CN103265545B - Method for preparing parazole iso-indole compound - Google Patents

Abstract

The invention relates to a method for preparing pyrazole isoindole compounds. The technical scheme of the invention includes the following steps: using o-bromobenzaldehyde derivatives and ethynyl compounds as raw materials, preparing o-alkynyl benzaldehyde derivatives by Sonogashira reaction Then use o-alkynyl benzaldehyde derivatives as raw materials, add methanol as a solvent, then add ketone compounds, hydrazine hydrochloride and alkali, stir evenly, and prepare pyrazole isoindole compounds in the next step under the condition of raising temperature and reflux. The method of the invention has the advantages of cheap and easy-to-obtain raw materials, short synthetic route, simple reaction operation, fast reaction speed, easy post-treatment, high yield, low environmental pollution, objective economic and practical value, and has broad application prospects in the field of drug synthesis .

Description

A kind of method for preparing pyrazole isoindole compound

technical field

The invention relates to a method for preparing pyrazole isoindole compounds, belonging to the technical field of drug synthesis.

Background technique

As an important kind of nitrogen-containing heterocyclic compounds, pyrazole-isoindole compounds have attracted much attention in recent years due to their wide application in medicine and pesticides. Therefore, the efficient synthesis of this type of compound is of great significance for the further promotion of the research and development of pyrazole isoindole related drugs.

The synthetic method of the reported pyrazole isoindole compound mainly contains following several kinds at present:

Method 1: In 2000, Sosnicki introduced the synthesis of pyrazole isoindole compound 4 from substrate 1-acetylmethylene-3,3-dimethyl-1,3-dihydroisobenzofuran 1 method, but the yield is only 5%.

Method 2: In 2005, the Voitenko group proposed another method for synthesizing pyrazole isoindole compounds, using phthalic acid derivative 5 as raw material, through addition, hydrazine condensation, intramolecular cycloaddition reaction, And a reduction reaction to obtain pyrazole isoindole derivatives.

Method 3: In 2008, Moyano used diazonium salts as raw materials to try a new method of pyrazole isoindole compounds. However, due to the many side reactions in the diazotization reaction, the yield of the target product is very low.

Method Four: In 2011, Using the multi-step synthesis of o-stilbene-methylene-sydney ketone 21 as the core intermediate, the target compound was further oxidized under the action of light. The key step of this method is the 1,3-dipolar cycloaddition reaction. It is worth noting that the two chromophores of compound 21, stilbene and Sydney ketone, are separated by methylene groups, which is conducive to the occurrence of different polycyclic structures and intramolecular 1,3-dipolar cycloaddition reactions, but it is also positive Because of this, Sydney ketone 21 has many resonance modes, which greatly reduces the reaction efficiency.

Method 5: Preparation of pyrazole-isoindole compounds by metal-catalyzed intramolecular cyclization

In 2010, Choi and his collaborators used intramolecular palladium-catalyzed C-H bond activation for the first time to synthesize pyrazole-isoindole compounds in one step, with the highest yield reaching 87%. The study found that the formation of by-product 25 can be effectively avoided by adjusting the amount of additives and lithium chloride.

Most of the existing literature methods have disadvantages such as complex preparation of raw materials, long synthetic routes, use of transition metals, harsh reaction conditions, and low yields, which do not meet the requirements of the development of "green chemistry".

Contents of the invention

The problem to be solved by the present invention is to provide a method for preparing pyrazole-isoindole compounds with short synthetic route and high yield.

The technical scheme provided by the invention is:

Using o-bromobenzaldehyde derivatives and ethynyl compounds as raw materials, o-alkynyl benzaldehyde derivatives are prepared by Sonogashira reaction; then using o-alkynyl benzaldehyde derivatives as raw materials, adding methanol as a solvent, and then adding ketone compounds, Hydrazine hydrochloride and alkali are stirred evenly, and pyrazole isoindole compounds are prepared under the condition of raising temperature and reflux.

The ketone compound is aliphatic ketone or aromatic ketone.

The base is an organic base or an inorganic base.

The organic base is triethylamine, and the inorganic base is sodium methylate, potassium tert-butoxide or potassium carbonate.

The reflux time is generally 12-24h.

As a preference, the molar ratio of the o-alkynyl benzaldehyde derivative, ketone compound, hydrazine hydrochloride and alkali is 1:2:10:20.

The synthetic route of the inventive method is as follows:

Wherein, R ¹ is hydrogen, halogen, alkyl, alkoxy, nitro or cyano, R ² is alkyl or aryl, R ³ is alkyl or aryl, R ⁴ is hydrogen or alkyl.

The pyrazole isoindole compounds prepared by the method of the present invention have the following structure:

Wherein, R ¹ is hydrogen, halogen, alkyl, alkoxy, nitro or cyano, R ² is alkyl or aryl, R ³ is alkyl or aryl, R ⁴ is hydrogen or alkyl.

The method of the invention has the advantages of simple operation, cheap and easy-to-obtain raw materials, simple reaction operation, fast reaction speed and little environmental pollution, and is a simple and effective method for preparing pyrazole-isoindole compounds. Thereby paving the way for the large-scale promotion and application of pyrazole isoindole related derivatives.

Detailed ways

A method for preparing pyrazole-isoindole compounds of the present invention will be described in detail below in conjunction with examples. The proportions in the eluent are volume ratios.

The synthesis of embodiment 1 2-phenylethynyl benzaldehyde

Take a 25mL two-necked bottle, add a magnet, and add 74.0mg (0.4mmol) of 2-bromobenzaldehyde, 14.0mg (0.02mmol) of triphenylphosphine palladium dichloride, and 14.0mg (0.02mmol) of triphenylphosphine 31.5mg (0.12mmol), 7.6mg (0.04mmol) of cuprous iodide, add 1mL of anhydrous DMF, 1mL of triethylamine, stir well, add 65.4mg (0.64mmol) of phenylacetylene, and place it in an oil bath at 80°C for reaction 8h, after the reaction was completed, 20 mL of saturated ammonium chloride solution was added to quench the reaction, and 25 mL of ethyl acetate was added for extraction. The organic layer was evaporated to dryness under reduced pressure. The crude product was separated by silica gel column chromatography, and the eluent ratio was petroleum ether: ethyl acetate 10:1, yield 85.1%. ¹ HNMR (400MHz, CDCl ₃ ) δ10.56(s, 1H), 7.88-7.84(m, 1H), 7.54(d, J=7.6Hz, 1H), 7.50-7.45(m, 3H), 7.35(t , J=7.5Hz, 1H), 7.30-7.27(m, 3H).

The synthesis of embodiment 2 2-(4-methyl-phenylethynyl) benzaldehyde

Take a 25mL two-necked bottle, add a magnet, and add 74.0mg (0.4mmol) of 2-bromobenzaldehyde, 14.0mg (0.02mmol) of triphenylphosphine palladium dichloride, and 14.0mg (0.02mmol) of triphenylphosphine 31.5mg (0.12mmol), cuprous iodide 7.62mg (0.04mmol), add anhydrous DMF1mL, triethylamine 1mL, stir well, add 4-methylphenylacetylene 74.3 (0.64mmol), put in 80℃ oil bath The reaction was carried out under the conditions for 8 hours. After the reaction was completed, 20 mL of saturated ammonium chloride solution was added to quench the reaction, and 25 mL of ethyl acetate was added for extraction. The organic layer was evaporated to dryness under reduced pressure. The crude product was separated by silica gel column chromatography, and the eluent ratio was petroleum ether: Ethyl acetate 10:1, yield 63.3%. ¹ HNMR (400MHz, CDCl ₃ ) δ10.57(s, 1H), 7.86(d, J=7.8Hz, 1H), 7.54(d, J=7.6Hz, 1H), 7.51-7.45(m, 1H), 7.38(s, 1H), 7.36(s, 1H), 7.34(d, J=7.4Hz, 1H), 7.10(d, J=7.9Hz, 2H), 2.30(s, 3H).

Example 3 Synthesis of 2-(4-fluoro-phenylethynyl)-benzaldehyde

Take a 25mL two-necked bottle, add a magnet, and add 74.0mg (0.4mmol) of 2-bromobenzaldehyde, 14.0mg (0.02mmol) of triphenylphosphine palladium dichloride, and 14.0mg (0.02mmol) of triphenylphosphine 31.5mg (0.12mmol), cuprous iodide 7.62mg (0.04mmol), add anhydrous DMF1mL, triethylamine 1mL, stir well, add 4-fluorophenylacetylene 76.9mg (0.64mmol), put in 80℃ oil bath The reaction was carried out under the conditions for 8 hours. After the reaction was completed, 20 mL of saturated ammonium chloride solution was added to quench the reaction, and 25 mL of ethyl acetate was added for extraction. The organic layer was evaporated to dryness under reduced pressure. The crude product was separated by silica gel column chromatography, and the eluent ratio was petroleum ether: Ethyl acetate 10:1, yield 73.0%. ¹ HNMR (400MHz, CDCl ₃ ) δ10.54(s, 1H), 7.86(d, J=7.8Hz, 1H), 7.57-7.45(m, 4H), 7.38(t, J=7.4Hz, 1H), 7.00(t, J=8.7Hz, 2H).

Example 4 Synthesis of 2-(2-thienylacetylene)-benzaldehyde

Take a 25mL two-necked bottle, add magnets, and add 74.0mg (0.4mmol) of 2-bromobenzaldehyde, 14.0mg (0.02mmol) of triphenylphosphine palladium dichloride, and 14.0mg (0.02mmol) of triphenylphosphine 31.5mg (0.12mmol), cuprous iodide 7.62mg (0.04mmol), add anhydrous DMF1mL, triethylamine 1mL, stir well, add 2-ethynylthiophene 69.2mg (0.64mmol), put in 80℃ oil bath The reaction was carried out under the conditions for 8 hours. After the reaction was completed, 20 mL of saturated ammonium chloride solution was added to quench the reaction, and 25 mL of ethyl acetate was added for extraction. The organic layer was evaporated to dryness under reduced pressure. The crude product was separated by silica gel column chromatography, and the eluent ratio was petroleum ether: Ethyl acetate 10:1, yield 65.0%. ¹ H NMR (400MHz, CDCl ₃ ) δ10.50(s, 1H), 7.86(d, J=7.9Hz, 1H), 7.50(ddd, J=11.1, 8.8, 4.4Hz, 2H), 7.36(t, J=7.5Hz, 1H), 7.24(d, J=1.3Hz, 2H), 6.96(dd, J=5.0, 3.8Hz, 1H).

Example 5 Synthesis of 4-methyl-2-(2-thienylacetylene)-benzaldehyde

Take a 25mL two-necked bottle, add magnets, and add 2-bromo-4-methylbenzaldehyde 79.6mg (0.4mmol) and triphenylphosphinepalladium dichloride 14.0mg (0.02mmol) in sequence under anhydrous and oxygen-free conditions , triphenylphosphine 31.5mg (0.12mmol), copper iodide 7.62mg (0.04mmol), add anhydrous DMF 1mL, triethylamine 1mL, stir well, add 2-ethynylthiophene 69.2mg (0.64mmol), set React in an oil bath at 80°C for 8 hours. After the reaction, add 20 mL of saturated ammonium chloride solution to quench the reaction, add 25 mL of ethyl acetate for extraction, and evaporate the organic layer to dryness under reduced pressure. The crude product is separated by silica gel column chromatography, and the eluent The ratio is petroleum ether: ethyl acetate 10:1, and the yield is 59.3%. ¹ H NMR (400MHz, CDCl ₃ ) δ10.52(s, 1H), 7.84(d, J=8.0Hz, 1H), 7.43(s, 1H), 7.34(t, J=4.6Hz, 2H), 7.25 (d, J=7.3Hz, 1H), 7.04(t, J=4.4Hz, 1H), 2.41(s, 3H).

Example 6 Synthesis of 8-phenyl-2-methyl-8H-pyrazol[5,1-a]isoindole

In a 25mL three-neck round bottom flask equipped with a reflux condenser, 82.4mg (0.4mmol) of 2-phenylethynylbenzaldehyde, hydrazine hydrochloride (419.9mg, 4mmol), acetone (46.5mg, 0.8mmol), and no Water methanol 5ml, after stirring evenly, add triethylamine (1.1ml, 8mmol), the system is heated to reflux, and the reaction process is detected by TLC. After the reaction is completed, the solvent is evaporated to obtain the crude product, which is separated by column chromatography. /Ethyl acetate=6/1; Yield: 85%; ¹ H NMR (400MHz, CDCl ₃ ) δ7.31 (d, J=7.5Hz, 1H), 7.17 (dd, J=9.9, 5.1Hz, 1H ), 7.08(dd, J=5.3, 1.7Hz, 3H), 7.03(m, J=7.6, 1.0Hz, 1H), 6.93(dd, J=7.0, 2.2Hz, 2H), 6.77(d, J= 7.6Hz, 1H), 5.98(s, 1H), 5.20(dd, J=8.4, 3.9Hz, 1H), 3.63(dd, J=13.6, 4.0Hz, 1H), 2.97(dd, J=13.6, 8.5 Hz, 1H), 2.32(s, 3H). ¹³ C NMR (100MHz, CDCl ₃ ) δ151.93, 144.70, 142.86, 134.55, 129.62, 128.67, 127.13, 127.07, 125.70, 125.47, 122.77, 119.12, 94.202, , 38.95, 13.42.

Example 7 Synthesis of 8-(4-fluorophenyl)-2-methyl-8H-pyrazol[5,1-a]isoindole

In a 25mL three-neck round bottom flask equipped with a reflux condenser, 2-(4-F-phenyl)ethynyl)benzaldehyde 89.6mg (0.4mmol), hydrazine hydrochloride (419.9mg, 4mmol), acetone ( 46.5mg, 0.8mmol), anhydrous methanol 5ml, after stirring evenly, triethylamine (1.1ml, 8mmol) was added, the system was heated to reflux, and the reaction process was detected by TLC. After the reaction was completed, the solvent was evaporated to obtain the crude product, which was separated by column chromatography , the eluent ratio is petroleum ether/ethyl acetate=6/1; yield: 79%; ¹ HNMR (400MHz, CDCl ₃ ) δ7.28(d, J=7.3Hz, 1H), 7.17(t, J =7.2Hz, 1H), 7.07(t, J=7.3Hz, 1H), 6.91(d, J=7.3Hz, 1H), 6.85-6.59(m, 4H), 5.95(s, 1H), 5.18(d , J=2.4Hz, 1H), 3.49(d, J=11.5Hz, 1H), 3.12(dd, J=13.7, 7.4Hz, 1H), 2.30(s, 3H). ¹³ C NMR (100MHz, CDCl ₃ )δ 162.96, 160.52, 153.09, 145.96, 143.64, 131.21, 131.13, 128.23, 126.63, 123.59, 120.28, 114.99, 114.78, 95.94, 63.15, 38.89, 14.45.

Example 8 Synthesis of 2,6-dimethyl-8-(4-methylphenyl)-8H-pyrazol[5,1-a]isoindole

In a 25mL three-necked round bottom flask equipped with a reflux condenser, 93.6mg (0.4mmol) of 4-methyl-2-phenylethynylbenzaldehyde, hydrazine hydrochloride (419.9mg, 4mmol), acetone (46.5mg, 0.8mmol), 5ml of anhydrous methanol, after stirring evenly, add triethylamine (1.1ml, 8mmol), the system is heated to reflux, and the reaction process is detected by TLC. The solvent is petroleum ether/ethyl acetate=6/1; yield: 72%; ¹ H NMR (400MHz, CDCl ₃ ) δ7.20(d, J=7.7Hz, 1H), 6.98(d, J=7.7Hz , 1H), 6.91(d, J=7.8Hz, 2H), 6.83(d, J=7.9Hz, 2H), 6.62(s, 1H), 5.93(s, 1H), 5.13(dd, J=8.4, 3.9Hz, 1H), 3.56(dd, J=13.7, 3.9Hz, 1H), 2.93(dd, J=13.7, 8.4Hz, 1H), 2.30(s, 3H), 2.18(d, J=5.6Hz, 6H). ¹³ C NMR (100MHz, CDCl ₃ ) δ152.84, 145.90, 144.47, 136.49, 136.22, 132.71, 129.65, 128.88, 128.72, 128.10, 124.64, 119.90, 95.42, 63.35, 14.63, 2

Example 9 Synthesis of 6-fluoro-2-methyl-8-(thiophen-2-ylmethyl)-8H-pyrazol[5,1-a]isoindole

