| 64.1% |
Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole In tetrahydrofuran at 80℃; for 24h;
Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water monomer for 4h; Reflux; Cooling with ice; |
I.1.1.5 Preparation of the intermediate 7
5-bromoisoindole-1,3-dione (10 g, 44.2 mmol) was added to THF (50 mL). The temperature was raised to 80 ° C, stirred for 24 h, ice water bath, methanol (30 mL) was added dropwise, 3N hydrochloric acid (30 mL), refluxed for 4 h, concentrated, diluted with water (100 mL), then washed with diethyl ether (50 mL × 2), water phase The mixture was adjusted to pH = 10 with saturated aqueous sodium carbonate, and extracted with EA (50mL×2), dried and concentrated to give 5.7 g (64.1%) of yellow oil. |
| 52% |
With dimethylsulfide borane complex In tetrahydrofuran at 20℃; Reflux; |
1 Step 1:
5-bromoisoindoline
To a solution of 4-bromophthalimide (22.6 g, 100 mmol) in dried tetrahydrofuran (250 mL) was added dropwise borane-dimethyl sulfide complex (51 mL, 500 mmol), stirred at room temperature for 2 hours, and then refluxed overnight. After cooling, methanol was carefully added dropwise to quench the excess borane. The resulting mixture was evaporated and concentrated, and then the residue was purified by silica gel column chromatography to give 5-bromoisoindoline (10.36 g). Yield: 52%. MS m/z[ESI]: 198.0[M+1]. |
| 41.3% |
Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With borane-THF In tetrahydrofuran at -5 - 80℃; for 19h;
Stage #2: With hydrogenchloride In methanol; water monomer at 0 - 80℃; for 3h; |
Preparation of 5-bromo-2,3-dihydro-1H-isoindole (13); 564.2 ml of a 1M borane/THF solution are added dropwise to 42.5 g (188 mmol) of 5-bromoisoindole-1,3-dione in 300 ml of THF (dry) at -5° C. over a period of 60 min. The mixture is subsequently stirred for 2 h at 22° C. and then for 16 h at 80° C. The mixture is then cooled to 0° C., before 200 ml of methanol (exothermic.) and 200 ml of 2M hydrochloric acid are slowly added. The resultant mixture is stirred for 3 h at 80° C., cooled to 22° C., and 100 ml of water are added. The aqueous solution is extracted three times with 150 ml of dichloromethane each time, dried over sodium sulfate, filtered and evaporated to dryness: 5-bromo-2,3-dihydro-1H-isoindole; yield 15.4 g of “13” (41.3%); MW 198.06; Rt 1.099 min (“polar” method). |
| 41% |
With borane-THF Reflux; |
|
| 22.16% |
With dimethylsulfide borane complex In tetrahydrofuran at 0 - 70℃; for 16h; Inert atmosphere; |
1.1 Step 1: Synthesis of Compound WX042-2
Under a nitrogen atmosphere, at 0° C., to a solution of WX042-1 (5.00 g, 22.12 mmol) in tetrahydrofuran (50.00 mL) was added borane dimethyl sulfide (10 M, 11.06 mL) dropwise, and the system was stirred at 70° C. for 16 hours. After the reaction was complete, at 0° C. to the system was added 100 mL methanol to quench the reaction system. After concentration under reduced pressure, the residue was purified by column chromatography (dichloromethane:methanol=20:1) to afford Compound WX042-2 (1.00 g, 22.16% yield, 97.1% purity), white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.43 (s, 1H), 7.40-7.34 (m, 2H), 7.11 (d, J=8.5 Hz, 1H), 4.48 (d, J=16.6 Hz, 4H). |
| 18.2% |
With dimethylsulfide borane complex In tetrahydrofuran at 80℃; for 17h; |
26 5-Bromoisoindo line
To a solution of 5-bromoisoindoline-1,3-dione (25.0 g, 0.11 mmol) in THF(1000 mL) were added BH3Me2S (100 mL). The resulting mixture was heated at 80 °C for 17h. After LCMS showed the reaction was completed, the reaction mixture was quenched withMeOH and concentrated. The residue was purified by column chromatograph on silica gel(eluted with PE: EA=20:1) to give the title compound (3.98 g, 18.2%). ‘HNMR(400MHz, MeOD) 5 7.62 (1 H, s) 7.55 (1 H, d, J=8.0 Hz) 7.35 (1 H, d, J=8.0 Hz) 4.62 (2 H, s)4.58 (2 H, s). |
|
With sodium tetrahydridoborate; boron trifluoride diethyl ether complex for 3h; Heating; |
|
|
Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With boron trifluoride diethyl ether complex In tetrahydrofuran at 25℃; for 0.5h;
Stage #2: With borane-THF In tetrahydrofuran at 40℃; for 24h;
Stage #3: With hydrogenchloride; methanol more than 3 stages; |
To a solution of 5-bromophthalimide (44.2 mmol; 1.0 equiv) in THF (221 mL) under N2 atmosphere is added BF3-OEt2 (265.5 mmol; 6.0 equiv) and the reaction is stirred for 30 minutes at 25 C. BH3-THF (353.6 mmol; 8.0 equiv) is added to the reaction mixture which is then heated to 40 C for 24 h. The reaction is cooled to room temperature and quenched with 60 mL MeOH until gas evolution ceases; 400 mL HCl is added and the reaction is refluxed for 3 h. The reaction is then cooled to room temperature and the water layer is washed with ethyl acetate. The water layer is then brought to pH 14 with 6 N NaOH and extracted with ethyl acetate. The combined organic extracts are dried (MgSO4), filtered, and concentrated to crude product 5-bromo-2,3-dihydro-lH-isoindole, which is carried onto the next step without further manipulation. |
|
Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With dimethylsulfide borane complex In tetrahydrofuran at 0℃; Heating / reflux;
Stage #2: With hydrogenchloride; water monomer In tetrahydrofuran; methanol for 3h; Heating / reflux;
Stage #3: With sodium hydroxide In water monomer |
1.1
Step 1: tert-butyl 5-bromo-1,3-dihydro-2H-isoindole-2-carboxylate To a solution of 5-bromo-1H-isoindole-1,3(2H)-dione (4 mmol) in THF (10 mL) was added borane-dimethyl sulfide complex (2M in THF, 14 mL) at 0° C. The reaction mixture was allowed to stir at reflux overnight and was then cooled to 0° C. The reaction mixture was quenched by the slow addition of MeOH (10 mL) and then 2N HCl (10 mL). The reaction mixture was allowed to stir at reflux for 3 hr and then concentrated. Water (10 mL) was added to the residue. Remaining starting material was removed by extraction with DCM. To the aqueous solution was added 4N NaOH until pH>9. The solution was extracted with DCM. The organic solutions from this basic extraction were combined, dried over Na2SO4, filtered and concentrated to give 5-bromoisoindoline, which was dissolved in THF (20 mL). To this solution was added potassium carbonate (8 mmol) in water (1 mL), and BOC2O. The reaction mixture was allowed to stir at rt over the weekend. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl 5-bromo-1,3-dihydro-2H-isoindole-2-carboxylate (2.5 mmol, 60%). |
|
Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With borane-THF In tetrahydrofuran at 0℃; Heating / reflux;
Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water monomer at 0℃; for 3h; Heating / reflux; |
C.C20
A mixture of 4-bromophthalic anhydride (25 g) in formamide (75 ml) was heated at 2000C for 16 hours then allowed to cool to room temperature. The reaction mixture was diluted with water (200 ml), filtered, the filter cake was washed with water then diethyl ether and sucked dry to give 20.85 g of light mustard solid.280 ml of 1 M Borane-THF complex was added dropwise to a stirred solution of 4-bromophthalimide (20.85 g; 92.2 mmol) in anhydrous THF (200 ml) at O0C then heated at reflux overnight. The reaction was cooled to 00C then treated cautiously with methanol (100 ml) followed by 2M HCI (100 ml) then heated at reflux for 3 hours. The reaction mixture was cooled and the organics evaporated. The aqueous was diluted with water (100 ml) the extracted with DCM (x3). The aqueous was basified with 2M NaOH then extracted with DCM (x3). The combined DCM extracts were dried (MgSO4), filtered and evaporated to give 6.99 g of 5-bromo-2,3-dihydro-1 H-isoindole as a dark brown gummy solid. 1H NMR (DMSO-d6) 7.45 (1H, s), 7.36 (1 H, d), 7.20 (1H, d), 4.05 (4H, s). |
|
Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With borane-THF In tetrahydrofuran at 0℃; Heating / reflux;
Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water monomer at 0℃; for 3h; Heating / reflux; |
C20
