Methyl 6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylate

8.9 g of compound IV was placed in a 500 mL three-necked flask, 210 mL of dichloromethane was added, and 100 mL of a saturated sodium bicarbonate solution was added dropwise after stirring.After cooling to 0 C, 6.6 g of chloroacetyl chloride was added dropwise under rapid stirring, and the reaction was performed at the same temperature for 3 hours.The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a red-brown solid.55 ml of DMF and 14.5 g of potassium carbonate were added to the concentrate, stirred until dissolved, and heated to 70 C. for 2 h.The temperature was raised to 75 C, and 6.3 g of dimethyl carbonate was added dropwise to the reaction solution, and the reaction was carried out for 3 hours.It was poured into ice water, filtered, and the filter cake was washed with water and dried under reduced pressure to obtain a white solid V10.38 g, with a yield of 92%.(1) DMF 500 ml was sequentially added to a four-necked flask at room temperature. 100 g of 6-chloro-3-oxo-3, 4-dihydro-2H-1, 4-benzoxazine-8-carboxylic acid methyl ester, 85 g of anhydrous potassium carbonate was added thereto with stirring, and the temperature was raised to 55 C. Continue to keep warm for 1h; (2) 100 g of methyl iodide was added to the solution after the step (1), and after reacting at 55 C for 1 h, 150 g of water was added, and the reaction was further kept at 55 C for 1 h. After the reaction is completed, the reaction solution is slowly poured into an appropriate amount of ice water, filtered, and the filter cake is washed until the pH of the eluate is neutral. The product was obtained after drying. The yield was 98%.7.68 g of compound V was placed in a 250 mL three-necked flask, 75 mL of ethanol and 75 mL of a 5% sodium hydroxide solution were sequentially added, and the temperature was raised to reflux for 3 h.The temperature was lowered to 10 C., and 10% hydrochloric acid was added dropwise to adjust the pH to 1-2, filtered, the filter cake was washed with water, and dried under reduced pressure to obtain 6.9 g of a white solid VI with a yield of 96%.500ml three bottles, After adding 150 ml of water and 12 g (0.3 mol) of sodium hydroxide, the mixture was stirred until the solid was completely dissolved, and 100 ml of ethanol was further added thereto. The temperature was lowered to 20C, 6-chloro-4-methyl-3, 4-dihydro- (0.1 mol) of methyl 2, 4-benzoxazin-8-carboxylate was added and stirred for 3 h. After the reaction was completed, the reaction mixture was cooled to 10 C or less, diluted hydrochloric acid was adjusted to pH 2, filtered and dried to give 4-methyl-3, 4-dihydro-3-oxo-2H-1, 4-benzoxazine-8-carboxylic acid as an off-white solid, 21.9 g, 91% yield.In a dry 500 ml three-necked flask, 6-chloro-4-methyl-3-oxo-3, 4-dihydro-2H-1, 4-benzoxazine-8-carboxylate, 150 ml of absolute ethanol and 5% aqueous NaH, 60 C reaction 3h, TLC tracking to the raw material reaction is completed. Cooling to room temperature, vacuum distillation to remove most of the ethanol, with 10ml ethyl acetate stripping reaction solution twice, with 6mol / L hydrochloric acid pH adjusted to 1 ~ 2 or so, stirring lh, suction filtration, washing, 60 C for 8 h to give 16.6 g of a light yellow powder in a yield of 86.1%.

Azasetron intermediate.

Molecular Weight:255.65
XLogP3:1.5
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:255.0298355
Monoisotopic Mass:255.0298355
Topological Polar Surface Area:55.8
Heavy Atom Count:17
Complexity:335
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes