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Method for synthesizing darunavir intermediate by using microchannel reactor

A microchannel reactor, darunavir technology, applied in chemical instruments and methods, chemical/physical/physical-chemical reactors, preparation of organic compounds, etc. It can reduce the amount of hydrogen, reduce the impurity content, and improve the purity and yield.

Pending Publication Date: 2022-01-07
LIVZON GROUP CHANGZHOU KONY PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0023] Therefore, in order to overcome the problems of existing darunavir intermediate reduction preparation methods such as complex process, high solvent demand, danger of violent explosion, and potential safety hazards in large-scale production, the present invention provides a method for synthesizing darunavir using a microchannel reactor. The method of Navir intermediate, specifically a darunavir intermediate 4-amino-N-(2R, 3S)-(3-amino-2-hydroxyl-4-phenyl-butyl)-N- The microchannel hydrogenation reduction preparation method of isobutyl-benzenesulfonamide, using 1-benzyl-2,3-epoxy n-propyl-carbamic acid tert-butyl ester as starting material, through amination, sulfonylation, de-Boc Protecting group, microchannel hydrogenation reduction reaction to generate darunavir intermediate 4-amino-N-(2R,3S)-(3-amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl -Benzenesulfonamide

Method used

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  • Method for synthesizing darunavir intermediate by using microchannel reactor
  • Method for synthesizing darunavir intermediate by using microchannel reactor
  • Method for synthesizing darunavir intermediate by using microchannel reactor

Examples

Experimental program
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Embodiment 1

[0058] A method utilizing a microchannel reactor to synthesize darunavir intermediates, specifically comprising the following steps:

[0059] (1), weigh 4-nitro-N-(2R, 3S)-(3-amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl-benzenesulfonamide hydrochloride 50.0 g (108mmol), dissolved in solvent A methanol 350.0g, stirred and dissolved;

[0060] (2), weigh 5.0g palladium carbon (palladium accounts for 5% of the total mass of the catalyst), add to the slurry and stir fully to obtain the mixture as material a;

[0061] (3), transport material a to preheating module 1 with material pump A at 30ml / min for preheating;

[0062] (4), the hydrogen is controlled by the flowmeter B and delivered to the preheating module 2 at 400ml / min for activation;

[0063] (5), the material a and hydrogen after step (3) and step (4) are processed pass into the reaction module group to react, and the 4-nitro-N-(2R, 3S)-(3 in hydrogen and material a -Amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl-benzenesulfon...

Embodiment 2

[0066] The difference between this embodiment and Example 1 is that the amount of palladium carbon in the step (2) of this embodiment is 1.5g, and the HPLC purity of the material in the filtered filtrate obtained is 97.26%, and the obtained 4-amino-N-(2R, 3S)- (3-Amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl-benzenesulfonamide 36.9 g, HPLC purity 99.0%, mass yield 87%.

Embodiment 3

[0068] This example differs from Example 1 in that: the solvent A in the step (1) of this example is ethanol, and the HPLC purity of the material in the filtered filtrate is 99.49%, and the obtained 4-amino-N-(2R, 3S)- (3-amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl-benzenesulfonamide 39.9 g, HPLC purity 99.6%, mass yield 94%.

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Abstract

The invention discloses a method for synthesizing a darunavir intermediate by using a microchannel reactor. The synthesis method comprises the following steps: taking 1-benzyl-2, 3 epoxy n-propyl-tert-butyl carbamate as an initial raw material, and carrying out amination, sulfonylation, Boc protecting group removal and microchannel hydrogenation reduction reaction to generate the darunavir intermediate 4-amino-N-(2R, 3S)-(3-amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl-benzenesulfonamide. The method has the advantages of simplicity in operation, safety, environment friendliness, easiness in batch synthesis, low energy consumption and high purity.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing a darunavir intermediate using a microchannel reactor, which is suitable for synthesizing the drug darunavir intermediate 4-amino-N-(2R, 3S )-(3-Amino-2-hydroxy-4-phenyl-butyl)-N-isobutyl-benzenesulfonamide. Background technique [0002] Darunavir (Darunavir) is a drug developed by Johnson & Johnson Pharmaceuticals for the treatment of AIDS. Darunavir Ethanolate (Darunavir Ethanolate) was first listed in the United States and Canada in 2006. [0003] Darunavir is a new non-peptide antiretroviral protease inhibitor for AIDS treatment, which was successfully developed for the first time by Tibotec, an Icelandic branch of Johnson & Johnson Pharmaceuticals. The most bioavailable of navir, indinavir, nalfinavir, amprenavir and ABT378 / r), by blocking the formation of new, mature virions released from the surface of infected host cells , It works by in...

Claims

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Application Information

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IPC IPC(8): C07C269/06C07C271/20C07C303/38C07C311/18C07C303/40C07C311/41B01J19/00B01J23/44
CPCC07C269/06C07C303/38C07C303/40B01J19/0093B01J23/44C07C271/20C07C311/18C07C311/41Y02P20/55
Inventor 华任茂卢兵刘可可陈争一李鸣海许雨恬范华玉
Owner LIVZON GROUP CHANGZHOU KONY PHARMA
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