| 73% |
With tetra-N-butylammonium tribromide; In tetrahydrofuran; methanol; at 20℃; |
To a suspension of 5-acetyl-8-(benzyloxy)quinolin-2(lH)-one (19.4 g, 66.4 mmol) in anhydrous THF (240 mL) and anhydrous methanol (165 mL) was added a solution of tetra-n-butylammonium tribromide (54.5 g, 1 13.0 mmol) in anhydrous THF (130 mL) dropwise over 1.5 hours. The resulting solution was stirred at RT overnight before concentrating under reduced pressure without heating. The residue was re-dissolved in methanol (200 mL). Saturated aqueous ammonium chloride solution (390 mL) was added with ice- cooling. The resulting suspension was filtered and the solid washed with water and air-dried under vacuum. The solid was suspended in DCM and methanol (1 : 1 v/v, 100 mL) for 90 minutes. The solid was collected by filtration, washed with DCM and air-dried to afford the title compound (18.0 g, 73%). NMR (400 MHz, DMSO-d6): delta 1 1.07 (s, 1 H), 8.51 (d, J = 10.0 Hz, 1 H), 7.94-7.83 (m, 1 H), 7.60 (d, J = 7.5 Hz, 2 H), 7.44-7.27 (m, 4 H), 6.79-6.65 (m, 1 H), 5.53-5.39 (s, 2 H); 4.93 (s, 2 H) |
| 73% |
With tetra-N-butylammonium tribromide; In tetrahydrofuran; methanol; at 20℃; |
To a suspension of <strong>[93609-84-8]5-acetyl-8-(benzyloxy)quinolin-2(1H)-one</strong> (19.4 g, 66.4 mmol) in anhydrous THF (240 mL) and anhydrous methanol (165 mL), a solution of tetra-n-butylammonium tribromide (54.5 g, 113.0 mmol) in anhydrous THF (130 mL) was added dropwise over 1.5 hours. The resultant solution was stirred at RT overnight before concentrating under reduced pressure without heating. The residue was re-dissolved in methanol (200 mL). Saturated aqueous ammonium chloride solution (390 mL) was added with ice-cooling. The resultant suspension was filtered, and the solid was washed with water and dried under vacuum. The solid was suspended in dichloromethane and methanol (1:1 v/v, 100 mL) for 90 minutes. The solid was collected by filtration, washed with dichloromethane and air-dried to afford the title compound (18.0 g, 73%). 1H NMR (400 MHz, CDCl3): delta 9.23 (br s, 1H), 8.78 (d, 1H), 7.67 (d, 1H), 7.40 (s, 5 H), 7.03 (d, 1H), 6.75 (d, 1H), 5.25 (s, 2H), 4.42 (s, 2H). |
| 73% |
With tetra-N-butylammonium tribromide; In tetrahydrofuran; methanol; at 20℃; |
Step 1: 8-(Benzyloxy)-5-(2-bromoacetyl)quinolin-2(1H)-one To a suspension of <strong>[93609-84-8]5-acetyl-8-(benzyloxy)quinolin-2(1H)-one</strong> (19.4 g, 66.4 mmol) in anhydrous THF (240 mL) and anhydrous methanol (165 mL) was added a solution of tetra-n-butylammonium tribromide (54.5 g, 113.0 mmol) in anhydrous THF (130 mL) dropwise over 1.5 hours. The resulting solution was stirred at RT overnight before concentrating under reduced pressure without heating. The residue was re-dissolved in methanol (200 mL). Saturated aqueous ammonium chloride solution (390 mL) was added with ice-cooling. The resulting suspension was filtered and the solid washed with water and air-dried under vacuum. The solid was suspended in DCM and methanol (1:1 v/v, 100 mL) for 90 minutes. The solid was collected by filtration, washed with DCM and air-dried to afford the title compound (18.0 g, 73%). 1H NMR (400 MHz, DMSO-d6): delta 11.07 (s, 1H); 8.51 (d, J=10.0 Hz, 1H); 7.94-7.83 (m, 1H); 7.60 (d, J=7.5 Hz, 2H); 7.44-7.27 (m, 4H); 6.79-6.65 (m, 1H); 5.53-5.39 (s, 2H); 4.93 (s, 2H) |
| 73% |
With tetra-N-butylammonium tribromide; In tetrahydrofuran; methanol; at 20℃; |
A suspension of 5-acetyl-8-(benzyloxy)quinolin-2(lH)-one (19.4 g, 66.4 mmol) in anhydrous THF (240 niL) and anhydrous methanol (165 niL) was added with a solution of fctra-n-butylammonium tribromide (Bu4NBr3) (54.5 g, 1 13.0 mmol) in anhydrous THF (130 mL) dropwise over 1.5 hours. The resulting solution was stirred at RT overnight before concentrating under reduced pressure without heating. The residue was re-dissolved in methanol (200 mL). Saturated aqueous ammonium chloride solution (390 mL) was added with ice-cooling. The resulting suspension was filtered and the solid washed with water and air-dried under vacuum. The solid was suspended in DCM and methanol (1 : 1 v/v, 100 mL) for 90 minutes. The solid was collected by filtration, washed with DCM and air- dried to afford the title compound (18.0 g, 73%). 1HNMR (400 MHz, DMSO-d6): delta 1 1.07 (s, 1 H); 8.51 (d, J = 10.0 Hz, 1 H); 7.94- 7.83 (m, 1 H); 7.60 (d, J = 7.5 Hz, 2 H); 7.44-7.27 (m, 4 H); 6.79-6.65 (m, 1 H); 5.53-5.39 (s, 2 H); 4.93 (s, 2 H) |
