Chiral alpha-amino phosphonate ester compounds having anti-virus activity and containing benzothiazole heterocycle, preparation and applications thereof

An antiviral activity and aminophosphonate technology, which is applied to a class of chiral α-aminophosphonate compounds containing benzothiazole heterocycles with antiviral activity and the fields of preparation and application, can solve the problem of poor catalytic efficiency of catalysts. higher question

Active Publication Date: 2015-10-21
GUIZHOU UNIV
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Problems solved by technology

[0022] According to the above-mentioned literature reports, the chiral catalysts mainly used in the synthesis of optically active α-aminophosphonates include biphenylnaphthols, Cinchona bases, thioureas, guanidines, pyrroles, etc., because these catalysts are suitable for substrate imines with specific structures and nucleophile phosphites, and the catalytic efficiency of the catalysts is not high
At present, there is no literature report on the catalytic synthesis of chiral α-aminophosphonate compounds containing heterocyclic benzothiazoles using thiourea-quinine chiral catalysts. The reaction conditions are mild and the catalysts are cheap and easy to obtain. , the yield and ee value are both higher than 90%, the operation is simple, and this kind of compound also has good anti-plant virus activity

Method used

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  • Chiral alpha-amino phosphonate ester compounds having anti-virus activity and containing benzothiazole heterocycle, preparation and applications thereof
  • Chiral alpha-amino phosphonate ester compounds having anti-virus activity and containing benzothiazole heterocycle, preparation and applications thereof
  • Chiral alpha-amino phosphonate ester compounds having anti-virus activity and containing benzothiazole heterocycle, preparation and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] Embodiment one, ( R )- O,O ’ -Diphenyl-1-(4-methylbenzo[ d ]thiazole-2-amino)-1-(phenyl)methylphosphonate (the compound number is ( R )-4a) Synthesis:

[0098] (1) Synthesis of (4-methylbenzothiazol-2-yl)-1-(phenyl)imine (3a):

[0099] Add 2-amino-4-methylbenzothiazole (1.64 g, 10 mmol), acetic acid (0.12 g, 20 mol %), toluene (50 mL) and benzaldehyde (1.02 g, 10 mmol ) into a 100 mL circle In a three-neck flask at the bottom, heat the system to reflux and divide water, cool to room temperature after reaction, evaporate the solvent under reduced pressure, and recrystallize petroleum ether to obtain a yellow solid imine with a yield of 56% and a melting point of 78-80 °C;

[0100] (2)( R )- O, O ’ -Diphenyl-1-(4-methylbenzo[ d Synthesis of ]thiazole-2-amino)-1-(phenyl)methylphosphonate

[0101] At room temperature, add 25 mg (0.1 mmol of phenyl-4-methylbenzothiazolimine, 6 mg (0.01 mmol ( S ) solid thiourea quinine catalyst, and 15 particles of freshly baked...

Embodiment 2

[0102] Embodiment two, ( R )- O, O ’ -Diphenyl-1-(4-methylbenzo[ d ]thiazole-2-amino)-1-(2-fluorophenyl)methylphosphonate (the compound number is ( R )-4b) Synthesis:

[0103](1) Synthesis of (4-methylbenzothiazol-2-yl)-1-(2-fluorophenyl)imine (3b):

[0104] Synthesize as in Example 1 (1) method and conditions. The difference is that 2-fluorobenzaldehyde (1.24 g, 10 mmol) was added, the reaction time was 10 h, the yield was 56%, and the melting point was 109-111°C.

[0105] (2) Prepared according to the method and conditions of Example 1 (2). The difference is that 27 mg (0.1 mmol) of (2-fluorophenyl)-1-(4-methylbenzothiazole)imine was added and reacted for 1 hour to obtain 49 mg of the target compound with a yield of 98%. The target compound was tested for optical purity, the results are shown in image 3 ,Depend on image 3 It can be seen that the ee value is 97%. (Chromatographic conditions: using a chiral IA column, at room temperature, the detection wavelength ...

Embodiment 3

[0106] Embodiment three, ( R )- O, O ’ -Diphenyl-1-(4-methylbenzo[ d ]thiazole-2-amino)-1-(2-chlorophenyl)methylphosphonate (the compound number is ( R )-4c) Synthesis:

[0107] (1) Synthesis of (4-methylbenzothiazol-2-yl)-1-(2-chlorophenyl)imine (3c):

[0108] Synthesize as in Example 1 (1) method and conditions. The difference is that 2-chlorobenzaldehyde (1.40 g, 10 mmol) was added, the reaction time was 10 h, the yield was 48%, and the melting point was 137-138°C.

[0109] (2) Prepared according to the method and conditions of Example 1 (2). The difference is that 29 mg (0.1 mmol) of (2-chlorophenyl)-1-(4-methylbenzothiazole)imine was added and reacted for 1 hour to obtain 51 mg of the target compound with a yield of 98%. The target compound was tested for optical purity, the results are shown in Figure 4 ,Depend on Figure 4 It can be seen that the ee value is 97%. (Chromatographic conditions: using a chiral IA column, at room temperature, the detection wavele...

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Abstract

The present invention discloses a class of chiral alpha-amino phosphonate ester compounds having anti-virus activity and containing benzothiazole heterocycle, preparation and applications thereof, wherein the structure of the compound is represented by the following general formula (I). According to the present invention, thiourea or thiourea quinidine is adopted as a chiral catalyst, a 4A molecular sieve is adopted as a cocatalyst, and dichloromethane is adopted as solvent to rapidly synthesize the high yield and high optical activity chiral alpha-amino phosphonate ester compound containing benzothiazole heterocycle at a room temperature; and especially treatment, protection and activity passivation of the compound R-4h on cucumber mosaic virus are superior to the commercial agent ningnanmycin, treatment, protection and activity passivation of the compound R-4q on tobacco mosaic virus are superior to the commercial agent ningnanmycin, and the compounds R-4h and R-4q provide good inhibition effects on tobacco mosaic virus (TMV), cucumber mosaic virus (CMV), Southern rice black-streaked dwarf virus (SRBSDV) and the like, have good universality, and can be used for anti-plant virus chiral pesticide preparation. The formula (1) is defined in the specification.

Description

technical field [0001] The invention relates to a high yield and high optical activity containing benzothiazole heterocycle α- An asymmetric preparation method of an amino phosphonate compound and an application with good inhibitory effect on tobacco mosaic virus disease, cucumber mosaic virus disease and southern rice black-streaked dwarf virus disease. Background technique [0002] According to statistics: among the 650 kinds of pesticides in the world, 173 kinds of chiral pesticides have been commercialized, and another 22 kinds of chiral pesticides are under development. Among them, there are more than 30 species with annual sales of more than 100 million US dollars, and more than 60 species with annual sales of more than 25 million US dollars; The annual sales of sexual pesticides are close to 3 billion, and chiral pesticides account for 35% of the global market. Moreover, monochiral pesticides have the advantages of high efficacy, low dosage, less waste, safer for cr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6541A01P1/00
Inventor 宋宝安张国平胡德禹薛伟李向阳陈美航潘建科罗亮指
Owner GUIZHOU UNIV
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