In a 25mL three-neck round bottom flask equipped with a reflux condenser, add 4-F-2-(thiophene-2-ethynyl)benzaldehyde 92.0mg (0.4mmol), hydrazine hydrochloride (419.9mg, 4mmol), acetone (46.5mg, 0.8mmol), 5ml of anhydrous methanol, after stirring evenly, add triethylamine (1.1ml, 8mmol), the system is heated to reflux, and the reaction process is detected by TLC. After the reaction is completed, the solvent is evaporated to obtain the crude product, and column chromatography Separation, the eluent is petroleum ether/ethyl acetate=6/1; yield: 78%; ¹ H NMR (400MHz, CDCl ₃ ) δ7.37 (dd, J=8.3, 4.9Hz, 1H), 7.04( dd, J=18.0, 3.6Hz, 2H), 6.81(dd, J=8.6, 3.4Hz, 2H), 6.59(d, J=3.2Hz, 1H), 6.05(s, 1H), 5.31(dd, J =7.4, 3.6Hz, 1H), 3.81(dd, J=14.9, 3.6Hz, 1H), 3.51(dd, J=14.9, 7.5Hz, 1H), 2.40(s, 3H). ¹³ C NMR (100MHz, CDCl ₃ ) δ153.82, 146.39, 142.49, 136.75, 130.88, 130.46, 129.94, 128.68, 127.02, 123.11, 121.73, 120.45, 96.18, 62.37, 38.98, 14.16.

Example 10 Synthesis of 8-(3,5-bis(trifluoromethyl)phenyl)-6-fluoro-2-methyl-8H-pyrazol[5,1-a]isoindole

In a 25mL three-necked round-bottomed flask equipped with a reflux condenser, add 144mg (0.4mmol) of 2-((3,5-bis(trifluoromethyl)phenyl)ethynyl)-4-F-benzaldehyde in sequence , hydrazine hydrochloride (419.9mg, 4mmol), acetone (46.5mg, 0.8mmol), anhydrous methanol 5ml, after stirring evenly, add triethylamine (1.1ml, 8mmol), the system is heated to reflux, and the reaction process is detected by TLC. Finally, the solvent was distilled off to obtain the crude product, which was separated by column chromatography, the eluent was petroleum ether/ethyl acetate=6/1; yield: 82%; ¹ H NMR (400MHz, CDCl ₃ ) δ7.52(s, 1H ), 7.41-7.28(m, 4H), 7.10(s, 2H), 5.95(s, 1H), 5.55-5.39(m, 1H), 3.78(dd, J=13.8, 5.3Hz, 1H), 3.50( dd, J=13.8, 3.3Hz, 1H), 2.39(s, 3H). ¹³ C NMR (100MHz, CDCl ₃ ) δ153.82, 146.39, 142.49, 136.75, 130.88, 130.46, 129.96, 128.68, 127.02, 124.44, 123.11, 121.73, 120.45, 96.18, 62.37, 38.98, 29.71.

Example 11 Synthesis of 8-phenyl-2-ethyl-8H-pyrazol[5,1-a]isoindole

In a 25mL three-necked round bottom flask equipped with a reflux condenser, 2-phenylethynylbenzaldehyde 82.4mg (0.4mmol), hydrazine hydrochloride (419.9mg, 4mmol), butanone (57.7mg, 0.8mmol), 5ml of anhydrous methanol, after stirring evenly, add triethylamine (1.1ml, 8mmol), the system is heated to reflux, and the reaction process is detected by TLC. /ethyl acetate=6/1; Yield: 74%; ¹ H NMR (400MHz, CDCl ₃ ) δ7.42(d, J=7.5Hz, 1H), 7.29(t, J=7.5Hz, 1H), 7.24-7.16(m, 3H), 7.14(d, J=7.6Hz, 1H), 7.01(dd, J=6.4, 2.8Hz, 2H), 6.90(d, J=7.6Hz, 1H), 6.11(s , 1H), 5.34(dd, J=8.4, 3.9Hz, 1H), 3.73(dd, J=13.6, 3.9Hz, 1H), 3.11(dd, J=13.6, 8.4Hz, 1H), 2.78(q, J=7.6Hz, 2H), 1.34(t, J=7.6Hz, 3H). ¹³ C NMR (100MHz, CDCl ₃ ) δ159.44, 145.64, 143.94, 135.56, 129.76, 128.14, 126.73, 126.52, 123.82, 120.15 , 94.36, 63.26, 40.01, 22.38, 14.38.

