Synthetic method of 4-fluoroindazole 3-carbonitrile or derivative thereof

Abstract

The invention is applicable to the technical field of chemical synthesis, and provides a synthesis method of 4-fluoroindazole 3-carbonitrile or derivatives thereof, which comprises the following steps: reacting 2-fluoro-6-nitrophenylacetaldehyde, ethanol, sodium bicarbonate, hydroxylamine hydrochloride and water to obtain 2-fluoro-6-nitrophenylethyloxime; reacting 2-fluoro-6-nitroacetoxime with acetic anhydride to obtain 2-fluoro-6-nitrophenylacetonitrile; reacting 2-fluoro-6-nitrophenylacetonitrile, tetrahydrofuran, methanol, water, ammonium chloride and iron powder, and reacting with glacialacetic acid and acetic anhydride to obtain 2-acetylamino-6-fluorophenylacetonitrile; reacting 2-acetylamino-6-fluorophenylacetonitrile, glacial acetic acid, acetic anhydride and isoamyl nitrite, andreacting with ethanol and sodium hydroxide to obtain the 4-fluoroindazole 3-carbonitrile. The synthesis method provided by the invention is mild in reaction condition and easy to operate, and the adopted raw materials are conventional and harmless.

Description

technical field

[0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a synthesis method of 4-fluoroindazole-3-carbonitrile or derivatives thereof. Background technique

[0002] At present, indazole 3 carbonitrile or indazole 3 formic acid generally have the following several synthetic routes:

[0003] 1. Use palladium reagent to catalyze nitrilation of 3-bromo or 3-iodoindazole. This method may also participate in the reaction for other halogens on the aromatic ring, which will generate by-products such as polynitrile compounds.

[0004] 2. Using isatin as a raw material, through ring opening, diazotization, and reduction ring synthesis to form indazole 3 formic acid, this method can synthesize indazole 3 formic acid substituted at 5, 6, and 7 positions. For 4 or 4, 6 Didifferently substituted indazoles 3 carboxylic acids, but not applicable. Moreover, with the increase of substituents, after the method opens the ring, the...

Examples

Embodiment 1

[0061] This embodiment provides a kind of synthetic method of 4 fluoroindazole 3 carbonitrile or derivatives thereof, it comprises the following steps:

[0062] S1. Add 1 kg (6.45 mol) of 2-fluoro-6-nitrotoluene, 1 L of dimethylformamide (DMF), and N,N-dimethylformamide to a 5L three-necked flask equipped with a heating mantle and mechanical stirring. Dimethyl acetal (DMFDMA) 3kg, tetrahydropyrrole 250mL, then, the system was heated up to 120°C to react for 12 hours, TLC reaction was complete, and cooled down. Add 15L of 6N HCl and 2L of tetrahydrofuran to a 50L reaction kettle equipped with mechanical stirring, and add the above reaction solution in batches under stirring. The red reactant was washed into the kettle, stirred for 2 hours, and the red color was completely removed, then the reaction solution was extracted with ethyl acetate, washed with saturated brine three times; the ethyl acetate layer was dried with anhydrous sodium sulfate to obtain the crude product 2fluor...

Embodiment 2

[0069] This embodiment provides a kind of synthetic method of 4 fluoroindazole 3 formic acid, it comprises the following steps:

[0070] Into a 5L three-necked flask equipped with mechanical stirring, add 1L of water, 1L of 98% concentrated sulfuric acid, 1L of glacial acetic acid, 440g (2.73mol) of 4-fluoroindazole-3-formonitrile under stirring, and heat up to 130°C for 8 hours. The TLC reaction is complete, the reaction solution is cooled to room temperature, and poured into ice water, a large amount of off-white solid is precipitated, filtered with suction, dried, and the obtained crude product is beaten with ethyl acetate at 60 ° C, and filtered with suction to obtain 4fluoroindazole 3 formic acid.

[0071] Wherein, the nuclear magnetic resonance analysis of the obtained 4 fluoroindazole 3 formic acid is as follows: 1 H NMR (400 MHz, DMSO- d 6 ) δ14.06 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.39 (td, J = 8.0, 4.5 Hz, 1H), 6.98(dd, J = 11.0, 7.5 Hz, 1H), see attached ...

Embodiment 3

[0075] The embodiment of the present invention can also combine the 4 fluoroindazole 3 formic acid that embodiment 2 obtains with SO 2 Cl and methanol were reacted to obtain methyl 4-fluoroindazole-3-formate. Wherein, the nuclear magnetic resonance analysis of 4 fluoroindazole 3 methyl formate is as follows: 1 H NMR (400 MHz, DMSO- d 6 ) δ 14.17 (s, 1H), 7.53 – 7.40 (m, 2H), 7.05 (ddd, J = 11.0, 7.4, 1.0Hz, 1H), 3.90 (s, 3H), specifically as image 3 shown.

[0076] In addition, the embodiments of the present invention can also replace all or part of the initial raw material 2-fluoro-6-nitrotoluene with 2-bromo-6-nitrotoluene and / or 2-chloro-6-nitrotoluene according to the methods provided in Examples 1-3, or The product obtained above was reacted with sodium methoxide to synthesize 4-chloroindazole-3-formic acid, 4-bromoindazole-3-formonitrile, 4-bromoindazole-3-formic acid, 4-methoxy-3-formonitrile, and 5-bromoindazole-3 Formonitrile, 4-bromo-6-chloroindazole-3-formic...

technical field

[0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a synthesis method of 4-fluoroindazole-3-carbonitrile or derivatives thereof. Background technique

[0002] At present, indazole 3 carbonitrile or indazole 3 formic acid generally have the following several synthetic routes:

[0003] 1. Use palladium reagent to catalyze nitrilation of 3-bromo or 3-iodoindazole. This method may also participate in the reaction for other halogens on the aromatic ring, which will generate by-products such as polynitrile compounds.

[0004] 2. Using isatin as a raw material, through ring opening, diazotization, and reduction ring synthesis to form indazole 3 formic acid, this method can synthesize indazole 3 formic acid substituted at 5, 6, and 7 positions. For 4 or 4, 6 Didifferently substituted indazoles 3 carboxylic acids, but not applicable. Moreover, with the increase of substituents, after the method opens the ring, the...

Examples

Embodiment 1

[0061] This embodiment provides a kind of synthetic method of 4 fluoroindazole 3 carbonitrile or derivatives thereof, it comprises the following steps:

[0062] S1. Add 1 kg (6.45 mol) of 2-fluoro-6-nitrotoluene, 1 L of dimethylformamide (DMF), and N,N-dimethylformamide to a 5L three-necked flask equipped with a heating mantle and mechanical stirring. Dimethyl acetal (DMFDMA) 3kg, tetrahydropyrrole 250mL, then, the system was heated up to 120°C to react for 12 hours, TLC reaction was complete, and cooled down. Add 15L of 6N HCl and 2L of tetrahydrofuran to a 50L reaction kettle equipped with mechanical stirring, and add the above reaction solution in batches under stirring. The red reactant was washed into the kettle, stirred for 2 hours, and the red color was completely removed, then the reaction solution was extracted with ethyl acetate, washed with saturated brine three times; the ethyl acetate layer was dried with anhydrous sodium sulfate to obtain the crude product 2fluor...

Embodiment 2

[0069] This embodiment provides a kind of synthetic method of 4 fluoroindazole 3 formic acid, it comprises the following steps:

[0070] Into a 5L three-necked flask equipped with mechanical stirring, add 1L of water, 1L of 98% concentrated sulfuric acid, 1L of glacial acetic acid, 440g (2.73mol) of 4-fluoroindazole-3-formonitrile under stirring, and heat up to 130°C for 8 hours. The TLC reaction is complete, the reaction solution is cooled to room temperature, and poured into ice water, a large amount of off-white solid is precipitated, filtered with suction, dried, and the obtained crude product is beaten with ethyl acetate at 60 ° C, and filtered with suction to obtain 4fluoroindazole 3 formic acid.

[0071] Wherein, the nuclear magnetic resonance analysis of the obtained 4 fluoroindazole 3 formic acid is as follows: 1 H NMR (400 MHz, DMSO- d 6 ) δ14.06 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.39 (td, J = 8.0, 4.5 Hz, 1H), 6.98(dd, J = 11.0, 7.5 Hz, 1H), see attached ...

Embodiment 3

[0075] The embodiment of the present invention can also combine the 4 fluoroindazole 3 formic acid that embodiment 2 obtains with SO 2 Cl and methanol were reacted to obtain methyl 4-fluoroindazole-3-formate. Wherein, the nuclear magnetic resonance analysis of 4 fluoroindazole 3 methyl formate is as follows: 1 H NMR (400 MHz, DMSO- d 6 ) δ 14.17 (s, 1H), 7.53 – 7.40 (m, 2H), 7.05 (ddd, J = 11.0, 7.4, 1.0Hz, 1H), 3.90 (s, 3H), specifically as image 3 shown.

[0076] In addition, the embodiments of the present invention can also replace all or part of the initial raw material 2-fluoro-6-nitrotoluene with 2-bromo-6-nitrotoluene and / or 2-chloro-6-nitrotoluene according to the methods provided in Examples 1-3, or The product obtained above was reacted with sodium methoxide to synthesize 4-chloroindazole-3-formic acid, 4-bromoindazole-3-formonitrile, 4-bromoindazole-3-formic acid, 4-methoxy-3-formonitrile, and 5-bromoindazole-3 Formonitrile, 4-bromo-6-chloroindazole-3-formic...

Images