Preparation of 6-bromo-2H-1,4-benzoxazin-3(4H)-one_Kain Industrial Additive

Background and overview^[1][2]

6-Bromo-2H-1,4-benzoxazin-3(4H)-one is an organic intermediate that can be prepared in one step. A class of drugs with PPAR agonistic activity can be prepared.

Preparation^[1-2]

Method 1

Weigh 2-amino-4-bromophenol (2.5g, 13mmol) and add it to the three-necked flask, measure 80mL of tetrahydrofuran and add it to the system, and measure and add triethylamine (2.4mL, 17mmol). The reaction system was cooled to 0°C, and chloroacetyl chloride (1.12 mL, 14 mmol) was measured and added dropwise to the reaction system. After the addition was completed, the mixture was stirred at 0°C for 10 minutes, then raised to room temperature and stirred for 2 hours. Then the system was lowered to 0°C, sodium hydride (1.05g, 26mmol) was added in batches, the reaction system was lowered to 0°C for 20 minutes and then raised to room temperature for 2 hours. Concentrate the reaction system, add 100 mL of water to quench the reaction, filter the precipitate, wash with water, and dry the filter cake. 2.5 g of red solid were obtained. 1HNMR(400MHz, CDCl3)δ4.62(s,2H),6.86(d,1H),6.96(d,1H),7.09(dd,1H)

Method 2

Compound 2-nitro-4-bromophenol (25g, 0.12mol) was dissolved in CH3CN (250ml), and K2CO3 (42g, 0.23mol) and ethyl 2-bromoacetate (30g, 0.18mol) were added. The mixture was stirred and refluxed for 2 hours, filtered, and the filtrate was concentrated to obtain crude product. The crude product was dissolved in acetic acid (250 ml), and Fe (20 g, 0.36 mol) was added. The mixture was stirred at 80°C for 2 hours, then poured into water, extracted with ethyl acetate (3x 200ml), then washed with aq.NaHCO3 (6 N), separated and purified by silica gel column chromatography (EtOAc/PE=1:1) to obtain Solid compound 6-bromo-2H-1,4-benzoxazin-3(4H)-one (22.2 g, 85%). HNMR(400MHz, DMSO-d6)10.8(s,1H),7.0-7.1 (m,2H),6.9-7.0(m, 1H),4.6(s,2H). MS(ESI)m/z:227.9/ 229.9(M+H)+.

Apply^[2]

CN201810054428 reported that 6-bromo-2H-1,4-benzoxazin-3(4H)-one can be used to prepare the following compound 21, which is a PPAR gamma with strong blood-brain barrier permeability. Equine subtype agonists.

Main reference materials

[1] [Invented in China] CN201810054428.2 PPAR agonist and its use in the treatment of Alzheimer’s disease and other diseases

[2] [Invented in China] CN201510175762.X Bruton’s tyrosine kinase inhibitor