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Preparation method of rifabutin intermediate

A technology for rifabutin and intermediates, which is applied in the field of preparation of rifabutin intermediates, can solve problems such as uneven properties, unfavorable industrialization, and difficulty in stratification, and achieves easy preservation, easy industrialization, and non-corrosive preservation. Effect

Inactive Publication Date: 2019-03-01
CHONGQING HUABANGSHENGKAI PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Synthesis of 3-bromorifamycin S according to the above-mentioned technical process has the following problems: 1) a large amount of insoluble matter is produced in the reaction solution, and the TLC spot plate (dichloromethane:methanol=8:2) shows More impurities ; 2) when the reaction solution was extracted with dichloromethane Severe emulsification heavy, not easy to layer , is not conducive to industrialization; 3) the concentrated product is thick, Uneven traits ;4) low yield , about 70.5%, The purity is not high , the HPLC content is about 94.3%, and its HPLC detection result is as shown in Figure 1

Method used

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  • Preparation method of rifabutin intermediate

Examples

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Effect test

Embodiment 1

[0045] A kind of preparation of rifabutin intermediate 3-bromorifamycin S

[0046] Add 3 g of potassium bromate, 30 g of potassium bromide, and 80 g of water into the three-necked flask, and stir to dissolve. Then add 90 g of ethyl acetate and 10 g of rifamycin S, continue stirring to dissolve completely, and lower the temperature to 10°C. Add 20 g of 30% sulfuric acid solution dropwise, drop it in 1-2 hours, and react at 40°C for 8 hours after dropping. They were washed with 2% sodium bicarbonate solution, 2% hydrochloric acid solution and saturated brine respectively, 150 g of n-hexane was added to the organic layer, the temperature was lowered to 10° C., and the crystallization was stirred for 3 h. Suction filtration, dry, obtain 3-bromorifamycin S10.2g, yield is 88.3%, HPLC content is 98.90%, the HPLC detection result of gained 3-bromorifamycin S is as shown in Figure 2, detection wavelength 254nm.

Embodiment 2

[0048] A kind of preparation of rifabutin intermediate 3-bromorifamycin S

[0049] Add 3 g of potassium bromate, 15.0 g of potassium bromide, and 70 g of water into the three-necked flask, and stir to dissolve. Then add 90 g of ethyl acetate and 10 g of rifamycin S, continue stirring to dissolve completely, and lower the temperature to 5°C. 45g of 20% sulfuric acid solution was added dropwise, and the drop was completed in 1-2 hours, and reacted at about 25°C for 3 hours after the drop was completed. Wash with 2% sodium thiosulfate solution, 1% sulfuric acid solution and saturated brine respectively, add 150 g of n-heptane to the organic layer, lower the temperature to 7° C., stir and crystallize for 2.5 h. After suction filtration and drying, 9.8 g of 3-bromorifamycin S was obtained, the yield was 91.2%, and the HPLC content was 98.85%. The HPLC detection result of the obtained 3-bromorifamycin S is shown in FIG. 3 .

Embodiment 3

[0051] A kind of preparation of rifabutin intermediate 3-bromorifamycin S

[0052] Add 3 g of potassium bromate, 3 g of potassium bromide, and 80 g of water into the three-necked flask, and stir to dissolve. Then add 90 g of ethyl acetate and 10 g of rifamycin S, continue stirring to dissolve completely, and lower the temperature to 0°C. Add 50 g of 30% hydrochloric acid solution dropwise, drop it in 1-2 hours, and react at -5°C for 1 hour after dropping.

[0053] They were washed with 2% sodium carbonate solution, 1% hydrochloric acid solution and saturated brine respectively, 12 g of isopropyl ether was added to the organic layer, the temperature was lowered to -5°C, and the mixture was stirred and crystallized for 2 h. After suction filtration and drying, 10.0 g of 3-bromorifamycin S was obtained with a yield of 90.1% and an HPLC content of 98.25%. The HPLC detection results of the obtained 3-bromorifamycin S are shown in FIG. 4 .

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Abstract

The invention belongs to the technical field of organic chemical synthesis, and in particular relates to a preparation method of a rifabutin intermediate. The intermediate is 3-bromo rifamycin S. Themethod includes adding potassium bromate and potassium bromide to water for dissolving, then adding ethyl acetate and rifamycin S, cooling, acidifying, conducting heat preservation reaction, washing,adding a solvent, cooling for crystallization and drying to obtain the 3-bromo rifamycin S. The preparation method has the advantage that raw materials are easy to obtain, the difficulty in transporting and preserving bromine is avoided, the reaction condition is mild, the initiation and the termination are easy, the operation is simple, the yield is high, the product purity is high, and the industrialization is easy.

Description

technical field [0001] The invention belongs to the technical field of organic chemical synthesis, and in particular relates to a preparation method of a rifabutin intermediate. Background technique [0002] 3-Bromorifamycin S is an intermediate in the synthesis of rifabutin. Rifabutin, whose chemical name is 4-N-isobutylspiropiperidine rifamycin S, is a rifamycin derivative containing a spiropiperazinyl group, which has broad-spectrum antibacterial activity. Its mechanism of action is the same as that of rifampicin, it can form a stable combination with the β subunit of DNA-dependent RNA polymerase of microorganisms, inhibit the enzyme activity, and thus inhibit the synthesis of bacterial RNA. It has been approved abroad for the prevention and treatment of the widely disseminated infection of Mycobacterium avium-Mycobacterium intracellulare complex (MAC) in HIV-infected patients, and also for the treatment of multidrug-resistant tuberculosis. [0003] [0004] Regardin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/08
CPCC07D498/08
Inventor 陈磊莫彬谭涛陈永流
Owner CHONGQING HUABANGSHENGKAI PHARM
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