CN112824411B - Bridged ring isoindolinone derivatives, and preparation method and application thereof - Google Patents

Abstract

The invention provides bridged ring isoindolinone derivatives, and a preparation method and application thereof, and relates to isoindolinone compounds which have a chemical structural general formula shown in III.

Description

Bridged ring isoindolinone derivatives, and preparation method and application thereof

The technical field is as follows:

the invention belongs to the field of chemistry, and particularly relates to a bridged ring isoindolinone compound, and a preparation method and application thereof.

Background art:

the compounds containing isoindolinone skeleton are a very important class of nitrogen-containing heterocyclic compounds, which are widely present in many natural products. Because of important biological activity, such as serving as antioxidant, anti-inflammatory, antiviral, anticancer, antibacterial and enzyme inhibitor, and the like, the isoindolinone structural unit-containing compound is also successfully applied to the field of biological medicine, the research on the synthesis and biological activity of the isoindolinone skeleton-containing compound is widely concerned by chemical and biological chemists, and a great deal of research on the synthesis method and properties of the isoindolinone derivative skeleton is continuously reported. Of the isoindolinone derivatives, polycyclic isoindolinone derivatives have also received great attention due to their novel structures and unique properties, and many synthetic methods have been developed (G za St. jer et al, Current Organic Chemistry, 2012, 16, 1005-1050). However, in these methods for constructing polycyclic isoindolinone derivatives, the substrate is complicated, the synthesis procedure is often long, and the operation is complicated. A new simple and rapid method for preparing the polycyclic isoindolinone compound is developed, and the method has important significance for laying a solid foundation for potential biomedical application. And the research on the synthesis method and activity of the endocyclic isoindolinone compound is less reported. The invention develops a class of endocyclic isoindolinone derivatives and a preparation method thereof, and finds that the endocyclic isoindolinone derivatives show good antibacterial activity at a lower concentration.

The invention content is as follows:

the invention aims to provide a preparation method and application of endocyclic isoindolinone derivatives.

The general chemical structure formula of the bridged ring isoindolinone derivative is shown in the specification in III:

wherein R is¹Selected from: hydrogen, methyl, methoxy, fluoro; r²、R³、R⁴Selected from: hydrogen, methyl, methoxy, bromo, fluoro.

The synthesis method of the bridged ring isoindolinone derivative III comprises the following steps:

wherein R is¹Selected from: hydrogen, methyl, methoxy, fluoro; ar is selected from: phenyl, 2-bromophenyl, 3-bromophenyl, 4-fluorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl; r²、R³、R⁴Selected from: hydrogen, methyl, methoxy, bromo, fluoro.

The method comprises the following steps:

A. preparation of starting material I:

under the protection of inert gas and at the temperature of-78 ℃, dropwise adding an equivalent amount of n-butyllithium hexane solution into an equivalent amount of o-bromobenzaldehyde imine tetrahydrofuran solution, stirring at low temperature for reaction for 30 minutes to prepare a corresponding lithium salt solution, then placing the lithium salt solution in a carbon monoxide atmosphere at normal pressure, stirring for reaction for 1 hour, adding water for hydrolysis, removing the solvent under reduced pressure, purifying the residue by a 200-300-mesh silica gel column chromatography, and obtaining an initial raw material I by using ethyl acetate/petroleum ether as an eluent.

Wherein the structural formula of the o-bromobenzaldehyde imine is as follows:

wherein R is¹Selected from: hydrogen, methyl, methoxy, fluoro.

B. Preparation of intermediate II:

under the protection of inert gas and at room temperature, dropwise adding 2.2 equivalents of tetrahydrofuran solution of bis (trimethylsilyl) amino potassium (KHMDS for short) into 1 equivalent of tetrahydrofuran solution of an initial raw material I, reacting at room temperature for 30 minutes, adding 2.5 equivalents of benzyl bromide or substituted benzyl bromide, stirring at room temperature for 12 hours, removing the solvent under reduced pressure, purifying the residue by 200-300-mesh silica gel column chromatography, and obtaining an intermediate II by using ethyl acetate/petroleum ether as an eluent; the substituted benzyl bromide is selected from o-benzyl bromide, m-benzyl bromide, p-benzyl fluorobromide, p-benzyl methylbromide, m-benzyl methoxybromide and p-benzyl methoxybromide.

C. Preparation of endocyclic isoindolinone derivative III:

under the protection of inert gas and at room temperature, adding 3.5 equivalents of powdery aluminum trichloride into 1 equivalent of dichloromethane solution of the intermediate II, stirring at room temperature for 12 hours, adding 40% sodium hydroxide aqueous solution for hydrolysis, separating liquid, extracting an aqueous phase with dichloromethane, combining organic phases, drying with anhydrous sodium sulfate, removing the solvent under reduced pressure, purifying the residue by 200-300-mesh silica gel column chromatography, and obtaining the endocyclic isoindolinone derivative III by using ethyl acetate/petroleum ether as an eluent.

Use of endocyclic isoindolinone derivatives III in the preparation of agricultural and horticultural plant fungicides.

