* 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 trifluoroacetic acid In ISOPROPYLAMIDE at 160℃; for 0.5 h; Microwave radiation
To a solution of 2-amino-4-bromo-benzamide (1 equiv) in DMA (0.14 M) were added triethyl orthoformate (10 equiv) and trifluoroacetic acid (1 equiv). The reaction vessel was sealed and exposed to microwave radiation (160 0C, medium absorption setting) for 30 minutes. The reaction mixture was concentrated in vacuo and the residue was filtered through a silica pad with 10 percent methanol in ethyl acetate yielding the required product as a pale yellow solid. <n="121"/>7-Bromo-3H-quinazolin-4-one: (71 percent yield, 100 percent purity) m/z (LC-MS, ESP): 268 [M+H]+ R/T = 2.94 min
at 130℃; for 2 h; Microwave irradiation; Inert atmosphere
2-Amino-4-bromobenzamide (107 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.The tube was nitrogen protected and placed in a single mode pressure microwave synthesizer (Discover CEM, USA). After the reaction mixture was reacted at 130 ° C for 2 hours, it was cooled 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: 80percent
Reference：
[1] Organic Letters, 2016, vol. 18, # 11, p. 2580 - 2583
[2] Patent: CN107337646, 2017, A, . Location in patent: Paragraph 0085; 0086; 0087; 0088
3
[ 112253-70-0 ]
[ 109-94-4 ]
[ 194851-16-6 ]
Yield
Reaction Conditions
Operation in experiment
84%
With sodium methylate In ethanol for 1.5 h; Heating / reflux
2) 4-Bromoanthranilic amide (40 g, 186 mmol) obtained in 1) was dissolved in ethanol (400 mL). Thereto was added sodium methoxide (54.2 g, 93 mmol) with stirring under ice-cooling and then ethyl formate (60.1 mL, 744 mmol) was added dropwise. The mixture was heated under reflux for 1.5 hrs. The reaction mixture was allowed to cool to room temperature and water (500 mL) was added and then acetic acid (40 mL) was added. The mixture was concentrated under reduced pressure and water (200 mL) was added. The precipitate was collected by filtration and dried to give 7-bromo-3H-quinazolin-4-one (35 g, 156 mmol, 84percent). 7-bromo-3H-quinazolin-4-one [0153] 1H NMR (DMSO-d6) δ ppm: 7.68 (dd, J=1.7, 8.5 Hz, 1H), 7.88 (d, J=1.7 Hz, 1H), 8.03 (d, J=8.5 Hz, 1H), 8.14 (s, 1H).
Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5 h; Stage #2: With ammonia In water; N,N-dimethyl-formamide at 20℃; for 15 h;
Compound 37 (9.3 g, 43.1 mmol), HOBT (13.4 g, 99 mmol) and EDC.HC1 (19 g, 99 mmol) were dissolved in DMF (40 mL). The solution was stirred at 20°C for 30 minutes. To the solution, H3.H2O (20 mL). was slowly added The reaction mixture was stirred for 15 hours at room temperature. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL). The mixture was washed with saturated NaHC03 and H4CI aqueous solution. The organic layer was dried over Na2S04 and concentrated under vacuum to give the compound 38 (6.2 g, 67percent yield).
53%
With ammonia; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 25℃; for 18.5 h; Inert atmosphere
To a solution of 2-amino-4-bromobenzoic acid (10g, 46.3 mmol) in tetrahydrofuran (THF) (10 mL) was added HOBT (16.30 g, 106 mmol) and EDC (20.41 g, 106 mmol). The mixture was stirred at 25 °C for 30 min when ammonia (30 mL, 1386 mmol) was added to the solution. The mixture was stirred at 25 °C for 18 hr. The solvent was removed in vacuo when EtOAc (200 mL) was added to the mixture. The organic phase was washed with NaHC03 (aq, 100 mL X 3) and dried with NaS204. The solvent was removed to afford 2-amino-4-bromobenzamide (5.5g, 24.55 mmol, 53 percent yield).
40%
With ammonium chloride; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In ISOPROPYLAMIDE at 20℃; for 24 h;
To a solution of 2-amino-4-bromobenzoic acid (1 equiv) in DMA (0.23 M), were added ammonium chloride (7 equiv), HBTU (1 equiv) and diisopropylethylamine (2 equiv). The reaction mixture was stirred for 24 hours at room temperature. DMA was evaporated and the residue was purified by flash column chromatography onto silica gel eluting with a gradient of TBME/hexane to yield the desired product as a white solid. 2-Amino-4-bromo-benzamide: 40 percent yield, 100 percent purity) m/z (LC-MS, ESP): 215 [M+H]+ R/T = 3.00 min
Reference：
[1] Patent: WO2012/13643, 2012, A1, . Location in patent: Page/Page column 48
[2] Patent: WO2017/98440, 2017, A1, . Location in patent: Page/Page column 120
[3] Patent: WO2008/23161, 2008, A1, . Location in patent: Page/Page column 119
[4] Patent: WO2011/75699, 2011, A2, . Location in patent: Page/Page column 206
[5] Journal of Agricultural and Food Chemistry, 2015, vol. 63, # 31, p. 6883 - 6889
5
[ 1152237-09-6 ]
[ 112253-70-0 ]
Yield
Reaction Conditions
Operation in experiment
67%
Stage #1: With tin(ll) chloride In ethyl acetate for 0.333333 h; Reflux Stage #2: With sodium hydroxide In ethyl acetate Stage #3: Acidic conditions
Synthesis of 3:A mixture of 2 (2.0 g, 10.6 mmol) in EtOAc (200 mL) was treated with SnCl2 (9.4 g, 42 mmol) at reflux for 20 min. After addition of 1N NaOH, the formed solid was filtered and washed with EtOAc. The organic phase was separated. The aqueous phase was neutralized (pH7) and extracted with EtOAc (2.x.70 mL). The combined organic extracts were concentrated to provide 3 (1.53 g, 67percent) as a tan solid.
Compound 37 (9.3 g, 43.1 mmol), HOBT (13.4 g, 99 mmol) and EDC.HC1 (19 g, 99 mmol) were dissolved in DMF (40 mL). The solution was stirred at 20C for 30 minutes. To the solution, H3.H2O (20 mL). was slowly added The reaction mixture was stirred for 15 hours at room temperature. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL). The mixture was washed with saturated NaHC03 and H4CI aqueous solution. The organic layer was dried over Na2S04 and concentrated under vacuum to give the compound 38 (6.2 g, 67% yield).
53%
With ammonia; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 25℃; for 18.5h;Inert atmosphere;
To a solution of 2-amino-4-bromobenzoic acid (10g, 46.3 mmol) in tetrahydrofuran (THF) (10 mL) was added HOBT (16.30 g, 106 mmol) and EDC (20.41 g, 106 mmol). The mixture was stirred at 25 C for 30 min when ammonia (30 mL, 1386 mmol) was added to the solution. The mixture was stirred at 25 C for 18 hr. The solvent was removed in vacuo when EtOAc (200 mL) was added to the mixture. The organic phase was washed with NaHC03 (aq, 100 mL X 3) and dried with NaS204. The solvent was removed to afford 2-amino-4-bromobenzamide (5.5g, 24.55 mmol, 53 % yield).
40%
With ammonium chloride; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 20℃; for 24h;
To a solution of 2-amino-4-bromobenzoic acid (1 equiv) in DMA (0.23 M), were added ammonium chloride (7 equiv), HBTU (1 equiv) and diisopropylethylamine (2 equiv). The reaction mixture was stirred for 24 hours at room temperature. DMA was evaporated and the residue was purified by flash column chromatography onto silica gel eluting with a gradient of TBME/hexane to yield the desired product as a white solid. 2-Amino-4-bromo-benzamide: 40 % yield, 100 % purity) m/z (LC-MS, ESP): 215 [M+H]+ R/T = 3.00 min
Example 5.25a. Synthesis of 2-amino-4-bromobenzamideA solution of 2-amino-4-bromobenzoic acid (1 g, 4.63 mmol), NH4C1 (1.8g, 32.41 mmol), TBTU (1.5 g, 4.63 mmol) and diisopropylethylamine (1.2 g, 9.26 mmol) in DMF (30 mL) was stirred at room temperature overnight. Then the mixture was adjusted to pH 8.0 with saturated Na2C03 and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over Na2S04 and concentrated to give the desired yellow product. MS (ESI): 215, 217 (MH+).
With trifluoroacetic acid; In ISOPROPYLAMIDE; at 160℃; for 0.5h;Microwave radiation;
To a solution of <strong>[112253-70-0]2-amino-4-bromo-benzamide</strong> (1 equiv) in DMA (0.14 M) were added triethyl orthoformate (10 equiv) and trifluoroacetic acid (1 equiv). The reaction vessel was sealed and exposed to microwave radiation (160 0C, medium absorption setting) for 30 minutes. The reaction mixture was concentrated in vacuo and the residue was filtered through a silica pad with 10 % methanol in ethyl acetate yielding the required product as a pale yellow solid. <n="121"/>7-Bromo-3H-quinazolin-4-one: (71 % yield, 100 % purity) m/z (LC-MS, ESP): 268 [M+H]+ R/T = 2.94 min
Reflux a solution of <strong>[112253-70-0]2-amino-4-bromobenzamide</strong> (27 g, 0.13 mol; see Joshi and Chaudhari (1987) Indian J. CHEM., Sect. B, 26B (6) : 602-4) in 2-CHLORO-1, 1, 1-TRIMETHOXYETHANE (50 mL) for 30 minutes, during which time a large precipitate appears. Evaporate the mixture fully and triturate with ether to collect 7-BROMO-2-CHLOROMETHYL-3H-QUINAZOLIN-4-ONE as a white solid
With sodium methylate; In ethanol; for 1.5h;Heating / reflux;
2) 4-Bromoanthranilic amide (40 g, 186 mmol) obtained in 1) was dissolved in ethanol (400 mL). Thereto was added sodium methoxide (54.2 g, 93 mmol) with stirring under ice-cooling and then ethyl formate (60.1 mL, 744 mmol) was added dropwise. The mixture was heated under reflux for 1.5 hrs. The reaction mixture was allowed to cool to room temperature and water (500 mL) was added and then acetic acid (40 mL) was added. The mixture was concentrated under reduced pressure and water (200 mL) was added. The precipitate was collected by filtration and dried to give 7-bromo-3H-quinazolin-4-one (35 g, 156 mmol, 84%). 7-bromo-3H-quinazolin-4-one [0153] 1H NMR (DMSO-d6) delta ppm: 7.68 (dd, J=1.7, 8.5 Hz, 1H), 7.88 (d, J=1.7 Hz, 1H), 8.03 (d, J=8.5 Hz, 1H), 8.14 (s, 1H).
With hydrogen;platinum(IV) oxide; In ethyl acetate; for 41.5h;
1) To a solution of 2,5-dibromonitrobenzene (80 g, 285 mmol) in DMF (500 mL) was added copper cyanide (I) (38 g, 427 mmol) and the mixture was stirred at 100 C. for 1.5 hrs. The reaction mixture was allowed to reach room temperature and toluene (750 mL)-water (1250 mL) was added. Then, Celite (50 g) was added, and after thorough stirring, insoluble material was filtered off. The filtrate was partitioned and the organic layer was washed successively with water (500 mL), 1% aqueous ammonia (250 mL×2), water (250 mL) and saturated brine (500 mL), and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure to give a yellow solid (61.4 g) containing 2-cyano-5-bromonitrobenzene as a main component. This was dissolved in ethyl acetate (270 mL) and platinum oxide monohydrate (330 mg, 1.35 mmol) was added. The inside of the reaction container was displaced with hydrogen and the mixture was stirred under a hydrogen atmosphere for 41.5 hrs. Insoluble material was filtered off and the residue was washed with ethyl acetate (200 mL) and then with ethanol (100 mL). The filtrate was evaporated under reduced pressure, and after drying, suspended in ether (250 mL). The suspension was stirred with heating under reflux. The mixture was allowed to cool to room temperature and the insoluble material was collected by filtration to give 4-bromoanthranilic amide (40 g, 186 mmol, 65%). [CHEMMOL-00365] 2-cyano-5-bromonitrobenzene [0150] 1H NMR (DMSO-d6) delta ppm: 8.10 (d, J=8.3 Hz, 1H), 8.21 (dd, J=1.8, 8.3 Hz, 1H), 8.57 (d, J=1.8 Hz, 1H) [CHEMMOL-00366] 4-bromoanthranilic amide [0151] 1H NMR (DMSO-d6) delta ppm: 6.61 (dd, J=1.8, 8.4 Hz, 1H), 6.81 (br s, 2H), 6.89 (d, J=1.8 Hz), 7.17 (br s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.79 (br s, 1H)
2-Amino-4-bromobenzonitrile was dissolved in 4: 1 AcOHZH2SO4 to form a suspension. The mixture was stirred for 4 h until it became clear and all starting material was consumed as monitored by LC-MS. The solution was poured into ice water and extracted by EtOAc three times. The combined organic layer was washed with brine and dried over Na2SO4. After filtration, the solvent was removed to provide 11-1. Substituted benzyloxy acetic acid (1.1 equiv) was treated with 2 M oxalyl chloride in DCM for 3 h and concentrated to give the corresponding acid chloride, which was then added to a stirred solution of 11-1 and pyridine (5 equiv) in DCM. The reaction mixture was stirred for 3 h until 11-1 was consumed as monitored by LC-MS. The precipitate was collected by filtration and was dried under vacuum to provide 11-2 as white solid. 11-2, potassium carbonate (4 equiv), boronic ester (1.5 equiv) and Pd(PPh3 )4( 10%) were dissolved in 4: 1 dioxane/water and sealed in a microwave tube. The reaction mixture was degassed and heated by microwave for 30min at 140 0C. The solvent was removed and the residue was subjected to preparative HPLC to provide product 11-3 as a TFA salt.
2-Amino-4-bromobenzonitrile was dissolved in 4: 1 AcOHZH2SO4 to form a suspension. The mixture was stirred for 4 h until it became clear and all starting material was consumed as monitored by LC-MS. The solution was poured into ice water and extracted by EtOAc three times. The combined organic layer was washed with brine and dried over Na2SO4. After filtration, the solvent was removed to provide 11-1. Substituted benzyloxy acetic acid (1.1 equiv) was treated with 2 M oxalyl chloride in DCM for 3 h and concentrated to give the corresponding acid chloride, which was then added to a stirred solution of 11-1 and pyridine (5 equiv) in DCM. The reaction mixture was stirred for 3 h until 11-1 was consumed as monitored by LC-MS. The precipitate was collected by filtration and was dried under vacuum to provide 11-2 as white solid. 11-2, potassium carbonate (4 equiv), boronic ester (1.5 equiv) and Pd(PPh3 )4( 10%) were dissolved in 4: 1 dioxane/water and sealed in a microwave tube. The reaction mixture was degassed and heated by microwave for 30min at 140 0C. The solvent was removed and the residue was subjected to preparative HPLC to provide product 11-3 as a TFA salt.
With sodium metabisulfite; In ISOPROPYLAMIDE; for 3h;Reflux;
Synthesis of 4:A mixture of 3 (1.5 g, 7.2 mmol) with benzaldehyde (0.73 mL, 7.2 mmol) and sodium bisulfite (1.1 g, 10.8 mmol) in dimethylacetamide (DMA) (5 mL) was heated at reflux for 3 h. After pouring into H2O (20 mL), the solution was allowed to warm up to room temperature. The solid which formed was filtered, washed with H2O, followed by Et2O to provide 4 (1.5 g, 69%) as a yellow solid, after recrystallization with MeOH/EtOAc.
Synthesis of 3:A mixture of 2 (2.0 g, 10.6 mmol) in EtOAc (200 mL) was treated with SnCl2 (9.4 g, 42 mmol) at reflux for 20 min. After addition of 1N NaOH, the formed solid was filtered and washed with EtOAc. The organic phase was separated. The aqueous phase was neutralized (pH7) and extracted with EtOAc (2×70 mL). The combined organic extracts were concentrated to provide 3 (1.53 g, 67%) as a tan solid.
(9H-fluoren-9-yl)methyl 2-(5-bromo-2-carbamoylphenylcarbamoyl)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In tetrahydrofuran; at 20℃;
Example 5.25c. Synthesis of (9H-fluoren-9-yl)methyl 2-(5-bromo-2- carbamoylphenylcarbamovDpyrrolidine- 1 -carboxylateA solution of (9H-fluoren-9-yl)methyl 2-(chlorocarbonyl)pyrrolidine- l-carboxylate (600 mg, 1.8 mmol), <strong>[112253-70-0]2-amino-4-bromobenzamide</strong> (400 mg, 1.8 mmol), and Et3N (2 mL) in THF was stirred at room temperature . The reaction was monitored by TLC. After diluting with H20 (50 mL), the mixture was extracted with ethyl acetate (3 x 100 mL). The organic layers were dried over Na2S04 and concentrated to give yellow residue, which was purified by column chromatography. MS (ESI): 534, 536(MH+)
Example 1N-{4-[2-tert-Butyl-4-(6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-quinazolin-7-yl]-phenyl}-methanesulfonamide (I-1; SCHEME A); step 1: To a suspension of 20a (3 g, 14 mmol, CASRN 112253-70-0) in DCM cooled to 0 C. and maintained under a N2 atmosphere was added TEA and the suspension stirred for 15 min. To the suspension was added slowly pivaloyl chloride (1.68 g, 14 mmol) the solution was stirred over night RT. The solution was recooled to 0 C. and a second aliquot of pivaloyl chloride (300 muL) was added and the resulting mixture stirred for 2 h at 0 C. for 2 h then at RT for 2 h. The reaction mixture was concentrated in vacuo to afford 20b which was used without additional purification.step 2: To a suspension of 20b (4.2 g, 14 mmol) and EtOH (28 mL) was added aqueous NaOH (2.8 mL, 28 mmol, 10M solution) and the resulting mixture was heated at reflux under an N2 atmosphere for 1.5 h. The solution was cooled to RT, poured over ice and neutralized with1N HCl. The resulting mixture was twice extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4), filtered and evaporated to afford 2.07 g of 22a as a yellow solid.step 3: A microwave vial was charged with 22a (0.5 g, 1.78 mmol), 4-methansulfonamido-phenyl boronic acid (0.421 g, 1.96 mmol, CASRN 380430-57-9), Pd(PPh3)4 (0.206 g, 0.178 mmol), Na2CO3 (0.566 g, 5.34 mmol), MeOH (3 mL) and toluene (1.5 mL). The vial was flushed with Ar for 5 min, sealed and irradiated in a microwave synthesizer at 115 C. The reaction mixture was cooled and concentrated. The insoluble material was triturated with Et2O which afford 0.55 g (84.3%) of 22b as a brown solid.step 4: To a suspension of 22b (0.1 g, 0.27 mmol) in benzene (0.5 mL) was added sequentially diethylaniline (73.0 muL, 0.45 mmol) and POCl3 (14.8 muL). The mixture was heated at reflux for 6 h, cooled and diluted with EtOAc. The resulting solution was washed sequentially with 1 N HCl, H2O, satd. aq. NaHCO3, H2O and brine. The solution was dried (MgSO4), filtered and evaporated to afford 24.step 5: A vial was charged with 24 (0.107 g, 0.274 mmol), 6-methyl-2-methoxy-pyridin-3-yl boronic acid (0.055 g, 0.33 mmol), PdC12(dPPf).CH2Cl2 (0.010 g, 0.014 mmol), Cs2CO3 (0.822 g, 0.268 mmol). dioxane (1 mL) and H2O (0.25 mL), purged with Ar for 10 min sealed and heated for 1 h. The solution was cooled to RT, diluted with EtOAc and sequentially extracted with twice with H2O and brine. The resulting solution was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (10 to 30% EtOAc) to afford 0.08 g of 26.step 6: A mixture of 26 (0.08 g, 0.169 mmol), 48% aq. HBr (52 muL) and HOAc was heated in sealed tube at 60 C. for 3 h. The tube was cooled and the mixture diluted with EtOAc, neutralized with satd. aq. NaHCO3 and stirred overnight at RT. The EtOAc had evaporated and the remaining yellow solid was filtered and washed with EtOAc and H2O. The solid was dried at 70 C. overnight in a vacuum oven which afforded I-1.
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.
Compound 45 (4 g, 15.9 mmol) and 38 (3.8 g, 17.7 mmol) were dissolved in dry THF (250 mL). The mixture was heated to 80C and stirred for 1 hour. Then4-(4,6-Dimethoxy [1.3.5] triazin-2-yl)-4-methylmo holinium chloride hydrate (DMTMM, 1.2 eq) was added and the mixture was stirred at 80C overnight. The mixture was concentrated, water (60 mL) was added and then extracted with CH2CI2 (3 x 150 mL). The organic phase was separated, dried over Na2S04, filtered and the solvent was removed under vacuum. The crude product was purified by preparative high-performance liquid chromatography (column: CI 8, eluent: CH3CN/H20 from 47/53 to 77/23, 0.1% CF3COOH). The desired fraction was collected and basified by saturated NaHC03 (aq.). The mixture was concentrated and extracted with CH2CI2 (2 x 200 mL). The organic layer was dried over Na2S04 and the solvent was evaporated under vacuum. The pure product was dried under vacuum (4.2 g, 59%). Method F; Rt: 1.63 min. m/z=: 470.0 (M+Na)+ Exact mass: 447.1
With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 1h;
To the solution of compound 29 (7.0 g, 26.1 mmol) in dry THF (100 mL) was added compound 38 (5.6 g, 26.1 mmol) and 1 N NaOH (aq. 52 mL, 52.2 mmol). The mixture was stirred for 1 hour at room temperature. The reaction mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with 1 N NaOH in water (50 mL), brine, dried over Na2S04 and concentrated under vacuum resulting in compound 39 (8.3g, 71% yield). Method Al; Rt: 1.37 min. m/z=: 468.1 (M+Na)+ Exact mass: 445.1
With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 1h;
To the solution of compound PR-6 (Crude 22 g) in dry THF (250 mL) was added <strong>[112253-70-0]2-amino-4-bromobenzamide</strong> (7.6 g, 35.3 mmol) and 1 N NaOH (aq. 85 mL, 85 mmol). The mixture was stirred for 1 hour at room temperature. The reaction mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with 1 N NaOH in water (15 mL), brine, dried over Na2S04 and concentrated in vacuo resulting in a crude residue (17 g). The crude residue, obtained similar as described above (25 g), and Na2C03 (17.8 g, 168 mmol) in ethanol (250 mL) and H20 (250 mL) was refluxed for 2 hour. The organic solvent was removed in vacuo. The mixture was extracted with dichloro methane (2 x 200 mL). The combined organic layers were washed with brine, dried over Na2S04 and purified by silica gel column chromatography (eluent: ethyl acetate). The desired fractions were evaporated to dryness. The obtained residue was stirred in ethyl acetate (50 mL), the precipitate was filtered off and washed with ethyl acetate resulting in compound QA-1 (17 g).
Step A: To a mixture of sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate from Example 2 Step B (2.05 g, 9.62 mmol) and <strong>[112253-70-0]2-amino-4-bromobenzamide</strong> (1.89 g, 8.75 mmol) was added trimethylsilyl polyphosphate (15 mL) and the mixture was stirred overnight at 120 C. Equal volumes of EtOAc and water were added and the resulting solution was stirred for 1 h. The EtOAc layer was washed with brine, dried over Na2SO4 and then concentrated under reduced pressure. Et2O was added and evaporated. Trituration of the residue with hexanes, followed by collection of the solid by filtration afforded 7-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-ol (2.49 g, 77%). 1H NMR (300 MHz, DMSO-d6) delta 11.37 (s, 1H), 8.76 (s, 1H), 7.97-8.07 (m, 2H), 7.88 (d, J=8.3 Hz, 1H), 7.69-7.81 (m, 2H); LC-MS (ESI) m/z 370/372 (M+H)+.
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; acetonitrile; at 160℃; for 0.333333h;Microwave irradiation; Inert atmosphere;
To bis(triphenylphosphine)palladium(II) dichloride (98 mg, 0.14 mmol), <strong>[112253-70-0]2-amino-4-bromobenzamide</strong> (600 mg, 2.79 mmol), and l-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (754 mg, 3.62 mmol) were added acetonitrile (9 mL) and 1M aq Na2CC>3 (9 mL, 9 mmol). The reaction vessel was evacuated and flushed with argon (3X). The mixture was heated in a microwave reactor at 160 C for 20 min. The mixture was allowed to cool to rt, the organic layer was decanted, and the aqueous layer was retained. The organic layer was concentrated under reduced pressure and the residue was diluted with water. The resulting solid was collected by filtration washing with water and acetonitrile. The retained aqueous layer from above was filtered, and the collected solid was washed with water and acetonitrile. The collected solids were combined to afford 2-amino-4-(l -methyl- 1H- pyrazol-4-yl)benzamide (520 mg, 86%). LCMS (ESI) m/z 217 (M + H)+.
2-(4-Fluorophenyl)-2,2-difluoroacetic acid[ No CAS ]
[ 1362910-88-0 ]
Yield
Reaction Conditions
Operation in experiment
79%
With trimethylsilyl polyphosphate; at 130℃;
