Method for preparing eribulin intermediate through micro-channel reactor

A technology of microchannel reactors and intermediates, applied in chemical instruments and methods, chemical/physical/physical chemical reactors, chemical/physical processes, etc., can solve problems such as high energy consumption, cumbersome operations, and low reaction yields , to achieve the effect of increasing the reaction temperature, shortening the reaction time, and reducing the energy consumption of the reaction

Pending Publication Date: 2021-07-16
NANTONG NUOTAI BIOLOGICAL PHARMA CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] Chinese patent CN104876896A discloses the method for preparing compound NT027a06 from compound NT027a04 through a two-step reaction, the total yield is 84.6%, the operation is cumbersome, and the reaction yield is low
[0013] The preparation method of compound NT027a06 in the prior art either consumes a lot of energy (need to react at -78°C), and uses flammable and explosive n-butyllithium; or the reaction yield is low

Method used

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  • Method for preparing eribulin intermediate through micro-channel reactor
  • Method for preparing eribulin intermediate through micro-channel reactor
  • Method for preparing eribulin intermediate through micro-channel reactor

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Experimental program
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Effect test

Embodiment 1

[0030] The preparation of embodiment 1 compound NT027a06

[0031] Weigh 35 grams of NT027a04 (0.173 moles) and 185.9 grams of triphenylmethylphosphine bromide (0.519 moles), add them into 1000 mL of tetrahydrofuran and stir, and dissolve fully to form material I, which is transported to reaction module 1;

[0032] In addition, 138.4 ml of 2.5M n-butyl lithium in n-hexane (0.346 mol) was taken as material II and transported to reaction module 2;

[0033] Adjust the slurry pump so that the flow rate of material I is 10.6 ml / min, and the flow rate of material II is 2.2 ml / min. The two materials are mixed and reacted at 30°C in the mixing module, and the residence time is 80 seconds. The reaction liquid at the outlet is collected , quenched the reaction by adding saturated brine, and extracted the aqueous phase with ethyl acetate after separation. The organic phases were combined, spin-dried and purified by column chromatography to obtain 31.6 g of NT027a06, with a yield of 91.2%....

Embodiment 2

[0034] The preparation of embodiment 2 compound NT027a06

[0035] Weigh 33 grams of NT027a04 (0.163 moles) and 192.4 grams of triphenylmethylphosphine bromide (0.539 moles), add them to 1000 mL of tetrahydrofuran and stir, and dissolve fully to form material I, which is transported to reaction module 1;

[0036] In addition, 196 milliliters of 2.5M n-butyl lithium in n-hexane (0.490 moles) was taken as material II and transported to reaction module 2;

[0037] Adjust the slurry pump so that the flow rate of material I is 10.7 ml / min, and the flow rate of material II is 2.1 ml / min. The two materials are mixed and reacted at 50°C in the mixing module, and the residence time is 30 seconds. The reaction liquid at the outlet is collected , quenched the reaction by adding saturated brine, and extracted the aqueous phase with ethyl acetate after separation. The organic phases were combined, spin-dried and purified by column chromatography to obtain 31.1 g of NT027a06 with a yield of ...

Embodiment 3

[0038] The preparation of embodiment 3 compound NT027a06

[0039] Weigh 30 grams of NT027a04 (0.148 moles) and 212.1 grams of triphenylmethylphosphonium bromide (0.592 moles), add them to 1000 mL of tetrahydrofuran and stir, and dissolve fully to form material I, which is transported to reaction module 1;

[0040] In addition, 236.8 ml of 2.5M n-butyl lithium in n-hexane solution (0.592 mol) was taken as material II and transported to reaction module 2;

[0041] Adjust the slurry pump so that the flow rate of material I is 11.8 ml / min, and the flow rate of material II is 2.1 ml / min. The two materials are mixed and reacted at 70°C in the mixing module, and the residence time is 20 seconds. The reaction liquid at the outlet is collected , quenched the reaction by adding saturated brine, and extracted the aqueous phase with ethyl acetate after separation. The organic phases were combined, spin-dried and purified by column chromatography to obtain 26.6 g of NT027a06, with a yield ...

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Abstract

The invention provides a preparation method of an eribulin intermediate, and particularly provides a method for preparing the eribulin intermediate through a micro-channel reactor. Compared with the prior art, the method provided by the invention has the advantages that the reaction temperature is increased to be less than or equal to 50 DEG C from -78 DEG C, so that the reaction energy consumption is reduced, and meanwhile, a n-butyl lithium solution runs in a relatively closed system, so that the risk that the n-butyl lithium solution is in contact with air to cause combustion is reduced. In addition, according to the method provided by the invention, the reaction yield is remarkably improved.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a method for preparing an eribulin intermediate through a microchannel reactor. Background technique [0002] Eribulin mesylate was developed by Japan's Eisai Pharmaceutical Co., Ltd., and was approved by the FDA in the United States in November 2010. The product name is HALAVEN. It is the first single-drug chemotherapy for patients with metastatic breast cancer to improve overall survival It provides a new treatment method for patients with locally advanced breast cancer or metastatic breast cancer to improve the survival rate and quality of life, and is a drug with great application value. Its chemical structure is: [0003] [0004] Compound NT027a06 is an intermediate for the preparation of Eribulin, [0005] [0006] Kishi et al. disclosed the preparation method of NT027a06 (see: Org.Lett., Vol.11, No.20, 20094517). The reaction temperature for preparin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/04B01J19/00
CPCC07D493/04B01J19/0093
Inventor 徐安佗周宁张晓光
Owner NANTONG NUOTAI BIOLOGICAL PHARMA CO LTD
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