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A method for preparing the key intermediate of remdesivir by using a microchannel reaction device

A channel reaction device and a technology for microchannel reaction, which can be used in the preparation of sugar derivatives, chemical instruments and methods, chemical/physical/physical-chemical reactors, etc., and can solve the problems of harsh reaction conditions, low reaction efficiency, and difficulty in industrial amplification. , to achieve the effect of simple operation, improved safety factor, good ability to remove reaction heat and cooling ability

Active Publication Date: 2021-10-01
NANJING TECH UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Purpose of the invention: The technical problem to be solved by the present invention is to address the deficiencies of the prior art, and to provide a method for preparing the key intermediate (3R, 4R, 5R)-2-(4-aminopyrrolo) of Remdesivir using a microchannel reaction device. [2,1-f][1,2,4]triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol method to solve the problems of harsh reaction conditions, low reaction efficiency, and difficulty in industrial scale-up in the prior art

Method used

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  • A method for preparing the key intermediate of remdesivir by using a microchannel reaction device
  • A method for preparing the key intermediate of remdesivir by using a microchannel reaction device
  • A method for preparing the key intermediate of remdesivir by using a microchannel reaction device

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Embodiment 1

[0038] This example provides a method for preparing the key intermediate of remdesivir (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4] using a microchannel reaction device Triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol, such as figure 1Shown, concrete synthesis method comprises the following steps:

[0039] Weigh 5.20g (20mmol, 1.0equiv) of 7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine, fully dissolve in tetrahydrofuran solvent, and add 5.0mL TMS-Cl (40mmol, 2.0equiv), prepared into 100mL solution, as material Ⅰ; measure PhMgCl 2 (2M, 40mmol, 2.0equiv) tetrahydrofuran solution 20mL and 20mL i PrMgCl 2 LiCl (1M, 20mmol, 1.0equiv) was mixed with THF solution as material II; 8.36g (20mmol, 1.0 equiv), fully dissolved in tetrahydrofuran solvent, prepared into 50mL solution, as material III. Simultaneously pump material I and material II, wherein, material I is pumped at a flow rate of 2.5 mL / min, and material II is pumped at a flow rate of 1.0 mL / min. Aft...

Embodiment 2

[0041] This example provides a method for preparing the key intermediate of Remdesivir (3R, 4R, 5R)-2-(4-aminopyrrolo[2,1-f][1,2,4] using a microchannel reaction device Triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol, such as figure 1 Shown, concrete synthesis method comprises the following steps:

[0042] Weigh 5.20g (20mmol, 1.0equiv) of 7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine, fully dissolve it in tetrahydrofuran solvent, and add 5.0mL TMS-Cl (40mmol, 2.0equiv), prepared into 80mL solution, as material Ⅰ; measure PhMgCl 2 (2M, 40mmol, 2.0equiv) tetrahydrofuran solution 20mL and 20mL i PrMgCl 2 LiCl (1M, 20mmol, 1.0equiv) was mixed with tetrahydrofuran solution as material II; 8.36g (20mmol, 1.0 equiv), fully dissolved in tetrahydrofuran solvent, prepared into 50mL solution, as material III. Simultaneously pump material Ⅰ and material Ⅱ, wherein, the pumping flow rate of material Ⅰ is 2.5 mL / min, and the pumping flow rate of material Ⅱ is 1...

Embodiment 3

[0044] This example provides a method for preparing the key intermediate of remdesivir (3R,4R,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4] using a microchannel reaction device Triazin-7-yl)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol, such as figure 1 Shown, concrete synthesis method comprises the following steps:

[0045] Weigh 5.20g (20mmol, 1.0equiv) of 7-iodopyrrolo[2,1-f][1,2,4]triazin-4-amine, fully dissolve it in tetrahydrofuran solvent, and add 5.0mL TMS-Cl (40mmol, 2.0equiv), prepared into 50mL solution, as material Ⅰ; measure PhMgCl 2 (2M, 40mmol, 2.0equiv) tetrahydrofuran solution 20mL and 20mL i PrMgCl 2 LiCl (1M, 20mmol, 1.0equiv) was mixed with tetrahydrofuran solution as material II; 8.36g (20mmol, 1.0 equiv), fully dissolved in tetrahydrofuran solvent, prepared into 50mL solution, as material III. Simultaneously pump material I and material II, wherein, material I is pumped at a flow rate of 2.5 mL / min, and material II is pumped at a flow rate of 2...

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Abstract

The invention discloses a method for preparing a key intermediate of remdesivir by using a microchannel reaction device, which comprises the following steps: (1) 7-iodopyrrolo[2,1-f][1,2,4]three The oxazine-4-amine is added to the organic solvent, then trimethylchlorosilane is added, and the resulting mixed solution is used as the first material; the organic mixed solution of phenylmagnesium chloride and isopropylmagnesium chloride·magnesium chloride is used as the second material; 2, 3,5-Tris-O-benzyl-D-ribose-1,4-lactone is added to the organic solvent as the third material; (2) the first material and the second material are pumped into the microchannel reaction device simultaneously. In the first micro-mixer, the first micro-reactor reacts after mixing; (3) the first micro-reactor effluent and the third material are simultaneously pumped into the second micro-mixer of the micro-channel reaction device, and after mixing Pass into the second microreactor for reaction, collect the effluent, and get it.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and specifically relates to a method for preparing the key intermediate (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 method. Background technique [0002] After a large number of screenings and preliminary clinical experiments, scientific research teams at home and abroad have proved that a batch of existing antiviral drugs such as favipiravir, chloroquine phosphate, remdesivir, etc. can play a positive role in the treatment of new coronary pneumonia. As a drug with the most potential for the treatment of new coronary pneumonia, decivir has received great attention. [0003] Remdesivir, the chemical name is (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, is a Nucleotide a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H15/18C07H1/00B01J19/00
CPCB01J19/0093C07H1/00C07H15/18
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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