A method for synthesizing 3,3'-disubstituted isoindolinone compounds

Abstract

The invention discloses a method for synthesizing 3,3'-disubstituted isoindolinone compounds, and relates to the technical field of organic synthesis. The method is to carry out a dehydration coupling reaction of 2-acylbenzoic acid compounds, diphenylphosphine oxide compounds and aliphatic amine compounds under the action of a heteropolyacid catalyst to synthesize 3,3'-disubstituted isoindolinone compounds. The method uses an efficient and green catalyst, and the amount of catalyst is small, the reaction conditions are mild, and the only by-product is water. The method provides a simple, efficient, high-yield, environmentally friendly green synthesis method for synthesizing 3,3'-disubstituted isoindolinone compounds.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing 3,3'-disubstituted isoindolinone compounds. Background Art

[0002] Isoindolone compounds are an important class of nitrogen heterocyclic compounds, which are widely found in natural products and play an important role in the fields of biopharmaceuticals, organic synthesis and functional materials. In particular, 3,3'-disubstituted isoindolinone compounds (polysubstituted isoindolinone compounds) with a quaternary carbon center at the C3 position show unique biological and medicinal value. Many biologically active molecules, such as rhodamine B spiroamide compounds used for subcellular imaging, cyclic lactam compounds as serotonin receptors and acetylcholine receptors, have a 3,3'-disubstituted isoindolinone skeleton structure. Therefore, it is particularly important to explore efficient synthesis methods for polysubstituted isoindolinone compounds. In recent years, important progress has been made in the synthesis of polysubstituted isoindolinone compounds. According to different synthetic strategies, they can be divided into two categories; one is to directly construct a polysubstituted lactam skeleton. For example, the intermolecular (intramolecular) cyclization reaction of benzamide compounds catalyzed by palladium, ruthenium, rhodium, iridium, etc. The reaction substrates required for this strategy are simple, but catalysts such as palladium, ruthenium, and rhodium are expensive, and there are problems such as metal residues and the production of toxic byproducts. The second is to modify the existing isoindolinone skeletons. For example, nucleophilic substitution of 3-substituted isoindolinone or cycloaddition reaction of 3-methyleneisoindolinone. However, this strategy requires complex organic phosphoric acid or organic base as a catalyst, and is based on the existence of isoindolinone skeletons. The complex catalysts and reaction substrates limit its scope of application. Therefore, starting from simple substrates, using green and cheap catalysts to achieve efficient synthesis of polysubstituted isoindolinone compounds is an urgent problem to be solved. Summary of the invention

[0003] In view of the shortcomings of the current synthesis method, the present invention proposes to use heteropolyacids (HPAs) as catalysts to catalyze the three-component reaction of 2-acylbenzoic acid compounds, diphenylphosphine oxide compounds and fatty amine compounds to synthesize 3,3'-disubstituted isoindolinone compounds. HPAs is a cheap, non-toxic, low-corrosive environmentally friendly solid catalyst, and water is the only by-product, which is green and environmentally friendly; at the same time, the reaction product is a phosphorus atom-substituted 3,3'-disubstituted isoindolinone compound that is difficult to synthesize by conventional methods. This method uses HPAs as a green catalyst, has a high yield, and does not produce toxic by-products, which meets the requirements of green production.

[0004] In order to achieve the above-mentioned object of the invention, the present invention proposes the following technical solutions:

[0005] 3,3'-disubstituted isoindolinone compounds were prepared by using 2-acylbenzoic acid compounds, diphenylphosphine oxide compounds and fatty amine compounds as raw materials and HPAs as catalyst under organic solvent conditions.

[0006] In the above preparation method, the raw materials are 2-acylbenzoic acid compounds, diphenylphosphine oxide compounds and fatty amine compounds; wherein the general structural formula of the 2-acylbenzoic acid compounds is as follows:

[0007]

[0008] R 1 At least one selected from hydrogen, methyl, chlorine, and bromine; R 2 One selected from hydrogen, methyl and n-hexyl.

[0009] The general structural formula of diphenylphosphine oxide compounds is as follows:

[0010]

[0011] R 3 One selected from hydrogen, methyl, methoxy, fluorine and chlorine.

[0012] The general structural formula of fatty amine compounds is as follows:

[0013]

[0014] R is selected from one of methyl, ethyl, n-propyl, isopropyl, n-hexyl, phenyl and benzyl.

