6-Chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid

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, 91percent 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 5percent 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 86.1percent.Into a 250 ml three-necked flask, 16.6 g of intermediate III, 15.1 g of 3-aminoquinuclidine dihydrochloride and 24.3 g of TBTU were added, followed by the addition of 150 ml of methylene chloride. The mixture was sufficiently mixed to lower the temperature of the system to 0 At 10 C, 23.0 g of triethylamine was added dropwise. After 20 min, the reaction was completed at 0 to 10 C for 1.5 h. TLC was followed until the reaction was complete. Washed with 75 ml of saturated aqueous sodium chloride twice, 75 ml of purified water twice, and then methylene chloride was distilled off under reduced pressure, and further recrystallized from ethyl acetate to give an intermediate IV of 20.8 g in a yield of 86.3% and a purity of 99.2%.Add 100 mL of dry dichloromethane and 2.7 g of 3-aminoquinuclidine dihydrochloride to a 250 mL single-necked flask, cool to 0 C, and add 4.14 g of triethylamine dropwise with stirring. After stirring for 0.5 h, VI 3.25g, TBTU 4.77g, after the addition, react at the same temperature for 1h.Filter and concentrate under reduced pressure to give a pale yellow solid.30 mL of absolute ethanol was added to the concentrate, the temperature was raised to 45 C., and concentrated hydrochloric acid was added dropwise to adjust the pH to 2 to 3, stirred for 0.5 h, and then cooled to room temperature. After standing for 1 h, a large amount of white solids precipitated.It was filtered with suction, washed with absolute ethanol and dried under reduced pressure to obtain 4.43 g of white powder I with a yield of 94%.6-Chloro-4-methyl-3-oxo-3, 4-dihydro -2H-1, 4- benzoxazine-8-carboxylic acid (12.0g, 0.05mol), triethyl phosphite ( 9.7g, 0.06mol), 2, 2'- dibenzothiazyl disulfide (19.4g, 0.06mol) and tetrahydrofuran (100ml) was added to a dried reaction flask, stirred at room temperature 1h, the ice-water bath temperature below 20 , containing added dropwise triethylamine (8.6ml) in tetrahydrofuran (20ml) was added.Bi drops at room temperature the reaction 3h, the reaction was reserved.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%.

Used as intermediate of drug azastron

Molecular Weight:241.63
XLogP3:1.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:241.0141854
Monoisotopic Mass:241.0141854
Topological Polar Surface Area:66.8
Heavy Atom Count:16
Complexity:322
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes