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Chemical Structure| 103361-99-5
Chemical Structure| 103361-99-5

*Storage: Sealed in dry,Room Temperature.

7-Fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one

CAS No.: 103361-99-5

4.5 *For research use only!

Cat. No.: A117106 Purity: 98%

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Product Details of [ 103361-99-5 ]

CAS No. :103361-99-5
Formula : C8H6FNO2
M.W : 167.14
MDL No. :MFCD07774200
InChI Key :TXRXHEOGQVPEBT-UHFFFAOYSA-N
Pubchem ID :13731295

Safety of [ 103361-99-5 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338

Application In Synthesis [ 103361-99-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 103361-99-5 ]

[ 103361-99-5 ] Synthesis Path-Downstream   1~24

  • 1
  • [ 103361-99-5 ]
  • sodium hydrogensulfite [ No CAS ]
  • [ 153122-66-8 ]
YieldReaction ConditionsOperation in experiment
With Iodine monochloride; In N-methyl-acetamide; acetic acid; Step A 6-Iodo-<strong>[103361-99-5]7-fluoro-2H-1,4-benzoxazin-3(4H)-one</strong> 7-Fluoro-2H-1,4-benzoxazin-3(4H)-one (15.8 g) was mixed with iodine monochloride (15.6 g) in acetic acid (150 ml) and heated to reflux for 36 h. The cooled mixture was treated with saturated aqueous sodium bisulfite until the color was dissipated. The solid was filtered and washed well with water. The solid was air dried and dried further by dissolution in dimethylformamide (100 ml) and evaporated to dryness under reduced pressure to give the desired product (26.3 g) contaminated with some starting material. (The reaction can be taken to completion by addition of more iodine monochloride and refluxing for 24 h longer.) The crude product was used in Step B.
  • 2
  • [ 103361-99-5 ]
  • [ 79-04-9 ]
  • [ 495416-00-7 ]
YieldReaction ConditionsOperation in experiment
50% Aluminum chloride (1.9 g; 2.2 eq) and chloroacetyl chloride (0.6 mL; 1.2 eq) were added at r. t. to a suspension of 7-fluoro-4H-benzo [1,4] oxazin-3-one (1.1 g; 6.58 MMOL) in dry 1, 2-dichloroethane (10 mL). The reaction mixture was stirred at 80C under nitrogen for 3 h, then poured into a saturated aq. solution of ammonium chloride (10 mL) and extracted into ethyl acetate (3X10 mL). The organic layers were combined, dried (NA2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with 60% ethyl acetate in cyclohexane to afford the title compound (D23) as a white solid (0.8 g; yield 50%). MS; (ES) m/z: 244.1 [MH+]. C,OH7CIFN03 requires 243. 1H-NMR (300 MHz, DMSO) S : 10.58 (s, 1 H), 7.41 (d, 1H), 7.05 (d, 1 H), 7.48 (d, 1 H), 4.95 (d, 2 H), 4.74 (s, 2 H).
YieldReaction ConditionsOperation in experiment
93% 7-Fluoro-4H-benzo[1,4]oxazin-3-one (111MF12) 2-Amino-5-flourophenol (111MF10) (10.3 g, 81 mmol), 2-chloroacetyl chloride (10.1 g, 89 mmol) and K2CO3 (23.5 g, 170 mmol) were mixed according to GP1. CC (SiO2; Heptane/EtOAc 4:1-4) to give the title compound (111MF12) (12.6 g, 93%); 1H NMR (DMSO) delta10.68 (s, 1 H), 6.83-6.91 (m, 2 H), 6.75-6.80 (m, 1 H), 4.57 (s, 2 H); 13C NMR (DMSO) delta164.2, 157.8 (d, J=238.6 Hz), 144.0 (d, J=12.4 Hz), 123.9 (d, J=2.7 Hz), 116.3 (d, J=9.6 Hz), 108.6 (d, J=22.7 Hz), 104.0 (d, J=26.5 Hz), 66.7.
93% 7-Fluoro-4H-benzo[1,4]oxazin-3-one (111MF12) 2-Amino-5-flourophenol (111MF10) (10.3 g, 81 mmol), 2-chloroacetyl chloride (10.1 g, 89 mmol) and K2CO3 (23.5 g, 170 mmol) were mixed according to GP1. CC (SiO2; Heptane/EtOAc 4:1-4) to give the title compound (111MF12) (12.6 g, 93%); 1H NMR (DMSO) d 10.68 (s, 1 H), 6.83-6.91 (m, 2 H), 6.75-6.80 (m, 1 H), 4.57 (s, 2 H); 13C NMR (DMSO) d 164.2, 157.8 (d, J=238.6 Hz), 144.0 (d, J=12.4 Hz), 123.9 (d, J=2.7 Hz), 116.3 (d, J=9.6 Hz), 108.6 (d, J=22.7 Hz), 104.0 (d, J=26.5 Hz), 66.7.
93% With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; General procedure: To a flask or vial was charged 2-aminophenol (1.0 equiv)dissolved in DMF (0.1 gmL) and 2-Chloroacetyl chloride(1.1 equiv) was added. The reaction was stirred in rt for12-20 hours and K2C03 (2.1 equiv) was added. The reaction was stirred in rt for another 12-20 hours then evaporated to dryness, redissolved in water (10 mL) and extracted usingEtOAc (3x20 mL); The combined organic phases concen? trated to a crude that was used directly or purified by CC(Heptane:EtOAc).3-Amino-4-thiopyridine (0.10 g, 0.79 mmol) and 2-Chlo-roacetyl chloride (0.098 g, 0.87 mmol) and K2C03 (0.23 g, 1.66 mmol) were mixed according to GP1 to give the title compound as a crude (81MF939a) (0.087 g)
Step B Preparation of 7-fluoro-2H-1,4-benzoxazin-3(4H)-one To a solution of the compound of Step A, Example 3, (50.0 gm) in THF (100 mL), under N2, was carefully added 10% Palladium on carbon (catalytic amount). The reaction vessel was pressurized with H2 (45 psi) and shaken on a Parr hydrogenator for 4 hours. The reaction mixture was filtered through a CELITE (siliceous earth) bed and the filtrate was evaporated to dryness under vacuum. The residue was triturated with Et2 O to obtain the title compound of Step B as a white solid (32.0 gm), 93%; m.p. 200-202 C.; 1 H NMR delta: 4.58 (s,2H), 6.79-6.90 (m,3H), 10.72 (s,1H).
Step A: Preparation of 7-fluoro-2 H -1,4-benzoxazin-3(4 H)-one A mixture of 3-fluoro-5-nitrophenol (50 g, 0.318 mol), ethyl bromoacetate (63.78 g) and potassium carbonate (44 g) in anhydrous dimethylformamide (350 mL) was stirred at room temperature under an argon atmosphere for 12 h. The reaction mixture was diluted with ethyl acetate (1 L), washed with water (twice with 300 mL) and brine (twice with 300 mL). The organic phase was separated, dried and the solvent was removed under reduced pressure to give the corresponding ether compound (74 g, 96%). A suspension of the above compound (27.3 g, 0.112 mol) in tetrahydrofuran (110 mL) containing palladium adsorbed on charcoal (10%, 1.5 g) was hydrogenated using a Parr shaker at 48 psi of hydrogen. After completion of the reaction the catalyst was removed by filtration through a pad of Celite, and the solvent was removed under reduced pressure to give the title compound of Step A as a solid melting at 209-210 C (18 g, 96%). 1H NMR (CDCl3): delta 6.94 (m, 1H), 6. 72 (m, 2H), 4.59 (s, 2H), 3.52 (s, 3H). 1.39 (d, 6H).

  • 4
  • [ 6974-77-2 ]
  • [ 103361-99-5 ]
  • [ 560084-59-5 ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In acetonitrile; (R,S)-4-(3-Chloro-2-methylpropyl)-7-fluoro-4H-benzo[ 1,4]oxazin-3-one (112KK1 9-c) 7-Fluoro-4H-benzo[1,4]oxazin-3-one (0.498 g, 2.98 mmol), (R,S)-1-bromo-3-chloro-2-methylpropane (0.613 g, 3.58 mmol), and Cs2CO3 (1.985 g, 6.09 mmol) in MeCN (4 mL) were reacted and worked up according to GP18 to give the crude title compound (112KK1 9-c) (0.694 g).
  • 5
  • [ 103361-99-5 ]
  • [ 513-38-2 ]
  • 7-fluoro-4-isobutyl-2H-1,4-benzoxazin-3(4H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% In water; N,N-dimethyl-formamide; c. 7-fluoro-4-isobutyl-2H-1,4-benzoxazin-3(4H)-one To 3.96 g (99 mmol) of hexanes washed 60% sodium hydride in 150 ml of N,N-dimethylformamide was added portionwise as a solid 15 g (90 mmol) of <strong>[103361-99-5]7-fluoro-2H-1,4-benzoxazin-3(4H)-one</strong>. When the addition was complete the reaction was stirred at room temperature for 10 min, after which time 19.8 g (108 mmol) of isobutyl iodide was added. The reaction was then stirred overnight before quenching onto 200 ml of water. The aqueous phase was extracted with EtOAc (2*150 ml) and the combined organics were dried over Na2 SO4, filtered and evaporated in vacuo to give the desired alkylated product, as a yellow oil (13 g, 65% yield).
65% In water; N,N-dimethyl-formamide; c. 7-fluoro-4-isobutyl-2H-1,4-benzoxazin-3(4H)-one To 3.96 g (99 mmol) of hexanes washed 60% sodium hydride in 150 ml of N,N-dimethylformamide was added portionwise as a solid 15 g (90 mmol) of <strong>[103361-99-5]7-fluoro-2H-1,4-benzoxazin-3(4H)-one</strong>. When the addition was complete the reaction was stirred at room temperature for 10 min, after which time 19.8 g (108 mmol) of isobutyl iodide was added. The reaction was then stirred overnight before quenching into 200 ml of water. The aqueous phase was extracted with EtOAc (2*150 ml) and the combined organics were dried over Na2 SO4, filtered and evaporated in vacuo to give the desired alkylated product, as a yellow oil (13 g, 65% yield).
  • 6
  • [ 116355-65-8 ]
  • [ 103361-99-5 ]
YieldReaction ConditionsOperation in experiment
With hydrogen;palladium-carbon; In ethanol; b. 7-fluoro-2H-1,4-benzoxazin-3(4H)-one To 500 mg of 5% Pd/C in a Parr bottle was added 100 ml of EtOH followed by 5.0 g (21.8 mmol) of methyl 5-fluoro-2-nitrophenoxyacetate. The flask was placed in a Parr Apparatus, evacuated and then charged with hydrogen. The suspension was then shaken for 2 hours. After evacuating the flask and recharging with nitrogen, the solids were removed by vacuum filtration through Celite. Since some product does precipitate, the filter cake is repeatedly rinsed with EtOAc (200 ml). The filtrate is refluxed for 4 hours and then evaporated to dryness in vacuo to give the desired material, 7-fluoro-2H-1,4-benzoxazin-3(4H)-one, as a white solid (m.p. 201-202 C.) in quantitative yield.
With hydrogen;palladium-carbon; In ethanol; b. 7-fluoro-2H-1,4-benzoxazin-3(4H)-one To 500 mg of 5% Pd/C in a Parr bottle was added 100 ml of EtOH followed by 5.0 g (21.8 mmol) of methyl 5-fluoro-2-nitrophenoxyacetate. The flask was placed in a Parr Apparatus, evacuated and then charged with hydrogen. The suspension was then shaken for 2 hours. After evacuating the flask and recharging with nitrogen, the solids were removed by vacuum filtration through Celite. Since some product does precipitate, the filter cake is repeatedly rinsed with EtOAc (200 ml). The filtrate is refluxed for 4 hours and then evaporated to dryness in vacuo to give the desired material, 7-fluoro-2H-1,4-benzoxazin-3(4H)-one, as a white solid (m.p. 201-202 C.) in quantitative yield.
  • 7
  • [ 103361-99-5 ]
  • [ 151982-43-3 ]
YieldReaction ConditionsOperation in experiment
EXAMPLE 18 3-(3-dimethylamino-1,2,4-oxadiazol-5-yl)-7-fluoro-4H-imidazo(5,1-c)(1,4)benzoxazine Using the standard procedure as outlined in Example 1 and using 7-fluor-2H-1,4-benzoxazine-3-one and the 3-dimethylamino-1,2,4-oxadiazol-5-yl isocyanate the title Example 18 compound was prepared. Mp 239-40 C.
  • 8
  • [ 103361-99-5 ]
  • [ 106-96-7 ]
  • [ 68-12-2 ]
  • 7-fluoro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; EXAMPLE 93 7-Fluoro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one A mixture of 1.7 g of 7-fluoro-2,4-dihydro.1,4-benzoxazin-3-one., 2 g of barium oxide. 1.3 ml of propargyl bromide and 40 ml of dimethyl formamide was heated on the steam bath for 45 minutes. The cooled reaction mixture was diluted with water and the precipitated product was collected by filtration. The precipitate was dissolved in methylene chloride and the solution was washed with water, dried and evaporated. The residue was crystallized from ether/hexane to give colorless crystals of 7-fluoro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one with m.p. 98-100.
  • 9
  • [ 103361-99-5 ]
  • [ 103361-67-7 ]
YieldReaction ConditionsOperation in experiment
92% With sulfuric acid; nitric acid; at -10℃; for 0.166667h; To a solution of <strong>[103361-99-5]7-fluoro-4H-benzo[1,4]oxazin-3-one</strong> (3.00 g, 17.95 mmol) in concentrated H2SO4 (12 mL) at -10 C. was added a mixture of fuming nitric acid (1.131 g, 17.95 mmol, 0.75 mL) and concentrated H2SO4 (0.75 mL) dropwise, keeping the internal temperature below 0 C. After addition, the reaction mixture was stirred at -10 C. for 10 min. The reaction mixture was poured onto crushed ice (200 g) with care. The precipitate was collected by filtration, washed with water (50 mL) and dried in vacuo to give 7-fluoro-6-nitro-4H-benzo[1,4]oxazin-3-one as a light yellow solid (3.5 g, 92%). 1H NMR (DMSO-d6, 400 MHz): delta 11.02 (s, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.23 (d, J=12.0 Hz, 1H), 4.77 (s, 2H).
92% With sulfuric acid; nitric acid; at -15℃; for 0.5h; Add 7-fluoro-2H-benzo[b][1,4]oxazine-3(4H)one (20 mmol) to 40 mL of 80% by weight concentrated sulfuric acid, And cooled to -15 C. A mixture of 22 mmol of concentrated nitric acid (65% by weight) and 2.2 mL of 80% by weight of concentrated sulfuric acid was slowly added dropwise with stirring. After the dropwise addition was completed, the reaction was further stirred for 30 minutes. After the reaction was completed, the reaction solution was poured into 100 g of ice water and stirred vigorously for 15 min. The obtained solid is suction filtered, washed with water,After drying in vacuo, a pale yellow solid 3.9 g was obtained. The yield was 92%.
92% With sulfuric acid; nitric acid; at -15℃; for 0.5h; 3) 7-Fluoro-2H-benzo[b][1,4]oxazin-3(4H)one (20 mmol) was added to 40 mL of 80% concentrated sulfuric acid and cooled to -15 C. A mixture of 22 mmol of concentrated nitric acid (65%) and 2.2 mL of 80% concentrated sulfuric acid was slowly added dropwise with stirring.After the dropwise addition was completed, the reaction was further stirred for 30 min. After the reaction was completed, the reaction solution was poured into 100 g of ice water and stirred vigorously for 15 min. The resulting solid was filtered off with suction, washed with water, and dried in vacuo to give a pale yellow solid, yield 92%
With nitric acid; In sulfuric acid; EXAMPLE 9 Production of the compound (III) from the compound (X): A solution of <strong>[103361-99-5]7-fluoro-2H-1,4-benzoxazin-3(4H)-one</strong> (2.0 g) in 80% aqueous sulfuric acid (30 ml) was cooled to 0 to 5 C., and 60% nitric acid (1.6 g) was gradually added thereto at 0 to 5 C. The resultant mixture was stirred at the same temperature for 30 minutes and poured onto ice water. The precipitated crystals were collected by filtration, washed with water and dried to give 7-fluoro-6-nitro-2H-1,4-benzoxazin-3(4H)-one (2.1 g) as pale brown crystals. m.p., 205.9 C. 1 H-NMR (CDCl3 +DMSO-D6) delta ppm: 3.2 (1H, broad), 4.62 (2H, s), 6.76 (1H, d, J=10 Hz), 7.6 (1H, d, J=6 Hz).
With nitric acid; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; sulfuric acid; ethyl acetate; Step B: Preparation of 7-fluoro-6-nitro-2 H -1,4-benzoxazin-3(4 H)-one To a stirred solution of the title compound of Step A (10 g, 59 mmol) in concentrated sulfuric acid (35 mL) was added a mixture of concentrated nitric acid (7 mL) and concentrated sulfuric acid (7 mL) at 0 to 5 C over a period of 30 minutes. After the addition was finished, the reaction mixture was stirred for another 30 minutes. The solution was poured into 1 L of ice water. After the product precipitated, it was isolated by filtration and was then dissolved in ethyl acetate (500 mL). The organic layer was separated, dried and concentrated under reduced pressure to afford the title compound of Step B as a colorless solid melting at 185-189 C (10.5 g, 84%). 1H NMR ((CD3)2SO): delta 7.62 (d, 1H), 7.24 (d, 1H), 4.78 (s, 2H), 3.52 (s, 3H). 1.39 (d, 6H).