To <strong>[112253-70-0]2-amino-4-bromobenzamide</strong> (2.0 g, 9.3 mmol) and 2, 2- difluoro-2-(4-fluorophenyl) acetic acid from Example 1 Step A was addedtrimethylsilyl polyphosphate (20 mL) and the mixture was heated at 130 C overnight. After being allowed to cool, the mixture was partitioned between equal volumes of DCM and water, and the organic layer was dried over Na2S04 and concentrated under reduced pressure. The residue was dissolved in diethyl ether with warming. The solution was stored at -30 C and the resulting solid (1.32 g) was collected by filtration. The filtrate was concentrated and the residue was triturated with hot hexanes to afford a solid (1.44 g). The solids were combined to afford 7-bromo-2- (difiuoro(4-fluorophenyl)methyl)quinazolin-4-ol (2.74 g, 79%). LCMS (ESI) m/z 367/369 (M - H)"
With sodium hydroxide; In tetrahydrofuran; water; at 25℃; for 1h;
PR-8 QA-3 To the solution of compound PR-8 (7 g, 21 mmol) in THF (70 mL) was added <strong>[112253-70-0]2-amino-4-bromobenzamide</strong> (4.5 g, 21 mmol) and IN NaOH (42 mL, 42 mmol). The mixture was stirred for 1 hour at 25C. The mixture was extracted with ethyl acetate. The organic layers were collected, washed with 0.5 N NaOH, brine, dried and concentrated in vacuo, resulting in a crude residue (9 g).This residue (9 g) and Na2C03 (5.7 g, 54 mmol) in H20 (200 mL) and THF (200 mL) was stirred and refluxed for 2 hour. The mixture was concentrated in vacuo and extracted with CH2C12 (2x), washed with brine, dried and evaporated in vacuo. The residue was dissolved in CH2C12 and washed with 1 N HC1 (3 x), brine, dried and evaporated in vacuo, resulting in QA-3 (4.4 g). Method A2; Rt: 1.27 min. m/z=: 484.0 (M+H)+ Exact mass: 483.1
With sodium hydroxide; In tetrahydrofuran; water; at 25℃; for 1h;
To the solution of compound PR-8 (7 g, 21 mmol) in THF (70 mL) was added <strong>[112253-70-0]2-amino-4-bromobenzamide</strong> (4.5 g, 21 mmol) and IN NaOH (42 mL, 42 mmol). The mixture was stirred for 1 hour at 25C. The mixture was extracted with ethyl acetate. The organic layers were collected, washed with 0.5 N NaOH, brine, dried and concentrated in vacuo, resulting in a crude residue (9 g).This residue (9 g) and Na2C03 (5.7 g, 54 mmol) in H20 (200 mL) and THF (200 mL) was stirred and refluxed for 2 hour. The mixture was concentrated in vacuo and extracted with CH2C12 (2x), washed with brine, dried and evaporated in vacuo. The residue was dissolved in CH2C12 and washed with 1 N HC1 (3 x), brine, dried and evaporated in vacuo, resulting in QA-3 (4.4 g). Method A2; Rt: 1.27 min. m/z=: 484.0 (M+H)+ Exact mass: 483.1
With pyridine; oxalyl dichloride; In dichloromethane; at 20℃; for 1h;
PR-9 QA-4 Oxalyl dichloride (2.5 mL, 13.11 mmol) was added drop wise to a mixture of the compound PR-9 (2.5 g, 8.74 mmol), <strong>[112253-70-0]2-amino-4-bromobenzamide</strong> (2.5 g, 10.49 mmol) in dichloromethane (20 mL) and pyridine (20 mL) at room temperature. The mixture was stirred for 1 hour at room temperature. The solvent was removed in vacuo. The residue was purified by column chromatography (petroleum ether: acetate ether=l : 1) . The obtained intermediate amide compound (0.98 g), Na2C03 (1.08 g. 10.15 mmol), H20 (5 mL) and CH3CH2OH (5 mL) were stirred for 2 hours under reflux. Most of CH3CH2OH was removed in vacuo and the obtained residue was extracted with ethyl acetate. The organic layer was dried over Na2S04 and concentrated in vacuo. The residue was washed with t-butyl methyl ether resulting in compound QA-4 (0.89 g).
With pyridine; oxalyl dichloride; In dichloromethane; at 20℃; for 1h;
Oxalyl dichloride (2.5 mL, 13.11 mmol) was added drop wise to a mixture of the compound PR-9 (2.5 g, 8.74 mmol), <strong>[112253-70-0]2-amino-4-bromobenzamide</strong> (2.5 g, 10.49 mmol) in dichloromethane (20 mL) and pyridine (20 mL) at room temperature. The mixture was stirred for 1 hour at room temperature. The solvent was removed in vacuo. The residue was purified by column chromatography (petroleum ether: acetate ether=l : 1) . The obtained intermediate amide compound (0.98 g), Na2C03 (1.08 g. 10.15 mmol), H20 (5 mL) and CH3CH2OH (5 mL) were stirred for 2 hours under reflux. Most of CH3CH2OH was removed in vacuo and the obtained residue was extracted with ethyl acetate. The organic layer was dried over Na2S04 and concentrated in vacuo. The residue was washed with t-butyl methyl ether resulting in compound QA-4 (0.89 g).
Oxalyl chloride (2.9 mL, 33 mmol) was added drop wise to the mixture of compound PR-1 (5 g, 22 mmol), <strong>[112253-70-0]2-amino-4-bromobenzamide</strong> (4.7 g, 22 mmol) and pyridine (50 mL). The mixture was stirred for 1 hour at room temperature. The solvent was removed in vacuo. The obtained residue was purified by chromatography (petroleum ether: acetate ether=5: l) resulting in a intermediate (3.6 g). Method A2; Rt: 1.15 min. m/z=:447.7 (M+Na)+ Exact mass: 425.1 The above obtained intermediate (3.6 g,), Na2C03 (2.7 g. 25.4 mmol), H20 (20 mL) and CH3CH2OH (20 mL) were stirred for 2 hours under reflux. Most of CH3CH2OH was removed in vacuo. The residue was extracted with ethyl acetate (3 x 20 mL). The organic layer was dried over Na2S04 and concentrated in vacuo. The residue was washed with t-butyl methyl ether resulting in compound QA-6 (3.4 g)
3.6 g
With pyridine; oxalyl dichloride; at 20℃; for 1h;
Oxalyl chloride (2.9 mL, 33 mmol) was added drop wise to the mixture of compound PR-1 (5 g, 22 mmol), <strong>[112253-70-0]2-amino-4-bromobenzamide</strong> (4.7 g, 22 mmol) and pyridine (50 mL). The mixture was stirred for 1 hour at room temperature. The solvent was removed in vacuo. The obtained residue was purified by chromatography (petroleum ether: acetate ether=5: l) resulting in a intermediate (3.6 g). Method A2; Rt: 1.15 min. m/z=:447.7 (M+Na)+ Exact mass: 425.1 The above obtained intermediate (3.6 g,), Na2C03 (2.7 g. 25.4 mmol), H20 (20 mL) and CH3CH2OH (20 mL) were stirred for 2 hours under reflux. Most of CH3CH2OH was removed in vacuo. The residue was extracted with ethyl acetate (3 x 20 mL). The organic layer was dried over Na2S04 and concentrated in vacuo. The residue was washed with t-butyl methyl ether resulting in compound QA-6 (3.4 g)
With sodium hydroxide; In tetrahydrofuran; water; at 25℃; for 1h;
To the solution of compound PR-11 (2.5 g) in THF (30 mL) was added 2-amino-4- bromobenzamide (1.57 g, 7.3 mmol) and 1 N NaOH (14.6 mL, 14.6 mmol). The mixture was stirred for 1 hour at 25C. The mixture was extracted with ethyl acetate (2x). The organic layers were combined, washed with 0.5 N NaOH, brine, dried and concentrated in vacuo, resulting in a residue (3.5 g) that was stirred with Na2C03 (2.32 g, 21.9 mmol) in H20 (50 mL) and THF (50 mL) and refluxed for 2 hours. The volatiles were removed in vacuo. The mixture was extracted with CH2C12 (2x), washed with brine, dried and the volatiles were removed in vacuo. The residue was dissolved in CH2C12 and washed with 1 N HC1 (3x), brine, dried and the volatiles were removed in vacuo, resulting in compound QA-8 (1.5 g). Method A2; Rt: 1.15 min. m/z=:453.9 (M+H)+ Exact mass: 453.1
3.5 g
With sodium hydroxide; In tetrahydrofuran; water; at 25℃; for 1h;
To the solution of compound PR-11 (2.5 g) in THF (30 mL) was added 2-amino-4- bromobenzamide (1.57 g, 7.3 mmol) and 1 N NaOH (14.6 mL, 14.6 mmol). The mixture was stirred for 1 hour at 25C. The mixture was extracted with ethyl acetate (2x). The organic layers were combined, washed with 0.5 N NaOH, brine, dried and concentrated in vacuo, resulting in a residue (3.5 g) that was stirred with Na2C03 (2.32 g, 21.9 mmol) in H20 (50 mL) and THF (50 mL) and refluxed for 2 hours. The volatiles were removed in vacuo. The mixture was extracted with CH2C12 (2x), washed with brine, dried and the volatiles were removed in vacuo. The residue was dissolved in CH2C12 and washed with 1 N HC1 (3x), brine, dried and the volatiles were removed in vacuo, resulting in compound QA-8 (1.5 g). Method A2; Rt: 1.15 min. m/z=:453.9 (M+H)+ Exact mass: 453.1
With pyridine; oxalyl dichloride; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere;
C1COCOC1 ( 44.4 mL, 510.2 mmol) was added dropwise to the mixture of PR-13 (100.6 g, 374 mmol), <strong>[112253-70-0]2-amino-4-bromobenzamide</strong> (73.2 g, 340 mmol) and pyridine (760 mL) under nitrogen at 0C. The mixture was stirred for 2 hour at room temperature. The solvent was removed in vacuo. Saturated NaHC03 was added to the residue and the resulting mixture was extracted by ethyl acetate for three times. The combined organic layers were washed with saturated NaHC03, brine and dried over Na2S04. The solvent was removed in vacuo. The obtained residue was purified by chromatography (CH2Cl2:MeOH=50: l) resulting in an intermediate amide compound (50.6 g). Method A2; Rt: 1.15 min. m/z=:490.1 (M+Na)+ Exact mass: 467.1 A solution of the above obtained intermediate (50.61g), Na2C03 (34.5 lg. 325.6 mmol), H20 (300 mL) and CH3CH2OH (300 mL) was stirred for 3 hours at reflux. EtOH was removed in vacuo and the mixture was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were dried over Na2S04 and concentrated in vacuo. The obtained residue was washed with t-butyl methyl ether resulting in compound QA-9 (39.2 g). Method A2; Rt: 1.37 min. m/z=:448.1 (M+H)+ Exact mass: 447.1
50.6 g
With pyridine; oxalyl dichloride; at 0 - 20℃; for 2h;Inert atmosphere;
C1COCOC1 ( 44.4 mL, 510.2 mmol) was added dropwise to the mixture of PR-13 (100.6 g, 374 mmol), <strong>[112253-70-0]2-amino-4-bromobenzamide</strong> (73.2 g, 340 mmol) and pyridine (760 mL) under nitrogen at 0C. The mixture was stirred for 2 hour at room temperature. The solvent was removed in vacuo. Saturated NaHC03 was added to the residue and the resulting mixture was extracted by ethyl acetate for three times. The combined organic layers were washed with saturated NaHC03, brine and dried over Na2S04. The solvent was removed in vacuo. The obtained residue was purified by chromatography (CH2Cl2:MeOH=50: l) resulting in an intermediate amide compound (50.6 g). Method A2; Rt: 1.15 min. m/z=:490.1 (M+Na)+ Exact mass: 467.1 A solution of the above obtained intermediate (50.61g), Na2C03 (34.5 lg. 325.6 mmol), H20 (300 mL) and CH3CH2OH (300 mL) was stirred for 3 hours at reflux. EtOH was removed in vacuo and the mixture was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were dried over Na2S04 and concentrated in vacuo. The obtained residue was washed with t-butyl methyl ether resulting in compound QA-9 (39.2 g). Method A2; Rt: 1.37 min. m/z=:448.1 (M+H)+ Exact mass: 447.1
