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CAS No. : | 1082674-24-5 | MDL No. : | MFCD18633063 |
Formula : | C10H5BrN2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NOTGHQFEQASFGA-UHFFFAOYSA-N |
M.W : | 233.06 | Pubchem ID : | 77174826 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.4% | With tris-(dibenzylideneacetone)dipalladium(0) In dimethyl sulfoxide; ethyl acetate; Petroleum ether | Step 3. Synthesis of 6-amino isoquinoline (#E3). A solution of #A2 (4.0 g, 51.7 mmol), 6-bromoisoquinoline-1-carbonitrile #A3 (6.0 g, 25.9 mmol), BINAP (3.2 g, 5.2 mmol), Pd2(dba)3 (2.3 g, 2.6 mmol) and potassium phosphate (11.0 g, 51.7 mmol) in anhydrous DMSO (35 mL) was heated at 80° C. for 2 h. The complete disappearance of the 6-bromoisoquinoline-1-carbonitrile #A3 was observed on TLC. The reaction mixture was cooled to room temperature, filtered through Celite™ pad and the filtrate was diluted with water (100 mL). The mixture was extracted with EtOAc (100 mL*3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude material which was purified by silica gel (100-200 mesh) column chromatography using 40percent EtOAc in petroleum ether as an eluting system to give #E3 as yellow solid (1.5 g, 25.4percent). Rf: 0.4 (60percent EtOAc in petroleum ether). LCMS m/z=227.9 (M+H); 1H NMR (400 MHz, d6-DMSO): δ 1.18 (d, J=6.8 Hz, 3H), 3.36-3.47 (m, 1H), 3.48-3.53 (m, 1H), 3.60-3.66 (m, 1H), 6.80-6.82 (m, 2H), 7.32 (dd, J=2.4 Hz, 8.8 Hz, 1H), 7.72 (d, J=5.6 Hz, 1H), 7.87 (d, J=9.6 Hz, 1H), 8.30 (d, J=5.6 Hz, 1H). |
24.3% | With tris-(dibenzylideneacetone)dipalladium(0) In dimethyl sulfoxide | Step 3. Synthesis of 6-amino isoquinoline (#F3). A solution of #F2 (4.5 g, 51.7 mmol), 6-bromoisoquinoline-1-carbonitrile (6.0 g, 25.9 mmol), BINAP (3.2 g, 5.1 mmol), Pd2(dba)3 (2.3 g, 2.6 mmol) and potassium phosphate (11.0 g, 51.7 mmol) in anhydrous DMSO (35 mL) was heated at 80° C. for 2 h. The complete disappearance of the 6-bromoisoquinoline-1-carbonitrile was observed on TLC. The reaction mixture was cooled to room temperature, filtered through a Celite™ pad and the filtrate was diluted with water (100 mL). The mixture was extracted with EtOAc (100 mL*3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude material. The product was purified by chromatography on silica gel (100-200 mesh) using 10percent MeOH in DCM as eluant to give racemic #F3 as yellow solid (1.5 g, 24.3percent). Rf: 0.4 (50percent EtOAc in petroleum ether). Chiral HPLC: two enantiomers (61.0percent, 39.0percent). LCMS m/z=240.1 (M+H). H NMR (400 MHz, d6-DMSO): δ 2.19-2.27 (m, 1H), 2.36-2.45 (m, 1H), 3.67-3.84 (m, 3H), 4.02-4.07 (m, 1H), 4.33-4.39 (m, 1H), 5.09 (t, J=4.8 Hz, 1H), 6.83 (d, J=1.6 Hz, 1H), 7.33 (dd, J=8.8 Hz, J=2.0 Hz, 1H), 7.78 (d, J=6.4 Hz, 1H), 7.97 (d, J=8.8 Hz, 1H), 8.36 (d, J=5.6 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 25℃; for 1.25 h; | Trimethylsilyl cyanide (52.0 mL, 580.0 mmol) was added dropwise to the stirred solution of A2 (65.0 g, 290.0 mmol) and DBU (50.0 mL, 348.0 mmol) in THF (500 mL) at room temperature over a period of 15 minutes. The reaction mixture was stirred at room temperature for 1 h. Water was added to the reaction mixture, and the solution was extracted with DCM. The organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to give crude product. The product was purified by column chromatography using silica gel (100 - 200 mesh) with 0 - 4percent EtOAc in petroleum ether as an eluent to give A3 as white solid. Yield: 41 g (61 percent). Rf: 0.6 (30percent EtOAc in petroleum ether). LCMS m/z = 233 (M + 1 ). 