280 ml of 1M Borane-THF complex was added dropwise to a stirred solution of 4-bromophthalimide (20.85 g; 92.2 mmol) in anhydrous THF (200 ml) at O0C then heated at reflux overnight. The reaction was cooled to 00C then treated cautiously with methanol (100 ml) followed by 2M HCI (100 ml) then heated at reflux for 3 hours. The reaction mixture was cooled and the organics evaporated. The aqueous was diluted with water (100 ml) the extracted with DCM (x3). The aqueous was basified with 2M NaOH then extracted with DCM (x3). The combined DCM extracts were dried (MgSO4), filtered and evaporated to give 6.99 g of 5-bromo-2,3-dihydro-1 H-isoindole as a dark brown gummy solid. 1H NMR (DMSO-d6) 7.45 (1 H, s), 7.36 (1H, d), 7.20 (1H, d), 4.05 (4H, s). |
|
With borane-THF In tetrahydrofuran at 0℃; Heating / reflux; |
C.20
280 ml of 1 M Borane-THF complex was added dropwise to a stirred solution of 4-bromophthalimide (20.85 g; 92.2 mmol) in anhydrous THF (200 ml) at O0C then heated at reflux overnight. The reaction was cooled to 00C then treated cautiously with methanol (100 ml) followed by 2M HCI (100 ml) then heated at reflux for 3 hours. The reaction mixture was cooled and the organics evaporated. The aqueous was diluted with water (100 ml) the extracted with DCM (x3). The aqueous was basified with 2M NaOH then extracted with DCM (x3). The combined DCM extracts were dried (MgSO4), filtered and evaporated to give 6.99 g of 5-bromo-2,3-dihydro-1 H-isoindole as a dark brown gummy solid. 1H NMR (DMSO-d6) 7.45 (1 H, s), 7.36 (1H, d), 7.20 (1 H, d), 4.05 (4H, s). |
|
Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With borane-THF In tetrahydrofuran at 0℃; Heating / reflux;
Stage #2: With methanol In tetrahydrofuran |
C20
A mixture of 4-bromophthalic anhydride (25 g) in formamide (75 ml) was heated at 2000C for 16 hours then allowed to cool to room temperature. The reaction mixture was diluted with water (200 ml), filtered, the filter cake was washed with water then diethyl ether and sucked dry to give 20.85 g of light mustard solid.280 ml of 1 M Borane-THF complex was added dropwise to a stirred solution of 4-bromophthalimide (20.85 g; 92.2 mmol) in anhydrous THF (200 ml) at O0C then heated at reflux overnight. The reaction was cooled to O0C then treated cautiously with methanol (100 ml) followed by 2M HCI (100 ml) then heated at reflux for 3 hours. The reaction mixture was cooled and the organics evaporated. The aqueous was diluted with water (100 ml) the extracted with DCM (x3). The aqueous was basified with 2M NaOH then extracted with DCM (x3). The combined DCM extracts were dried (MgSO4), filtered and evaporated to give 6.99 g of 5-bromo-2,3-dihydro-1H-isoindole as a dark brown gummy solid. 1H NMR (DMSO-d6) 7.45 (1H, s), 7.36 (1 H1 d), 7.20 (1H, d), 4.05 (4H, s). |
|
With borane In tetrahydrofuran |
|
|
With borane-THF In tetrahydrofuran at 0℃; Reflux; |
C.20
280 ml of 1M Borane-THF complex was added dropwise to a stirred solution of 4-bromophthalimide (20.85 g; 92.2 mmol) in anhydrous THF (200 ml) at 0° C. then heated at reflux overnight. The reaction was cooled to 0° C. then treated cautiously with methanol (100 ml) followed by 2M HCl (100 ml) then heated at reflux for 3 hours. The reaction mixture was cooled and the organics evaporated. The aqueous was diluted with water (100 ml) the extracted with DCM (×3). The aqueous was basified with 2M NaOH then extracted with DCM (×3). The combined DCM extracts were dried (MgSO4), filtered and evaporated to give 6.99 g of 5-bromo-2,3-dihydro-1H-isoindole as a dark brown gummy solid. 1H NMR (DMSO-d6) 7.45 (1H, s), 7.36 (1H, d), 7.20 (1H, d), 4.05 (4H, s). |
|
Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With boron trifluoride diethyl ether complex
Stage #2: With borane-THF at 40℃; |
|
|
Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With borane-THF In tetrahydrofuran Reflux;
Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water monomer for 2h; Reflux; |
11.2 Step 2) 5-bromoisoindoline
