* 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.
at 130℃; for 2 h; Inert atmosphere; Microwave irradiation
2-Amino-5-fluorobenzamide (77 mg, 0.5 mmol), [Cp * Ir (2,2'-bpyO) (H2O)](5.4 mg, 0.005 mmol, 1 molpercent),Cesium carbonate (49 mg, 0.15 mmol, 0.3 equiv.) And methanol (0.5 ml) were sequentially added to a dried 5 mL microwave reaction tube. Nitrogen gas in the microwave tube was placed in a single-mode pressure microwave synthesizer (Discover CEM,USA). After the reaction mixture was reacted at 130 ° C for 2 hours,Cool to room temperature. Rotary evaporation to remove the solvent,Pure target compound was then obtained by column chromatography (developing solvent: petroleum ether / ethyl acetate), yield: 77percent
Reference：
[1] Organic Letters, 2016, vol. 18, # 11, p. 2580 - 2583
[2] Patent: CN107337646, 2017, A, . Location in patent: Paragraph 0055; 0056; 0057; 0058
2
[ 63069-49-8 ]
[ 149-73-5 ]
[ 16499-56-2 ]
Yield
Reaction Conditions
Operation in experiment
70%
at 170℃; for 2 h; Autoclave
This compound was previously reported [25] but we used another method for preparation of thiscompound to improve the yield. In a 10 mL volume stainless steel pressure-resistant vessel were placed(1.54 g, 0.01 mol) of 2-amino-5-fluorobenzamide 2, (1.06 g, 0.01 mol) of trimethoxymethane, and 5 mLof DMF. The reaction was heated at 170°C for 2 h. After the reaction was completed the product wascooled, collected, and crystallized from ethyl alcohol. Yield 70percent; mp: 252–254°C; 1H-NMR (DMSO-d6,300 MHz) δ: 7.67 (d, 1H, J = 8.6 Hz, ArH), 7.85 (d, 1H, J = 9.7 Hz, ArH), 8.12 (s, 1H, ArH), 8.73 (dd, 1H,J = 8.4 Hz and 4.8 Hz, ArH), 11.83(s, 1H, NH), C8H5FN2O (164.04): MS (ESI) m/z 165.04 [M + 1].
Reference：
[1] Molecules, 2017, vol. 22, # 2,
3
[ 63069-49-8 ]
[ 16499-61-9 ]
Reference：
[1] Molecules, 2017, vol. 22, # 2,
4
[ 446-08-2 ]
[ 63069-49-8 ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: With phosgene In tetrahydrofuran; toluene at 20℃; for 18 h; Stage #2: With ammonia In tetrahydrofuran; water; toluene at 0 - 20℃; for 1 h;
Intermediate 32; 2-Amino-5-fluorobenzamide A round-bottomed flask was charged with 5-fluororanthranilic acid (3 g, 19.34 mmol) in tetrahydrofuran (64.5 mL) and a 20percent solution of phosgene (11.2 mL, 21.3 mmol) in toluene was added dropwise at room temperature. The mixture was stirred for 18 hr at room temperature, then cooled to 0° C., at which time concentrated ammonium hydroxide (27.9 mL, 193 mmol) was added cautiously. The mixture was then allowed to warm to room temperature and then stirred for 1 hr. The organic phase was diluted with EtOAc, washed with aqueous dipotassium hydrogen phosphate and brine, then dried over sodium sulfate and concentrated to give a white solid (2.46 g, 82percent yield). MS: M(C7H7FN2O)=154.14, (M+H-NH3)-=138.
75%
Stage #1: With thionyl chloride In benzene for 4 h; Reflux Stage #2: With ammonia In benzene at 20℃;
A suspension of 2-amino-5-fluorobenzoic acid (1) (1.0 g, 6.3 mmol) in benzene (30 mL) underreflux was mixed with thionyl chloride (1.5 g, 12.6 mmol). The resulting mixture was stirred underreflux for 4 h, and then evaporated. The residue was dissolved in 200 mL of benzene and treated with anhydrous ammonia gas at room temperature. After removing the solvent, compound 2 wascrystalized from ethanol and obtained as brown powder [25]. Yield 75percent; m.p.: 144–146°C; 1H-NMR(DMSO-d6, 300 MHz) δ: 5.72(s, 2H, NH2,), 6.54(s, CONH2, 2H) 7.63 (d, 1H, J = 8.6 Hz, Ar-H),7.92 (d, 1H, J = 7.4 Hz, Ar-H), 8.14 (s, 1H, Ar-H). C7H7FN2O (154.05): MS (ESI) m/z 155.05 [M + 1].