Example 12 Synthesis of 8-phenyl-2-phenyl-8H-pyrazol[5,1-a]isoindole

In a 25mL three-neck round bottom flask equipped with a reflux condenser, add 2-phenylethynylbenzaldehyde 82.4mg (0.4mmol), hydrazine hydrochloride (419.9mg, 4mmol), acetophenone (96.1mg, 0.8mmol) in sequence , anhydrous methanol 5ml, after stirring evenly, add triethylamine (1.1ml, 8mmol), the system is heated to reflux, and the reaction process is detected by TLC. Ether/ethyl acetate=6/1; Yield: 75%; ¹ H NMR (400MHz, CDCl ₃ ) δ7.83(d, J=7.7Hz, 2H), 7.43-7.34(m, 3H), 7.25( dd, J=13.8, 7.3Hz, 3H), 7.15-7.06(m, 4H), 7.00-6.93(m, 2H), 6.90(d, J=7.6Hz, 1H), 6.52(s, 1H), 5.38 (dd, J=7.9, 4.1Hz, 1H), 3.68(dd, J=13.7, 4.0Hz, 1H), 3.16(dd, J=13.7, 8.0Hz, 1H). ¹³ C NMR (100MHz, CDCl ₃ ) δ155.93, 146.39, 143.83, 135.39, 134.26, 130.52, 129.82, 128.70, 128.32, 128.21, 127.69, 126.89, 126.82, 125.66, 123.88, 120.42, 93.49, 6403.031,

Example 13 Synthesis of 8-phenyl-2-(4-methylphenyl)-8H-pyrazol[5,1-a]isoindole

In a 25mL three-neck round bottom flask equipped with a reflux condenser, 82.4mg (0.4mmol) of 2-phenylethynylbenzaldehyde, hydrazine hydrochloride (419.9mg, 4mmol), 4-methylacetophenone (107.2mg , 0.8mmol), anhydrous methanol 5ml, after stirring evenly, add triethylamine (1.1ml, 8mmol), the system is heated to reflux, and the reaction process is detected by TLC. The removal agent is petroleum ether/ethyl acetate=6/1; yield: 68%; ¹ H NMR (400MHz, CDCl ₃ ) δ7.80(d, J=8.1Hz, 2H), 7.48(d, J=7.7 Hz, 1H), 7.36-7.29(m, 2H), 7.26(s, 1H), 7.18-7.10(m, 4H), 7.03(dd, J=6.3, 3.0Hz, 2H), 6.97(d, J= 7.6Hz, 1H), 6.57(s, 1H), 5.45(dd, J=8.0, 4.0Hz, 1H), 3.76(dd, J=13.7, 4.0Hz, 1H), 3.23(dd, J=13.7, 8.1 Hz, 1H), 2.40(s, 3H). ¹³ C NMR (100MHz, CDCl ₃ ) δ156.02, 146.31, 143.86, 137.44, 135.42, 131.60, 131.46, 130.58, 129.82, 129.38, 128.49, 128.28, 126.19 , 126.82, 125.56, 123.85, 120.37, 93.26, 63.66, 40.02, 21.33.

Example 14 Synthesis of 8-phenyl-2-(4-fluorophenyl)-8H-pyrazol[5,1-a]isoindole

In a 25mL three-neck round bottom flask equipped with a reflux condenser, 82.4mg (0.4mmol) of 2-phenylethynylbenzaldehyde, hydrazine hydrochloride (419.9mg, 4mmol), and 4-fluoroacetophenone (110.4mg, 0.8mmol), 5ml of anhydrous methanol, after stirring evenly, add triethylamine (1.1ml, 8mmol), the system is heated to reflux, and the reaction process is detected by TLC. The solvent is petroleum ether/ethyl acetate=6/1; yield: 71%; ¹ H NMR (400MHz, CDCl ₃ ) δ7.86 (dd, J=8.2, 5.6Hz, 2H), 7.48 (d, J= 7.1Hz, 1H), 7.35(dd, J=7.0, 2.8Hz, 1H), 7.31(d, J=7.6Hz, 1H), 7.22-7.15(m, 4H), 7.12(t, J=8.6Hz, 2H), 7.07-7.02(m, 2H), 6.97(d, J=7.6Hz, 1H), 6.54(s, 1H), 5.44(dd, J=8.0, 4.1Hz, 1H), 4.77-4.60(m , 0H), 3.75 (dd, J=13.7, 4.1Hz, 1H), 3.21 (dd, J=13.7, 8.1Hz, 1H). ¹³ C NMR (100MHz, CDCl ₃ ) δ155.01, 146.50, 143.83, 135.37 , 133.09, 131.55, 130.40, 129.79, 129.04, 128.96, 128.58, 128.35, 128.24, 127.32, 127.24, 126.97, 126.86, 123.89, 120.44, 115.68, 115.46, 933.32,

