CN105037369B - A kind of synthetic method of pyrazolo [5,1 a] Carbox amide of iso-indoles 3 - Google Patents

Abstract

The invention discloses a method for synthesizing pyrazolo[5,1- a ]isoindole-3-carboxamide compounds, belonging to the technical field of organic synthesis. The main points of the technical scheme of the present invention are: dissolving 1-(2-bromophenyl)-2,3-butadiene-1-one or its derivatives and hydrazide in a solvent, adding isocyanide after reacting at room temperature for 1 hour , a catalyst transition metal salt, an oxidizing agent and a base, and then react in an air atmosphere at 80-140°C to prepare pyrazolo[5,1- a ]isoindole-3-carboxamide compounds. The synthesis process of the present invention is a one-pot multi-step series reaction, which avoids the waste of resources and environmental pollution caused by the purification treatment of intermediates in the existing method, the raw materials used in the synthesis process are cheap and easy to obtain or easy to prepare, and the reaction operation is simple and convenient. The scope of application of the substrate is wide.

Description

A kind of synthetic method of pyrazolo[5,1-a]isoindole-3-carboxamides

technical field

The invention belongs to the technical field of organic synthesis, and in particular relates to a synthesis method of pyrazolo[5,1- a ]isoindole-3-carboxamide compounds.

Background technique

Fused pyrazole structural units widely exist in natural products, and many fused pyrazole derivatives also show good biological activities, which have attracted the attention of chemists and pharmacologists for many years. Among them, pyrazolo[5,1- a ]isoindole has activities such as regulating plant growth, reducing blood pressure, antibacterial and antidepressant, and has broad application prospects in the development of related drugs. At present, the synthesis methods of this kind of compounds mainly include the intramolecular Wittig reaction of phosphorus ylides, the Suzuki coupling of pyrazole boronate, and the intramolecular Friedel-Crafts acylation of N -formyl pyrazoline, etc. Most of these literature methods require multi-step synthesis and tedious separation and purification process, the raw materials used are difficult to obtain, and the reaction conditions are harsh, which limits their application in actual production. On the other hand, pyrazole-4-carboxamide is an advantageous structural unit in medicinal chemistry research, and many clinical drugs and lead compounds contain this structural skeleton. The existing method of synthesizing pyrazole-4-carboxamide is mainly through pyrazole-4-formic acid and amine in benzotriazol-1-yloxy tris(dimethylamino)phosphonium hexafluorophosphate (BOP Reagent) is activated by ammonolysis, or it is prepared by multi-step solid-phase synthesis using immobilized pyrazole-4-carboxylic acid derivatives as raw materials. These synthetic methods still have problems such as many reaction steps, expensive reagents, and poor atom economy. In view of this, the development of a simple and efficient new method for the synthesis of pyrazolo[5,1- a ]isoindole-3-carboxamides containing pyrazole-4-carboxamide structural units has great potential in organic synthetic chemistry and pharmaceuticals. Research fields such as chemistry are of great significance.

Contents of the invention

The technical problem solved by the present invention is to provide a synthetic method of pyrazolo[5,1- a ]isoindole-3-carboxamides, the synthetic method starts from commercial reagents or simple and easy-to-prepare raw materials, Through a one-pot multi-step series reaction, the pyrazolo[5,1- a ]isoindole-3-carboxamide compound is directly obtained, that is, the pyrazole ring and the isoindole ring are simultaneously constructed in the one-pot reaction, and The formamide structural unit is introduced into the 4-position of the pyrazole ring, the operation is convenient, the atom economy is good, the substrate has a wide application range, and is suitable for industrial production.

In order to solve the above-mentioned technical problems, the present invention adopts the following technical scheme, a synthetic method of pyrazolo[5,1- a ]isoindole-3-carboxamides, which is characterized in that: 1-(2-bromobenzene Base)-2,3-butadien-1-one or its derivatives and hydrazide are dissolved in a solvent, react at room temperature for 1 hour, add isonitrile, catalyst transition metal salt, oxidizing agent and base, and then in air atmosphere React at 80-140°C to prepare pyrazolo[5,1- a ]isoindole-3-carboxamides. The reaction equation in this synthesis method is:

^Wherein R is hydrogen, fluorine, chlorine, trifluoromethyl, methyl or alkoxy, R is ^hydrogen , alkyl, phenyl or substituted phenyl, ^R is alkyl, phenyl or substituted phenyl, R is alkyl, phenyl or substituted phenyl, and the substituents ^on the above-mentioned substituted phenyl benzene ring are respectively one or more of fluorine, chlorine, bromine, methyl, trifluoromethyl or methoxy, The position of the substituent is the ortho, meta or para position on the benzene ring, the solvent is N,N-dimethylformamide, 1,4-dioxane or toluene, the catalyst transition metal salt is palladium acetate, chlorine Palladium chloride, bis(triphenylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium or tetrakis(triphenylphosphine)palladium, the oxidant is oxygen, silver acetate, silver carbonate or copper acetate, the base is Potassium carbonate, triethylamine, 1,8-diazabicycloundec-7-ene, sodium carbonate, cesium carbonate, or potassium hydroxide.

It is further defined that the ratio of the amount of the 1-(2-bromophenyl)-2,3-butadien-1-one or its derivatives, hydrazide and isonitrile is 1:1-1.5 :2-4.

Compared with the prior art, the present invention has the following advantages: (1) the synthesis process is a one-pot multi-step series reaction, which avoids resource waste and environmental pollution caused by the purification of intermediates in the existing method; (2) the synthesis process The raw materials used in the method are cheap and easy to obtain or easy to prepare; (3) the reaction operation is simple; (4) the substrate has a wide range of applications. Therefore, the present invention provides an economical, practical and efficient new method for the synthesis of pyrazolo[5,1- a ]isoindole-3-carboxamide compounds.

detailed description

The above-mentioned contents of the present invention are described in further detail below through the embodiments, but this should not be interpreted as the scope of the above-mentioned themes of the present invention being limited to the following embodiments, and all technologies realized based on the above-mentioned contents of the present invention all belong to the scope of the present invention.

Example 1

Add 1-(2-bromophenyl)-2,3-butadien-1-one (1a, 0.2 mmol, 44.4 mg), acetylhydrazide (2a, 0.22 mmol, 16.3 mg) and N,N-Dimethylformamide (1 mL), stirred at room temperature for 1 hour, then added palladium acetate (0.01 mmol, 2.2 mg), copper acetate (0.2 mmol, 36.2 mg), tert-butylisonitrile (3a, 0.44 mmol , 36.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg). The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine, Dry over anhydrous sodium sulfate. It was filtered, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate=20/1) to obtain the product 4a (55 mg, 82%) as a white solid. The characterization data of this compound are as follows: ¹ H NMR (400MHz, CDCl ₃ ) δ: 1.50 (s, 9H), 1.60 (s, 9H), 2.50 (s, 3H), 5.69 (s, 1H), 7.36(t, 13 C NMR ₍ 100 MHz , CDCl ³ ) δ: 14.7, 29.0, 29.1, 51.8, 55.6, 111.3, 118.3, 122.5, 123.7, 129.3, _131.3 , _136.9 , _152.8 , 157.3, 162.7 ^. , found: 339.2189.

Example 2

Add 1a (0.2 mmol, 44.4 mg), 2a (0.4 mmol, 29.6 mg) and N,N-dimethylformamide (1 mL) into a 25 mL reaction flask, stir at room temperature for 1 hour, then add palladium acetate ( 0.01 mmol, 2.2 mg), copper acetate (0.2 mmol, 36.2 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg). The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine, Dry over anhydrous sodium sulfate. It was filtered, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate=20/1) to obtain the product 4a (51 mg, 75%) as a white solid.

Example 3

Add 1a (0.2 mmol, 44.4 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) into a 25 mL reaction flask, stir at room temperature for 1 hour, then add palladium acetate ( 0.01 mmol, 2.2 mg), copper acetate (0.2 mmol, 36.2 mg), tert-butylisonitrile (3a, 0.8 mmol, 66.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg). The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine, Dry over anhydrous sodium sulfate. After filtration, spin-drying, and silica gel column separation (petroleum ether/ethyl acetate=20/1), the product 4a (54 mg, 80%) was obtained as a white solid.

Example 4

Add 1a (0.2 mmol, 44.4 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) into a 25 mL reaction flask, stir at room temperature for 1 hour, then add palladium acetate ( 0.01 mmol, 2.2 mg), copper acetate (0.2 mmol, 36.2 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and 1,8-diazabicycloundec-7-ene (0.4 mmol, 60.8 mg). The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine, Dry over anhydrous sodium sulfate. After filtration, spin-drying, and silica gel column separation (petroleum ether/ethyl acetate=20/1), the product 4a (42 mg, 62%) was obtained as a white solid.

Example 5

Add 1a (0.2 mmol, 44.4 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) into a 25 mL reaction flask, stir at room temperature for 1 hour, then add palladium acetate ( 0.01 mmol, 2.2 mg), copper acetate (0.2 mmol, 36.2 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and cesium carbonate (0.4 mmol, 130.3 mg). The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine, Dry over anhydrous sodium sulfate. It was filtered, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate=20/1) to obtain the product 4a (51 mg, 75%) as a white solid.

Example 6

Add 1a (0.2 mmol, 44.4 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) into a 25 mL reaction flask, stir at room temperature for 1 hour, then add chloride Palladium (0.01 mmol, 1.8 mg), tri-tert-butylphosphine tetrafluoroborate (0.02 mmol, 5.8 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg). The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine, Dry over anhydrous sodium sulfate. It was filtered, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate=20/1) to obtain the product 4a (28 mg, 42%) as a white solid.

Example 7

Add 1a (0.2 mmol, 44.4 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) into a 25 mL reaction flask, stir at room temperature for 1 hour, then add di( triphenylphosphine) palladium dichloride (0.01 mmol, 7.0 mg), tri-tert-butylphosphine tetrafluoroborate (0.02 mmol, 5.8 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg). The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine, Dry over anhydrous sodium sulfate. Filtration, spin-drying, and silica gel column separation (petroleum ether/ethyl acetate=20/1) gave the product 4a (20 mg, 30%) as a white solid.

Example 8

Add 1a (0.2 mmol, 44.4 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) into a 25 mL reaction flask, stir at room temperature for 1 hour, and then add tri( Dibenzylideneacetone) dipalladium (0.01 mmol, 9.2 mg), tri-tert-butylphosphine tetrafluoroborate (0.02 mmol, 5.8 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate (0.4 mmol , 55.2 mg). The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine, Dry over anhydrous sodium sulfate. Filtration, spin-drying, and silica gel column separation (petroleum ether/ethyl acetate=20/1) gave the product 4a (22 mg, 32%) as a white solid.

Example 9

Add 1a (0.2 mmol, 44.4 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) into a 25 mL reaction vial, stir at room temperature for 1 hour, then add four ( triphenylphosphine) palladium (0.01 mmol, 11.6 mg), tri-tert-butylphosphine tetrafluoroborate (0.02 mmol, 5.8 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg). The resulting mixture was stirred and reacted at 120°C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), combined the organic phases, and washed with water and saturated brine successively , dried over anhydrous sodium sulfate. It was filtered, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate=20/1) to obtain the product 4a (17 mg, 25%) as a white solid.

Example 10

Add 1a (0.2 mmol, 44.4 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) into a 25 mL reaction flask, stir at room temperature for 1 hour, then add palladium acetate (0.01 mmol, 2.2 mg), tri-tert-butylphosphine tetrafluoroborate (0.02 mmol, 5.8 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg). The resulting mixture was stirred and reacted under an oxygen atmosphere and a temperature of 120 °C for 8 hours, and then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), combined the organic phases with water and saturated saline Washed successively and dried over anhydrous sodium sulfate. It was filtered, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate=20/1) to obtain the product 4a (31 mg, 46%) as a white solid.

Example 11

Add 1a (0.2 mmol, 44.4 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) into a 25 mL reaction flask, stir at room temperature for 1 hour, then add palladium acetate (0.01 mmol, 2.2 mg), tri-tert-butylphosphine tetrafluoroborate (0.02 mmol, 5.8 mg), silver acetate (0.2 mmol, 33.4 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate ( 0.4 mmol, 55.2 mg). The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine, Dry over anhydrous sodium sulfate. It was filtered, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate=20/1) to obtain the product 4a (39 mg, 58%) as a white solid.

Example 12

Add 1a (0.2 mmol, 44.4 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) into a 25 mL reaction flask, stir at room temperature for 1 hour, then add palladium acetate (0.01 mmol, 2.2 mg), tri-tert-butylphosphine tetrafluoroborate (0.02 mmol, 5.8 mg), silver carbonate (0.2 mmol, 55.2 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate ( 0.4 mmol, 55.2 mg). The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed with water and saturated brine in sequence, Dry over anhydrous sodium sulfate. It was filtered, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate=20/1) to obtain the product 4a (35 mg, 52%) as a white solid.

Example 13

Add 1a (0.2 mmol, 44.4 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) into a 25 mL reaction flask, stir at room temperature for 1 hour, then add palladium acetate (0.01 mmol, 2.2 mg), tri-tert-butylphosphine tetrafluoroborate (0.02 mmol, 5.8 mg), copper acetate (0.2 mmol, 36.3 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate ( 0.4 mmol, 55.2 mg). The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine, Dry over anhydrous sodium sulfate. It was filtered, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate=20/1) to obtain the product 4a (49 mg, 72%) as a white solid.

Example 14

Add 1a (0.2 mmol, 44.4 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) into a 25 mL reaction flask, stir at room temperature for 1 hour, then add palladium acetate (0.01 mmol, 2.2 mg), copper acetate (0.2 mmol, 36.2 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg). The resulting mixture was stirred and reacted at 140 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed with water and saturated brine in sequence, Dry over anhydrous sodium sulfate. It was filtered, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate=20/1) to obtain the product 4a (49 mg, 72%) as a white solid.

Example 15

Add 1a (0.2 mmol, 44.4 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) into a 25 mL reaction flask, stir at room temperature for 1 hour, then add palladium acetate (0.01 mmol, 2.2 mg), copper acetate (0.2 mmol, 36.2 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg). The resulting mixture was stirred and reacted at 100 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine, Dry over anhydrous sodium sulfate. It was filtered, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate=20/1) to obtain the product 4a (42 mg, 62%) as a white solid.

Example 16

Add 1a (0.2 mmol, 44.4 mg), 2a (0.22 mmol, 16.3 mg) and 1,4-dioxane (1 mL) into a 25 mL reaction flask, stir at room temperature for 1 hour, then add palladium acetate ( 0.01 mmol, 2.2 mg), copper acetate (0.2 mmol, 36.2 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg). The resulting mixture was refluxed and stirred for 8 hours in an air atmosphere, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine, and anhydrous Na2SO4 dried. It was filtered, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate=20/1) to obtain the product 4a (38 mg, 56%) as a white solid.

Example 17

Add 1a (0.2 mmol, 44.4 mg), 2a (0.22 mmol, 16.3 mg) and toluene (1 mL) into a 25 mL reaction flask, stir at room temperature for 1 hour, then add palladium acetate (0.01 mmol, 2.2 mg), Copper acetate (0.2 mmol, 36.2 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg). The resulting mixture was refluxed and stirred for 8 hours in an air atmosphere, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine, and anhydrous Na2SO4 dried. It was filtered, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate=20/1) to obtain the product 4a (35 mg, 52%) as a white solid.

Example 18

According to the method described in Example 1, 1a (0.2 mmol, 44.4 mg), 2b (0.22 mmol, 30.0 mg) and N,N-dimethylformamide (1 mL) were added to a 25 mL reaction vial, at room temperature After stirring for 1 hour, additional palladium acetate (0.01 mmol, 2.2 mg), copper acetate (0.2 mmol, 36.2 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg) were added. The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed with water and saturated brine in sequence, Dry over anhydrous sodium sulfate. It was filtered, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate=20/1) to obtain the product 4a (35 mg, 52%) as a white solid.

Example 19

According to the method described in Example 1, 1a (0.2 mmol, 44.4 mg), 2c (0.22 mmol, 36.5 mg) and N,N-dimethylformamide (1 mL) were added to a 25 mL reaction vial, at room temperature After stirring for 1 hour, palladium acetate (0.01 mmol, 2.2 mg), copper acetate (0.2 mmol, 36.2 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg) were added. The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine. water and sodium sulfate to dry. It was filtered, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate=20/1) to obtain the product 4a (30 mg, 45%) as a white solid.

Example 20

According to the method described in Example 1, 1b (0.2 mmol, 47.2 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) were added to a 25 mL reaction vial, at room temperature After stirring for 1 hour, palladium acetate (0.01 mmol, 2.2 mg), copper acetate (0.2 mmol, 36.2 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg) were added. The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine. water and sodium sulfate to dry. After filtration, spin-drying, and silica gel column separation (petroleum ether/ethyl acetate=20/1), the product 4b (61 mg, 86%) was obtained as a white solid. The characterization data of this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.50(s, 9H), 1.60 (s, 9H), 2.40 (s, 3H), 2.49 (s, 3H), 5.67 (s , 1H), 7.25 (d, J =6.0 Hz, 1H), 7.58 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H). ¹³ C NMR (100 MHz, CDCl ₃ )δ: 14.6, 21.6 , 28.9, 29.1, 51.7, 55.5, 111.8, 117.9, 122.2, 124.3, 126.7,131.9, 138.1, 139.7, 148.5, 152.8, 162.8. HRMS calcd for C ₂₁ H ⁺ ₂₉ N ₄ O: 363 [ found: 353.2347.

Example 21

According to the method described in Example 1, 1c (0.2 mmol, 50.4 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) were added to a 25 mL reaction vial, at room temperature After stirring for 1 hour, palladium acetate (0.01 mmol, 2.2 mg), copper acetate (0.2 mmol, 36.2 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg) were added. The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine. water and sodium sulfate to dry. It was filtered, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate=20/1) to obtain the product 4c (66 mg, 89%) as a white solid. The characterization data of this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.50(s, 9H), 1.59 (s, 9H), 2.49 (s, 3H), 3.89 (s, 3H), 5.67 (s , 1H), 6.85 (d, J =9.2 Hz, 1H), 7.58 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H). ¹³ C NMR (100 MHz, CDCl ₃ )δ: 14.5, 29.0 , 29.1, 51.7, 55.4, 55.7, 107.9, 111.6, 114.6, _125.0 , _129.1,130.8 , 137.5, _147.6 , 152.6, 162.4, ^162.7 _. , found: 369.2296.

Example 22

According to the method described in Example 1, 1d (0.2 mmol, 48.0 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) were added to a 25 mL reaction vial, at room temperature After stirring for 1 hour, palladium acetate (0.01 mmol, 2.2 mg), copper acetate (0.2 mmol, 36.2 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg) were added. The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine. water and sodium sulfate to dry. Filtration, spin-drying, and silica gel column separation (petroleum ether/ethyl acetate=20/1) gave the product 4d (51 mg, 72%) as a white solid. The characterization data of this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.49(s, 9H), 1.58 (s, 9H), 2.50 (s, 3H), 5.67 (s, 1H), 7.11-7.15 (m, 1H), 7.44(dd, J1 ₌ 7.6 Hz, J2 = _2.0 Hz, 1H), 8.11 (dd, J1 ₌ ^8.4 Hz, J2 = 0.8 Hz, 1H ₎ . , CDCl ₃ ) δ: 14.8, 28.9, 29.0, 51.8, 55.7, 111.2, 111.4, 111.5, 117.9, 118.1, 124.7, 124.8, 125.4, _139.4 , 148.5, 156 F.2, _162.5 cal H for ₂ 357.2085 [M+H] ⁺ , found: 357.2097.

Example 23

According to the method described in Example 1, 1e (0.2 mmol, 48.0 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) were added to a 25 mL reaction vial. After stirring for 1 hour, palladium acetate (0.01 mmol, 2.2 mg), copper acetate (0.2 mmol, 36.2 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg) were added. The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine. water and sodium sulfate to dry. After filtration, spin-drying, and silica gel column separation (petroleum ether/ethyl acetate=20/1), the product 4e (50 mg, 70%) was obtained as a white solid. The characterization data of this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.50(s, 9H), 1.59 (s, 9H), 2.51 (s, 3H), 5.67 (s, 1H), 7.00-7.05 (m, 1H), 7.71(dd, J1 ₌ ^8.4 Hz, J2 = 4.8 Hz, 1H), 7.86 (dd, J1 ₌ 8.0 Hz, J2 = _2.0 Hz, 1H ₎ . , CDCL ₃ ) Δ: 14.8, 28.8, 28.9, 51.8, 55.7, 110.5, 110.8, 112.2,115.8, 116.1, 125.23, 125.3, 131.3, 136.8, 147.7, 152.162.3, 163.6. HRMS CALCD for C ₂₀ H ₂₆ FN ₄ O: 357.2085 [M+H] ⁺ , found: 357.2098.

