Solux Corporation

Synbias Pharma Ag

Synbias Pharma Ltd.

Alexey Matvyeyev

Alexander F Zabudkin

Victor Matvienko

Aleksandr M Itkin

The present invention relates to a method for the synthesis of 4-demethoxydaunorubicin (idarubicin) having the chemical structure of formula (I), which involves the demethylation of 3'-Prot-daunorubicin in the presence of a soft Lewis acid. The method of the present invention does not comprise cleavage of the glycosidic linkage at carbon C7, thus resulting in a faster synthesis cycle and an improved yield of the final product. 

Method of producing 4-demethoxydaunorubicin

A crystalline form of epirubicin hydrochloride, named herein as 'type II' crystalline epirubicin hydrochloride, has excellent thermal stability. Type II crystalline epirubicin hydrochloride has a powder X-ray diffraction pattern having average values of diffraction angle (2&#x3b8;) and relative intensity P(%) as presented in the following table: 

Thermally stable crystalline epirubicin hydrochloride and method of making the same

A method of synthesizing R1, R2-substituted-4' (ax. or eq.)-OH anthracyclines and their corresponding salts of Formula (1) from daunorubicin or N-Trifluoroacetyl-4-R1-derivatives of daunorubicin, wherein R1 is defined as H, OH, and 4&#x2032;-HO is defined as ax[ial]. The method includes producing N-Trifluoroacetyl daunorubicin and treating the N-Trifluoroacetyldaunorubicin or N-Trifluoroacetyl-4-R-derivatives of daunorubicin, wherein Ris defined as H, OH, with dimethylsulfoxide activated by different acylating agents. The attained intermediate product is then treated with a strong base (ex. tertiary amines) resulting in the 4&#x2032;-keto-N-Trifluoroacetyl-4-Rdaunorubicin wherein Ris defined as H, OH, OMe. The 4&#x2032;-keto-N-Trifluoroacetyl-4-R-daunorubicin is reacted with a reducing agent, a derivative of a borohydride of an alkaline metal MHBL, to produce N-Trifluoroacetyl-4&#x2032;-epi-4-R-daunorubicin. The N-Trifluoroacetyl-4&#x2032;-epi-4-R-daunorubicin undergoes hydrolysis in a basic solution to produce a derivate of an anthoacyclin which is halogenized [by complex halogenides] to form a 14-Hal-derivative. This result is then hydrolyzed by well-known methods in the presence of a formate of an alkaline metal to form the desired final compound.

[object Object]

A method of synthesizing 4-R-substituted anthracyclines and their corresponding salts from 4-demethyldaunorubicin includes the steps of treating 4-demethyldaunorubicin with a sulfonylating agent to form 4-demethyl-4-sulfonyl-R-daunorubicin. 4-Demethyl-4-R-sulfonyl-daunorubicin is then subject to a reducing agent in the presence of a transition metal catalyst in a temperature range of about 30&#xb0; C. to about 100&#xb0; C. in a polar aprotic solvent in an inert atmosphere. Protected 4-demethoxy-4-R-daunomycin then undergoes hydrolysis in a basic solution to form the 4-R-substituted anthracyclines. The novel method lacks the step of forming a stereospecific glycoside bond between aglycone and aminoglycoside. The method also increases the yield of the final product up to 30 to 40%.

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Kharkiv, Ukraine

Alexey Matvyeyev