| 73% |
With tetra-N-butylammonium tribromide; In tetrahydrofuran; methanol; at 20℃; |
A suspension of 5-acetyl-8-(benzyloxy)quinolin-2 (1H)-one (19.4 g, 66.4 mmol) in anhydrous THF (240 mE) and anhydrous methanol (165 mE) was added with a solution of tetra-n-butylammonium tribromide (54.5 g, 113.0 mmol) in anhydrous THF (130 mE) drop-wise over 1.5 hours. The resulting solution was stirred at room temperature overnight before concentrating under reduced pressure without heating. The residue was re-dissolved in methanol (200 mE). Saturated aqueous ammonium chloride solution (390 mE) was added with ice-cooling. The resulting suspension was filtered and the solid washed with water and air-dried under vacuum. The solid was suspended in DCM and methanol (1:1 v/v, 100mE) for 90 minutes. The solid was collected by filtration, washed with DCM and air-dried to afford the title compound(18.0 g, 73%). 1H NMR (400 MHz, DMSO-d5): oe 11.07 (s, 1H),8.51 (d, J=10.OHz, 1H), 7.94-7.83 (m, 1H), 7.60 (d, J=7.5 Hz,2H), 7.44-7.27 (m, 4H), 6.79-6.65 (m, 1H), 5.53-5.39 (s, 2H),4.93 (s, 2H) |
| 73% |
With tetra-N-butylammonium tribromide; In tetrahydrofuran; methanol; at 20℃; |
To a suspension of <strong>[93609-84-8]5-acetyl-8-(benzyloxy)quinolin-2(1H)-one</strong> (19.4 g, 66.4 mmol) in anhydrous THF (240 mL) and anhydrous methanol (165 mL) was added a solution of tetra-n-butylammonium tribromide (54.5 g, 113.0 mmol) in anhydrous THF (130 mL) drop-wise over 1.5 hours. The resulting solution was stirred at room temperature overnight before concentrating under reduced pressure without heating. The residue was re-dissolved in methanol (200 mL). Saturated aqueous ammonium chloride solution (390 mL) was added with ice-cooling. The resulting suspension was filtered and the solid washed with water and air-dried under vacuum. The solid was suspended in DCM and methanol(1 : 1 v/v, 100 mL) for 90 minutes. The solid was collected by filtration, washed with DCM and air-dried to afford the title compound (18.0 g, 73%). NMR (400 MHz, DMSO-d6): delta 11.07 (s, 1 H), 8.51 (d, J = 10.0 Hz, 1 H),7.94-7.83 (m, 1 H), 7.60 (d, J = 7.5 Hz, 2 H), 7.44-7.27 (m, 4 H), 6.79-6.65 (m, 1 H), 5.53-5.39 (s, 2 H), 4.93 (s, 2 H) |
| 73% |
With tetra-N-butylammonium tribromide; In tetrahydrofuran; methanol; at 20℃; |
To a suspension of 5-acetyl-8-(benzyloxy)quinolin-2(lH)-one (19.4 g, 66.4 mmol) in anhydrous THF (240 mL) and anhydrous methanol (165 mL) was added a solution of tetra-n-butylammonium tribromide (54.5 g, 113.0 mmol) in anhydrous THF (130 mL) drop- wise over 1.5 hours. The resulting solution was stirred at room temperature overnight before concentrating under reduced pressure without heating. The residue was re-dissolved in methanol (200 mL). Saturated aqueous ammonium chloride solution (390 mL) was added with ice-cooling. The resulting suspension was filtered and the solid washed with water and air-dried under vacuum. The solid was suspended in DCM and methanol (1 :1 v/v, 100 mL) for 90 minutes. The solid was collected by filtration, washed with DCM and air-dried to afford the title compound (18.0 g, 73%). NMR (400 MHz, DMSO-d6): delta 11.07 (s, 1 H), 8.51 (d, J= 10.0 Hz, 1 H), 7.94- 7.83 (m, 1 H), 7.60 (d, J= 7.5 Hz, 2 H), 7.44-7.27 (m, 4 H), 6.79-6.65 (m, 1 H), 5.53-5.39 (s, 2 H), 4.93 (s, 2 H) |
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d. Synthesis of 5-(2-bromo-1-oxy)ethyl-8-benzyloxy-2(1H)-quinolinone (R); 5-Acetyl-8-benzyloxy-2(1H)-quinolinone (EE) (20.0 g, 68.2 mmol) was dissolved in dichloromethane (200 ml) and cooled to 0 C. Boron trifluoride diethyl etherate (10.4 ml, 82.0 mmol) was added via syringe and the mixture was warmed to room temperature to give a thick suspension. The suspension was heated at 45 C. (oil bath) and a solution of bromine (11.5 g, 72.0 mmol) in dichloromethane (100 ml) was added over 40 minutes. The mixture was kept at 45 C. for an additional 15 minutes and then cooled to room temperature. The mixture was concentrated under reduced pressure and then triturated with 10% aqueous sodium carbonate (200 ml) for 1 hour. The solids were collected on a Buchner funnel, washed with water (4×1 00 ml) and dried under reduced pressure. The product of two runs was combined for purification. The crude product (52 g) was triturated with 50% methanol in chloroform (500 ml) for 1 hour. The product was collected on a Buchner funnel and washed with 50% methanol in chloroform (2×50 ml) and methanol (2×50 ml). The solid was dried under reduced pressure to give 5-(2-bromo-1-oxy)ethyl-8-benzyloxy-2(1H)-quinolinone (R) (34.1 g) as an off white powder. |
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The product from step (c) (20.0 g, 68.2 mmol) was dissolved in dichloromethane (200 mL) and cooled to 0 C. Boron trifluoride diethyl etherate (10.4 mL, 82.0 mmol) was added via syringe and the mixture was warmed to room temperature to give a thick suspension. The suspension was heated at 45 C. (oil bath) and a solution of bromine (11.5 g, 72.0 mmol) in dichloromethane (100 mL) was added over 40 min. The mixture was kept at 45 C. for an additional 15 min and then cooled to room temperature. The mixture was concentrated under reduced pressure and then triturated with 10% aqueous sodium carbonate (200 mL) for 1 hour. The solids were collected on a Buchner funnel, washed with water (4×100 mL) and dried under reduced pressure. The product of two runs was combined for purification. The crude product (52 g) was triturated with 50% methanol in chloroform (500 mL) for 1 hour. The product was collected on a Buchner funnel and washed with 50% methanol in chloroform (2×50 mL) and methanol (2×50 mL). The solid was dried under reduced pressure to give the title compound (34.1 g) as a powder. |
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With bromine; trifluoroborane diethyl ether; In dichloromethane; at 0 - 45℃; for 0.25h; |
(a) 8-Benzyloxy-5-(2-Bromoacetyl)-1H-quinolin-2-one 5-Acetyl-8-benzyloxy-1H-quinolin-2-one (Preparation 6) (20.0 g, 68.2 mmol) was dissolved in dichloromethane (200 ML) and cooled to 0 C. boron trifluoride diethyl etherate (10.4 ML, 82.0 mmol) was added via syringe and the mixture was warmed to room temperature to give a thick suspension.The suspension was heated at 45 C. (oil bath) and a solution of bromine (11.5 g, 72.0 mmol) in dichloromethane (100 ML) was added over 40 min.The mixture was kept at 45 C. for an additional 15 min and then cooled to room temperature.The mixture was concentrated under reduced pressure and then triturated with 10% aqueous sodium carbonate (200 ML) for 1 hour.The solids were collected on a Buchner funnel, washed with water (4*100 ML) and dried under reduced pressure.The product of two runs was combined for purification.The crude product (52 g) was triturated with 50% methanol in chloroform (500 ML) for 1 hour.The product was collected on a Buchner funnel and washed with 50% methanol in chloroform (2*50 ML) and methanol (2*50 ML).The solid was dried under reduced pressure to give the title compound (34.1 g) as a powder. |
