* 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 ammonia In tetrahydrofuran; methanol at 20℃; for 0.666667 h;
A solution of 5-bromo-2-bromomethyl-benzoic acid methyl ester (1 equiv) in a 1:1 THF/MeOH mixture was treated by gentle bubbling of ammonia gas for 40 minutes at room temperature. The reaction mixture was concentrated in vacuo. The residue was sonicated in CH2Cl2 for 15 minutes then filtered to give the desired product as a white solid.6-Bromo-2,3-dihydro-isoindol-l-one: (98 percent yield, 90 percent purity) m/z (LC-MS, ESP): 212.3/214.3 [M+H]+ R/T = 2.98 min
87%
With ammonium hydroxide In methanol at 80℃; for 10 h;
3) The compound obtained in step (2) (150 g, 0.49 mol) was dissolved in 600 ml of methanol.The system then added 25percent of ammonia to 4.5 liters of ammonia and the system reacted at 70°C for 5 hours.It was cooled and filtered to give 90 g of a pale yellow powder in a yield of 87percent.
Reference：
[1] Patent: WO2008/23161, 2008, A1, . Location in patent: Page/Page column 117
[2] Organic and Biomolecular Chemistry, 2017, vol. 15, # 48, p. 10172 - 10183
[3] Patent: CN107474006, 2017, A, . Location in patent: Paragraph 0050; 0051; 0054; 0056-0057; 0060; 0062-0063; 0066
[4] Patent: WO2008/20306, 2008, A2, . Location in patent: Page/Page column 38
[5] E-Journal of Chemistry, 2011, vol. 8, # 3, p. 1108 - 1113
[6] Patent: US2004/58970, 2004, A1, . Location in patent: Page 8
2
[ 79669-50-4 ]
[ 675109-26-9 ]
Yield
Reaction Conditions
Operation in experiment
71%
With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 85℃; for 2 h;
Step 2 Compound 1251 B (1.219g, 5.32 mmol) was dissolved in CCI4 (30 mL). NBS (947 mg, 5.32 mmol) and benzoyl peroxide (66 mg, 0.27 mmol) was added. The solution was stirred at 850C for 2 hours. After cooling down, the solid was filtered and the organic layer was washed with water (10 mL). The organic layer was dried over Na2SO4, concentrated by rotary evaporator, dried under vacuum. The residue was then dissolved in NH3-MeOH (7N, 10 mL) and transferred into a 75 mL pressure bottle. The solution was stirred at 90 0C for over night. The product was purified by C18 chromatography (CH3CN/water: 5percent to 90percent, with addition of 0.1percent HCO2H) to give compound 1251C (800mg, 71percent).
Reference：
[1] Patent: WO2007/84451, 2007, A1, . Location in patent: Page/Page column 160
[2] E-Journal of Chemistry, 2011, vol. 8, # 3, p. 1108 - 1113
[3] Organic and Biomolecular Chemistry, 2017, vol. 15, # 48, p. 10172 - 10183
[4] Patent: CN107474006, 2017, A,
3
[ 480-91-1 ]
[ 675109-26-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 6, p. 3091 - 3107
4
[ 1200444-64-9 ]
[ 1972-28-7 ]
[ 675109-26-9 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 21, p. 3707 - 3712
5
[ 79669-49-1 ]
[ 675109-26-9 ]
Reference：
[1] E-Journal of Chemistry, 2011, vol. 8, # 3, p. 1108 - 1113
[2] Patent: CN107474006, 2017, A,
[3] Patent: WO2007/84451, 2007, A1,
6
[ 118-90-1 ]
[ 675109-26-9 ]
Reference：
[1] E-Journal of Chemistry, 2011, vol. 8, # 3, p. 1108 - 1113
[2] Organic and Biomolecular Chemistry, 2017, vol. 15, # 48, p. 10172 - 10183
With potassium acetate In 1,4-dioxane at 70 - 120℃; for 18 h;
To a solution of 6-bromo-2,3-dihydro-isoindol-l-one (1 equiv) in dry dioxan (0.1 M) were added bis(pinacolato)diboron (1.1 equiv), potassium acetate (3.5 equiv) and dppf (0.05 equiv). The reaction mixture was degassed with nitrogen for 20 minutes. PdCl2(dppf) (0.05 equiv) was added to the reaction mixture, which was degassed for a further 5 minutes. The reaction mixture was heated to 70°C for 2 hours under nitrogen then heated to 1200C for 16 hours. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic phases dried (MgSO4), filtered and concentrated in vacuo. The residue was sonicated in EtOAc, the suspension was filtered onto a sintered funnel and the collected grey solid was dried and used without further purification. 6-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-l-one: (82 percent yield, 29 percent purity, main impurity being the boronic acid 43 percent) m/z (LC-MS, ESP): 519.5 [2M+H]+ R/T = 3.38 min
Reference：
[1] Patent: WO2008/23161, 2008, A1, . Location in patent: Page/Page column 117
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 23, p. 9542 - 9555
[3] Patent: WO2017/107089, 2017, A1, . Location in patent: Page/Page column 37; 38
[4] Patent: WO2017/68412, 2017, A1, . Location in patent: Page/Page column 208; 209
[5] Journal of Medicinal Chemistry, 2018, vol. 61, # 11, p. 4978 - 4992
10
[ 675109-26-9 ]
[ 919346-89-7 ]
Reference：
[1] Patent: CN107474006, 2017, A, . Location in patent: Paragraph 0050; 0051; 0055; 0056; 0057; 0061-0063; 0067
11
[ 675109-26-9 ]
[ 74-88-4 ]
[ 1254319-51-1 ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: With sodium iodide In N,N-dimethyl-formamide at 0℃; for 0.5 h; Inert atmosphere Stage #2: at 20℃; for 1 h; Inert atmosphere
General procedure: Bromoisoindolin-1-one (2.0 g, 9.43 mmol) was dissolved with warming in DMF (150 mL),then cooled to 0°C. NaH (415 mg, 10.4 mmol) was added and the mixture stirred under N2 at 0°C for 0.5 h. Methyl iodide (0.65 mL, 10.4 mmol) was added dropwise and the reaction allowed to warm to room temperature and stir for another I h. A small quantity of water was added to quench the reaction then the DMF removed under reduced pressure to give an oily yellow residue which was dissolved in EtOAc (150 mL). This solution waswashed with water (3x100 mL), brine (100 mL) and dried (Na2SO4)., Removal of the solvent under reduced pressure gave a solid which was purified by filtration through a plug of silica gel (10percent acetone/CH2C12 as eluant). The title compound was isolated as a very pale yellow crystalline solid (1.64 g, 80percent). ‘ H NMR [400 MHz, (CD3)2S0] ö 7.85 (dd, J= 1.5, 0.6 Hz, 1 H), 7.66 (dd, J= 8.0, 1.7 Hz, 1 H), 7.59 (d, J— 8.0 Hz, I H), 4.46 (s,2 H), 3.05 (s, 3 H). LRMS (APCI) calcd for C9H8BrNO 226, 228 (MH), found 226, 228.
Reference：
[1] Patent: WO2014/28968, 2014, A1, . Location in patent: Page/Page column 64; 107
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 23, p. 9542 - 9555
[3] E-Journal of Chemistry, 2011, vol. 8, # 3, p. 1108 - 1113
12
[ 675109-26-9 ]
[ 1313399-38-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 23, p. 9542 - 9555
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 85℃; for 2h;
Step 2 Compound 1251 B (1.219g, 5.32 mmol) was dissolved in CCI4 (30 mL). NBS (947 mg, 5.32 mmol) and benzoyl peroxide (66 mg, 0.27 mmol) was added. The solution was stirred at 850C for 2 hours. After cooling down, the solid was filtered and the organic layer was washed with water (10 mL). The organic layer was dried over Na2SO4, concentrated by rotary evaporator, dried under vacuum. The residue was then dissolved in NH3-MeOH (7N, 10 mL) and transferred into a 75 mL pressure bottle. The solution was stirred at 90 0C for over night. The product was purified by C18 chromatography (CH3CN/water: 5% to 90%, with addition of 0.1% HCO2H) to give compound 1251C (800mg, 71%).
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 24.3333h;
6-(4-Hydroxy-but-1-ynyl)-2,3-dihydro-isoindolin-1-oneTo a mixture of 6-Bromo-2, 3-dihydro-isoindolin-1-one (3Og, 0.14mole), bis (triphenylphosphine) palladium dichloride (5 g, 0.007 mole), CuI (2.6 g, 0.01 mole), dry Et3N (700 mL) in dry DMF (700 mL) was added 3-butyn-1-ol (21.3 mL, 0.28 mole) slowly drop- wise. The reaction mixture was bubbled with argon for 20 min and heated at 100 C for 24 h. The solvent was evaporated and the crude residue was washed with DCM (100 mL), filtered and dried to 6-(4-Hydroxy-but-1-ynyl)-2,3-dihydro-isoindolin-1-one as a pale grey solid (24 g, <n="40"/>85%). 1H-NMR (DMSO-d6, 300 MHz): delta 8.6 (1H1 s), 7.5-7.6 (2H, d), 7.5 (1H,s), 4.9 (1H, t), 4.3 (2H1 s), 3.6-3.7 (2H, t), 2.4-2.6 (2H, t); MS: M+1: 202 (201)
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 24.3333h;
6-(5-Hydroxy-pent-1 -ynyl)-2,3-dihydro-isoindolin-1 -oneTo a mixture of 6-Bromo-2, 3-dihydro-isoindolin-1-one (40 g, 0.18 mol), bis(triphenylphosphine) palladium dichloride (6.6 g, 0.009 mol), CuI (3.57 g, 0.01 mol) and Et3N 5 (930 mL) in dry DMF (930 mL) was slowly added 4-pentyn-1-ol (33.2 mL, 0.37 mol). The reaction mixture was bubbled with argon for 20 min and heated at 100 "C for 24 h. The solvent in the reaction mixture was evaporated and the crude residue was washed with DCM(100 mL), filtered and dried to give e-^-Hydroxy-pent-i-ynyl^.S-dihydro-isoindolin-i-one as a black solid (25 g, 61%). 1H-NMR (DMSO-d6, 300 MHz): delta 8.6 (1H, s), 7.5-7.6 (2H, d), 7.5 0 (1H, S), 4.5 (1H, t), 4.3 (2H, s), 3.5 (2H, s), 2.4-2.5 (2H, s), 1.6 (2H, q); MS: AP: M+1: 216(215).
With ammonia; In tetrahydrofuran; methanol; at 20℃; for 0.666667h;
A solution of 5-bromo-2-bromomethyl-benzoic acid methyl ester (1 equiv) in a 1:1 THF/MeOH mixture was treated by gentle bubbling of ammonia gas for 40 minutes at room temperature. The reaction mixture was concentrated in vacuo. The residue was sonicated in CH2Cl2 for 15 minutes then filtered to give the desired product as a white solid.6-Bromo-2,3-dihydro-isoindol-l-one: (98 % yield, 90 % purity) m/z (LC-MS, ESP): 212.3/214.3 [M+H]+ R/T = 2.98 min
87%
With ammonium hydroxide; In methanol; at 80℃; for 10h;
3) The compound obtained in step (2) (150 g, 0.49 mol) was dissolved in 600 ml of methanol.The system then added 25% of ammonia to 4.5 liters of ammonia and the system reacted at 70C for 5 hours.It was cooled and filtered to give 90 g of a pale yellow powder in a yield of 87%.
67%
With ammonia; In methanol; at 40℃;Sealed tube;
To a saturated solution of NH3 in CH3OH (50 mL) was added 5-bromo-2-bromomethyl-benzoic acid methyl ester (4.8 g, 16 mmol). The reaction mixture was stirred in a sealed tube at 40 C. overnight. The mixture was cooled to room temperature and the resultant white solid was collected to afford 6-bromoisoindolin-1-one (2.2 g, 67%). 1H NMR (400 MHz, DMSO) delta 8.71 (s, 1H), 7.75 (d, 2H), 7.53 (s, 1H), 4.32 (s, 2H).
With ammonia; water; In tetrahydrofuran;Heating / reflux;
6-Bromo-2, 3-dihydro-isoindolin-1-oneTo a solution of Methyl 5-bromo-2- (bromomethyl) benzoate (crude 100 g) in THF (1 L) was added slowly an ammonia solution (1 L). A white precipitate was formed. The reaction mixture was heated at refluxed overnight, cooled, filtered, washed with hexane, dried to give 6-Bromo-2, 3-dihydro-isoindolin-1-one as an off white solid (60 g, 65%; 2 steps). 1H-NMR (DMSO-d6, 300 MHz): delta 8.7 (1H, s), 7.7-7.8 (2H, d), 7.5 (1H, d), 4.3 (2H, s); MS: M+1 : 212 (211
With ammonia; In tetrahydrofuran; methanol; diethyl ether; hexane; water;
Methyl 2-bromomethyl-5-bromobenzoate (0.1 mol) was dissolved in THF/methanol (200 ml) (1:1) and the solution obtained was saturated with dry ammonia gas.The solvent was removed and the residue was triturated with water, diethyl ether and hexane and then recrystallized from ethanol/dichloromethane to obtain 6-bromo-2,3-dihydro-isoindol-1-one (12.5 g).1H NMR (400 MHz, d6 DMSO) delta 8.70 (1H, bs), 7.78 (1H,s), 7.77 (1H, d, J=7 Hz), 7.55 (1H, d, J=7 Hz), 4.35 (2H,s).m/z (ES+) 212 (M+).
With ammonia; In tetrahydrofuran; water; at 70℃; for 3h;
Compound WX005-2 (10.00 g, 32.47 mmol, 1.00 mL, 1.00 eq) was dissolved in tetrahydrofuran (80.00 mL), and aqueous ammonia (91.06 g, 2.60 mol, 100.07 mL, 80.01 eq) was added dropwise. The mixture was reacted at 70 C. for 3 hours. After the reaction was complete, a new point was generated. The reaction solution was cooled to 0 C. and filtered. The obtained filter cake was washed with n-hexane (20 mL) and dried. Compound WX005-3 was obtained, 1H NMR (400 MHz, DMSO-d6) delta ppm 8.72 (s., 1H), 7.76-7.79 (m, 2H), 7.55-7.57 (m, 1H), 4.29-4.36 (s, 2H). MS m/z: 212.0 [M+H]+.
Combine 6-bromo-2, 3-dihydro-isoindol-1-one (0.200 g, 0.94 mmol), bis- pinocalatodiboron (0.264 g, 1.04 mmol), palladium (II) acetate (16 mg, 0.07 mmol) and tricyclohexylphosphine (26 mg, 0.09 mmol) in a 50 mL flask. Add acetonitrile (10 mL) and cesium fluoride (0.428 g, 2.82 mmol); fit flask with condenser and heat in a 90 C oil bath for 1 hour. Cool to room temperature and add trifluoro-methanesulfonic acid 6- methoxy-1- [4- (2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-yl ester (0.200 mg, 0.38 mmol), palladium (II) acetate (13 mg, 0.05 mmol) and tricyclohexylphosphine (20 mg, 0.07 mmol), cesium fluoride (0.172 g, 1.13 mmol) and acetonitrile (5 mL). Heat mixture in a 90 C oil bath for 1 hour. Cool reaction to room temperature and filter through celite and wash celite pad with ethyl acetate (60 mL). Concentrate the filtrate and pre-adsorb the crude product onto silica gel. Chromatograph the residue on a Si02 column eluting the material with methanol in dichloromethane (0 to 15%) to give 110 mg of the title compound (57 %).
General procedure: Bromoisoindolin-1-one (2.0 g, 9.43 mmol) was dissolved with warming in DMF (150 mL),then cooled to 0C. NaH (415 mg, 10.4 mmol) was added and the mixture stirred under N2 at 0C for 0.5 h. Methyl iodide (0.65 mL, 10.4 mmol) was added dropwise and the reaction allowed to warm to room temperature and stir for another I h. A small quantity of water was added to quench the reaction then the DMF removed under reduced pressure to give an oily yellow residue which was dissolved in EtOAc (150 mL). This solution waswashed with water (3x100 mL), brine (100 mL) and dried (Na2SO4)., Removal of the solvent under reduced pressure gave a solid which was purified by filtration through a plug of silica gel (10% acetone/CH2C12 as eluant). The title compound was isolated as a very pale yellow crystalline solid (1.64 g, 80%). ? H NMR [400 MHz, (CD3)2S0] oe 7.85 (dd, J= 1.5, 0.6 Hz, 1 H), 7.66 (dd, J= 8.0, 1.7 Hz, 1 H), 7.59 (d, J- 8.0 Hz, I H), 4.46 (s,2 H), 3.05 (s, 3 H). LRMS (APCI) calcd for C9H8BrNO 226, 228 (MH), found 226, 228.
With sodium carbonate;4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 20 - 85℃;Inert atmosphere;
Example 265: (S)-3-Oxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)- pyridin-2-yl)methyl)isoindoline-5-carboxamide To a 25 mL round bottom flask containing (S)-(4-(trifluoromethyl)- phenyl)(3 -(trifiuoromethyl)pyridin-2-yl)methanamine hydrochloride (Intermediate 1) (120 mg, 0.336 mmol) was added toluene (3 mL). The resulting mixture was stirred at rt for 2 min. At this time,sodium carbonate (143 mg, 1.346 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (3.89 mg, 6.73 muiotaetaomicron), palladium (II) acetate (1.5 mg, 6.7 muiotaetaomicron) and 6-bromo-2,3-dihydro-isoindol-l-one (71.3 mg, 0.336 mmol) were added to the flask. The reaction vessel was flushed with argon and then left under 1.0 atm of carbon monoxide gas (from a lecture bottle, in hood). The flask was heated to 85 C overnight, filtered though Celite brnad filter agent, and eluted with EtOAc. Purification by reverse phase HPLC, and concentration of the containing fractions gave (S)-3-oxo-N-((4-(trifiuoromethyl)- phenyl)(3-(trifiuoromethyl)pyridin-2-yl)methyl)isoindoline-5-carboxamide as a yellow foamy solid. 1H NMR (300MHz , CDC13): delta ppm 8.92 (d, J = 4.5 Hz, 1H), 8.40 (d, J = 7.7 Hz, 1 H), 7.60 - 7.56 (m, 5 H), 7.46 - 7.48 (m, 2 H), 6.90 (d, J = 7.6 Hz, 1 H), 4.54 (s, 2 H). MS 480.1 (M+H).
General procedure: Methyl 4-bromo-2-methylbenzoate (19.90 g, 86.9 mmol) was dissolved in benzene (200 mL), to which was added N-bromosuccinimide (18.56 g, 100 mmol) and 2,2?-azobis(2-methylpropionitrile) (1.43 g, 8.69 mmol). This mixture was heated at 80C overnight then upon cooling, filtered and the filtrate diluted with Et20 (300 mL). This solution was washed with sat.sodium metabisuiphite solution (which was also back-extracted with 2x50 mL Et20), then all Et20 fractions combined and washed with brine (150 mL), dried (Na2SO4) and filtered. The solvent was removed under reduced pressure to yield an oil which was purified by filtration through a plug of silica (5% EtOAc/hexanes as eluant), giving an oil which solidified to a white solid under vacuum. ?H NMR shows this material to be 93% thedesired bromide, along with 7% unreacted starting material and a trace of dibromide (total of 26.7 g). This solid was dissolved in MeOH (500 mL) and NH3 (g) bubbled through the solution until saturated. This mixture was stirred overnight at room temperature then all solvent removed under reduced pressure. The resulting solid was suspended and stirred in Et20 (200 mL), then collected by filtration. This procedure was repeated, but using waterand the solid again collected by filtration and dried under vacuum. The title compound was isolated as a crystalline cream solid (13.30 g, 72%). ?H NMR [400 MHz, (CD3)2S01 6 8.59 (br s, 1 H), 7.83 (dd, J = 1.5, 0.6 Hz, 1 H), 7.66 (dd, J = 8.0, 1.7 Hz, 1 H), 7.59 (d, J 8.1 Hz, I H), 4.37 (s, 2 H). LRMS (APCI) calcd for C8H6BrNO 212, 214 (MH), found 212,214.
