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[ CAS No. 530084-79-8 ]

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Chemical Structure| 530084-79-8
Chemical Structure| 530084-79-8
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Product Details of [ 530084-79-8 ]

CAS No. :530084-79-8 MDL No. :MFCD20484048
Formula : C18H16BrNO3 Boiling Point : 595.8°C at 760 mmHg
Linear Structure Formula :- InChI Key :-
M.W :374.23 g/mol Pubchem ID :11530884
Synonyms :

Safety of [ 530084-79-8 ]

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:

Application In Synthesis of [ 530084-79-8 ]

  • Upstream synthesis route of [ 530084-79-8 ]
  • Downstream synthetic route of [ 530084-79-8 ]

[ 530084-79-8 ] Synthesis Path-Upstream   1~16

  • 1
  • [ 100331-89-3 ]
  • [ 530084-79-8 ]
YieldReaction ConditionsOperation in experiment
95%
Stage #1: With dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole In tetrahydrofuran at 0 - 30℃; Inert atmosphere
Stage #2: With hydrogenchloride In tetrahydrofuran at 0 - 30℃;
10068] To a mixture of tetrahydroffiran (1400 ml) and Bromo compound (100 g), R-methyl CBS (7.5 g) was slowly added at 25-30° C. under nitrogen atmosphere and cooled to 0-5° C., followed by the addition of Boron Dimethyl Sulfide complex (24.3 g) at 0-10° C. The reaction mass was stirred for 1-2 hr at 0-10° C. The progress of the reaction was monitored by HPLC. After the completionthe reaction, methanol (100 ml) was slowly added to the reaction mass for 30 minutes and stirred for 15 minutes0-10° C. The contents were distilled under vacuum attemperature of 40-45° C. and cooled to 25-30° C. The cooled reaction mixture was slowly added to hydrochloric acid solution at 25-30° C. and stirred for 1-2 hours at the same temperature. The resulted solid was filtered, washed with water (300 ml) and dried at 65-70° C. for 8 hours. percent Yield:95percent
81%
Stage #1: With Trimethylboroxine; (R)-α,α-diphenylprolinol In toluene at 20 - 150℃;
Stage #2: With borane In tetrahydrofuran; toluene at -10℃; for 4.75 h;
Stage #3: With methanol In tetrahydrofuran; toluene at -10℃;
EXAMPLE 2; Synthesis of N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine (PP); a. Synthesis of 5-(2-bromo-(R)-1-hydroxy)ethyl-8-benzyloxy-2(1H)-quinolinone (FF); (R)-(+)-α,α-Diphenylprolinol (30.0 g, 117 mmol) and trimethylboroxine (11.1 ml, 78 mmol) were combined in toluene (300 ml) and stirred at room temperature for 30 minutes. The mixture was placed in a 150° C. oil bath and liquid was distilled off. Toluene was added in 20 ml aliquots, and distillation was continued for 4 hours. A total of 300 ml toluene was added. The mixture was finally cooled to room temperature. A 500 μL aliquot was evaporated to dryness, weighed (246 mg) to determine that the concentration of catalyst was 1.8 M. [0128] 5-(2-Bromo-1-oxy)ethyl-8-benzyloxy-2(1H)-quinolinone (R) (90.0 g, 243 mmol) was placed under nitrogen, tetrahydrofuran (900 mL) was added followed by the catalyst from above (1.8 M in toluene, 15 ml, 27 mmol). The suspension was cooled to -10+5° C. in an ice/isopropanol bath. Borane (1.0 M in THF, 294 ml, 294 mmol) was added over 4 hours. The reaction was stirred an additional 45 minutes at -10° C., then methanol (250 ml) was added slowly. The mixture was concentrated under vacuum. The residue was dissolved in boiling acetonitrile (1.3 l), filtered while hot and cooled to room temperature. The crystals were filtered, washed with acetonitrile and dried under vacuum to give 5-(2-bromo-(R)-1-hydroxy)ethyl-8-benzyloxy-2(1H)-quinolinone (FF) (72.5 g, 196 mmol, 81percent yield, 95percent ee, 95percent pure by HPLC area ratio).
81% With borane In tetrahydrofuran; toluene at -10℃; for 4.75 h; (R)-(+)-α,α-Diphenylprolinol (30.0 g, 117 mmol) and trimethylboroxine (11.1 mL, 78 mmol) were combined in toluene (300 mL) and stirred at room temperature for 30 min. The mixture was placed in a 150° C. oil bath and liquid was distilled off. Toluene was added in 20 mL aliquots and distillation was continued for 4 h. A total of 300 mL toluene was added. The mixture was then cooled to room temperature. A 500 μL aliquot was evaporated to dryness and weighed (246 mg) to determine that the concentration of catalyst was 1.8M. [0523] 8-Benzyloxy 5-(2-bromoacetyl)-1H-quinolin-2-one (90.0 g, 243 mmol) was placed under nitrogen and tetrahydrofuran (900 mL) was added followed by the catalyst described above (1.8 M in toluene, 15 mL, 27 mmol). The suspension was cooled to -10+5° C. in an ice/isopropanol bath. Borane (1.0 M in THF, 294 mL, 294 mmol) was added over 4 h. The reaction was then stirred an additional 45 min at -10° C. and then methanol (250 mL) was added slowly. The mixture was concentrated under vacuum and the residue was dissolved in boiling acetonitrile (1.3 L), filtered while hot and then cooled to room temperature. The crystals were filtered, washed with acetonitrile and dried under vacuum to give the title compound (72.5 g, 196 mmol, 81percent yield, 95percent ee, 95percent pure by HPLC).
81%
Stage #1: With Trimethylboroxine In toluene at 20 - 150℃; for 4.5 h;
Stage #2: With borane In tetrahydrofuran; toluene at -10℃; for 4.75 h;
(b)
8-Benzyloxy-5-((R)-2-bromo-1-hydroxyethyl)-1H-quinolin-2-one
(R)-(+)-α,α-Diphenylprolinol (30.0 g, 117 mmol) and trimethylboroxine (11.1 ML, 78 mmol) were combined in toluene (300 ML) and stirred at room temperature for 30 min.The mixture was placed in a 150° C. oil bath and liquid was distilled off.toluene was added in 20 ML aliquots and distillation was continued for 4 h.A total of 300 ML toluene was added.The mixture was then cooled to room temperature.A 500 μL aliquot was evaporated to dryness and weighed (246 mg) to determine that the concentration of catalyst was 1.8M.
8-Benzyloxy 5-(2-bromoacetyl)-1H-quinolin-2-one (90.0 g, 243 mmol) was placed under nitrogen and tetrahydrofuran (900 ML) was added followed by the catalyst described above (1.8 M in toluene, 15 ML, 27 mmol).The suspension was cooled to -10+5° C. in an ice/isopropanol bath.Borane (1.0 M in THF, 294 ML, 294 mmol) was added over 4 h.The reaction was then stirred an additional 45 min at -10° C. and then methanol (250 ML) was added slowly.The mixture was concentrated under vacuum and the residue was dissolved in boiling acetonitrile (1.3 L), filtered while hot and then cooled to room temperature.The crystals were filtered, washed with acetonitrile and dried under vacuum to give the title compound (72.5 g, 196 mmol, 81percent yield, 95percent ee, 95percent pure by HPLC).
81%
Stage #1: With borane-THF In toluene at -10℃; for 4.75 h; Cooling with isopropanol-ice
Stage #2: With methanol In toluene
(R)-(+)-α,α-Diphenylprolinol (30.0 g, 117 mmol) and trimethylboroxine (11.1 mL, 78 mmol) were combined in toluene (300 mL) and stirred at room temperature for 30 min.
The mixture was placed in a 150° C. oil bath and liquid was distilled off.
Toluene was added in 20 mL aliquots and distillation was continued for 4 h.
A total of 300 mL toluene was added.
The mixture was then cooled to room temperature.
A 500 μL aliquot was evaporated to dryness and weighed (246 mg) to determine that the concentration of catalyst was 1.8 M.
8-Benzyloxy 5-(2-bromoacetyl)-1H-quinolin-2-one (90.0 g, 243 mmol) was placed under nitrogen and tetrahydrofuran (900 mL) was added followed by the catalyst described above (1.8 M in toluene, 15 mL, 27 mmol).
The suspension was cooled to -10+-5° C. in an ice/isopropanol bath.
Borane (1.0 M in THF, 294 mL, 294 mmol) was added over 4 h.
The reaction was then stirred an additional 45 min at -10° C. and then methanol (250 mL) was added slowly.
The mixture was concentrated under vacuum and the residue was dissolved in boiling acetonitrile (1.3 L), filtered while hot and then cooled to room temperature.
The crystals were filtered, washed with acetonitrile and dried under vacuum to give the title compound (72.5 g, 196 mmol, 81percent yield, 95percent ee, 95percent pure by HPLC).
81%
Stage #1: With Trimethylboroxine; (R)-α,α-diphenylprolinol In toluene at 20 - 150℃; for 4.5 h;
Stage #2: With trimethylborane In tetrahydrofuran; toluene at -15 - -5℃; for 4.75 h; Cooling with ice-isopropanol
(7?)-(+)-a,a-Diphenylprolinol (30.0 g, 117 mmol) and trimethylboroxine (11.1 mL, 78 mmol) were combined in toluene (300 mL) and stirred at room temperature for 30 min. The mixture was placed in a 150 °C oil bath and liquid was distilled off. Toluene was added in 20 mL aliquots and distillation was continued for 4 h. A total of 300 mL toluene was added. The mixture was then cooled to room temperature. A 500 uL aliquot was evaporated to dryness and weighed (246 mg) to determine that the concentration of catalyst was 1.8 M.8-Benzyloxy 5-(2-bromoacetyl)-l//-quinolin-2-one (90.0 g, 243 mmol) was placed under nitrogen and tetrahydrofuran (900 mL) was added followed by the catalyst described above (1.8 M in toluene, 15 mL, 27 mmol). The suspension was cooled to -10+-5 °C in an ice/isopropanol bath. Borane (1.0 M in THF, 294 mL, 294 mmol) was added over 4 h. The reaction was then stirred an additional 45 min at -10 °C and then methanol (250 mL) was added slowly. The mixture was concentrated under vacuum and the residue was dissolved in boiling acetonitrile (1.3 L), filtered while hot and then cooled to room temperature. The crystals were filtered, washed with acetonitrile and dried under vacuum to gjve the title compound (72.5 g, 196 mmol, 81percent yield, 95percent ee, 95percent pure by HPLC).