With nitric acid; In sulfuric acid; B. A solution of <strong>[103361-99-5]7-fluoro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine</strong> (2.0 gram) in 80% aqueous sulfuric acid (30 ml) is cooled to 0 to 5 C., and 60% nitric acid (1.6 g) is gradually added thereto at 0 to 5 C. The resultant mixture is stirred at the same temperature for 30 minutes and poured onto ice water. The precipitated crystals are collected by filtration, washed with water and dried to give 7-fluoro-3,4-dihydro-3-oxo-6-nitro-2H-1,4-benzoxazine.
60 With sulfuric acid; nitric acid; at 20℃; for 0.75h; To compound 21A (5 g, 30 mmol) in concentrated H2SO4 (17 mL) was added a 1:1 mixture of fuming HNO3 and conc. H2SO4 (7 mL) over 15 min. The mixture was stirred for additional 30 min at RT and was slowly poured into ice water (500 mL). The mixture was filtered to collect solid and washed with water (4×). The solid was placed under high vacuum in an 80 C. oil bath for 5 h to provide 21B (3.82 g, 60%).
2.6 g With sulfuric acid; nitric acid; at 0℃; for 0.5h;Inert atmosphere; To a stirred solution of step 2 intermediate (2.7 g, 16.157 mmol) in sulphuric acid (3 ml) a mixture of nitric acid (69 %, 0.72 ml, 16.157 mmol) and concentrated sulphuric acid (2 ml) was drop wise added at 0 C under nitrogen atmosphere. The reaction mixture was stirred at 0 C for 30 min. The reaction mixture was quenched with ice-cooled water and solid was precipitated. The precipitated solid was dissolved in ethyl acetate (30 ml) and washed with aqueous saturated solution of sodium bicarbonate (150 ml). The ethyl acetate layer was dried and filtered and dried (Na2S04) and concentrated to yield 2.6 g of product as yellow solid. 1H NMR (300 MHz, DMSO-d6) delta 4.79 (s, 2H), 7.26 (d, J = 12.0 Hz, 1H), 7.63 (d, / = 7.2 Hz, 1H), 1 1.03 (br s, 1H).
With sulfuric acid; nitric acid; at 0℃; 100066] A mixture of <strong>[103361-99-5]7-fluoro-2H-1,4-benzoxazin-3(4H)-one</strong> (35 gm, 0.209 mol)and 80% sulphuric acid (525 mL) was cooled to 0C. 70% nitric acid was addeddropwise to the above mixture for over a period of 45-60 mins. The reaction mixturewas stirred for 1 hr at 0C and monitored by HPLC. After completion of reaction, thereaction mixture was slowly quenched with water at 0-5C and stirred well till densesolid appeared. The reaction mixture was then filtered and washed with water. Thesolid 6-nitro-7-fluoro-2H- 1 ,4-benoxazin-3(4H)-one obtained was dried under vacuumat 55-60C for 8 h at 500 mm of Hg.Drywt. :36gmYield : 81%HPLC Purity : 92.5%
With sulfuric acid; nitric acid; at 50℃; for 2.5h; A certain amount of concentrated sulfuric acid is put into the nitration tank and the temperature is controlled to be less than 50C.Add a certain amount of intermediate 2 slowly and stir for 30 min; control the reactor temperature below 50C,A certain amount of 70% nitric acid was added dropwise to the mixture and dripped for about 60 minutes; the addition was completed.Incubate and stir for 60 minutes under 50C, sample material <0.5% qualified;The above materials are slowly dripped into the high water tank containing water to quench the phase, and the precipitated solids are stirred and filtered.The filter cake is beaten with a certain amount of water once, and a certain amount of sodium bicarbonate is added, filtered, and the filter cake is dried to obtain intermediate 3 .
A certain amount of concentrated sulfuric acid is put into the nitration tank, and the temperature is controlled to be less than 60C.Slowly add a certain amount of dichloroethane,<strong>[103361-99-5]7-fluoro-2H-1,4-benzoxazin-3(4H)-one</strong>,Stir for 30 min. A certain amount of acetic anhydride is added dropwise,Then add a certain amount of 60-98% nitric acid, about 1-2 hours, temperature 30-60 C.After the addition, the mixture is stirred at 30-60C for 1 hour.Sampling material <0.5% qualified. The above materials were slowly dropped into a reaction vessel containing water under stirring for quenching, and the solids were precipitated by stirring. After filtration, the filter cake is beaten with a certain amount of water and put in a certain amount of sodium bicarbonate.Filtration, filter cake drying to get the product.Among them, the product is C8H5FN2O4,Water H2O; C8H5FN2O4, water H2O mass ratio of 212:18;Among them, the <strong>[103361-99-5]7-fluoro-2H-1,4-benzoxazin-3(4H)-one</strong> (167),The mass ratio of concentrated nitric acid HNO3 (63) was 167:63.In step (1),The conversion rates of the nitration and hydrogenation reactions were all greater than 99.5%.

  • 10
  • [ 103362-07-8 ]
  • [ 7439-89-6 ]
  • [ 103361-99-5 ]
YieldReaction ConditionsOperation in experiment
In acetic acid; ethyl acetate; EXAMPLE 10 Production of the compound (X) from the compound (IX): Iron powder (36.42 g) was suspended in 5% aqueous acetic acid (69 ml) and heated to 80 C. To the suspension, a solution of ethyl 5-fluoro-2-nitrophenoxyacetate (15.86 g) in acetic acid (65 ml) and ethyl acetate (65 ml) was dropwise added, and the resultant mixture was heated at 60 to 80 C. under reflux for 3 hours. After removal of residue by filtration, the filtrate was extracted with ethyl acetate. The extract was washed with water and sodium bicarbonate solution, dried and concentrated to give 7-fluoro-2H-1,4-benzoxazin-3(4H)-one (6.82 g). m.p., 186.7 C. 1 H-NMR (CDCl3 +DMSO-D6) delta ppm: 4.2 (1H, broad), 4.51 (2H, s), 6.5-7.0 (3H, m).
In acetic acid; ethyl acetate; A. Iron powder (36.42 g) is suspended in 5% aqueous acetic acid (69 ml) and heated to 80 C. To the suspension, a solution of ethyl 5-fluoro-2-nitrophenoxyacetate (15.86 g) in acetic acid (65 ml) and ethyl acetate (65 ml) is dropwise added, and the resulting mixture is heated at 60 to 80 C. under reflux for 3 hours. After removal of residue by filtration, the filtrate is extracted with ethyl acetate. The extract is washed with water and sodium bicarbonate solution, dried and concentrated to give 7-fluoro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine.
In acetic acid; Step B: 7-Fluoro-2H-1,4-benzoxazin-3(4H)-one A solution of the 49.0 grams (0.20 mole) of ethyl 2-(5-fluoro-2-nitrophenoxy)acetate in 100 ml of glacial acetic acid was added to a warm (60 C.), stirred mixture of iron powder (50.0 grams, 0.90 mole) in 300 ml of glacial acetic acid. The reaction temperature was allowed to reach 100 C., and the mixture was stirred for approximately three hours. This mixture was poured into water, forming a precipitate. The precipitate was collected by filtration and was recrystallized from ethanol to yield 25.0 grams of 7-fluoro-2H-1,4-benzoxazin-3(4H)-one; another sample of this compound prepared in a similar manner, and then purified further, had a melting point of 205-206 C. and an nmr spectrum which was consistent with the proposed structure.
  • 11
  • [ 103361-99-5 ]
  • [ 56346-41-9 ]
YieldReaction ConditionsOperation in experiment
55.01% With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 16h;Inert atmosphere; To lithium tetrahydroaluminum (284mg, 7.48mmol)Tetrahydrofuran (5mL)To the suspension was added compound 2 (500 mg, 2.99 mmol).The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours.The reaction system is water,15% sodium hydroxide aqueous solution was quenched, suction filtered, and the filtrate was extracted with ethyl acetate.Concentration and purification by column chromatography gave Compound 3 (252 mg, yield: 55.01%) as a yellow oil.
  • 12
  • [ 53981-24-1 ]
  • [ 79-04-9 ]
  • [ 103361-99-5 ]
YieldReaction ConditionsOperation in experiment
87% With tetra-N-butylammonium tribromide; potassium carbonate; In acetonitrile;Reflux; To a suspension of 2-amino-5-fluorophenol (Alfa, 15.00 g, 118 mmol), K2CO3 (48.9 g, 354 mmol) and tetrabutyl-ammonium bromide (3.80 g, 11.80 mmol) in MeCN (200 mL) was added 2-chloroacetyl chloride (14.66 g, 130 mmol) dropwise at 0 C. The reaction mixture was warmed to rt and then heated at reflux overnight. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The solid was collected, washed with water (100 mL) and dried in vacuo to give 7-fluoro-4H-benzo[1,4]oxazin-3-one as a pale solid (17.2 g, 87%). 1H NMR (DMSO-d6, 400 MHz): delta10.71 (s, 1H), 6.84-6.88 (m, 2H), 6.76-6.81 (m, 1H), 4.57 (s, 2H).
76.05% With tetrabutylammomium bromide; potassium carbonate; In acetonitrile; at 65℃; for 15h;Inert atmosphere; To 2-amino-5-fluorophenol (500mg, 3.94mmol)Acetonitrile (5mL)Chloroacetyl chloride (490mg, 4.33mmol),Potassium carbonate (1.63g, 11.82mmol)And tetrabutylammonium bromide (126 mg, 0.39 mmol).The reaction mixture was heated to 65 C under a nitrogen atmosphere for 15 hours.Cool to room temperature, suction filter, and concentrate the filtrate in vacuo.Purification by column chromatography gave the compound as a yellow oil (500 mg, yield: 76.05%).
  • 13
  • [ 103361-99-5 ]
  • [ 355423-58-4 ]
YieldReaction ConditionsOperation in experiment