The specific implementation mode is as follows:

the following examples are intended to illustrate the invention only and are not intended to limit the invention.

Example 1

Synthesis of 2- (2, 2-diethoxyethyl) -5-methyl-2, 3-dihydro-1H-isoindolin-1-one (starting Material Ia)

To a 25 ml round bottom flask were added 5-methyl-2-bromobenzaldehyde (4.0 g, 20 mmol), aminoacetal (3.7 ml, 25 mmol) in that order, and then the reaction was heated to 100 ℃ and stirred for 5 hours. After cooling to room temperature, add 10Ml of ethyl acetate, the layers were separated and the organic phase was dried over anhydrous sodium sulfate. Removing ethyl acetate under reduced pressure, distilling under reduced pressure, collecting 119 ℃ and 121 ℃/76 Pa fractions to obtain a yellow oily substance, namely 2, 2-diethoxy-N- [ (2-bromo-5-methylphenyl) methylene]Ethylamine. Yield 71% (4.46 g).¹H NMR(400MHz，CDCl₃)：δ8.62(s，1H)，7.81(s，1H)，7.44-7.40(m，1H)，7.08-7.04(m，1H)，4.82(t，J＝4.8Hz，1H)，3.84-3.81(m，2H)，3.77-3.70(m，2H)，3.63-3.55(m，2H)，2.31(s，3H)，1.25-1.20(m，6H)。

Tetrahydrofuran (30 ml) and 2, 2-diethoxy-N- [ (2-bromo-5-methylphenyl) methylene were added sequentially to a 100 ml reaction flask under argon protection]Ethylamine (0.63 g, 2 mmol), then the reaction was cooled to-78 deg.C and a solution of n-butyllithium in hexane (1.6 mol/l, 1.25 ml, 2 mmol) was added and stirring continued for 30 minutes after addition. The reaction mixture was then placed under an atmosphere of carbon monoxide at normal pressure, stirred for 1 hour, then water (0.20 ml, 11 mmol) was slowly added thereto, and the reaction was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, the residue was passed through a 200-mesh 300-mesh silica gel column, purified with ethyl acetate/petroleum ether (60-90 ℃ C.) (2: 5 by volume) as an eluent, and the solvent was removed under reduced pressure to give the starting material Ia. Yellow oil, yield 44% (0.23 g).¹H NMR(400MHz，CDCl₃)：δ7.72(d，J＝7.8Hz，1H)，7.26-7.24(m，2H)，4.69(t，J＝5.4Hz，1H)，4.49(s，2H)，3.79-3.73(m，2H)，3.70(d，J＝5.4Hz，2H)，3.60-3.52(m，2H)，2.45(s，3H)，1.20(t，J＝7.1Hz，6H)。

Example 2

Synthesis of 2- (2, 2-diethoxyethyl) -3, 3-dibenzyl-5-methyl-2, 3-dihydro-1H-isoindolin-1-one (intermediate IIa)

Under the protection of argon and at room temperature, a tetrahydrofuran solution (1.0 mol/L, 2.2 ml, 2.2 mmol) of potassium bis (trimethylsilyl) amide (KHMDS) is added dropwise into a tetrahydrofuran solution (20 ml) of the starting material Ia (0.31 g, 1 mmol), after reaction for 30 minutes at room temperature, benzyl bromide (0.30 ml, 2.5 mmol) is added, and the reaction is continued for 12 hours under stirring at room temperature, and then reducedRemoving the solvent under reduced pressure, purifying the residue by 200-300 mesh silica gel column chromatography, eluting with ethyl acetate/petroleum ether (60-90 deg.C) (1: 3, volume ratio) as eluent, and removing the solvent under reduced pressure to obtain intermediate IIa. Yellow oil, 68% yield (0.30 g).¹H NMR(400MHz，CDCl₃)：δ7.38(d，J＝7.7Hz，1H)，7.05-7.00(m，7H)，6.74-6.72(m，4H)，6.48(s，1H)，5.01(t，J＝5.1Hz，1H)，3.78-3.70(m，2H)，3.57(d，J＝5.0Hz，2H)，3.54-3.49(m，2H)，3.39(d，J＝14.1Hz，2H)，3.06(d，J＝14.1Hz，2H)，2.24(s，3H)，1.10(t，J＝7.0Hz，6H)。

Example 3

Synthesis of endocyclic isoindolinone derivative III-9

Powdery aluminum trichloride (0.23 g, 1.75 mmol) was added to a dichloromethane solution (20 ml) of intermediate IIa (0.22 g, 0.5 mmol) under argon atmosphere at room temperature, stirred at room temperature for 12 hours, added with 40% aqueous sodium hydroxide (5 ml) for hydrolysis, separated, the aqueous phase was extracted three times with dichloromethane, 10 ml each time, the organic phases were combined and dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, the residue was purified by 200-300 mesh silica gel column chromatography, ethyl acetate/petroleum ether (60-90 ℃) (1: 2, volume ratio) was used as an eluent, and the solvent was removed under reduced pressure to give III-9, 0.13 g of a yellow oil.

