Preparation method of eribulin intermediate

A technology of compound and hydroxyl protecting group, applied in the field of preparation of eribulin intermediates, can solve the problems of difficult to realize scale-up production, complex, difficult to scale-up production and application, etc.

Inactive Publication Date: 2016-02-17
UNITRIS BIOPHARMA
View PDF0 Cites 6 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The chiral compound shown in formula II is the key intermediate for the synthesis of eribulin. The synthesis of compound II has attracted great interest and attention from chemists. Synthetic method (Org.Lett.2002, 4, 4435; Org.Lett.2009, 11, 4520; J.Am.Chem.Soc.2009, 131, 15636) which is the key technology, however, NHK reaction requires the use of high toxicity The substance chromium dichloride, and the NHK reaction is extremely sensitive to water and oxygen, and needs to be carried out under extremely strict anhydrous and oxygen-free conditions, and the reproducibility of the reaction is poor, which makes it difficult to scale up the production of this method
The research group of Professor Philips of the University of Colorado in the United States reported a synthetic method (Angew.Chem.Intl.Ed.2009,48,2346) with Noyori asymmetric hydrogenation and rearrangement of diazoketone compounds as the key steps. Although the synthesis process Relatively simple, but requires the use of explosive diazomethane and expensive chiral noble metal catalysts, making it difficult to scale up the synthesis
Recently, the Canadian Alphora Research Company disclosed a method for synthesizing the compound of formula II using natural sugar compounds as chiral sources. However, this synthetic route is relatively lengthy and complicated, and it is difficult to be applied in scale-up production.
In summary, the synthesis method of the compound of formula II reported publicly above not only has harsh reaction conditions, high synthesis cost, cumbersome operation, but also has potential safety hazards, and is not suitable for large-scale production

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 eribulin intermediate
  • Preparation method of eribulin intermediate
  • Preparation method of eribulin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Embodiment 1: preparation compound VIIa

[0083] Compound IXa (13.1 g, prepared according to literature Tetrahedron Lett. 2001, 42, 9233) was dissolved in tetrahydrofuran (240 mL), cooled to -10 ° C, dropwise added LDA tetrahydrofuran solution (46 mL, 1.0 M), at -10 ° C After reacting at low temperature for 2 hours, add compound VIIIa (6.5g, prepared according to the literature Angew.Chem.Intl.Ed.2009, 48, 5121), and react at -10°C for 2 hours, add saturated aqueous ammonium chloride (56mL ) to quench the reaction, add 200mL ethyl acetate, separate the organic phase, dry the organic phase with anhydrous sodium sulfate, concentrate and purify by column chromatography to obtain compound VIIa (14.2g).

[0084] 1 HNMR (CDCl 3 ,400MHz)δ=7.67-7.62(m,4H),7.46-7.32(m,11H),4.50(s,2H),4.12-4.07(m,1H),3.94-3.88(m,1H),3.67( t,J=6.0Hz,2H),3.54-3.48(m,2H),3.28(d,J=5.0Hz,0.6H),2.83-2.68(m,2H),2.58(t,J=7.4Hz, 2H), 2.08-1.69(m, 7H), 1.05(s, 9H).

Embodiment 2

[0085] Embodiment 2: Preparation of compound VIa

[0086]Compound VIIa (12.2g) was dissolved in tetrahydrofuran (330mL), cooled to -30°C, DIBAL-H hexane solution (66mL, 1.0M) was added dropwise, reacted at -30°C for 5 hours, and 8mL of methanol was added The reaction was quenched with 160 mL saturated potassium sodium tartrate aqueous solution, 300 mL ethyl acetate was added, the organic phase was separated, the organic phase was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to obtain compound VIa (9.6 g).

[0087] 1 HNMR (CDCl 3 ,400MHz)δ=7.68-7.64(m,4H),7.46-7.32(m,11H),4.51(s,2H),4.10-4.07(m,1H),3.97-3.86(m,3H),3.73- 3.67 (m, 2H), 3.55-3.49 (m, 2H), 1.05 (s, 9H).

Embodiment 3

[0088] Embodiment 3: preparation compound Va

[0089] Dissolve compound VIa (8.0g) in tetrahydrofuran (300mL), cool to 0°C, add silver oxide (3.2g) and silver trifluoromethanesulfonate (3.5g), react at 20°C for 18 hours, add Saturated aqueous sodium bicarbonate solution was used to quench the reaction, and 200 mL of ethyl acetate was added to separate the organic phase. The organic phase was dried with anhydrous sodium sulfate, concentrated and purified by column chromatography to obtain compound Va (6.9 g).

[0090] 1 HNMR (CDCl 3 ,400MHz)δ=7.68-7.64(m,4H),7.42-7.32(m,11H),4.51(s,1.6H),4.50(s,0.4H),4.25-4.15(m,1.6H),4.05 -3.92(m,0.8H),3.79-3.74(td,J=2.9,6.9Hz,1H),3.70-3.65(m,2H),3.56-3.47(m,2H),2.09-1.99(m,2H ), 1.04(s,9H).

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 relates to a preparation method of an eribulin intermediate. Specifically, the invention relates to a compound shown as a formula IV; R1 represents a hydroxyl protecting group, preferably (C1-10 alkyl or aryl) 3 silicon alkyl, more preferably TBDPS; R2 represents a hydroxyl protecting group, preferably benzyl or (C1-10 alkyl or aryl) 3 silicon alkyl, and more preferably benzyl or TBS. The invention particularly relates to the preparation method of the compound shown as formula IV. The method has the advantages of mild reaction conditions, simple operation, low cost for synthesis and is applicable to mass production.

Description

technical field [0001] The invention relates to a preparation method of an eribulin intermediate. Background technique [0002] Eribulin (as shown in formula I) is a derivative of the macrolide compound halichondrinB extracted from the marine biological sponge Halichondriaokadai, and is a tubulin inhibitor. On November 15, 2010, the FDA approved Eribulin mesylate (Halaven) injection for the treatment of patients with metastatic breast cancer who have received at least two chemotherapy regimens, and its mechanism of action may be through direct binding to tubulin Inhibits mitosis, inhibits the growth of microtubules, and inhibits the growth of cancer cells to exert a therapeutic effect. As a tubulin polymerization inhibitor with a new mechanism of action, eribulin mesylate provides a new treatment for patients with locally advanced breast cancer or metastatic breast cancer to improve the survival rate and quality of life. [0003] [0004] The molecular structure of Erib...

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 Applications(China)
IPC IPC(8): C07F7/18C07D493/22
CPCC07F7/18Y02P20/55C07D493/22C07D307/20C07D307/32C07F7/1892C07C31/20
Inventor 张富尧雷生辉张歆宁管忠俊
Owner UNITRIS BIOPHARMA
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