A method for preparing rifamycin O, an intermediate of rifaximin

Abstract

This invention discloses a method for preparing rifamycin O, an intermediate of rifaximin, in the field of organic synthesis. The method uses rifamycin B as a starting material, and rifamycin O is obtained by oxidative coupling under the action of a solvent and a catalyst; the catalyst is a FeCl3 / Al2O3 solid oxidant. This invention uses FeCl3 / Al2O3 solid oxidant to oxidize rifamycin B to prepare rifamycin O. The oxidative coupling reaction conditions are mild, the post-processing is simple, the process cycle is short, and the yield and product purity are high, making it suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing rifamycin O, an intermediate of rifaximin. Background Technology

[0002] Rifamycins are used to treat tuberculosis and are more effective than isoniazid and streptomycin, making them highly sought after due to market demand. However, a drawback is the ease with which bacteria develop resistance. Therefore, finding new rifamycin derivatives to combat drug-resistant bacteria is a key direction for the chemical modification of rifamycin products. Rifamycin O (CAS: 14487-05-9) is a key intermediate in the preparation of the non-aminoglycoside intestinal antibiotic rifaximin, as shown in the following formula:

[0003]

[0004] Currently, there are few domestic reports on the oxidation process for synthesizing rifamycin O from rifamycin B. A 2007 report in *Chemical World* described the synthesis of rifamycin O from rifamycin B by oxidation with sodium nitrate solution, but the yield and purity were low, and the amount of saline wastewater was large, which is not conducive to industrial production. Therefore, it is necessary to improve the existing oxidation preparation methods for rifamycin O to solve the above problems. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing rifamycin O, an intermediate of rifaximin, with improved yield and purity. The process is simple, scalable, environmentally friendly, and suitable for industrial production.

[0006] To achieve the above-mentioned objectives, the preparation method of rifaximin intermediate rifamycin O of the present invention adopts the following technical solution:

[0007] A method for preparing rifamycin O, an intermediate of rifaximin, is disclosed, which uses rifamycin B as a starting material and prepares rifamycin O by oxidative coupling under the action of a solvent and a catalyst; wherein the catalyst is a FeCl3 / Al2O3 solid oxidant.

[0008] Preferably, the synthesis circuit is as follows:

[0009]

[0010] Preferably, the steps include:

[0011] (1) Preparation of catalyst by impregnation method: After grinding Al2O3 support into fine powder, it is added to FeCl3 aqueous solution, stirred evenly, and then the water is removed by vacuum evaporation. After drying, FeCl3 / Al2O3 solid oxidant is obtained.

[0012] (2) Oxidative coupling reaction: Rifamycin B and solvent were added to the reaction vessel and stirred to dissolve. FeCl3 / Al2O3 solid oxidant was added, and argon gas was introduced for protection. The reaction was carried out in an oil bath, filtered, the filtrate was decolorized, the solvent was removed by vacuum evaporation, and then recrystallized in toluene to obtain the product rifamycin O.

[0013] Preferably, the filter cake obtained after filtration in step (2) is washed with tetrahydrofuran, dried, calcined, oxidized with H2O2, evaporated under reduced pressure, and dried under vacuum to obtain a regenerated solid oxidant.

[0014] Preferably, the solvent is a weakly polar solvent, and the solvent is one or more of xylene, toluene, and chlorobenzene.

[0015] Preferably, the concentration of FeCl3 in the FeCl3 solution is 5%-20%.

[0016] Preferably, the concentration of FeCl3 in the FeCl3 solution is 10%.

[0017] Preferably, the reaction concentration of rifamycin B is 0.1–0.5 M.

[0018] Preferably, the reaction concentration of rifamycin B is 0.2M.

[0019] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0020] (1) The oxidation catalyst used in this invention is FeCl3 / Al2O3 solid oxidant, which can oxidize rifamycin B to rifamycin O with a high yield;

[0021] (2) FeCl3 / Al2O3 solid oxidant is easy to prepare and has stable performance, and can be recycled and reused;

[0022] (3) The oxidative coupling reaction conditions are mild, the post-processing is simple, the process cycle is short, the product purity is high, and it is suitable for industrial production.

[0023] (4) It reduces the discharge of three wastes, which is more conducive to environmental protection. Attached Figure Description

[0024] Figure 1 The NMR spectrum of rifamycin O prepared in Example 1;

[0025] Figure 2 The image shows the HPLC chromatogram of rifamycin O prepared in Example 1. Detailed Implementation

[0026] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. After reading the present invention, any modifications of the present invention in various equivalent forms by those skilled in the art will fall within the scope defined by the appended claims.

[0027] Example 1

[0028] (1) Take 475 g of Al2O3 carrier and grind it to 200 mesh. Add it to 1250 g of FeCl3 aqueous solution, where the concentration of FeCl3 in the FeCl3 solution is 10%. Then, stir evenly and let stand for 24 h. Stir for 10-15 min, evaporate to dryness in a water bath at 80℃, and vacuum dry for 8 h under vacuum conditions of ≤0.95MPa and 150℃ to obtain 490 g of FeCl3 / Al2O3 solid oxidant.

[0029] (2) Add 75.5 g of 0.1 mol rifamycin B and 500 mL of toluene to a three-necked flask. After stirring and dissolving completely, add 382 g of FeCl3 / Al2O3 solid oxidant. Probe with argon gas for protection and react in an oil bath. Then filter. After filtration, filtrate and filter cake are obtained. The filter cake is regenerated and treated. The filtrate is decolorized and the solvent is removed by vacuum evaporation. The obtained solid substance is recrystallized in toluene to obtain 72.9 g of yellow rifamycin O crystals, with a yield of 95%.

[0030] The steps for the post-regeneration treatment of the above filter cake are as follows: the filter cake after filtration is washed with tetrahydrofuran, dried and then calcined in a muffle furnace at 400℃ for 2 hours. It is then oxidized with 5 times its weight of H2O2, evaporated under reduced pressure, and then vacuum dried at 150℃ and a vacuum degree ≤0.95MPa for 8 hours to obtain the regenerated solid oxidant.

[0031] Example 2

[0032] (1) Take 475 g of Al2O3 carrier and grind it to 200 mesh. Add it to 1250 g of FeCl3 aqueous solution, where the concentration of FeCl3 in the FeCl3 solution is 20%. Then, stir evenly and let stand for 24 h. Stir for 10-15 min, evaporate to dryness in a water bath at 80℃, and vacuum dry for 8 h under vacuum conditions of ≤0.95 MPa and 150℃ to obtain 490 g of FeCl3 / Al2O3 solid oxidant.

[0033] (2) Add 0.1 mol rifamycin B (75.5 g) and 500 mL xylene to a three-necked flask. After stirring and dissolving completely, add 360 g of FeCl3 / Al2O3 solid oxidant. Probe with argon gas for protection and react in an oil bath. Then filter, decolorize the filtrate, evaporate the solvent under reduced pressure, and recrystallize the obtained solid in toluene to obtain 70.6 g of yellow rifamycin O crystals, with a yield of 92%.

[0034] The steps for the post-regeneration treatment of the above filter cake are as follows: the filter cake after filtration is washed with tetrahydrofuran, dried and then calcined in a muffle furnace at 400℃ for 2 hours. It is then oxidized with 5 times its weight of H2O2, evaporated under reduced pressure, and then vacuum dried at 150℃ and a vacuum degree ≤0.95MPa for 8 hours to obtain the regenerated solid oxidant.

[0035] Example 3

[0036] (1) Take 475 g of Al2O3 carrier and grind it to 200 mesh. Add it to 1250 g of FeCl3 aqueous solution, where the concentration of FeCl3 in the FeCl3 solution is 15%. After stirring evenly, let it stand for 24 h, then stir for 10-15 min, evaporate it by rotary evaporation in a water bath at 80℃, and vacuum dry it for 8 h under vacuum conditions of ≤0.95MPa and 150℃ to obtain 490 g of FeCl3 / Al2O3 solid oxidant.

