JPS6241673B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel industrial method for producing rifampicin. Rifuampicin is a useful substance that exhibits excellent antituberculous activity and is widely used as a tuberculosis treatment agent. The method for producing rifampicin has been described in patent publications as described in Japanese Patent Publication No. 42-26800.
Publication No. 47-23303, Special Publication No. 53-
A method described in Publication No. 39400 and the like is known. However, none of the manufacturing methods described in these patent publications are satisfactory for use on an industrial scale. Specifically, Japanese Patent Publication No. 42-26800 describes a method for producing rifampicin by reacting 3-formyl rifamycin SV with 1-amino-4-methylpiperazine. −
In order to obtain formyllifamycin SV, complicated operational steps are required, and due to equipment problems and yield problems, it cannot be said to be a satisfactory industrial manufacturing method. Publication No. 23303 describes a method in which rifamycin S is converted into a Mannitz base, then oxidized to obtain a Schiff base, and then the quinone-type Schiff base is reduced, and then the hydroxyquinone Schiff base is transiminated. However, this is also not suitable as an industrial production method due to the complexity of the operational steps and low yield. In particular, even though the manganese dioxide used in the oxidation reaction mentioned above is a trace amount, it is
Since contact with amino-4-methylpiperazine causes an explosion, this separate step is essential in this process, which is also not entirely satisfactory. In addition, special public relations
Publication No. 39440 describes rifamycin S as (In the formula, R ¹ is a lower alkyl group, a lower alkenyl group, a cycloalkyl group having 5 to 6 carbon atoms, a phenyl group, a benzyl group, or an α- and β-phenethyl group, and R ² is hydrogen or a lower alkyl group. A method is described which consists of treatment with a compound of However, it is difficult to reliably obtain the substance represented by the above formula using the method described in this publication. For example, when R ² is a lower alkyl group, the desired yield and purity cannot be achieved. It is not possible to obtain substances that
If R ² is hydrogen, the production method itself is not disclosed at all in this publication, so it is impossible to carry out, and the method described in this publication cannot be called an industrial method at all. .

The present inventors have conducted intensive research into a method that can reliably obtain rifuapicin with higher yield and purity than these conventional methods, and have found that rifamycin S and the general formula: (In the formula, R represents hydrogen or a lower alkyl group) is reacted with 1,3-oxazolidine in the presence of an organic acid, and then the reaction product and 1
It has been found that rifampicin can be produced in good yield by reacting it with -amino-4-methylpiperazine.

That is, the present invention involves reacting rifamycin S with a 1,3-oxazolidine represented by the above formula () in the presence of an organic acid, and reacting the reaction product with 1-amino-4-methylpiperazine. The present invention provides a method for producing rifampicin. The present invention will be explained in detail below.

The method of the present invention consists of first reacting rifamycin S with a 1,3-oxazolidine represented by the above formula ().
1 to 1,3-oxazolidine per 1 mole
It is suitable to use 3.5 mol, preferably 1.1 to 3.3 mol. This reaction is carried out in the presence of an organic acid, and it is desirable to maintain the pH during the reaction in the range of 5.5 to 6.8. Preferred examples of the organic acids used include weak acids such as acetic acid and oxalic acid.

Suitable solvents are aprotic polar solvents, such as dimethylformamide, dimethylacetamide or dimethylsulfoxide.

To carry out the method of the present invention, rifamycin S, the compound of the above formula and the above organic acid are usually added to a solvent, which is maintained at 45-55°C. The reaction solution will gradually turn blue. Usually, most of the raw material rifamycin S in the reaction solution is completely reacted within 2 to 3 hours. This can be determined by confirming the disappearance of rifamycin S by thin layer chromatography.

Next, 1-amino-4 was added to the obtained reaction solution.
- Addition of methylpiperazine and holding at a temperature of 50-90°C produces rifampicin. This reaction usually completes in 1 to 5 hours.

Note that when the reaction solution turns blue, the blue substance present in the reaction solution is once isolated, and the blue substance is added to the solvent and 1-amino-4 is added to the solvent.
- The reaction may be carried out with methylpiperazine.
Different blue substances can be obtained depending on the type of R in formula (), that is, the alkyl group, and the physical properties of these substances are shown in the reference examples below.

The rifampicin produced in this way can be obtained by, for example, mixing the reaction solution with water under weakly acidic conditions, and then extracting it using a suitable organic solvent that is immiscible with water.
It can be isolated by distilling off the organic solvent. The isolated rifampicin is purified by conventional methods, such as by recrystallization.

The 1,3-oxazolidines of the above formula (), which are one of the raw materials for the method of the present invention, are manufactured by, for example, Bretan Société Simique France (Bull.Soc.
Chim. Fr.) 1967, No. 2, p. 571, it can be easily produced.

Using 1,3-oxazolidines represented by the above formula () and adjusting the pH of the above reaction solution.
Maintaining the ratio within the range of 5.5 to 6.8 is an important characteristic of the method of the present invention, and these characteristic requirements not only increase the reaction rate, but also suppress the formation of by-products and produce the desired rifampicin. The yield can be improved.

The method of the present invention will be explained below using Examples and Reference Examples, but the present invention is not limited to these Examples.

Example 1 15g of rifamycin S was dissolved in dimethylformamide.
Dissolve in 100 ml, add 1.94 g of oxalic acid, and add 7.2 g of 4,4-dimethyl-1,3-oxazolidine.
g was added thereto, and the mixture was stirred at 50°C for 2 hours. This reaction product was then treated with 1-amino-4-methylpiperazine.
8.25g was added dropwise and stirred at 90°C for 1.5 hours. The reaction mixture was then diluted with a large amount of chloroform,
This is washed with 2% acetic acid water and then repeatedly washed with water. Then, after drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure. Dissolve the obtained red crystalline powder in a small amount of chloroform,
When n-hexane was added to this for precipitation, red crystals of crude rifampicin were obtained. When this was recrystallized from acetone, 14.5 g of rifampicin was obtained (yield 81.7%). The melting point, infrared absorption spectrum, NMR spectrum, and thin layer chromatograph R _f value of this material were consistent with those of the standard rifampicin.

Example 2 9g of rifamycin S was dissolved in dimethylformamide
Dissolve in 90ml, add 1.16g of oxalic acid, and add 3.93g of 4,4-dimethyl-1,3-oxazolidine.
g was added thereto, and the mixture was stirred at 55°C for 3 hours. After dropwise addition of 4.95 g of 1-amino-4-methylpiperazine, 90
Stirred at ℃ for 1 hour. Next, this reaction mixture is diluted with a large amount of chloroform, washed with 2% acetic acid water, and then washed repeatedly with water. Next, after drying it over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 6.9 g of red crystalline powder of crude rifampicin. When this was recrystallized from acetone, 6.48 g of rifapicin was obtained (yield 61%). The melting point, infrared absorption spectrum, and thin layer chromatographic R _f value of this substance were consistent with those of the standard rifupicin.

Example 3 15g of rifamycin S was dissolved in dimethylacetamide.
The mixture was dissolved in 100 ml, 1.94 g of oxalic acid was added thereto, 7.2 g of 4,4-dimethyl-1,3-oxazolidine was further added thereto, and the mixture was stirred at 50°C for 3 hours. Next, 8.25 g of 1-amino-4-methylpiperazine was added dropwise, followed by stirring at 90°C for 2 hours. The reaction mixture was then diluted with large amounts of chloroform and then
After washing with 2% acetic acid water, repeated washings with water were performed.
Then, after drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a red powdery substance as a residue. When this was recrystallized from acetone, 13.2 g of rifampicin was obtained (yield:
74.4%). The melting point, infrared absorption spectrum, and thin layer chromatograph R _f value of this material were consistent with those of the standard rifampicin.

Example 4 10g of rifamycin S in dimethylformamide
The mixture was dissolved in 60 ml of water, 1.292 g of oxalic acid was added thereto, 3.46 g of 1,3-oxazolidine was further added, and the mixture was stirred at 50°C for 3 hours. Next, 5.46 g of 1-ammino-4-methylpiperazine was added dropwise to the reaction mixture while cooling it in an ice-water bath, and the mixture was stirred at 90°C for 3 hours. Next, this reaction mixture was diluted with a large amount of chloroform, washed with 2% aqueous acetic acid, and then repeatedly washed with water. Then, after drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, leaving a red material. When this was recrystallized from acetone, 7.08 g of rifampicin was obtained (yield 59.8%). The melting point, infrared absorption spectrum, and thin layer chromatograph R _f value of this substance were consistent with those of the standard rifampicin.

Reference example 1 15g of rifamycin S in dimethylformamide
Dissolve in 100ml, add 3.25g of oxalic acid, and add 12g of 4.4-dimethyl-1,3-oxazolidine.
was added and stirred at 50°C for 2 hours. This reaction mixture was diluted with a large amount of chloroform, washed with 2% aqueous acetic acid, and then repeatedly washed with water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure and the residue was treated with chloroform-n-hexane to give 28.7 g of a blue powdery substance.
was gotten. The melting point of this product was 185-186.5°C, and its infrared absorption spectrum showed characteristic absorption lines at 1735, 1670, and 1600 cm ^-1 (KBr) in the carbonyl region. In addition, its ultraviolet absorption spectra are 224, 275 (inf), 312, 344 in methanol.
(inf), showed maximum absorption at 445 and 590 nm. Also, in the thin layer chromatography of this substance, R
_{The f} value was 0.55 (15% methanol-chloroform).

Reference example 2 9g of rifamycin S in dimethylformamide
75 ml, add 1.16 g of oxalic acid and 0.783 g of paraformaldehyde, and then add 4.4-dimethyl-
3.93 g of 1,3-oxazolidine was added and stirred at 50°C for 3 hours. The reaction mixture was diluted with a large amount of chloroform, washed with 2% aqueous acetic acid, and then repeatedly washed with water. It was then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was treated with chloroform-n-hexane to yield 9.24 g of a blue powder material. The melting point, infrared absorption spectrum, ultraviolet absorption spectrum, and R _f value in thin layer chromatography of this substance matched those of the blue substance obtained in Reference Example 1.

Claims (1)

[Claims] 1. Rifamycin S and general formula (In the formula, R represents hydrogen or a lower alkyl group) is reacted with 1,3-oxazolidine in the presence of an organic acid, and then the reaction product and 1-amino-4-methylpiperazine are reacted. A method for producing rifampicin, which comprises reacting.