67%
With N-hydroxybenzotriazole ammonium salt; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6 h;
To a stirred solution of 2-amino-5-fluoro-benzoic acid (15 g, 96.69 mmol) in THF (300 mL),EDC.HCl (27.70 g, 145.03 mmol), HOBt·NH3 (21.75 g, 145.03 mmol) and DIPEA (51.0 mL,290.07 mmol) were added at RT and stirred for 6 h (TLC indicated complete consumption ofstarting material). The reaction mixture was concentrated under reduced pressure to give thecrude residue which was diluted with water (150 mL) and extracted with EtOAc (3 x 150mL). The combined organic extracts were washed with water (2 x 100 mL), brine (1 x 100mL), dried over Na2S04, and concentrated under reduced pressure to give the crude residue.The crude material was purified by column chromatography (100-200 silica gel, 300 g, 40percentEtOAc-Hexane) to provide 2-amino-5-fluoro-benzamide (10.0 g, 67percent) as a pale yellow solid.LCMS: mlz: 155.38 [M+Ht.
To a dry flask purged with N2 was added 10percent Pd/C (483 mg) followed by 5-fluoro-2- nitrobenzamide (Example 14, 4.83 g, 26.2 mmol) as a solution in ethanol (130 mL). The mixture was stirred under an H2 atmosphere for 5 h. The mixture was filtered through a pad of Celite and the solvent was evaporated under reduced pressure to afford 4.03 g (99percent) of the desired product. 1H NMR (300 MHz, DMSO-c/6) δ 7.75 (br s, 1 H), 7.45-7.29 (m, 1 H), 7.18 (br s, 1 H), 7.10-6.93 (m, 1 H), 6.74-6.58 (m,i H), 6.43 (br s, 2H); ES-MS m/z 155.0 [M+Hf, LCMS RT (min) 0.27
82%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 2 h;
Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of 5-fluoro-2-nitrobenzamide (17.5 g, 95.04 mmol, 1.00 equiv) and palladium carbon (10percent) (1.75 g, 0.10 equiv) in methanol (150 mL). To the above H2 (enough) was introduced. The resulting solution was stirred for 2 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 12.0 g (82percent) of 2- amino-5-fluorobenzamide as a white solid. MS (ESI) m/z 155 ([M + H]+)
0.8 g
With palladium 10% on activated carbon; hydrogen In methanol
General procedure: (a) Thionyl chloride (1.5 g, 12.6 mmol) was added dropwise to a suspension of a 5-substituted-2-nitrobenzoic acid (1a: 1.1 g, 6.3 mmol; 1b: 1.2 g, 6.3 mmol) in dichloroethane (30 mL) under reflux. The resulting mixture was stirred under reflux for 4 h and dried under vacuum. (b) The residue was dissolved in 200 mL of dichloroethane and treated with anhydrous ammonia gas at room temperature. (c) After removing solvent, the intermediate 5-substituted-2-nitrobenzamide (2a,b) was dissolved in MeOH and hydrogenated over 10percent Pd/C for 1-2 h. The catalyst was removed by filtration, and the solution was dried under vacuum to afford the 5-substituted-2-aminobenzamides as pale yellow powders (3a: 0.7 g, 85percent; 3b: 0.8 g, 85percent).
Reference：
[1] Patent: WO2006/34491, 2006, A2, . Location in patent: Page/Page column 43
[2] Patent: WO2014/143960, 2014, A1, . Location in patent: Page/Page column 40
[3] European Journal of Medicinal Chemistry, 2011, vol. 46, # 7, p. 2709 - 2721
6
[ 61272-77-3 ]
[ 63069-49-8 ]
Yield
Reaction Conditions
Operation in experiment
79%
With water; potassium carbonate In water at 150℃; for 0.5 h; Microwave irradiation
General procedure: Adapted from a literature procedure,1 the appropriate organonitrile (1.0 eq.) and K2CO3(0.2eq.)wereaddedtoamicrowavetubewithastir-barwithdeionizedwater(8.5mLpermmolsubstrate).Afterirradiationundermicrowaveat150°Cfor30minutes,thereactionmixturewascooled,extractedwithEtOAc(320mL),thecombinedphasesdriedoverMgSO4andexcesssolventremovedinvacuo.TheresiduewaspurifiedbyFCC,ifrequired,togivethetitlecompound.
Intermediate 32; 2-Amino-5-fluorobenzamide A round-bottomed flask was charged with 5-fluororanthranilic acid (3 g, 19.34 mmol) in tetrahydrofuran (64.5 mL) and a 20% solution of phosgene (11.2 mL, 21.3 mmol) in toluene was added dropwise at room temperature. The mixture was stirred for 18 hr at room temperature, then cooled to 0 C., at which time concentrated ammonium hydroxide (27.9 mL, 193 mmol) was added cautiously. The mixture was then allowed to warm to room temperature and then stirred for 1 hr. The organic phase was diluted with EtOAc, washed with aqueous dipotassium hydrogen phosphate and brine, then dried over sodium sulfate and concentrated to give a white solid (2.46 g, 82% yield). MS: M(C7H7FN2O)=154.14, (M+H-NH3)-=138.
75%
A suspension of 2-amino-5-fluorobenzoic acid (1) (1.0 g, 6.3 mmol) in benzene (30 mL) underreflux was mixed with thionyl chloride (1.5 g, 12.6 mmol). The resulting mixture was stirred underreflux for 4 h, and then evaporated. The residue was dissolved in 200 mL of benzene and treated with anhydrous ammonia gas at room temperature. After removing the solvent, compound 2 wascrystalized from ethanol and obtained as brown powder [25]. Yield 75%; m.p.: 144-146C; 1H-NMR(DMSO-d6, 300 MHz) delta: 5.72(s, 2H, NH2,), 6.54(s, CONH2, 2H) 7.63 (d, 1H, J = 8.6 Hz, Ar-H),7.92 (d, 1H, J = 7.4 Hz, Ar-H), 8.14 (s, 1H, Ar-H). C7H7FN2O (154.05): MS (ESI) m/z 155.05 [M + 1].
67%
With N-hydroxybenzotriazole ammonium salt; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 6h;
To a stirred solution of 2-amino-5-fluoro-benzoic acid (15 g, 96.69 mmol) in THF (300 mL),EDC.HCl (27.70 g, 145.03 mmol), HOBt·NH3 (21.75 g, 145.03 mmol) and DIPEA (51.0 mL,290.07 mmol) were added at RT and stirred for 6 h (TLC indicated complete consumption ofstarting material). The reaction mixture was concentrated under reduced pressure to give thecrude residue which was diluted with water (150 mL) and extracted with EtOAc (3 x 150mL). The combined organic extracts were washed with water (2 x 100 mL), brine (1 x 100mL), dried over Na2S04, and concentrated under reduced pressure to give the crude residue.The crude material was purified by column chromatography (100-200 silica gel, 300 g, 40%EtOAc-Hexane) to provide 2-amino-5-fluoro-benzamide (10.0 g, 67%) as a pale yellow solid.LCMS: mlz: 155.38 [M+Ht.
With thionyl chloride; In benzene;
2-Amino-5-fluorobenzamide (3). To a suspension of 2-amino-5-fluorobenzoic acid (1) (1.0 g, 6.3 mmol) in benzene (30 ml) under reflux was added dropwise thionyl chloride (1.5 g, 12.6 mmol). The resulting mixture was stirred under reflux for 4 h, and then evaporated. The residue was dissolved in 200 ml of benzene and treated with anhydrous ammonia gas at room temperature. After removing solvent, compound 3 was obtained (0.9 g) as brown powder; MS m/z 154 (M+).
EXAMPLE I (IV) (V) 6-FLUORO-2-METHYL-4- (3H) quinazolinone (I) 5-Fluoro-anthranilamide hydrochloride was prepared by adding 20 ml of concentrated hydrochloric acid (37% by weight) to a solution of 27.3 g of <strong>[63069-49-8]5-fluoro-anthranilamide</strong> in 200 ml of methanol. This mixture was cooled in an ice bath to precipitate the hydrochloride which was then collected and dried to obtain a product. A 17.4 g (0.1 mole) portion of the hydrochloride thus obtained was refluxed for 3 hours with 100 ml acetic anhydride and allowed to stand overnight. The mixture was then cooled in an ice bath and the solids collected by filtration on a Buchner funnel. The filter cake was slurried in 100 ml of water, and warmed to enhance dissolution and then 28% aqueous ammonia was added until the mixture was alkaline. After cooling, the 6-FLUORO-2-METHYL-4- (3H) quinazolinone precipitated as a solid, was then collected, washed with a small amount of cold water and dried at 70C to obtain the desired product.
o-Anisoyl chloride (15.7 g, 92 mmol) was added dropwise to a solution ofaminobenzamide <strong>[63069-49-8]2-amino-5-fluorobenzamide</strong> (13.0 g, 84 mmol) and triethylamine (16 mL, 110 mmol) in tetrahydrofuran (100 mL) cooled in an ice bath. Immediately a precipitate started forming. Stirring of the solution was continued for 5 hours at room temperature. The formed precipitate was collected by filtration and was washed twice with diethyl ether and dried at 50 C in vacuo. The dried solid was suspended in 2 N aqueous sodium hydroxide solution (250 mL) and heated at reflux until a clear solution was obtained (3 hours). The reaction mixture was cooled to room temperature and filtered. The filtrate was acidified to pH<l with concentrated aqueous HC1. The formed precipitate was collected by filtration and washed twice with water,twice with methanol, and twice with diethyl ether. The solid was dried in an oven at 45 C to yield 6-fmoro-2-(2-methoxyphenyl)-3No.-quinazolin-4-one (18.2 g, 80%) as a white solid.
80%
6-Fluoro-2-(2-methoxyphenyl)-3H-quinazolin-4-one o-Anisoyl chloride (15.7 g, 92 mmol) was added dropwise to a solution of <strong>[63069-49-8]2-amino-5-fluorobenzamide</strong> (13.0 g, 84 mmol) and triethylamine (16 mL, 110 mmol) in tetrahydrofuran (100 mL) cooled in an ice bath. Immediately a precipitate started forming. Stirring of the solution was continued for 5 hours at room temperature. The formed precipitate was collected by filtration and was washed twice with diethyl ether and dried at 50 C. in vacuo. The dried solid was suspended in 2 N aqueous sodium hydroxide solution (250 mL) and heated at reflux until a clear solution was obtained (3 hours). The reaction mixture was cooled to room temperature and filtered. The filtrate was acidified to pH<1 with concentrated aqueous HCl. The formed precipitate was collected by filtration and washed twice with water, twice with methanol, and twice with diethyl ether. The solid was dried in an oven at 45 C. to yield 6-fluoro-2-(2-methoxyphenyl)-3H-quinazolin-4-one (18.2 g, 80%) as a white solid.
With ammonium hydroxide; dihydrogen peroxide; In dimethyl sulfoxide; at 20 - 30℃; for 4h;Sealed tube;
General procedure: A sealed tube was charged with isatin 1 (1a 147 mg, 1.0 mmol), ammonia hydrate 2 (25%, 421 mg, 3.0 mmol) and H2O2 (30%, 227 mg, 2.0 mmol) at room temperature, and then solvent DMSO (4 mL) was added. The resulting mixture was stirred at 30 C in a sealed vessel under air after 4 h, then added 50 mL water to the mixture, extracted with CH3COOC2H5 3 times (3 x 50 mL). The extract was washed with 30% NaCl solution (V/V), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Petroleum ether/Ethyl acetate = 3:1) to yield the desired product 3a as a yellow solid (89% yield).
5-Fluoro-li7-indole-2,3-dione (35.3 g, 213 mmol) was heated in acetic acid (300mL), 1 mL concentrated sulfuric acid, and 22 mL 35% aq. hydrogen peroxide at 70 C. The solution was kept at that temperature one and a half hours during which time a solid formed in the reaction mixture. After cooling to room temperature this solid was collected by filtration and was washed three times with water. The wet solid was suspended in 150 mL water, and 40 mL of a 25% aq. ammonia solution was added. This mixture was stirred at room temperature 3 days. The formed solid was collected by filtration and was washed twice with water. The solid was dried by azeotropic distillation with toluene (3 x 100 mL) to yield 2-amino-5-fluorobenzamide (9.5 g). The combined filtrates were extracted with ethyl acetate (2x100 mL). The combined extracts were dried over sodium sulfate, filtered, and evaporated to dryness to yield 2-amino-5-fluorobenzamide (3.5 g) as an off-white solid. Both fractions were combined for use in the next reaction step.
2-Amino-5-fluorobenzamide 5-Fluoro-1H-indole-2,3-dione (35.3 g, 213 mmol) was heated in acetic acid (300 mL), 1 mL concentrated sulfuric acid, and 22 mL 35% aq. hydrogen peroxide at 70 C. The solution was kept at that temperature one and a half hours during which time a solid formed in the reaction mixture. After cooling to room temperature this solid was collected by filtration and was washed three times with water. The wet solid was suspended in 150 mL water, and 40 mL of a 25% aq. ammonia solution was added. This mixture was stirred at room temperature 3 days. The formed solid was collected by filtration and was washed twice with water. The solid was dried by azeotropic distillation with toluene (3*100 mL) to yield 2-amino-5-fluorobenzamide (9.5 g). The combined filtrates were extracted with ethyl acetate (2*100 mL). The combined extracts were dried over sodium sulfate, filtered, and evaporated to dryness to yield 2-amino-5-fluorobenzamide (3.5 g) as an off-white solid. Both fractions were combined for use in the next reaction step.