44% With N-Bromosuccinimide; In acetonitrile; at 20℃; for 5h; INTERMEDIATE 76-Bromo-7-fluoro-4H-benzori.4]oxazin-3-oneTo a solution of Intermediate 6 (4.1 g, 25.0 mmol) in MeCN (120 mL) was added NBS (5.41 g, 30 mmol). The reaction mixture was stirred for 4 h at r.t. before addition of further NBS (0.45 g, 2.5 mmol) and MeCN (30 mL) and stirring for a further 1 h. It was then concentrated in vacuo. The resulting residue was slurried in water (10O mL). The solid material was filtered off, washed with water and dried in vacuo to give the title compound (2.7 g, 44%) as an off-white solid. deltaeta (DMSO-d6) 10.81 (IH, s), 7.12 (IH, d, J 9.4 Hz), 7.09 (IH, d, J 7.0 Hz), 4.63 (2H, s).
  • 14
  • [ 137472-06-1 ]
  • [ 103361-99-5 ]
YieldReaction ConditionsOperation in experiment
78% With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 2h; To a solution of 2-chloro-N-(4-fluoro-2-hydroxyphenyl)acetamide (5.5 g, 27 mmol) in acetonitrile (40 mL) was added DIPEA (7 g, 54 mmol) and the reaction solution was stirred at 80C for 2 h. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (50 mL) and water (50 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 3.5 g (78%) of 7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one as a brown solid. 1H NMR (400 MHz, ODd3) 6 8.35 (br. s, 1 H) 6.67-6.77 (m, 3 H) 4.62 (5, 2 H).
In tetrahydrofuran; acetonitrile; at 70℃; for 6h; INTERMEDIATE 67-Fluoro-4H-benzof 1.41oxazin-3-oneTo an ice-bath cooled solution of 2-amino-5-fluorophenol (15.0 g, 118 mmol) and DIPEA (22.6 mL, 130 mmol) in THF (80 mL) was added, dropwise, a solution of chloroacetyl chloride (10.4 mL, 130 mmol) in THF (20 mL). After stirring with cooling for 10 minutes, an additional portion of DIPEA (22.6 mL, 130 mmol) was added, and the reaction mixture allowed to warm to r.t. It was stirred overnight at r.t. Then acetonitrile (100 mL) was added, and the mixture heated to 700C for 6 h. After cooling to r.t. the mixture was filtered through a pad of silica and washed with EtOAc. The filtrate was concentrated in vacuo. The resulting residue was partitioned between water and EtOAc (100 mL each) causing precipitation of a solid which was filtered off, dissolved in THF (300 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (15.9 g, 81%) as a brown solid. LCMS (ES+) 209 (M+MeCN)+, RT 2.41 minutes (Method 1).
  • 15
  • [ 1183246-92-5 ]
  • [ 103361-99-5 ]
YieldReaction ConditionsOperation in experiment
93% With iron; acetic acid; for 2.5h;Inert atmosphere; Reflux; General procedure: To a stirred solution of 2a (2 mmol) in acetic acid (10 mL), powdered Fe (12 mmol) was added and the reaction mixture was then refluxed for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and the acetic acid was removed under reduced pressure, EtOAc (20 mL) was added and was stirred for 2 min and then filtered to remove any iron impurities. The insoluble iron residue was washed with EtOAc (20 mL). The filtrate and washings were combined and dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the crude product thus obtained was purified by column chromatography to obtain the pure product 3a.
With iron; acetic acid; for 2h;Reflux; General procedure: To a stirred solution of 2-(2-nitrophenoxy)acetonitrile (2 mmol) in acetic acid (10 mL), powdered Fe (12 mmol) was added and the reaction mixture was then refluxed for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature and the acetic acid was removed under reduced pressure, EtOAc (20 mL) was added and was stirred for 2 min and then filtered to remove any iron impurities. The insoluble iron residue was washed with EtOAc (20 mL). The filtrate and washings were combined and dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the crude 2H-benzo[b][1,4]oxazin-3(4H)-one derivative thus obtained was purified by column chromatography to obtain the pure product.
  • 17
  • [ 103361-99-5 ]
  • C20H28FN3O5S [ No CAS ]
  • 18
  • [ 103361-99-5 ]
  • 4-carboxymethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one [ No CAS ]
  • 19
  • [ 103361-99-5 ]
  • [ 96-32-2 ]
  • [ 1259323-80-2 ]
  • 20
  • [ 103361-99-5 ]
  • [ 335104-34-2 ]
YieldReaction ConditionsOperation in experiment
With Lawessons reagent; In toluene; at 100℃; for 0.0833333h;Microwave; To a solution of 2H-1 ,4-benzothiazin-3(4H)-one (intermediate 33, 3.1 g, 18.55 mmol) in dry Toluene (15 mL) in a glass tube was added Lawesson's reagent (4.50 g, 1 1 .13 mmol, 0.6 eqv) and the mixture reacted in a microwave reactor at 100 C for 5 minutes). Cyclohexane was added, and the resulting solid was filtered. The solid was dissolved in Et^O and the solvent removed not quite to dryness. This concentrated mixture was purified using a Biotage SP1 purification system using Normal phase Silica SNAP 4x50 g (because of low solubility) column in the gradient of ethyl acetate in cyclohexane (8 % in 1 CV, 8-30 % in 10 CV, 30-66 % in 10 CV) to give the title compound (2 g); m/z (ES): 184.10 [M+H]+; 1H NMR (600 MHz, DMSO-d6) delta ppm 4.86 (s, 2 H) 6.84 - 6.88 (m, 1 H) 6.92 - 6.97 (m, 1 H) 7.07 - 7.1 1 (m, 1 H) 12.77 (s, 1 H).
  • 21
  • [ 103362-07-8 ]
  • [ 103361-99-5 ]
YieldReaction ConditionsOperation in experiment
86% With iron; acetic acid; for 3h;Reflux; Ethyl 2-nitro-5-fluorophenoxyacetate (50 mmol) was added to 50 mL of glacial acetic acid.Heat to reflux under stirring and iron powder (100 mmol) was added in three portions.After the addition was completed, the reaction was continued for 3 hours. After the reaction is completed, the iron powder is removed by filtration through diatomaceous earth while hot.The filtrate was cooled, poured into 200 mL of water and stirred vigorously for 30 min.The resulting solid was suction filtered, washed with water,After drying in vacuo, 7.18 g of a white solid was obtained.The yield was 86%.
86% With iron; acetic acid; for 3h;Reflux; 2) Ethyl 2-nitro-5-fluorophenoxyacetate (50 mmol) was added to 50 mL of glacial acetic acid, heated to reflux with stirring, and iron powder (100 mmol) was added in three portions.After the addition was completed, the reaction was continued for 3 hours. After completion of the reaction, the iron powder was removed by filtration through celite, and the filtrate was cooled, poured into 200 mL of water, and stirred vigorously for 30 min.The resulting solid was filtered off with suction, washed with water, and dried in vacuo to give a white solid, yield 86%
70.7% With iron; acetic acid; In ethyl acetate; at 70℃; for 1.75h; [00065] A solution of 5% acetic acid (340 mL) and iron powder (172.5 gm) was stirred and heated to 70C. A mixture of acetic acid (300 mL), ethyl-2-(2-nitro-5-fluorophenoxy) acetate (75 gm, 0.308 mol) and ethyl acetate (300 mL) were added drop wise to the above solution at 70C over a period of 45 mm and the reaction mixture was allowed to stir for 1 h. The reaction was monitored by HPLC. After completion of reaction, the reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3 x 50 mL) at 40C and allowed to stir for 30 mins.Organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to afford crude product which was purified by preparative HPLC to give pure product as white solid, 7-fluoro-2H-1,4- benzoxazin-3 (4H)-one.Drywt. :36.5gmYield 70.7%HPLC Purity : 99.2%
With iron; ammonium chloride; In methanol; water; at 80℃; for 2h; Intermediate 33: 7-fluoro-2H-1 ,4-benzoxazin-3(4H)-oneTo a suspension of ethyl [(5-fluoro-2-nitrophenyl)oxy]acetate (intermediate 32, 7.6 g, 31 .3 mmol) in methanol (40 mL) / water (40 mL) was added ammonium chloride (16.72 g, 313 mmol) followed by iron (10.47 g, 188 mmol) powder and the mixture was heated at 80 C for 2hr. The reaction mixture was filtered through celite, the filtrate was evaporated under vacuo, and the residue was extracted with EtOAc (4x40 mL). The organic phases were washed with brine and dried over IS^SC^. The mixture was filtered through a phase separator filter tube and the mixture was removed in vacuo to give the title product; m/z (ES): 168.10 [M+H]+; 1 H NMR (500 MHz, DMSO-d6) delta ppm 4.59 (s, 2 H) 6.77 - 6.83 (m, 1 H) 6.85 - 6.91 (m, 2 H) 10.68 - 10.74 (m, 1 H).
2.75 g With iron; ammonium chloride; In methanol; water; at 80℃; for 2h; Ammonium chloride (1 1 g, 205.58 mmol) was added to stirred suspension of step 1 intermediate (5.0 g, 20.558 mmol), methanol (30 ml) and water (80 ml) followed by addition of iron powder (6.8 g, 123.306), the reaction mixture was stirred at 80 C for 2 h. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure to obtain residue. To the residue, water (150 ml) and ethyl acetate (150 ml) was added and stirred for 15 min. the organic layer was separated and washed with brine (100 ml). The mixture was dried (Na2S04) and concentrated under reduced pressure. The product was purified by column chromatography to yield 2.75 g of product as an off-white solid; 1H NMR (300 MHz, DMSO-J6) delta 4.58 (s, 2H), 6.77-6.89 (m, 3H), 10.72 (br s, 1H); APCI-MS (m/z) 166.24 (M-H)".

