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Atazanavir bulk drug impurity or salt thereof, preparation method and applications thereof

A technology of atazanavir and raw material medicine, applied in the field of atazanavir raw material medicine impurity or its salt, its preparation and application, can solve the problems of containing impurities, unable to effectively identify, unable to effectively control the quality of atazanavir, etc. , to achieve the effect of high yield and purity, simple operation

Pending Publication Date: 2017-08-08
SHANGHAI INST OF PHARMA IND +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The technical problem to be solved by the present invention is to overcome the existing atazanavir or its salt containing impurities, can not effectively identify, and then can not effectively control the technical problems of atazanavir quality, and provides a kind of atazanavir Drug substance impurity or its salt, its preparation method and application

Method used

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  • Atazanavir bulk drug impurity or salt thereof, preparation method and applications thereof
  • Atazanavir bulk drug impurity or salt thereof, preparation method and applications thereof
  • Atazanavir bulk drug impurity or salt thereof, preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Compound N-methoxycarbonyl tert-leucine (3.5g, 18.5mmol), EDCI (3.9g, 21.1mmol), HOBt (2.85g, 21.1mmol) and dichloromethane (40mL) were added into a 250mL three-necked flask at room temperature to respond in the bottle. Stir at 20°C-30°C for 0.5-1 hour, add K 2 HPO 4 Aqueous solution (8.8 g, 5 mL / g), stirring was continued for 1 hour.

[0037] Dissolve 2.5g (5.3mmol) of the trihydrochloride salt of the compound represented by formula (II) in 15-25ml of water, slowly drop into the above reaction solution, and stir at room temperature for 24 hours; water (100mL×2), NaHCO 3 (100mL×2) and brine (100mL) wash the reaction solution, collect the organic phase, concentrate, and dry to obtain a yellow solid, which is separated by preparative liquid phase (the HPLC figure is shown in image 3 ), collecting the eluent with a retention time of 35 minutes-40 minutes, concentrated and dried to obtain the target compound with a yield of 85%; HPLC purity greater than 98%.

[0038] A...

Embodiment 2

[0055] Compound N-methoxycarbonyl tert-leucine (3.5g, 18.5mmol), EDCI (3.9g, 21.1mmol), HOBt (2.85g, 21.1mmol) and dichloromethane (40mL) were added into a 250mL three-necked flask at room temperature. in the bottle. Stir at 20-30°C for 0.5-1 hour, add K 2 HPO 4 Aqueous solution (8.8 g, 5 mL / g), stirring was continued for 1 hour. Add 2.0 g (5.3 mmol) of the compound shown in formula (II), stir at room temperature for 24 hours, water (100 mL×2), NaHCO 3 (100mL×2) and brine (100mL) to wash the reaction solution, collect the organic phase, concentrate, and dry to obtain a yellow solid, which is separated by liquid phase preparation, and the eluate with a retention time of 35 minutes to 40 minutes is collected, concentrated and dried to obtain The yield of the target compound (the structure identification data is the same as that in Example 1) is 90%, and the HPLC purity is greater than 98%.

[0056] Other experimental conditions and results are as follows:

[0057]

Embodiment 3

[0059] Compound N-methoxycarbonyl tert-leucine (3.5g, 18.5mmol), EDCI (3.9g, 21.1mmol), HOBt (2.85g, 21.1mmol) and dichloromethane (40mL) were added into a 250mL three-necked flask at room temperature. in the bottle. Stir at 20-30°C for 0.5-1 hour, add K 2 HPO 4 Aqueous solution (8.8 g, 5 mL / g), stirring was continued for 1 hour.

[0060] Dissolve 3.8g (8.0mmol) of the compound of formula (II) in 15-25ml of water, slowly drop it into the above reaction solution, and stir at room temperature for 24 hours; water (100mL×2), NaHCO 3 (100mL×2) and brine (100mL) wash the reaction solution, collect the organic phase, concentrate, and dry to obtain a yellow solid, which is separated from the preparation liquid phase (the specific conditions are the same as in Example 1, and its HPLC figure is shown in Figure 4 ), collecting and washing the eluent with a retention time of 20 minutes to 30 minutes, concentrating and drying to obtain atazanavir, the HPLC purity is greater than 98%. ...

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Abstract

The present invention discloses an atazanavir bulk drug impurity or a salt thereof, a preparation method and applications thereof. The preparation method of the atazanavir bulk drug impurity represented by a formula (I) comprises: in a solvent, under the catalysis of a condensation agent, carrying out a condensation reaction defined in the specification on a compound represented by a formula (II) or a hydrochloride thereof and a compound represented by a formula (III) to prepare the atazanavir bulk drug impurity represented by the formula (I). The invention further discloses applications of the atazanavir bulk drug impurity represented by the formula (I) or the salt thereof as an impurity reference substance in atazanavir quality control. According to the present invention, the atazanavir bulk drug impurity or the salt thereof is the essential substance for the quality control of the atazanavir or the salt thereof, and can effectively identify the impurity in the atazanavir or the salt product thereof so as to control the quality of the atazanavir or the salt thereof; and the operation of the preparation method is simple. The condensation reaction process is defined in the specification.

Description

technical field [0001] The invention relates to an atazanavir raw material drug impurity or a salt thereof, a preparation method and application thereof. Background technique [0002] Atazanavir Sulfate, trade name Reyataz, was developed by Bristol-Myers Squibb and was approved by the US FDA in June 2003. It is mainly used in combination with other antiretroviral drugs to treat HIV infection . [0003] Atazanavir sulfate or atazanavir bisulfate, chemical name is (3S,8S,9S,12S)-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4, 11-Dioxo-9-(phenylmethyl)-6-[[4-(2-pyrimidine)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid Dimethyl sulfate (1:1), the structure is as follows: [0004] Contents of the invention [0005] The technical problem to be solved by the present invention is to overcome the existing atazanavir or its salt containing impurities, can not effectively identify, and then can not effectively control the technical problems of atazanavir quality, and provide...

Claims

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Application Information

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IPC IPC(8): C07D213/42G01N30/02G01N30/34
Inventor 黄军海葛渊源张一凯李淑群邹存媛杨婷婷
Owner SHANGHAI INST OF PHARMA IND
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