O-aminobenzoic acid and derivatives thereof, and synthesis method and application thereof

Abstract

The invention discloses a synthesis method of o-aminobenzoic acid and derivatives thereof. O-methyl(hetero)aryl nitro compounds are used as a reaction raw material in a reaction solvent to synthesize the o-aminobenzoic acid and the derivatives thereof under the action of water, a catalyst, alkali and an additive. According to the synthesis method, the raw materials are cheap and easy to obtain, the reaction operation is simple, the yield is high, the tolerance of functional groups is excellent, and a simple and efficient method is provided for synthesizing o-aminobenzoic acid which is widely applied to the aspects of dyes, medicines, pesticides, spices and the like. The invention further discloses the o-aminobenzoic acid and derivatives thereof, and application thereof. The o-aminobenzoic acid and the derivatives thereof have wide application prospects.

Description

technical field

[0001] The invention belongs to the technical field of organic compound technology application, and specifically relates to anthranilic acid and its derivatives and a synthesis method thereof. Background technique

[0002] Anthranilic acid and its derivatives are a very important class of chemical raw materials, which widely exist in various natural products, medicines, pesticides, and dyes, and more than 200,000 tons of anthranilic acid are produced every year for the synthesis of billions of Drugs (such as Alprazolam, Furosemide, Clonazepam, etc.) and thousands of tons of pesticides (such as Bentazone). Based on the importance of anthranilic acid, it is particularly important to efficiently construct anthranilic acid and its derivatives from raw materials with simple structures and commercially available in large quantities.

[0003]

[0004] Drug molecules, dyes and pesticides with anthranilic acid skeleton

[0005] The traditional method of synthesiz...

Examples

Embodiment 1

[0042] Synthesis of compound 2

[0043] The methanol solution of sodium chloride was added dropwise to the above mixture (dropping time 5h), the reaction system was stirred at 90°C, and the raw material o-nitrotoluene was completely consumed by TLC monitoring. The reaction system was cooled to room temperature, and the pH was adjusted to 3-4 with hydrochloric acid in an ice bath. HPLC (external standard method) assay productive rate is 75%; 1 H NMR (400MHz, Methanol-d 4 )δ7.80(dd,J=8.1,1.5Hz,1H),7.22(ddd,J=8.5,7.1,1.6Hz,1H),6.76–6.68(m,1H),6.61–6.51(m,1H) . 13 C NMR (101MHz, Methanol-d 4 )δ171.60, 152.78, 134.98, 132.65, 117.74, 116.57, 111.73. -1 .

Embodiment 2

[0045] Synthesis of compound 3

[0046] Take a 50mL reaction tube to strictly remove water, then replace the air in the system with nitrogen, add selenium powder (28.4mg, 0.36mmol), 1,2-dimethylnitrobenzene (161μL, 1.2mmol), water (44μL, 2.4mmol), nitrobenzene (25μL, 0.24mmol), methanol (1mL), DMSO (0.2mL), the mixture was stirred at 90 ° C; 1mL of methanol, the methanol solution of lithium tert-butoxide was added dropwise to the above mixture through a syringe pump (dropping time 5h), the reaction system 172.48, 150.56, 140.97, 132.63, 121.03, 116.02, 115.78, 22.90. -1 .HRMS(EI) Calcd for C 8 h 9 NO 2 151.0633,Found 151.0633.

Embodiment 3

[0048] Synthesis of Compound 4

[0049] The mixture was stirred at 90°C; another weighed sodium hydroxide (96mg, 2.4mmol) was dissolved in 1mL of methanol, and the methanol solution of sodium hydroxide was added dropwise to the above mixture through a syringe pump (dropping time 5h), the reaction system Stir at 90°C, and monitor by TLC until the raw material 2,5-dimethylnitrobenzene is completely consumed. The reaction system was cooled to room temperature, the solvent was spin-dried, and NaOH (2N aq., 20 mL) was added to the residue and stirred for 5 minutes. The resulting mixture was washed with tert-butyl methyl ether (10 mL×2), and the combined organic layers were washed with NaOH (2N aq., 10 mL) again. The combined aqueous phases were acidified with HCl (6N) to pH = 3.9, then extracted with ethyl acetate, and the combined organic layers were dried, filtered and concentrated. Weigh the crude product, take 1 / 15 of it, and use MeNO 2 As an internal standard, the NMR yie...

technical field

[0001] The invention belongs to the technical field of organic compound technology application, and specifically relates to anthranilic acid and its derivatives and a synthesis method thereof. Background technique

[0002] Anthranilic acid and its derivatives are a very important class of chemical raw materials, which widely exist in various natural products, medicines, pesticides, and dyes, and more than 200,000 tons of anthranilic acid are produced every year for the synthesis of billions of Drugs (such as Alprazolam, Furosemide, Clonazepam, etc.) and thousands of tons of pesticides (such as Bentazone). Based on the importance of anthranilic acid, it is particularly important to efficiently construct anthranilic acid and its derivatives from raw materials with simple structures and commercially available in large quantities.

[0003]

[0004] Drug molecules, dyes and pesticides with anthranilic acid skeleton

[0005] The traditional method of synthesiz...

Examples

Embodiment 1

[0042] Synthesis of compound 2

[0043] The methanol solution of sodium chloride was added dropwise to the above mixture (dropping time 5h), the reaction system was stirred at 90°C, and the raw material o-nitrotoluene was completely consumed by TLC monitoring. The reaction system was cooled to room temperature, and the pH was adjusted to 3-4 with hydrochloric acid in an ice bath. HPLC (external standard method) assay productive rate is 75%; 1 H NMR (400MHz, Methanol-d 4 )δ7.80(dd,J=8.1,1.5Hz,1H),7.22(ddd,J=8.5,7.1,1.6Hz,1H),6.76–6.68(m,1H),6.61–6.51(m,1H) . 13 C NMR (101MHz, Methanol-d 4 )δ171.60, 152.78, 134.98, 132.65, 117.74, 116.57, 111.73. -1 .

Embodiment 2

[0045] Synthesis of compound 3

[0046] Take a 50mL reaction tube to strictly remove water, then replace the air in the system with nitrogen, add selenium powder (28.4mg, 0.36mmol), 1,2-dimethylnitrobenzene (161μL, 1.2mmol), water (44μL, 2.4mmol), nitrobenzene (25μL, 0.24mmol), methanol (1mL), DMSO (0.2mL), the mixture was stirred at 90 ° C; 1mL of methanol, the methanol solution of lithium tert-butoxide was added dropwise to the above mixture through a syringe pump (dropping time 5h), the reaction system 172.48, 150.56, 140.97, 132.63, 121.03, 116.02, 115.78, 22.90. -1 .HRMS(EI) Calcd for C 8 h 9 NO 2 151.0633,Found 151.0633.

Embodiment 3

[0048] Synthesis of Compound 4

[0049] The mixture was stirred at 90°C; another weighed sodium hydroxide (96mg, 2.4mmol) was dissolved in 1mL of methanol, and the methanol solution of sodium hydroxide was added dropwise to the above mixture through a syringe pump (dropping time 5h), the reaction system Stir at 90°C, and monitor by TLC until the raw material 2,5-dimethylnitrobenzene is completely consumed. The reaction system was cooled to room temperature, the solvent was spin-dried, and NaOH (2N aq., 20 mL) was added to the residue and stirred for 5 minutes. The resulting mixture was washed with tert-butyl methyl ether (10 mL×2), and the combined organic layers were washed with NaOH (2N aq., 10 mL) again. The combined aqueous phases were acidified with HCl (6N) to pH = 3.9, then extracted with ethyl acetate, and the combined organic layers were dried, filtered and concentrated. Weigh the crude product, take 1 / 15 of it, and use MeNO 2 As an internal standard, the NMR yie...

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