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Preparation method of key intermediate isomer of eribulin mesylate

A technology of intermediates and isomers, which is applied in the field of preparation of key intermediate isomers of eribulin mesylate, can solve the problem of preparing chiral isomers of key intermediates of eribulin that have not been found in literature reports And other issues

Pending Publication Date: 2022-04-29
NANJING GEAR PHARMA & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] At present, there is no method reported in the literature to prepare the chiral isomers of the key intermediate of eribulin

Method used

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  • Preparation method of key intermediate isomer of eribulin mesylate
  • Preparation method of key intermediate isomer of eribulin mesylate
  • Preparation method of key intermediate isomer of eribulin mesylate

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Preparation of compound 2

[0026] Glove box weighing CrCl 2 , (R)-N-(2-(4-isopropyl-4,5-dihydrooxazolin-2-yl)-6-methylphenyl)methanesulfonamide, cobalt phthalocyanine, Mn, LiCl and Et 3 Mix N HCl into the reaction flask, protect it with argon, stir vigorously, add the DME mixture of compound 1 and (S)-2,4-diiodo-3-methyl-1-butene to the system, and stir at room temperature 30min, then Zr(CP) 2 Cl 2 Add it to the above system, complete the addition, react at room temperature under an argon atmosphere, and when the reaction is complete, add 100mL MTBE to the system for dilution, add dropwise 30mL saturated sodium bicarbonate solution to quench the reaction, stir, filter with suction, and wash with 60mL MTBE, separate layer, and the organic phase was washed once with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain 1.5 g of compound 2 ...

Embodiment 2

[0028] Preparation of compound 3

[0029] Put 0.47g of compound 2, p-nitrobenzoic acid and triphenylphosphine into a 50mL single-port reaction flask, and add 10mL of anhydrous tetrahydrofuran, magnetically stir, nitrogen atmosphere, ice bath to cool down, and then add DIAD dropwise to the reaction system , After the addition, keep the reaction for 0.5h, remove the ice bath, and react at room temperature for 3h. After the reaction was completed, 50 mL of EA was added to the reaction system for dilution, and 20 mL of water was added to wash once, 20 mL of saturated saline was washed once, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the concentrate was mixed with silica gel, and purified by column chromatography to obtain 530 mg of compound 3. The yield is 86%.

Embodiment 3

[0031] Preparation of Compound 4

[0032] Put 530mg of compound 3 into a 50mL single-port reaction flask, add 8mL of methanol, and add 175mg of K to the reaction system 2 CO 3 , after addition, react at room temperature, after the reaction is over, remove methanol by rotary evaporation under reduced pressure, add 80mL EA to the residue for dilution, and add water (20mL x2) to wash twice, saturated brine (20mL x1) to wash once, anhydrous sodium sulfate After drying and concentration under reduced pressure, the concentrate was mixed with silica gel and purified by column chromatography to obtain 150 mg of compound 4 with a purity of 98% and a yield of 37%.

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Abstract

The invention provides a preparation method of an eribulin mesylate key intermediate isomer, which comprises the following steps: (1) reacting a compound 1 with (S)-2, 4-diiodo-3-methyl-1-butene to obtain a compound 2; (2) reacting the compound 2 with p-nitrobenzoic acid under the action of triphenylphosphine and diisopropyl azodicarboxylate to obtain a compound 3; and (3) removing a PNB protecting group from the compound 3 under the action of potassium carbonate to obtain a compound 4. The isomer obtained by the method has high purity, can meet the requirements of structure identification, impurity spectrum research and methodology verification, has the advantages of mild reaction conditions in each step, easy purification, simple operation and high yield, avoids the use of a liquid phase for preparation, and reduces the cost.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a preparation method of a key intermediate isomer of eribulin mesylate. Background technique [0002] In 1985, Uemura et al. isolated a polyether macrolide from the rare Japanese sponge Halichondria okadai, and named it halichondrin B (halichondrin B). Biological experiments have shown that halichondrin B has a strong inhibitory effect on cancer cells in vivo and in vitro in mice. Halichondrin B contains 32 chiral molecules, which is difficult to synthesize. [0003] In recent years, people have continuously optimized the structure of halichondrin B to obtain eribulin, compound 6, which is a macrocyclic ketone structure and has a significant therapeutic effect on metastatic breast cancer. At present, Eribulin mesylate injection has been marketed in many countries. [0004] [0005] The structure of Eribulin contains 19 chiral carbon molecules, and its synthesis and preparati...

Claims

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Application Information

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IPC IPC(8): C07D307/28
CPCC07D307/28
Inventor 陈磊蒋晓龙
Owner NANJING GEAR PHARMA & TECH CO LTD
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