* 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.
With hydrogenchloride; dihydrogen peroxide In sodium hydroxide
Reference Example 2-37 2-Amino-3-fluorobenzoic acid A solution of 7-fluoro-1H-indol-2,3-dione (13.0 g, 78.7 mmol) in 10N sodium hydroxide (125 mL) was heated and stirred at 70° C. for 1 hour. 30percent Hydrogen peroxide (25 mL) was added dropwise over 20 minutes at the same temperature, and the mixture was heated and stirred at the same temperature further for 1 hour. The solution was ice cooled, and conc. hydrochloric acid was added to the solution carefully until the pH of the solution became 4. Organic matter was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The crystals thus obtained were collected by filtration to give the title compound (7.15 g, 59percent yield). NMR (CDCl3) δ: 6.00 (2H, br s), 6.60 (1H, dt, J=5.2 Hz, 8.0 Hz), 7.16 (1H, ddd, J=1.4 Hz, 8.0 Hz, 11.2 Hz), 7.72 (1H, td, J=1.4 Hz, 8.0 Hz), hidden (1H).
Reference：
[1] Organic Syntheses, 2002, vol. 79, p. 196 - 196
[2] Patent: US2003/187014, 2003, A1,
[3] Proceedings of the Royal Society of London, Series B: Biological Sciences, 1958, vol. 148, p. 481,488
[4] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 7, p. 2151 - 2163
[5] European Journal of Medicinal Chemistry, 1994, vol. 29, # 10, p. 743 - 751
[6] Patent: US4736033, 1988, A,
[7] Patent: US4486438, 1984, A,
[8] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 6, p. 3163 - 3170
3
[ 38470-28-9 ]
[ 825-22-9 ]
Yield
Reaction Conditions
Operation in experiment
55%
With tert.-butylhydroperoxide; sodium hydroxide In water
C. To a solution of 4.4 g (0.11 mol) of NaOH and 11 g (0.11 mol) of t-butyl hydroperoxide in 40 mL of water was added 3.0 g (0.018 mol) of 8-fluoro-2,3-dihydroquinolin-4-one. The mixture was heated to 90° C. for 48 hr at which time an additional 11 g of t-butyl hydroperoxide were added and heating was continued for an additional 72 hr. After cooling, most of the reaction liquid was evaporated under reduced pressure and the residue was diluted with 100 mL of water and acidified to a pH of about 5. The precipitated 3-fluoroanthranilic acid was collected by filtration and dried to give 1.4 g (55 percent yield) of solid. 1 H NMR (dmso-d6): δ7.65 (d, 1H), 7.15 (t, 1H) and 6.45 (m, 1H).
51%
With tert.-butylhydroperoxide; sodium methylate In methanol
A. A solution of 0.25 g (1.5 mmol) of 8-fluoro-2,3-dihydroquinolin-4-one, 0.8 g (6.2 mmol) of 70 percent t-butyl hydroperoxide, 2 mL of 25 percent sodium methoxide in methanol and 3 mL of methanol were stirred at 75° C. for 72 hr. An additional 1 mL of 70 percent t-butyl hydroperoxide and 2 mL of 25 percent sodium methoxide in methanol were added and heating was continued for 72 more hr. The reaction mixture was cooled, poured into water and neutralized with acetic acid. The mixture was extracted with methylene chloride and the organic phase was collected. Evaporation of the solvent gave 0.12 g (51 percent yield) of 3-fluoroanthranilic acid, identical in all respects to an authentic sample.
Reference：
[1] Patent: US5189210, 1993, A,
[2] Patent: US5189210, 1993, A,
4
[ 148356-14-3 ]
[ 825-22-9 ]
Yield
Reaction Conditions
Operation in experiment
40%
With tert.-butylhydroperoxide; sodium methylate In methanol
EXAMPLE 1 Preparation of 3-Fluoroanthranilic Acid from 8-Fluoroquinolin-2,4-dione A solution of 0.1 g (0.6 mmol) of 8-fluoroquinolin-2,4-dione, 0.1 g (7.8 mmol) of 70 percent t-butyl hydroperoxide, 0.2 g of 25 percent sodium methoxide in methanol and an additional 2 mL of methanol was heated at 75° C. with stirring for 48 hr. An additional 0.2 g of t-butyl hydroperoxide and 0.5 mL of 25 percent sodium methoxide in methanol were added and heating was continued for 24 more hr. The reaction mixture was cooled, poured into water, and neutralized with acetic acid. The mixture was extracted with methylene chloride and the organic phase was collected. Evaporation of the solvent gave 0.35 g (40 percent yield) of 3-fluoroanthranilic acid, mp 172° C.
