Synthesis process of microbial pesticide phenazino-1-carboxylic acid

Abstract

The invention relates to a synthesis process of microbial pesticide phenazino-1-carboxylic acid, which comprises the following steps: by taking o-aminotoluene as a raw material, carrying out nitration and reduction to prepare 2, 3-diaminotoluene, and carrying out ring closing, chlorination and hydrolysis on the 2, 3-diaminotoluene and catechol to prepare a target product. The synthesis process provided by the invention has the advantages of easily available raw materials, simple operation, high product yield, good purity and the like, and is suitable for industrial application.

Description

Technical Field

[0001] The invention relates to the field of pesticides, and in particular to a synthesis process of microbial-derived pesticide shinazomib. Background Art

[0002] Shenqinmycin (phenazine-1-carboxylic acid, M18 for short) is extracted from the fermentation liquid of antagonistic bacteria screened from the soil of crop roots. It is a broad-spectrum, low-toxic, high-efficiency, environmentally compatible, and naturally degradable biological antibacterial agent that can effectively inhibit fungal stem rot and root rot of vegetables such as watermelon, pepper, and cucumber. It is a biological pesticide that can effectively inhibit stubborn diseases such as fungal stem rot and root rot. Its main preparation methods include biological fermentation and chemical synthesis. Although the biological fermentation method has the advantages of cheap and easy-to-obtain raw materials, mild reaction conditions, and small equipment investment, it is not conducive to large-scale production selection due to the disadvantages of cumbersome raw material screening, low fermentation efficiency, long reaction time, and difficulty in purification. In the early stage of chemical synthesis, nitrobenzene and o-aminobenzoic acid were used as raw materials. The one-step method and o-phenylenediamine and 1-methyl-2,3-dihydroxycyclohexene were mainly used as raw materials. Both methods have the disadvantages of low reaction efficiency, toxic raw materials, complex by-products, and difficult separation and purification. Summary of the invention

[0003] In view of the above defects, the present invention uses cheap and easily available o-aminotoluene as a raw material, and synthesizes the microbial source pesticide shinamicin with a total yield of 44.3% through 7 steps of chemical reaction.

[0004] The present invention provides the following technical solutions: A synthesis process of microbial source pesticide shinazomib, which is prepared by the following synthesis route: .

[0005] The beneficial effects of the present invention are as follows: in this case, cheap o-aminotoluene is used as a raw material, and after amino protection, low-temperature nitration, and reduction, 2,3-diaminotoluene (calculated as o-aminotoluene) is prepared with a yield of 66.5%; under nitrogen protection, 2,3-diaminotoluene reacts with catechol in a molten state to undergo a ring-closing condensation reaction to obtain 1-methylphenazine with a yield of 76.2%; the obtained 1-methylphenazine reacts with chlorine to undergo α-methyl chlorination reaction, and hydrolyzes to obtain phenazine-1-carboxylic acid with a yield of 87.5%. The synthesis process of the present invention has the advantages of easy availability of raw materials, simple operation, high product yield, good purity, etc., and is suitable for industrial application. DETAILED DESCRIPTION

[0006] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0007] In addition, the technical features involved in the different embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0008] Experimental Section 1.1 Main reagents and instruments Catechol, o-methylaniline, glacial acetic acid, analytical grade, Aladdin Reagent Company; concentrated nitric acid, acetic anhydride, stannous chloride, analytical grade, Shanghai Sinopharm Group. Anhydrous sodium sulfate, hydrochloric acid, ethyl acetate, chemically pure, Shanghai Wusi Chemical Reagent Factory.

[0009] Bruker 400Mz NMR instrument (CDCl3 or DMSO- d 6 as solvent, TMS as internal standard); Bruker BioTOF III mass spectrometer; X-4 digital melting point instrument.

[0010] 1.2 Synthesis Experiment 1.2.1: Synthesis of N-(2-methyl-6-nitrophenyl)-acetamide Add 350 mL of acetic anhydride to a four-necked flask, start stirring, and drop 64.2 g (0.6 mol) of o-aminotoluene. After the drop is complete, continue stirring for 30 minutes. Cool the solution to below 5 °C and drop 63 mL of concentrated nitric acid. Pour the mixture into ice water, stir, filter under reduced pressure, and wash with ice water to obtain a red solid, which is the intermediate N-(2-methyl-6-nitrophenyl)-acetamide.

