KR800000907B1 - Process for preparing rifamycin compounds - Google Patents

Abstract

Rifamycin compds. [I; R=H or COCH3 and their 16, 17, 18, 19-tetrahydro deriv. or 16, 17, 18, 18, 28, 29-hexahydro derivs. charcaterized by the solubility in most organic solvents and partic. effective on Mycobacterium Tuberculosis were prepd. by reacting a compd. of II in an ether or aromatic hydrocarbon at 0-30≰C with gaseous NH3 and isolating.

Description

Method of Preparation of Rifamycin Compound

The present invention relates to a rifamycin compound of formula (I) having a high antibacterial activity, a 16,17,18,19 tetrahydro derivative thereof, and a method for preparing 16,17,18,19,28,29 hexahydro derivative.

In the above structural formula

R is hydrogen or -COCH ₃ .

German Patent No. 1,670,377 describes 3-amino-rifamycin S and its 16,17,18,19 tetrahydro derivatives and 16,17,18,19,28,29 hexahydro derivatives of the following formula (II): . This compound also exhibits antimicrobial activity.

In the above structural formula

R is -COCH ₃ .

The process for the preparation of the compound of formula (II) has been put to practical use by the present applicant and described in German Patent Application Publication No. 2,548,148.

16,17,18,19 tetrahydro derivatives and 16,17,18,19,28,29 hexahydroderivatives can be obtained from rifamycin compounds, respectively, and the performance of these derivatives is comparable to that of rifamycin compounds. Methods for preparing such derivatives are obvious to the expert and are described, for example, in the above mentioned German Patent No. 1,670,377 and Experientia 20, 336 (1964).

The compound of formula (I) according to the present invention is reacted by reacting 3-amino-rifamycin S of formula (II) with gaseous ammonia in ether and / or aromatic hydrocarbons at a temperature of 0 ° to 30 ° C. for at least 3 hours. The obtained compound is produced by liberation.

The compound of formula (I) was reduced under mild conditions at room temperature with zinc in acetic acid or iron in acetic acid, and then separated from the reaction mixture to give the compound of formula (III) and its 16,17,18,19 tetrahydro Derivatives and 16, 17, 18, 19, 28, 29 hexahydro derivatives are prepared.

In the above structural formula

R represents hydrogen or a -COCH ₃ group. Aromatic hydrocarbons include ethylene glycol, dimethyl ether, tetrahydrofuran, dioxane or benzene. The temperature is preferably + 15 ° C to + 25 ° C and preferably 15 to 20 hours.

The rifamycin compound according to the present invention has a strong antibacterial action against gram positive bacteria and gram negative bacteria and is particularly effective against tuberculosis bacteria.

Rifamycin compounds according to the invention are rosy powders, insoluble in water, soluble in most organic solvents such as chlorinated solvents, alcohols, ethers, partially soluble in aromatic hydrocarbons and crystallized therefrom.

In order to clearly understand the features of the present invention, the compounds and preparations thereof are described in the following examples, which do not limit the scope of the present invention.

Example 1

20 g of 3-amino-rifamycin S are dissolved in 100 ml of tetrahydrofuran saturated with ammonia gas at 20 ° C. The solution is stirred at room temperature for 15 hours without further ammonia. 200 ml of dichloromethane is added to the reaction solution, washed thoroughly with dilute acetic acid and again with mole. The organic layer is dehydrated over sodium sulfate and the solvent is removed under reduced pressure. The residue is recrystallized from 2-methoxyethanol.

Yield: 17 g

The characteristics of the obtained product are as follows:

Visual formula: C ₃₇ H ₄₇ N ₃ O ₁₁ (by elemental analysis)

Infrared spectrum peaks (Nuzol oil of the product obtained with dichloromethane) 3,400 (shoulder), 3300,1705,1650,1605, 1582, 1560 (shoulder), 1512, 1425, 1355, 1290, 1265, 1240 (shoulder), 1175, 1142, 1071, 1050, 1020 (Shoulder), 970, 952, 920, 890, 840, 815 772 cm ^-1

Peaks in the electron absorption spectrum (in methanol solution) 475, 310, 270 235 nm;

-Peak of ¹ HNMR spectrum (in CDCl ₃ -CD ₃ SOCD ₃ (1: 1) using tetramethylsilane as internal standard) (the most significant peak)

delta: -0.04 (d); +0.66 (d); +0.92 (d); +1.02 (d); +1.81 (s); +2.07 (s); +2.31 (s); +3.08 (s); +5.09 (dd); +5.25 (d); + 5.8 / 6.7 (m); +8.70 (s); +14.13 (s) and 15.13 (s) ppm and the last 3 peaks are characteristic of disappearance in the presence of deuterated water.

