| 85% |
With 2,6-dimethylpyridine; In dichloromethane; at 0 - 20℃; |
Step 3: (R)-8-(Benzyloxy)-5-(2-bromo-1-((tert-butyldimethylsilyl)oxy)ethyl)quinolin-2(1H)-one 2,6-Lutidine (6.9 mL, 59.5 mmol) was added to a solution of <strong>[530084-79-8](R)-8-(benzyloxy)-5-(2-bromo-1-hydroxyethyl)quinolin-2(1H)-one</strong> (10.1 g, 27.0 mmol) in DCM (100 mL) at 0 C. The reaction mixture was stirred for 5 minutes then tert-butyldimethylsilyl trifluoromethanesulfonate (13.0 mL, 56.8 mmol) was added dropwise over 15 minutes. The mixture was stirred at 0 C. for 30 minutes, followed by RT overnight. After this time the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with DCM (*3). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated under reduced pressure. Iso-hexane (500 mL) was added to the crude material and the resulting solid collected by filtration. The solid was recrystallised from ethyl acetate and petroleum ether (40:60) to afford the title compound (11.3 g, 85%). 1H NMR (400 MHz, CDCl3): delta 9.19 (s, 1H); 8.23 (dd, J=9.9, 4.4 Hz, 1H); 7.43 (d, J=4.6 Hz, 5H); 7.17 (dd, J=8.3, 4.5 Hz, 1H); 7.03 (dd, J=8.2, 4.4 Hz, 1H); 6.71 (dd, J=9.9, 3.7 Hz, 1H); 5.18 (d, J=4.5 Hz, 3H); 3.63-3.56 (m, 1H); 3.49 (dd, J=10.4, 4.8 Hz, 1H); 0.88 (t, J=4.4 Hz, 9H); 0.14 (d, J=4.4 Hz, 3H); -0.11 (d, J=4.4 Hz, 3H). |
| 85% |
|
2,6-Lutidine (6.9 mL, 59.5 mmol) was added to a solution of (R)-8- (benzyloxy)-5-(2-bromo-l-hydroxyethyl)quinolin-2(lH)-one (10.1 g, 27.0 mmol) in DCM (100 mL) at 0 C. The reaction mixture was stirred for 5 minutes then tert-butyldimethylsilyl trifluoromethanesulfonate (tBuMeaSiOtf) (13.0 mL, 56.8 mmol) was added dropwise over 15 minutes. The mixture was stirred at 0C for 30 minutes, followed by RT overnight. After this time the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with DCM (x 3). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated under reduced pressure. ZsO-hexane (500 mL) was added to the crude material and the resulting solid collected by filtration. The solid was recrystallised from ethyl acetate and petroleum ether (40 : 60) to afford the title compound (1 1.3 g, 85%). 1HNMR (400 MHz, CDC13): delta 9.19 (s, 1 H); 8.23 (dd, J = 9.9, 4.4 Hz, 1 H); 7.43 (d, J = 4.6 Hz, 5 H); 7.17 (dd, J = 8.3, 4.5 Hz, 1 H); 7.03 (dd, J = 8.2, 4.4 Hz, 1 H); 6.71 (dd, J = 9.9, 3.7 Hz, 1 H); 5.18 (d, J = 4.5 Hz, 3 H); 3.63-3.56 (m, 1 H); 3.49 (dd, / = 10.4, 4.8 Hz, 1 H); 0.88 (t, J = 4.4 Hz, 9 H); 0.14 (d, J = 4.4 Hz, 3 H); - 0.1 1 (d, J= 4.4 Hz, 3 H). |
| 85% |
With 2,6-dimethylpyridine; In dichloromethane; at 0 - 20℃; |
2,6-Lutidine (6.9 mE, 59.5 mmol) was added tosolution of (R)-8-(benzyloxy)-5-(2-bromo- 1 -hydroxyethyl) quinolin-2(1H)-one (10.1 g, 27.0 mmol) in DCM (100 mE) at 00 C. The reaction mixture was stirred for 5 minutes then tert-butyldimethylsilyl trifluoromethanesulfonate (13.0 mE, 56.8 mmol) was added dropwise over 15 minutes. The mixture was stirred at 00 C. for 30 minutes, followed by room temperature overnight. After this time the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with DCM (x3). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated under reduced pressure. Iso-hexane (500 mE) was added to the crude material and the resulting solid collected by filtration. The solid was recrystallised from ethyl acetate and petroleum ether (40:60) to afford the title compound(11.3 g, 85%). 1H NMR (400 MHz, CDC13): oe 9.19 (s, 1H), 8.23 (dd, J=9.9, 4.4 Hz, 1H), 7.43 (d, J=4.6 Hz, 5H), 7.17 (dd, J=8.3, 4.5 Hz, 1H), 7.03 (dd, J=8.2, 4.4 Hz, 1H), 6.71 (dd, J=9.9, 3.7 Hz, 1H), 5.18 (d, J=4.5 Hz, 3H), 3.63-3.56 (m, 1H), 3.49 (dd, J=10.4, 4.8 Hz, 1H), 0.88 (t, J=4.4 Hz, 9H), 0.14 (d, J=4.4 Hz, 3H), -0.11 (d, J=4.4 Hz, 3H). |
| 85% |
With 2,6-dimethylpyridine; In dichloromethane; at 0 - 20℃; |