81% With borane In tetrahydrofuran at -10 - 5℃; for 4.75 h; (R)-(+)-α,α-Diphenylprolinol (30.0 g, 117 mmol) and trimethylboroxine (11.1 mL, 78 mmol) were combined in toluene (300 mL) and stirred at room temperature for 30 minutes. The mixture was placed in a 150° C. oil bath and liquid was distilled off. Toluene was added in 20 mL aliquots, and distillation was continued for 4 hours. A total of 300 mL toluene was added. The mixture was finally cooled to room temperature. A 500 μL aliquot was evaporated to dryness, weighed (246 mg) to determine that the concentration of catalyst was 1.8 M. 5-(2-Bromo-1-oxy)ethyl-8-benzyloxy-2(1H)-quinolinone (R) (90.0 g, 243 mmol) was placed under nitrogen, tetrahydrofuran (900 mL) was added followed by the catalyst from above (1.8 M in toluene, 15 mL, 27 mmol). The suspension was cooled to -10+/-5° C. in an ice/isopropanol bath. Borane (1.0 M in THF, 294 mL, 294 mmol) was added over 4 hours. The reaction was stirred an additional 45 minutes at -10° C., then methanol (250 mL) was added slowly. The mixture was concentrated under vacuum. The residue was dissolved in boiling acetonitrile (1.3 L), filtered while hot and cooled to room temperature. The crystals were filtered, washed with acetonitrile and dried under reduced pressure to give 5-(2-bromo-(R)-1-hydroxy)ethyl-8-benzyloxy-2(1H)-quinolinone (FF) (72.5 g, 196 mmol, 81percent yield, 95percent ee, 95percent pure by HPLC area ratio).
81%
Stage #1: at 20 - 150℃; for 4.5 h;
Stage #2: With borane In tetrahydrofuran; methanol; toluene at -15 - -5℃; for 4.75 h; Cooling with ice/isopropanol bath
(R)-(+)-α,α-DIPHENYLPROLINOL (30.0 g, 117 mmol) and trimethylboroxine (11.1 mL, 78 mmol) were combined in toluene (300 mL) and stirred at room temperature for 30 min. The mixture was placed in a 150 °C oil bath and liquid was distilled off. Toluene was added in 20 mL aliquots and distillation was continued for 4 h. A total of 300 mL toluene was added. The mixture was then cooled to room temperature. A 500 pL aliquot was evaporated to dryness and weighed (246 mg) to determine that the concentration of catalyst was 1. 8 M. 8-BENZYLOXY 5- (2-bromoacetyl)-lH-quinolin-2-one (90.0 g, 243 mmol) was placed under nitrogen and tetrahydrofuran (900 mL) was added followed by the catalyst described above (1. 8 M in toluene, 15 mL, 27 mmol). The suspension was cooled TO-1 °C in an ice/isopropanol bath. Borane (1.0 M in THF, 294 mL, 294 mmol) was added over 4 h. The reaction was then stirred an additional 45 min at-10 °C and then methanol (250 mL) was added slowly. The mixture was concentrated under vacuum and the residue was dissolved in boiling acetonitrile (1.3 L), filtered while hot and then cooled to room temperature. The crystals were filtered, washed with acetonitrile and dried under vacuum to give the title compound (72.5 g, 196 mmol, 81percent yield, 95percent EE, 95percent pure by HPLC).
81%
Stage #1: With Trimethylboroxine; borane; (R)-α,α-diphenylprolinol In tetrahydrofuran; toluene; acetonitrile at -15 - 20℃; for 5.25 h;
Stage #2: With methanol In tetrahydrofuran
Preparation 5
8-Benzyloxy-5-((R)-2-bromo-1-hydroxyethyl)-1H-quinolin-2-one
(R)-(+)-α,α-Diphenylprolinol (30.0 g, 117 mmol) and trimethylboroxine (11.1 mL, 78 mmol) were combined in toluene (300 mL) and stirred at room temperature for 30 min.
The mixture was placed in a 150° C. oil bath and liquid was distilled off.
Toluene was added in 20 mL aliquots and distillation was continued for 4 h.
A total of 300 mL toluene was added.
The mixture was then cooled to room temperature.
A 500 μL aliquot was evaporated to dryness and weighed (246 mg) to determine that the concentration of catalyst was 1.8 M. 8-Benzyloxy 5-(2-bromoacetyl)-1H-quinolin-2-one (90.0 g, 243 mmol) was placed under nitrogen and tetrahydrofuran (900 mL) was added followed by the catalyst described above (1.8 M in toluene, 15 mL, 27 mmol).
