Epoxy curing agent Knowledge Preparation of 2-fluoro-4-iodoaniline_Kain Industrial Additive

Preparation of 2-fluoro-4-iodoaniline_Kain Industrial Additive

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Background and Overview[1]

2-Fluoro-4-iodoaniline is one of the most important intermediates in the dye industry. In the dye industry, it can be used to manufacture acid ink blue G, acid medium BS, acid bright yellow, direct orange S, direct pink, and indigo. , dispersed yellow brown, cationic pink FG and reactive bright red X-SB, etc.; in terms of organic pigments, it is used to produce golden red, golden red g, bright red powder, phenol cyanine red, oil-soluble black, etc. In the printing and dyeing industry, it is used for the dye aniline black; in the pesticide industry, it is used to produce many insecticides and fungicides such as DDV, herbicide, piclochlor, etc.; aniline is an important raw material for rubber additives and is used to manufacture antioxidants A, Anti-aging agent D, antioxidant RD and antioxidant 4010, accelerators M, 808, D and CA, etc.; can also be used as raw materials for pharmaceutical sulfa drugs, and are also intermediates in the production of spices, plastics, varnishes, films, etc.; and can be used as It is used as a stabilizer in explosives, an anti-explosion agent in gasoline, and as a solvent; it can also be used to make hydroquinone, 2-phenylindole, etc.

2-Fluoro-4-iodoaniline is also an important raw material for the production of pesticides. N-alkyl aniline, alkyl aniline, o-nitroaniline, cyclohexylamine, etc. can be derived from aniline. It can be used as the fungicide sodium dimethoate, Intermediates for seed dressing spirit, insecticides triazophos, pyridazinophos, quinalphos, herbicides alachlor, cyclazinone, imidazoquinolinic acid, etc.

2-Fluoro-4-iodoaniline is an aniline derivative that can be used to synthesize antidepressant, antitumor, and antibacterial drugs.

2-fluoro-4-iodoaniline

Apply[3]

Preparation of cobimetinib:

Combine [2,3,4-trifluorophenyl][3-hydroxy-3-(2S)-N-Boc-2-piperidinyl-1-azetidinyl]methanone with 2- Fluorine-4-iodoaniline undergoes a substitution reaction in a system composed of an acid-binding agent base and a solvent, and then undergoes a deamination protection reaction to obtain cobimetinib.

Preparation[2]

Synthesis of 2-fluoro-4-iodoaniline

Diisopropylamine (13 ml, 91.0 mmol) was dissolved in tetrahydrofuran (100 ml). Under nitrogen protection, 2.5M n-butyllithium solution (36.4 ml, 91.0 mmol) was added dropwise at -20°C. After the dripping is completed, stir at 0°C for 30 minutes. Then, a solution of o-fluoroiodobenzene (18.4 g, 82.8 mmol) in tetrahydrofuran (50 ml) was added dropwise, and stirring was continued at -70°C for 1 hour. Dry ice (50g) was added, allowed to warm to room temperature and stirred overnight. 100 ml of water was added to the above reaction mixture, and the organic phase was separated. The aqueous phase was acidified with concentrated hydrochloric acid to pH 1-2, extracted three times with ethyl acetate, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain 15.5 g of yellow solid 2-fluoro-4-iodoaniline, yield: 70.5%.

Synthesis of tert-butyl 2-fluoro-4-iodophenylcarbamate

Compound (2) (13.3g, 50.0 mmol), triethylamine (20.8 ml, 150.0 mmol) and DPPA (26.7g, 100.0 mmol) were dissolved in tert-butanol (50 ml) and toluene (50 ml), heated to 80°C and stirred overnight. Distill under reduced pressure, and the residue is subjected to silica gel column chromatography (200 to 300 mesh, petroleum ether: ethyl acetate = 100: 1 to 20: 1), and vacuum dried to obtain 2-fluoro-4-iodophenylcarbamic acid as a colorless liquid Tert-butyl ester 9.31g, yield: 55.3%.

Synthesis of 2-fluoro-4-iodoaniline

Compound 2-fluoro-4-iodophenylcarbamate tert-butyl ester (9.31g, 27.7 mmol) was dissolved in methanol (50 ml), concentrated hydrochloric acid (10 ml) was added, and the mixture was stirred at room temperature for 3 hours. The methanol was evaporated under reduced pressure, and the saturated sodium bicarbonate solution was alkalized to pH 8-9. Extract with ethyl acetate and dry over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain 6.6 g of off-white solid 2-fluoro-4-iodoaniline, yield: 100%.

1H‑NMR (DMSO‑d6, 400MHz): δ6.35~6.49 (2H, m), δ7.01 (1H, d), δ4.19 (2H, brs).

Separation and purification

1) Select a mixture of 2-fluoro-4-iodoaniline and 2-fluoro-3-iodoaniline with 2-fluoro-4-iodoaniline accounting for 85% of the total mass as raw material, and grind it into powder , get grade A;

2) Put product A into the crystallizer, then open the crystallizer, heat product A to 45°C, so that product A is completely melted, and product B is obtained;

3) Cool product B at a rate of 1.5°C/h to crystallize it. After reaching the final crystallization temperature of 20°C, grow the crystal for 8 hours, and then release the mother liquor to obtain product C;

4) Gradually heat product C to sweat at a rate of 1.5°C/h until the final temperature of sweating is 25°C, sweat is released, and the remaining crystals are purified 2-fluoro-4-iodoaniline.

Main reference materials

[1] Shao Dong, & Shao Wenqi. Preparation method of 2-fluoro-3-iodoaniline.

[2] Chen Yunhua, Zhou Xurong, & Bai Hua. (2010). New synthesis method of anti-tumor drug sunitinib. Chinese Journal of Medicinal Chemistry (02), 27-29.

[3] Gao Min. (2013). Research on the catalytic reaction of synthesizing 2-mercaptobenzothiazole compounds from o-haloaniline. (Doctoral dissertation, Inner Mongolia University of Technology).

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