2,6-Lutidine (6.9 mL, 59.5 mmol) wa as added to a solution of ( ?j-8-(benzyloxy)-5- (2-bromo-1-hydroxyethyl)quinolin-2(1H)-one (10.1 g, 27.0 mmol) in DCM (100 mL) at 0C. The reaction mixture was stirred for 5 minutes then tert-butyldimethylsilyl trifluoromethanesulfonate (13.0 mL, 56.8 mmol) was added dropwise over 15 minutes. The mixture was stirred at 0C for 30 minutes, followed by room temperature overnight. After this time the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with DCM (x 3). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated under reduced pressure. Zso-hexane (500 mL) was added to the crude material and the resulting solid collected by filtration. The solid was recrystallised from ethyl acetate and petroleum ether (40 : 60) to afford the title compound (11.3 g, 85%). NMR (400 MHz, CDC13): delta 9.19 (s, 1 H), 8.23 (dd, J = 9.9, 4.4 Hz, 1 H), 7.43 (d, J = 4.6 Hz, 5 H), 7.17 (dd, J = 8.3, 4.5 Hz, 1 H), 7.03 (dd, J = 8.2, 4.4 Hz, 1 H), 6.71 (dd, J= 9.9, 3.7 Hz, 1 H), 5.18 (d, J= 4.5 Hz, 3 H), 3.63-3.56 (m, 1 H), 3.49 (dd, J= 10.4, 4.8 Hz, 1 H), 0.88 (t, J= 4.4 Hz, 9 H), 0.14 (d, J = 4.4 Hz, 3 H), -0.1 1 (d, J = 4.4 Hz, 3 H). |
| 85% |
|
2,6-Lutidine (6.9 mL, 59.5 mmol) was added to a solution of (R -8-(benzyloxy)-5- (2-bromo-l-hydroxyethyl)quinolin-2(lH)-one (10.1 g, 27.0 mmol) in DCM (100 mL) at 0C. The reaction mixture was stirred for 5 minutes then tert-butyldimethylsilyl trifluoromethanesulfonate (13.0 mL, 56.8 mmol) was added dropwise over 15 minutes. The mixture was stirred at 0C for 30 minutes, followed by room temperature overnight. After this time the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with DCM (x 3). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated under reduced pressure. Zso-hexane (500 mL) was added to the crude material and the resulting solid collected by filtration. The solid was recrystallised from ethyl acetate and petroleum ether (40 : 60) to afford the title compound (11.3 g, 85%). NMR (400 MHz, CDC13): delta 9.19 (s, 1 H), 8.23 (dd, J= 9.9, 4.4 Hz, 1 H), 7.43 (d, J= 4.6 Hz, 5 H), 7.17 (dd, J= 8.3, 4.5 Hz, 1 H), 7.03 (dd, J= 8.2, 4.4 Hz, 1 H), 6.71 (dd, J= 9.9, 3.7 Hz, 1 H), 5.18 (d, J= 4.5 Hz, 3 H), 3.63-3.56 (m, 1 H), 3.49 (dd, J= 10.4, 4.8 Hz, 1 H), 0.88 (t, J= 4.4 Hz, 9 H), 0.14 (d, J= 4.4 Hz, 3 H), -0.11 (d, J= 4.4 Hz, 3 H). |
| 80% |
With 2,6-dimethylpyridine; In N,N-dimethyl-formamide; at 20℃; for 0.75h; |
b. Synthesis of 5-(2-bromo-(R)-1-tert-butyldimethylsiloxy)ethyl-8-benzyloxy-2(1H)-quinolinone (HH); Compound FF (70.2 g, 189 mmol) was treated with N,N-dimethylformamide (260 ml) and cooled in an ice bath under nitrogen. 2,6-Lutidine (40.3 g, 376 mmol) was added over 5 minutes followed slowly by tert-butyldimethylsilyl trifluoromethanesulfonate (99.8 g, 378 mmol), keeping the temperature below 20 C. The mixture was allowed to warm to room temperature for 45 minutes. Methanol (45 ml) was added to the mixture dropwise over 10 minutes and the mixture was partitioned between ethyl acetate/cyclohexane(1:1, 500 ml) and water/brine (1:1, 500 ml). The organics were washed twice more with water/brine (1:1, 500 ml each). The combined organics were evaporated under reduced pressure to give a light yellow oil. Two separate portions of cyclohexane (400 ml) were added to the oil and distillation continued until a thick white slurry was formed. Cyclohexane (300 ml) was added to the slurry and the resulting white crystals were filtered, washed with cyclohexane (300 ml) and dried under reduced pressure to give 5-(2-bromo-(R)-1-tert-butyldimethylsiloxy)ethyl-8-benzyloxy-2(1H)-quinolinone (HH) (75.4 g, 151 mmol, 80% yield, 98.6% ee). |
| 80% |
With 2,6-dimethylpyridine; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 0.833333h; |
To the product of step (b) (70.2 g, 189 mmol) was added N,N-dimethylformamide (260 mL) and this mixture was cooled in an ice bath under nitrogen. 2,6-Lutidine (40.3 g, 376 mmol) was added over 5 min and then tert-butyldimethylsilyl trifluoromethanesulfonate (99.8 g, 378 mmol) was added slowly while maintaining the temperature below 20 C. The mixture was allowed to warm to room temperature for 45 min. Methanol (45 mL) was added to the mixture dropwise over 10 min and the mixture was partitioned between ethyl acetate/cyclohexane(1:1, 500 mL) and water/brine (1:1, 500 mL). The organics were washed twice more with water/brine (1:1, 500 mL each). The combined organics were evaporated under reduced pressure to give a light yellow oil. Two separate portions of cyclohexane (400 mL) were added to the oil and distillation continued until a thick white slurry was formed. Cyclohexane (300 mL) was added to the slurry and the resulting white crystals were filtered, washed with cyclohexane (300 mL) and dried under reduced pressure to give the title compound (75.4 g, 151 mmol, 80% yield, 98.6% ee). |
| 80% |
With 2,6-dimethylpyridine; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 0.75h; |
(c) 8-Benzyloxy-5-[(R)-2-bromo-1-(tert-butyldimethylsilanyloxy)ethyl]-1H-quinolin-2-one To the product of step (b) (70.2 g, 189 mmol) was added N,N-dimethylformamide (260 ML) and this mixture was cooled in an ice bath under nitrogen. 2,6-Lutidine (40.3 g, 376 mmol) was added over 5 min and then tert-butyldimethylsilyl trifluoromethanesulfonate (99.8 g, 378 mmol) was added slowly while maintaining the temperature below 20 C. The mixture was allowed to warm to room temperature for 45 min.methanol (45 ML) was added to the mixture dropwise over 10 min and the mixture was partitioned between ethyl acetate/cyclohexane(1:1, 500 ML) and water/brine (1:1, 500 ML).The organics were washed twice more with water/brine (1:1, 500 ML each).The combined organics were evaporated under reduced pressure to give a light yellow oil.Two separate portions of cyclohexane (400 ML) were added to the oil and distillation continued until a thick white slurry was formed.cyclohexane (300 ML) was added to the slurry and the resulting white crystals were filtered, washed with cyclohexane (300 ML) and dried under reduced pressure to give the title compound (75.4 g, 151 mmol, 80% yield, 98.6% ee). |
| 80% |
With 2,6-dimethylpyridine; In N,N-dimethyl-formamide; at 0 - 20℃; for 0.833333h; |
To the product of step (b) (70.2 g, 189 mmol) was added N,N-dimethylformamide (260 mL) and this mixture was cooled in an ice bath under nitrogen. 2,6-Lutidine (40.3 g, 376 mmol) was added over 5 min and then tert-butyldimethylsilyl trifluoromethanesulfonate (99.8 g, 378 mmol) was added slowly while maintaining the temperature below 20 C. The mixture was allowed to warm to room temperature for 45 min. Methanol (45 mL) was added to the mixture dropwise over 10 min and the mixture was partitioned between ethyl acetate/cyclohexane (1:1, 500 mL) and water/brine (1:1, 500 mL). The organics were washed twice more with water/brine (1:1, 500 mL each). The combined organics were evaporated under reduced pressure to give a light yellow oil. Two separate portions of cyclohexane (400 mL) were added to the oil and distillation continued until a thick white slurry was formed. Cyclohexane (300 mL) was added to the slurry and the resulting white crystals were filtered, washed with cyclohexane (300 mL) and dried under reduced pressure to give the title compound (75.4 g, 151 mmol, 80% yield, 98.6% ee). |
| 80% |
With 2,6-dimethylpyridine; at 0 - 20℃; for 0.833333h; |