With hydrogen;palladium 10% on activated carbon; In ethanol; for 5h;
To a dry flask purged with N2 was added 10% Pd/C (483 mg) followed by 5-fluoro-2- nitrobenzamide (Example 14, 4.83 g, 26.2 mmol) as a solution in ethanol (130 mL). The mixture was stirred under an H2 atmosphere for 5 h. The mixture was filtered through a pad of Celite and the solvent was evaporated under reduced pressure to afford 4.03 g (99%) of the desired product. 1H NMR (300 MHz, DMSO-c/6) delta 7.75 (br s, 1 H), 7.45-7.29 (m, 1 H), 7.18 (br s, 1 H), 7.10-6.93 (m, 1 H), 6.74-6.58 (m,i H), 6.43 (br s, 2H); ES-MS m/z 155.0 [M+Hf, LCMS RT (min) 0.27
82%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 2h;
Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of 5-fluoro-2-nitrobenzamide (17.5 g, 95.04 mmol, 1.00 equiv) and palladium carbon (10%) (1.75 g, 0.10 equiv) in methanol (150 mL). To the above H2 (enough) was introduced. The resulting solution was stirred for 2 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 12.0 g (82%) of 2- amino-5-fluorobenzamide as a white solid. MS (ESI) m/z 155 ([M + H]+)
0.8 g
With palladium 10% on activated carbon; hydrogen; In methanol;
General procedure: (a) Thionyl chloride (1.5 g, 12.6 mmol) was added dropwise to a suspension of a 5-substituted-2-nitrobenzoic acid (1a: 1.1 g, 6.3 mmol; 1b: 1.2 g, 6.3 mmol) in dichloroethane (30 mL) under reflux. The resulting mixture was stirred under reflux for 4 h and dried under vacuum. (b) The residue was dissolved in 200 mL of dichloroethane and treated with anhydrous ammonia gas at room temperature. (c) After removing solvent, the intermediate 5-substituted-2-nitrobenzamide (2a,b) was dissolved in MeOH and hydrogenated over 10% Pd/C for 1-2 h. The catalyst was removed by filtration, and the solution was dried under vacuum to afford the 5-substituted-2-aminobenzamides as pale yellow powders (3a: 0.7 g, 85%; 3b: 0.8 g, 85%).
With sodium hydrogensulfite; In ISOPROPYLAMIDE; at 150℃;Microwave irradiation;
Step 2The condensation is carried out by a sulfite-mediated procedure analogous to the procedure described by Imai, Yoshio; Sato, Sadayuki; Takasawa, Ryuichi; Ueda, Mitsuru, Synthesis; 1 , 1981; 35-36:A mixture of the aldehyde V (1 mmol), o-aminobenzamide III (1 mmol) and sodium hydrogen sulfite(1 mmol) in dry dimethylacetamide (4 ml.) is heated in a microwave oven at 150 C for periods of 30 min until the reaction is complete as judged by LC-MS or TLC, typically for 1-3 hrs in all. The solvent is evaporated off, and the residue is partitioned between ethyl acetate and water. The organic phase is washed with water and brine, dried and filtered, and the solvent is then evaporated off and the crude quinazolinone IV is purified chromatographically. Step 2; From 3-tert-butyl-5-chloro-2-hydroxy-6-methyl-benzaldehyde and <strong>[63069-49-8]2-amino-5-fluoro-benzamide</strong>; yellow crystals, mp 224-225 C; 1H NMR (CDCI3): delta 10.89 (br, 1 H), 10.27 (br, 1 H), 7.94-7.88 (m, dd-like, 1 H), 7.82-7.76 (m, dd-like, 1 H), 7.56 (m, ddd-like, 1 H), 7.41 (s, 1 H), 2.52 (s, 3H), 1.42 (s, 9H);LC-MS: m/z 361 (M+H), 383 ( M+Na), Rt = 2.36 min
With sodium hydrogensulfite; In ISOPROPYLAMIDE; at 150℃;microwave irradiation;
From 3-tert-butyl-5-chloro-2-hydroxy-6-methyl-benzaldehyde and <strong>[63069-49-8]2-amino-5-fluoro-benzamide</strong>; yellow crystals, mp 224-225 C.; 1H NMR (CDCl3): delta 10.89 (br, 1H), 10.27 (br, 1H), 7.94-7.88 (m, dd-like, 1H), 7.82-7.76 (m, dd-like, 1H), 7.56 (m, ddd-like, 1H), 7.41 (s, 1H), 2.52 (s, 3H), 1.42 (s, 9H); LC-MS: m/z 361 (M+H), 383 (M+Na), Rt=2.36 min. A mixture of the aldehyde V (1 mmol), o-aminobenzamide III (1 mmol) and sodium hydrogen sulfite(1 mmol) in dry dimethylacetamide (4 mL) is heated in a microwave oven at 150 C. for periods of 30 min until the reaction is complete as judged by LC-MS or TLC, typically for 1-3 hrs in all. The solvent is evaporated off, and the residue is partitioned between ethyl acetate and water. The organic phase is washed with water and brine, dried and filtered, and the solvent is then evaporated off and the crude quinazolinone IV is purified chromatographically.
