HU193679B - Improved process for preparing 4-demethoxy-daunorubicin - Google Patents

Abstract

4-Demethoxy daunorubicin of formula (I) is made from optically-active 4-demethoxy daunomycinone, which is condensed in organic solvent in presence of silver trifluoromethanosulphonate, with a N,O-trifluoroacetyl-protected 1-chloro daunosamine, to obtain the N,O-protected alpha-anomeric glucoside. By elimination of the protective gps., first with methanol and then by mild alkaline hydrolysis, e.g. with dil. aq. NaOH soln., the free glucoside base (I) is obtd., which is isolated as the hydrochloride.

Description

The present invention relates to an improved process for the preparation of 4-demethoxydaunorubicin of formula (I).

The 4-demethoxy-daunorubicin is 4,046,878. U.S. Pat. No. 6, September 7, 1977, and a patented anticancer agent

This compound was previously prepared by condensing the racemic 4-demethoxy-daunomycinone with 2,3,6-trideoxy-3-trifluoroacetamido-4-O-trifluoroacetyl-α-α-L-lyxo-hexapyranosyl chloride. 'they said. The condensation reaction was carried out in a suitable anhydrous organic solvent in the presence of mercury (II) oxide, mercury (II) bromide and a molecular sieve as dehydrating agent according to the known Koenigs-Knorr procedure. However, under these conditions, a complex mixture of glycosides is formed which contains the alpha and beta anomers of the glycosides, which must be separated by chromatography.

Furthermore, since they are based on racemic 4-demethoxy-daunomycinone in the above process, the alpha and beta anomers of glycosides are still mixtures of diastereomers after separation, namely the (-) -dunosaminyl] -7S; 9S-configuration in the aglycone. Mixtures of -4-demethoxy-daunomycinone and aglycone of the non-natural 7R;

Separation of such diastereomeric but otherwise very similar compounds is a lengthy and very laborious process that severely degrades the gross yield of the desired end product.

The improved process described in this application eliminates the above drawbacks and thus provides 4-demethoxydaunorubicin in high yield and purity.

The process of the present invention is based on the natural optically active 4-demethoxy-daunomycinone of the 7S; 9S configuration (British Patent No. 1,500,421) and is dissolved in a suitable solvent such as chloroform or dichloromethane, a soluble silver salt. and condensing it with the 1-halo derivative of the protected daunosamine in the presence of a motecula filter used as a dehydrating agent.

Since the silver salt used, the silver salt of trifluoromethanesulfonic acid (AgSO ₃ CF ₃ ) is soluble in the organic solvent, condensation can be carried out in a homogeneous phase, thereby avoiding the Koenigs-Knorr reaction in the presence of insoluble silver or mercury compounds. well known difficulties of the reaction [Günther Wullf et al., Ang. Chem. Int. Ed. 13, 157 (1974)],

The condensation reaction proceeds rapidly and the protected glycoside can be isolated in high yield. Furthermore, a very important and surprising feature of the process of the present invention is that the reaction is stereospecific 2 and only the alpha anomer is formed, so that the anomers need not be separated by laborious chromatography.

The invention is further illustrated by the following non-limiting examples.

Example 1

N-Trifluoro-acetyl-4-demethoxy-daunorubicin

In a solution of 1.2 g of 1-chloro-N, O-bis-trifluoroacetyldaunosamine in 100 ml of anhydrous dichloromethane, 1 g of optically active 4-demethoxydaunomycinone (British Patent No. 1,500,421) is dissolved in 10 g of Merck. A solution of 0.86 g of silver salt of trifluoromethanesulfonic acid in 40 ml of diethyl ether is added in the presence of a 4 A molecular weight filter. After 20 minutes at room temperature, the mixture was neutralized with saturated sodium bicarbonate solution. The organic phase is then separated and the solvent is distilled off under reduced pressure. The resulting Ν, Ο-protected glycoside was heated with 200 ml of methanol at 50 ° C for half an hour.

The solvent was distilled off and the crude product (1.4 g) was crystallized from chloroform. This gave 1.3 g of pure N-trifluoroacetyl-4-demethoxy-daunorubicin, m.p. 155-157 ° C: [alpha] ™ = + 188 ° (C = 0.1, dioxane).

Example 2

4-Demethoxy-daunorubicin hydrochloride (I)

0.6 g of N-trifluoroacetyl-4-demethoxy daunorubicin obtained in the same manner as in Example 1 is dissolved in 5 ml of acetone, 40 ml of 0.1 N sodium hydroxide solution are added and the mixture is kept at room temperature for half an hour. . The pH of the mixture was then adjusted to 8 with hydrochloric acid and the mixture was extracted several times with chloroform. The chloroform portions were dried, concentrated to a small volume, acidified to pH 3.5 with anhydrous methanolic hydrochloric acid, and excess diethyl ether was added. 0.35 g of pure 4-demethoxy-daunorubicin hydrochloride are obtained, m.p. 183-185 ° C; [.alpha.] D @ 20 = +205 DEG (0, t, methanol).

Claims (1)

A process for the preparation of 4-demethoxy-daunorubicin hydrochloride of formula (I), characterized in that the 7S: 9S-configuration of formula (II) is optically active in anhydrous dichloromethane as a solvent at room temperature in trifluoromethane. in the presence of a silver sulfonic acid salt and a molecular sieve, is reacted with 1-chloro-N, O-bis-trifluoroacetyldaunosamine (III) to yield N, O-bis-trifluoroacetyl-4 (IV). -demethoxy-daunorubicin, which is then deprotected by first treating the N-trifluoroacetyl compound with methanol-2193679 and then treating the latter with dilute aqueous sodium hydroxide. , 4-demethoxy dauno rubicin of formula (I) and the resulting glycoside base are isolated in the form of the corresponding hydrochloride