Reference：
[1] Patent: US5189210, 1993, A,
5
[ 83506-95-0 ]
[ 825-22-9 ]
Reference：
[1] Patent: US4343951, 1982, A,
6
[ 434-76-4 ]
[ 825-22-9 ]
Reference：
[1] Patent: US4343951, 1982, A,
7
[ 349-24-6 ]
[ 825-22-9 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1994, vol. 29, # 10, p. 743 - 751
[2] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 7, p. 2151 - 2163
[3] Proceedings of the Royal Society of London, Series B: Biological Sciences, 1958, vol. 148, p. 481,488
8
[ 348-54-9 ]
[ 825-22-9 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 7, p. 2151 - 2163
[2] Organic Syntheses, 2002, vol. 79, p. 196 - 196
9
[ 53314-99-1 ]
[ 825-22-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 15, p. 4670 - 4677
Stage #1: With hydrogen bromide In water; acetonitrile at 0℃; for 0.166667 h; Stage #2: With sodium nitrite In water; acetonitrile at 0℃; for 1.08333 h; Stage #3: With copper(I) bromide In water; acetonitrile at 70℃; for 1.5 h;
Example 127 Preparation of 5-fluoro-2-methyl-8-nitro-3,4-dihydro-2H-isoquinolin-1-one In a 1 L, three necked, round-bottomed flask fitted with a dropping funnel and a thermometer, were charged 20 g (0.13 mol) of 2-amino-3-fluoro-benzoic acid and 160 mL of acetonitrile. After cooling to 0° C., 160 mL of hydrobromic acid (47percent) was added dropwise over 10 min. To the resulting solution, 10 g of NaNO2 (0.145 mol) in water (20 mL) was added dropwise over 1 hour. After addition, the reaction mixture was stirred at 0° C. for 5 min, and 21.8 g of Cu(I) Br (0.15 mol) was added portionwise over 30 min. Stirring was continued at 70° C. in an oil bath for 1 hour. After cooling to 0° C., 700 mL of H2O was added and the precipitate was filtered, washed with cold water and dried under vacuum to give an orange solid corresponding to 2-bromo-3-fluoro-benzoic acid (22 g, 78percent).
Reference：
[1] Patent: US2008/293708, 2008, A1, . Location in patent: Page/Page column 37
[2] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 7, p. 2151 - 2163
14
[ 825-22-9 ]
[ 111721-75-6 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 7, p. 2151 - 2163
Reference：
[1] Journal of Medicinal Chemistry, 1995, vol. 38, # 14, p. 2763 - 2773
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 6, p. 1593 - 1597
17
[ 825-22-9 ]
[ 57-13-6 ]
[ 959236-96-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 6, p. 1593 - 1597
[2] Patent: WO2012/14109, 2012, A1, . Location in patent: Page/Page column 14
[3] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 4, p. 681 - 693
18
[ 590-28-3 ]
[ 825-22-9 ]
[ 959236-96-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 1995, vol. 38, # 14, p. 2763 - 2773
19
[ 825-22-9 ]
[ 854538-94-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 19, p. 5810 - 5831
[2] Advanced Synthesis and Catalysis, 2017, vol. 359, # 13, p. 2191 - 2195
20
[ 825-22-9 ]
[ 874784-14-2 ]
Yield
Reaction Conditions
Operation in experiment
82%
With N-Bromosuccinimide In dichloromethane at 0 - 20℃; for 1 h;
2-Amino-3-fluoro-benzoic acid (2.00 g, 12.9 mmol) was suspended in dichloromethane (34.0 mL) and N-bromosuccinimide (2.39 g, 12.9 mmol) was added in small portions at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and the solid was washed with dichloromethane (30 mL) and dried in air for 15 min to give the desired product as a white solid (2.46 g, 10.5 mmol, 82percent Yield). LCMS: 0.82 min; ES+ 234/236 ( M+H+); XH NMR (DMSO-d6, 400MHz): δ (ppm) 7.62-7.66 (s, 1H), 7.52 (d, 1H).
80%
With N-Bromosuccinimide In N,N-dimethyl-formamide at -10℃; for 1 h; Inert atmosphere
[00535] Step 1: To a solution of 2-amino-3-fluorobenzoic acid (1.0 g, 6.45 mmol) in DMF (10 mL) at - 10 °C, NBS (1.15 g, 6.45 mmol) in DMF (4 mL) was added dropwise over 10 min. After the addition was complete, the reaction mixture was stirred at -10 °C for 1 h. The reaction was quenched with aqueous sodium bisulfate (50 mL) and large amount of solid precipitated out. The resulting solid was collected by filtration and dried in vacuum to afford 2-amino-5-bromo-3-fluorobenzoic acid (1.2 g, yield: 80percent) as a yellow solid.
80%
With N-Bromosuccinimide In dichloromethane at 20℃; for 3 h;
Step a. NBS (114.8 g, 645 mmol) was added in a portion wise manner over 1 h to a stirred orange/brown suspension of 2-amino-3-fluorobenzoic acid (100 g, 645 mmol) in DCM (1000 ml) at rt, and the resulting mixture was stirred at rt for 2 h. The mixture was then filtered and the resulting solid was washed sequentially with DCM (2 x 250 ml) and water (3 x 400 ml) before being dried under vacuum at 55°C for 7 h to give the desired product as a beige solid (121.4 g, 80percent). LCMS (Method S): rt 2.93 min, m/z 232/234 [M-H]-; NMR (400 MHz, DMSO-d6) δ ppm 7.64 (m, 1H), 7.52 (dd, J= 10.9, 2.3 Hz, 1H)
78%
With N-Bromosuccinimide In dichloromethane at 20℃; for 2 h;
Synthesis of 2-amino-5-bromo-3-fluorobenzoic acid. A solution of 2-amino-3-fluorobenzoic acid (10.85 g, 70 mmol) in dichloromethane (175 mL) was added N-bromosuccinimide (12.46 g, 70 mmol), and the mixture was stuffed at RT for 2 h. LCMS showed the reaction was completed. The precipitate was filtered and washed with dichloromethane (100 mL*3) to give the title compound (12.7 g, 78percent) as a grey solid, which was directly used in the next step without further purification. MS (ES+) C7H5BrFNO2 requires:233, 235, found: 232, 234 [M - H].
78%
With N-Bromosuccinimide In dichloromethane at 20℃; for 2 h;
A solution of 2-amino-3-fluorobenzoic acid (10.85 g, 70 mmol) in dichloromethane (175 mL) was added N-bromosuccinimide (12.46 g, 70 mmol), and the mixture was stirred at room temperature for 2 hours. The precipitate was filtered and washed with dichloromethane (100 mL*3) to give the title compound (12.7 g, 78percent) as a grey solid, which was directly used in the next step without further purification. MS (ES+) C7H5BrFNO2 requires: 233, 235, found: 232, 234 [M+H]+.
Intermediate 10. A solution of 2-amino-3-fluorobenzoic acid (559 mg, 3.62 mmol) and 1.7 mL of concentrated H2S04 in 11 mL of anhydrous methanol was heated for 66 hours. After cooling to room temperature, methanol was concentrated under reduced pressure. Residue was taken up in 30 mL of water and added to a separatory funnel. Solid sodium carbonate was added slowly until gas evolution ceased (pH 9-10). Aqueous layer was extracted with ethyl acetate (3x40 mL). The combined organic layers were washed with 100 mL sat. NaHC03(aq) and 100 mL of Brine, separated, dried (MgS04), filtered, and concentrated under reduced pressure. Column chromatography (5percent Ethyl Acetate in Hexanes) yielded intermediate 10 (491 mg, 80percent) as a white solid.1H-NMR (CDC13, 300 MHz): δ 7.66-7.63(m, 1H), 7.15-7.08 (m, 1H), 6.60-6.55 (m, 1H), 5.40 (br s, 2H), 3.89 (s, 3H),LCMS m/z [M+H]+ C8H8FN02 requires: 170.05. Found 170.10
80%
for 66 h; Heating
Example 104 Preparation of Intermediate 106 [0808] [0809] A solution of 2-amino-3-fluorobenzoic acid (559 mg, 3.62 mmol) and 1.7 mL of concentrated H2SO4 in 11 mL of anhydrous methanol was heated for 66 hours. After cooling to room temperature, methanol was concentrated under reduced pressure. The residue was taken up in 30 mL of water and added to a separatory funnel. Solid sodium carbonate was added slowly until gas evolution ceased (pH 9-10). The aqueous layer was extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with 100 mL sat. NaHCO300 and 100 mL of brine, separated, dried (MgSO4), filtered, and concentrated under reduced pressure. Column chromatography (5percent ethyl acetate in hexanes) yielded intermediate 106 (491 mg, 80percent) as a white solid. [0810] 1H-NMR (CDCl3, 300 MHz): δ 7.66-7.63 (m, 1H), 7.15-7.08 (m, 1H), 6.60-6.55 (m, 1H), 5.40 (br s, 2H), 3.89 (s, 3H), [0811] LCMS m/z [M+H]+ C8H8FNO2 requires: 170.05. Found 170.10
Reference：
[1] Patent: WO2011/163518, 2011, A1, . Location in patent: Page/Page column 158
[2] Patent: US2013/273037, 2013, A1, . Location in patent: Paragraph 0808-0811
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 4, p. 1630 - 1643
[4] Patent: WO2009/27730, 2009, A1, . Location in patent: Page/Page column 55
[5] Chemical Communications, 2018, vol. 54, # 90, p. 12766 - 12769
With hydrogenchloride; dihydrogen peroxide; In sodium hydroxide;
Reference Example 2-37 2-Amino-3-fluorobenzoic acid A solution of <strong>[317-20-4]7-fluoro-1H-indol-2,3-dione</strong> (13.0 g, 78.7 mmol) in 10N sodium hydroxide (125 mL) was heated and stirred at 70 C. for 1 hour. 30% Hydrogen peroxide (25 mL) was added dropwise over 20 minutes at the same temperature, and the mixture was heated and stirred at the same temperature further for 1 hour. The solution was ice cooled, and conc. hydrochloric acid was added to the solution carefully until the pH of the solution became 4. Organic matter was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The crystals thus obtained were collected by filtration to give the title compound (7.15 g, 59% yield). NMR (CDCl3) delta: 6.00 (2H, br s), 6.60 (1H, dt, J=5.2 Hz, 8.0 Hz), 7.16 (1H, ddd, J=1.4 Hz, 8.0 Hz, 11.2 Hz), 7.72 (1H, td, J=1.4 Hz, 8.0 Hz), hidden (1H).
