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Eribulin intermediate and synthesis method and application thereof

A compound and a selected technology, which are applied in the field of intermediates of Eribulin and its synthesis, can solve the problems of long synthetic route, difficult control of optical purity of starting materials, complicated purification of intermediates, etc.

Active Publication Date: 2020-10-30
BEIJING TIENYI LUFU PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

For example, the synthetic route is too lengthy, the optical purity of the starting materials is difficult to control, and the purification of intermediates is complicated and costly
In addition, some of the reactions used in the above synthesis methods also have the disadvantage of poor stereoselectivity. In addition, there are many chiral carbon atoms in the product molecule, and it is very easy to form isomers with similar properties and difficult to remove during the synthesis process, which is not conducive to ensuring product purity

Method used

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  • Eribulin intermediate and synthesis method and application thereof
  • Eribulin intermediate and synthesis method and application thereof
  • Eribulin intermediate and synthesis method and application thereof

Examples

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preparation example Construction

[0182] The preparation method of the present invention will be further described in detail in conjunction with specific examples below. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies realized based on the above contents of the present invention are covered within the scope of protection intended by the present invention.

[0183] The experimental methods used in the following examples are conventional methods unless otherwise specified; the reagents and materials used in the following examples can be obtained from commercial sources unless otherwise specified.

Embodiment 1

[0184] The synthesis of embodiment 1 compound 9

[0185] 1.1 Synthesis of Compound 4

[0186]

[0187] Dissolve deoxyribose 1 (100g) in water (400mL), lower the temperature to about 5°C, slowly add liquid bromine (200g) dropwise over 3 hours, and raise the temperature to 30°C for 24h after the drop (the raw material disappears as detected by spotting). Post-processing: 1) Add ethyl acetate (100mL×2) for extraction, the organic phase is in the lower layer, add ethyl acetate (50mL) for the third extraction, and the organic phase is in the upper layer; 2) Combine the organic phases and add water (50mL×2) Extract the product contained therein; 3) Combine the aqueous phases, neutralize bromine (with a small amount) with saturated sodium thiosulfate, then cool down to 0°C, adjust the pH of the solution to about 3 (the amount of solid NaOH is about 61g), Diatomaceous earth filtration; 4) When the filtrate is concentrated to a viscous liquid containing a small amount of solid, add...

Embodiment 2

[0199] The synthesis of embodiment 2 compound 10

[0200]

[0201] Dissolve compound 9 (149.5g) in DCM (818mL), add PPTs (5.4g), add trimethyl orthoacetate (82.4mL) dropwise, react at room temperature for 1h, and evaporate the solvent to obtain the product epimer Mixture 9a.

[0202] Compound 9a obtained above was redissolved in DCM (818mL), acetyl bromide (47.9mL) was added dropwise, and reacted at room temperature for 0.5h after dropping, and the solvent was evaporated to obtain a mixture of compounds 9b-1 and 9b-2.

[0203] The above mixture of compounds 9b-1 and 9b-2 was dissolved in anhydrous methanol (1500 mL), potassium carbonate (119 g) was added, and reacted at room temperature for 8 h. Post-processing: adding saturated ammonium chloride solution, extracting with DCM, drying, filtering, concentrating, and silica gel column chromatography to obtain 123 g of the refined compound 10 with a yield of 87%. 1 H NMR (400MHz, CDCl 3 )δ7.38–7.25(m,7H),6.87(d,J=13.2Hz,2H),...

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Abstract

The invention belongs to the field of drug synthesis, and particularly relates to an eribulin intermediate and a synthesis method and application thereof. The invention provides an intermediate whichcan be used for synthesizing halichondrin B, eribulin or analogues thereof, particularly C27-C35 structural fragments thereof, as well as a preparation method and application of the intermediate. Theinitial raw materials of the synthetic route are cheap and easy to obtain, and the optical purity of the synthetic route can be guaranteed so that the optical purity of C27-C35 structural fragments inhalichondrin, eribulin or analogues thereof is guaranteed; according to the method, the chiral center of the C27-C35 structural fragment is constructed, the diastereoselectivity and yield are high, and especially the preparation method of the compounds shown in the formula (X), the formula (XI), the formula (XVI) and the formula (XV) is provided; partial reaction by-products can be removed only by recrystallization so that purification is facilitated, and the cost is greatly reduced.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to an intermediate of eribulin and its synthesis method and application. Background technique [0002] Halichondrin B (Halichondrin B) is a natural product with a complex structure existing in the cavernous body, which has strong anti-tumor effects and broad medicinal prospects. However, due to the limited supply of halichondrin B from natural sources, its research and development progress has also been limited. [0003] Eribulin (Eribulin) is a macrocyclic ketone analog obtained by structure optimization of halichondrin B. Eribulin mesylate injection has been approved by the US FDA for the treatment of metastatic breast cancer. [0004] [0005] Eribulin has a complex structure, and its molecule contains 19 chiral carbon atoms. The total synthesis route currently used is as long as 62 steps, and the stereo control during the total synthesis process is a technical prob...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C43/23C07C41/26C07D303/04C07D301/24C07D317/22C07D407/06C07F7/08C07F7/18
CPCC07C43/23C07D303/04C07D301/24C07F7/083C07D317/22C07D407/06C07F7/1804C07F7/081C07F7/188C07F7/1892Y02P20/55C07D493/22
Inventor 徐为平
Owner BEIJING TIENYI LUFU PHARMATECH CO LTD
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