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Preparation method of eribulin intermediate

A technology for ligands and compounds, applied in the field of medicine, can solve the problems of high synthesis cost, harsh reaction conditions, and unsuitable for industrial production.

Active Publication Date: 2020-10-20
NANTONG NUOTAI BIOLOGICAL PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] WO9317690A1 discloses a method for preparing ERB. In this method, ketone phosphate iodide and NaH are used in the reaction process. The reaction needs to be carried out strictly under anhydrous conditions. The reaction conditions are harsh, and the NaH used is easy to explode. In large-scale production, there is a great potential safety hazard
And the CuH[P(C 6 h 6 ) 3 ] 6 No regular suppliers, high cost
[0009] In summary, the synthesis method of the compound ERB disclosed above not only has harsh reaction conditions, high synthesis cost, cumbersome operation, but also has potential safety hazards and is not suitable for industrial production. high production cost

Method used

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  • Preparation method of eribulin intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Embodiment 1: the preparation of compound ERB-5a

[0071]

[0072] ERB-6 (5 g, 11.4 mmol) was dissolved in 50 mL of dry pyridine, and 4-methoxytriphenylchloromethane (4.58 g, 14.8 mmol) was added with stirring. After the addition, the reaction solution was stirred at room temperature for 17 hours. Add 20 milliliters of ethanol to quench the reaction after TLC detects that the reaction is complete. After the solvent is removed by rotary evaporation, the crude product is dispersed in 40 milliliters of saturated aqueous sodium bicarbonate and 100 milliliters of dichloromethane, left to separate liquids, and the organic phase is dried and concentrated to the column layer Analysis gave 7.62 grams of product ERB-5a, with a yield of 94%.

Embodiment 2

[0073] Embodiment 2: the preparation of compound ERB-4a

[0074]

[0075] ERB-5a (6 g, 8.44 mmol) was dissolved in 50 ml of anhydrous tetrahydrofuran, and tetrabutylammonium fluoride (1M in THF, 11 ml, 11 mmol) was added under stirring at room temperature under nitrogen atmosphere , the reaction was continued for 16 hours. After the reaction was detected by TLC, 50 ml of saturated ammonium chloride aqueous solution was added, followed by extraction with tertiary methyl ether; the organic phases were combined, dried, concentrated, and purified by column chromatography to obtain 3.82 g of ERB-4a with a yield of 96%.

Embodiment 3

[0076] Embodiment 3: the preparation of compound ERB-3a

[0077]

[0078] ERB-4a (3 g, 6.35 mmol) and DMAP (44.4 mmol) were dissolved in 40 ml of dichloromethane, ice water cooling reaction system to 0 ~ 5 ° C, then dropwise added pivaloyl chloride (4.98 g, 41.27 mmol). Return to room temperature after the dropwise addition is complete, stir; add after the completion of the TLC detection reaction, add dichloromethane and sodium bicarbonate aqueous solution, after liquid separation, the organic phase is washed with salt water, after concentration, obtain 3.25 grams of ERB-3a, yield 92%.

[0079] Embodiment 3: the preparation of compound ERB-2

[0080]

[0081] ERB-3a (2.5 g, 4.49 mmol) was dissolved in 20 ml of dichloromethane, cooled to 0 ° C, and 20 ml of 4% methanol solution of p-toluenesulfonic acid was added dropwise thereto under stirring, and TLC detected that the reaction was complete, adding The aqueous solution of sodium bicarbonate was adjusted to pH=7-8, an...

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Abstract

The invention provides a preparation method of an eribulin intermediate. According to the preparation method, a brand-new route and an intermediate are adopted to prepare a key intermediate ERB, compared with the prior art, the reaction route is greatly simplified, the reaction yield and the selectivity of a new chiral center of a target product are remarkably improved; and the preparation methodis especially suitable for industrial application.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of an eribulin intermediate. Background technique [0002] Halichondrin B (Halichondrin B) is a polyether macrolide compound containing only C, H, and O atoms isolated from the sponge Halichondria okadai by Japanese scientists Hirata and Uemura in 1986. Antitumor activity. The molecular structure of halichondrin B is very complex, including 32 chiral centers, with more than 4 billion isomers, and the synthesis is very difficult. Eribulin is a derivative of halichondrin B, and is a tubulin inhibitor. WO9965894 discloses the structure and synthesis method of Eribulin for the first time. 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. [0003] The molecular structure of eribulin contains 19 chiral centers,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/28C07D493/22C07F7/18
CPCC07D307/28C07D493/22C07F7/1804Y02P20/55
Inventor 徐安佗周宁袁建栋
Owner NANTONG NUOTAI BIOLOGICAL PHARMA CO LTD
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