With sodium hydroxide; dihydrogen peroxide; acetic acid; In water;
STEP C: 2-amino-3-fluoro-benzoic acid A mixture of 19.27 g of the product of Step B and 197 ml of 10N sodium hydroxide solution was heated to 70 C. with stirring and heating was ceased to add 36.5 ml of 30% hydrogen peroxide over 20 minutes during which the temperature rose to 80 C. and descended to 70 C. At the end of the addition, the mixture was heated to 80 C. and held there for 10 minutes and then was cooled during which a mass formed. The latter was added to 200 ml of water with stirring and the pH was adjusted to 1 by addition of concentrated hydrochloric acid at a temperature less than 20 C. The mixture was stirred for 90 minutes and was vacuum filtered. The product was empasted twice with iced water and dried under reduced pressure at 70 C. The product was crystallized from 100 ml of a 1-1 ethanol-water mixture and 3 ml of acetic acid. The mixture was iced for one hour and was vacuum filtered. The product was empasted with a 1-1 ethanol-water mixture and dried at 70 C. under reduced pressure to obtain 14.8 g of 2-amino-3-fluoro-benzoic acid melting at 188 C.
With sodium hydroxide; dihydrogen peroxide; acetic acid; In water;
STEP C 2-amino-3-fluoro-benzoic acid A mixture of 19.27 g of the product of Step B and 197 ml of 10N sodium hydroxide solution was heated to 70 C. with stirring and heating was ceased to add 36.5 ml of 30% hydrogen peroxide over 20 minutes during which the temperature rose to 80 C. and descended to 70 C. At the end of the addition, the mixture was heated to 80 C. and held there for 10 minutes and then was cooled during which a mass formed. The latter was added to 200 ml of water with stirring and the pH was adjusted to 1 by addition of concentrated hydrochloric acid at a temperature less than 20 C. The mixture was stirred for 90 minutes and was vacuum filtered. The product was empasted twice with iced water and dried under reduced pressure at 70 C. The product was crystallized from 100 ml of a 1-1 ethanol-water mixture and 3 ml of acetic acid. The mixture was iced for one hour and was vacuum filtered. The product was empasted with a 1-1 ethanol-water mixture and dried at 70 C. under reduced presssure to obtain 14.8 g of 2-amino-3-fluoro-benzoic acid melting at 188 C.
Example 127 Preparation of 5-fluoro-2-methyl-8-nitro-3,4-dihydro-2H-isoquinolin-1-one In a 1 L, three necked, round-bottomed flask fitted with a dropping funnel and a thermometer, were charged 20 g (0.13 mol) of 2-amino-3-fluoro-benzoic acid and 160 mL of acetonitrile. After cooling to 0 C., 160 mL of hydrobromic acid (47%) was added dropwise over 10 min. To the resulting solution, 10 g of NaNO2 (0.145 mol) in water (20 mL) was added dropwise over 1 hour. After addition, the reaction mixture was stirred at 0 C. for 5 min, and 21.8 g of Cu(I) Br (0.15 mol) was added portionwise over 30 min. Stirring was continued at 70 C. in an oil bath for 1 hour. After cooling to 0 C., 700 mL of H2O was added and the precipitate was filtered, washed with cold water and dried under vacuum to give an orange solid corresponding to 2-bromo-3-fluoro-benzoic acid (22 g, 78%).
Reference Example 2-38 3-Fluoro-2-iodobenzoic acid Following the procedure described in Reference Example 2-21, the title compound was prepared from 2-amino-3-fluorobenzoic acid (19% yield). NMR (CDCl3) delta: 7.26 (1H, ddd, J=1.6 Hz, 7.6 Hz, 8.2 Hz), 7.42 (1H, ddd, J=5.6 Hz, 7.6 Hz. 8.2 Hz), 7.79 (1H, ddd, J=0.8 Hz, 1.6 Hz, 7.6 Hz), hidden (1H).
Step A: Preparation of 3-Fluoro-2-iodobenzoic acid; [0906] Sodium nitrite (6.7 g, 97 mmol) in water (25 mL) was added to a solution of 2-amino-3-fluorobenzoic acid ( 10.0 g. 64 mmol) in DMSO (25 m L) and 30% H2SO4 (75mL) at O0C. The mixture was stirred lor 1 hour at O0C and <n="205"/>then potassium iodide (27 g, 161 mmol) was added dropwise as a solution in water (25 mL). The ice bath was removed and the mixture was stirred at room temperature for 4 hours, and then partitioned between EtOAc and 2M sodium sulfite. The layers were mixed, separated, and the organic layer was washed with 2M sodium sulfite once and brine once, dried over anhydrous MgSU4, and concentrated in vacuo to give 14.90 g of a yellow solid. MS m/e = 265 (M-H)^.
With N-chloro-succinimide In N,N-dimethyl-formamide at 20℃; for 3h;
71%
With N-chloro-succinimide In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
11.a (a) 2-Amino-5-chloro-3-fluorobenzoic acid (A23)
A mixture of 2-amino-3-fluorobenzoic acid (5.0 g, 0.03 mol) and NCS (5.6 g, 0.04 mmol) in DMF (80 mL) was stirred at room temperature under N2 overnight. DCM (60 mL) was added and the mixture was washed with water (2 x 60 mL). During the second wash, a precipitate formed, which was collected by filtration and washed with water then dried under vacuum to give the title compound (4.0 g, 71%) as a brown solid. LCMS-B (ES-API): rt 3.3 min, m/z 189.9, 191.9 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ 7.51 - 7.50 (m, 1 H), 7.44 (dd, J = 11.2, (0547) 2.5 Hz, 1 H).
3.78 g
With N-chloro-succinimide In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
74 2-Amino-5-chloro-3-fluorobenzoic acid
2-Amino-3-fluorobenzoic acid (5.0 g, 32.2 mmol) and 25 ml of dry DMF were placed in a reaction flask. N-Chlorosuccinimide (5.60 g, 41.9 mmol) was added and the reaction mixture was stirred overnight at rt under nitrogen. DCM (30 ml) was added and the mixture was washed twice with 50 ml of water. During the second wash, a precipitation was formed. The precipitation was filtered, washed twice with 20 ml of water, and dried to give 2.64 g of 2-amino-5-chloro-3-fluorobenzoic acid. A second precipitation was formed in the mother liquor. 50 ml of DCM was added to the mother liquor to dissolve the precipitation and phases were separated. Organic phase was washed with 50 ml of water, dried by filtration through a phase separation funnel, and evaporated to dryness to give additionally 3.78 g of 2-amino-5-chloro-3-fluoro-benzoic acid. 1H-NMR (400 MHz, 6-DMSO): δ 3.31 (br s, 3H), 7.45 (dd, 1H), 7.51 (dd, 1H).
3-Fluoroanthranilic acid (3 g, 0.019 mol) was suspended in water/AcOH (107 ml/1.18 ml). KOCN (2 g, 1.3 eq) in water (11 ml) was added dropwise at 35 C. Once the addition was complete the mixture was heated at 35 C. for 3 h. The mixture was cooled to 0 C. and NaOH (40 g) was added, maintaining the temperature below 40 C. The resulting solid was collected, dissolved in hot water, acidified to pH 3 and 1.5 g (0.0083 mol) of solid was collected by filtration. The solid was dissolved in POCl3 (9 ml), N,N-dimethylaniline (0.65 ml, 0.0051 mol) was added and the mixture heated at 130 C. for 5 h. The mixture was then cooled to rt and added to ice; the resulting solid was collected to give compound 30. 1H NMR (DMSO) delta 7.80-7.86 (m, 1H), 8.00 (dd, J=10, 8 Hz, 1H), 8.08 (d, J=8 Hz, 1H).
Intermediate 10. A solution of 2-amino-3-fluorobenzoic acid (559 mg, 3.62 mmol) and 1.7 mL of concentrated H2S04 in 11 mL of anhydrous methanol was heated for 66 hours. After cooling to room temperature, methanol was concentrated under reduced pressure. Residue was taken up in 30 mL of water and added to a separatory funnel. Solid sodium carbonate was added slowly until gas evolution ceased (pH 9-10). Aqueous layer was extracted with ethyl acetate (3x40 mL). The combined organic layers were washed with 100 mL sat. NaHC03(aq) and 100 mL of Brine, separated, dried (MgS04), filtered, and concentrated under reduced pressure. Column chromatography (5% Ethyl Acetate in Hexanes) yielded intermediate 10 (491 mg, 80%) as a white solid.1H-NMR (CDC13, 300 MHz): delta 7.66-7.63(m, 1H), 7.15-7.08 (m, 1H), 6.60-6.55 (m, 1H), 5.40 (br s, 2H), 3.89 (s, 3H),LCMS m/z [M+H]+ C8H8FN02 requires: 170.05. Found 170.10
80%
With sulfuric acid; for 66h;Heating;
Example 104 Preparation of Intermediate 106 [0808] [0809] A solution of 2-amino-3-fluorobenzoic acid (559 mg, 3.62 mmol) and 1.7 mL of concentrated H2SO4 in 11 mL of anhydrous methanol was heated for 66 hours. After cooling to room temperature, methanol was concentrated under reduced pressure. The residue was taken up in 30 mL of water and added to a separatory funnel. Solid sodium carbonate was added slowly until gas evolution ceased (pH 9-10). The aqueous layer was extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with 100 mL sat. NaHCO300 and 100 mL of brine, separated, dried (MgSO4), filtered, and concentrated under reduced pressure. Column chromatography (5% ethyl acetate in hexanes) yielded intermediate 106 (491 mg, 80%) as a white solid. [0810] 1H-NMR (CDCl3, 300 MHz): delta 7.66-7.63 (m, 1H), 7.15-7.08 (m, 1H), 6.60-6.55 (m, 1H), 5.40 (br s, 2H), 3.89 (s, 3H), [0811] LCMS m/z [M+H]+ C8H8FNO2 requires: 170.05. Found 170.10
With hydrogenchloride; for 2h;Heating / reflux;
2-amino-3-fluoro benzoic acid was dissolved in HCl (3 M solution in MeOH). The reaction mixture was heated to reflux for 2 h. Then, solvent was evaporated and the residue was partitioned between DCM and sat. sol. NaHCO3. The aqueous phase was separated and extracted several times withn DCM. The combined organic layers were dried (Na2SO4) and solvent was evaporated under reduced pressure to afford the title compound as a yellow oil.1H NMR (300 MHz, CDCl3) delta: 7.72-7.58 (m, IH), 7.18-7.02 (m, IH), 6.65-6.48 (m, IH), 3.88 (s, 3H). MS (ES) C8H8FNO2 requires: 169, found: 170 (M+H)+.
To a round bottomed flask containing 2-amino-3-fluorobenzoic acid (15.7 g, 101 mmol) was added 100 mL of anhydrous THF. The reaction was cooled to 0 C. and lithium aluminum hydride (7.68 g, 202 mmol) was added as a solution in 200 mL of anhydrous Et2O. The reaction was allowed to warm to rt and stirred for 3 h, after which time it was quenched with 7.7 mL water, 7.7 mL of 15% NaOH, and 30 mL of water. The reaction was diluted with 300 mL of Et2O and filtered. The filtrated was dried over MgSO4 and filtered and concd to afford (2-amino-3-fluorophenyl)methanol. 1H NMR (400 MHz, CDCl3) delta 6.91 (ddd, J=10.8, 8.2, 1.2 Hz, 1H), 6.86 (br d, J=7.4 Hz, 1H), 6.64 (td, J=7.6, 5.1 Hz, 1H), 4.69 (s, 1H).
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 4.0h;Inert atmosphere;
To a stirred suspension of LiAlH4 (740 mg, 19.5 mmol) in THF (20 mL) was added a solution of 6-fluoroanthranilic acid (1.01 g, 6.51 mmol) in THF (10 mL) at 0 C under an Ar atmosphere and stirred at rt. After 4 h with stirring, AcOEt and saturated Na2SO4 aqueous solution were added to the solution. The resulting solid was removed by filtration and the obtained filtrate was basified (pH 9) with saturated NaHCO3 aqueous solution, and extracted with AcOEt three times. The combined organic extracts were washed with brine, dried over Na2SO4, and evaporated in vacuo. The crude compound was chromatographed on silica gel, but not purified completely. The resulting compound 2a was used for the next reaction without further purification.
