SU650507A3 - Method of obtaining glycoside antibiotics or their hydrochlorides - Google Patents

Description

This invention relates to an improved method for producing glycosidic antibiotics or their hydrochlorides having valuable pharmacological properties.

A known method for producing 1 glycosidic antibiotic of general formula I

with glycal of formula I

n

n-o off

He to

n

R, 0

Otim

he

pine to

Thats

.he

he

about

-o GSnL

NIGHT NH

where R is hydrogen or its hydrochloride by reacting daunomycin with the general formula V

Hjco about he n he

in an anhydrous solvent, such as dioxane.

The disadvantages of this method are the duration of the process (over 200 hours) with a yield of the target product of about 50%. By the method of reacting adriamycinone with said glycal, it is also not possible to obtain adriamycin.

The aim of the invention is to intensify the process and increase the yield of the target product.

The goal is achieved by using a new glycal.

An improved method for the preparation of GLYCOSID antibiotics of general formula I is described.

where R is hydrogen or hydroxyl, by reacting an anthracyclinone of the general formula II

where Ri is a group - COCH (daupicinon) or (adriamytson)

UN, I-cn,

v °

with protected glycale 1,2,3,6-tetradeoxy-4-O-trifluoroacetyl-3-triftra, racetamido-iloxohex-1-ano-11 Pranozoic (III) in the presence of "-toluenesulfonic acid in an anhydrous solvent at 30-50 ° C, e and despreading NO-trifluoroacyl protecting groups and isolating the desired product as a base or hydrochloride.

The O-Trifluoroacetyl protecting group is usually removed by boiling with methanol;

K-trifluoroacetyl ziguignu group by alkaline hydrolysis; Absolute benzene is preferably used as a solvent. The reaction scheme can be represented as follows:

reaction scheme

oh he

1G +

he

W

 dDljHOflUifUHJ

oh ok he ochj

  R

..y V °

h SKZ SK,

oh he to he

(adriopitz uhohj

116

Example 1. Synthesis of daunomycin (RH).

200 g of daunomycinone (II) are dissolved in 100 ml of anhydrous benzene and treated with 320 mg of compound III in anhydrous benzene (5 ml) and 13 mg of l-toluene sulfonic acid. The mixture is heated at 50 ° C for 4 hours. After cooling and neutralization with pyridium; the solution is dry. The residue was dissolved in anhydrous metaiol (50 ml) and heated at 55 ° C for 1 hour. The solvent was removed by evaporation under vacuum and the residue was dissolved in chloroform. The solution is washed with water and dried with sodium sulfate, concentrated to a small volume and passed through a silica gel column, which is washed with chloroform containing added amounts of ethyl acetate. The yield is 145 mg (50%) of N-nitrofluoroacetyl daunomycin (IV), crystallized from tetrahydrofuran and hexane, m.p. 170-171 ° C;

 + 235 ° (s 0.1, СНС1з).

N-Trifluoroacetyl daunomycin (100 mg) is dissolved in 0.1N. an aqueous solution of sodium hydroxide (20 ml). After 1 h at room temperature, the solution is treated with 0.5 n. aqueous solution of hydrogen chloride to pH 8.5, then extracted with chloroform. The extract, dried with sodium sulfate, is concentrated to a small volume and by the addition of an equivalent of 1N. methylated hydrogen chloride get crystalline daunomycin (1a) in the form of the hydrochloride salt. The yield is 70 mg; m.p. 188-189 ° C (decomposition); + 240 ° (s 0.1, SNZON).

Example 2. Synthesis of adriamycin (R-OH).

Compound Pb (560 mg) is dissolved in anhydrous benzene (100 ml) and treated with 650 mg of Compound III in anhydrous benzene (10 ml) and 26 mg of p-toluene-sulfonic acid. The mixture is heated at 30 ° C for 3 hours, then neutralized with pyridine and evaporated to dryness. The residue was dissolved in acetone (10 ml) and treated with an aqueous solution of sodium hydroxide (50 ml). After 30 minutes at room temperature, the pH was adjusted to 8.4 with an aqueous solution of hydrogen chloride, and the solution was newly extracted with chloroform. The combined extracts were dried with anhydrous sodium sulfate, filtered, and evaporated in vacuo. The residue is dissolved in 0.1N. an aqueous solution of hydrogen chloride and left at room temperature for 36 hours

The acidic solution is washed with chloroform extraction to remove traces of aglycone. Then a pH of 8.6 is established, the pH of the hydrochloride is added and in the presence of chloroform (50 ml) by slow addition of 0.1 p of aqueous sodium hydroxide. The organic phase is separated, dried with anhydrous sodium sulfate and concentrated to 10 ml. Adriamycin (16) hydrochloride is crystallized by adding the equivalent of 1N. methylated hydrogen chloride. The yield is 420 mg in the form of crystals; m.p. 204-205 ° C;

 + 230 ° (with 0.05, SNZON).

Claims (4)

1. A method for producing glycosidic antibiotics of general formula I where R is hydrogen or hydroxyl, or hydrochlorides thereof, by reacting anthracyclinone with glycal in an anhydrous solvent, followed by isolating the desired product as a base or hydrochloride, characterized in that, in order to intensify the process and increase the yield of the target product, anthracyclinone of the general formula I ABOUT Hjco where RI is the grind-COCH3 or OSSN CH, -C about sn SNH interact with a protected glycal - 1,2,3,6-tetradeoxy-4-O-trifluoroacetyl-3-trifluoroacetamido-alyxohex-1-ene-pyranose in the presence of "-toluene sulfonic acid at 30-50 ° C with subsequent removal of N-, O - trifluoroacyl protective gruip. 2. The method according to claim 1 is also distinguished by the fact that the 0-trifluoroacetyl protecting group is removed by boiling with methanol. 3. A method according to claim 1, wherein the N-trifluoroacetyl protecting group is removed by alkaline hydrolysis. 4. A method according to claim 1, characterized in that the process is carried out in anhydrous benzene. Sources of information taken into consideration and examination 45 1. France Patent Ns 2183710, cl. And 61К 21/00, publ. 1973.