5-CHLORO-3,1-BENZOXAZIN-2,4-DIONE

In a 250 mL round-bottom flask under NExample 101A A solution of potassium hydroxide (1.68 g, 30 mmol) and 2-amino-6-chlorobenzoic acid (3.43 g, 20 mmol) in water (25 ML) at 0° C. was treated dropwise with 20percent phosgene in toluene (16.8 ML, 32 mmol) resulting in a precipitate.The mixture was stirred for 1 hour and the solid was collected by filtration, washed with water and dried to give the title compound (3.6 g, 91percent).1H NMR (300 MHz, DMSO-d6) δ 7.11 (d, J=7.35 Hz, 1H), 7.31 (d, J=6.99 Hz, 1H), 7.66 (t, J=8.09 Hz, 1H), 11.83 (s, 1H). 5-chloro-2H-3, 1-benzoxazine-2, 4(1H)-dione Intermediate D: 5-chloro-1H-benzo[d][1, 3]oxazine-2, 4-dioneGeneral procedure: Toa solution of amino-benzoic acid (2.90 mmol, 1 eq) in anhydrous THF (25 mL), triethylamine (2.90 mmol, 1 eq) was added and the mixture was cooled down to 0°C. Then triphosgene (0.97 mmol, 1 eq) was added portion wise and the reaction allowed to reach room temperature and left stirring for 18 hours. 1mL of HThe compound 2-amino-6-chlorobenzoic acid (1.00 g, 5.83 mmol) was suspended in 1, 4-dioxane (20 mL)The bis (trichloromethyl) carbonate (605 mg, 2.04 mmol) was then added to the reaction and the reaction mixture was heated to reflux and stirred for 3 hours. It was then cooled to room temperature and filtered with suction. The filter cake was washed with petroleum ether (50 mL) Washed and then dried under vacuum to give the title compound as a light brown solid (954 mg, 83percent).2-Amino-6-chlorobenzoic acid (1 g, 6 mmol, 1 eq) was suspended in 1, 4-dioxane (60 mL) under 0 °C. Triphosgene (1.4 g, 5 mmol, 0.8 eq) was added and the solution stirred for 3 h at a temperature under 20 °C. The solid was collected by filtration and washed with water to give product 2c (0.95 g, 82percent): mp > 260 °C; IR (KBr) υ 3436, 1774, 1701 cmExample 32. Preparation of 5-chloro-2-(4-(2-hydroxyethoxy)-3, 5-dimethyIphenyl)quinazolin-4(3H)-oneA mixture of 2-amino-6-chlorobenzoic acid (5.00 g, 29.1 mmol) in acetonitrile (50.0 mL) was stirred at room temperature under nitrogen. Pyridine (4.72 mL, 58.3 mmol) was added, followed by drop-wise addition of triphosgene (2.85 g, 9.60 mmol) in CHExample [1] [1 2-DIHVDRO-4-HYDROXY-5-CHLORO-L-METHVL-2-OXO-QUINOLINE-3-CARBOXYLIC] acid methyl ester 2-Amino-6-chlorobenzoic acid (30 g) was suspended in 1, 4-dioxane (225 ml) and ethyl chloroformate (75 ml) was added. The mixture was heated at reflux for 1 hour, then cooled to [50°C, ] and acetyl chloride (75 ml) was added. The mixture was stirred for 10 hours, after which the precipitated product was filtered off and washed with toluene. Drying in vacuum yields 5-chloroisatoic anhydride (33 g, 97percent yield). 5-Chloroisatoic anhydride [(30] gram) was dissolved in dimethylacetamide (300 ml), and cooled to [5°C] over a nitrogen atmosphere. Sodium hydride (5.8 g, 70 percent) was added portionwise, followed by addition of methyl iodide (11.5 ml). The reaction mixture was stirred at room temperature for 18 hours and the evacuated (40 mbar) for 1 hour in order to remove excess methyl iodide. Sodium hydride (5. [8] g, 70 percent) was added followed by addition of dimethyl malonate (20 ml), and the mixture was heated to [85°C.] After 3 hours at [85°C, ] the mixture was cooled and diluted with cold water (2.4 litre). The product was precipitated by addition [OF 5 M HCL] (aq) until pH=1.5-2. Filtration of the precipitated product and recrystallisation from methanol gave the title compound (29 g, 70 percent yield). In essentially the same manner the ethyl ester is obtained from the corresponding starting materials.After suspending 2-(Boc)amino-6-chlorobenzoic acid (1.51 g, 5.56 mmol) in toluene (20 mL), the mixture was heated to reflux. Oxalyl chloride (0.572 mL, 6.67 mmol) was added dropwise thereto, and the mixture was vigorously stirred for 10 minutes. After cooling the reaction mixture on ice, the precipitated crystals were filtered out, washed with n-hexane and dried in a desiccator to obtain 5-chloroisatoic anhydride. Yield: 769 mg (70percent), M+1 = 198.0.1H-NMR (270 MHz, DMSO-d6): δ11.8(1H, s), 7.65(1H, t, J=8.2Hz), 7.30(1H, d, J=8.2Hz), 7.10(1H, d, J=8.2Hz) ppm.Iodomethane (2 mL, 4.6 mmol, 4 eq) and DIPEA (1 mL, 0.74 mol) were suspended in DMA (10 mL) for 10 min at RT. Then 5-chloroisatoic anhydride (200 mg, 1.01 mmol, 1eq) was added and the reaction mixture was stirred at for 5 H at 40 C. The resulted product 2d was collected by filtration and washed with water (150 mg, 70%). mp = 224 C, IR (KBr) upsilon 1774, 1716, 1593 cm-1 1H NMR (DMSO-d6, 300 MHz) delta 7.78 (t, J = 8.1 Hz, 1H), 7.42 (m, 2H), 3.45 (s, 3H). Anal. Calcd for C9H6ClNO3: C, 51.08; H, 2.86; Cl, 16.75; N, 6.62; O, 22.68. Found: C, 51.12; H, 2.36; Cl, 16.71; N, 6.58.In a 250 mL round-bottom flask under N2 was dissolved Example 101A A solution of potassium hydroxide (1.68 g, 30 mmol) and A solution of potassium hydroxide (1.68 g, 30 mmol) and Phosgene (51 g, 0.52 mol) dissolved in 150 ml of dioxane was added in portions to a mechanically stirred slurry of 2-amino-6-chloro-benzoic acid (30 g, 0.175 mol) and sodium bicarbonate (44 g, 0.52 mol) in 300 ml of dioxane. Violent reaction with gas evolution occurred and the reaction mixture was cooled to keep the temperature below 50C. Then stirring was continued at 50C for 1 hour. The reaction mixture was cooled to 15C, the resulting precipitate was collected, washed with water and dried to give the isatoic anhydride.In the same manner, from the appropriate aminobenzoic acids, the following compounds were synthesised: 6-chloroisatoic anhydride 6-bromoisatoic anhydride 6-methylisatoic anhydride B. 1, 2, 3, 4-tetrahydro-3-methyl-2, 4-dioxo-quinazoline[3-2] Synthesis of 2-amino-6-chloro-N-(2, 6-dioxopiperidin-3-yl)benzamide (Compound <3-3>) To the solution of

Molecular Weight:197.57
XLogP3:1.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:196.9879707
Monoisotopic Mass:196.9879707
Topological Polar Surface Area:55.4
Heavy Atom Count:13
Complexity:256
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes