JPS6241672B2 - - 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 is as follows:
Conventionally, methods described in Japanese Patent Publication No. 42-26800, Japanese Patent Publication No. 47-23303, Japanese Patent Publication No. 53-39400, etc. are known. However, none of the manufacturing methods described in these patent publications can be carried out on an industrial scale.
This is not a satisfactory method. In other words, the special public official
Publication No. 26800 describes 3-formyllifamycin
A method for producing lianpicin by reacting SV with 1-amino-4-methylpiperazine has been described, but in order to obtain the raw material 3-formyllifamycin SV, complicated operational steps are required. However, it cannot be said to be a satisfactory industrial production method due to equipment problems and yield problems, and Japanese Patent Publication No. 47-23303 discloses that rifamycin S is converted into a Mannitz base and then oxidized to form a Schiff A method has been described in which a base is obtained, a quinone-type Schiff base is further reduced, and then a hydroxyquinone Schiff base is transiminated, but this method also has the disadvantages of complicated operational steps and low yields. It is not suitable as an industrial manufacturing method. In particular, even if the manganese dioxide used in the oxidation reaction mentioned above is a trace amount, it is 1-amino-
Since contact with 4-methylpiperazine causes an explosion, this separate step is essential in this process, which is also not entirely satisfactory. In addition, in Japanese Patent Publication No. 53-39440, rifamycin S is formulated 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 cause R ²
When is hydrogen, the production method itself is not disclosed at all in this publication, and therefore the method described in this publication cannot be called an industrial method.

The present inventors have conducted extensive research on a method that can reliably obtain rifampicin with higher yield and purity than these conventional methods, and have found that rifampicin S and the general formula: (In the formula, R represents an alkyl group) is reacted with 1,3-di-alkyl-1,3-diaza-5-oxacyclohexane 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 combines rifamycin S and 1.3
- a rifampicin produced by reacting di-alkyl-1,3-diaza-5-oxacyclohexane in the presence of an organic acid, and reacting the reaction product with 1-amino-4-methylpiperazine. It provides a manufacturing method. The present invention will be explained in detail below.

In the method of the present invention, first, rifamycin S and 1,3-di-alkyl-1,3-diaza-5-oxacyclohexane represented by the above formula () are reacted. It is appropriate to use 1 to 2 moles of 1,3-dialkyl-1,3-diaza-5-oxacyclohexane, preferably 1.2 to 1.5 moles, per mole of rifamycin S. This reaction is carried out in the presence of an organic acid, and the pH of the reaction solution is 5.5 to 6.8.
It is desirable to keep it within this range. 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 process of the present invention, rifamycin S, a compound of the above formula and the above organic acid are usually added to the solvent and maintained at a temperature of 45-55°C. The reaction solution gradually turns 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 50-55°C produces rifampin. This reaction usually completes in 2 to 5 hours.

Note that when the reaction solution turns blue, the blue substance present in the reaction solution is once isolated, the blue substance is added to a solvent, and 1-amino-
The reaction may also be carried out with 4-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 recrystallization.

1,3-di-alkyl-1,3-diaza-5-oxacyclohexane of the formula (), which is one of the raw materials for the method of the present invention, is available from, for example, the Journal of Chemical Society Perkin (J.
Chem.Soc.Perkin), p. 377, 1978. The alkyl groups at the 1st and 3rd positions of the compound of this formula may be linear, branched or cyclic alkyl groups.

1,3-di-alkyl- represented by formula ()
The use of 1,3-diaza-5-oxacyclohexane and the maintenance of the pH of the reaction solution in the range of 5.5 to 6.8 are important features of the method of the present invention. Not only can the reaction rate be increased, but also the production of by-products can be suppressed, and the yield of the target rifampicin 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 20 g of rifamycin S was dissolved in 80 ml of dimethylformamide, 7 g of glacial acetic acid was added thereto, and further 5.8 g of 1,3-di-t-butyl-1,3-diaza-5-oxacyclohexane was added. Stirred at 50°C for 2 hours. To this reaction mixture was added 14.4 g of 1-
Add amino-4-methylpiperazine and further heat to 50°C.
The mixture was stirred for 4 hours. The resulting reaction mixture was diluted with a large amount of methylene chloride, washed with 2% aqueous acetic acid, washed repeatedly with distilled water, dried over magnesium sulfate, and then diluted under reduced pressure.
When the solvent was distilled off, a red crystalline powder was obtained. This was purified by silica gel column chromatography and recrystallized from acetone to obtain 20.8 g of rifampicin. Yield 88%. The melting point, infrared spectrum, NMR spectrum, and thin layer chromatograph Rf value of this material were consistent with the authentic standard of rifampicin.

Example 2 2.5 g of rifamycin S was dissolved in 10 ml of dimethylformamide, and 0.25 g of glacial acetic acid and
Add 750 mg of 1,3-di-n-butyl-1,3-diaza-5-oxacyclohexane and heat at 50°C for 2.5
Stir for hours. After adding 1.8 g of 1-amino-4-methylpiperazine to the reaction mixture and further stirring 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 diluted with distilled water several times. After washing with water and drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a red crystalline powder. When this was purified by silica gel column chromatography and then recrystallized from acetone, 2.5g
of rifampicin was obtained. Yield 85%. The melting point, infrared absorption spectrum, NMR spectrum, and Rf value of the thin layer chromatograph of this substance were consistent with the authentic standard of rifampicin.

Example 3 2.5 g of rifamycin S was dissolved in 10 ml of dimethylformamide, and 0.25 g of glacial acetic acid and
0.75 g of 1,3-dicyclopentyl-1,3-diaza-5-oxacyclohexane was added and stirred at 50°C for 2 hours. Then add 1.8 g of 1 to the reaction mixture
- Add amino-4-methylpiperazine for another 50
After stirring at ℃ for 4 hours, the reaction mixture was diluted with a large amount of chloroform, washed with 2% aqueous acetic acid, washed several times with distilled water, dried over magnesium sulfate, and evaporated under reduced pressure to give a red color. A crystalline powder was obtained. When this was purified by silica gel column chromatography and then recrystallized from acetone, it became 2.4
g of rifampicin was obtained. Yield 84%. The melting point, infrared absorption spectrum, NMR spectrum, and Rf value of this product in thin layer chromatography were consistent with the standard product of rifampicin.

Reference example 1 20 g of rifamycin S was dissolved in 80 ml of dimethylformamide, and 7 g of glacial acetic acid and 5.8
g of 1,3-t-butyl-1,3-diaza-5-
Oxacyclohexane was added and stirred at 50°C for 2 hours. The reaction solution was diluted with chloroform, washed with 2% aqueous acetic acid and then distilled water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a deep blue crystalline powder. This was further purified by silica gel column chromatography to obtain 18 g of a blue substance. This substance was confirmed to be a single substance by silica gel thin layer chromatography. Yield 77%, melting point
183-185℃. The visible/ultraviolet absorption spectrum (in methanol) of this material includes 223, 275, 358 and
Maximum absorption is shown at 603 nm (logε4.58, 4.32, 4.28 and 4.00), and the infrared absorption spectrum (in chloroform) is 3450, 1725, 1660, 1580, 1560,
It showed characteristic absorption at 1525, 1460, 1378, 1070, and 975 cm ^-1 . In addition, the NMR spectrum (in deuterochloroform) showed characteristic peaks at δ8.84, 14.56, and 16.40 (ppm). According to mass spectrometry using the FD method, the molecular weight (molecular ion) of this blue substance is m/
The e-value was 792.

Reference example 2 Dissolve 2.5 g of rifamycin S in 10 ml of dimethylformamide, add 0.25 g of glacial acetic acid and
Add 0.75 g of 1,3-di-n-butyl-1,3-diaza-5-oxacyclohexane at 50°C.
Stirred for 2.5 hours. The reaction mixture was then diluted with chloroform, washed with 2% aqueous acetic acid and distilled water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a blue crystalline powder. This was further purified by silica gel column chromatography to obtain 3.2 g of a blue substance. yield
69%. This substance exhibits a melting point of 156-158°C, and its visible/ultraviolet absorption spectrum (in methanol) is
223, 272, 358 and 595nm (logε4.55, 4.30,
4.24 and 4.01), and the NMR spectrum (in deuterochloroform) is δ8.65,
Characteristic peaks were shown at 14.55 and 16.50 (ppm).

Reference example 3 Dissolve 2.5 g of rifamycin S in 10 ml of dimethylformamide, add 0.25 g of glacial acetic acid and
Add 0.75 g of 1,3-dicyclopentyl-1,3-diaza-5-oxacyclohexane and heat at 50℃ for 2 hours.
Stir for hours. The reaction mixture was then diluted with methylene chloride, washed with 2% aqueous acetic acid, then with distilled water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a blue-green powder. This was purified by silica gel column chromatography to obtain 2.5 g of a blue substance. Yield 88%. The melting point of this blue substance is 178.5-180℃, and its visible/ultraviolet absorption spectrum (in methanol)
shows maximum absorption at 226, 312, 356, 420, 486 and 566 nm, and the infrared absorption spectrum is 3450,
It showed characteristic absorption at 1730, 1650, 1540, 1460, 1370, 1230, 1065 and 975 cm ^-1 . The NMR spectrum (in deuterated chloroform) showed characteristic peaks at δ8.84, 14.80 and 16.52 (ppm).

Reference example 4 2.5 g of rifamycin S was dissolved in 10 ml of dimethylformamide, and 0.5 g of oxalic acid and 0.81
g of 1,3-dicyclopentyl-1,3-diaza-5-oxacyclohexane was added thereto, and the mixture was stirred at 50°C for 2.5 hours. The reaction mixture was then diluted with methylene chloride, washed with 2% aqueous acetic acid, then with distilled water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a blue-green powder. This was purified by silica gel column chromatography to obtain 2.55 g of a blue substance. Yield 89%. The melting point visible/ultraviolet absorption spectrum of this blue substance,
The infrared absorption spectrum and NMR spectrum were the same as those obtained in Reference Example 3.

Claims (1)

[Claims] 1 Rifamycin S and general formula, (In the formula, R represents an alkyl group) is reacted with 1,3-di-alkyl-1,3-diaza-5-oxacyclohexane in the presence of an organic acid, and then the reaction product is A method for producing rifampicin, which comprises reacting rifampicin with 1-amino-4-methylpiperazine.