Solux Corporation

Aleksandr M Itkin

Alexander F Zabudkin

Victor Matvienko

Alexey Matvyeyev

Alexey Matveev

A method of preparing the anthracyclin carminomycin using a starting material comprising daunorubicin. The method comprises reacting daunorubicin or N-protected daunorubicin with soft Lewis acids for the demethylation of the 4-methoxy group, resulting in a reaction mass. The reaction mass is treated with an aqueous solution of a strong organic acid or a mineral acid. After decomposition of the resulting carminomycin and Lewis acids reactive complex, the reaction mass is extracted using a water insoluble organic solvent. As a result, carminomycin is extracted as a base.

Method for preparing 4-demethyldaunorubicin

A method of preparing an anthracyclin such as epirubicin from a starting material comprising 13-dihydrodaunorubicine (13-daunorubicinol). The method comprises producing N-Trifluoroacetyl-13-daunorubicinol from 13-daunorubicinol by acylation. The N-Trifluoroacetyl-13-daunorubicinol is reacted with an aprotic solvent and an acylating agent to produce an intermediate sulfoxy salt which is treated with a strong base to produce 4'-keto-N-Trifluoroacetyldaunorubicin. The 4&#x2032;-keto-N-Trifluoroacetyldaunorubicin is reacted with a reducing agent, such as borohydride of an alkaline metal, to produce N-Trifluoroacetyl-4&#x2032;-epi-daunorubicin. The N-Trifluoroacetyl-4&#x2032;-epi-daunorubicin is hydrolyzed in a basic solution to produce an intermediate compound. The intermediate compound is reacted with a halogenizing agent to produce a 14-Hal-derivative. The 14-Hal derivative is hydrolized in the presence of a formate of an alkaline metal to produce the desired final compound.

Synthesis of epirubicin from 13-dihydrodaunorubicine

A method for the aralkylation of anthracyclins by utilizing an aralkylating agent R&#x2014;CHX (for example, BnBr) in accordance with the reaction pathway describe by the scheme shown in FIG.. The present invention recognizes that 4-R, 3'-N-Daunomycines are suitable substrates for selective 4&#x2032;-O-benzylation, yielding 4-R, 3&#x2032;-N-4&#x2032;-O-Aralkyl-Daunorubicines (in particular, 4&#x2032;-O-Bn-Daunomycines). Thus, the present invention provides a pathway for a simple production of 4&#x2032;-O-aralkylated derivatives of anthracyclines which can be effectively used to produce anthracyclines.

Method of aralkylation of 4'-hydroxyl group of anthracylins

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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San Diego, CA, United States of America

Aleksandr M Itkin