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Intermediate for preparing eribulin, and preparation method thereof

A compound and a defined technology, applied in the field of intermediates for the preparation of eribulin, can solve the problems of unsuitability for large-scale production, harsh reaction conditions, and potential safety hazards, and achieve the effects of low synthesis cost, easy operation, and frequent replacement

Active Publication Date: 2018-10-23
SELECTION BIOSCI LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] To sum up, the synthetic method of the above-mentioned publicly reported compound of formula II not only has harsh reaction conditions, cumbersome steps, high synthesis cost, but also has potential safety hazards, and is not suitable for large-scale production

Method used

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  • Intermediate for preparing eribulin, and preparation method thereof
  • Intermediate for preparing eribulin, and preparation method thereof
  • Intermediate for preparing eribulin, and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0170] Embodiment 1: preparation compound VIIa

[0171] Weigh VIa (10g, 36.7mmol) and MeONHMe·HCl (4.6g) into the flask, add 100mL THF to suspend, and slowly add 2.0M isopropylmagnesium chloride-tetrahydrofuran solution (30mL) to it at -30~0°C . After the reaction was stirred at -30~0°C for 30 minutes, TLC showed complete conversion of starting material. The reaction was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, concentrated and purified to obtain compound VIIa (10.3 g).

[0172] MS(ESI)m / z: 302(M+H + )

[0173] 1 H NMR (400MHz, Chloroform-d) δ7.87-7.73 (m, 2H), 7.36 (d, J=8.2Hz, 2H), 4.22 (dd, J=9.5, 8.2Hz, 1H), 3.99 (dd, J=9.5, 6.1Hz, 1H), 3.72(s, 3H), 3.35-3.30(m, 1H), 3.17(s, 3H), 2.46(s, 3H), 1.11(d, J=7.0Hz, 3H ).

Embodiment 2

[0174] Embodiment 2: Preparation of compound VIIa

[0175] VIa (10 g, 36.7 mmol), MeONHMe·HCl (4.6 g) and potassium carbonate (3.2 g) were weighed into the flask, suspended in 100 mL of DMF, stirred at 50° C. for 6 h, and TLC showed complete conversion of the raw materials. The reaction was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, concentrated and purified to obtain compound VIIa (9.8 g).

Embodiment 3

[0176] Embodiment 3: preparation compound VIIa

[0177] Via (10 g, 36.7 mmol), MeONHMe (6.5 g) and diisopropylethylamine (4.9 mL) were weighed into the flask, 200 mL of toluene was added, and after stirring at 80° C. for 12 h, TLC showed complete conversion of the starting material. The reaction was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, concentrated and purified to obtain compound VIIa (9.6 g).

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PUM

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Abstract

The invention relates to a preparation method of an eribulin intermediate, concretely relates to a compound represented by formula III, formula IV or formula X (R<1> is an alkyl group or a substitutedor unsubstituted aryl group), and especially relates to a preparation method of the compound represented by formula III, formula IV or formula X. The method has the advantages of mild reaction conditions, simplicity in operation, and low synthesis cost, and is suitable for large-scale production.

Description

technical field [0001] The invention relates to an intermediate for preparing eribulin and a preparation method thereof. Background technique [0002] Eribulin (as shown in formula I) is a derivative of halichondrin B, a macrolide compound extracted from the marine natural product Halichondria okadai, which is structurally optimized, and is a halichondrin-like microtubule dynamics inhibitor. Since the FDA first approved Eribulin Mesylate (Halaven) Injection on November 15, 2010 for the treatment of patients with metastatic breast cancer who have received at least two chemotherapy regimens, Eisai has actively expanded Eribulin's new indications. On January 28, 2016, the FDA approved it for the second-line treatment of unresectable or metastatic liposarcoma, becoming the world's first new anticancer drug that can significantly prolong the survival of patients with advanced soft tissue sarcoma. At present, the drug has been approved for the treatment of metastatic breast canc...

Claims

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Application Information

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IPC IPC(8): C07C17/093C07C21/17C07C303/30C07C309/73C07C21/22C07C17/087
CPCC07C17/093C07C303/30C07C309/73C07C17/04C07D493/22C07C21/22C07C21/17
Inventor 张富尧李火明
Owner SELECTION BIOSCI LLC
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