To a suspension of 5-bromoisoindoline-l,3-dione (2.73 g, 12.1 mmol) in THF (20 mL) was added Borane-THF complex (1 M, 48 mL). The reaction was heated at reflux overnight, then cooled to 0 °C, and treated with MeOH (30 mL), followed by 2 M HCI (30 mL). The mixture was heated at reflux for 2 h, then cooled to rt and concentrated in vacuo. The residue was partitioned between DCM (50 mL) and H20 (50 mL). The separated aqueous phase was washed with DCM (50 mL x 2), then adjusted to pH 11 with 1 M NaOH (6 mL), and extracted with DCM (80 mL x 4). The combined organic phases were dried over anhydrous a2S04, filtered and concentrated in vacuo to give the crude product as dark brown oil (1.3 g, 54%), which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 198.0 [M + H]+. |
| 22 g |
Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With boron trifluoride In tetrahydrofuran at 0℃; for 1.5h; Inert atmosphere;
Stage #2: With BH3 In tetrahydrofuran at 0 - 80℃; for 20h; Inert atmosphere; |
|
|
Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With borane-THF In tetrahydrofuran Reflux;
Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water monomer at 0℃; for 2h; Reflux; |
11.2 Step 2) Preparation of 5-bromoisoindoline
5-bromoisoindoline-1,3-dione (2.73 g, 12.1 mmol)Was suspended in tetrahydrofuran (20 mL)To this was added borane-tetrahydrofuran (1 M, 48 mL).The reaction was refluxed overnight and cooled to 0 ° C,Followed by methanol (30 mL),2M hydrochloric acid (30 mL).The mixture was refluxed for 2 hours,Cooled to room temperature and concentrated under reduced pressure.The residue was partitioned between dichloromethane(50 mL) and water (50 mL). The separated aqueous phase was washed with dichloromethane (50 mL x 2) and adjusted to pH with 1 M sodium hydroxide solutionTo 11 and extraction with dichloromethane (80 mL x 4). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure,The crude product was obtained as a dark brown oil (1.3 g, 54%),The product was purified and used directly in the next step. |
|
Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With boron trifluoride In tetrahydrofuran at 0℃; for 1.5h; Inert atmosphere;
Stage #2: With BH3 In tetrahydrofuran at 0 - 80℃; for 20h; Inert atmosphere; |
5-Bromoisoindoline (4).
To a solution of 5-bromoisoindoline- 1, 3-dione (3) (25 g, 110.6 mmol, 1.0 equiv) in THF (60 mL) was added BF3 (30 g, 442.4 mmol, 4.0 equiv) dropwise at 0 °C. The mixture was stirred at 0 °C for 1.5 h and BH3 (650 ml, 1.0 M, 6.0 equiv) was added dropwise at 0 °C. Then the mixture was heated to 80°C for 20 h and quenched by addition of methanol (100 mL) dropwise for 1 h at 0°C. The mixture was concentrated to give a crude product of 5-bromoisoindoline (4) (22 g), which was used for next step directly. |
|
Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With boron trifluoride In tetrahydrofuran Reflux;
Stage #2: With borane-THF In tetrahydrofuran for 16h; Reflux;
Stage #3: With hydrogenchloride; water monomer In tetrahydrofuran at 0 - 20℃; |
1.30.A
Step A: Preparation of 5-BromoisoindoIine.To a solution of 5-bromoisoindoline-l,3-dione (8.117 g, 35.9 mmol) in THF (10 mL) was added boron trifluoride (8.40 mL, 108 mmol) dropwise. The reaction mixture was heated to reflux. After refluxing temperature was reached, borane tetrahydrofuran complex (144 mL, 144 mmol) was added dropwise and the reaction was stirred at reflux for 16 h. The mixture was cooled to 0 0C, cautiously treated with 3 N HCl (10 mL), and stirred at room temperature for 1 h. The aqueous mixture was washed with EtOAc, and the organic phase was discarded. The aqueous layer was basifed (pH 9-10) and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (4.02 g). LCMS m/z = 198.0 [M+H]+. |
|
Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With borane-THF In tetrahydrofuran for 24h; Inert atmosphere; Reflux;
Stage #2: With hydrogenchloride In methanol; water monomer at 0℃; for 1.66667h; Inert atmosphere; Reflux; |
|
|
With BH3 In tetrahydrofuran for 24h; Reflux; |
|
|
With sodium tetrahydridoborate; borane-THF In tetrahydrofuran at -10℃; for 24h; Reflux; |
4.1.35. 5-Bromo-isoindoline (47)
Sodium borohydride (3.48 g, 92.0 mmol) was added to the solutionof 5-bromopthalamide (2.0 g, 8.8 mmol) in THF, and theresultant suspensionwas cooled to 10 C. Then, BF3.Et2O (12.7 mL,102.6 mmol) was added slowly and the reaction mixture wasrefluxed. After 24 h, the reaction mixture was allowed to cool to0 C and cold H2O (18 mL) was added. EtOAc (100 ml) was addedand the reaction mixture was made alkaline using 6.0 M aqueousNaOH. The organic layer was separated and concentrated using arotary evaporator. The residue was diluted with Et2O (50 mL) andacidified to pH 2. The aqueous layerwas separated, made alkaline topH 10 using 6.0 M aqueous NaOH and extracted with EtOAc(70 mL). The organic layer was separated, washed with brine(3 70 mL), dried (Na2SO4) and concentrated using rotary evaporatorto yied the 5-bromo-isoindoline (47). The residue was used infurther reactions without purification. |
|
With dimethylsulfide borane complex In tetrahydrofuran at 80℃; for 12h; |
13.1
Step 1: BH3•SMe2 (10 M, 38.49 mL, 3 eq) was added to a solution of compound 13_1 (29 g, 128.30 mmol, 1 eq) in THF (300 mL). The mixture was reacted at 80 °C for 12 hours, then cooled to 0°C and quenched by adding methanol (100 mL). Then, dilute hydrochloric acid (90 mL, 1 M) was added to the mixture, and the mixture was stirred at 80 °C for 1 hour, concentrated under reduced pressure to remove the solvent. The residue was diluted with water (100 mL), extracted with ethyl acetate (150 mL 2). The pH value of the aqueous phase was adjusted to 10-11 by sodium hydroxide aqueous solution (1 M), the obtained aqueous phase was then extracted with ethyl acetate (150 mL 2). The organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 13_2. |
|
Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With dimethylsulfide borane complex In tetrahydrofuran at 80℃; for 12h;
Stage #2: With hydrogenchloride In methanol; water monomer at 80℃; for 1h; |
1.1 Step 1:
to a solution of compound 1_1 (29 g, 128.30 mmol, 1 eq) in THF (300 mL) was added BH3•SMe2 (10 M, 38.49 mL, 3 eq). The mixture was reacted at 80°C for 12 h, then cooled to 0°C, and quenched with methanol (100 mL); diluted hydrochloric acid (90 mL, 1 M) was then added by stirring at 80°C for 1 h, and the mixture was concentrated under reduced pressure to remove the solvent; the residue was diluted with water (100 mL) and extracted with ethyl acetate (150 mL 2); the aqueous layer was then adjusted to pH = 10-11 with aqueous sodium hydroxide (1 M) and the resulting aqueous phase was extracted with ethyl acetate (150 mL 2); the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain Compound 1_2. |
|
Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With borane-THF at 70℃;
Stage #2: With hydrogenchloride In water monomer at 70℃; for 4h; |
8.1.2 8.1.2 Synthesis of 5-bromoisoindoline (40b)
5-bromoisoindole-1,3-dione (4 g, 17.7 mmol) was added to 120 ml of BH3/THF, overnight at 70°C, and the reaction was stopped by adding 10 ml of MeOH dropwise. The mixed solution was concentrated under vacuum, and the blend was added. 40 ml of hydrochloride was added, and the mixture was stirred at 70°C for 4 hours. Then 1M NaOH aq was added to adjust the pH to 14. After static separation of layers, the aqueous layer was extracted with DCM 100 ml×3. Then the organic layer was mixed and washed with brine 50ml×2, water 50ml, and the organic solvent was concentrated under vacuum to obtain 2.0 g of crude product. LC-MS: RT = 0.95 min; ESI m/z [M+H]+=198 FA mobile system. |
|
Stage #1: 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole With borane-THF at 70℃;
Stage #2: With hydrogenchloride In water monomer at 70℃; for 4h; |
8.1.2 8.1.2 Synthesis of 5-bromoisoindoline (40b)
5-bromoisoindole-1,3-dione (4 g, 17.7 mmol) was added to 120 ml of BH3/THF, overnight at 70°C, and the reaction was stopped by adding 10 ml of MeOH dropwise. The mixed solution was concentrated under vacuum, and the blend was added. 40 ml of hydrochloride was added, and the mixture was stirred at 70°C for 4 hours. Then 1M NaOH aq was added to adjust the pH to 14. After static separation of layers, the aqueous layer was extracted with DCM 100 ml×3. Then the organic layer was mixed and washed with brine 50ml×2, water 50ml, and the organic solvent was concentrated under vacuum to obtain 2.0 g of crude product. LC-MS: RT = 0.95 min; ESI m/z [M+H]+=198 FA mobile system. |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
