* 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-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: 82percent
Reference：
[1] Organic Letters, 2016, vol. 18, # 11, p. 2580 - 2583
[2] Patent: CN107337646, 2017, A, . Location in patent: Paragraph 0080; 0081; 0082; 0083
With N-Bromosuccinimide In acetonitrile at 20℃; for 0.5 h;
A stirred solution of 2-aminobenzamide (1.00 g, 7.34 mmol) in acetonitrile (20 mL) at room temperature was treated with N-bromosuccinimide (1.36 g, 7.70 mmol). The mixture was stirred at room temperature for 0.5 h and then quenched with an ice-cold water. The resulting precipitate was filtered and the residue was recrystallized from acetonitrile to afford a pale yellow solid 2-amino-5-bromobenzamide (2) (1.47 g, 93percent), mp 186-187 °C (185-187 °C 27 ).
Reference：
[1] Tetrahedron, 2016, vol. 72, # 1, p. 123 - 133
[2] Tetrahedron Letters, 2006, vol. 47, # 23, p. 3889 - 3892
[3] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 14, p. 4040 - 4043
[4] Archiv der Pharmazie, 1981, vol. 314, # 2, p. 176 - 180
[5] Molecules, 2017, vol. 22, # 1,
7
[ 5794-88-7 ]
[ 16313-66-9 ]
Yield
Reaction Conditions
Operation in experiment
84%
With ammonia; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In water; N,N-dimethyl-formamide at 20℃; for 15 h;
Compound 26 (9.1 g, 42.1 mmol), HOBT (13.6 g, 101.1 mmol) and EDC.HC1 (19.4 g, 101.1 mmol) were dissolved in DMF (60 mL) and NH3.H20 (30 mL) was added slowly. The reaction mixture was stirred for 15 hours at room temperature. The solvent was then removed in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with 1 N NaOH (20 mL), followed by brine, dried over Na2S04 andconcentrated under vacuum resulting in compound 27 (7.6 g, 84percent yield).
84%
With benzotriazol-1-ol; ammonium hydroxide; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 15 h;
12464] To a suspension of compound 69-4 (9.1 g, 42.1 mmol), HOST (13.6 g, 101.1 mmol) and EDC.HC1 (19.4 g, 101.1 mmol) in DMF (60.0 mE) was added NH3.H20 (30.0 mE) dropwise. At the end of addition, the mixture was stirred at rt for 15 irs. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (100 mE). The resulting mixture was washed with NaOH aqueous solution (20 mE, 1 M) and brine, dried over anhydrous Na2504 and concentrated in vacuo to give the title compound 69-5 (7.6 g, 84percent). The compound was characterized by the following spectroscopic data:12465] MS (ESI, pos.ion) mlz: 216.5 [M+H]12466] ‘H NMR (400 MHz, CDC13) ö (ppm): 7.57 (d, 1H),7.22,7.19 (d, d, 1H), 6.58, 6.56 (d, d, 1H), 6.40 (s, 2H), 5.98 (brs, 2H).
82%
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 20 h; Stage #2: With ammonium hydroxide In tetrahydrofuran at 20℃; for 14 h;
To a stirred solution of 2-amino-5-bromobenzoic acid (14.0 g, 0.065 mol) dissolved in THF (230 mL) was added CDI (12.6 g, 0.077 mol). The reaction mixture was stirred for 2 h at rt. To this mixture ammonia (321 mL, 25percent solution in water) wasadded and the mixture was stirred at room temperature for 14 h. The volatiles were evaporated to dryness; water (100 mL) was added and the mixture was extracted with ethyl acetate (2 x 150 mL). The combined organic extracts were concentrated under reduced pressure to afford a residue. The product was purified by silica gel colunm chromatography using 70percent ethyl acetate in hexanes. The required fractions werecollected and concentrated under reduced pressure to afford 2-amino-5- bromobenzamide (14.0 g, 0.065 mol, 82percent yield) as a brown solid. LCMS (ESI) m/e 215.0 (bromo pattern) [(M+H), calcd for C7H8BrN2O, 214.97]; LC/MS retention time (method B): ti = 0.93 mm.
80%
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2 h; Inert atmosphere; Sealed tube Stage #2: With ammonium hydroxide In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Sealed tube
To a suspension of compound 28-7 (1.52 g, 7.00 mmol) in dry THF (5.0 mL) was added CDI (0.83 g, 5.12 mmol) dropwise. At the end of the addition, the mixture was stirred at rt for 2.0 hrs, and then NH3.H2O (20 mL) was added dropwise at 0 °C. At the end of the addition, the mixture was stirred at rt overnight. After the reaction was completed, the THF solvent was removed. The residue was dissolved in EtOAc (100 mL). The resulting mixture was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to give the title compound as a pale yellow solid (1.2 g, 80percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 215 [M+H] ; and *H NMR (400 MHz, CDC13) δ (ppm): 7.78 (s, 1H), 7.45 (d, 1H, J = 8.0 Hz), 7.15 (s, 1H), 6.89 (d, 1H, J = 2.0 Hz), 6.79 (s, 1H), 6.61 (dd, 1H, J= 8.0 Hz, 2.0 Hz).
80%
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2 h; Stage #2: With ammonium hydroxide In tetrahydrofuran at 0 - 20℃;
To a mixture of compound 1-18 (1.51 g.7.00 mmol) in dry THF (5.0 mL) was added CD1 (0.83 g.5.12 mmol). At the end of the addition, the mixture was stirred at rt for 2.0 hrs. And then NH3.H2O (20 mL) was added dropwise at 0 °C. At the end of the addition, the mixture was stirred at rt overnight. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (100 mL). The resulting mixture was washed with brine, dried over anhydrous a^SC^ and concentrated in vacuo to give the title compound as a pale yellow solid (1.2 g. 80percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 217 [M+H] : and NMR (400 MHz. CDCL) δ (ppm): 7.78 (s, 1H), 7.45 (d, 1H. J= 8.0 Hz), 7.15 (s.1H).6.89 (d. \W.J = 2.0 Hz), 6.79 (s.1H).6.61 (dd.1 H. J= 8.0 Hz.2.0 Hz).
80%
Stage #1: With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2 h; Stage #2: With ammonium hydroxide In tetrahydrofuran; water at 20℃;
To a solution of compound 24-2 (1.51 g, 7.00 mmol) in anhydrous THF (5 mL) was added CDI (0.83 g, 5.12 mmol). After the mixture was stirred at rt for 2 hours, the mixure was cooled to 0 °C and ammonium hydroxide (20 mL) was added dropwise. At the end of the addition, the mixture was stirred at rt overnight. After the reaction was completed, the THF was removed in vacuo and the rediue was dissolved in EtOAc (100 mL). The solution was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2S04 and concentrated in vacuo to afford a pale yellow solid (1.2 g, 80 percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 217 [M+H]+; and lU NMR (400 MHz, CDC13): δ 7.78 (s, 1H), 7.45 (d, 1H, J = 8.0 Hz), 7.15 (s, 1H), 6.89 (d, 1H, J = 2.0 Hz), 6.79 (s, 1H), 6.61 (dd, 1H, J = 8.0 Hz, 2.0 Hz) ppm.
Reference：
[1] Patent: WO2012/13643, 2012, A1, . Location in patent: Page/Page column 43
[2] Patent: US2015/79028, 2015, A1, . Location in patent: Paragraph 2454; 2463; 2464; 2465; 2466
[3] Patent: WO2016/53794, 2016, A1, . Location in patent: Page/Page column 132
[4] Patent: WO2014/82380, 2014, A1, . Location in patent: Paragraph 00585; 00592
[5] Patent: WO2014/82379, 2014, A1, . Location in patent: Page/Page column 112; 1113; 118
[6] Patent: WO2014/131315, 2014, A1, . Location in patent: Page/Page column 187; 188
[7] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 3, p. 383 - 391
[8] Journal of Chemical Research, Miniprint, 1987, # 7, p. 1839 - 1868
[9] European Journal of Medicinal Chemistry, 2014, vol. 76, p. 343 - 351
[10] Organic Letters, 2016, vol. 18, # 14, p. 3342 - 3345
[11] Biochemistry, 2017, vol. 56, # 49, p. 6491 - 6502
8
[ 39263-32-6 ]
[ 16313-66-9 ]
Yield
Reaction Conditions
Operation in experiment
88%
With Acetaldehyde oxime; copper(II) oxide In water for 14 h; Reflux
General procedure: To a 25 mL round-bottom flask equipped with magnetic stirrer were added nitrile (2.5 mmol), acetaldoxime (3.75 mmol), copper oxide (0.25 mmol) and H2O (10 mL). The mixture was heated to reflux for 2-14 h. After cooling to room temperature, the solution was directly evaporated to dryness and the residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give the corresponding amides. The commercially available amides were characterised by melting points, 2-amino-5-bromobenzamide (Table 2, entry 6) and 3,4-dichloropicolinamide (Table 2, entry 13) were characterised by NMR spectra and LC-MS.
60%
With dihydrogen peroxide; sodium hydroxide In methanol; water; dimethyl sulfoxide at 60℃; for 1 h;
To a solution of 2-amino-5-bromobenzonitrile (2 g, 10.2 mmol) in methanol(20 mL) and DMSO (1.5 g, 20 mmol) was added hydrogen peroxide (30 percent solutionin water, 1.4 g, 40 mmol) dropwise followed by the addition of sodium hydroxide(0.2 g, 5 mmol) in water (5 mL). The resultant mixture was heated at 60 °C for 1 h.Upon reaction completion the volatiles were removed under reduced pressure and theresidue was diluted with water (5 mL). The solid obtained was filtered, washed withwater and dried under vacuum to afford 2-amino-5-bromobenzamide (1.3 g, 60percentyield): ‘H NMR (400 MHz, DMSO-d6) ö 7.84 (bs, 1 H), 7.71 (s, 1 H), 7.25 (dd, J2.4 Hz, J= 8.8 Hz, 1 H), 7.17 (bs, 1 H), 6.71 (bs, 2 H), 6.66 (d, J 8.8 Hz, 1 H).
With ammonia In methanol at 20℃; for 336 h; Inert atmosphere
Methyl 2-amino-5-bromobenzoate (1 equiv) was added to a solution of NH3 in MeOH (7 M, 10 equiv) under a N2 atmosphere. The reaction mixture was stirred for 2 weeks at room temperature. After evaporation of the solvent the remaining solid was purified by CC (n-hexane/EtOAc 1:1) to provide the pure compound; white solid, yield: 11percent. 1H NMR (500 MHz, DMSO-d6) δ = 7.84 (br. s., 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 8.8, 2.3 Hz, 1H), 7.22-7.09 (m, 1H), 6.70 (s, 2H, NH2), 6.66 (d, J = 8.8 Hz, 1H) ppm. 13C NMR (125 MHz, DMSO-d6) δ = 169.9, 149.4, 134.3, 130.8, 118.5, 115.2, 104.7 ppm. LC/MS: m/z = 215 and 217 [M + H+], 198 and 200 [M+ - NH2]; tR = 6.65 min; 97.0percent pure (UV).
