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Eribulin intermediate and preparation method thereof

A compound and reaction technology, applied in the field of preparation of eribulin intermediates, can solve the problems of low diastereoselectivity, additional steps, high synthesis cost, etc., and achieve reduction of redox reactions, high diastereoselectivity, Synthetic green and efficient effects

Active Publication Date: 2018-10-16
SELECTION BIOSCI LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The first one starts from dihydrofuran (Synlett 2013, 24, 327). The reaction stereoselectivity in the whole synthetic route is very poor. It needs to be prepared and separated by chiral HPLC in two stages to obtain qualified optical isomers. mass production
The second route starts from D-quinic acid (Angew.Chem.Intl.Ed.2015, 54, 5108), the linear steps are as long as 27 steps, and the cost of raw material D-quinic acid is relatively high
However, judging from the synthesis strategy of the whole Eribulin, this route is very important for R 1 , R 2 The oxidation state of the connected carbon atoms has been repeatedly changed, thereby increasing the non-skeleton strategic synthesis steps such as redox reactions, protection and deprotection reactions, and reducing the overall synthesis efficiency
[0011] To sum up, the synthetic method of the above-mentioned publicly reported compound of formula II not only has harsh reaction conditions, cumbersome steps, low diastereoselectivity, high synthesis cost, but also has potential safety hazards, and is not suitable for large-scale production

Method used

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  • Eribulin intermediate and preparation method thereof
  • Eribulin intermediate and preparation method thereof
  • Eribulin intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0165] Embodiment 1: Preparation of compound XIIIa

[0166] Dissolve N-methyl-N'-methoxy-chloroacetamide (132g, 959mmol) and triphenylphosphine (239g, 911mmol) in toluene, stir at room temperature for 15 hours, wash with 2N aqueous potassium hydroxide ( 1L*2), then washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 279g of XIIIa as a white powdery solid.

[0167] MS (ESI) m / z: 364 (M+H + )

[0168] 1 H NMR (400MHz, Chloroform-d) δ7.82-7.61(m, 6H), 7.63-7.52(m, 3H), 7.50-7.43(m, 6H), 3.75(s, 3H), 3.56(s, 1H ), 3.10(s, 3H).

Embodiment 2

[0169] Example 2: Preparation of Compound XIa

[0170] Compound XII (19.4g, 114mmol) was dissolved in 100mL of acetonitrile, and compound XIIIa (46g, 114mmol) was added in three batches. The reaction solution was stirred at room temperature for 10min, and the reaction solution was concentrated and separated by column chromatography to obtain 31g of XIa. Yellow viscous oil.

[0171] MS (ESI) m / z: 256 (M+H + )

[0172] 1 H NMR (400MHz, Chloroform-d) δ7.15(d, J=15.4Hz, 1H), 6.91(d, J=15.4Hz, 1H), 6.17(d, J=5.3Hz, 1H), 5.54(d , J=2.6Hz, 1H), 5.39(dd, J=5.3, 2.6Hz, 1H), 3.76(s, 3H), 3.30(s, 3H), 1.48(s, 3H), 1.45(s, 3H) .

Embodiment 3

[0173] Embodiment 3: preparation compound Xa

[0174] Compound XIa (31g, 114mmol) was dissolved in 500mL of tetrahydrofuran, added with 10% Pd / C (water content 60%), hydrogenated at 60°C for 19h under normal pressure, the reaction was complete, filtered and concentrated to obtain 24.4g of colorless Xa Oil.

[0175] MS (ESI) m / z: 260 (M+H + )

[0176] 1 H NMR (400MHz, Chloroform-d) δ 5.76 (d, J = 4.0Hz, 1H), 4.72 (ddd, J = 6.3, 4.0, 1.3Hz, 1H), 4.30-4.03 (m, 1H), 3.68 ( s, 3H), 3.16(s, 3H), 2.67-2.53(m, 2H), 2.32-2.04(m, 2H), 1.92(m, 2H), 1.54(s, 3H), 1.30(s, 3H) .

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Abstract

The invention relates to an eribulin intermediate and a preparation method thereof. In particular, the invention relates to a compound represented by a formula II shown in the description, wherein X is a halogen or halogenoid group, preferably chloro, bromo, iodo, or a trifluoromethanesulfonate group, and more preferably the iodo; R<1> and R<2> are acetal protecting groups or thioacetal protectinggroups, and independently C1-10 alkyloxy or C1-10 alkyl thiol, or the R<1> and the R<2> are combined to form a cyclic acetal or cyclic thioacetal structure. The R<1> and the R<2> are preferably cyclic acetal or cyclic thioacetal substituents, and more preferably a substituted or unsubstituted ethylene glycol acetal structure or a substituted or unsubstituted propylene glycol acetal structure. Theinvention particularly relates to the preparation method of the compound represented by the formula II. The method disclosed by the invention has the advantages of mild reaction conditions, high selectivity, easy purification, low synthetic costs and the like, and is suitable for large-scale production.

Description

technical field [0001] The invention relates to a preparation method of an eribulin intermediate. 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 cancer in more than 60 coun...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D407/06C07D409/06C07D309/24C07D309/22C07D309/26C07D309/30C07D309/10C07D493/04C07F9/535
CPCC07B2200/07C07D309/10C07D309/22C07D309/24C07D309/26C07D309/30C07D407/06C07D409/06C07D493/04C07F9/5352Y02P20/55
Inventor 张富尧张歆宁李火明
Owner SELECTION BIOSCI LLC
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