[0015] In the above preparation method, a heteropoly acid (such as H 3 PMo 12 O 40 , H 3 PW 12 O 40 , H 4 S W 12 O 40 etc.) as catalyst, 2-acylbenzoic acid compounds, diphenylphosphine oxide compounds and fatty amine compounds as raw materials, under organic solvent conditions, 60-120°C effective reaction, in a short time, high yield 3,3'-disubstituted isoindolinone compounds are prepared, the reaction of the 3,3'-disubstituted isoindolinone compounds structure formula is as follows:

[0016]

[0017] R 1 is selected from hydrogen, methyl, chlorine, bromine; R 2 is selected from hydrogen, methyl, n-hexyl; R 3is selected from one of hydrogen, methyl, methoxy, fluorine and chlorine; R is selected from one of methyl, ethyl, n-propyl, isopropyl, n-hexyl, phenyl and benzyl.

[0018] In the 2-acylbenzoic acid compounds of the present invention, R 1 is a substituent group on the benzene ring, R 1 The substituent can be selected from one of hydrogen, methyl, chlorine, and bromine. 2 is a substituent group on the acyl group, which can be selected from hydrogen, methyl, and n-hexyl. The yield of 3,3'-disubstituted isoindolinone compounds can reach up to 87%.

[0019] In the diphenylphosphine oxide compounds of the present invention, R 3 is a substituent group on the benzene ring, and can be selected from one of hydrogen, methyl, methoxy, fluorine and chlorine.

[0020] In the fatty amine compounds of the present invention, various primary fatty amines can smoothly undergo the reaction, and the yield of the corresponding 3,3'-disubstituted isoindolinone compounds can reach up to 85%.

[0021] The present invention uses 2-acylbenzoic acid compounds, diphenylphosphine oxide compounds and fatty amine compounds as raw materials, and uses HPAs, which are easy to obtain and environmentally friendly, as a catalyst to simply and efficiently synthesize 3,3'-disubstituted isoindolinone compounds, and water is the only byproduct. The synthesis method is environmentally friendly, meets the requirements of green production, does not require special equipment, has a high yield, and is pollution-free to the environment. It is in line with the concept of ecological civilization construction proposed by the country.

[0022] In a preferred embodiment, the amount of 2-acylbenzoic acid compound is 0.2-1 mmol, the amount of diphenylphosphine oxide compound is 0.2-1 mmol, and the amount of fatty amine compound is 0.2-1 mmol. The addition ratio is 1:1-1.5:1-1.5.

[0023] The general formula of heteropoly acid is H n [XM 12 O 40 ] n- , where X=P, Si, Ge, As..., M=Mo, W, V.

[0024] The preferred embodiment is that the catalyst is H 3 PMo 12 O 40 , H 3 PW 12 O 40 , H 4 S W 12 O 40 et al., H. 4 S W12 O 40 It is the best catalyst, and the amount of catalyst used is 1 to 5 mol% of the amount of raw materials used.

[0025] In a preferred embodiment, the added solvent is one of water, dimethyl carbonate (DMC), N,N-dimethylformamide, 1,2-dichloroethane, chlorobenzene, nitromethane, tetrahydrofuran, 1,4-dioxane, and acetonitrile; among which dimethyl carbonate is the best organic solvent.

[0026] In a preferred embodiment, the temperature of the conventional method is 60-120° C., and the reaction time is 1-3 hours.

[0027] The general synthesis reaction formula of the 3,3'-disubstituted isoindolinone compounds of the present invention is as follows:

[0028]

[0029] The present invention has at least one of the following beneficial effects: the method provided by the present invention opens up a new economic and green way for the synthesis of 3,3'-disubstituted isoindolinone compounds, and its advantages are: low raw material cost, green catalyst, high yield, simple experimental operation, the only by-product is water, and it is green and environmentally friendly. DETAILED DESCRIPTION

[0030] The implementation steps of a new method for synthesizing 3,3'-disubstituted isoindolinone compounds are as follows: weighing a certain amount of 2-acylbenzoic acid compounds, diphenylphosphine oxide compounds, fatty amine compounds and heteropolyacid catalysts into a reaction bottle, adding an organic solvent, adding a stirring magnetic bar and sealing the bottle, stirring and reacting at a certain temperature for a certain time; after the reaction is completed, separating by column chromatography to obtain the target product.

[0031] The present invention is described in detail below in conjunction with specific embodiments.

[0032] Example 1

[0033] 2-Acetylbenzoic acid (0.2 mmol), diphenylphosphine oxide (0.2 mmol), n-hexylamine (0.2 mmol), heteropoly acid (2.5 mol%) and DMC (1 mL) were added to a 4 mL reaction bottle. The reaction was then carried out at 100°C for 2 hours. After the reaction was completed, the target product was obtained by column chromatography. 4 S W 12 O 40 When the yield is 87%; the heteropoly acid is H 3 PMo 12 O 40 When the yield is 78%, the heteropoly acid is H 3 PW 12 O 40The yield was 82%.

[0034] The specific results of the nuclear magnetic resonance and high-resolution mass spectrometry characterization data of the corresponding products are as follows:

[0035] NMR characterization data:

[0036] 1 H NMR(500MHz,Chloroform-d)δ7.77–7.67(m,3H),7.54(t,J=7.4Hz,1H),7.50–7.39(m,4H),7.37–7.30(m,3H),7.26–7.21(m,2H),6.69(d,J=7.7Hz,1 H),3.63–3.45(m,2H),2.01(d,J=12.1Hz,3H),1.82–1.68(m,1H),1.47(td ,J=17.9,17.4,8.5Hz,1H),1.25(d,J=10.7Hz,6H),0.85(t,J=6.8Hz,3H);

[0037] 13 C NMR (126 MHz, CDCl 3 )δ167.84,143.86,132.98(d,J=2.9Hz),132.57(d,J=2.5Hz),132.49(d,J=2.5Hz),13 2.17(d,J=8.7Hz),131.68(d,J=8.2Hz),130.96,129.49(d,J=92.4Hz),128.95,128.33 (d,J=2.6Hz),128.33(d,J=20.0Hz),127.36(d,J=96.1Hz),123.40(d,J=1.8Hz),123.2 6,67.46(d,J=71.6Hz),41.91,31.32,28.88,26.77,22.44,19.11(d,J=3.0Hz),13.99;

[0038] 31 P NMR (202 MHz, CDCl 3 )δ33.16(d,J=10.1Hz).

[0039] High resolution mass spectrometry characterization data:

[0040] HRMS(ESI):m / z,calcd.for C 27 H 30 NO 2 P[M+H] +requires 432.2087,found432.2083.

[0041] Through the above characterization data, the structure of the product obtained by the reaction can be determined as follows:

[0042]

[0043] Example 2

[0044] 4-Chloro-2-acetylbenzoic acid (0.2 mmol), diphenylphosphine oxide (0.2 mmol), n-hexylamine (0.2 mmol), heteropoly acid (2.5 mol%) and DMC (1 mL) were added to a 4 mL reaction bottle. The reaction was then carried out at 100°C for 2 hours. After the reaction was completed, the target product was obtained by column chromatography. 4 S W 12 O 40 When the yield is 80%; the heteropoly acid is H 3 PMo 12 O 40 The yield is 71% when the heteropoly acid is H 3 PW 12 O 40 The yield was 76%.

[0045] The specific results of the nuclear magnetic resonance and high-resolution mass spectrometry characterization data of the corresponding products are as follows:

[0046] NMR characterization data:

[0047] 1 H NMR (500 MHz, CDCl 3 )δ7.70(t,J=9.3Hz,3H),7.55(dt,J=15.4,7.4Hz,2H),7.45(td,J=7.5,2.4Hz,2H ),7.39(td,J=7.5,2.8Hz,2H),7.33(dd,J=11.2,6.1Hz,3H),6.67(d,J=8.2Hz,1H ),3.45(tq,J=14.0,6.9,5.8Hz,2H),1.99(d,J=11.8Hz,3H),1.76–1.66(m,1H),1 .45(dd,J=15.0,8.3Hz,1H),1.25(dd,J=16.4,8.6Hz,6H),0.85(t,J=6.8Hz,3H);

[0048] 13 C NMR (126 MHz, CDCl 3)δ166.59,142.40,135.32(d,J=2.1Hz),134.68(d,J=2.9Hz),132.82(d,J=2.6Hz),132.7 1(d,J=2.6Hz),132.13(d,J=8.6Hz),131.72(d,J=8.3Hz),131.18(d,J=1.8Hz),129.11(d, J=93.1Hz),128.55(d,J=2.8Hz),128.55(d,J=25.8Hz),127.44(d,J=96.1Hz),124.76,12 3.41, 67.47 (d, J = 71.1Hz), 42.17, 31.33, 28.81, 26.79, 22.49, 19.15 (d, J = 2.9Hz), 14.02;

[0049] 31 P NMR (202 MHz, CDCl 3 )δ32.3(d,J=10.1Hz).

[0050] High resolution mass spectrometry characterization data:

[0051] HRMS(ESI):m / z,calcd.for C 27 H 29 ClNO 2 P[M+H] + requires 466.1697,found466.1698.

[0052] Through the above characterization data, the structure of the product obtained by the reaction can be determined as follows:

[0053]

[0054] Example 3

[0055] 2-Acetylbenzoic acid (0.2 mmol), diphenylphosphine oxide (0.2 mmol), p-methylbenzylamine (0.2 mmol), heteropoly acid (2.5 mol%) and DMC (1 mL) were added to a 4 mL reaction bottle. The reaction was then carried out at 100°C for 2 hours. After the reaction was completed, the target product was obtained by column chromatography. The heteropoly acid is H 4 S W 12 O 40 When the yield is 77%; the heteropoly acid is H 3 PMo 12 O 40 When the yield is 70%; the heteropoly acid is H 3 PW 12 O 40The yield was 75%.