3-Fluoro anthranilic acid (3 g) was mixed with urea (6.97 g) in a two-neck round bottom flask fitted with an open condenser and heated up to 190C to 200C with stirring for 2 hours. During heating, the solid first melted and then started solidifying. After all the liquid became solid, heating was removed and the reaction mixture was allowed to come to room temperature. To this reaction mixture, water was added and stirred at same temperature for one hour. The solid so obtained was filtered out, washed with diethyl ether and dried over anhydrous phosphorous pentoxide. Yield: 3.0 g
In neat (no solvent); at 150℃; for 7.0h;
General procedure: 5.2.1.1 Quinazoline-2,4(1H,3H)-dione (2a) The mixture of 2-amino-benzoic acid (5 g, 36.46 mmol) and urea (50 g, 83.25 mmol) was stirred at 150 C for 7 h. The reaction mixture was cooled to 100 C and then water (50 mL) was added to quench the reaction. The crude product was obtained by filtration, then dissolved in NaOH aq (6 M, 500 mL). The pH was adjusted to 3 and a precipitate was formed. After filtration and dried under vacuum condition, compound 2a was obtained as white solid (4.5 g, 76.1%); 5.2.1.5 8-Fluoroquinazoline-2,4(1H,3H)-dione (2e) Following the preparation protocol of Section 5.2.1.1 , starting from 2-amino-3-fluorobenzoic acid (500 mg, 3.22 mmol), the title compound 2e was obtained as yellow solid (350 mg, 60.3%); mp 241-243 C; 1H NMR (300 MHz, DMSO-d6) delta (ppm): 11.43 (s, 1H), 11.28 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.56 (ddd, J1 = 10.8 Hz, J2 = 8.4 Hz, J3 = 1.2 Hz, 1H), 7.16 (td, J1 = 8.1 Hz, J2 = 4.8 Hz, 1H); HR-MS (ESI): m/z, Calcd for C8H6N2O2F [M+H]+ 181.0408, Found: 181.0405.
With ammonium chloride; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 6h; Inert atmosphere;
12.A
Step A: To 2-amino-3-fluorobenzoic acid (1.55 g, 10 mmol) in DMF (5 mL) at rt were added hydroxybenzatriazole (2.0 g, 13 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.3 g, 12 mmol), ammonium chloride (2.3 g, 42 mmol), and DIEA (7.5 ml, 42 mmol). The mixture was purged with nitrogen and stirred for 6 h. The mixture was then poured into water and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine (2×20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was treated with DCM (10 mL) resulting in a precipitate that was collected by filtration to afford 2-amino-3-fluorobenzamide (670 mg). LC-MS (ESI) m/z 155 (M+H+)
63%
With N-hydroxybenzotriazole ammonium salt; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 4h;
20.1 Step-1
To a stirred solution of 2-amino-3-fluoro-benzoic acid (400 mg, 2.57 mmol) in THF (10 mL),EDC.HCl (738 mg, 3.86 mmol), HOBt·NH3 (580 mg, 3.86 mmol) and DIPEA (1.38 mL,7.73 mmol) were added at RT and stirred for 4 h (TLC indicated complete consumption ofstarting material). The reaction mixture was diluted with water (30 mL) and extracted withEtOAc (3 x 40 mL). The combined organic extracts were dried over Na2S04, concentratedunder reduced pressure to get the crude compound which was purified by flash columnchromatography (100-200 mesh silica gel, 5g, 50% EtOAc-Hexane) to provide 2-amino-3-fluoro-benzamide (250 mg, 63%) as a white solid.LCMS: m/z: 155.42 [M+Ht.
Multi-step reaction with 2 steps
1: thionyl chloride / N,N-dimethyl-formamide / 2 h / 75 °C
2: ammonium hydroxide / dichloromethane / 1 h
Multi-step reaction with 5 steps
1: N-Bromosuccinimide / dichloromethane / 2 h / 20 °C
2: borane-THF / tetrahydrofuran / 0 - 20 °C
3: manganese(IV) oxide / dichloromethane / 20 °C
4: 2 h / 180 °C
5: trichlorophosphate / 5 h / Reflux
Multi-step reaction with 5 steps
1: bromine / chloroform / 16 h / 20 °C
2: borane-THF / tetrahydrofuran / 40 h / 0 - 20 °C
3: manganese(IV) oxide / dichloromethane / 18 h / 20 °C
4: 0.25 h / 175 °C
5: trichlorophosphate / 0.5 h / 110 °C
Multi-step reaction with 5 steps
1: N-Bromosuccinimide / dichloromethane / 3 h / 20 °C
2: dimethylsulfide borane complex / tetrahydrofuran / 4 h / 0 - 20 °C
3: manganese(IV) oxide / dichloromethane / 12 h / 20 °C
4: 4 h / 180 °C
5: trichlorophosphate / 2 h / 110 °C
Multi-step reaction with 5 steps
1: N-Bromosuccinimide / dichloromethane / 3 h / 20 °C
2: dimethylsulfide borane complex / tetrahydrofuran / 4 h / 20 °C
3: manganese(IV) oxide / dichloromethane / 12 h / 20 °C
4: 4 h / 180 °C
5: trichlorophosphate / 2 h / 110 °C
With potassium carbonate In ethyl acetate at 20℃; for 24h;
8-fluoro-2H-benzo[d] [1,3] oxazine-2,4(1H)-dione (1-2a).
