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[0015] In summary, the currently reported synthetic strategies have a lot in common, that is, the oxidation state of the C14 position is basically an alcohol, and this oxidation state needs to be adjusted by adding an oxidant during the subsequent reaction.
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Embodiment 1
[0298] Embodiment 1: preparation compound VIIa
[0299] To a solution of Villa (8.17 g, 18 mmol) in THF (150 mL) at room temperature was first added Et 3 N (16.2 g) was then slowly added MsCl (12.1 g). After the addition was complete, the reaction continued to stir under these conditions for 1 h. After the completion of the reaction as detected by TLC, the reaction solution was quenched with saturated aqueous sodiumbicarbonate solution, extracted with ethyl acetate, and the concentrated solution was purified by column to obtain compound VIIa (8.76 g).
[0303] To a solution of VIIIb (1.02g, 2.1mmol) in dichloromethane (15mL) was added pyridine (2.3g) at -30°C, followed by the slow addition of Ms 2 O (1.59 g). After the addition was complete, the reaction continued to stir under these conditions for 3h. After the completion of the reaction as detected by TLC, the reaction solution was quenched with saturated aqueous sodiumbicarbonate solution, extracted with ethyl acetate, and the concentrated solution was purified by column to obtain compound VIIb (1.06 g).
[0304] MS (ESI) m / z: 529 (M+H + )
Embodiment 3
[0305] Embodiment 3: preparation compound VIIc
[0306] To a solution of VIIIc (0.68g, 1.3mmol) in ethyl acetate (15mL) was added 2,6-lutidine (2.1g) at -10°C, followed by the slow addition of Ms 2 O (1.06g). After the addition was complete, the reaction continued to stir under these conditions for 30 min. After the completion of the reaction as detected by TLC, the reaction solution was quenched with saturated aqueous sodiumbicarbonate solution, extracted with ethyl acetate, and the concentrated solution was purified by column to obtain compound VIIc (0.72 g).
[0307] MS (ESI) m / z: 557 (M+H + )
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Abstract
The invention relates to Eribulin intermediates and a preparation method thereof. Particularly, the invention relates to compound shown in a formula II, formula III and formula V, wherein Ar is a C1-10 alkyl substituted or alkyloxy substituted or unsubstituted aryl group, R1 and R2 are aldehydeacetal protecting groups or thioacetal protecting groups, R3 is hydrogen or a hydroxy protecting group,and X is halogen or a leaving group. The invention particularly relates to the preparation method of the compounds shown in the formula II, formula III and formula V. The preparation method has the advantages of mild reaction conditions, high selectivity, easy purification, low synthesis cost and the like, and is suitable for large-scale production.
Description
technical field [0001] The invention relates to an eribulin intermediate 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 EribulinMesylate (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 tissuesarcoma. At present, the drug has been approved for the treatment of metastatic breast cancer in more tha...
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