Other compounds of the invention may be prepared by reference to the above examples.

The structure of the bridged ring isoindolinone derivative with a partial chemical structural general formula III is shown in table 1, and the physical and chemical parameters are shown in table 2.

Example 4

The endocyclic isoindolinone derivative III is used for carrying out in-vitro antibacterial activity tests on various fungal diseases of plants. The bactericidal activity assay results were as follows:

the names and codes of common plant pathogenic fungi tested by the present invention include CA: brown spot fungus of peanut (Cercospora arachidicola); AS: early blight of tomato (Alternaria solani); BC: botrytis cinerea (Botrytis cinerea); PP: physalospora piricola (Physalospora piricola); and SS: sclerotinia sclerotiorum (sclerotiorum); RC: rhizoctonia cerealis (Rhizoctonia cerealis); PS: rhizoctonia solani (Pellicularia sasakii). The results of thallus growth rate method determination show that at 50 microgram/ml, the endocyclic isoindolinone derivatives III-3, III-5, III-8, III-9, III-10, III-11, III-12, III-13, III-14, III-15, III-16, III-17 and III-18 have different degrees of bactericidal activity on SS and BC, wherein the bactericidal activity of III-3, III-5 and III-15 on SS is higher than 70%, and the bactericidal activity of III-9 on BC is higher than 60%; III-2 also has good bactericidal activity on CA, AS and PS, the bactericidal activity of III-2 on CA is higher than 70%, and the bactericidal activity on AS and PS is higher than 50%; the bactericidal activity of III-15 and III-18 on RC is higher than 70 percent; the bactericidal activity of III-15, III-17 and III-18 on PP is higher than 50%. Therefore, the compounds show better bactericidal activity to a certain extent.

TABLE 1 chemical structures of some endocyclic isoindolinone derivatives of the general formula III

TABLE 2 physicochemical parameters of bridged isoindolinone derivatives of the general formula III

Claims (3)

1. A bridged ring isoindolinone derivative with a chemical structure general formula III:

wherein R is¹Selected from: hydrogen, methyl, methoxy, fluoro; r²、R³、R⁴Selected from: hydrogen, methyl, methoxy, bromo, fluoro.

2. The method for synthesizing endocyclic isoindolinone derivative III according to claim 1, which comprises the following steps:

wherein R is¹Selected from: hydrogen, methyl, methoxy, fluoro; ar is selected from: phenyl, 2-bromophenyl, 3-bromophenyl, 4-fluorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl; r2, R3, R4 are selected from: hydrogen, methyl, methoxy, bromo, fluoro;

the method comprises the following steps:

A. preparation of starting material I:

under the protection of inert gas and at the temperature of-78 ℃, dropwise adding an equivalent amount of n-butyllithium hexane solution into an equivalent amount of tetrahydrofuran solution of o-bromobenzaldehyde imine, stirring at low temperature for reaction for 30 minutes to prepare a corresponding lithium salt solution, then placing the lithium salt solution in a carbon monoxide atmosphere at normal pressure, stirring for reaction for 1 hour, adding water for hydrolysis, removing the solvent under reduced pressure, purifying the residue by 200-300-mesh silica gel column chromatography, and obtaining an initial raw material I by using ethyl acetate/petroleum ether as an eluent;

wherein: the structural formula of the o-bromobenzaldehyde imine is as follows:

wherein R is¹Selected from: hydrogen, methyl, methoxy, fluoro;

B. preparation of intermediate II:

under the protection of inert gas and at room temperature, dropwise adding 2.2 equivalents of tetrahydrofuran solution of bis (trimethylsilyl) amino potassium (KHMDS for short) into 1 equivalent of tetrahydrofuran solution of an initial raw material I, reacting at room temperature for 30 minutes, adding 2.5 equivalents of benzyl bromide or substituted benzyl bromide, stirring at room temperature for 12 hours, removing the solvent under reduced pressure, purifying the residue by 200-300-mesh silica gel column chromatography, and obtaining an intermediate II by using ethyl acetate/petroleum ether as an eluent; the substituted benzyl bromide is selected from o-benzyl bromide, m-benzyl bromide, p-benzyl fluorobromide, p-benzyl methylbromide, m-benzyl methoxybromide and p-benzyl methoxybromide;

C. preparation of endocyclic isoindolinone derivative III:

under the protection of inert gas and at room temperature, adding 3.5 equivalents of powdery aluminum trichloride into 1 equivalent of dichloromethane solution of the intermediate II, stirring at room temperature for 12 hours, adding 40% sodium hydroxide aqueous solution for hydrolysis, separating liquid, extracting an aqueous phase with dichloromethane, combining organic phases, drying with anhydrous sodium sulfate, removing the solvent under reduced pressure, purifying the residue by 200-300-mesh silica gel column chromatography, and obtaining the endocyclic isoindolinone derivative III by using ethyl acetate/petroleum ether as an eluent.

3. Use of the bridged isoindolinone derivative III according to claim 1 for the preparation of fungicides for agricultural and horticultural plants.