1H NMR (400 MHz, cf6-DMSO): δ 8.07 (dd, J = 1 1.2, 2.0 Hz, 1 H), 8.21 (m, 2H), 8.55 (br s, 1 H), 8.77 (d, J = 7.6 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.4% | With tris-(dibenzylideneacetone)dipalladium(0); In dimethyl sulfoxide; ethyl acetate; Petroleum ether; | Step 3. Synthesis of 6-amino isoquinoline (#E3). A solution of #A2 (4.0 g, 51.7 mmol), 6-bromoisoquinoline-1-carbonitrile #A3 (6.0 g, 25.9 mmol), BINAP (3.2 g, 5.2 mmol), Pd2(dba)3 (2.3 g, 2.6 mmol) and potassium phosphate (11.0 g, 51.7 mmol) in anhydrous DMSO (35 mL) was heated at 80° C. for 2 h. The complete disappearance of the 6-bromoisoquinoline-1-carbonitrile #A3 was observed on TLC. The reaction mixture was cooled to room temperature, filtered through Celite? pad and the filtrate was diluted with water (100 mL). The mixture was extracted with EtOAc (100 mL*3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude material which was purified by silica gel (100-200 mesh) column chromatography using 40percent EtOAc in petroleum ether as an eluting system to give #E3 as yellow solid (1.5 g, 25.4percent). Rf: 0.4 (60percent EtOAc in petroleum ether). LCMS m/z=227.9 (M+H); 1H NMR (400 MHz, d6-DMSO): delta 1.18 (d, J=6.8 Hz, 3H), 3.36-3.47 (m, 1H), 3.48-3.53 (m, 1H), 3.60-3.66 (m, 1H), 6.80-6.82 (m, 2H), 7.32 (dd, J=2.4 Hz, 8.8 Hz, 1H), 7.72 (d, J=5.6 Hz, 1H), 7.87 (d, J=9.6 Hz, 1H), 8.30 (d, J=5.6 Hz, 1H). |
24.3% | With tris-(dibenzylideneacetone)dipalladium(0); In dimethyl sulfoxide; | Step 3. Synthesis of 6-amino isoquinoline (#F3). A solution of #F2 (4.5 g, 51.7 mmol), 6-bromoisoquinoline-1-carbonitrile (6.0 g, 25.9 mmol), BINAP (3.2 g, 5.1 mmol), Pd2(dba)3 (2.3 g, 2.6 mmol) and potassium phosphate (11.0 g, 51.7 mmol) in anhydrous DMSO (35 mL) was heated at 80° C. for 2 h. The complete disappearance of the 6-bromoisoquinoline-1-carbonitrile was observed on TLC. The reaction mixture was cooled to room temperature, filtered through a Celite? pad and the filtrate was diluted with water (100 mL). The mixture was extracted with EtOAc (100 mL*3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude material. The product was purified by chromatography on silica gel (100-200 mesh) using 10percent MeOH in DCM as eluant to give racemic #F3 as yellow solid (1.5 g, 24.3percent). Rf: 0.4 (50percent EtOAc in petroleum ether). Chiral HPLC: two enantiomers (61.0percent, 39.0percent). LCMS m/z=240.1 (M+H). H NMR (400 MHz, d6-DMSO): delta 2.19-2.27 (m, 1H), 2.36-2.45 (m, 1H), 3.67-3.84 (m, 3H), 4.02-4.07 (m, 1H), 4.33-4.39 (m, 1H), 5.09 (t, J=4.8 Hz, 1H), 6.83 (d, J=1.6 Hz, 1H), 7.33 (dd, J=8.8 Hz, J=2.0 Hz, 1H), 7.78 (d, J=6.4 Hz, 1H), 7.97 (d, J=8.8 Hz, 1H), 8.36 (d, J=5.6 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With caesium carbonate; In ethyl acetate; toluene; Petroleum ether; | Step 6. Synthesis of coupling product (#B6). Pd2dba3 (0.094 g, 0.10 mmol), BINAP (0.19 g, 0.31 mmol) and Cs2CO3 (3.3 g, 10.3 mmol) were added to a degassed solution of <strong>[1082674-24-5]6-bromoisoquinoline-1-carbonitrile</strong> (0.8 g, 3.4 mmol) in toluene (10 mL) followed by the addition of #B5 (0.52 g, 3.8 mmol) under nitrogen atmosphere. The resulting reaction mixture was irradiated in a microwave at 110 C. for 20 minutes. The reaction mixture was cooled to room temperature, diluted with EtOAc, filtered and the filtrate was washed with water. The organic layer was separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over Na2SO4 and evaporated under reduced pressure to afford the crude mixture which was chromatographed on silica gel (100-200 mesh) using 25% EtOAc in petroleum ether to give #B6 as a light brown solid (0.25 g, 25%). Rf: 0.4 (25% EtOAc/petroleum ether). Racemic: LCMS m/z=288.1 (M+H). 1H NMR (300 MHz, CDCl3): delta 1.41 (d, J=6.3 Hz, 3H), 2.27-2.38 (m, 1H), 2.71-2.79 (m, 1H), 3.30-3.38 (m, 1H), 3.50-3.58 (m, 1H), 4.38-4.44 (m, 1H), 7.67 (d, J=2.1 Hz, 1H), 7.71 (dd, J=2.1, 9.3 Hz, 1H), 7.83 (d, J=5.7 Hz, 1H), 8.35 (d, J=9 Hz, 1H), 8.61 (d, J=5.7 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; Petroleum ether; | Step 3. Synthesis of carbinol products (#J3, #J4). Pd2(dba)3 (55.0 mg, 0.06 mmol), xanthphos (110.0 mg, 0.19 mmol) and Cs2CO3 (2.0 g, 6.4 mmol) were added to a mixture of #J2 (0.50 g, 2.1 mmol) and <strong>[1082674-24-5]6-bromoisoquinoline-1-carbonitrile</strong> (0.50 g, 4.3 mmol) in 1,4-dioxane (10 mL) under nitrogen atmosphere. The reaction mixture was heated to 110 C. for 2.5 h. After the consumption of the starting material, the mixture was diluted with EtOAc, washed with water and brine. The organic layer was dried over Na2Sa4and concentrated in vacuo to get crude material. This was purified by column chromatography using 100-200 silica gel and eluted with 70% EtOAc in petroleum ether to get pure #J3 and #J4 as a racemic mixture. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.5% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In dimethyl sulfoxide; at 105℃; for 2h;Inert atmosphere; | K3P04 (6.1 g, 28.8 mmol), BINAP (0.44 g, 0.72 mmol) and Pd2(dba)3 (0.32.0 g, 0.36 mmol) was added to the degassed suspension of 6-bromo-1 -cyanoisoquinoline A3 (1.7 g, 7.2 mmol), D2 (1.2 g, 14.5 mmol) in DMSO at room temperature. The reaction mixture was heated at 105 C for 2 h. The reaction was cooled to room temperature, water (500 ml_) followed by EtOAc (100 ml_) were added, and the mixture was stirred for 10 minutes. The biphasic mixture was filtered through a Celite pad and washed with EtOAc (100 ml_). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 x 100 ml_). The combined organic layers were dried over anhydrous Na2S04, concentrated under reduced pressure to get a crude material. This was purified by column chromatography on 100 - 200 mesh silica gel, using 50 - 70% EtOAc in petroleum ether as the eluent to obtain D3 (0.5 g, 48.5%) as a yellow solid. Rf: 0.4 (60% EtOAC in petroleum ether). LCMS m/z = 242.0 (M + H). 1 H NMR (400 MHz, cf6-DMSO): delta 0.97 (d, J = 6.4 Hz, 3H), 1.87 - 1.99 (m, 1 H), 2.92 - 2.99 (m, 1 H), 3.20 - 3.27 (m, 1 H), 3.38 - 3.42 (m, 2H), 4.59 (t, J = 5.2 Hz, 1 H), 6.77 (d, J = 2.0, 1 H), 7.01 (t, J = 5.6 Hz, 1 H), 7.34 (dd, J = 9.2 Hz, J = 2.0 Hz, 1 H), 7.73 (d, J = 6.0 Hz, 1 H), 7.88 (d, J = 8.8 Hz, 1 H), 8.312 (d, J = 6.0 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 2-methyltetrahydrofuran; at 70.0℃; for 3.0h;Inert atmosphere; | Into a 2L 3-neck round bottom flask equipped with a mechanical stirrer, reflux condenser and thermocouple with heating mantle was placed 2-methyltetrahydrofuran (2-MeTHF) (10 mL/g; 8.15 moles; 817 mL; 702 g) followed by racemic-2,2'- bis(diphenylphosphino)-1 , 1 '-binaphthyl (BINAP) (0.04 equiv (molar); 14.0 mmol; 8.74 g) and bis(dibenzylideneacetone)palladium (Pd2(dba)3) (0.04 equiv (molar); 14.0 mmol; 8.07 g). The mixture was degassed by pulling vacuum and refilling with nitrogen three times then heated to 75 C for 15 minutes and cooled to ambient temperature. In a separate flask, (S)-3-amino-2-methylpropan-1 -ol (1.60 equiv; 561 mmol; 50.0 g, prepared using literature methods for example as disclosed in EP-A-0,089,139 published on 21 st September 1983) was dissolved in 2-methyltetrahydrofuran (5 mL/g; 4.08 moles; 409 mL; 351 g) and degassed by pulling vacuum and refilling with nitrogen three times. Into the pot containing the catalyst was added 6-(bromoisoquinoline-1 - carbonitrile) (1.00 equiv; 351 mmol; 81.75 g) and cesium carbonate (1.6 equiv (molar); 561 mmol; 185 g) in single portions followed by the solution of the aminoalcohol via addition funnel. The reaction mixture was again degassed by pulling vacuum and refilling with nitrogen three times. The reaction was heated to 70 C for 3 hours. The reaction was cooled to ambient temperature