NZ208147A - Preparation of 4-demethoxy-daunorubicin hydrochloride - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £08147 2,0$^ Priority Data(s): Complete Specification Filed: llf.TMh'Qtf Cld.cr,; CCTj.VrU ^ j Putl.cat on Date:: . ... .5.). jy.k ! P °J :l:nal' ' NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION IMPROVED PROCESS FOR THE PREPARATION OF 4-DEMETHOXY-DAUNORUBICIN X/We, FARMITALIA CARLO ERBA S.p.A., Via Imbonati 24, 20159 Milan, Italy, an Italian company, hereby declare the invention for which HX/ we pray that a patent may be granted to Htfe/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - (followed by la) 2 08i47 TITLE: Improved process for the preparation of 4-demethoxy--daunorubicin.

! O C W The present invention is concerned with an improved process for the synthesis of 4-demethoxy-daunorubicin of formula I: CCCK.

. HC1 (I) a useful antitumoral compound already described and claimed in the U.S.P. 4.046.878 (Sept. 6, 1977).

The compound had been then prepared by condensing a racemic 4-derr.ethoxy-daunomycinone with a 2 , 3 , 6-1 r i deoxy - 3-1 r i f 1 uo r£ acetamido-4-O-trifluoroacetyl-c^-L-lyxo-hexopyranosyl chl£ ride.

The condensing reaction had been carried out in a suitable anhydrous organic solvent and in the presence of mercuric oxide, mercuric bromide and molecular sieves as dehydrating ? 'j 31 agents, following the known Koenigs-Knorr synthesis procedure. In these conditions, however, a complex mixture of glycosidic compounds was obtained, such a mixture comprising the and ^anoms r i c glycosides which had to be separated by chromatography.

Moreover f owing to the use as starting material of a racemic 4-demethoxy-daunomycinone , each oL. or ^ separated anomeric gl^ coside was still a diastereomeric mixture of (-)daunosaminy1 (+)4-demethoxy-daunomycinone in which the aglycone moiety had the natural 7S:9S configuration and of (-) daunosanri nyl(-)4-demethoxy-daunomycinone in which the aglycone moiety had the unnatural 7R:9R configuration.

The separation of such diastereomeric but very similar compounds required a lonq and very troublesome procedure which badly influenced the over all yields of the desired final product.

By the improved process claimed in the present specification all those inherent disadvantages have been eliminated so that 4-demethoxy-daunorubicin can be obtained in high yield and in a pLre form.

The used starting material is an optically active 4-deme-thoxy-daunomycincr. e, (B.P. 1.500.621) having the natural 75:95 configuration, which is condensed with the protected 1-halo derivative of daunosamine in a suitable organic \ solvent, such as chloroform or methylene chloride, in the nnj Ijpresence of a soluble silver salt and mclecular sieves as ■•"TV -IV - I :e-§ fOl - 3 - 208 1 4 dehydrating agents.

The solubility in the organic solvents of the used silver salt, which is the silver trifluoromethanesulphonate (AgSOjCF^), enables the condensation to take place in a homogeneous phase, thereby avoiding the well-known complications of the ^5 Koenigs-Knorr reaction in the presence of insoluble silver or mercury compounds./ Gunther Wulff et al., Ang. Chem. Int. Ed. 13, 157 (19 7 4_) / * The condensation reaction goes to completion in a short time and the protected glycoside can be obtained in high yield. Moreover, it is very important and quite surprising that the reaction is stereospecific, that is, only the o(anomer is formed in the reaction so that any troublesome chromato-f graphic separation of anomeric compounds is no more neces sary. The following example illustrates the invention.

Example 1 N -1 r i f 1 u^>o roacetyl-4-demethoxy-daunorubicin 1 g of optically active 4-demethoxy-daur.omycinone (8.P. 1.500.421) dissolved in 100 ml of anhydrous methylene chl£ ride containing 1.2 g of 1-chloro-N,0-trif1uoroacety1-daunosamine was treated in the presence of 10 g of molecu- o lar sieve (4 A Merck) with 0.86 g of AgSO^CF^ dissolved in 40 ml of diethyl ether. After 20 minutes at room temperature the reaction mixture was neutralized with a saturated solui tion of NaHCO^ and the organic phase was separated and eva

Claims (2)

- 4 D 208147 porated under vacuum. The resulting N,0 protected glycoside was treated with 200 ml of methanol for 30 minutes at 50 °C . By evaporation of the solvent, 1.4 g of crude product were obtained which, after crystallization from chloroform, gave 1.3 g of pure N-trifluoroacety1-4-demethoxy-daunorubicin - . -20 m.p. 155-157°C; J_ oi _/^ = +188° (C = 0.1 dioxane) Example 2 O 4-demethoxy-daunorubicin hydrochloride (I) 0.6 g of N-trifluoroacetyl-4-derr.ethoxy-daunorubicin, prepared as described in Example 1, were dissolved in 5 ml of acetone and treated with 40 ml of NaOH 0.1 N. After 30 minutes at room temperature the solution was adjusted to pH 8 with HC1 and repeatedly extracted with chloroform. The combined chloroform extracts, after being dried and concentrated to a small volume/were acidified to pH 3.5 with anhydrous methanolic hydrogen chloride. O Upon addition of an excess of diethyl ether there was obtained 0.35 g of pure 4-demethoxy-daunorubicin as the — on hydrochloride, m.p. 183-185°C; //q = +205° (C = 0.1 MeOH). What we claim is:

1) A process tor the preparation of 4-demethoxy -daunorubicin hydrochloride of formula I:

CCCH.

HC1

CI)

characterized in that an optically active 4-demethoxy--daunomycinone, having the 7S:9S configuration, of formula

OH

COCH.

(II)

21 MAY 1987

■: — "t

"T*;I*

- 6 -

208147

dissolved in anhydrous methylene chloride, is reacted, at room temperature, in the presence of silver t r i f luoromethanei sulphanate and molecular sieves, with 1-chloro-N,0-tri-fluoroacetyl daunosamine of formula III:

©

O

NH-COCF.

(Ill)

to give the N,0 trifluoroacety1 protected 4-demethoxy--daunorubicin of formula IV:

o

0 OH

CF3C00

NH-COCF.

COCH.

(IV)

KJ

■ W .Vk V ,V «W.

- 7 -

from which, after removing of the protecting groups first with methanol to obtain the N-trif1uoroacety1 protected derivative and subsequently with dilute aqueous sodium hydroxide, the desired 4-demethoxy-daunorubicin (I) is obtained as free glycosidic base finally isolated as the cor responding hydrochloride.

2) 4-demethoxy-daunorubicin hydrochloride of formula I whenever prepared by the process claimed in claim 1.