The suspension was cooled to -10+-5° C. in an ice/isopropanol bath.
Borane (1.0 M in THF, 294 mL, 294 mmol) was added over 4 h.
The reaction was then stirred an additional 45 min at -10° C. and then methanol (250 mL) was added slowly.
The mixture was concentrated under vacuum and the residue was dissolved in boiling acetonitrile (1.3 L), filtered while hot and then cooled to room temperature.
The crystals were filtered, washed with acetonitrile and dried under vacuum to give the title compound (72.5 g, 196 mmol, 81percent yield, 95percent ee, 95percent pure by HPLC).
76%
Stage #1: With dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole In tetrahydrofuran; toluene at -20℃; for 4 h; Inert atmosphere
Stage #2: With methanol In tetrahydrofuran; toluene at -20 - 20℃; for 0.333333 h;
Stage #3: With hydrogenchloride In water at 20℃; for 18 h;
Preparation intermediate 4(R)-8-(Benzyloxy)-5-(2-bromo-l-hydroxyethyl)quinolin-2(l//)-one8-(Benzyloxy)-5-(2-bromoacetyl)quinolin-2(lH)-one (26.0 g, 69.9 mmol) and (R)-3,3-diphenyl-l -methyltetrahydro-3H-pyrrolo[l ,2- c][ l ,3,2]oxazaborole (21.3 g, 76.8 mmol) were azeotroped with toluene (x 3) then suspended in anhydrous THF (400 mL) under an atmosphere of nitrogen. The suspension was cooled to -20°C (external temperature) and borane dimethyl sulfide complex solution (45.4 mL, 90.8 mmol, 2.0 M solution in THF) was added by syringe pump over 3 hours. After complete addition the reaction mixture was stirred for an hour before quenching with methanol (25 mL). The reaction was warmed to T over 20 minutes. The mixture was concentrated in vacuo and the residue was suspended in aqueous hydrochloric acid (500 mL, 1 M solution) and stirred at RT for 18 hours. After this time the solid was collected by filtration and washed with water (x 3). The solid was partially dissolved in ethyl acetate and heated at reflux for 2 hours. The remaining solid was removed by hot filtration and the filtrate was evaporated to afford the title compound. The solid collected from the hot ethyl acetate was again partially dissolved in ethyl acetate and heated at reflux for 2 hours then filtered to give filtrate containing pure product. This process was repeated four more times. The combined solid was recrystallised from ethyl acetate and petroleum ether to afford the title compound (20.0 g, 76percent). NMR (400 MHz, DMSO): δ 10.68 (s, 1 H), 8.19 (d, J = 9.9 Hz, 1 H), 7.58 (d, J = 7.5 Hz, 2 H), 7.41 -7.36 (m, 2 H), 7.34-7.29 (m, 1 H), 7.23-7.19 (m, 2 H), 6.57 (d, J = 9.8 Hz, 1 H), 5.94 (d, J = 4.7 Hz, 1 H), 5.31 (s, 2 H), 5.25-5.19 (m, 1 H), 3.71 -3.58 (m, 2 H).
76%
Stage #1: With dimethylsulfide borane complex In tetrahydrofuran; toluene at -20℃; for 3 h; Inert atmosphere
Stage #2: With methanol In tetrahydrofuran; toluene at 20℃; for 0.333333 h;
Stage #3: With hydrogenchloride In water at 20℃; for 18 h;
8-(Benzyloxy)-5-(2-bromoacetyl)quinolin-2(lH)-one (26.069.9 mmol) and fR -S^-diphenyl- l-methyltetrahydro-SH-pyrrolof l ^- c][l ,3,2]oxazaborole (21.3 g, 76.8 mmol) were azeotroped with toluene (x 3) then suspended in anhydrous THF (400 mL) under an atmosphere of nitrogen. The suspension was cooled to -20°C (external temperature) and borane dimethyl sulfide complex solution (45.4 mL, 90.8 mmol, 2.0 M solution in THF) was added by syringe pump over 3 hours. After complete addition the reaction mixture was stirred for one hour before quenching with methanol (25 mL). The reaction was warmed to RT over 20 minutes. The mixture was concentrated under reduced pressure and the residue was suspended in aqueous hydrochloric acid (500 mL, 1 M solution) and stirred at RT for 18 hours. After this time the solid was collected by filtration and washed with water (3 x 100 mL). The solid was partially dissolved in ethyl acetate and heated at reflux for 2 hours. The remaining solid was removed by hot filtration and the filtrate was evaporated to afford the title compound. The solid collected from the hot ethyl acetate was again partially dissolved in ethyl acetate and heated at reflux for 2 hours then filtered to give filtrate containing pure product. This process was repeated four more times. The combined solid was recrystallised from ethyl acetate and petroleum ether to afford the title compound (20.0 g, 76percent). NMR (400 MHz, DMSO-d6): δ 10.68 (s, 1 H); 8.19 (d, J = 9.9 Hz, 1 H); 7.58 (d, J = 7.5 Hz, 2 H); 7.41 -7.36 (m, 2 H); 7.34-7.29 (m, 1 H); 7.23-7.19 (m, 2 H); 6.57 (d, J = 9.8 Hz, 1 H); 5.94 (d, J = 4.7 Hz, 1 H); 5.31 (s, 2 H); 5.25-5.19 (m, 1 H); 3.71 -3.58 (m, 2 H).