and filtered through a pad of Celite. The contents of the flask were rinsed out with three 100 mL portions of 2- methyltetrahydrofuran. The filtrate was transferred into a 2L round bottom flask equipped with a thermocouple and mechanical stirrer under nitrogen. Silica Gel (Silicylate SiliaMet Thiol) (0.4 g/g-pure-LR; 544 mmol; 32.7 g) was charged and the flask was stirred at 40 C overnight. The following morning, the reaction was cooled to < 30 C and filtered again through Celite. The pad was washed with 100mL of 2- methyltetrahydrofuran (or until no yellow color persisted in the filtrate). The filtrate was placed into a 3L round bottom flask equipped with a magnetic stir bar, distillation head (with condenser and receiving flask), and thermocouple. The mixture was heated to 60 C and placed under vacuum (-450-500 mbar) to distil out 1.3 L total of 2- methyltetrahydrofuran. 500 mL of toluene was added to precipitate the desired product. The heating mantle was removed and the reaction was allowed to reach ambient temperature. The mixture was stirred for 1 hour at ambient temperature and then the solids were collected by vacuum filtration on a sintered glass funnel. The cake was dried overnight on the funnel under vacuum. The following morning, the solids were transferred into an amber bottle and weighed (71.9 g; 298 mmol). The product was used in the next step without further purification. | |
71.9 g | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 2-methyltetrahydrofuran; at 70.0℃; for 3.0h;Inert atmosphere; | Into a 2L 3-neck round bottom flask equipped with a mechanical stirrer, reflux condenser and thermocouple with heating mantle was placed 2-methyltetrahydrofuran(2-MeTHF) (10 mL/g; 8.15 moles; 817 mL; 702 g) followed by racemic-2,2?- bis(diphenylphosphino)-1,1?-binaphthyl (BINAP) (0.04 equiv (molar); 14.0 mmol; 8.74 g) and bis(dibenzylideneacetone)palladium (Pd2(dba)3) (0.04 equiv (molar); 14.0 mmol; 8.07 g). The mixture was degassed by pulling vacuum and refilling with nitrogen three times then heated to 75 00 for 15 minutes and cooled to ambient temperature. In aseparate flask, (S)-3-amino-2-methylpropan-1-ol (1.60 equiv; 561 mmol; 50.0 g, prepared using literature methods, for example as disclosed in EP-A-0,089,139 published on 21st September 1983) was dissolved in 2-methyltetrahydrofuran (5 mL/g; 4.08 moles; 409 mL; 351 g) and degassed by pulling vacuum and refilling with nitrogen three times. Into the pot containing the catalyst was added <strong>[1082674-24-5]6-(bromoisoquinoline-1-carbonitrile)</strong> (1.00 equiv; 351 mmol; 81.75 g) and cesium carbonate (1.6 equiv (molar); 561 mmol; 185 g) in single portions followed by the solution of the aminoalcohol via addition funnel. The reaction mixture was again degassed by pulling vacuum and refilling with nitrogen three times. The reaction was heated to 70 00 for 3 hours. Thereaction was cooled to ambient temperature and filtered through a pad of Celite. The contents of the flask were rinsed out with three 100 mL portions of 2- methyltetrahydrofuran. The filtrate was transferred into a 2L round bottom flask equipped with a thermocouple and mechanical stirrer under nitrogen. Silica Gel (Silicylate SiliaMet Thiol) (0.4 g/g-pure-LR; 544 mmol; 32.7 g) was charged and theflask was stirred at 40 00 overnight. The following morning, the reaction was cooled to <30 00 and filtered again through Celite. The pad was washed with lOOmL of 2- methyltetrahydrofuran (or until no yellow color persisted in the filtrate). The filtrate was placed into a 3L round bottom flask equipped with a magnetic stir bar, distillation head (with condenser and receiving flask), and thermocouple. The mixture was heated to 6000 and placed under vacuum (-450-500 mbar) to distil out 1.3 L total of 2- methyltetrahydrofuran. 