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Method of preparing 4-R-substituted 4-demethoxydaunorubicin

A technology of daunorubicin and alkenyl, which is applied in the field of preparation of anthracycline antibiotics, and can solve problems such as complex methods

Inactive Publication Date: 2006-06-21
苏洛克股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, these methods of synthesizing aglycone are due to the 7 and C 9 form an optically active center and become complex

Method used

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  • Method of preparing 4-R-substituted 4-demethoxydaunorubicin
  • Method of preparing 4-R-substituted 4-demethoxydaunorubicin
  • Method of preparing 4-R-substituted 4-demethoxydaunorubicin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] First, 2g of 3’-trifluoroacetamido-4-desmethyldaunomycin (R 1 =H, R 2 = Trifluoroacetyl) dissolved in 0.2 L of pyridine.

[0046] Next, 4 ml of diisopropylethylamine and 0.5 g of 4-dimethylaminopyridine were added to the solution of step (a) in Example 1.

[0047] Next, the solution of step (b) in Example 1 was quenched to 0°C, and 2.5 ml of trifluoromethanesulfonic anhydride that had just been distilled was added.

[0048] Next, the solution of step (c) in Example 1 was incubated for 1 hour at room temperature.

[0049] After incubation, 0.15L concentrated hydrochloric acid, 0.2kg ice and 0.2L dichloromethane were added to the incubation solution.

[0050] Next, the organic layer was washed in 0.2 L of distilled water, and the dichloromethane was removed by evaporation under partial vacuum.

[0051] After evaporation, 1.5 g of 4-trifluoromethanesulfonyl-3'-trifluoroacetamido-4-desmethyldaunorubicin with a purity of 85% (confirmed by HPLC) was prepared.

Embodiment 2

[0054] 1.5g of 4-trifluoromethanesulfonyl-3'-trifluoroacetamido-4-desmethyldaunorubicin (R 1 =H, R 2 = Trifluoroacetyl, R 3 = Trifluoromethyl) dissolved in 0.1 L of dimethylformamide.

[0055] During the stirring process, 2 g of triethylamine formate and 50 mg of palladium acetate were added to the mixture of step (a) in Example 2, and a stream of argon was passed through the mixture.

[0056] Then, the mixture of step (b) in Example 2 was heated to 50°C, and 200 mg of 1,1'-bis(diphenylphosphino)ferrocene was added.

[0057] Then, the mixture of step (c) in Example 2 was heated at 50°C for 8 hours.

[0058] Then, the mixture of step (d) in Example 2 was poured into water under vigorous stirring to form a precipitate (4-demethoxy-3'-trifluoroacetamidodaunorubicin).

[0059] The precipitate (4-demethoxy-3'-trifluoroacetamidodaunorubicin) was filtered, and then purified by preparative chromatography.

[0060] The output of this method is 0.8-0.85 g of 4-demethoxy-3'-trifluoroacetamid...

Embodiment 3

[0062] 0.85 g of 4-demethoxy-3'-trifluoroacetamido daunorubicin was added to a stirred aqueous solution of 0.1N NaOH (0.06 L) and kept at 30°C for 30 minutes. The color of the solution became dark blue-purple.

[0063] Then, under vigorous stirring, the reaction mixture was poured into 0.5 L of a 10-12% solution of chloroform in butanol (heated to 40°C).

[0064] Then, under vigorous stirring, hydrochloric acid (1:3) was added to the mixture and titrated to a pH of 8.8-9.0.

[0065] Then, the obtained organic layer was washed in distilled water.

[0066] Then, 0.1 L of distilled water was added to the organic layer washed in step (d) of Example 3, and 0.8N hydrochloric acid was added, and the pH was titrated to 3.5. The solution of step (e) in Example 3 was stirred vigorously, and the aqueous layer containing 4-demethoxydaunorubicin hydrochloride (idarubicin) was separated. The idarubicin hydrochloride solution was evaporated to 50% of its original volume and purified by chromatog...

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Abstract

The method for synthesizing 4-R-substituted anthracycline antibiotics and corresponding salts thereof from 4-demethyldaunorubicin comprises the following steps: treating 4-demethyldaunorubicin with a sulfonating agent to form 4-demethyldaunorubicin Methyl-4-sulfonyl-R3-daunorubicin; then in an inert atmosphere, in an aprotic polar solvent, in the temperature range of about 30-100 ° C, in the presence of a transition metal catalyst to make 4- Demethyl-4-R3-sulfonyl-daunorubicin reacts with reducing agent. Then, the protected 4-desmethoxy-4-R-daunorubicin is hydrolyzed in alkaline solution to form 4-R-substituted anthracycline antibiotics. The new method eliminates the step of forming a stereospecific glycoside between the aglycone and the aminoglycoside. The method also increases the yield of the final product by up to 30 to 40%.

Description

[0001] Related application [0002] This application claims the priority of U.S. Provisional Application No. 60 / 472192 filed on May 21, 2003 and U.S. Application No. 10 / 831448 filed on April 23, 2004. The two applications mentioned above are incorporated herein by reference in their entirety. Invention field [0003] The field of the invention relates to the use of chemical methods for the preparation of anthracyclines. More specifically, the field of the present invention relates to the preparation of 4-demethyldaunomycin with the general formula (I) described more fully herein. method. When R=H, the present invention relates to a chemical method and process for preparing idarubicin from 4-desmethyldaunorubicin. Background of the invention [0004] Anthracycline antibiotics form the largest class of naturally occurring biologically active compounds. Several compounds in this category have been shown to be clinically effective anti-tumor drugs. These include, for example, daunorub...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/252
Inventor A·扎布金V·马廷科A·马特维耶夫A·伊特金
Owner 苏洛克股份有限公司
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