To a 100 mL round bottomed flask was added 2-amino-3-fluorobenzoic acid (5.000 g, 32.2 mmol), ethyl acetate (43 mL), potassium carbonate (5.350g, 38.68 mmol). The triphosgene (10.520 g, 35.45 mmol) was splited into the mixture in an ice-bath atmosphere. Then the mixture was stirred at room temperature for 24 h. To the mixture was added saturated sodium bicarbonate aqueous solution slowly, and then extracted by ethyl acetate, washed with saturated brine, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure to afford light brown solid. The crude product was purified by recrystallization to afford light brown solid (4.948 g, yield 84.5 %). 1H-NMR (400 MHz, DMSO-d6) δ11.93 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.68 (ddd, J =10.7, 8.2, 1.2 Hz, 1H), 7.24 (td, J = 8.1, 4.7 Hz, 1H). LC-MS(ESI) calc. Mass for C8H5FNO3[M-H]-: 180.01found: 180.10.
84.5%
With potassium carbonate In ethyl acetate at 20℃; for 24h;
8-fluoro-2H-benzo[d] [1,3] oxazine-2,4(1H)-dione (1-2a).
To a 100 mL round bottomed flask was added 2-amino-3-fluorobenzoic acid (5.000 g, 32.2 mmol), ethyl acetate (43 mL), potassium carbonate (5.350g, 38.68 mmol). The triphosgene (10.520 g, 35.45 mmol) was splited into the mixture in an ice-bath atmosphere. Then the mixture was stirred at room temperature for 24 h. To the mixture was added saturated sodium bicarbonate aqueous solution slowly, and then extracted by ethyl acetate, washed with saturated brine, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure to afford light brown solid. The crude product was purified by recrystallization to afford light brown solid (4.948 g, yield 84.5 %). 1H-NMR (400 MHz, DMSO-d6) δ11.93 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.68 (ddd, J =10.7, 8.2, 1.2 Hz, 1H), 7.24 (td, J = 8.1, 4.7 Hz, 1H). LC-MS(ESI) calc. Mass for C8H5FNO3[M-H]-: 180.01found: 180.10.
42%
With potassium carbonate In ethyl acetate at 20℃; Inert atmosphere;
21.1 First step: Preparation of 8-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione
Dissolve 2-amino-3-fluorobenzoic acid (1g, 6.5mmol), triphosgene (2.3g, 7.8mmol) in anhydrous ethyl acetate solution (10mL), then add potassium carbonate (2.7, 19.5 mmol), the reaction solution was stirred overnight at room temperature, and after the reaction was over, water and ethyl acetate (3*20 mL) were added for extraction. Combine the organic layers, dry with anhydrous sodium sulfate, filter, concentrate, and purify by column to obtain the target product 8-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (0.5 g, yield: 42%).
36%
With potassium carbonate In ethyl acetate at 20℃; for 24h;
In tetrahydrofuran at 20℃; for 6h;
4.1.1. Synthetic procedure for 2
General procedure: To a solution of different 2-aminobenzoic acid (5.0 mmol) in 20 mLanhydrous tetrahydrofuran (THF) was added triphosgene (BTC, 0.445 g,1.67 mmol) in batches. The reaction mixture was stirred at room temperaturefor 6 h and then poured into ice water. The resulting solid werefiltrated to obtain compounds 1, which were dissolved in 10 mL ofanhydrous N,N-dimethyl formamide (DMF), and then sodium hydride(NaH, 0.096 g, 4.0 mmol) was added in batches at 0. The reactionmixture was stirred at 0 for 30 min, and then methyl iodide (CH3I,0.469 g, 3.3 mmol) was added dropwise. The reaction was detected byTLC. After completion, the reaction mixture was poured into the icewater. The resulting solid were filtrated to obtain compounds 2.
8-fluoro-3-(4-aminosulphonylphenyl)-2-mercapto-3H-quinazolin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With triethylamine; In ethanol; for 3h;Inert atmosphere; Reflux;
General procedure: A suspention of anthranilic acid A1-A17 (0.001mol), a catalytic amount of triethylamine and <strong>[51908-29-3]4-isothiocyanato-benzenesulfonamide</strong> B17b (0.169g, 0.001mol) in absolute ethanol (25ml) was refluxed for 3. The reaction mixture was filtered while hot, left to cool and the solvent was removed under reduced pressure. The obtained residue was triturated from diethyl ether, filtered and dried under vacuo to obtain titled compound C: 1-17 as a whitish solid.
With ammonium chloride; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;
1 Step1. 2-Amino-3-fluorobenzamide
To a solution of 2-amino-3-fluorobenzoic acid (1 g, 6. 5 mmol) in DMF (3 mL), 1H-benzo[d][1,2,3]triazol-1-ol (1.13 g, 8.4 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (1.2 g, 7.7 mmol), NH4Cl (1.45 g, 21.1 mmol) and DIPEA (4.7 mL, 27.1 mmol) were added. The reaction mixture was stirred at r.t. overnight. Water was then added and it was extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4 and concentrated under vacuum. The crude product was slurried in DCM (6.5 mL). The solids were filtered, washed with cold DCM and dried under vacuum to afford the title compound (444 mg, 45% yield)
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