To the product of step (b) (70.2 g, 189 mmol) was added 7V,Af-dimethylformamide (260 mL) and this mixture was cooled in an ice bath under nitrogen. 2,6-Lutidine (40.3 g, 376 mmol) was added over 5 min and then ferf-butyldimethylsilyl trifiuoromethanesulfonate (99.8 g, 378 mmol) was added slowly while maintaining the temperature below 20 C. The mixture was allowed to warm to room temperature for 45 min. Methanol (45 mL) was added to the mixture dropwise over 10 min and the mixture was partitioned between ethyl acetate/cyclohexane(l :1, 500 mL) and water/brine (1:1, 500mL). The organics were washed twice more with water/brine (1:1, 500 mL each). The combined organics were evaporated under reduced pressure to give a light yellow oil. Two separate portions of cyclohexane (400 mL) were added to the oil and distillation continued until a thick white slurry was formed. Cyclohexane (300 mL) was added to the slurry and the resulting white crystals were filtered, washed with cyclohexane (300 mL) and dried under reduced pressure to give the title compound (75.4 g, 151 mmol, 80% yield, 98.6 % ee). |
| 80% |
With 2,6-dimethylpyridine; In methanol; DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 0.833333h; |
Compound FF (70.2 g, 189 mmol) was treated with N,N-dimethylformamide (260 ML) and cooled in an ice bath under nitrogen. 2,6-Lutidine (40.3 g, 376 mmol) was added over 5 minutes followed slowly by tert-butyldimethylsilyl trifluoromethanesulfonate (99.8 g, 378 mmol), keeping the temperature below 20 C. The mixture was allowed to warm to room temperature for 45 minutes.methanol (45 ML) was added to the mixture dropwise over 10 minutes and the mixture was partitioned between ethyl acetate/cyclohexane(1:1,500 ML) and water/brine (1:1,500 ML).The organics were washed twice more with water/brine (1:1,500 ML each).The combined organics were evaporated under reduced pressure to give a light yellow oil.Two separate portions of cyclohexane (400 ML) were added to the oil and distillation continued until a thick white slurry was formed.cyclohexane (300 ML) was added to the slurry and the resulting white crystals were filtered, washed with cyclohexane (300 ML) and dried under reduced pressure to give 5-(2-bromo-(R)-1-tert-butyldimethylsiloxy)ethyl-8-benzyloxy-2(1H)-quinolinone (HH) (75.4 g, 151 mmol, 80% yield, 98.6% ee). |
| 80% |
With 2,6-dimethylpyridine; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 0.833333h; |
To the product of step (b) (70.2 g, 189 mmol) was added N,N-dimethylformamide (260 mL) and this mixture was cooled in an ice bath under nitrogen. 2,6-Lutidine (40.3 g, 376 mmol) was added over 5 min and then TERT-BUTYLDIMETHYLSILYL TRIFLUOROMETHANESULFONATE (99. 8 g, 378 mmol) was added slowly while maintaining the temperature below 20C. The mixture was allowed to warm to room temperature for 45 min. Methanol (45 ML) was added to the mixture dropwise over 10 min and the mixture was partitioned between ethyl acetate/cyclohexane (1 : 1, 500 mL) and WATER/BRINE (1: 1, 500ML). The organics were washed twice more with WATER/BRINE (1: 1,500 mL each). The --86-- combined organics were evaporated under reduced pressure to give a light yellow oil. Two separate portions of cyclohexane (400 mL) were added to the oil and distillation continued until a thick white slurry was formed. Cyclohexane (300 mL) was added to the slurry and the resulting white crystals were filtered, washed with cyclohexane (300 mL) and dried under reduced pressure to give the title compound (75.4 g, 151 mmol, 80% yield, 98. 6 % ee). |
| 80% |
With 2,6-dimethylpyridine; In methanol; DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 1h; |
