Device and method for rapidly constructing quinolone compound library

Abstract

The invention provides a device and a method for quickly constructing a quinolone compound library. According to the method, all the synthesis steps are continuously carried out in the reactor, and the intermediate does not need to be treated or separated, so that the required product is provided at a good yield. According to the method, the reaction is rapid and efficient, the reagent switching is simple, and hundreds of or more quinolone compounds with definite structures can be rapidly synthesized on a large scale. Knowledge technologies such as program design and automatic control are combined and integrated, drug molecules are continuously synthesized for researchers, and the research progress is accelerated. Various quinolone compound molecules can be obtained by adopting the quinolone compound library construction method disclosed by the invention, and can be directly applied to activity research.

Description

technical field

[0001] The invention relates to a device and method for rapidly constructing a library of quinolone compounds. Background technique

[0002] Continuous flow chemistry technology is a technology that uses pumps to provide power to carry out chemical reactions in microchannels in a continuous flow mode. Continuous flow chemistry technology has been transformed from a niche academic application research to a recognized industrial technology with broad application prospects in the pharmaceutical field. Several cases of rapid synthesis of multiple drugs or molecules have been reported based on continuous flow chemistry techniques. For example, in 2016, the research group of Jamison and Jensen of the Massachusetts Institute of Technology developed a continuous flow drug synthesis platform system with compact structure and flexible assembly configuration (Science, 2016, 352, 61-67.), which can be completed every day. Continuous synthesis of 1,000 doses of diphenhy...

Examples

Embodiment 1

[0062] Because the first feed pump, the second feed pump and the fourth feed pump in the synthesis process need to change different reaction reagents, a multi-channel electromagnetic selector valve is connected to these three pumps respectively, and all pre-prepared The reagents are respectively connected to different positions of the multi-channel electromagnetic selection valve, and the multi-channel electromagnetic selection valve is used to complete the switching of the reagents.

[0063] First, a series of primary amines (cyclopropylamine, ethylamine, 2,4-difluoro) were selected from ethyl 3-ethoxy-2-(2,4,5-trifluorobenzoyl)acrylate Aniline, etc.) and secondary amines (piperazine, N-methylpiperazine, 2-methylpiperazine, 2,6-dimethylpiperazine, 3-aminopyrrolidine, tetrahydropyrrole, piperidine, etc.) to construct A library of quinolones.

[0064] A total of 70 compounds are to be synthesized in this project, and 70 synthesis cycles are required. The operation process of ...

Embodiment 2

[0069] ethyl 3-ethoxy-2-(2,6-dichloro-5-fluoronicotinoyl)acrylate and 3-ethoxy-2-(2,4,5-trifluoro-3-chlorobenzene, respectively formyl) ethyl acrylate as the starting material, a series of primary amines (cyclopropylamine, ethylamine, 2,4-difluoroaniline, etc.) and secondary amines (piperazine, N-methylpiperazine, 2-methyl piperazine, 2,6-dimethylpiperazine, 3-aminopyrrolidine, tetrahydropyrrole, piperidine, etc.) to construct a library of quinolone compounds. According to the method of Example 1, a total of 140 quinolones were synthesized, and the automatically synthesized compounds were as follows:

[0070]

[0071]

Embodiment 3

[0073] Using 3-ethoxy-2-(2,3,4,5-tetrafluorobenzoyl) ethyl acrylate as the starting material and dimethyl sulfoxide as the solvent, S-(+)-2- Aminopropanol is a primary and a series of secondary amines (N-methylpiperazine, piperazine, piperidine, 1-[(3S)-3-pyrrolidine]-piperidine, cis-7-azabicyclo[ 3.3.0] octane, etc.) to construct a library of quinolone compounds. According to the method of Example 1, 9 quinolones including levofloxacin were synthesized, and the automatically synthesized compounds were as follows:

[0074]

[0075] The mass spectrometry characterization data of the compounds in the examples are as follows:

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

technical field

[0001] The invention relates to a device and method for rapidly constructing a library of quinolone compounds. Background technique

[0002] Continuous flow chemistry technology is a technology that uses pumps to provide power to carry out chemical reactions in microchannels in a continuous flow mode. Continuous flow chemistry technology has been transformed from a niche academic application research to a recognized industrial technology with broad application prospects in the pharmaceutical field. Several cases of rapid synthesis of multiple drugs or molecules have been reported based on continuous flow chemistry techniques. For example, in 2016, the research group of Jamison and Jensen of the Massachusetts Institute of Technology developed a continuous flow drug synthesis platform system with compact structure and flexible assembly configuration (Science, 2016, 352, 61-67.), which can be completed every day. Continuous synthesis of 1,000 doses of diphenhy...

Examples

Embodiment 1

[0062] Because the first feed pump, the second feed pump and the fourth feed pump in the synthesis process need to change different reaction reagents, a multi-channel electromagnetic selector valve is connected to these three pumps respectively, and all pre-prepared The reagents are respectively connected to different positions of the multi-channel electromagnetic selection valve, and the multi-channel electromagnetic selection valve is used to complete the switching of the reagents.

[0063] First, a series of primary amines (cyclopropylamine, ethylamine, 2,4-difluoro) were selected from ethyl 3-ethoxy-2-(2,4,5-trifluorobenzoyl)acrylate Aniline, etc.) and secondary amines (piperazine, N-methylpiperazine, 2-methylpiperazine, 2,6-dimethylpiperazine, 3-aminopyrrolidine, tetrahydropyrrole, piperidine, etc.) to construct A library of quinolones.

[0064] A total of 70 compounds are to be synthesized in this project, and 70 synthesis cycles are required. The operation process of ...

Embodiment 2

[0069] ethyl 3-ethoxy-2-(2,6-dichloro-5-fluoronicotinoyl)acrylate and 3-ethoxy-2-(2,4,5-trifluoro-3-chlorobenzene, respectively formyl) ethyl acrylate as the starting material, a series of primary amines (cyclopropylamine, ethylamine, 2,4-difluoroaniline, etc.) and secondary amines (piperazine, N-methylpiperazine, 2-methyl piperazine, 2,6-dimethylpiperazine, 3-aminopyrrolidine, tetrahydropyrrole, piperidine, etc.) to construct a library of quinolone compounds. According to the method of Example 1, a total of 140 quinolones were synthesized, and the automatically synthesized compounds were as follows:

[0070]

[0071]

Embodiment 3

[0073] Using 3-ethoxy-2-(2,3,4,5-tetrafluorobenzoyl) ethyl acrylate as the starting material and dimethyl sulfoxide as the solvent, S-(+)-2- Aminopropanol is a primary and a series of secondary amines (N-methylpiperazine, piperazine, piperidine, 1-[(3S)-3-pyrrolidine]-piperidine, cis-7-azabicyclo[ 3.3.0] octane, etc.) to construct a library of quinolone compounds. According to the method of Example 1, 9 quinolones including levofloxacin were synthesized, and the automatically synthesized compounds were as follows:

[0074]

[0075] The mass spectrometry characterization data of the compounds in the examples are as follows:

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

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