76%
Stage #1: With (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole In tetrahydrofuran at -20 - 20℃; for 4.33333 h; Inert atmosphere
Stage #2: With hydrogenchloride In water at 20℃; for 18 h;
8-(Benzyloxy)-5-(2-bromoacetyl)quinolin-2(1H)-one (26.0 g, 69.9 mmol) and (R)-3,3-diphenyl-1-methyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole (21.3 g, 76.8 mmol) were azeotroped with toluene (*3) then suspended in anhydrous THF (400 mL) under an atmosphere of nitrogen.
The suspension was cooled to -20° C. (external temperature), and borane dimethyl sulfide complex solution (45.4 mL, 90.8 mmol, 2.0 M solution in THF) was added by syringe pump over 3 hours.
After complete addition the reaction mixture was stirred for an hour before quenching with methanol (25 mL).
The reaction was warmed to RT over 20 minutes.
The mixture was concentrated in vacuo and the residue was suspended in aqueous hydrochloric acid (500 mL, 1 M solution) and stirred at RT for 18 hours.
After this time, the solid was collected by filtration and washed with water (*3).
The solid was partially dissolved in ethyl acetate and heated at reflux for 2 hours.
The remaining solid was removed by hot filtration, and the filtrate was evaporated to afford the title compound.
The solid collected from the hot ethyl acetate was again partially dissolved in ethyl acetate and heated at reflux for 2 hours then filtered to give filtrate containing pure product.
This process was repeated four more times.
The combined solid was recrystallised from ethyl acetate and petroleum ether to afford the title compound (20.0 g, 76percent).
1H NMR (400 MHz, DMSO): δ 10.68 (s, 1H), 8.19 (d, J=9.9 Hz, 1H), 7.58 (d, J=7.5 Hz, 2H), 7.41-7.36 (m, 2H), 7.34-7.29 (m, 1H), 7.23-7.19 (m, 2H), 6.57 (d, J=9.8 Hz, 1H), 5.94 (d, J=4.7 Hz, 1H), 5.31 (s, 2H), 5.25-5.19 (m, 1H), 3.71-3.58 (m, 2H).
76% With dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole In tetrahydrofuran at -20℃; for 4 h; Step 2:
(R)-8-(Benzyloxy)-5-(2-bromo-1-hydroxyethyl)quinolin-2(1H)-one
8-(Benzyloxy)-5-(2-bromoacetyl)quinolin-2(1H)-one (26.0 g, 69.9 mmol) and (R)-3,3-diphenyl-1-methyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole (21.3 g, 76.8 mmol) were azeotroped with toluene (*3) then suspended in anhydrous THF (400 mL) under an atmosphere of nitrogen.
The suspension was cooled to -20° C. (external temperature) and borane dimethyl sulfide complex solution (45.4 mL, 90.8 mmol, 2.0 M solution in THF) was added by syringe pump over 3 hours.
After complete addition the reaction mixture was stirred for one hour before quenching with methanol (25 mL).
The reaction was warmed to RT over 20 minutes.
The mixture was concentrated under reduced pressure and the residue was suspended in aqueous hydrochloric acid (500 mL, 1 M solution) and stirred at RT for 18 hours.
After this time the solid was collected by filtration and washed with water (3*100 mL).
The solid was partially dissolved in ethyl acetate and heated at reflux for 2 hours.
The remaining solid was removed by hot filtration and the filtrate was evaporated to afford the title compound.
The solid collected from the hot ethyl acetate was again partially dissolved in ethyl acetate and heated at reflux for 2 hours then filtered to give filtrate containing pure product.
This process was repeated four more times.
The combined solid was recrystallised from ethyl acetate and petroleum ether to afford the title compound (20.0 g, 76percent).
1H NMR (400 MHz, DMSO-d6): δ 10.68 (s, 1H); 8.19 (d, J=9.9 Hz, 1H); 7.58 (d, J=7.5 Hz, 2H); 7.41-7.36 (m, 2H); 7.34-7.29 (m, 1H); 7.23-7.19 (m, 2H); 6.57 (d, J=9.8 Hz, 1H); 5.94 (d, J=4.7 Hz, 1H); 5.31 (s, 2H); 5.25-5.19 (m, 1H); 3.71-3.58 (m, 2H).