Preparation 6 8-Benzyloxy-5-[(R)-2-bromo-1-(tert-butyldimethylsilanyloxy)ethyl]-1H-quinolin-2-one To the product of Preparation 5 (70.2 g, 189 mmol) was added N,N-dimethylformamide (260 mL) and this mixture was cooled in an ice bath under nitrogen. 2,6-Lutidine (40.3 g, 376 mmol) was added over 5 min and then tert-butyldimethylsilyl trifluoromethanesulfonate (99.8 g, 378 mmol) was added slowly while maintaining the temperature below 20 C. The mixture was allowed to warm to room temperature for 45 min. Methanol (45 mL) was added to the mixture dropwise over 10 min and the mixture was partitioned between ethyl acetate/cyclohexane (1:1, 500 mL) and water/brine (1:1, 500 mL). The organics were washed twice more with water/brine (1:1, 500 mL each). The combined organics were evaporated under reduced pressure to give a light yellow oil. Two separate portions of cyclohexane (400 mL) were added to the oil and distillation continued until a thick white slurry was formed. Cyclohexane (300 mL) was added to the slurry and the resulting white crystals were filtered, washed with cyclohexane (300 mL) and dried under reduced pressure to give the title compound (75.4 g, 151 mmol, 80% yield, 98.6% ee). |
|
With 2,6-dimethylpyridine; In dichloromethane; at 4 - 20℃; for 18.2h; |
tert-Butyldimethylsilyl triflate (21.4ml, 93.15mmol) was added dropwise over 10 minutes to a stirred suspension of the compound from preparation 2 (17.42g, 46.6mmol) and 2,6-lutidine (10.9ml, 93.15mmol) in anhydrous dichloromethane (460ml) under nitrogen at 4C. The mixture was allowed to warm to room temperature and stirred for 18 hours. The solution was washed with hydrochloric acid (1M, 2 × 150ml), water (2 × 200ml), dried (MgSO4) and concentrated under reduced pressure. The residue was azeotroped twice with cyclohexane (300ml) to give an orange gum (27.2 g). The crude product was purified by column chromatography on silica gel, eluting with dichloromethane:ethyl acetate (90:10). The product was recrystallised from cyclohexane to give the title compound as a colourless solid, 18.4g.1H nmr (CDCl3, 400MHz) delta: -0.15 (s, 3H), 0.10 (s, 3H), 0.85 (s, 9H), 3.46 (dd, 1H), 3.56 (dd, 1H), 5.14 (s, 2H), 5.15 (dd, 1H), 6.67 (d, 1H), 7.00 (d, 1H), 7.14 (d, 1H), 7.40 (s, 5H), 8.20 (d, 1H), 9.17 (br s, 1H). LRMS :m/z ES+ 488, 490 [MH+]. |
|
With 2,6-dimethylpyridine; In dichloromethane; at 0 - 20℃; |
Compound FF (15 g, 40 mmol) and 2,6-lutidine (9.3 mL, 80 mmol) were suspended in dichloromethane at 0 C. tert-Butyldimethylsilyl trifluoromethanesulfonate (18.5 mL, 80 mmol) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was diluted with dichloromethane (200 mL) and washed twice with 1N hydrochloric acid, then three times with brine. The organics were dried over magnesium sulfate and the volume was reduced to 100 mL under vacuum. The organics were applied to a silica gel column equilibrated with 30% ethyl acetate in hexanes and the product was eluted with 50% ethyl acetate in hexanes. Removal of the solvent under reduced pressure gave 5-(2-bromo-(R)-1-tert-butyldimethylsiloxy)ethyl-8-benzyloxy-2(1H)-quinolinone (HH). (10.3 g). Unreacted starting material (compound FF, 2 g) was also recovered. |
|
With 2,6-dimethylpyridine; In N,N-dimethyl-formamide; at 0 - 20℃; |
iii) 8-(Benzyloxy)-5-((li?)-2-bromo-l-[tert-butyl(dimethyl)silyl]oxy}ethyl)quinolin- 2(lH)-one; A solution of the product of step (ii) (8-(benzyloxy)-5-[(li?)-2-bromo-l- hydroxyethyl]quinolin-2(lH)-one) (1.00 g) in DMF (4 mL) was stirred and cooled to O0C and to it was added dropwise 2,6-lutidine (0.622 mL) followed by fert-butyldimethylsilyl triflate (1.23 mL). The reaction mixture was stirred at room temperature overnight then the volatiles partially evaporated. The residue was dissolved in EtOAc and washed with H2O, 2M aqueous HCl, H2O and saturated aqueous NaCl. The organics collected, dried (Na2SO4) and the volatiles evaporated. The crude material was purified using a Biotage 4OS column, eluting with 1:1 EtOAc :isohexane to afford the sub-title compound as a white solid. Yield: 1.3gMS APCI+ 488/490[M+H]+ |
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