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Method for continuously preparing retegravir intermediate by using micro-channel reactor

A technology of microchannel reactors and intermediates, applied in chemical instruments and methods, chemical/physical/physical chemical processes, organic chemistry, etc., can solve problems such as harsh reaction conditions, cumbersome operation process, and difficulty in industrial scale-up, and achieve operational Simple, improve safety factor, good material mixing effect

Active Publication Date: 2021-01-29
NANJING ADVANCED BIOLOGICAL MATERIALS & PROCESS EQUIP INST CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Technical problem: The technical problem to be solved by the present invention is to provide a method for continuously preparing Remdesivir intermediate (2R, 3R, 4R, 5R)-2-(4-aminopyrrolo[2,1- f] method of [1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-carbonitrile to solve existing There are technical problems such as harsh reaction conditions, cumbersome operation process, environmental pollution, and difficulty in industrial scale-up

Method used

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  • Method for continuously preparing retegravir intermediate by using micro-channel reactor
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  • Method for continuously preparing retegravir intermediate by using micro-channel reactor

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Embodiment 1

[0042] This example provides a continuous preparation of remdesivir intermediate (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2, 4] The method of triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-carbonitrile, such as figure 1 Shown, concrete synthesis method comprises the following steps:

[0043] Weigh (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy) -5-((Benzyloxy)methyl)tetrahydrofuran-2-ol 27.60g (50mmol, 1.0equiv), fully dissolved in dichloromethane, prepared into a 50mL solution, as material Ⅰ; measure 8.8mL TfOH (100mmol , 2.0equiv), dissolved with an appropriate amount of dichloromethane, added 18.0mL TMSOTf (100mmol, 2.0equiv) to prepare a 50.0 mL solution as material II; measure 25.0mL TMSCN (200mmol, 4.0equiv) as material III. Pump material Ⅰ and material Ⅱ into the reaction system through a syringe pump, and then pump into material Ⅲ after being fully mixed. Among them, the feeding flow rate of material Ⅰ is 5.0mL / min,...

Embodiment 2

[0045] This example provides a continuous preparation of remdesivir intermediate (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2, 4] The method of triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-carbonitrile, such as figure 1 Shown, concrete synthesis method comprises the following steps:

[0046] Weigh (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy) -5-((Benzyloxy)methyl)tetrahydrofuran-2-ol 27.60g (50mmol, 1.0equiv), fully dissolved in dichloromethane, prepared into a 50mL solution, as material Ⅰ; measure 8.8mL TfOH (100mmol , 2.0equiv), dissolved with an appropriate amount of dichloromethane, added 18.0mL TMSOTf (100mmol, 2.0equiv) to prepare a 50.0 mL solution as material II; measure 25.0mL TMSCN (200mmol, 4.0equiv) as material III. Pump material Ⅰ and material Ⅱ into the reaction system through a syringe pump, and then pump into material Ⅲ after being fully mixed. Among them, the feeding flow rate of material Ⅰ is 5.0mL / min,...

Embodiment 3

[0048] This example provides a continuous preparation of remdesivir intermediate (2R,3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2, 4] The method of triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-carbonitrile, such as figure 1 Shown, concrete synthesis method comprises the following steps:

[0049] Weigh (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy) -5-((Benzyloxy)methyl)tetrahydrofuran-2-ol 27.60g (50mmol, 1.0equiv), fully dissolved in dichloromethane, prepared into a 50mL solution, as material Ⅰ; measure 8.8mL TfOH (100mmol , 2.0equiv), dissolved with an appropriate amount of dichloromethane, added 18.0mL TMSOTf (100mmol, 2.0equiv) to prepare a 50.0 mL solution as material II; measure 25.0mL TMSCN (200mmol, 4.0equiv) as material III. Pump material Ⅰ and material Ⅱ into the reaction system through a syringe pump, and then pump into material Ⅲ after being fully mixed. Among them, the feeding flow rate of material Ⅰ is 5.0mL / min,...

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Abstract

The invention discloses a method for continuously preparing a retegravir intermediate (2R, 3R, 4R, 5R)-2- (4-aminopyrrolo [2, 1-f] [1, 2, 4] triazine- 7-yl)-3, 4-bis (benzyloxy)-5 -((benzyloxy)methyl)tetrahydrofuran- 2-nitrile by using a micro-channel reactor, which comprises the following steps: pumping a material I and a material II into a mixer for mixing, and pumping a material III into the mixer for mixing; after mixing, conveying the mixture into a reaction module for reaction, pumping organic alkali into the reaction module to be mixed with reaction liquid, collecting effluent at a sample outlet, and performing aftertreatment to obtain the product. The micro-channel reactor provided by the invention has the characteristics of low price, convenience in transportation and cleaning, high mass and heat transfer efficiency, easiness in industrial amplification and the like.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, in particular to a method for continuously preparing an antiviral drug remdesivir intermediate (2R, 3R, 4R, 5R)-2-(4-aminopyrrolo[2,1- f] The method of [1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-carbonitrile. 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)methoxy)(phenoxy)phosphoryl)amino)propanoate, CAS No.: 1809249-37-3. It is an adenosine-like amino acid phospholipid precursor broad-spectrum antiviral drug, which has broad-spectrum antiviral activity against RNA viruses, and can inhibit atypical pneumonia (SARS coronavirus), Ebola coronavirus and other Coronavirus. On January 31, 2020, the "New England Journal of Medicine" reported the world's first case of using remdesivir to cure a patient diagnosed with new coronary...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04B01J19/00
CPCC07D487/04B01J19/00B01J2219/00984
Inventor 郭凯覃龙州邱江凯袁鑫陈琳孙蕲段秀吴蒙雨刘杰
Owner NANJING ADVANCED BIOLOGICAL MATERIALS & PROCESS EQUIP INST CO LTD