation filtrate containing rifamycin SV 43 million, add 860ml butyl acetate, dropwise add 460 grams of sodium hypochlorite with a concentration of 7.8%, carry out oxidation reaction to generate rifamycin S, add dropwise under stirring Adjust the pH to 6.0 with 10% dilute hydrochloric acid, let it stand still, and measure that the aqueous phase contains rifamycin S below 30u / ml, separate the aqueous phase, and use 1% NaHCO for the organic phase 3 Wash with aqueous solution, and then wash with deionized water for several times, then recover butyl acetate, concentrate to dryness under reduced pressure, add 60ml of dimethylformamide to dissolve, add 17.7g of dimethylol terbutylamine dropwise under stirring, and react at 50°C for two N-tertidine-1,3-oxazine [5,6-C] rifamycin was obtained in 1 hour, dimethylformamide was recovered under reduced pressure to dryness, then 90 ml of n-butanol was added to dissolve, and 9.0 g of Morpholine, 12.24 gr...

Embodiment 3

[0039] Get 1066ml of butyl acetate solution containing rifamycin SV15.22 million (gained after separation and purification by macroporous resin, 14280u / ml), add dropwise 88 grams of 11.46% sodium hypochlorite aqueous solution under stirring to carry out oxidation reaction, and the reaction solution is passed through Thin layer chromatography shows a spot of rifamycin S, that is, the butyl acetate oxidation solution of rifamycin S is obtained, first washed with salt water, then washed with deionized water, separated to remove the aqueous phase, and organic phase thin layer chromatography A spot appeared, recovered butyl acetate, concentrated to dryness under reduced pressure, then added 35ml of dimethylformamide to dissolve, added dropwise 7.7g of dimethylol terbutylamine under stirring, and reacted at 50°C for two hours to obtain N-tert Buta-1,3-oxazine[5,6-C]rifamycin, one spot on TLC. Recover dimethylformamide under reduced pressure to dryness. After the recovery is complete...

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Abstract

The invention synthetics benemicin by means of strewed in one pan, solving basically the side reaction formed by using much of inorganic acid and alkali of prior art, it's based on isolated purified nancimycin SV as raw material, to oxygenate to nancimycin S by using sodium hypochlorite as oxidant, without crystallization separating nancimycin S sodium salt and the acidifying process by concentrated sulfuric acid, with direct ring jointing, hydrolyzing and condensation reacting, the intermediate to synthetic benemicin by means of strewed in one pan free of separation. It simplifies the process, decreases mating equipment, and meanwhile well controls each side reaction, for removing the use of inorganic base employ and controlling the dosage of hydrogenous acid, and the quality of intermediate be basically guaranteed, so the quality of product is perfect, and the yield of benemicin is improved. Moreover, morpholine used in the condensation reaction lowering the dosage of valuable raw material 1-methyl-4-amidogen vermex, so plenty of chemical materials are saved, energy consumption is lowered, and the cost decreases dramatically.

Description

technical field [0001] The present invention relates to a kind of preparation method of semi-synthetic rifamycin antimicrobial drug, especially a kind of rifamycin S S that takes separated and purified rifamycin SV as the starting material, uses sodium hypochlorite as oxidant to oxidize into rifamycin S, does not A method for synthesizing rifampicin by direct cyclization, hydrolysis and condensation reactions through rifamycin S-Na salt crystallization separation and concentrated sulfuric acid acidification process. Background technique [0002] Rifampicin is a semi-synthetic antibiotic of the rifamycin class and is an important anti-tuberculosis drug. In 1966, Maggi et al. from the Italian Leptit company successfully developed it by the semi-synthetic method. It was clinically completed in 1968 and officially put into production in 1969. my country successfully trial-produced it in 1972, and the domestic and foreign production methods are similar. It uses Nocardia mediterr...

Claims

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Application Information

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IPC IPC(8): C07D493/08
Inventor 薛守礼薛荔杜明山黄健杜雪青宋伶香
Owner 薛荔
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