  • 22
  • [ 103361-99-5 ]
  • 6-amino-7-[(3-ethoxypropyl)amino]-2H-1,4-benzoxazin-3(4H)-one [ No CAS ]
  • 23
  • [ 103361-99-5 ]
  • [ 1610611-94-3 ]
  • [ 1610612-24-2 ]
YieldReaction ConditionsOperation in experiment
42% Potassium tert-butoxide (75 mg, 0.666 mmol) was added to a stirred solution of 7-f luoro2H-benzo[b][1 ,4]oxazin-3(4H)-one (1-22, 100 mg, 0.606 mmol) in dry THE at rt. After 5 mm, a solution of 3-bromo-5-(1-bromoethyl) pyrazolo[1,5-a]pyridine (1-18, 202 mg, 0.666 mmol) in dry THE was added drop wise to reaction mixture at rt. The resulting reaction mixture was heated to ref lux for overnight and subsequently cooled to room temperature. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography over silica gel (chloroform/EtOAc, 0 - 4% EtOAc) to afford 110 mg (42%) of 4-(1-(3- bromopyrazolo[1 , 5-a]pyridin-5-yl) ethyl)- 7-fluoro-2H-benzo[b][ 1, 4]oxazin-3(4H)-one 1-67 as a yellow solid. ESI-LC/MS (Method 1) (m/z): [M÷H] 389.9, [(M+2)+H] + 391 .9.
  • 24
  • [ 103361-99-5 ]
  • [ 1610611-94-3 ]
  • [ 1610610-83-7 ]
 

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