Peak in ¹³ CNMR spectra (in dioxane-d ₈ using tetramethylsilane as internal standard) (the most significant peak)

δ: 197.4; 184.7; 172.6; 172.4; 170.8 and 170.6 ppm (Compared with similar spectra of compounds of formula (II), it can be seen that the product is a compound of formula (I) wherein R is -COCH ₃ )

Thin layer chromatography (on silica gel plates)

Eluent: benzene-methylisobutylketone-methanol (5: 5: 1)

R _f value: 0.74

Example 2

Dissolve 28 g of 3-amino-rifamycin S in 200 ml dioxane and add ammonia stream slowly and continuously at 15 ° C. for 10 hours. The solution is further stirred at 15 ° C. for 10 hours. The resulting precipitate is filtered off, washed with a small amount of cold dioxane, again with xylene and finally with petroleum ether.

Yield: 20 g

The obtained product has the same chemical and physical properties as the product of Example 1.

Example 3

21 g of 3-amino-rifamycin S is dissolved in 150 ml of dioxane at 23 ° C. and saturated with ammonia gas. The solution is stirred at 23 ° C. for 15 hours, saturated with ammonia gas and finally stirred for another 3 hours. 200 ml of dichloromethane is added, washed with dilute acetic acid and then with water. After dehydration over sodium sulfate, the solvent is evaporated under reduced pressure and the residue is recrystallized from 2-methoxyethanol.

Yield: 16.8 g

Also in this case, the obtained product is the same as the compound obtained in Example 1.

Example 4

14 g of the product obtained in Examples 1, 2 and 3 are mixed with 2 g of zinc, 60 ml of acetic acid and 50 ml of dioxane are added followed by stirring. After 15 minutes excess zinc is filtered off and precipitated in 300 ml of water containing 5 g of EDTA and 30 g of sodium chloride. The reaction product is filtered again, washed with water and dried. Yield: 11 g

The product obtained is a reduced form of starting material. The electron absorption spectra in the methanol solution show peaks at 415 and 300 nm. The same final product can be obtained by reacting the same reaction conditions using iron in acetic acid instead of zinc in acetic acid as a reducing agent.

Example 5

10 g of 3-amino-25-disacetyl-rifamycin S is dissolved in 150 ml of tetrahydrofuran and the solution is left in a stream of ammonia gas at 7 ° C. for 4 hours. In the same manner as in Example 1, 9g of the product was obtained, and thin layer chromatography on a silica gel plate using benzene-methyl isobutylketone-methanol (5: 5: 1) eluent yielded an R _f value of 0.5. The formula of the obtained compound is C ₃₅ H ₄₅ N ₃ O ₁₈ .

Example 6

14 g of 3-amino-rifamycin S are dissolved in 70 ml of 27 g at 27 ° C. in styreneglycol dimethyl ether and exposed to a stream of slowly and continuously flowing ammonia gas for 15 minutes. After stirring for 3 hours, the solution was saturated with ammonia gas and further reacted at 27 ° C for 16 hours. The reaction mixture is diluted with 200 ml of dichloromethane, washed with dilute acetic acid and again with water. The reaction product is dehydrated with sodium sulfate, dichloromethane is evaporated and the residue is recrystallized from benzene.

Yield: 12.5 g

The product is the same as the product in Example 1.

Example 7

7 g of 3-amino-rifamycin S is mixed with 60 ml of benzene at 18 ° C. Ammonia gas is passed through for 10 minutes every hour for 10 minutes. The reaction mixture is diluted with 200 ml dichloromethane, washed with diluted acetic acid and washed again with water. The solution is dehydrated with sodium sulfate and evaporated to dryness. Recrystallization from 2-methoxyethanol yields 5.5 g of the same product as in Example 1.

Except when using 3-amino-16,17,18,19-tetrahydro rifamycin S and 3-amino-16,17,18,19,28,29-hexahydro rifamycin S as starting materials, 3-amino-4-desoxo corresponding to 3-amino-4-desoxo-4-amino-16,17,18,29-tetrahydro rifamycin S by the same method as identified in the previous example Obtain 4-amino-16,17,18,19,28,29-hexahydro rifamycin S. The compound thus obtained can be converted into the corresponding reduced product by the method according to example 4.

Claims (1)

A compound of formula (I) by reacting a compound of formula (II), 16,17,18,19-tetrahydro or 16,17,18,19,28,29-hexahydro derivative with ammonia gas in ether or aromatic hydrocarbon , 16,17,18,19-tetrahydro derivative or 16,17,18,19,28,29-hexahydro derivative thereof.

R in the above formula is hydrogen or -COCH ₃ .