[0037] (2) Add 0.1 mol rifamycin B 75.5 g and 200 mL chlorobenzene to a three-necked flask. After stirring and dissolving completely, add 382 g of FeCl3 / Al2O3 solid oxidant. Probe with argon gas for protection and react in an oil bath. Then filter, decolorize the filtrate, evaporate the solvent under reduced pressure, and recrystallize the obtained solid in toluene to obtain 69.1 g of rifamycin O yellow crystals, with a yield of 90%.

[0038] The steps for the post-regeneration treatment of the above filter cake are as follows: the filter cake after filtration is washed with tetrahydrofuran, dried and then calcined in a muffle furnace at 400℃ for 2 hours. It is then oxidized with 5 times its weight of H2O2, evaporated under reduced pressure, and then vacuum dried at 150℃ and a vacuum degree ≤0.95MPa for 8 hours to obtain the regenerated solid oxidant.

[0039] Figure 1 The NMR spectrum of rifamycin O prepared in Example 1 is shown below. Figure 2 The HPLC chromatogram of rifamycin O prepared in Example 1 is shown below. The corresponding chromatogram analysis is as follows:

[0040] Figure 1 Analysis: 1 H NMR (400MHz, CDCl3) δ: 1.45 (s, 9H), 1.64, 1.55 (m, 12H, 2.05 (m, 2H), 3.5 (brs, 1H), 5.27 (d, J = 8.8Hz, 2H).

[0041] Figure 2 Analysis: mp 177~179℃; purity 99.9%, tR = 11.01 min [HPLC normalization method: Chiralpak AD-H column (4.6 mm × 250 mm, 5 μm), mobile phase V] 异丙醇 ∶V 正己烷 =20:80, detection wavelength 215nm, flow rate 1mL / min, column temperature 35℃.

[0042] As can be seen from Example 1, the new process adopted in this invention has a high synthesis yield, high purity, simple operation, low waste, and is easy to industrialize.

[0043] The above description is merely a preferred embodiment of this application and is not intended to limit this application.

Claims

1. A process for the preparation of a rifaximin intermediate, rifamycin O, characterized by, The rifamycin B is used as a starting material, and a rifamycin O is prepared by oxidative coupling under the action of a solvent and a catalyst; the catalyst is a FeCl3 / Al2O3 solid oxidant; the preparation method comprises the following steps: (1) catalyst preparation by impregnation method: after the Al2O3 carrier is finely ground, it is added into a FeCl3 aqueous solution, stirred uniformly, and then water is evaporated under vacuum, and the FeCl3 / Al2O3 solid oxidant is obtained after drying; (2) oxidative coupling reaction: the rifamycin B and a solvent are added into a reaction container, the solvent is one or more of dimethylbenzene, toluene and chlorobenzene; after stirring and dissolving, the FeCl3 / Al2O3 solid oxidant is added, argon is introduced for protection, reaction is carried out in an oil bath, filtration is carried out, the filtrate is decolorized, the solvent is evaporated under reduced pressure, then the product rifamycin O is obtained by recrystallization in toluene; After the filtration in step (2), the filter cake is washed with tetrahydrofuran, dried, calcined, then treated by oxidation with H2O2, evaporated under reduced pressure, and dried under vacuum, to obtain the regenerated solid oxidant.

2. The process for the preparation of rifaximin intermediate rifamycin O according to claim 1, characterized by, The synthesis line is as follows: 。 3. The process for the preparation of rifaximin intermediate rifamycin O according to claim 1, characterized by, The concentration of FeCl3 in the FeCl3 solution is 5%-20%.

4. The process for the preparation of rifaximin intermediate rifamycin O according to claim 3, characterized by, The concentration of FeCl3 in the FeCl3 solution is 10%.

5. The process for the preparation of rifaximin intermediate rifamycin O according to claim 1, characterized by, The reaction concentration of the rifamycin B is 0.1-0.5M.

6. The process for the preparation of rifaximin intermediate rifamycin O according to claim 5, characterized by, The reaction concentration of the rifamycin B is 0.2M.

Images