500 mL of toluene was added to precipitate the desired product. The heating mantle was removed and the reaction was allowed to reach ambient temperature. The mixture was stirred for 1 hour at ambient temperature and then the solids were collected by vacuum filtration on a sintered glass funnel. The cake wasdried overnight on the funnel under vacuum. The following morning, the solids were transferred into an amber bottle and weighed (71.9 g; 298 mmol). The product was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (2.83 g, 11.2 mmol), 6-bromoisoquinoline-l-carbonitrile (2.00 g, 8.58 mmol), and potassium acetate (2.53 g, 25.7 mmol) in dioxane (20 mL) was degassed for 30 min before addition of PdCl2(dppf)-CH2Cl2 adduct (0.701 g, 0.858 mmol). The resulting mixture was heated at 100C overnight. After cooling to rt the mixture was filtered through celite, the filtrate was concentrated and the residue was partitioned between 0. IN NaOH (200 mL) and DCM (200 mL). The alkaline phase was extracted with DCM twice. The alkaline phase was then acidified by 2N HC1 to pH 5 and extracted with 30% isopropanol/DCM three times. The combined isopropanol/DCM phase was dried over Na2S04, concentrated to give (l-cyanoisoquinolin-6- yl)boronic acid. LC/MS: (M+l)+: 199.10. | ||
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100.0℃; | Step A: (1-cyanoisoquinolin-6-yl)boronic acid (0776) A mixture of 4,4,4?,4?,5,5,5?,5?-octamethyl-2,2?-bi(1,3,2-dioxaborolane) (2.83 g, 11.2 mmol), <strong>[1082674-24-5]6-bromoisoquinoline-1-carbonitrile</strong> (2.00 g, 8.58 mmol), and potassium acetate (2.53 g, 25.7 mmol) in dioxane (20 mL) was degassed for 30 min before addition of PdCl2(dppf)-CH2Cl2 adduct (0.701 g, 0.858 mmol). The resulting mixture was heated at 100 C. overnight. After cooling to rt the mixture was filtered through celite, the filtrate was concentrated and the residue was partitioned between 0.1N NaOH (200 mL) and DCM (200 mL). The alkaline phase was extracted with DCM twice. The alkaline phase was then acidified by 2N HCl to pH 5 and extracted with 30% isopropanol/DCM three times. The combined isopropanol/DCM phase was dried over Na2SO4, concentrated to give (1-cyanoisoquinolin-6-yl)boronic acid. LC/MS: (M+1)+: 199.10 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24.3% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In dimethyl sulfoxide; at 80.0℃; for 2.0h; | A solution of F2 (4.5 g, 51.7 mmol), 6- bromoisoquinoline-1 -carbonitrile (6.0 g, 25.9 mmol), BINAP (3.2 g, 5.1 mmol), Pd2(dba)3 (2.3 g, 2.6 mmol) and potassium phosphate (1 1.0 g, 51.7 mmol) in anhydrous DMSO (35 ml_) was heated at 80 C for 2 h. The complete disappearance of the 6- bromoisoquinoline-1 -carbonitrile was observed on TLC. The reaction mixture was cooled to room temperature, filtered through a Celite pad and the filtrate was diluted with water (100 ml_). The mixture was extracted with EtOAc (100 ml_ x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude material. The product was purified by chromatography on silica gel (100-200 mesh) using 10% MeOH in DCM as eluant to give racemic F3 as yellow solid (1.5 g, 24.3%). Rf: 0.4 (50% EtOAc in petroleum ether). Chiral HPLC: two enantiomers (61.0%, 39.0%). LCMS m/z = 240.1 (M + H).1H NMR (400 MHz, d6 ~ DMSO): delta 2.19 - 2.27 (m, 1 H), 2.36 - 2.45 (m, 1 H), 3.67 - 3.84 (m, 3H), 4.02 - 4.07 (m, 1 H), 4.33 - 4.39 (m, 1 H), 5.09 (t, J = 4.8 Hz, 1 H), 6.83 (d, J = 1.6 Hz, 1 H), 7.33 (dd, J = 8.8 Hz, J = 2.0 Hz, 1 H), 7.78 (d, J = 6.4 Hz, 1 H), 7.97 (d, J = 8.8 Hz, 1 H), 8.36 (d, J = 5.6 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With copper(l) iodide; potassium carbonate; In dimethyl sulfoxide; at 90.0℃; for 5.0h; | A mixture of 6-bromoisoquinoline-1 -carbonitrile A3 (4.5 g, 19.3 mmol), (ft)-piperidine carboxylic acid (2.7 g, 20.9 mmol), Cul (3.2 g, 1.9 mmol) and K2C03 (5.4 g, 39.1 mmol) in DMSO (15 ml_) was heated at 90 C for 5 h. The consumption of 6-bromoisoquinoline-1 -carbonitrile was observed on TLC. The reaction mixture was cooled to room temperature, filtered through a Celite pad, rinsed with EtOAc and the filtrate was diluted with water (200 ml_). The filtrate was washed with EtOAc (100 ml_ x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude material. This was triturated with pentane to give H1 as a pure yellow solid (4 g, 72%). Rf: 0.1 (EtOAc). LCMS m/z = 281.9 (M + H). 1 H NMR (300 MHz, cf6-DMSO): delta 1.56 - 1.89 (m, 3H), 2.26 (d, J = 12.6 Hz, 1 H), 2.71 (dd, J = 15.3 Hz, 17.4 Hz, 1 H), 3.16 (td, J = 12.6 Hz, 3.6 Hz, 1 H), 3.90 (d, J = 1 1.7 Hz, 1 H), 4.99 (d, J = 3.3 Hz, 1 H), 7.26 (d, J = 2.7 Hz, 1 H), 7.75 (dd, J = 9.2 Hz, J = 2.4 Hz, 1 H), 7.86 (d, J = 5.4 Hz, 1 H), 7.98 (d, J = 9.0 Hz, 1 H), 8.41 (d, J = 6.3 Hz, 1 H), 12.60 (br s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 25.0℃; for 1.25h; | Trimethylsilyl cyanide (52.0 mL, 580.0 mmol) was added dropwise to the stirred solution of A2 (65.0 g, 290.0 mmol) and DBU (50.0 mL, 348.0 mmol) in THF (500 mL) at room temperature over a period of 15 minutes. The reaction mixture was stirred at room temperature for 1 h. Water was added to the reaction mixture, and the solution was extracted with DCM. The organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to give crude product. The product was purified by column chromatography using silica gel (100 - 200 mesh) with 0 - 4% EtOAc in petroleum ether as an eluent to give A3 as white solid. Yield: 41 g (61 %). Rf: 0.6 (30% EtOAc in petroleum ether). LCMS m/z = 233 (M + 1 ). 1H NMR (400 MHz, cf6-DMSO): delta 8.07 (dd, J = 1 1.2, 2.0 Hz, 1 H), 8.21 (m, 2H), 8.55 (br s, 1 H), 8.77 (d, J = 7.6 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In dimethyl sulfoxide; at 90.0℃; for 1.5h;Inert atmosphere; | 17 (3.4 g, 29.9 mmol) was added to degassed DMSO. K3P04 (7.3 g, 34.5 mmol) was added to the solution and stirring was continued for 5 minutes, followed by the addition of Pd2(dba3) (0.27 g, 0.30 mmol), BINAP (0.55 g, 0.88 mmol) and 6-bromoisoquinoline-1 -carbonitrile A3 (2.3 g, 9.9 mmol) under an argon atmosphere. The resulting reaction mixture was heated at 90 C under argon atmosphere for 1 .5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through a Celite pad. The filtrate was washed with water followed by brine. The organic layer was dried over Na2S04, evaporated under reduced pressure to get the crude mixture which was chromatographed on silica gel (100 - 200 mesh) using 20-80% EtOAc in petroleum ether as eluent to give 18 as a yellow solid (3.8 g, 48%). Rf: 0.2 (50% EtOAc in petroleum ether, UV active) LCMS m/z = 268.4 (M + H). 1 H NMR (400 MHz, cf6-DMSO): delta 1 .27 (d, J = 6 Hz, 3H), 1 .72 - 1 .79 (m, 1 H), 1 .91 - 2.03 (m, 2H), 2.1 1 - 2.19 (m, 1 H), 3.38 - 3.44 (m, 1 H), 3.58 - 3.63 (m, 1 H), 3.93 - 4.03 (m, 2H), 4.94 (t, J = 5.6 Hz, 1 H), 6.94 (d, J = 2 Hz, 1 H), 7.47 (dd, J = 2.4, 9.2 Hz, 1 H), 7.80 (d, J = 5.6 Hz, 1 H), 7.94 (d, J = 9.6 Hz, 1 H), 8.33 (d, J = 6.4 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 2.5h;Inert atmosphere; | Pd2(dba)3 (55.0 mg, 0.06 mmol), xanthphos (1 10.0 mg, 0.19 mmol) and CS2CO3 (2.0 g, 6.4 mmol) were added to a mixture of J2 (0.50 g, 2.1 mmol) and 6-bromoisoquinoline-1 -carbonitrile (0.50 g, 4.3 mmol) in 1 ,4-dioxane (10 ml_) under nitrogen atmosphere. The reaction mixture was heated to 1 10 C for 2.5 h. After the consumption of the starting material, the mixture was diluted with EtOAc, washed with water and brine. The organic layer was dried over Na2S04and concentrated in vacuo to get crude material. This was purified by column chromatography using 100 - 200 silica gel and eluted with 70% EtOAc in petroleum ether to get pure J3 and J4 as a racemic mixture. The reaction was repeated three times. The combined crude products were separated by chiral prep HPLC to give J3 (350 mg) and J4 (350 mg) as pale brown solids. Absolute configuration was arbitrarily assigned as shown. Rf: 0.2 (EtOAc). LCMS m/z = 268.1 (M + H). 