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Synthesis method of eribulin intermediate

A synthesis method and intermediate technology, which are applied in the field of pharmaceutical intermediate synthesis, can solve the problems of high cost, poor selectivity, difficult purification and the like, and achieve the effects of simple operation, mild conditions and low cost.

Active Publication Date: 2020-03-27
杭州励德生物科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0022] The purpose of the present invention is to solve the existing problems of long synthetic route, poor selectivity, high cost, difficult purification, and difficulty in industrial production of such compounds, and provide a synthetic method for eribulin intermediates, which has the advantages of converging synthesis, Short route, high yield, mild conditions, easy operation, etc., suitable for industrial scale-up production

Method used

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  • Synthesis method of eribulin intermediate
  • Synthesis method of eribulin intermediate
  • Synthesis method of eribulin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065]

[0066] 1. Preparation of compound XIVa

[0067] Dissolve 4-penten-1-ol (30.0g, 0.35mol) in 150mL DMF, add imidazole (35.6g, 0.52mol), cool down to 0 degrees, and add TBDPSCl (100.5g, 0.365mol) dropwise to the reaction solution . Stir for 1 hour, quench with water, extract with 300 mL of tert-butyl methyl ether, wash with 150 mL of 5% HCl water and 150 mL of saturated brine successively. Concentration gave 110 g of a colorless oily product of formula XIVa, with a yield of 97.3%.

[0068] 1H NMR (400MHz, CDCl3) 7.68-7.66(m, 4H), 7.43-7.35(m, 6H), 5.84-5.75(m, 1H), 4.99(dd, 1H), 4.93(d, 1H), 3.67( t, 2H), 2.17-2.12 (m, 2H), 1.67 (q, 2H), δ1.07 (s, 9H).

[0069] 2. Preparation of Compound XIIIa

[0070] Formula XIVa (25g, 77mmol) was dissolved in 400mL of anhydrous DCM, 30% hydrogen peroxide (460mmol) and Ti-cis-salalen catalyst (23mmol) of 50mL were added, and 30% hydrogen peroxide ( 460mmol), and 50mL of 30% hydrogen peroxide (460mmol) was added again after 24 h...

Embodiment 2

[0099]

[0100] 1. Preparation of compound VIIIb

[0101]

[0102] The Julia reagent (28.8g, 77.4mmol) of the compound of formula IXb was added to 200mL of tetrahydrofuran, the temperature was lowered, and the temperature was controlled below -50°C, 77.4mL of 1.0M KHDMS solution in tetrahydrofuran was added dropwise to the reaction flask, and stirred for 15- 20 minutes. Control the temperature below -50°C, add 25.0 g of aldehyde (formula Xa, 51.2 mmol) in tetrahydrofuran (100 mL) dropwise into the reaction flask, and HPLC / TLC detects that the reaction of the raw materials is complete. Add 200 mL of saturated ammonium chloride and 500 mL of tetrahydrofuran, stir for 30 minutes, separate and discard the water layer. The organic layer was washed with 150 mL of saturated sodium chloride water, concentrated, and passed through the column to obtain 28 g of the product (Formula VIIIb), with a yield of 86.0%.

[0103] 1 H-NMR (CDCl-400MHz): 7.69-7.66 (m, 4H), 7.42-7.36 (m, 6H...

Embodiment 3

[0116] Embodiment 3 A kind of synthetic method of Eribulin intermediate B-13

[0117] The synthesis path is as follows:

[0118] (1)

[0119] (2)

[0120] For the specific process of step (1) of this embodiment, refer to [0015] to [0017] in the specification of CN105330686A.

[0121] For the specific process of step (2) of this embodiment, refer to the document J.AM.CHEM.SOC.2009, 131, 15636-15641.

[0122] The compound shown in formula V is synthesized by the synthetic method of Example 1 or Example 2.

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Abstract

The invention discloses a synthesis method of an eribulin intermediate. The synthesis method comprises the following steps: (1) carrying out an alkene-forming reaction Julia Olefination on a compoundrepresented by formula X and a compound represented by formula IX to obtain a compound represented by formula VIII; (2) performing hydroxyl deprotection on the compound of formula VIII to obtain a compound represented by formula VII; (3) performing sulfonyl chloride protection on hydroxyl groups of the compound of the formula VII to obtain a compound represented by formula VI; and (4) carrying outan intramolecular cyclization reaction on the compound of formula VI to obtain the compound represented by formula V. The method has the advantages of convergence synthesis, short route, high yield,mild conditions, simplicity in operation and the like, and is suitable for industrial large-scale production.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a synthesis method of an eribulin intermediate. Background technique [0002] In 1985, Uemura et al. isolated a macrocyclic polyether macrolide containing only C, H and O from Halichondria Okadai, a rare sponge in Japan, and named it halichondrin B (formula I, halichondrin B). Biological experiments have shown that it has a strong inhibitory effect on cancer cells in vivo and in vitro in mice. The National Cancer Institute (NCI) conducted in-depth activity research and evaluation on 60 cancer cell lines and found that halichondrin B has a unique anti-cancer mechanism. In 1992, professors such as Kashi from Harvard University characterized the structure of halichondrin B: molecular formula C61H88O36, containing 32 chiral carbon atoms, 18 polyether segments, and 12 macrolides. Afterwards, Kashi artificially synthesized halichondrin B and its simpl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18C07D307/28
CPCC07D307/28C07F7/1804C07F7/1892Y02P20/55
Inventor 胡高强孙立波李传兵林浩任国宝吴彦
Owner 杭州励德生物科技有限公司
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