Example 24

According to the method described in Example 1, 1f (0.2 mmol, 51.2 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) were added to a 25 mL reaction vial. After stirring for 1 hour, palladium acetate (0.01 mmol, 2.2 mg), copper acetate (0.2 mmol, 36.2 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg) were added. The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine. water and sodium sulfate to dry. Filtration, spin-drying, and silica gel column separation (petroleum ether/ethyl acetate=20/1) gave the product 4f (57 mg, 76%) as a white solid. The characterization data of this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.50(s, 9H), 1.58 (s, 9H), 2.51 (s, 3H), 5.67 (s, 1H), 7.32 (dd , J ₁ = 8.4 Hz, J ₂ =2.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H). ¹³ C NMR (100MHz, CDCl ₃ ) δ : 14.8, 28.9, _29.0 , 51.8, 54.5, 112.2, 123.1, 124.7, _129.2,130.7 , _134.9 , 137.4, ^147.6 , 152.3, 162.3. found: 395.1624.

Example 25

According to the method described in Example 1, add 1g (0.2 mmol, 58.0 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) into a 25 mL reaction vial, After stirring for 1 hour, palladium acetate (0.01 mmol, 2.2 mg), copper acetate (0.2 mmol, 36.2 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg) were added. The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine. water and sodium sulfate to dry. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=20/1) to obtain 4 g (54 mg, 67%) of white solid product. The characterization data of this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.51(s, 9H), 1.60 (s, 9H), 2.53 (s, 3H), 5.67 (s, 1H), 7.63 (d , J = 8.0 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 8.36 (s, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ: 14.7,28.9, 29.1, 29.7, 51.9, 56.1, 112.5, _119.69 , _119.73 , 119.8, 124.0, 126.15, _126.19 , 130.0, 133.4, 136.6, 139.8, 147.4, _153.0 , 162.2 ^. found: 407.2065.

Example 26

According to the method described in Example 1, add 1h (0.2 mmol, 53.2 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) into a 25 mL reaction vial, room temperature After stirring for 1 hour, palladium acetate (0.01 mmol, 2.2 mg), copper acetate (0.2 mmol, 36.2 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg) were added. The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine. water and sodium sulfate to dry. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=20/1) to obtain the white solid product 4h (66 mg, 87%). The characterization data of this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.48(s, 9H), 1.57 (s, 9H), 2.47 (s, 3H), 5.63 (s, 1H), 6.02 (s , 2H), 7.18 (s,1H), 7.62 (s, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ: 14.8, 28.9, 29.0, 51.7, 55.5,101.8, 104.0, 104.7, 106.7, 110.8, 115.2, 124.2, 131.5, 148.7, 150.2, 151.7, 162.7. HRMS calcd for C ₂₁ H ₂₇ N ₄ O ₃ : 383.2078 [M+H] ⁺ , found: 383.2089.

Example 27

According to the method described in Example 1, 1i (0.2 mmol, 47.2 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) were added to a 25 mL reaction vial, at room temperature After stirring for 1 hour, palladium acetate (0.01 mmol, 2.2 mg), copper acetate (0.2 mmol, 36.2 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg) were added. The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine. water and sodium sulfate to dry. It was filtered, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate=20/1) to obtain the product 4i (57 mg, 81%) as a white solid. The characterization data of this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.37(t, J = 7.6 Hz, 3H), 1.50 (s, 9H), 1.60 (s, 9H), 2.87 (q, J = 7.2 Hz, 2H),5.72 (s, 1H), 7.34-7.38 (m, 1H), 7.43-7.47 (m, 1H), 7.77 (d, J = 8.0 Hz, 1H),7.97 (d, J = 8.4 Hz, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ: 12.6, 22.2, 28.9, 29.0,51.8, 55.6, 111.1, 122.1, 123.7, 129.2, 129.4, 131.3, 158.9, 1347.9, 162.8. HRMS calcd for C ₂₁ H ₂₉ N ₄ O: 353.2336 [M+H] ⁺ , found: 353.2349.