76% With dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole In tetrahydrofuran; toluene at -20 - 20℃; Inert atmosphere 8-(Benzyloxy)-5-(2-bromoacetyl)quinolin-2(lH)-one (26.0 g, 69.9 mmol) and (^-3,3-diphenyl- 1 -methyltetrahydro-3H-pyrrolo[ 1 ,2-c][ 1 ,3,2]oxazaborole (21.3 g, 76.8 mmol) were azeotroped with toluene (x 3) then suspended in anhydrous THF (400 mL) under an atmosphere of nitrogen. The suspension was cooled to -20 °C (external temperature) and borane dimethyl sulfide (BH3-Me2S) complex solution (45.4 mL, 90.8 mmol, 2.0 M solution in THF) was added by syringe pump over 3 hours. After complete addition the reaction mixture was stirred for one hour before quenching with methanol (25 mL). The reaction was warmed to RT over 20 minutes. The mixture was concentrated under reduced pressure and the residue was suspended in aqueous hydrochloric acid (500 mL, 1 M solution) and stirred at RT for 18 hours. After this time the solid was collected by filtration and washed with water (3 x 100 mL). The solid was partially dissolved in ethyl acetate and refluxed for 2 hours. The remaining solid was removed by hot filtration and the filtrate was evaporated to afford the title compound. The solid collected from the hot ethyl acetate was again partially dissolved in ethyl acetate and refluxed for 2 hours then filtered to give filtrate containing pure product. This process was repeated four more times. The combined solid was recrystallised from ethyl acetate and petroleum ether to afford the title compound (20.0 g, 76percent). 1HNMR (400 MHz, DMSO-d6): δ 10.68 (s, 1 H); 8.19 (d, J = 9.9 Hz, 1 H); 7.58 (d, J = 7.5 Hz, 2 H); 7.41-7.36 (m, 2 H); 7.34-7.29 (m, 1 H); 7.23-7.19 (m, 2 H); 6.57 (d, J = 9.8 Hz, 1 H); 5.94 (d, J = 4.7 Hz, 1 H); 5.31 (s, 2 H); 5.25-5.19 (m, 1 H); 3.71-3.58 (m, 2 H).
76%
Stage #1: With (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole In tetrahydrofuran; toluene at -20℃; Inert atmosphere
Stage #2: With dimethyl sulfide borane In tetrahydrofuran; toluene at -20℃; for 4 h; Inert atmosphere
8-(l3enzyloxy)-5-(2-bromoacetyl)quinolin-2(1 H)- one (26.0 g, 69.9 mmol) and (R)-3,3-diphenyl-1-methyltet- rahydro-3H-pyrrolo[1 ,2-c] [1 ,3,2]oxazaborole (21.3 g, 76.8 mmol) were azeotroped with toluene (x3) then suspended in anhydrous THF (400 mE) under an atmosphere of nitrogen. The suspension was cooled to —20° C. (external temperature) and borane dimethyl sulfide complex solution (45.4 mE, 90.8 mmol, 2.0 M solution in THF) was added by syringe pump over 3 hours. Afier complete addition the reaction mixture was stirred for one hour before quenching with methanol (25 mE). The reaction was warmed to room temperature over 20 minutes. The mixture was concentrated under reduced pressure and the residue was suspended in aqueous hydrochloric acid (500 mE, 1 M solution) and stirred at room temperature for 18 hours. After this time the solid was collected by filtration and washed with water (3x100 mE). The solid was partially dissolved in ethyl acetate and heated at reflux for 2 hours. The remaining solid was removed by hot filtration and the filtrate was evaporated to afford the title compound. The solid collected from the hot ethyl acetate was again partially dissolved in ethyl acetate and heated at reflux for 2 hours then filtered to give filtrate containing pure product. This process was repeated four more times. The combined solid was recrystallised from ethyl acetate and petroleum ether to afford the title compound (20.0 g, 76percent). 1H NMR (400 MHz, DMSO-d5): ö 10.68 (s, 1H),8.19 (d, J=9.9 Hz, 1H), 7.58 (d, J=7.5 Hz, 2H), 7.41-7.36 (m,2H), 7.34-7.29 (m, 1H), 7.23-7.19 (m, 2H), 6.57 (d, J=9.8 Hz,1H), 5.94 (d, J=4.7 Hz, 1H), 5.31 (s, 2H); 5.25-5.19 (m, 1H),3.71-3.58 (m, 2H).
76% With borane dimethyl sulfide complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole In tetrahydrofuran; toluene at -20℃; for 4 h; Inert atmosphere 8-(benzyloxy)-5-(2-bromoacetyl)quinolin-2(1H)-one (26.0 g, 69.9 mmol) and (R)- 3 ,3-diphenyl- 1 -methyltetrahydro-3H-pyrrolo [ 1 ,2-c] [ 1 ,3 ,2]oxazaborole (21.3 g, 76.8 mmol) were azeotroped with toluene (x 3) then suspended in anhydrous THF (400 mL) under an atmosphere of nitrogen. The suspension was cooled to -20°C (external temperature) and borane dimethyl sulfide complex solution (45.4 mL, 90.8 mmol, 2.0 M solution in THF) was added by syringe pump over 3 hours. After complete addition the reaction mixture was stirred for one hour before quenching with methanol (25 mL). The reaction was warmed to room temperature over 20 minutes. The mixture was concentrated under reduced pressure and the residue was suspended in aqueous hydrochloric acid (500 mL, 1 M solution) and stirred at room temperature for 18 hours. After this time the solid was collected by filtration and washed with water (3 x 100 mL). The solid was partially dissolved in ethyl acetate and heated at reflux for 2 hours. The remaining solid was removed by hot filtration and the filtrate was evaporated to afford the title compound. The solid collected from the hot ethyl acetate was again partially dissolved in ethyl acetate and heated at reflux for 2 hours then filtered to give filtrate containing pure product. This process was repeated four more times. The combined solid was recrystallised from ethyl acetate and petroleum ether to afford the title compound (20.0 g, 76percent). NMR (400 MHz, DMSO-d6): δ 10.68 (s, 1 H), 8.19 (d, J= 9.9 Hz, 1 H), 7.58 (d, J = 7.5 Hz, 2 H), 7.41-7.36 (m, 2 H), 7.34-7.29 (m, 1 H), 7.23-7.19 (m, 2 H), 6.57 (d, J = 9.8 Hz, 1 H), 5.94 (d, J = 4.7 Hz, 1 H), 5.31 (s, 2 H); 5.25-5.19 (m, 1 H), 3.71-3.58 (m, 2 H).
76% With dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole In tetrahydrofuran; toluene at -20℃; for 4 h; Inert atmosphere 8-(Benzyloxy)-5-(2-bromoacetyl)quinolin-2(lH)-one (26.0 g, 69.9 mmol) and (R)- 3,3-diphenyl-l-methyltetrahydro-3H-pyrrolo[l,2-c][l,3,2]oxazaborole (21.3 g, 76.8 mmol) were azeotroped with toluene (x 3) then suspended in anhydrous THF (400 mL) under an atmosphere of nitrogen. The suspension was cooled to -20°C (external temperature) and borane dimethyl sulfide complex solution (45.4 mL, 90.8 mmol, 2.0 M solution in THF) was added by syringe pump over 3 hours. After complete addition the reaction mixture was stirred for one hour before quenching with methanol (25 mL). The reaction was warmed to room temperature over 20 minutes. The mixture was concentrated under reduced pressure and the residue was suspended in aqueous hydrochloric acid (500 mL, 1 M solution) and stirred at room temperature for 18 hours. After this time the solid was collected by filtration and washed with water (3 χ 100 mL). The solid was partially dissolved in ethyl acetate and heated at reflux for 2 hours. The remaining solid was removed by hot filtration and the filtrate was evaporated to afford the title compound. The solid collected from the hot ethyl acetate was again partially dissolved in ethyl acetate and heated at reflux for 2 hours then filtered to give filtrate containing pure product. This process was repeated four more times. The combined solid was recrystallised from ethyl acetate and petroleum ether to afford the title compound (20.0 g, 76percent). NMR (400 MHz, DMSO-d6): δ 10.68 (s, 1 H), 8.19 (d, J= 9.9 Hz, 1 H), 7.58 (d, J= 7.5 Hz, 2 H), 7.41-7.36 (m, 2 H), 7.34-7.29 (m, 1 H), 7.23-7.19 (m, 2 H), 6.57 (d, J= 9.8 Hz, 1 H), 5.94 (d, J= 4.7 Hz, 1 H), 5.31 (s, 2 H); 5.25-5.19 (m, 1 H), 3.71-3.58 (m, 2 H).
95 % ee With borane-THF In tetrahydrofuran; toluene at -10℃; for 4.75 h; (R)-(+)-α,α-Diphenylprolinol (30.0 g, 117 mmol) and trimethylboroxine (11.1 mL, 78 mmol) were combined in toluene (300 mL) and stirred at room temperature for 30 min. The mixture was placed in a 150° C. oil bath and liquid was distilled off. Toluene was added in 20 mL aliquots and distillation was continued for 4 h. A total of 300 mL toluene was added. The mixture was then cooled to room temperature. A 500 μL aliquot was evaporated to dryness and weighed (246 mg) to determine that the concentration of catalyst was 1.8 M. 8-Benzyloxy 5-(2-bromoacetyl)-1H-quinolin-2-one (90.0 g, 243 mmol) was placed under nitrogen and tetrahydrofuran (900 mL) was added followed by the catalyst described above (1.8 M in toluene, 15 μL, 27 mmol). The suspension was cooled to -10+/-5° C. in an ice/isopropanol bath. Borane (1.0 M in THF, 294 mL, 294 mmol) was added over 4 h. The reaction was then stirred an additional 45 min at -10° C. and then methanol (250 mL) was added slowly. The mixture was concentrated under vacuum and the residue was dissolved in boiling acetonitrile (1.3 L), filtered while hot and then cooled to room temperature. The crystals were filtered, washed with acetonitrile and dried under vacuum to give the title compound (72.5 g, 196 mmol, 81percent yield, 95percent ee, 95percent pure by HPLC).

Reference: [1] Patent: US2016/326118, 2016, A1, . Location in patent: Paragraph 0067; 0068
[2] Patent: US2004/224982, 2004, A1, . Location in patent: Page 3; 10
[3] Patent: US2004/242622, 2004, A1, . Location in patent: Page 30
[4] Patent: US2004/167167, 2004, A1, . Location in patent: Page/Page column 34
[5] Patent: US2006/35933, 2006, A1, . Location in patent: Page/Page column 25
[6] Patent: WO2006/23457, 2006, A1, . Location in patent: Page/Page column 66
[7] Patent: US2003/229058, 2003, A1, . Location in patent: Page 49-50
[8] Patent: WO2004/89892, 2004, A2, . Location in patent: Page 86
[9] Patent: US2005/182092, 2005, A1, . Location in patent: Page/Page column 11
[10] Patent: WO2012/168349, 2012, A1, . Location in patent: Page/Page column 31-32
[11] Patent: WO2012/168359, 2012, A1, . Location in patent: Page/Page column 57; 58
[12] Patent: US2013/34504, 2013, A1, . Location in patent: Paragraph 0123; 0124; 0125
[13] Patent: US2014/163066, 2014, A1, . Location in patent: Paragraph 0212-0214
[14] Patent: WO2014/86924, 2014, A1, . Location in patent: Page/Page column 40; 41; 42
[15] Patent: US2016/235734, 2016, A1, . Location in patent: Paragraph 0358; 0359; 0360
[16] Patent: WO2016/193241, 2016, A1, . Location in patent: Page/Page column 38-39
[17] Patent: WO2017/93208, 2017, A1, . Location in patent: Page/Page column 28; 29; 30
[18] Patent: EP1574501, 2005, A1, . Location in patent: Page/Page column 23
[19] Patent: US2006/35931, 2006, A1, . Location in patent: Page/Page column 13-14
[20] Patent: US2003/229058, 2003, A1, . Location in patent: Page 48
[21] Patent: US2012/46467, 2012, A1, . Location in patent: Page/Page column 20
[22] Organic Process Research and Development, 2015, vol. 19, # 1, p. 315 - 319
[23] Patent: WO2007/102771, 2007, A1, . Location in patent: Page/Page column 63-64
[24] Patent: WO2008/104781, 2008, A1, . Location in patent: Page/Page column 40
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Reference: [1] Patent: JP2015/17075, 2015, A, . Location in patent: Paragraph 0122-0124
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YieldReaction ConditionsOperation in experiment
76% liquid HCl Step 2:
(R)-8-(Benzyloxy)-5-(2-bromo-1-hydroxyethyl)quinolin-2(1H)-one
8-(Benzyloxy)-5-(2-bromoacetyl)quinolin-2(1H)-one (26.0 g, 69.9 mmol) and (R)-3,3-diphenyl-1-methyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole (21.3 g, 76.8 mmol) were azeotroped with toluene (*3) then suspended in anhydrous THF (400 mL) under an atmosphere of nitrogen.
The suspension was cooled to -20° C. (external temperature) and borane dimethyl sulfide (BH3-Me2S) complex solution (45.4 mL, 90.8 mmol, 2.0 M solution in THF) was added by syringe pump over 3 hours.
After complete addition the reaction mixture was stirred for one hour before quenching with methanol (25 mL).
The reaction was warmed to RT over 20 minutes.
The mixture was concentrated under reduced pressure and the residue was suspended in aqueous hydrochloric acid (500 mL, 1 M solution) and stirred at RT for 18 hours.
After this time the solid was collected by filtration and washed with water (3*100 mL).
The solid was partially dissolved in ethyl acetate and heated at reflux for 2 hours.
The remaining solid was removed by hot filtration and the filtrate was evaporated to afford the title compound.
The solid collected from the hot ethyl acetate was again partially dissolved in ethyl acetate and heated at reflux for 2 hours then filtered to give filtrate containing pure product.
This process was repeated four more times.
The combined solid was recrystallised from ethyl acetate and petroleum ether to afford the title compound (20.0 g, 76percent).
1H NMR (400 MHz, DMSO-d6): δ 10.68 (s, 1H); 8.19 (d, J=9.9 Hz, 1H); 7.58 (d, J=7.5 Hz, 2H); 7.41-7.36 (m, 2H); 7.34-7.29 (m, 1H); 7.23-7.19 (m, 2H); 6.57 (d, J=9.8 Hz, 1H); 5.94 (d, J=4.7 Hz, 1H); 5.31 (s, 2H); 5.25-5.19 (m, 1H); 3.71-3.58 (m, 2H).
Reference: [1] Patent: US2014/161736, 2014, A1, . Location in patent: Page/Page column
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Reference: [1] Patent: US2012/46467, 2012, A1,
[2] Patent: WO2012/168349, 2012, A1,
[3] Patent: WO2012/168359, 2012, A1,
[4] Patent: US2013/34504, 2013, A1,
[5] Patent: US2014/161736, 2014, A1,
[6] Patent: US2014/163066, 2014, A1,
[7] Patent: WO2014/86924, 2014, A1,
[8] Patent: US2016/235734, 2016, A1,
[9] Patent: WO2016/193241, 2016, A1,
[10] Patent: WO2017/93208, 2017, A1,
[11] Patent: WO2007/102771, 2007, A1,
[12] Patent: WO2008/104781, 2008, A1,
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Reference: [1] Patent: US2012/46467, 2012, A1,
[2] Patent: WO2008/104781, 2008, A1,
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Reference: [1] Organic Process Research and Development, 2015, vol. 19, # 1, p. 315 - 319
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