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 95℃; for 36h;
Intermediate 34; 2-[(2,5-Dichloro-4-pyrimidinyl)amino]-5-fluorobenzamide A vessel was charged with 2,4,5-trichloropyrimidine (2.29 mL, 20 mmol), 2-amino-5-difluorobenzamide (1.54 g, 10 mmol), di-isopropyl-ethylamine (7.43 mL, 425 mmol) and 33 mL isopropanol. The vessel was sealed and heated with stirring at 95 C. for 36 h. A white solid appeared in the reaction mixture. The reaction was cooled to room temperature, and the solid was filtered off and washed with isopropanol followed by Et2O. After drying, the white solid (2.36 g, 78% yield) was identified as 2-[(2,5-dichloro-4-pyrimidinyl)amino]-5-fluorobenzamide. MS: M(C11H7Cl2FN4O)=301.10, (M+H)+=301,303,305.
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 2h;
Step 1 To a solution of <strong>[63069-49-8]2-amino-5-fluorobenzamide</strong> (2.00 g, 13.0 mmol) and triethylamine (1.45 g, 14.3 mmol) in THF (40 mL) was added dropwise ethyl chloroglyoxylate (1.95 g, 14.3 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol to give ethyl ((2-(aminocarbonyl)-4-fluorophenyl)amino)(oxo)acetate as a white powder (2.88 g, 87%).
87%
With triethylamine; In tetrahydrofuran; at 35℃; for 2h;Cooling with ice;
Step 1 To a solution of <strong>[63069-49-8]2-amino-5-fluorobenzamide</strong> (2.00 g, 13.0 mmol) and triethylamine (1.45 g, 14.3 mmol) in THF (40 mL) was added dropwise ethyl chloroglyoxylate (1.95 g, 14.3 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was diluted with ethyl acetate, the mixture was washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The obtained concentrated residue was washed with ethanol to give ethyl ((2-(aminocarbonyl)-4-fluorophenyl)amino)(oxo)acetate as a white powder (2.88 g, 87%).
With sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃; for 3h;
General procedure: Sodium hydrogen sulfite (0.8 g, 7.5 mmol) was added to a solution of 2-aminobenzamide (3a) (1.0 g, 7.3 mmol) and benzaldehyde (0.8 g, 7.3 mmol) in N,N-dimethylacetamide (DMAC) (20 mL). The mixture was heated with stirring at 150 C for 3 h and poured into ice water (200 mL). The precipitate was collected, washed with water, and dried in vacuo. After purification by column chromatography (silica gel; chloroform) and followed recrystallization from EtOH, 2-phenyl-4-quinazolinone (4) was obtained (1.1 g) as white needles. Yield, melting point, and spectral data of 4 and all subsequent compounds are summarized in Table 1. The method used to prepare 4 was used with the indicated substituted benzaldehyde and benzamide to afford 5-7.
With oxygen; In dimethyl sulfoxide; N,N-dimethyl-formamide; at 120℃; for 5h;
General procedure: In a typical experiment, a solution of phenylacetic acid (0.3mmol, 40.8mg) in DMF (0.5mL) was added to a 10mL vial with the VNU-21 catalyst (5.5mg, 5mol%). The mixture was stirred at 120C for 4h under an oxygen atmosphere. After that, the catalyst was removed by filtration. A solution of 2-aminobenzamide (0.2mmol, 27.2mg) in DMSO (0.5mL) was then added to the reactor. The mixture was additionally stirred at 120C for 5h under oxygen. The GC yield of benzaldehyde and 2-phenylquinazolin-2(3H)-one were monitored by withdrawing samples from the reaction mixture, quenching with brine (1mL), extracting with ethyl acetate (3×1mL), drying over anhydrous Na2SO4, and analyzing by GC regarding diphenyl ether as internal standard. After the completion of the second step, the reaction mixture was cooled to room temperature. Resulting solution was quenched with brine (5mL), extracted by ethyl acetate (3×5mL), dried over anhydrous Na2SO4 prior to the removal of solvent under vacuum. The crude product was purified by silica gel column chromatography using hexane and ethyl acetate (1:1, v/v) as eluent. The structure of 2-phenylquinazolin-4(3H)-one was verified by GC-MS, 1H NMR and 13C NMR. For the leaching test, after the first 4h reaction time, the catalyst was removed by filtration. The solution phase was transferred to a new and clean reactor. New phenylacetic acid was added, and the resulting mixture was subsequently stirred for additional 4h at 120C under an oxygen atmosphere. The yield of benzaldehyde was monitored by GC.
With sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃; for 3h;
General procedure: Sodium hydrogen sulfite (0.8 g, 7.5 mmol) was added to a solution of 2-aminobenzamide (3a) (1.0 g, 7.3 mmol) and benzaldehyde (0.8 g, 7.3 mmol) in N,N-dimethylacetamide (DMAC) (20 mL). The mixture was heated with stirring at 150 C for 3 h and poured into ice water (200 mL). The precipitate was collected, washed with water, and dried in vacuo. After purification by column chromatography (silica gel; chloroform) and followed recrystallization from EtOH, 2-phenyl-4-quinazolinone (4) was obtained (1.1 g) as white needles. Yield, melting point, and spectral data of 4 and all subsequent compounds are summarized in Table 1. The method used to prepare 4 was used with the indicated substituted benzaldehyde and benzamide to afford 5-7.
With triethylamine; HATU; In N,N-dimethyl-formamide; at 60℃;
A mixture of <strong>[63069-49-8]2-amino-5-fluorobenzamide</strong> (0.50 g, 3.24 mmol), mono-tert-butyl succinate (0.678 g, 3.89 mmol), HATU (1.480 g, 3.89 mmol) and TEA (0.904 mL, 6.49 mmol) in DMF was stirred at 60 C overnight. The mixture was poured into water and then extracted with EtOAc three times. The combined organic layers were washed with brine, dried and concentrated to afford tert-butyl 4-((2-carbamoyl-4- fluorophenyl)amino)-4-oxobutanoate (0.98 g, 3.16 mmol, 97 % yield) as an off-white solid, which was used without further purification, m/z (ESI) 255.2.
6-fluoro-2-(3,4,5-trimethoxyphenyl)quinazolin-4-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydrogensulfite; In N,N-dimethyl acetamide; at 140℃;
Into a 250-mL round-bottom flask, was placed a solution of <strong>[63069-49-8]2-amino-5-fluorobenzamide</strong> (13.02 g, 84.47 mmol, 1.00 equiv) in dimethylacetamide (200 mL), 3,4,5-trimethoxybenzaldehyde (17.97 g, 91.59 mmol, 1.08 equiv) and NaHS03 (8.85 g). The resulting solution was stirred overnight at 140 C in an oil bath. The reaction was then quenched by the addition of 400 mL of water/ice. The solids were collected by filtration. This resulted in 28 g (crude) of 6-fluoro-2-(3,4,5- trimethoxyphenyl)quinazolin-4-ol as a brown solid. MS (ESI) m/z 331 ([M + H]+)
With [Cp*Ir(2,2'-bpyO)(H2O)]; caesium carbonate; at 130℃; for 2h;Inert atmosphere; Microwave irradiation;
2-Amino-5-fluorobenzamide (77 mg, 0.5 mmol), [Cp * Ir (2,2'-bpyO) (H2O)](5.4 mg, 0.005 mmol, 1 mol%),Cesium carbonate (49 mg, 0.15 mmol, 0.3 equiv.) And methanol (0.5 ml) were sequentially added to a dried 5 mL microwave reaction tube. Nitrogen gas in the microwave tube was placed in a single-mode pressure microwave synthesizer (Discover CEM,USA). After the reaction mixture was reacted at 130 C for 2 hours,Cool to room temperature. Rotary evaporation to remove the solvent,Pure target compound was then obtained by column chromatography (developing solvent: petroleum ether / ethyl acetate), yield: 77%
2-(4-chlorobutanamido)-5-fluorobenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With triethylamine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;
General procedure: Asolutionoftheappropriatesubstituted2-aminobenzamide(1.0eq)inTHF(2.5mLpermmolsubstrate)wascooledto0Candtriethylamine(2.0eq)thentheappropriateacidchloride(1.2eq)inTHF(2mLpermmolsubstrate)wereaddedtothestirredsolution.ThereactionwasstirredatroomtemperatureuntilcompletionasindicatedbyTLC,whenthemixturewasdilutedwithEtOAcandquenchedwithNaHSO4(20mL).TheaqueousphasewasextractedwithEtOAc(320mL),combinedorganicphasesdriedoverMgSO4,excesssolventremovedinvacuoandtheresiduepurifiedbyFCC.
With water; potassium carbonate; In water; at 150℃; for 0.5h;Microwave irradiation;
General procedure: Adapted from a literature procedure,1 the appropriate organonitrile (1.0 eq.) and K2CO3(0.2eq.)wereaddedtoamicrowavetubewithastir-barwithdeionizedwater(8.5mLpermmolsubstrate).Afterirradiationundermicrowaveat150Cfor30minutes,thereactionmixturewascooled,extractedwithEtOAc(320mL),thecombinedphasesdriedoverMgSO4andexcesssolventremovedinvacuo.TheresiduewaspurifiedbyFCC,ifrequired,togivethetitlecompound.
In N,N-dimethyl-formamide; at 170℃; for 2h;Autoclave;
This compound was previously reported [25] but we used another method for preparation of thiscompound to improve the yield. In a 10 mL volume stainless steel pressure-resistant vessel were placed(1.54 g, 0.01 mol) of 2-amino-5-fluorobenzamide 2, (1.06 g, 0.01 mol) of trimethoxymethane, and 5 mLof DMF. The reaction was heated at 170C for 2 h. After the reaction was completed the product wascooled, collected, and crystallized from ethyl alcohol. Yield 70%; mp: 252-254C; 1H-NMR (DMSO-d6,300 MHz) delta: 7.67 (d, 1H, J = 8.6 Hz, ArH), 7.85 (d, 1H, J = 9.7 Hz, ArH), 8.12 (s, 1H, ArH), 8.73 (dd, 1H,J = 8.4 Hz and 4.8 Hz, ArH), 11.83(s, 1H, NH), C8H5FN2O (164.04): MS (ESI) m/z 165.04 [M + 1].
2-(3-((4S,4aR,5S,7S,8S,9aS)-4,8-dimethyl-3-oxo-3,4,4a,5,6,7,8,9-octahydro-5,8-epoxy-7,9a-methanobenzo[7]annulen-4-yl)propanamido)-5-fluorobenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;
General procedure: To a solution of PTMA (1d) (29.0 mg, 0.10 mmol) and aminobenzoates 2 (1.5 mmol or 0.20 mmol) in DMF (1.0 mL) at room temperature were added Et3N or pyridine (0.42 mmol) and HATU(76.1 mg, 0.20 mmol). The mixture was stirred at room temperature overnight and monitored by TLC. Then brine (10 mL) was added.The resulting mixture was extracted with EtOAc (3 5.0 mL), and the combined organic portions were dried over anhydrous sodium sulfate and concentrated in vacuo. compounds 3 were finally prepared through flash column chromatography (eluent: EtOAc/lightpetroleum ether 1:20e5:1).
6-fluoro-2-phenyl-2,3-dihydroquinazolin-4(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In water; for 2h;Reflux;
2-Amino-5-fluorobenzamide(154 mg, lmmol), Benzaldehyde (106 mg, lmmol), Water (1 · OmL)And then added to 5mL single-mouth bottle. The mixture was reacted at reflux temperature for 2 hours and then cooled to room temperature. Then join[Cp * Ir (H20) 3] [0Tf] 2 (6.8 mg, 0. ol mmol, 1 mol%) was reacted at reflux temperature for 1 hour and then cooled to room temperatureTheThe solvent was removed under vacuum under reduced pressure and then passed through a column chromatography (developing solvent): Ethyl acetate / n-hexane) to give the pure title compoundObjects,Yield: 81%.
6-fluoro-2-(3-phenyl-1H-pyrazol-4-yl)-2,3-dihydroquinazolin-4(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With 1,3,5-trichloro-2,4,6-triazine; In acetonitrile; at 20℃;
General procedure: Cyanuric chloride (0.15mmol) was added to a mixture of 3a-3x (1mmol) and 4a (206mg, 1.2mmol) in CH3CN, MeOH or DMSO (3mL). The mixture was stirred at room temperature for 0.5-2h. After completion, the mixture was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (30/1) to afford H1, A1-A23.
With ammonium hydroxide; at 100℃; for 12h;Sealed tube;
General procedure: The syntheses of compounds 3a-3x were mainly referred to literature method [35]. A mixture of 1a-1q, 1w, 1x (2mmol), EDC?HCl (575mg, 3mmol), HOBt (446mg, 3.3mmol), NH4Cl (348mg, 6.5mmol) and DIPEA (2.3mL, 13mmol) in DMSO (7mL) was stirred at room temperature for 15h. The mixture was extracted with EtOAc three times, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 3a-3q, 3w, 3x. A mixture of 2r-2v (2mmol) and NH3·H2O (25-28wt%, 80mmol) in sealed tube was heated at 100C for 12h. The mixture was cooled to room temperature and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 3r-3v.
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