DE1132918B - Process for the preparation of 12a-bromo-anhydrotetracyclines - Google Patents

Description

Process for the preparation of 12a-bromo-anhydrotetracyclines In the line of the recently discovered class of antibiotics comes the compound of the formula because of their valuable therapeutic properties. The total synthesis of this compound has not yet been successful.

It has now been found that 12a-bromoanhydrotetracyclines in the Way can be prepared that one unsubstituted anhydrotetracyclines in the 12a-position treated with N-bromo acid amides or imides.

The bromination of the tetracyclic compounds is expedient carried out in solvents. Only such solvents are advantageously used Compounds in question that are resistant to bromine. As such, lower ones are aliphatic Chlorinated hydrocarbons such as carbon tetrachloride, tetrachloroethane, chlorinated aromatic hydrocarbons such as o-dichlorobenzene, trichlorobenzene, and others Compounds such as nitrobenzene and glacial acetic acid should be mentioned. The implementation is expedient carried out at elevated temperature. However, it can also be used at room temperature be performed. Usually one works in the temperature range between approx 40 and 100 ° C. It is a particularly simple implementation of the method in which Use of low molecular weight chlorinated aliphatic hydrocarbons as solvents to work in the boiling range of the solvent. The response time depends on the temperature and, in general, the longer the lower the temperature chosen will.

Examples of tetracyclic compounds include: desdimethylaminoanhydrodesoxytetracycline, desdimethylaminoanhydrodeoxytetracycline monomethyl ether, and desdimethylaminoanhydrotetracycline dimethyl ether. The tetracychic compounds of the type are particularly suitable for the process according to the invention where R ,. Hydrogen or chlorine, R, and R3 are hydrogen or an alkyl radical, in particular a low molecular weight alkyl radical, such as methyl or ethyl, R4 is hydrogen or a hydroxyl group.

As N-bromo derivatives of acid amides or acid imides come above all Things the bromine compounds of phthalimide, acetamide and especially des Succinimids in question. It is advisable to use a catalytically active one during the reaction add a small amount of a peroxide, for example dibenzoyl peroxide.

The resulting bromine derivatives of the tetracyclic compounds can by washing the reaction solution several times with water and evaporating the solvent, are advantageously isolated in solid form in vacuo under nitrogen. Next to the Introduction of a bromine atom in the 12a-position are in the Carrying out the reaction according to the invention in the 1-position existing oxy groups converted into oxo oxygen atoms. The connections can be cleaned by loosening of the distillation residue and adsorption of the solution on silica gel.

When a bromine atom is introduced according to the present invention at the carbon atom 12a of the tetracyclic structure, the two sterically possible forms arise next to one another. Adsorption on silica gel generally results in their separation. Example 1 Desdimethylaminodeoxy-12 a-bromoanhydrotetracycline monomethyl ether 510 mg of N-bromosuccinimide and a trace of dibenzoyl peroxide are added to a solution of 1 g of desdimethylamino-12a-deoxyanhydrotetracycline monomethyl ether in 400 cc of boiling carbon tetrachloride, and the mixture is heated to 60 to 70 ° C. for 35 minutes while stirring. After cooling, the reaction mixture is washed several times with water, the organic phase is dried over sodium sulfate and the solvent is distilled off in vacuo in a nitrogen atmosphere.

The residue obtained is dissolved in a small amount of a mixture of chloroform and benzene (1: 1) and the solution is adsorbed on an acidic silica gel column. When washing with the solvent mixture mentioned above, a yellow zone quickly migrates through the column. It is followed by a broad yellow zone, the eluate of which, when concentrated, 650 mg of the crystallized 12a-bromine compound of the formula results. The compound turns dark on heating to 170 ° C and melts with decomposition at 202 to 210 ° C. The UV absorption in methanol is Amax 390 to 398 m # t (s = 6200), 268 to 270 mp. (s = 43500), 223 m # t (s = 34000). Example 2 1 g of desdimethylamino-12a-deoxyanhydrotetracycline 10-methyl ether is stirred in 150 cc of glacial acetic acid with 690 mg of 86% N-bromophthalimide for 35 minutes at 65 to 70.degree. The solution is then diluted with 800 ccm of water and the yellow amorphous precipitate is filtered off with suction. The filter residue is washed with water and dried in a desiccator. The yield is 1.11 g of crude product. The dry crude product is then dissolved in a mixture of chloroform-benzene-butanol (500: 500: 1) and chromatographed on silica gel. A yellow and a red-brown zone run quickly through the column, the eluates of which are discarded. This is followed by a third, dark yellow zone, the eluate of which, after the solvent has been stripped off, gives 775 mg (70.7% of theory) of the 12a-bromine compound. Melting point and mixed melting point with the authentic compound: 202 to 210 ° C with a dark color above 170 ° C. Example 3 If, in the reaction described above, the equivalent amount of N-bromoacetamide is used instead of N-bromophthalimide under otherwise identical reaction conditions, 388 mg of the 12α-bromine compound are obtained, which melts above 170 ° C. at 202 to 210 ° C. with a dark color . The mixed melting point with samples prepared using N-bromosuccinimide or -phthalimide shows no depression.

Claims (1)

PATENT CLAIM: Process for the production of 12a-bromo-anhydrotetracychnen, characterized in that there are unsubstituted anhydrotetracyclines in the 12a position treated with N-bromo acid amides or imides.