[0011] 1.2.2: Synthesis of 2-methyl-6-nitroaniline The solid was transferred to a 500 mL round-bottom flask, 300 mL of concentrated hydrochloric acid was added, refluxed for 1 h, and steam distilled to obtain 65.1 g of orange-yellow solid (Yield: 71.4%), mp: 92-94°C. 1 H NMR: (400Hz, CDCl3) d 2.17 (3H, s,CH3), 6.13 (2H, s, NH2), 6.56(1H, t, Ar-H, J = 7.2 Hz), 7.20 (1H, t, Ar-H, J= 7.2Hz), 7.96 (1H, d, Ar-H, J = 8.8 Hz). 1.2.3: Synthesis of 3-methyl-o-phenylenediamine Under nitrogen atmosphere, 2-methyl-6-nitroaniline (7.8 g, 0.051 mol) was dissolved in 180 mL of ethyl acetate, 33 g (0.174 mol) of stannous chloride was added, and refluxed for 6 h. The reaction solution was adjusted to pH = 9, separated, and the aqueous layer was extracted with EA 30 mL × 3. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain a brown solid. Recrystallization from anhydrous ethanol gave 5.8 g of reddish-brown block crystals, with a yield of 93.2% and a melting point of 59-60 °C. 1 H NMR: (400Hz, DMSO- d 6 ) d 2.19 (3H, s, CH3), 3.32 (4H, s, NH2), 6.61-6.64 (3H, m, Ar-H). 1.2.4: Synthesis of 1-methylphenazine Under nitrogen atmosphere, add 5.0 g (0.045 mol) of catechol to a 250 mL four-necked flask, start stirring, then add 5.5 g (0.045 mol) of 3-methyl-o-phenylenediamine, heat to 200°C, and keep warm for 40 hours. Stop heating, cool, and purify by column chromatography (filled with silica gel, petroleum ether: ethyl acetate = 10:1), and separate 8.7 g of light yellow crystals, with a melting point of 169-170°C. The yield is about 76.2%. 1 H NMR: (400Hz, CDCl3) d 2.94 (3H, s, CH3),7.64 (1H, d, Ar-H, J = 6.25 Hz), 7.73 (1H, t, Ar-H, J = 6.8 Hz),7.81-7.85 (2H, m,Ar-H), 8.10 (1H, d, Ar-H, J = 8.65 Hz), 8.26 (1H, t, Ar-H, J = 5.5 Hz), 8.31 (1H,d, Ar-H, J = 1.65 Hz). 1.2.5: Synthesis of trichloromethylphenazine Add 194 mg (0.001 mol) of 1-methylphenazine to a four-necked flask, add 10 mL of carbon tetrachloride, heat to reflux, pass chlorine gas, and track the reaction by TLC. After the reaction is completed, evaporate the solvent and recrystallize from ethanol to obtain 281 mg of a yellow-green solid with a yield of 94.6%. 1 H NMR: (400Hz, CDCl3) d 7.74 (1H, d, Ar-H, J = 6.25 Hz), 7.79-7.83 (2H,m, Ar-H),7.91 (1H, d, Ar-H, J = 6 Hz), 8.15-8.20 (2H, m, Ar-H), 8.27 (1H, d,Ar-H, J = 5.5 Hz). 1.2.6: Synthesis of phenazine-1-carboxylic acid Add 148.8 mg (0.5 mmol) of 1-trichloromethylphenazine to a flask, add 10 mL of 50% methanol, heat under reflux for 24 hours, adjust the pH to 2-3 with HCl, extract with ethyl acetate, evaporate the solvent, and recrystallize from ethanol to obtain 103.6 mg of a yellow-green solid with a yield of 92.5%. 1 H NMR: (400Hz, CDCl3) d 7.84 (1H, d, Ar-H, J = 6.25 Hz), 7.92-8.04 (2H, m, Ar-H), 8.11 (1H, d, Ar-H, J = 6 Hz), 8.25-8.23 (2H, m, Ar-H), 8.34(1H, d, Ar-H, J = 5.5 Hz),10.9(1H, s, COOH). 2 Results and discussion In this case, cheap o-aminotoluene was used as the raw material. After amino protection, low-temperature nitration and reduction, 2,3-diaminotoluene (calculated as o-aminotoluene) was obtained with a yield of 66.5%. Under nitrogen protection, 2,3-diaminotoluene reacted with catechol in a molten state to obtain 1-methylphenazine with a yield of 76.2%. The obtained 1-methylphenazine reacted with chlorine gas to undergo α-methyl chlorination and hydrolysis to obtain phenazine-1-carboxylic acid with a yield of 87.5%.

[0012] Using o-aminotoluene as the starting material, shinamicin was synthesized through nitration, reduction, ring closure, chlorination, hydrolysis and other reactions. The total yield of shinamicin was 44.3% (based on o-aminotoluene).

[0013] Although the embodiments of the present invention have been disclosed as above, they are not limited to the applications listed in the specification and the implementation modes. They can be fully applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily implemented. Therefore, without departing from the general concept defined by the claims and the scope of equivalents, the present invention is not limited to specific details.

Claims

1. A synthesis process of microbial source pesticide shenqinmycin, characterized in that: Prepared by the following synthetic route: 。

Images