Epirubicin

Epirubicin Chemische Eigenschaften,Einsatz,Produktion Methoden

• Originator

  Ellence,Pharmacia and Upjohn Co.

• Verwenden

  Antineoplastic.

• Verwenden

  Epirubicin is a cell permeable Topo II inhibitor.

• Definition

  ChEBI: An anthracycline that is the 4'-epi-isomer of doxorubicin.

• Manufacturing Process

  Conversion of daunorobicin hydrochloride to 4'-epi-doxorubicin hydrochloride employing the trifluoroacetyl moiety for the 3'-amino group protection:
  To a solution of 8 g (14 mmol) of daunorubicin hydrochloride in 500 ml of dry MeOH, 5.9 ml (79 mmol, 5.6 eq.) of acetylchloride was added. After refluxing for 1 h the solvents were evaporated in vacuo. Addition of CHCl3 to the residue caused precipitation of daunosamine. After the aminosugar had been filtered off, the filtrate was evaporated in vacuo. Diisopropylether was added to the remaining solid and the mixture was sonicated for 15 min to yielddaunomycinone. In total, 2.55 g (91%) of daunosamine (4-amino-6-methoxy- 2-methyltetrahydropyran-3-ol hydrochloride) and 5.5 g (99%) of daunomycinone were obtained, m.p. 209-233°C (dec.).
  Under an argon atmosphere, a solution of 1.24 ml (2.5 eq.) of Br2 in 72.8 ml CHCl3 was added to a solution of 3.90 g (9.8 mmol) of daunomycinone in 390 ml of CHCl3. After stirring the reaction mixture over night at room temperature, the pure bromide 4 precipitated and was filtered out. Yield 4.1 g (88%).The bromide was dissolved in 1.17 L of acetone, 16.7 g of AcOK was added to the mixture which was then refluxed for 5 min. Thereafter the solvents were evaporated in vacuo. The residue was dissolved in CHCl3 and washed with water and brine. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Diisopropylether was added and the mixture was sonicated and filtrated to give doxorubicinone acetate, 3.8 g (97%), m.p. 226-229°C (dec.).
  Daunosamine modification:
  To a solution of 2.55 g (12.9 mmol) of daunosamine in 64 ml of dry diethylether under an argon atmosphere 5 ml (4.8 eq.) of pyridine was added. The reaction mixture was cooled to -20°C and 3.63 ml of trifluoroacetic acid anhydride was added. After stirring overnight at room temperature, the mixture was filtered and the filtrate was washed with diethylether. The filtrate was subsequently washed with 10% citric acid solution, saturated NaHCO3 and brine. The combined extracts were dried over MgSO4, filtrated and evaporated in vacuo. The residue was purified by flash column chromatography (5% MeOH in CHCl3) to give 2.69 g (81%) of (3-hydroxy-6-methoxy-2- methyltetrahydropyran-4-yl)carbamic acid trifluoromethyl ester, m.p. 137- 152°C.
  To a solution of 2.5 g (9.7 mmol) of (3-hydroxy-6-methoxy-2- methyltetrahydropyran-4-yl)carbamic acid trifluoromethyl ester in 100 ml of CH2Cl2 2.45 g (11.4 mmol) of pyridinium chlorochromate (PCC) was added. After 2 and after 4 hours of refluxing 1.08 g (5.0 mmol) of PCC was added. Again after refluxing the reaction mixture for 8 hours 1.5 g (7.0 mmol) of PCC was added and the mixture was stirred over night. The mixture was poured into 436 ml of diethylether, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (2% acetone in CH2Cl2) to give 2.10 g (85%) of (6-methoxy-2-methyl-3-oxotetrahydropyran-4-yl)-carbamic acid trifluoromethyl ester, m.p. 74-98°C.
  10 ml of 1 M BH3·THF was added dropwise to a solution of 2.6 g (10 mmol) of (6-methoxy-2-methyl-3-oxotetrahydropyran-4-yl)carbamic acid trifluoromethyl ester dissolved in a mixture of 200 ml of dry THF and 125 ml of dry MeOH under an argon atmosphere at 0°C. After stirring for 10 min, 1 ml of H2O was added and the solvents were evaporated in vacuo. The remaining oil was purified by flash column chromatography (3% MeOH in CH2Cl2) to give 2.08 g (80%) of 4'-epidaunosamine derivative as a white solid, m.p. 165-167°C. A solution of 2.08 g (8.1 mmol) of 4'-epidaunosamine derivative in 20% of AcOH was refluxed for 3 hours at 90°C. The solution was freeze-dried and purified by flash column chromatography (10% MeOH in CH2Cl2) to give 1.38 g (70%) of hemiacetal, m.p. 180-185°C.
  3.3 ml (23.5 mmol) of trifluoroacetic anhydride was added to a stirred suspension of 272 mg (1.12 mmol) of hemiacetal in 10 ml of dry diethylether under an argon

• Trademarks

  Ellence(Pfizer).

• Therapeutic Function

  Antineoplastic

Epirubicin Upstream-Materialien And Downstream Produkte

Epirubicin Anbieter Lieferant Produzent Hersteller Vertrieb Händler.

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