[0056] The specific results of the nuclear magnetic resonance and high-resolution mass spectrometry characterization data of the corresponding products are as follows:

[0057] NMR characterization data:

[0058] 1 H NMR (400 MHz, CDCl 3 )δ7.80(d,J=7.5Hz,1H),7.74–7.67(m,2H),7.56–7.49(m,2H),7.48–7.41(m,3H),7.39–7.33(m,3H),7.26(dd,J=12.8,5.1Hz,2H),7.17(d,J= 7.9Hz,2H),7.02(d,J=7.9Hz,2H),6.67(d,J=7.7Hz,1H),5.02(d,J=15.5Hz,1H),4.73(d,J=15.5Hz,1H),2.27(s,3H),1.76(d,J=12.1Hz,3H);

[0059] 13 C NMR (101 MHz, CDCl 3 )δ168.12,144.16,136.61,135.44,132.73,132.73(d,J=5.1Hz),132.57(d,J=2.8Hz), 132.36(d,J=8.7Hz),131.85(d,J=8.2Hz),131.20(d,J=2.0Hz),129.60(d,J=92.3Hz),1 29.06,128.97,128.46(d,J=6.3Hz),128.46(d,J=29.1Hz),128.05,127.50(d,J=95.9Hz ),123.79,123.49(d,J=2.2Hz),68.12(d,J=70.9Hz),44.29,21.08,19.83(d,J=3.0Hz);

[0060] 31 P NMR (162 MHz, CDCl 3 )δ31.44.

[0061] High resolution mass spectrometry characterization data:

[0062] HRMS(ESI):m / z,calcd.for C 29 H 26 ClNO 2 P[M+H] +requires 452.1774,found452.1778.

[0063] Through the above characterization data, the structure of the product obtained by the reaction can be determined as follows:

[0064]

[0065] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the present invention. It should be pointed out that for those skilled in the art, any equivalent replacement or partial improvement made under the principle of the spirit of the present invention will be deemed to be within the scope of protection of the present invention.

Claims

1. A method for synthesizing 3,3'-disubstituted isoindolinone compounds, characterized in that: The product is prepared by using 2-acylbenzoic acid compounds, diphenylphosphine oxide compounds and fatty amine compounds as raw materials, heteropoly acid as catalyst, and reacting in an organic solvent. In the method, the heteropoly acid is H4SiW 12 O 40 、H3PMo 12 O 40 、H3PW 12 O 40 ; The general structural formula of the 2-acylbenzoic acid compound is as follows: ； R 1 is selected from one of hydrogen, methyl, chlorine and bromine; R 2 One selected from hydrogen, methyl, and n-hexyl; The diphenylphosphine oxide compound has the following general structural formula: ； R 3 One selected from hydrogen, methyl, methoxy, fluorine and chlorine; The general structural formula of the fatty amine compound is as follows: ； R is selected from one of methyl, ethyl, n-propyl, isopropyl, n-hexyl, phenyl and benzyl; The general structural formula of the 3,3'-disubstituted isoindolinone compound is as follows: ； R 1 At least one selected from hydrogen, methyl, chlorine, and bromine; R 2 is selected from one of hydrogen, methyl and n-hexyl; R 3 is selected from one of hydrogen, methyl, methoxy, fluorine and chlorine; R is selected from one of methyl, ethyl, n-propyl, isopropyl, n-hexyl, phenyl and benzyl.

2. A method for synthesizing 3,3'-disubstituted isoindolinone compounds according to claim 1, characterized in that: The organic solvent is one of dimethyl carbonate, N, N-dimethylformamide, 1,2-dichloroethane, chlorobenzene, nitromethane, tetrahydrofuran, 1,4-dioxane, and acetonitrile.

3. The method for synthesizing 3,3'-disubstituted isoindolinone compounds according to claim 1, characterized in that: The reaction temperature is 60-120°C, and the reaction time is 1-5 h.

4. A method for synthesizing 3,3'-disubstituted isoindolinone compounds according to claim 1, characterized in that: The amount of the catalyst used is 1-5 mol% of the amount of the raw material used, and the unit of amount is the amount of substance.

5. The method for synthesizing 3,3'-disubstituted isoindolinone compounds according to claim 1, characterized in that: The molar ratio of the added 2-acylbenzoic acid compound, the diphenylphosphine oxide compound and the fatty amine compound is 1:1-1.5:1-1.5.

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