Method for the preparation of anti-tumor Etoposide

A manufacturing method and compound technology, applied in the field of improving the synthesis of Etoposide, can solve the problems of long reaction time, separation method, low yield, etc.

Inactive Publication Date: 2002-10-23
PHYTOGEN LIFE SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Although Wang et al. removed the chlorinated acetyl group protection required for compound (

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Preparation of 2,3-Di-O-dichloroacetyl-(4,6-O-ethylene)-β-D-glucopyranose (hydrogenated) (13)

[0048]Into a completely dry 100 ml three-necked round bottom flask were placed a stir bar, a low temperature thermometer, a diaphragm and a hydrogen inlet and 2,3-di-O-dichloroacetyl-1-O-benzyloxycarbonyl (4, 6-O-Ethylene)-β-D-glucopyranose (1.8 mmol) is violently reacted in acetone (15-30% concentration) and activated carbon powder (0.2 mmol) containing 10% platinum. The solution was stirred until homogeneous, and then cooled to -10°C to 0°C. After the reaction, the glass was sintered, and the catalyst was filtered out under reduced pressure and containing diatomaceous earth. The sintered glass was washed once with the entire reaction volume of dry acetone, and the filtrate was combined, and then concentrated and dried under reduced pressure at a temperature close to 30°C. The crude residue was dried under vacuum at room temperature, and the obtained compound (13) was a white fo...

Embodiment 2

[0050] Preparation of 4′-desmethyl-epipdophyllotoxin-4-(2,3-di-O-dichloroacetyl-4,6-O-ethylene)-β-D-glucopyranoside (14 )

[0051] Put a stirring rod, a low temperature thermometer, a diaphragm and an argon inlet into a completely dry 250 ml round bottom flask, and introduce 4′-desmethyl-epipodophyllotoxin (2) (1 mmol), dry molecular sieve (1 / 16 "granules) and anhydrous dichloromethane (20-50% concentration), 2,3-di-O-dichloroacetyl-(4,6-O-ethylene)-β-D-grapepyran Sugar (13) (1.7 mmol) was added to dichloromethane (10-20% concentration) through the same needle at both ends. The suspension was stirred until uniform, and then cooled to-under argon atmosphere without moisture. 40°C to -60°C. After stirring the suspension for more than 30 minutes, add trimethylsilyl trifluoromethanesulfonate (2 mmol) via a syringe. The reaction is maintained between -50°C and -40°C for 30 minutes. Minutes. During the process, the coupling reaction was monitored by thin-layer chromatography. The suspe...

Embodiment 3

[0053] Preparation of 4′-desmethyl-epipdophyllotoxin-4-(4,6-O-ethylene)-β-D-glucopyranose (Etoprese)

[0054] In 0.8 mmol of 4′-desmethyl-epipdophyllotoxin-4-(2,3-di-O-dichloroacetyl-4,6-O-ethylene)-β-D-gaupyr 1.5 mmol of zinc acetate dihydrate was added to the 10-25% methanol solution of pyranoside (14). The reaction mixture was stirred and heated under reflux for 90 minutes. After the reaction is complete, the mixture is cooled, and the volume is reduced to one third by rotary vacuum distillation. Effectively dilute the reaction solution with 100 ml of dichloromethane and 100 ml of water. The aqueous layer was washed with 50 ml of dichloromethane. The combined methylene chloride phase was washed twice with 50 ml of water. 15 ml of methanol was added to the first washed material to produce Etoproxil precipitation. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain an amorphous solid. This solid is recrystallized f...

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Abstract

The invention discloses a synthetic method for producing the antineoplastic drug Etoposide. The method involves the direct condensation of 4′-desmethyl-epipodophyllotoxin with 2,3-di-O-dichloroacetyl-(4,6 -O-ethylene)-β-D-glucopyranose to produce 4′-desmethyl-epipodophyllotoxin-4-(2,3-di-O-dichloroacetyl-4,6- O-ethylidene)-β-D-glucopyranoside, which is then transformed into Etoposide. Other methods include using different Lewis acids as catalysts, and different substituted glucopyranosides. This method can provide yields over existing techniques, reduce reaction times, and allow for more favorable separation of reaction steps.

Description

Technical field [0001] The present invention relates to improving the synthetic method for preparing etoposide, especially to improving the yield, reducing reaction time and simplifying the separation steps. Background of the invention [0002] Etoposide (etoposide) is an anti-tumor drug with the following structure (1): [0003] Etoplast has been effectively used as an anti-tumor drug in various situations. For example, it has been used to treat acute monocytic leukemia (Schilling's leukemia), and myelomonocytic leukemia, and has been promoted to be used in reticulocyte sarcoma, histiocytic lymphoma, lymphoma, and Hodgkin's disease. Due to its well-recognized activity, several synthetic techniques have been developed. [0004] One technique was published in Swiss Patent No. 514,578 by Kuhn et al., and related techniques were also disclosed in US Patent Nos. 3,408,411 and 3,524,844. Kuhn et al. disclosed that the preparation of Etoprene is based on 4′-demethyl-epipodophyllotoxin...

Claims

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Application Information

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IPC IPC(8): C07H17/08
CPCC07H17/08
Inventor 雷吉纳·南度
Owner PHYTOGEN LIFE SCI INC
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