Preparation method for rifamycin S derivative

A kind of technology of rifamycin, imino-rifamycin is applied in the field of preparing rifamycin S derivatives shown in formula I, and can solve the problem that the yield of rifamycin S derivatives is low and the reaction time is long. , low production efficiency and other problems, to achieve the effect of overcoming long reaction time, shortening reaction time and improving utilization rate

Active Publication Date: 2017-01-04
CHONGQING HUABANGSHENGKAI PHARM
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  • Claims
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Problems solved by technology

[0005] Document Journal of Inbelled Compounds and Radiopharmaceuticals-Vol.XXIV, NO.11.1347 also introduced in organic solvent, the derivative of 3-amino-4-imine rifamycin S, 4-piperidone and ammonium acetate/zinc The powders are mixed together and reacted at 5°C for 64 hours to obtain the corresponding rifamycin S derivatives. The reaction time of this method is too long and the production efficiency is low
[0006] Known from above-mentioned prior art, the method for preparing rifamycin S derivative commonly us...

Method used

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  • Preparation method for rifamycin S derivative
  • Preparation method for rifamycin S derivative
  • Preparation method for rifamycin S derivative

Examples

Experimental program
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Embodiment 1

[0044] Example 1 3-amino-4-imine rifamycin S was reduced and hydrolyzed under the action of zinc powder and ammonium acetate

[0045]Add 400ml of ethyl acetate, 2.2g of ammonium acetate, 2.2g of zinc powder, 30g (42.25mmol) of 3-amino-4-imine rifamycin S into the reactor, and react at 50°C-60°C for 24 hours. Filter, wash with 50ml of ethyl acetate, combine filtered solution, wash with 300ml of 15% aqueous hydrochloric acid solution, then wash with 300ml of 5% aqueous sodium carbonate solution, and finally wash with 300ml of water, dry over sodium sulfate, and concentrate the mother liquor to dryness in vacuo. Column chromatographic separation, eluting with a mixture of n-hexane and ethyl acetate (the volume ratio of n-hexane and ethyl acetate is 20:1), to obtain 3,4-diaminorifamycin S and 3-amino - 4-imino-25-hydroxyrifamycin S.

[0046] The imine at the 4-position of 3-amino-4-imine rifamycin S is reduced to 3,4-diamino rifamycin S, 3-amino-4-imine rifamycin under the action...

Embodiment 2

[0048] The preparation of embodiment 2 N-methyl-4-piperidone rifamycin S

[0049] Add 400ml of ethyl acetate, 2.2g of ammonium acetate, 2.2g of zinc powder, 7.3g (64.52mmol) of N-methyl-4-piperidone into the reactor, stir at 10°C-20°C for 10 minutes, then slowly add 3 -Amino-4-imine rifamycin S 30g (42.25mmol), after adding for 40 minutes, react at 20°C-30°C for 5 hours, filter, wash with 50ml of ethyl acetate, combine filter solution, and use 15% hydrochloric acid aqueous solution Wash with 300ml, then wash with 300ml of 5% aqueous sodium carbonate solution, and finally wash with 300ml of water, dry over sodium sulfate, concentrate and dry in vacuo, and recrystallize from isooctane to obtain 32.3g of N-methyl-4-piperidone rifamycin S , the calculated yield was 93.2%, and the HPLC detection content was 98.5%.

[0050] The chemical reaction is as follows:

[0051]

[0052] As industrialized production, in the production system (as shown in Figure 1), the production is magn...

Embodiment 34

[0054] Example 3 Preparation of 4-piperidone rifamycin S

[0055] Add 200ml of tetrahydrofuran, 6.6g of ammonium acetate, and 6.6g of zinc powder into the reactor, stir at 10°C-20°C for 10 minutes, slowly add 8.4g (84.50mmol) of 4-piperidone, 3-amino-4-imine Rifamycin S30g (42.25mmol), tetrahydrofuran 200ml solution, after 120 minutes, react at 10°C-20°C for 10 hours, filter, add 300ml of dichloromethane, wash with 300ml of 15% hydrochloric acid aqueous solution, and then wash with 5% Wash with 300ml of sodium carbonate aqueous solution, and finally wash with 300ml of water, dry over sodium sulfate, concentrate to dryness in vacuo, recrystallize from n-hexane to obtain 28.5g of 4-piperidone rifamycin S, the calculated yield is 85.3%, and the content detected by HPLC is 98.8 %.

[0056] The chemical reaction is as follows:

[0057]

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Abstract

The invention relates to a preparation method for a rifamycin S derivative. According to the preparation method, 3-amino-4-imine rifamycin S as shown in a formula II which is described in the specification and a 4-piperidone derivative as shown in a formula III which is described in the specification are added according to a certain feeding mode and subjected to a condensation reaction in the presence of an organic solvent, ammonium acetate and zinc dust so as to produce the rifamycin S derivative as shown in a formula I which is described in the specification. The feeding mode is that the 3-amino-4-imine rifamycin S is added into a reaction system in a final step, so 3-amino-4-imine rifamycin S is prevented from reduction and hydrolysis. The preparation method increases the utilization rate of materials and is shortened in reaction time, so high-efficiency high-yield preparation of the rifamycin S derivative is realized, and the yield and content of the rifamycin S derivative reach 80% or above and 95% or above, respectively; and the preparation method overcomes the problems of long reaction time, low yield, many impurities and high cost, and is simple to operate, highly efficient, environment friendly and beneficial for large-scale production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a method for preparing rifamycin S derivatives as shown in formula I. Background technique [0002] Rifamycin is a mixture isolated from the culture medium of Streptomyces mediterranei by Italian Lipeti Company in 1957 (5 components A, B, C, D, and E can be separated, the main component of which is rifamycin B ), the rifamycin SV transformed from its component rifamycin B (the first semi-synthetic rifamycin) is a highly effective antibiotic mainly against Gram-positive bacteria and Mycobacterium tuberculosis, and subsequently with Rifamycin SV is the mother nucleus to synthesize rifamycin S derivatives such as rifampicin, rifampin, rifabutin, rifaximin, rifapentine, and rifalazil, among which only rifamycin Forbutin and rifalazil are effective drugs against drug resistance and anti-AIDS. Rifabutin is a spiropiperidine derivative among rifamycin S derivatives, and its inhibito...

Claims

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Application Information

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IPC IPC(8): C07D498/22
CPCC07D498/22
Inventor 陈小舟
Owner CHONGQING HUABANGSHENGKAI PHARM
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