1 H NMR (400 MHz, CDCI3): delta 2.22 (m, 1 H), 2.39 (m, 1 H), 2.62 (m, 1 H), 2.84 (m, 1 H), 3.73 (m, 1 H), 3.83 (m, 1 H), 4.60 (m, 1 H), 7.85 (d, J = 5.6 Hz, 1 H), 8.00 (dd, J = 1.6, 9.2 Hz, 1 H), 8.20 (d, J = 2.0 Hz, 1 H), 8.34 (d, J = 9.2 Hz, 1 H), 8.61 (d, J = 5.6 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110℃; for 3h;Inert atmosphere; | Pd2(dba)3 (350 mg, 0.06 mmol), BINAP (790.0 mg, 0.2 mmol), Cs2C03 (6.2 g, 3.0 mmol) were added to a mixture of 6- bromoisoquinoline-1 -carbonitrile A3 (1.5 g, 6.4 mmol) and K1 (1.3 g, 12.8 mmol) in toluene (10 mL) under nitrogen atmosphere. The reaction mixture was heated to 1 10 °C for 3 h. The mixture was diluted with EtOAc and washed with water and brine solution. Organic layer was dried over Na2S04 and concentrated to give crude material. The crude material was purified by column chromatography on silica gel (100 - 200 mesh) eluted with 40percent EtOAc in petroleum ether to give racemic material (K2, K3, 1 g, 33percent). The isomers were separated by chiral preparative HPLC to give K2 (500 mg) and K3 (450 mg). Rf: 0.2 (EtOAc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In dimethyl sulfoxide; at 110.0℃; for 3.0h;Inert atmosphere; | Pd2(dba)3 (235.0 mg, 0.25 mmol), BINAP (480.0 mg, 0.77 mmol), K3P04 (1.9 g, 9.0 mmol) were added to a mixture of 6- bromoisoquinoline-1 -carbonitrile (600.0 mg, 2.57 mmol) and L7 (1 g, 4.1 mmol) in DMSO (5 mL) under nitrogen atmosphere. The reaction mixture was heated to 1 10 C for 3 h. The mixture was diluted with EtOAc and washed with water and brine. Organic layer was dried over Na2S04 and concentrated to give crude compound. The crude material was purified by column chromatography using silica gel (100 - 200 mesh) eluted with 40% EtOAc in petroleum ether to get pure L8 (400 mg, 58 %) as pale yellow solid. Rf: 0.4 (50% EtOAc in petroleum ether). LCMS m/z = 268.2 (M + 1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100.0℃; for 3.0h;Inert atmosphere; | General procedure: A solution of A3 (1 eq.) in toluene (50 mL) was degassed by bubbling with argon gas for 15 min and then Pd2dba3 (0.03 eq.), BINAP (0.06 eq.) and Cs2C03 (3 eq.) were added to the solution followed by the addition aminoalcohol (2 eq.). The mixture was heated at 100 C under argon atmosphere for 3 h. Reaction mixture was cooled to room temperature, diluted with EtOAC and washed with water and brine. The organic layer was dried over Na2S04 and concentrated to get crude product. The crude compounds were purified by silica gel (100 - 200 mesh) column chromatography by using 0 - 5% MeOH in DCM. Yields: 25 - 45%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110.0℃; for 0.333333h;Inert atmosphere; Microwave irradiation; | Pd2dba3 (0.094 g, 0.10 mmol), BINAP (0.19 g, 0.31 mmol) and CS2CO3 (3.3 g, 10.3 mmol) were added to a degassed solution of 6-bromoisoquinoline-1 -carbonitrile (0.8 g, 3.4 mmol) in toluene (10 mL) followed by the addition of B5 (0.52 g, 3.8 mmol) under nitrogen atmosphere. The resulting reaction mixture was irradiated in a microwave at 1 10 C for 20 minutes. The reaction mixture was cooled to room temperature, diluted with EtOAc, filtered and the filtrate was washed with water. The organic layer was separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over Na2S04 and evaporated under reduced pressure to afford the crude mixture which was chromatographed on silica gel (100 - 200 mesh) using 25% EtOAc in petroleum ether to give B6 as a light brown solid (0.25 g, 25%). Rf: 0.4 (25% EtOAc/petroleum ether). Racemic: LCMS m/z = 288.1 (M + H). 