Example 28

According to the method described in Example 1, 1j (0.2 mmol, 50.0 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) were added to a 25 mL reaction vial, at room temperature After stirring for 1 hour, palladium acetate (0.01 mmol, 2.2 mg), copper acetate (0.2 mmol, 36.2 mg), tert-butylisonitrile (3a, 0.44 mmol, 36.5 mg) and potassium carbonate (0.4 mmol, 55.2 mg) were added. The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine. water and sodium sulfate to dry. It was filtered, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate=20/1) to obtain the product 4j (61 mg, 83%) as a white solid. The characterization data of this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ) δ: 1.02-1.06 (m, 3H), 1.50 (s, 9H), 1.60 (s, 9H), 1.79-1.82 (m, 2H) , 2.81 (t, J = 6.8Hz, 2H), 5.71 (s, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H). ¹³ C NMR (100 MHz, CDCl ₃ )δ: 13.9, 21.7, 29.0, 29.1, 30.5, 51.8, 55.7, 111.3, 122.1, 123.7, 129.2, 129.4, 131.3, 136.9, 137.9, 147.8, 157.0, 162.8. HRMS calcd for C ₂₂ H ₃₁ N ₄ O: 367.2492 [M+H] ⁺ , found: 367.2487.

Example 29

According to the method described in Example 1, 1k (0.2 mmol, 59.8 mg), 2a (0.22 mmol, 16.3 mg) and N,N-dimethylformamide (1 mL) were added to a 25 mL reaction vial. After stirring for 1 h, palladium acetate (0.01 mmol, 2.2 mg), copper acetate (0.2 mmol, 36.2 mg), 2,6-dimethylphenylisonitrile (3b, 0.44 mmol, 57.7 mg) and potassium carbonate ( 0.4 mmol, 55.2 mg). The resulting mixture was stirred and reacted at 120 °C in an air atmosphere for 8 hours, then quenched by adding 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (6 mL × 3), and then the organic phase was washed successively with water and saturated brine, Dry over anhydrous sodium sulfate. Filtered, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate=20/1) to obtain the target product 4k.

The above embodiments have described the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments. What are described in the above embodiments and description are only to illustrate the principles of the present invention. Without departing from the scope of the principle of the present invention, there will be various changes and improvements in the present invention, and these changes and improvements all fall within the protection scope of the present invention.

Claims (2)

1. a kind of pyrazolo [5,1-a] iso-indoles -3- Carbox amides synthetic method, it is characterised in that：By 1- (2- bromines Phenyl) -2,3- butadiene -1- ketone or derivatives thereof and hydrazides be dissolved in solvent, and room temperature reaction adds isonitrile, is catalyzed after 1 hour Agent transition metal salt, oxidant and alkali, are then obtained pyrazolo [5,1- in air atmosphere in 80-140 DEG C of reactiona] different Yin Diindyl -3- Carbox amides, the reaction equation in the synthetic method is：

Wherein R¹It is hydrogen, fluorine, chlorine, trifluoromethyl, methyl, methoxyl group or methylene-dioxy, R²For hydrogen, methyl, ethyl, phenyl or Substituted-phenyl, R³It is methyl, phenyl or substituted-phenyl, R⁴It is the tert-butyl group, phenyl or substituted-phenyl, on above-mentioned substituted-phenyl phenyl ring Be respectively in fluorine, chlorine, bromine, methyl, trifluoromethyl or methoxyl group one or more of substitution base, the position for replacing base is phenyl ring On ortho position, meta or para position, solvent be DMF, Isosorbide-5-Nitrae-dioxane or toluene, catalyst transition metal Salt is palladium, palladium bichloride, two（Triphenylphosphine）Palladium chloride, three（Dibenzalacetone）Two palladiums or four（Triphenylphosphine）Palladium, Oxidant is oxygen, silver acetate, silver carbonate or copper acetate, and alkali is potassium carbonate, triethylamine, the carbon -7- of 1,8- diazabicylos 11 Alkene, sodium carbonate, cesium carbonate or potassium hydroxide.

2. pyrazolo [5,1- according to claim 1a] iso-indoles -3- Carbox amides synthetic method, it is special Levy and be：The amount of the material that feeds intake of described 1- (2- bromophenyls) -2,3- butadiene -1- ketone or derivatives thereof, hydrazides and isonitrile The ratio between be 1:1-1.5:2-4.