6-BROMO-LH-BENZO [d] [1, 3] oxazine-2,4-dione (5g, 20mmol) was suspended in 30ML of tetrahydrofuran and to it was bubbled NH3 gas for 1. 5hr. The solvent was removed in a rotary evaporator and residue partitioned between methylene chloride and water. The solid was filtered and dried to yield title compound (3. 8G, 85percent).
76%
With ammonium hydroxide In tetrahydrofuran at 20℃;
Synthesis of 2:To a stirred solution of 6-bromoisatoic anhydride 1 (10 g, 41.3 mmol) in THF to (500 mL) was added slowly NH4OH (20 mL) at room temperature. The suspension became clear. The solution was then stirred at room temperature overnight and concentrated to provide a white solid. The resulting solid was collected by filtration, washed with H2O (50 mL), and dried to afford 2 (6.7 g, 76percent) as an off-white solid.
71.2%
With ammonia In water at 20℃; for 72 h;
6-Bromo-lNo.-benzo[d][l,3]oxazine-2,4-dione (56.0 g, 230 mmol) was suspendedin 1 N aq. NH4OH (600 mL, 2.6 equivalents), and the suspension was stirred 3 d at room temperature. After filtration, the collected solid was washed with water and subsequently dissolved in tetrahydrofuran. This solution was filtered, evaporated to dryness, and dried by repeated azeotropic distillation with toluene. The solid was suspended in CH2CI2, filtered, and washed once CH2CI2 with yielding 35.4 g (71.2percent) 2-amino-5-bromo-benzamide.
Reference：
[1] Journal of Chemical Research, Miniprint, 1987, # 7, p. 1839 - 1868
[2] Patent: WO2004/81009, 2004, A1, . Location in patent: Page 46
[3] Patent: US2010/160314, 2010, A1, . Location in patent: Page/Page column 64
[4] Patent: WO2006/28904, 2006, A1, . Location in patent: Page/Page column 169-170
[5] Patent: WO2004/78733, 2004, A1, . Location in patent: Page 422-423
[6] Patent: WO2010/56758, 2010, A1, . Location in patent: Page/Page column 57
[7] European Journal of Medicinal Chemistry, 2011, vol. 46, # 7, p. 2786 - 2796
[8] European Journal of Medicinal Chemistry, 2013, vol. 65, p. 427 - 435
[9] Biochemistry, 2017, vol. 56, # 49, p. 6491 - 6502
6-BROMO-LH-BENZO [d] [1, 3] oxazine-2,4-dione (5g, 20mmol) was suspended in 30ML of tetrahydrofuran and to it was bubbled NH3 gas for 1. 5hr. The solvent was removed in a rotary evaporator and residue partitioned between methylene chloride and water. The solid was filtered and dried to yield title compound (3. 8G, 85%).
76%
With ammonium hydroxide; In tetrahydrofuran; at 20℃;Product distribution / selectivity;
Synthesis of 2:To a stirred solution of 6-bromoisatoic anhydride 1 (10 g, 41.3 mmol) in THF to (500 mL) was added slowly NH4OH (20 mL) at room temperature. The suspension became clear. The solution was then stirred at room temperature overnight and concentrated to provide a white solid. The resulting solid was collected by filtration, washed with H2O (50 mL), and dried to afford 2 (6.7 g, 76%) as an off-white solid.
71.2%
With ammonia; In water; at 20℃; for 72h;
6-Bromo-lNo.-benzo[d][l,3]oxazine-2,4-dione (56.0 g, 230 mmol) was suspendedin 1 N aq. NH4OH (600 mL, 2.6 equivalents), and the suspension was stirred 3 d at room temperature. After filtration, the collected solid was washed with water and subsequently dissolved in tetrahydrofuran. This solution was filtered, evaporated to dryness, and dried by repeated azeotropic distillation with toluene. The solid was suspended in CH2CI2, filtered, and washed once CH2CI2 with yielding 35.4 g (71.2%) 2-amino-5-bromo-benzamide.
With ammonia; In water; at 20℃; for 48h;
[00310] 2-Amino-5-bromo-benzamide. The isatoic anhydride (15 g, 0.062 mol) was combined with 1 M aq. NH40H (340 mL) and stirred for 2 d at RT. The solid product was collected by filtration and dried in vacuo (6.6 g). LC/MS retention time 2.47 min, m/z obs = 215.2.
With ammonia; water; at 20℃; for 2h;
<strong>[4692-98-2]5-bromoisatoic anhydride</strong> (5.0 g, 1 equiv) was dissolved in aqueous ammonia and stirred at room temperature for 2 hours, during which time a precipitate forms.
With ammonia; In water; at 20℃; for 1h;
General procedure: A mixture of 0.01 mol of 2H-3,1-benzoxazine-2,4(1H)-diones 9b,c and 25 ml of aqueous ammonia solution (25%) was stirred for 1 h. The solid precipitate was removed by filtration, washed with an aqueous ammonia solution (5%) and crystallized from ethanol.
With ammonium hydroxide; for 1h;
General procedure: A mixture of 0.01 mol of 6-R-7-R1-1H-benzo[d] [1,3] oxazine-2,4-diones 8b,c and 25 ml of aqueous ammonia solution (25%) was stirred for 1 h. The solid precipitate was removed by filtration,washed with an aqueous ammonia solution (5%) and crystallized from ethanol
With ammonium carbonate; In 1,4-dioxane; at 60℃;
General procedure: Compound 13 was prepared according to the procedurepreviously reported.37 A suspension of isatoic anhydride 12 (40mmol), ammonium carbonate (160 mmol), and 1,4-dioxane(150 mL) was heated at 60 C. After being stirred for 5-8 h,the reaction mixture was cooled to room temperature andevaporated under reduced pressure, and then water (200 mL)was added to the residue, which was extracted three times withEtOAc (300 mL). The organic layer was washed with brine(100 mL), dried over anhydrous Na2SO4, filtered, andconcentrated to afford compound 13 in yields of 80-85%.
With ammonia; benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In lithium hydroxide monohydrate; N,N-dimethyl-formamide at 20℃; for 15h;
Compound 26 (9.1 g, 42.1 mmol), HOBT (13.6 g, 101.1 mmol) and EDC.HC1 (19.4 g, 101.1 mmol) were dissolved in DMF (60 mL) and NH3.H20 (30 mL) was added slowly. The reaction mixture was stirred for 15 hours at room temperature. The solvent was then removed in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with 1 N NaOH (20 mL), followed by brine, dried over Na2S04 andconcentrated under vacuum resulting in compound 27 (7.6 g, 84% yield).
84%
With benzotriazol-1-ol; ammonium hydroxide; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 15h;
69.3 12463] Step 3) the Preparation of Compound 69-5
12464] To a suspension of compound 69-4 (9.1 g, 42.1 mmol), HOST (13.6 g, 101.1 mmol) and EDC.HC1 (19.4 g, 101.1 mmol) in DMF (60.0 mE) was added NH3.H20 (30.0 mE) dropwise. At the end of addition, the mixture was stirred at rt for 15 irs. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (100 mE). The resulting mixture was washed with NaOH aqueous solution (20 mE, 1 M) and brine, dried over anhydrous Na2504 and concentrated in vacuo to give the title compound 69-5 (7.6 g, 84%). The compound was characterized by the following spectroscopic data:12465] MS (ESI, pos.ion) mlz: 216.5 [M+H]12466] ‘H NMR (400 MHz, CDC13) ö (ppm): 7.57 (d, 1H),7.22,7.19 (d, d, 1H), 6.58, 6.56 (d, d, 1H), 6.40 (s, 2H), 5.98 (brs, 2H).
82%
Stage #1: 5-Bromo-2-aminobenzoic acid With 1,1′-carbonyldiimidazole In tetrahydrofuran at 20℃; for 20h;
Stage #2: With ammonium hydroxide In tetrahydrofuran at 20℃; for 14h;
37.B Part B. 2-Amino-5-bromobenzamide
To a stirred solution of 2-amino-5-bromobenzoic acid (14.0 g, 0.065 mol) dissolved in THF (230 mL) was added CDI (12.6 g, 0.077 mol). The reaction mixture was stirred for 2 h at rt. To this mixture ammonia (321 mL, 25% solution in water) wasadded and the mixture was stirred at room temperature for 14 h. The volatiles were evaporated to dryness; water (100 mL) was added and the mixture was extracted with ethyl acetate (2 x 150 mL). The combined organic extracts were concentrated under reduced pressure to afford a residue. The product was purified by silica gel colunm chromatography using 70% ethyl acetate in hexanes. The required fractions werecollected and concentrated under reduced pressure to afford 2-amino-5- bromobenzamide (14.0 g, 0.065 mol, 82% yield) as a brown solid. LCMS (ESI) m/e 215.0 (bromo pattern) [(M+H), calcd for C7H8BrN2O, 214.97]; LC/MS retention time (method B): ti = 0.93 mm.
80%
Stage #1: 5-Bromo-2-aminobenzoic acid With 1,1′-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; Sealed tube;
Stage #2: With ammonium hydroxide In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Sealed tube;
28.7 the preparation of compound 28-8
To a suspension of compound 28-7 (1.52 g, 7.00 mmol) in dry THF (5.0 mL) was added CDI (0.83 g, 5.12 mmol) dropwise. At the end of the addition, the mixture was stirred at rt for 2.0 hrs, and then NH3.H2O (20 mL) was added dropwise at 0 °C. At the end of the addition, the mixture was stirred at rt overnight. After the reaction was completed, the THF solvent was removed. The residue was dissolved in EtOAc (100 mL). The resulting mixture was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo to give the title compound as a pale yellow solid (1.2 g, 80%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 215 [M+H] ; and *H NMR (400 MHz, CDC13) δ (ppm): 7.78 (s, 1H), 7.45 (d, 1H, J = 8.0 Hz), 7.15 (s, 1H), 6.89 (d, 1H, J = 2.0 Hz), 6.79 (s, 1H), 6.61 (dd, 1H, J= 8.0 Hz, 2.0 Hz).
80%
Stage #1: 5-Bromo-2-aminobenzoic acid With 1,1′-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2h;
Stage #2: With ammonium hydroxide In tetrahydrofuran at 0 - 20℃;
1.16 the preparation of compound 1-19
To a mixture of compound 1-18 (1.51 g.7.00 mmol) in dry THF (5.0 mL) was added CD1 (0.83 g.5.12 mmol). At the end of the addition, the mixture was stirred at rt for 2.0 hrs. And then NH3.H2O (20 mL) was added dropwise at 0 °C. At the end of the addition, the mixture was stirred at rt overnight. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (100 mL). The resulting mixture was washed with brine, dried over anhydrous a^SC^ and concentrated in vacuo to give the title compound as a pale yellow solid (1.2 g. 80%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 217 [M+H] : and NMR (400 MHz. CDCL) δ (ppm): 7.78 (s, 1H), 7.45 (d, 1H. J= 8.0 Hz), 7.15 (s.1H).6.89 (d. W.J = 2.0 Hz), 6.79 (s.1H).6.61 (dd.1 H. J= 8.0 Hz.2.0 Hz).
80%
Stage #1: 5-Bromo-2-aminobenzoic acid With 1,1′-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2h;
Stage #2: With ammonium hydroxide In tetrahydrofuran; lithium hydroxide monohydrate at 20℃;
24.2 Step 2) the preparation of compound 24-3
To a solution of compound 24-2 (1.51 g, 7.00 mmol) in anhydrous THF (5 mL) was added CDI (0.83 g, 5.12 mmol). After the mixture was stirred at rt for 2 hours, the mixure was cooled to 0 °C and ammonium hydroxide (20 mL) was added dropwise. At the end of the addition, the mixture was stirred at rt overnight. After the reaction was completed, the THF was removed in vacuo and the rediue was dissolved in EtOAc (100 mL). The solution was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2S04 and concentrated in vacuo to afford a pale yellow solid (1.2 g, 80 %). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 217 [M+H]+; and lU NMR (400 MHz, CDC13): δ 7.78 (s, 1H), 7.45 (d, 1H, J = 8.0 Hz), 7.15 (s, 1H), 6.89 (d, 1H, J = 2.0 Hz), 6.79 (s, 1H), 6.61 (dd, 1H, J = 8.0 Hz, 2.0 Hz) ppm.
With ammonia; benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In lithium hydroxide monohydrate; N,N-dimethyl-formamide at 20℃;
Multi-step reaction with 2 steps
1: 71 percent / NEt3 / 6 h / Heating
2: 88 percent / 2percent NH3 / 4 h / Ambient temperature
Multi-step reaction with 2 steps
1: thionyl chloride / 24 h / 0 °C / Reflux
2: ammonia / methanol / 336 h / 20 °C / Inert atmosphere
Stage #1: 5-Bromo-2-aminobenzoic acid With benzotriazol-1-ol; diisopropyl-carbodiimide In N,N-dimethyl-formamide at 20℃; for 2h;
Stage #2: With trifluoroacetic acid In dichloromethane at 20℃; for 0.5h;
Multi-step reaction with 2 steps
1.1: tetrahydrofuran / 0.5 h / -10 °C
1.2: -10 - 25 °C
2.1: ammonium bicarbonate / 1,4-dioxane / 60 °C
Stage #1: 5-Bromo-2-aminobenzoic acid With thionyl chloride at 80℃; for 2h;
Stage #2: With ammonia In tetrahydrofuran at 0℃; for 0.5h;
1.1 Step 1: Synthesis of Compound BB1-2
Compound BB1-1 (20.00 g, 92.58 mmol) was added to dichlorosulfoxide (110.14 g, 925.79 mmol, 67.16 mL), and stirred at 80° C. for 2 hours. The dichlorosulfoxide was then removed under reduced pressure, the residue was dissolved in tetrahydrofuran (550 mL), and the ammonia gas was introduced to the above system at 0° C. for 30 minutes. After the reaction was completed, the solvent was removed under reduced pressure to obtain compound BB1-2, which was directly used in the next reaction.
Stage #1: 5-Bromo-2-aminobenzoic acid With 4-methyl-morpholine; benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In tetrahydrofuran for 0.166667h;
Stage #2: With ammonium hydroxide In tetrahydrofuran at 20℃;
With triethylamine In tetrahydrofuran at 20℃; for 3h;
142
To a solution of 2-amino-5-bromo-benzamide (29.2 g, 136 mmol) andtriethylamine (25.0 mL, 173 mmol) in THF (500 mL) was added dropwise o-anisoyl chloride (24.0 g, 140 mmol). Stirring at room temperature was continued for 3 h, after which the formed precipitate was filtered and washed once with THF and twice with dichloromethane yielding 2-(o-anisoyl)-amino-5-bromo-benzamide (51.4 g, 84%) with 1 equivalent of triethylamine hydrochloride.
With 4-methyl-morpholine; HATU In N,N-dimethyl-formamide at 20℃;
5
To a solution of the carboxylic acid (1 equiv) and 2-amino-5- bromobenzamide (1 equiv) in DMF (0.3 mL) was added HATU (1.2 equiv) and N-methylmorpholine (2 equiv). The resulting mixture was stirred at room temperature overnight. After removal of solvent by rotary evaporation, the residue was dissolved in ethyl acetate (15 mL) and washed with an aqueous 1 Ν HCl solution (2 x 10 mL), a saturated aqueous Na2CCh solution (2 x 10 mL), and brine (20 mL), dried over Na2SO4, and filtered. The solvent was removed in vacuo and the crude amide product was taken to the next reaction without further purification.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
To a solution of the carboxylic acid (0.2 mmol) and 2-amino-5- bromobenzamide (0.2 mmol) in DMF (1 mL) was added HATU (0.2 mmol) and DIEA (0.6 mmol). The resulting mixture was stirred at room temperature until started material completely disappeared. Saturated NaHCtheta3 was added and EtOAc was used to extract the organic phase. The combined organic phase was washed with brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the crude amide product was dissolved in dioxane and to this solution was added bis(pinacolato)diboron (0.4 mmol), potassium acetate (0.6 mmol), and PdCl2(dppf) (0.02 mmol). The reaction mixture was degassed, purged with argon, and heated to 80 0C for 2 h in oil bath. After the reaction was determined to be complete by LC-MS, the mixture was diluted with ethyl acetate (50 mL) and washed with brine (5 mL). The organic layer was dried over Na2SO4, and concentrated in vacuo to yield the crude aryl boronic ester. The residue was dissolved in a 1 : 1 mixture of dioxane: H2O and to this mixture was added 5-bromo-l-tosyl-lH-pyrrolo [2,3-b]pyridine-3-carbonitrile (0.24 mmol), Na2Ctheta3 (0.6 mmol), and PdCl2dppf (0.02 mmol). The reaction mixture was degassed, purged with argon, and heated to 140 0C for 15 min. by microwave. After cooling to room temperature, the mixture was concentrated in vacuo and dissolved in a solution of NaOH (2 mmol) in MeOH (2 mL). After stirred in room temperature Ih, the mixture was treated with an aqueous 10% solution of TFA (1 mL) and the solvent was removed by rotary evaporation. The residue was purified by preparative HPLC to afford the desired final product.
With 4-methyl-morpholine; HATU; In N,N-dimethyl-formamide; at 20℃;
To a solution of the carboxylic acid (1 equiv) and 2-amino-5- bromobenzamide (prepared according to the procedure in Scheme 2. 1 equiv) in DMF (0.3 mL) was added HATU (1.2 equiv) and N-methylmorpholine (2 equiv). The resulting mixture was stirred at room temperature overnight. After removal of solvent by rotary evaporation, the residue was dissolved in ethyl acetate (15 mL) and washed with an aqueous 1 Nu HCl solution (2 x 10 mL), a saturated aqueous Nua2C03 solution (2 x 10 mL), and brine (10 mL), dried over Na2SO4, and filtered. The solvent was removed in vacuo and the crude amide product was taken to the next reaction without further purification.
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane
16
DCM and EDC (1.2eq) was added. The reaction mixture was stirred overnight to 5 days until LC-MS suggested the complete consumption of starting aniline and formation of product. The reaction mixture was diluted with EtOAc and the resulting organic layer was washed with IM HCl, brine, sated. NaHCθ3, and brine consequently. It was concentrated to provide crude product for next step. The crude amide was dissolved in 4: 1 1,4-dioxane/water and pyrazole-4-boronic acid pinacol ester (1.4eq), sodium bicarbonate (4eq) and tetrakis(triphenylphosphene) palladium (O) (10%) was added. The reaction mixture was sealed in a microwave vial and degassed under vacuum and filled with argon. It was heated with microwave to 120 degree for Ih until completion of reaction as indicated by LC-MS. The reaction mixture was then concentrated and diluted with EtOAc. The resulting organic layer was washed with water and brine. It was concentrated and purified by preparative HPLC.
With iodine In ethanol for 4h; Inert atmosphere; Reflux;
68%
With toluene-4-sulfonic acid; sodium hydrogensulfite In N,N-dimethyl acetamide at 135℃; for 2.5h;
10
Example 10. Preparation of 2-(4-hydroxy-3,5-dimethylphenyl)-6-((4-methylpiperazin-1-yl)methyl)quinazolin-4(3H)-one [018O] A solution of 2-amino-5-bromobenzamide (12.0 g, 55.8 mmol) and 4-hydroxy-3,5-dimethylbenzaldehyde (8.4 g, 55.8 mmol) in DMA (200 ml_) was treated with NaHSO3 (7.7 g, 72.5 mmol) and p-TsOH (1.1 g, 5.6 mmol). The reaction was heated at 135°C for 2.5 hours, at which time, H2O (10 ml_) and CH2CI2 (100 ml_) were added and the solids were collected by filtration. The solids were washed with CH2CI2 and dried in vacuo to afford 6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (13.1 g, 68%).[0181 ] A solution of 6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (2.0 g, 5.8 mmol) in DMF (20 mL) was treated with vinyltributyltin (2.6 mL, 8.70 mmol), Pd(PPh3)4 (0.670 g, 0.58 mmol), and LiCI (0.730 g, 17.4 mmol). The reaction was stirred at reflux for 30 minutes, then concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 30% to 100% of 92:7:1 CHCI3/MeOH/concentrated NH4OH in CH2CI2, to afford 2-(4-hydroxy-3,5-dimethylphenyl)-6-vinylquinazolin-4(3H)-one (0.780 g, 46%). [0182] To a suspension of 2-(4-hydroxy-3,5-dimethylphenyl)-6- vinylquinazolin-4(3H)-one (0.500 g, 1.70 mmol) in THF (30 mL) and H2O (10 mL) was added NaIO4 (1.09 g, 5.10 mmol), followed by OsO4 (0.2 mL, 0.017 mmol). The reaction was stirred overnight, then concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 92:7:1 to 6:3:1 CHCI3/MeOH/ concentrated NH4OH to afford 2-(4-hydroxy-3,5-dimethylphenyl)-4- oxo-3,4-dihydroquinazoline-6-carbaldehyde (0.475 g, 95%). [0183] To a solution of 2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazoline-6-carbaldehyde (0.115 g, 0.40 mmol) in DCE/CH2CI2 (1 :1 , 15 mL) was added 1-methylpiperazine (0.13 mL, 1.20 mmol) and NaBH(OAc)3 (0.250 g, 1.20 mmol). The reaction stirred at room temperature overnight. After this time, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel eluting with 92:7:1 CHCI3/MeOH/concentrated NH4OH to afford the title compound (0.036 g, 25%) as a white solid: 1H NMR (300 MHz, DMSO-Cf6): δ11.63 (br s, 1 H), 8.77 (br s, 1 H), 8.00 (s, 1 H), 7.85 (s, 2H), 7.65-7.69 (m, 2H), 3.57(s, 2H), 2.15-2.39 (m, 17H); APCI MS m/z 377 [M-H]-.
68%
With sodium hydrogen sulfate; toluene-4-sulfonic acid In N,N-dimethyl acetamide at 135℃; for 2.5h;
10
A solution of 2-amino-5-bromobenzamide (12.0 g, 55.8 mmol) and 4-hydroxy-3,5-dimethylbenzaldehyde (8.4 g, 55.8 mmol) in DMA (200 mL) was treated with NaHSO3 (7.7 g, 72.5 mmol) and p-TsOH (1.1 g, 5.6 mmol). The reaction was heated at 135° C. for 2.5 hours, at which time, H2O (10 mL) and CH2Cl2 (100 mL) were added and the solids were collected by filtration. The solids were washed with CH2Cl2 and dried in vacuo to afford 6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (13.1 g, 68%)
With ammonia; In methanol; at 20℃; for 336h;Inert atmosphere;
<strong>[52727-57-8]Methyl 2-amino-5-bromobenzoate</strong> (1 equiv) was added to a solution of NH3 in MeOH (7 M, 10 equiv) under a N2 atmosphere. The reaction mixture was stirred for 2 weeks at room temperature. After evaporation of the solvent the remaining solid was purified by CC (n-hexane/EtOAc 1:1) to provide the pure compound; white solid, yield: 11%. 1H NMR (500 MHz, DMSO-d6) delta = 7.84 (br. s., 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 8.8, 2.3 Hz, 1H), 7.22-7.09 (m, 1H), 6.70 (s, 2H, NH2), 6.66 (d, J = 8.8 Hz, 1H) ppm. 13C NMR (125 MHz, DMSO-d6) delta = 169.9, 149.4, 134.3, 130.8, 118.5, 115.2, 104.7 ppm. LC/MS: m/z = 215 and 217 [M + H+], 198 and 200 [M+ - NH2]; tR = 6.65 min; 97.0% pure (UV).
General procedure for the synthesis of 3
General procedure: A dry 50 mL flask was charged with 2-aminobenzamides 1 (2.1 mmol), 5,5-dimethyl-1,3-cyclohexanedione 2 (1.0 mmol), iodine (0.026 g, 0.01 mmol) and toluene (10.0 mL). The mixture was stirred at reflux until the reactant 1 was consumed. After the completion of the reaction monitored by TLC, toluene was recovered by distillation under reduced pressure, and the residue was purified by silica column chromatography using ethyl acetate and petroleum ether (1:3) as the eluent to give products 3.
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 0 - 20℃; for 8h;Inert atmosphere; Sealed tube;
To a suspension of compound 28-8 (1.5 g, 7.00 mmol), compound 8-2-2 (2.85 g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in DCM (15 mL) and THF (10 mL) was added DIPEA (5.8 mL, 35 mmol) at 0 C. At the end of the addition, the mixture was stirred at rt for 8.0 hrs. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (100 mL), washed with water and brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 1/3) to give the title compound as colorless slurry (0.65 g, 20%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 469.5 [M+H] +; and H NMR (400 MHz, CDC13) delta (ppm): 11.92 (s, 1H), 8.63 (s, 1H), 7.39 (d, 1H, J = 8.0 Hz), 7.05 (d, 1H, J = 8.0 Hz), 5.57 (d, 1H, J = 8.0 Hz), 4.49-4.52 (m, 1H), 4.36-4.40 (m, 1H), 3.86-3.89 (m, 2H), 3.68 (s, 3H), 2.15-2.24 (m, 2H), 2.00-2.09 (m, 2H), 1.09 (d, 3H, J= 6.0 Hz), 0.97 (d, 3H, J= 6.0 Hz).
20%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 0 - 20℃; for 8h;Inert atmosphere;
To a suspension of compound 1-19 (1.5 g.7.00 mmol). compound 1-19-2 (2.85 g.10.47 mmol) and EDCI (2.67 g. 13.93 mmol) in DCM (15.0 mL) and THF (10.0 mL) was added DIPEA (5.8 mL.35mmol) via syringe dropw ise at 0 C under Ni. At the end of the addition, the mixture was stirred at rt for 8.0 hrs. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc ( 100 mL). and then washed with water and brine, dried over anhydrous NaiS0 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/3) to give the title compound as colorless slurry (0.66 g.20%). The compound was characterized by the following spectroscopic data: MS (ESI. pos.ion) mlz: 470.33 [M+H] and NMR (400 MHz. CDCh) d (ppm): 11.92 (s. III).8.63 (s.1H).7.39 (d. lH.,/= 8.0 Hz).7.05 (d.111../ = 8.0 Hz).5.57 (d. I H../ = 8.0 Hz).4.52-4.49 (m. IH).4.40-4.36 (m. 1H).3.89-3.86 fin.211).3.68 (s.3H). 2.24-2.15 (m.2H).2.09-2.00 (m.2H).1.09 (d.3H../= 6.0 Hz).0.97 (d.3H. J= 6.0 Hz).
20%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; dichloromethane; at 0 - 20℃;
A suspension of compound 24-3 (1.5 g, 7.00 mmol), compound 24-3-2 (2.85 g, 10.47 mmol) and EDCI (2.67 g, 13.93 mmol) in a mixed solvent of DCM (15 mL) and THF (10 mL) was stirred at 0 C and DIPEA (5.8 mL, 35 mmol) was added dropwise slowly. At the end of the addition, the mixture was stirred at rt for 8 hours. After the reaction was completed, the reaction mixture was concentrated and the residue was dissolved in EtOAc (100 mL). The solution was washed with an aqueous ammonium chloride solution, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/3) to give the title compound as colorless oil (0.66 g, 20%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 470.33 [M+H]+; and H NMR (400 MHz, CDC13): delta 11.92 (s, 1H), 8.63 (s, 1H), 7.39 (d, 1H, J = 8.0 Hz), 7.05 (d, 1H, J = 8.0 Hz), 5.57 (d, 1H, J = 8.0 Hz), 4.52-4.49 (m, 1H), 4.40-4.36 (m, 1H), 3.89-3.86 (m, 2H), 3.68 (s, 3H), 2.24-2.15 (m, 2H), 2.09-2.00 (m, 2H), 1.09 (d, 3H, J = 6.0 Hz), 0.97 (d, 3H, J= 6.0 Hz) ppm.
5-bromo-2-(4-methylpentanamido)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 14h;
37.C Part C. 5 -Bromo-2-(4-methylpentanamido)benzamide
To a stirred solution of 2-amino-5-bromobenzamide (7.8 g, 0.036 mol), 4-methyl pentanoic acid (8.41 g, 0.O72mmol), and TBTU (17.46 g, 0.054 mol) in DMF (100 mL) was added DIPEA (25 mL, 0.154 mol) and the reaction mixture was stirred at room temperature for 14 h. The reaction mixture was diluted with water (100 mL)and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with aq. sodium bicarbonate solution (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, and the volatiles were evaporated to dryness. The residue was purified by silica gel column chromatography using a gradient of 40% ethyl acetate in hexanes and the required fractions were collectedand volatiles were evaporated to give 5-bromo-2-(4-methylpentanamido)benzamide (7.0 g, 0.022 mol, 55% yield) as a brown solid. LCMS (ESI) m/e 313.0 (bromo pattern) [(M+H), calcd for C13H18BrN2O2, 313.05]; LC/MS retention time (LC/MS Method = Column - YMC PACK TMS (3X5Omm), 3.0 rim; Mphase A: 2%MeCN98%H20 - 10mM NH4OAc; Mphase B : 98%ACN - 2%H20 -10 mM NH4OAC;Flow: 1.2 mL/min)): ti = 2.12 mm.
With ammonium hydroxide; dihydrogen peroxide In dimethyl sulfoxide at 20 - 30℃; for 4h; Sealed tube;
5.3 Representative procedure for the synthesis of 4 (A)
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).
Multi-step reaction with 2 steps
1.1: sodium hydroxide; dihydrogen peroxide / lithium hydroxide monohydrate / 1 h / 80 °C
2.1: 1,1′-carbonyldiimidazole / tetrahydrofuran / 20 h / 20 °C
2.2: 14 h / 20 °C
Multi-step reaction with 2 steps
1.1: sodium hydroxide / lithium hydroxide monohydrate / 70 °C
1.2: 0.83 h / 70 °C
2.1: N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; benzotriazol-1-ol; 4-methyl-morpholine / tetrahydrofuran / 0.17 h
2.2: 20 °C
8-bromo-12-(4-methoxyphenyl)-6H-isoquinolino[2,1-a]quinazolin-6-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With silver nitrate; In dimethyl sulfoxide; at 120℃; for 4h;
General procedure: To a solution of 2-aminobenzamide 1 (0.24 mmol, 1 equiv) and 2-alkynylbenzaldehyde 2 (0.24 mmol, 1 equiv) in DMSO (4 mL) was added AgNO3 (8 mg, 20 mol%). The resulting mixture was then heated at 120 C for 4 h. After completion of the reaction, the mixture was extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4), and evaporated. The crude product was purified by chromatography (silica gel, acetone/hexane 20:80) to afford the product.
8-bromo-12-phenyl-6H-isoquinolino[2,1-a]quinazolin-6-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With silver nitrate In dimethyl sulfoxide at 120℃; for 4h; regioselective reaction;
12-Butyl- or 12-Aryl-6H-isoquinolino[2,1-a]quinazolin-6-ones 4
General procedure: To a solution of 2-aminobenzamide 1 (0.24 mmol, 1 equiv) and 2-alkynylbenzaldehyde 2 (0.24 mmol, 1 equiv) in DMSO (4 mL) was added AgNO3 (8 mg, 20 mol%). The resulting mixture was then heated at 120 °C for 4 h. After completion of the reaction, the mixture was extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4), and evaporated. The crude product was purified by chromatography (silica gel, acetone/hexane 20:80) to afford the product.
3-bromoisoindolo[2,1-a]quinazolin-5(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With hydrogenchloride In methanol at 20℃; for 24h;
Synthesis of 5-oxo-11, 12-dihydro-5H-isoindolo[2,1-a]quinazolin-12-ium chloride (3aHCl)
General procedure: A mixture ofanthranilamide (340 mg, 2.50 mmol), and o-phthalaldehyde(334.9 mg, 2.50 mmol) were taken in100 mL round bottom flask. Then to this reactionmixture, 30 mL MeOH and 2(N) HCl (10 mL) wereadded. This reaction mixture was stirred at roomtemperature for 24 h. Then, the precipitate appearedwas collected by filtration and washed with water toget 3aHCl (411 mg, 70%).
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