With pyridine; oxalyl dichloride; In dichloromethane; at 20℃; for 1h;
Oxalyl dichloride (2.5 mL, 13.11 mmol) was added drop wise to the mixture of compound PR-4 (3.3 g, 12 mmol), <strong>[112253-70-0]2-amino-4-bromobenzamide</strong> (3.1 g, 14.5 mmol) in dichloromethane (30 mL) and pyridine (30 mL). The mixture was stirred for 1 hour at room temperature. The solvent was removed in vacuo and the obtained The residue was purified by chromatography (petroleum ether: acetate ether=l : 1) resulting in an intermediate amide (0.7 g). This intermediate amide (0.7 g,) Na2C03 (0.82 g. 7.5 mmol), H20 (10 mL) and CH3CH2OH (10 mL) was stirred for 2 hours at reflux. After cooling, most of CH3CH2OH was removed in vacuo. The residue was extracted with ethyl acetate. The organic layer was dried over Na2S04 and concentrated in vacuo. The residue was washed with t-butyl methyl ether resulting in compound QA-11 (0.55 g). Method A2; Rt: 1.04 min. m/z=: 454.0 (M+H)+ Exact mass: 453.1
With acetic acid; In dichloromethane; acetonitrile; at 20℃; for 1h;
To a solution of 22 (1.19 g, 5.53 mmol) and benzaidehyde (594 mg, 5.60 mmoi) in CH2Ci (50 mL) and CH3CN (50 mL) was added acetic acid (0.2 mL), The mixture was stirred at rt for 1 h. Na BH(OAc)}(3.52 g, 16.59 mmol) was added. The mixture was stirred at rt for 8 h. The reaction was q uenched with saturated aq. NaHC03(50 mL) and concentrated, the residue was suspended in EtOAc (300 m L), washed with br ne (100 m L). The organic layer was separated, dried over sodium sulfate, filtered and concentrated . The residue was purified by chromatography (silica gel, 0-50% EtOAc/heptane) to afford 23 (2,01 mg, 12%) as an off-white solid:3H R (300 MHz, DMSO-d6) delta 8.75 (d, J = 5.7 Hz.. IH), 7,93 {br.s, IH}, 7.55 (d, J = 8.4 Hz, 1H), 7.38-7,31 (m, 6H), 6.76 (d, J = 1.8 Hz, IH), 6.69 (dd, J = 8.4, 1.8 Hz, IH), 4.39 (d, J = 6.0 Hz, 2H}.
With ammonium carbonate; In 1,4-dioxane; at 60℃; for 8h;
General procedure: A suspension of substituted isatoic anhydride (35 mmol), ammonium carbonate (140 mmol), and 1,4-dioxane (150 mL) was heated at 60 C. After stirring for 8 h, the reaction mixture was cooled to room temperature and evaporated under reduced pressure, and then water (200 mL) was added to the residue, which was extracted with CH2Cl2 (380 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to give compounds 9 in yields of 63-94%.
With hydrogenchloride; sodium nitrite; In water; N,N-dimethyl-formamide; at 0℃; for 1h;
General procedure: Intermediates 2a-h were preparedby the similar method described in the literature [1] (Scheme 1). At 0 C, to a solution of sodium nitrite (1.38 g, 20 mmol) in 0.5 M hydrochloric acid (80 mL) was added anthranilamide 1 (10 mmol) in DMF (8 mL) over a period of 30 min. After that, the above mixture was stirred for another 1 h at 0 C. Then the mixture was basified with 30% aqueous ammonia and reacidified with hydrochloric acid to pH 2.0. The precipitate was filtered off with suction, washed with water and dried to afford the crude product, which was finally recrystallized from ethanol to yield 2.
General procedure: A solution of anthranilamide (I, 30 mmol) in DMF (15 mL) was added dropwise to a well-stirred solution of sodium nitrite (4.14 g, 60 mmol) in 0.5 M HCl (240 mL) at 0 C over a period of 40 min. After the stirring was continued at 0-5 C for 1 h, 30% aqueous ammonia was added slowly to adjust the pH to 10.0, and then reacidified to pH 2.0. After vigorously stirring for 30 min, the mixture was filtered with suction, and the filter cake was washed with water (200 mL) and dried to afford 1,2,3-benzotriazin-4-one II in yields of above 80%.
With hydrogenchloride; sodium nitrite; In water; at 0℃; for 0.5h;Inert atmosphere;
To a solution of <strong>[112253-70-0]2-amino-4-bromobenzamide</strong> (5.0g, 23.25 mmol) in HCI (4.24 mL, 140 mmol) and water (50mL) was added sodium nitrite (3.21 g, 46.5 mmol) at 0 C. The mixture was stirred at 0 C for 30 min. The pH of the mixture was adjusted to 2 and the mixture was extracted with EtOAc (100 mL X 3). The organic phase was dried with Na2S04, filtered and removed in vacuo to afford 7-bromobenzo[d][1 ,2,3]triazin-4(3H)-one (5.0 g, 21 .24 mmol, 91 % yield) as white solid.
General procedure: A solution of anthranilamide (30 mmol) in 1N HCl (120 mL) was stirred at 0 C for 20 min. Then, sodium nitrite (60 mmol) dissolved in deionized water (100 mL) was added dropwise to the above solution for 40 min. After another 2 h of stirringat 0 C, 30% NaOH solution was added slowly to adjustp H value to 8.0. The reaction mixture was allowed to stir vigorously for 15 min. The precipitated product was filtered, washed with deionized water (200 mL), and dried to afford compounds 10 in yields of 40-92%.
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