Preparation method of epirubicin and its intermediate

A technology of epirubicin and trifluoroacetyl epirubicin, applied in the field of organic compound synthesis, can solve the problems of bromination reaction pollution, large environmental damage, numerous steps and the like, achieve fewer reaction steps and avoid serious pollution , the effect of reducing economic and environmental costs

Active Publication Date: 2017-12-12
ZHEJIANG HISUN PHARMA CO LTD
View PDF3 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] But this type of synthetic technique all will first generate epirubicin by multi-step reaction, then obtains epirubicin by bromination, hydrolysis reaction, not only step is various, yield is low (mass yield is about 22-27%) ), and the bromination reaction produces serious pollution and great damage to the environment

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of epirubicin and its intermediate
  • Preparation method of epirubicin and its intermediate
  • Preparation method of epirubicin and its intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1: Synthesis of N-trifluoroacetyl adriamycin

[0063] (a) Suspend 5 grams of doxorubicin in 200ml DCM and cool to 0°C, stir and slowly add dropwise a mixture of 8ml DCM and 15ml trifluoroacetic anhydride within 30 minutes, and stir and react for 30 minutes after completion;

[0064] (b) Add methanol to the obtained mixed solution at 0°C, stir for 30 minutes, and warm to room temperature;

[0065] (c) Add 200ml of saturated sodium bicarbonate to the mixed solution, and stir at room temperature for 10 hours to carry out the hydrolysis reaction;

[0066] (d) After completion of the hydrolysis (monitored by HPLC), separate the organic layer, dehydrate the organic phase and concentrate it to dryness under reduced pressure to obtain an oil, weighing 6 g, in which N-trifluoroacetyl adriamycin measured by HPLC The chromatographic purity of is 93%, all of which were directly used in the reaction of the following examples (no further purification is required, the same in the foll...

Embodiment 2

[0067] Example 2: Preparation of N-trifluoroacetyl-14-O-tert-butyldimethylsilyl adriamycin (compound 1)

[0068] (a) Add 50ml of DMF to dissolve the concentrate obtained in Example 1, then add 5g of dried molecular sieve and 1g of imidazole, stir and dissolve;

[0069] (b) Add a mixed solution of 1.5g tert-butyldimethylchlorosilane and 10ml DMF to the mixture obtained above at 25°C, and react for 6 hours;

[0070] (c) Add 200 ml of DCM and 100 ml of HCl aqueous solution with a pH of 2.0 to the reaction solution, and stir and separate. The organic phase was washed with 100 ml of water again, the organic layer was separated, and after dehydration, the organic phase was concentrated under reduced pressure and concentrated to dryness to obtain 6.0 g of solid. The N-trifluoroacetyl-14-O-tert-butyldimethyl was measured by HPLC. The chromatographic purity of silyl adriamycin is 91%.

[0071] All were directly used in the reaction of Example 3 below.

[0072] 1 H-NMR (400MHZ, DMSO):

[0073] 0...

Embodiment 3

[0074] Example 3: Preparation of 4'-keto-N-trifluoroacetyl-14-O-tert-butyldimethylsilyl adriamycin (compound 2)

[0075] (a) Mix 100ml of DCM and 5ml of DMSO under stirring, and cool to -60°C, then add a mixture of 5ml of trifluoroacetic anhydride and 10ml of DCM, and stir for 15min;

[0076] (b) Mix 6.0 g of N-trifluoroacetyl-14-O-tert-butyldimethylsilyl adriamycin obtained in Example 2 with 50 ml of DCM, and then add dropwise to the mixed solution obtained in step (a) , The dripping time is 30min, the temperature during the dripping process is controlled to -65℃~-60℃, after the dripping, continue to react at -65℃~-60℃ for 45 minutes;

[0077] (c) Add 5ml of DBN solution and continue to react at -65℃~-60℃ for 10 minutes;

[0078] (d) Add 3ml of glacial acetic acid to neutralize the reaction solution, then add 100ml of water, stir and separate the liquids, and then wash with 100ml of water once to separate the organic phase and dehydrate;

[0079] (e) After concentration under reduced ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention provides a method for preparing epirubicin and an intermediate compatible with the method. The preparation method may include: reacting tert-butyldimethylsilyl chloride with N-trifluoroacetyl doxorubicin to obtain compound 1N-trifluoroacetyl-14-O-tert-butyldimethylsilyl doxorubicin Oxidation of compound 1 gives compound 24'-ketone-N-trifluoroacetyl-14-O-tert-butyldimethylsilyl doxorubicin; reduction of compound 2 gives compound 3N-trifluoroacetyl-14-O ‑tert-butyldimethylsilyl epirubicin; and subsequent deprotection and hydrolysis of compound 3 to obtain epirubicin. The method of the invention not only has low cost, few reaction steps, high yield and product purity, but also avoids serious pollution caused by bromination reaction in the traditional method.

Description

Technical field [0001] The invention belongs to the field of organic compound synthesis, and particularly relates to a preparation method of epirubicin and an intermediate compatible with the method. Background technique [0002] Epirubicin is an antibiotic anti-tumor drug. It is an isomer of doxorubicin. Its mechanism of action is to directly intercalate between DNA nucleobase pairs, interfere with the transcription process, prevent the formation of mRNA, and thereby inhibit DNA and RNA. synthesis. In addition, it also has an inhibitory effect on topoisomerase II. Epirubicin is a cell cycle non-specific drug that is effective against a variety of transplanted tumors and has a wide range of clinical applications. [0003] In the known chemical synthesis methods of epirubicin, the starting material is mostly daunorubicin, for example, the method developed by Farmitalia to prepare epirubicin from daunorubicin as the starting material (see Suarato et al. US4345068), the core of the...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Patents(China)
IPC IPC(8): C07H15/22
CPCC07H15/252
Inventor 严伟童万增王建平杨伟强钱宏冠
Owner ZHEJIANG HISUN PHARMA CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap