CS240388B1 - Process for preparing 8-methylene-5-hydroxytetracycline - Google Patents

Abstract

A two-step process is described for the synthesis of the antibiotic 6-methylene-5-hydroxytetracycline from the starting material 11a-chloro-5-hydroxytetracycline-6,12-hemiketal without isolation of the intermediate product, which is the dehydration product of 11a-chloro-5-hydroxytetracycline, by dehydration of the starting material in liquid anhydrous hydrogen fluoride and reduction of the dehydration product with metallic zinc or sodium dithionite. The method according to the invention eliminates the need for isolation of 11a-chloro-6-methylene-5-hydroxytetracycline and the use of other chemicals (for example, toluenesulfonic acid), forming a salt with this product suitable for crystallization, and an approximately 15% higher yield is achieved.

Description

The invention relates to a method for preparing 6-methylene-5-hydroxytetracycline, which is an intermediate in the synthesis of the antibiotic deoxymycoin.

In the processes published so far (for example, J. Am. Chem. Soc., Vol. 85, 1963), 6-methylene-5-hydroxytetracycline (hereinafter substance C) was prepared from a suitable salt of 11a-chloro-6-methylene-5-hydroxy-tetracycline (hereinafter substance B) by reduction with sodium ditinate or metallic activated zinc. A disadvantage of the above processes is, among other things, the use of p-toluenesulfonic acid. Another disadvantage is the necessary isolation of the dehydration product, such as the p-toluenesulfonic salt, or as a hydroiodide. This reduces the yields of the final product, i.e. substance C.

The mentioned shortcomings of the previous processes are eliminated by the method of preparing 6-methylene-5-hydroxytetracycline by reduction of 11a-chloro-6-methylene-5-hydroxytetracycline, which is characterized in that the partially concentrated reaction mixture after dehydration of 11a-chloro-5-hydroxytetracycline-6,12-hemiketal is directly reduced to 6-methylene-5-hydroxytetracycline, which is isolated by a known procedure.

The method according to the invention allows obtaining the desired substance C in high yield and without isolating substance B, which is the product of dehydration of 11a-chloro-5-hydroxytetracycline-6,12-hemiketal (hereinafter substance A). This not only shortens the time of the entire synthesis, but above all reduces production costs and increases the yield of substance C by about 15 percent. The method according to the invention eliminates the use of p-toluenesulfonic acid, because the reaction mixture after dehydration of substance A in liquid anhydrous hydrogen fluoride is used directly for reduction after removal of excess hydrogen fluoride.

The method according to the invention is based on the possibility of performing dehydration of substance A in liquid anhydrous hydrogen fluoride at a temperature not exceeding +15 ^C C for the time necessary for quantitative dehydration to occur. The reaction mixture containing substance B and excess hydrogen fluoride with reaction water is suitably freed from part of the hydrogen fluoride and, after dilution with methanol or water, used for reduction. Reduction on zinc takes place in a strongly acidic environment of mineral acid, or also with sodium dithionite, in which case complete removal of the dehydrating agent is necessary. After reduction, the final substance C obtained is isolated from the reaction mixture either as sulfosalicylate or hydrochloride. The following scheme shows the synthesis procedure:

substance b substance u

11a-chloro-5-hydroxy tetracycline-6,12- hemlketal dehydration --¼ ratation 11-a-cChloro-6-. rnethylene-5- hydroxytetra- reduced- 6-methylene-5-hyd- rnxytetracycline > what- cycling -----~-~J

The reduction of substance B takes place in the crude reaction mixture both in an aqueous medium and in an organic solvent medium (most often methanol); for acidification, it is advantageous to use residual hydrogen fluoride after anhydrization, or other mineral acids, for example hydrochloric acid.

The following examples of embodiments only illustrate the method according to the invention, but are not intended to limit it in any way.

Example 1

30 ml of liquid anhydrous hydrogen fluoride was introduced into a 250 ml polyethylene reactor placed in an ethanol-solid carbon dioxide bath and the temperature of the dehydrating agent was reduced to -30 °C while stirring. After reaching this temperature, 11 g of 11a-chloro-5-hydroxytetracycline-6,12-hemiketal (substance A) was introduced into the hydrogen fluoride; the rate of introduction is limited by the increase in temperature inside the reactor and should not exceed the boiling point of the reaction mixture (19 °C). After the entire charge of substance A was introduced, the temperature of the reaction mixture was reduced to 0 °C using a bath and maintained at this value throughout the dehydration; under the given conditions, 3 hours are required for good dehydration. After this time, the bath temperature was raised to 35 °C and the excess hydrogen fluoride was evaporated using vacuum suction so that the original content of the reaction mixture was reduced to 1/3 of the volume. The concentrated reaction mixture was then diluted with 60 ml of methanol and after cooling to 0 °C, 8 g of zinc dust activated with 4% hydrochloric acid were added with very intensive stirring. The reduction with zinc then takes place at a temperature of up to 20 °C and a pH of less than 1.5 for approximately 1 hour; the rate of reduction of chlorine from the molecule of substance B can be influenced to a large extent by the intensity of stirring of the reaction mixture, i.e. by eliminating diffusion phenomena and, above all, by moving the reduction to the kinetic region. After the reduction was completed, the zinc was sucked off (filtered off), washed on the filter with 10 ml of methanol into the filtrate and 11 g of sulfosalicylic acid was dissolved in the filtrate. After diluting this solution with 440 ml of distilled water and stirring for 1 hour, yellow 6-methylene-5-hydroxytetracycline sulfosalicylate (12 g) crystallizes. After filtering off the mother liquors, the product was washed with anhydrous acetone, which releases colored impurities, until the filtrate runs colorless. Yield: 6-methylene-5-hydroxytetracycline sulfosalicylate (substance Cj.

Example 2

The dehydration process is identical to that of Example 1, the reduction is carried out in an aqueous medium. The reaction mixture after anhydrization and hydrogen fluoride discoloration is diluted with 440 ml of distilled water and 66 ml of methanol and 8 g of activated zinc powder are added with intensive stirring. The process is governed by the dependencies described in Example 1, the pH of the reaction mixture is maintained at a value of less than 1.5 by the addition of concentrated hydrochloric acid (approx. 4 ml of 37% MCI). After the reduction is completed and the zinc is filtered off, 11 g of crystalline sulfosalicylic acid is added to the filtrate with stirring and after 1 hour of stirring, the crystallized 6-methylene-5-hydroxytetracycline sulfosalicylate is processed in the same way as in Example 1.

Example 3

The dehydration process is identical to that of Example 1, the reduction is carried out with sodium dithionite (Na2S2O4). After anhydrification and removal of hydrogen fluoride, the reaction mixture is diluted according to Example 2, 8 g of Na2S2O4 is then added with stirring, the reduction is in this case very fast due to the homogeneity of the reaction mixture, usually 10 minutes with gentle stirring is sufficient. The crystallization process and product processing are identical to Example 2.

Claims (1)

SUBJECT Process for the preparation of 6-methylene-5-hydroxytetracycline by dehydration of 11a-chloro-5-hydroxytetracycline-6,12-hemiketal to 11α-chloro-6-methylene-5-hydroxytetracycline in liquid anhydrous hydrogen fluoride and reduction after partial or complete removal of the deVYNALEZ hydrating agent after dehydration of 11α-chloro-5-hydroxytetracycline-6,12-hemiketal, characterized in that, after dehydration, the reaction mixture is directly reduced to 6-methylene-5-hydroxytetracycline which is isolated.