Example 15 8-phenyl-2-(furan-2-yl)-8H-pyrrole[5,1-a]isoindole

In a 25mL three-necked round bottom flask equipped with a reflux condenser, 82.4mg (0.4mmol) of 2-phenylethynylbenzaldehyde, hydrazine hydrochloride (419.9mg, 4mmol), and 2-furanethanone (88.9mg, 0.8 mmol), anhydrous methanol 5ml, stir well and add sodium methylate (524.4mg, 8mmol), the system is heated to reflux, and the reaction process is detected by TLC. After the reaction is finished, the solvent is evaporated to obtain the crude product, which is separated by column chromatography. Petroleum ether/ethyl acetate=6/1; Yield: 68%, ¹ H NMR (400MHz, CDCl ₃ ) δ7.43(t, J=10.6Hz, 2H), 7.25(t, J=7.6Hz, 1H ), 7.20-7.08(m, 4H), 7.01-6.81(m, 3H), 6.66(d, J=3.3Hz, 1H), 6.51-6.30(m, 2H), 5.36(dd, J=8.3, 3.9 Hz, 1H), 3.73 (dd, J=13.7, 3.9Hz, 1H), 3.11 (dd, J=13.7, 8.3Hz, 1H). ¹³ C NMR (101MHz, CDCl ₃ ) δ149.37, 148.04, 146.15, 143.92, 141.75, 135.30, 130.15, 129.79, 128.34, 128.25, 127.05, 126.85, 123.92, 120.51, 111.32, 105.58, 93.29, 63.75, 39.91.

Example 16 8-phenyl-2-(thiophen-2-yl)-8H-pyrrole[5,1-a]isoindole

In a 25mL three-neck round bottom flask equipped with a reflux condenser, 82.4mg (0.4mmol) of 2-phenylethynylbenzaldehyde, hydrazine hydrochloride (419.9mg, 4mmol), and 2-thiophenethanone (109.4mg, 0.8 mmol), anhydrous methanol 5ml, after stirring evenly, add potassium carbonate (1105.6mg, 8mmol), the system is heated to reflux, and the reaction process is detected by TLC. Petroleum ether/ethyl acetate=6/1; Yield: 70%, ¹ H NMR (400MHz, CDCl ₃ ) δ7.38(d, J=7.5Hz, 1H), 7.31(d, J=3.5Hz, 1H ), 7.23(t, J=7.5Hz, 1H), 7.20-7.15(m, 1H), 7.15-7.06(m, 4H), 7.04-6.98(m, 1H), 6.98-6.91(m, 2H), 6.86(d, J=7.6Hz, 1H), 6.42(s, 1H), 5.35(dd, J=8.1, 4.0Hz, 1H), 3.68(dd, J=13.7, 4.0Hz, 1H), 3.11(dd , J=13.7, 8.2Hz, 1H). ¹³ C NMR (101MHz, CDCl ₃ ) δ150.92, 146.45, 143.86, 137.54, 135.30, 130.23, 129.81, 128.35, 128.23, 127.51, 127.03, 126.80, 123.39 123.47, 120.47, 93.52, 63.73, 39.98.

Claims (6)

1. prepare a method for parazole iso-indole compound, it is characterized in that:

With o-bromobenzaldehye derivative and acetylene compound for raw material, prepare adjacent alkynyl benzaldehyde derivative by Sonogashira reaction again with adjacent alkynyl benzaldehyde derivative for raw material, add methyl alcohol as solvent, then add ketone compounds hydrazine hydrochloride and alkali, stir, temperature rising reflux condition next step prepare parazole iso-indole compound described R1 is hydrogen or alkyl, described R ₂for aryl, described R ₃for alkyl or aryl, described R ₄for hydrogen.

2. method according to claim 1, is characterized in that, described alkali is organic bases or mineral alkali.

3. method according to claim 2, is characterized in that, described organic bases is triethylamine.

4. method according to claim 2, is characterized in that, described mineral alkali is sodium methylate, potassium tert.-butoxide or salt of wormwood.

5. method according to claim 1, is characterized in that, described return time is 12-24h.

6. method according to claim 1, is characterized in that, the mol ratio of adjacent alkynyl benzaldehyde derivative, ketone compounds, hydrazine hydrochloride, alkali is: 1:2:10:20.