34
[ 675109-26-9 ]
[ 74-89-5 ]
6-(methylamino)isoindolin-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
300 mg
With copper; In water; at 105℃;Sealed tube;
O2O3] &bromoisoindolin4-orse (1050 mg, SM m.mol% copper powder (32 mg, 0.5 mmol) and methylamine (40% in F120, 2.7 mL) were placed in a pressure vess& and the sealed reaction was heated at 105 C overnight. The reaction mixture was poured into ethyl acetate (150 niL) and washed with saturated NH4CI solution. The organic layer was dried over sodium sulfate, filtered and concenflted. The volatile was removed in vacua and the residue was then purified by silica gel chromatography eluting with MeOH and dichloromethane Rf 0.2, 5% MeOH in DCIVO to afford 300mg of the title compound. MS (m/z): 163.13 [M+H]t HPLC retention time 0.17 mm (248% acetonitrile: water with 0.05% trifluoroacetie acid). ?H NMR (400 MHz, dmso) 8 8.28 (s 1K), 7.20 (d, J= 8.2 Hz, 1H), 6.75 (dd, J 8.2, 2.2 Hz5 lH), 6.68 (d, J= 2.1 Hz, 1K), 5.83 (d, J 5.0 Hz, IH), 4.15 (s, 2K), 2.66 (d, J= 5,1 Hz, 3Ff).
(6-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-4′-methyl-5-sulfamoyl-[1,1′-biphenyl]-3-yl)boronic acid[ No CAS ]
C30H26N6O4S[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium phosphate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In ethanol; at 110℃; for 1.5h;Inert atmosphere; Microwave irradiation;
(6-( 1 - (and 2-)(4-methoxybenzyl)-2H-tetrazol-5 -yl)-4'-methyl-5-sulfamoyl- [ 1 , 1 '- biphenyl]-3-yl)boronic acid (40 mg, 0.083 mmol) and 6-bromoisoindolin-l-one (19.47 mg, 0.092 mmol) was suspended in ethanol (835 mu) and potassium phosphate tribasic (250 mu, 0.250 mmol). The reaction mixture was sparged with 2 for 5 min. 1 , l'-bis(di-tert- butylphosphino)ferrocene palladium dichloride (5.44 mg, 8.35 muiotaetaomicron) was added and the reaction mixture micro waved at 1 10C for 90 min. The crude reaction mixture was diluted with EtOAc and water. The aqueous phase was extract with EtOAc (x2), then the combined extracts were washed with brine, dried over Na2S04, filtered, and concentrated. The reaction mixture was purified by reverse phase HPLC on a Cis column and then eluted with 10% to 100% MeCN in water. The major UV active material was lyopholized to provide a white solid that was utilized directly in the deprotection. LC-MS: calculated for C3oH26N604S 566.2; observed m/e: 467.5 (M+H)+. The resulting solid was dissolved in TFA and heated to 45C overnight, then concentrated. The residue was purified by reverse phase HPLC on a Cis column eluted with 0% to 80% MeCN in water. The major UV active material was lyopholized to provide 4'-methyl-5- (l-oxoisoindolin-5-yl)-2-(2H-tetrazol-5-yl)-[l, l'-biphenyl]-3-sulfonamide. LC-MS: calculated for C22H18N603S 446.1 ; observed m/e: 447.4 (M+H)+; 1H NMR delta (ppm) (DMSO): 8.72 (s, 1H), 8.44 (s, 1H), 8.16 (s, 1H), 8.12 (d, 1H), 8.05 (s, 1H), 7.77 (d, 1H), 7.60 (s, 2H), 7.11-7.05 (m, 4H), 4.48 (s, 2H), 2.27 (s, 3H).
tert-butyl 6-bromo-1-oxo-2,3-dihydro-1H-isoindole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With dmap; triethylamine; In dichloromethane; at 20℃; for 18h;
Preparation 20: tert-butyl 6-bromo-1-oxo-2,3-dihydro-1 H-isoindole-2-carboxylate (1486) Di-terf-butyl dicarbonate (2.47 g, 1 1.3 mmol) was added to a suspension of 6-bromo-2,3- dihydro-1 H-isoindol-1-one (2.00 g, 9.43 mmol), DMAP (0.058 g, 0.47 mmol) and triethylamine (1.58 mL, 11.3 mmol) in DCM (50 mL) and the mixture was stirred at room temperature for 18 h. The resulting solution was diluted with water (50 mL). The phases were separated and the aqueous phase was extracted with DCM (2x50 mL). The combined organic phases were washed with brine (100 mL), dried (MgS04) and absorbed on silica. Purification by (1487) chromatography (S1O2, 50-100% ethyl acetate in iso-hexane) gave the title compound (2.44 g, 81 %) as a colourless solid. LC-MS: [M+Na]+ = 334
With dmap; In tetrahydrofuran; at 20℃; for 12h;
To a mixture of 6-bromo-2,3-dihydro-isoindol-1-one (10.0 g), DMAP (11.5 g) and THE (100 mL), (Boc)20 (15.4 g) was added and the mixture was stirred at room temperature for 12 hours. The resulting yellow mixture was partitioned between water and ethyl acetate, and the phases were separated. The organic phase was washed with brine anddried over Na2504. After filtration and evaporation of the solvent, the resulting residue was purified by column chromatography (silica gel, PE/EA = 15:1)to provide the subtitle compound. MS ESl: mlz = 256 [Mi-H-tBu].
6-bromo-2-[2-(morpholin-4-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With hydrogen; sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 18h;
Preparation 48: 6-bromo-2-[2-(morpholin-4-yl)ethyl]-2,3-dihydro-1 H-isoindol-1 -one (1544) (1545) Sodium hydride (60% dispersion in mineral oil, 34 mg, 1.40 mmol) was added to a suspension of 6-bromo-2,3-dihydro-1 H-isoindol-1 -one (250 mg, 1.18 mmol) in DMF (5 mL) and the mixture was stirred for 5 min after hydrogen gas evolution ceased. 4-(2-bromoethyl)morpholine (0.18 mL, 1.3 mmol) was added to the resulting brown solution and the mixture was stirred at RT for 18 h. The mixture was diluted with ethyl acetate and transferred into a separating funnel. Water was added and the crude product was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgS04) and concentrated under vacuum. The residue was triturated with a mixture of diethyl ether and iso-hexane and the resulting precipitate was filtered, washed with iso-hexane and dried under suction to afford the title compond (196 mg, 50%) as a pale yellow solid. LC-MS: [M+H]+ = 325/327.
6-bromo-2-(cyclopropylmethyl)-2,3-dihydro-1H-isoindol-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydride; In N,N-dimethyl-formamide; for 1h;Cooling with ice; Inert atmosphere;
Preparation 117: 6-bromo-2-(cyclopropylmethyl)-2,3-dihydro-1 H-isoindol-1 -one (1710) (1711) A stirred solution of 6-bromo-2,3-dihydro-1 H-isoindol-1 -one (350 mg, 1.65 mmol) and cyclopropylmethyl bromide (0.198 muIota_, 1.98 mmol) in DMF (6 mL) was cooled in an ice bath under nitrogen. Then NaH (99 mg, 2.48 mmol) was added in portions. The reaction was stirred for 1 hour and then quenched with NH4CI (sat., aq.). The mixture was extracted with IPA:CHCI3 (1 :3, x3). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under vacuum to yield the title compound as a brown oil (~30 % pure) which was used crude. MS: [M+H]+ = 266/268.
methyl 3-(6-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 18-crown-6 ether; caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 18h;Inert atmosphere;
Preparation 124: Methyl 3-(6-bromo-1 -oxo-2,3-dihydro-1 H-isoindol-2-yl)propanoate (1728) To a stirred solution of 6-bromo-2,3-dihydro-1 H-isoindol-1-one (550 mg, 2.59 mmol), 18-crown-6 (69 mg, 0.26 mmol) and methyl 3-bromopropionate (350 pL, 3.1 1 mmol) in DMF (9 ml.) was added CS2CO3 (2.113 g, 6.48 mmol) under nitrogen. The reaction was heated to 70 C (1729) (thermally) slowly and maintained at this temperature for 18 hours. After cooling and the reaction was quenched with NH4CI (sat., aq.). The mixture was extracted with EtOAc (x3) and the combined organic layers were washed with brine, dried over MgSO, filtered and (1730) concentrated under vacuum to yield methyl 3-(6-bromo-1-oxo-2,3-dihydro-1 H-isoindol-2- yl)propanoate as a yellow oil. LC-MS was consistent with a complex mixture which was taken on as is. To the residue was added bis(pinacolato)diboron (0.746 g, 2.91 mmol), AcOK (0.491 mg, 5.00 mmol) and anhydrous 1 ,4-dioxane (8 ml_). The reaction was degassed with nitrogen for 5 minutes. 1 ,1 '-Bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (61 mg, 0.08 mmol) was then added and the reaction heated at 90C under nitrogen for 16 hours. The reaction was allowed to cool to room temperature and was then diluted with water. The mixture was extracted with EtOAc (x3) and the combined organic layers were washed with brine, dried over MgSO, filtered and concentrated under vacuum to yield the title compound (1.5 g, 168 %) which was used without further purification. MS: [M+H]+ = 346.
