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A kind of method that microchannel reaction device prepares remdesivir

A micro-channel reaction and micro-reactor technology, applied in chemical instruments and methods, chemical/physical/physical-chemical reactors, compounds of elements of Group 5/15 of the periodic table, etc., can solve the cumbersome reaction process and the reaction yield. Low, industrial scale-up difficulties, etc.

Active Publication Date: 2021-08-20
NANJING TECH UNIV
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  • Abstract
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  • Claims
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Problems solved by technology

[0005] Purpose of the invention: The technical problem to be solved by the present invention is to aim at the deficiencies of the prior art, and to provide a method for efficiently preparing remdesivir (S)-2-ethylbutyl 2-(((((S) -(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3, 4-dihydroxytetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl) amino) propionate method, to solve the complex reaction process, low reaction yield, industrial amplification difficulties, etc. that exist in the prior art question

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  • A kind of method that microchannel reaction device prepares remdesivir
  • A kind of method that microchannel reaction device prepares remdesivir
  • A kind of method that microchannel reaction device prepares remdesivir

Examples

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Embodiment 1

[0031] This example provides a method for efficiently preparing remdesivir (S)-2-ethylbutyl 2-((((S)-(((2R,3S,4R,5R)-5 -(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy)phosphoryl)amino)propionate methods, such as figure 1 Shown, concrete synthesis method comprises the following steps:

[0032] Weigh (S)-2-ethylbutyl 2-((((S)-(((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1 ,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxotetracyclan-4-yl)methoxy )(phenoxy)phosphoryl)amino)propionate 13.12g (20mmol, 1.0equiv), fully dissolved in tetrahydrofuran, prepared into 100mL solution, as material Ⅰ; measure 20mL 37% hydrochloric acid (240mmol, 12.0equiv) , as material Ⅱ. Pumping material Ⅰ and material Ⅱ at the same time, wherein, the flow rate of material Ⅰ is 5.0mL / min, and the flow rate of material Ⅱ is 1.0mL / min. The materials are mixed in the micro mixer and sent to the micro reaction Reaction in the reacto...

Embodiment 2

[0034] This example provides a method for efficiently preparing remdesivir (S)-2-ethylbutyl 2-((((S)-(((2R,3S,4R,5R)-5 -(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy)phosphoryl)amino)propionate methods, such as figure 1 Shown, concrete synthesis method comprises the following steps:

[0035] Weigh (S)-2-ethylbutyl 2-((((S)-(((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1 ,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxotetracyclan-4-yl)methoxy )(phenoxy)phosphoryl)amino)propionate 13.12g (20mmol, 1.0equiv), fully dissolved in tetrahydrofuran, prepared into 100mL solution, as material Ⅰ; measure 20mL 37% hydrochloric acid (240mmol, 12.0equiv) , as material Ⅱ. Simultaneously pump material Ⅰ and material Ⅱ, wherein, the flow rate of material Ⅰ is 4.0mL / min, and the flow rate of material Ⅱ is 0.8mL / min. The materials are mixed in the micro mixer and sent to the micro reaction Reaction in the container, ...

Embodiment 3

[0037] This example provides a method for efficiently preparing remdesivir (S)-2-ethylbutyl 2-((((S)-(((2R, 3S, 4R, 5R)-5 -(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy)phosphoryl)amino)propionate methods, such as figure 1 Shown, concrete synthesis method comprises the following steps:

[0038] Weigh (S)-2-ethylbutyl 2-((((S)-(((3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1-f][1 ,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxotetracyclan-4-yl)methoxy )(phenoxy)phosphoryl)amino)propionate 13.12g (20mmol, 1.0equiv), fully dissolved in tetrahydrofuran, prepared into 100mL solution, as material Ⅰ; measure 20mL 37% hydrochloric acid (240mmol, 12.0equiv) , as material Ⅱ. At the same time, the material Ⅰ and material Ⅱ are pumped in. Among them, the flow rate of material Ⅰ is 2.5mL / min, and the flow rate of material Ⅱ is 0.5mL / min. The materials are mixed in the micro-mixer and then sent to the micro-reaction ...

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Abstract

The invention discloses a method for preparing remdesivir by a microchannel reaction device, comprising the following steps (1) dissolving the compound represented by formula I in an organic solvent to obtain a first reaction liquid; using hydrochloric acid as a second reaction liquid (2) The first reaction solution and the second reaction solution are pumped into the micro-mixer of the microchannel reaction device at the same time, and after mixing, they are passed into the micro-reactor for reaction, and the effluent is collected to obtain the product. Compared with the prior art, the microchannel reaction device adopted by the present invention has better ability to remove reaction heat and cooling capacity, can add strong acid at room temperature, and the microchannel reaction device has better mass and heat transfer efficiency, The safety factor of the reaction is improved. At the same time, the microchannel reaction device adopts the continuous flow method, which has good material mixing effect and extremely low back mixing, which can effectively improve the reaction selectivity and product quality. And the raw material conversion rate is 75-92%, and the product yield is as high as 70-86%.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, in particular to a method for efficiently preparing remdesivir (S)-2-ethylbutyl 2-((((S)-(((2R,3S,4R, 5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy)(phenoxy)phosphoryl)amino)propionate method. Background technique [0002] Remdesivir, chemical name: (2S)-2-ethylbutyl2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1f][1 ,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)met hoxy)(phenoxy)phosphoryl)amino)propanoate, CAS No.: 1809249-37-3, is a Nucleotide analog prodrugs, which have good broad-spectrum antiviral activity against RNA viruses, can inhibit atypical pneumonia (SARS coronavirus), Ebola coronavirus and other coronaviruses (bioRxiv.2020). Since December 2019, the novel coronavirus pneumonia (COVID-19) epidemic has been raging around the world, and the World Health Organization declared it a global pandemic. As of now, the cu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561B01J19/00
CPCB01J19/0093C07F9/6561
Inventor 郭凯覃龙州邱江凯袁鑫崔玉声庄恺强陈琳孙蕲段秀
Owner NANJING TECH UNIV
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