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Intermediate for preparing eribulin, and preparation method thereof

A chiral center and configuration technology, applied in the field of intermediates for the preparation of eribulin, can solve the problems of difficult purification process, hazardous reagents, harsh reaction conditions, etc.

Pending Publication Date: 2021-08-06
SELECTION BIOSCI LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Aiming at the shortcomings of the existing synthetic method of the key intermediate of eribulin shown in formula II, the reaction conditions are harsh, the reagents are harmful, the purification process is difficult, and the purity is low, the present invention provides a kind of eribulin shown in formula II A new synthetic method for the intermediate of eribulin, which has mild and safe reaction conditions, simple and convenient operation and purification, high product purity, and is suitable for large-scale production of the intermediate of eribulin shown in formula II

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

[0048] Embodiment 1: preparation compound III

[0049] At 0°C, compound IV (20g, 31.90mmol, 1eq.) was dissolved in a mixed solvent of acetone (200mL) and water (50mL), and potassium osmate (117mg) and NMO (4.93g) were added successively, and the reaction was carried out at 20 Stirring at ℃ for 6 h, TLC showed that the conversion of the raw material was complete, and the reaction was quenched by adding an aqueous solution of sodium thiosulfate. After extraction with ethyl acetate, the organic phase was concentrated and purified by column chromatography to obtain 19.95 g of compound III.

[0050] MS (ESI) m / z: 661 (M+H + ).

[0051] 1H NMR (400MHz, Chloroform-d) δ7.74(d, J=7.9Hz, 2H), 7.34(d, J=7.9Hz, 2H), 3.92-3.76(m, 2H), 3.76-3.60(m, 5H), 3.61-3.45(m, 2H), 3.44-3.35(m, 2H), 3.31(d, J=6.5Hz, 3H), 3.00(dd, J=7.5, 3.9Hz, 2H), 2.68(q , J=7.6Hz, 2H), 2.50(q, J=6.1, 4.6Hz, 1H), 2.02-1.84(m, 2H), 1.87-1.51(m, 7H), 1.20(t, J=7.6Hz, 3H), 0.80(dd, J=3.8, 1.0Hz, 18H), 0.00(s, 6H),...

Embodiment 2

[0052] Embodiment 2: preparation compound III

[0053] At 20°C, compound IV (20g, 31.90mmol, 1eq.) was dissolved in a mixed solvent of tert-butanol (200mL) and water (50mL), and osmium tetroxide (95mg) and K 3 Fe(CN) 6 (15.75 g), the reaction was stirred at 40° C. for 2 h, TLC showed that the conversion of the starting material was complete, and an aqueous solution of sodium thiosulfate was added to quench the reaction. After extraction with ethyl acetate, the organic phase was concentrated and purified by column chromatography to obtain 19.02 g of compound III.

[0054] MS (ESI) m / z: 661 (M+H + ).

[0055] 1 H NMR (400MHz, Chloroform-d) δ7.74(d, J=7.9Hz, 2H), 7.34(d, J=7.9Hz, 2H), 3.92-3.76(m, 2H), 3.76-3.60(m, 5H), 3.61-3.45(m, 2H), 3.44-3.35(m, 2H), 3.31(d, J=6.5Hz, 3H), 3.00(dd, J=7.5, 3.9Hz, 2H), 2.68(q , J=7.6Hz, 2H), 2.50(q, J=6.1, 4.6Hz, 1H), 2.02-1.84(m, 2H), 1.87-1.51(m, 7H), 1.20(t, J=7.6Hz, 3H), 0.80(dd, J=3.8, 1.0Hz, 18H), 0.00(s, 6H), -0.04(s, 6H).

Embodiment 3

[0056] Embodiment 3: preparation compound II

[0057] At 0°C, compound III (18g, 27.23mmol, 1eq.) was dissolved in a mixed solvent of tetrahydrofuran (200mL) and water (200mL), sodium periodate (6.99g) was added, and the reaction was stirred at 25°C for 2h, TLC showed that the conversion of the raw material was complete, the reaction solution was filtered through celite, and the filter cake was washed with ethyl acetate. The filtrate was concentrated and purified by column chromatography to obtain 16.4 g of compound II. HPLC purity 99.3%.

[0058] MS (ESI) m / z: 629 (M+H + ).

[0059] 1 H NMR (400MHz, Chloroform-d) δ9.63 (t, J = 1.4Hz, 1H), 7.83-7.60 (m, 2H), 7.39-7.25 (m, 2H), 3.94-3.81 (m, 2H), 3.78-3.63(m, 2H), 3.49(dd, J=10.2, 5.5Hz, 1H), 3.38(dd, J=10.2, 5.5Hz, 1H), 3.29(s, 3H), 3.22(dd, J= 14.1, 5.1Hz, 1H), 3.00 (dd, J = 14.1, 8.9Hz, 1H), 2.81 (ddd, J = 17.5, 6.5, 1.8Hz, 1H), 2.78 (q, J = 7.6Hz, 2H), 2.70(ddd, J=17.5, 5.9, 1.2Hz, 1H), 2.42(ddd, J=8.9, 5.0, 1.2Hz, 1...

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Abstract

The invention relates to an eribulin intermediate and a preparation method thereof. Specifically, the invention relates to a compound shown as a formula III. The invention also particularly relates to a preparation method of the compound as shown in the formula III, and a method for preparing the compound as shown in the formula II from the compound as shown in the formula III. The method has the advantages of mild and safe reaction conditions, simplicity and convenience in operation and purification, high product purity and the like, 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. Eribulin mesylate injection (Halaven) was first approved by the FDA on November 15, 2010, for the treatment of patients with metastatic breast cancer who have received at least two chemotherapy regimens, and was approved in China on July 17, 2019. Listed in batches. [0003] [0004] Eribulin has a complex molecular structure, containing 40 carbon atoms, of which 19 carbon atoms have chiral centers. The current market supply of drugs can only be achieved through total synthesis. Patent CN108659031 discloses an eribulin intermediate represented by formula II, which is prepared from a...

Claims

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Application Information

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IPC IPC(8): C07F7/18C07D493/22
CPCC07D493/22C07F7/1804C07F7/1892
Inventor 张富尧李火明
Owner SELECTION BIOSCI LLC
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