6-bromo-2-[2-oxo-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1H-isoindol-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 1h;Cooling with ice; Inert atmosphere;
A stirred solution of 6-bromo-2,3-dihydro-1 H-isoindol-1 -one (3.4 g, 14.16 mmol) and 2-chloro-1- (1 ,2,3,4-tetrahydroisoquinolin-2-yl)ethan-1-one (3.6 g, 17.00 mmol) in DMF (47 mL) was cooled in an ice bath under nitrogen before adding NaH (0.70 g, 17.00 mmol) in portions. The reaction was allowed to warm to room temperature over an hour and was then quenched with NH4CI (sat., aq.). The pH was adjusted to pH 7 with citric acid (5%, aq.) and the product was extracted with IPAiCHCh (1 :3, x3). The combined organic layers were washed brine, dried over MgS04, filtered and concentrated under vacuum to yield 6-bromo-2-[2-oxo-2-(1 ,2,3,4- tetrahydroisoquinolin-2-yl)ethyl]-2,3-dihydro-1 H-isoindol-1 -one as a brown solid which was used crude. MS: [M+H]+ = 385.
2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(6-ethylpyridin-2-yl)-2-hydroxyethyl]acetamide trifluoroacetate salt[ No CAS ]
tert-butyl (3R)-3-{(1R)-1-[2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetamido]ethyl}piperidine-1-carboxylate[ No CAS ]
tert-butyl (3S)-3-{(1R)-1-[2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)acetamido]ethyl}piperidine-1-carboxylate[ No CAS ]
2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-[6-(dimethylamino)pyridin-2-yl]-2-hydroxyethyl]acetamide[ No CAS ]
2-[2-(7-chloro-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)-2-oxoethyl]-6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2,3-dihydro-1H-isoindol-1-one[ No CAS ]
2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]acetamide[ No CAS ]
6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-[2-(1-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl)-2-oxoethyl]-2,3-dihydro-1H-isoindol-1-one[ No CAS ]
6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-{2-[(1 R)-5-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl]-2-oxoethyl}-2,3-dihydro-1H-isoindol-1-one[ No CAS ]
6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-{2-[(1S)-5-(hydroxymethyl)-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl]-2-oxoethyl}-2,3-dihydro-1H-isoindol-1-one[ No CAS ]
6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-2-{2-[7-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl]-2-oxoethyl}-2,3-dihydro-1H-isoindol-1-one[ No CAS ]
2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S,2S)-2-hydroxy-1-(3-methoxyphenyl)propyl]acetamide[ No CAS ]
2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-{4-[(dimethylamino)methyl]phenyl}-2-hydroxyethyl]acetamide hydrochloride[ No CAS ]
6-(5-chloro-2-[(2,4-dimethoxyphenyl)methyl](oxan-4-yl)amino}pyrimidin-4-yl)-2-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-2,3-dihydro-1H-isoindol-1-one[ No CAS ]
6-(5-chloro-2-[(2,4-dimethoxyphenyl)methyl](oxan-4-yl)amino}pyrimidin-4-yl)-2-[(3-methyl-1,2-oxazol-5-yl)methyl]-2,3-dihydro-1H-isoindol-1-one[ No CAS ]
2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S,2S)-2-hydroxy-1-(3-methylphenyl)propyl]acetamide[ No CAS ]
2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2, 3-dihydro-1H-isoindol-2-yl)-N-[2-(hydroxymethyl)-2,3-dihydro-1H-inden-1-yl]acetamide[ No CAS ]
2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S,2S)-2-hydroxy-1-[3-(trifluoromethyl)phenyl]propyl]acetamide[ No CAS ]
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