1H NMR (300 MHz, CDCI3): delta 1.41 (d, J = 6.3 Hz, 3H), 2.27 - 2.38 (m, 1 H), 2.71 - 2.79 (m, 1 H), 3.30 - 3.38 (m, 1 H), 3.50 - 3.58 (m, 1 H), 4.38 - 4.44 (m, 1 H), 7.67 (d, J = 2.1 Hz, 1 H), 7.71 (dd, J = 2.1 , 9.3 Hz, 1 H), 7.83 (d, J = 5.7 Hz, 1 H), 8.35 (d, J = 9 Hz, 1 H), 8.61 (d, J = 5.7 Hz, 1 H). The racemic compound was chromatographed for enantiomeric separation. Conditions: Column: CHIRAL PAK IA, 4.6 X 250mm, 5 muGammaeta; Column ID: ANL_CHIR IA_145; Mobile Phase: A = hexane, B = isopropyl alcohol; ISOCRATIC: 60:40; FLOW: 0.8 mL/min; Column Temp: 25C; Eluent: EtOH Enantiomer of 8: Chiral HPLC purity: 99.38 % (retention time 12.55 minutes) LCMS m/z = 287.9 (M + H). 1 H NMR (300 MHz, cf6-DMSO): delta 1.30 (d, J = 6.3 Hz, 3H), 2.10 - 2.17 (m, 1 H), 2.65 - 2.76 (m, 1 H), 3.51 - 3.55 (m, 1 H), 3.70 - 3.79 (m, 1 H), 4.50 - 4.57 (m, 1 H), 7.81 (d, J = 2.1 Hz, 1 H), 7.87 (dd, J = 2.7, 9.0 Hz, 1 H), 8.20 (d, J = 5.4 Hz, 1 H), 8.28 (d, J = 9.0 Hz, 1 H), 8.64 (d, J = 5.7 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.4% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In dimethyl sulfoxide; at 80.0℃; for 2.0h; | A solution of A2 (4.0 g, 51.7 mmol), 6-bromoisoquinoline-1 -carbonitrile A3 (6.0 g, 25.9 mmol), BINAP (3.2 g, 5.2 mmol), Pd2(dba)3 (2.3 g, 2.6 mmol) and potassium phosphate (1 1.0 g, 51.7 mmol) in anhydrous DMSO (35 ml_) was heated at 80 C for 2 h. The complete disappearance of the 6- bromoisoquinoline-1 -carbonitrile A3 was observed on TLC. The reaction mixture was cooled to room temperature, filtered through Celite pad and the filtrate was diluted with water (100 ml_). The mixture was extracted with EtOAc (100 ml_ x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude material which was purified by silica gel (100 - 200 mesh) column chromatography using 40% EtOAc in petroleum ether as an eluting system to give E3 as yellow solid (1.5 g, 25.4%). Rf: 0.4 (60% EtOAc in petroleum ether). LCMS m/z = 227.9 (M + H); 1 H NMR (400 MHz, cf6-DMSO): delta 1.18 (d, J = 6.8 Hz, 3H), 3.36 - 3.47 (m, 1 H), 3.48 - 3.53 (m, 1 H), 3.60 - 3.66 (m, 1 H), 6.80 - 6.82 (m, 2H), 7.32 (dd, J = 2.4 Hz, 8.8 Hz, 1 H), 7.72 (d, J = 5.6 Hz, 1 H), 7.87 (d, J = 9.6 Hz, 1 H), 8.30 (d, J = 5.6 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100.0℃;Sealed tube; | 1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-3-amine (546 mg, 2.15 mmol, 1.00 eq), <strong>[1082674-24-5]6-bromoisoquinoline-1-carbonitrile</strong> (500 mg, 2.15 mmol, 1.00 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (186 mg, 0.322 mmol, 0.150 eq), tris(dibenzylideneacetone)dipalladium(O) (196 mg, 0.215 mmol, 0.100 eq) and cesium carbonate (1.47 g, 4.51 mmol, 2.10 eq) were suspended in 1,4-dioxane (43 mL) in a sealed vial and heated at 100 C. overnight. The reaction was cooled, filtered over celite and washed with 5% methanol in DCM. The organics were concentrated and purified by flash chromatography on silica gel using 0-20% hexanes/ethyl acetate to afford 661 mg (76%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 10.24 (s, 1H), 8.52 (s, 1H), 8.50-8.47 (m, 2H), 8.19 (d, J=8.5 Hz, 1H), 8.09 (s, 2H), 7.94 (d, J=5.7 Hz, 1H), 7.46 (dd, J=4.3, 8.5 Hz, 1H), 7.34 (d, J=8.2 Hz, 2H), 6.89 (d, J=8.3 Hz, 2H), 5.56 (s, 2H), 3.68 (s, 3H); ES-MS [M+1]+: 407.2. |
Tags: 1082674-24-5 synthesis path| 1082674-24-5 SDS| 1082674-24-5 COA| 1082674-24-5 purity| 1082674-24-5 application| 1082674-24-5 NMR| 1082674-24-5 COA| 1082674-24-5 structure
[ 27224-09-5 ]
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