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A solution of tetra-n-butylammonium tribromide (109g, 0.226mol) in tetrahydrofuran (250ml) was added dropwise over 90 minutes to a stirred suspension of 8-(benzyloxy)-5-(1-oxoethyl)-1H-quinol-2-one (WO 2003/042164) (38.9g, 0.133mol) in a mixture of tetrahydrofuran (470ml) and methanol (325ml) at room temperature. The resulting mixture was stirred for 17 hours, concentrated under reduced pressure at 30C and the brown solid residue was suspended in methanol (390ml). Water (780ml) was added slowly with cooling using a cold water bath. The resulting brown suspension was stirred for 30 minutes and filtered, washing with water (600ml), and the solid was dried by suction overnight. The crude product (89.2g) was triturated with a mixture of dichloromethane and methanol (1:1, 2 ml/g) for 90 minutes. The solid was filtered and washed with dichloromethane (53ml). The solid was then heated in a mixture of dichloromethane (39ml) and methanol (8ml) for 2 hours under reflux, cooled to room temperature and stirred for 1 hour. Filtration of the solid followed by washing with dichloromethane:methanol (9:1, 30ml) afforded the title compound as a pale brown solid, 37.15 g.1H nmr (CDCl3, 400MHz) delta: 4.42 (s, 2H), 5.25 (s, 2H), 6.75 (d, 1H), 7.03 (d, 1H), 7.40 (s, 5H), 7.67 (d, 1H), 8.78 (d, 1H), 9.23 (br s, 1H). LRMS : m/z ES+ 372, 374 [MH+] |
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With boron trifluoride diethyl etherate; bromine; In dichloromethane; at 0 - 45℃; for 0.916667h; |
The product from step (c) (20.0 g, 68.2 mmol) was dissolved in dichloromethane (200 mL) and cooled to 0 C. Boron trifluoride diethyl etherate (10.4 mL, 82.0 mmol) was added via syringe and the mixture was warmed to room temperature to give a thick suspension. The suspension was heated at 45 C. (oil bath) and a solution of bromine (11.5 g, 72.0 mmol) in dichloromethane (100 mL) was added over 40 min. The mixture was kept at 45 C. for an additional 15 min and then cooled to room temperature. The mixture was concentrated under reduced pressure and then triturated with 10% aqueous sodium carbonate (200 mL) for 1 hour. The solids were collected on a Buchner funnel, washed with water (4*100 mL) and dried under reduced pressure. The product of two runs was combined for purification. The crude product (52 g) was triturated with 50% methanol in chloroform (500 mL) for 1 hour. The product was collected on a Buchner funnel and washed with 50% methanol in chloroform (2*50 mL) and methanol (2*50 mL). The solid was dried under reduced pressure to give the title compound (34.1 g) as a powder. |
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The product from step (c) (20.0 g, 68.2 mmol) was dissolved in dichloromethane (200 mL) and cooled to 0 C. Boron trifluoride diethyl etherate (10.4 mL, 82.0 mmol) was added via syringe and the mixture was warmed to room temperature to give a thick suspension. The suspension was heated at 45 C. (oil bath) and a solution of bromine (11.5 g, 72.0 mmol) in dichloromethane (100 mL) was added over 40 min. The mixture was kept at 45 C. for an additional 15 min and then cooled to room temperature. The mixture was concentrated under reduced pressure and then triturated with 10% aqueous sodium carbonate (200 mL) for 1 hour. The solids were collected on a Buchner funnel, washed with water (4×100 mL) and dried under reduced pressure. The product of two runs was combined for purification. The crude product (52 g) was triturated with 50% methanol in chloroform (500 mL) for 1 hour. The product was collected on a Buchner funnel and washed with 50% methanol in chloroform (2×50 mL) and methanol (2×50 mL). The solid was dried under reduced pressure to give the title compound (34.1 g) as a powder. |
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The product from step (c) (20.0 g, 68.2 mmol) was dissolved in dichloromethane (200 mL) and cooled to 0 C. Boron trifluoride diethyl etherate (10.4 mL, 82.0 mmol) was added via syringe and the mixture was warmed to room temperature to give a thick suspension. The suspension was heated at 45 C (oil bath) and a solution of bromine (11.5 g, 72.0 mmol) in dichloromethane (100 mL) was added over 40 min. The mixture was kept at 45 C for an additional 15 min and then cooled to room temperature. The mixture was concentrated under reduced pressure and then triturated with 10% aqueous sodium carbonate (200 mL) for 1 hour. The solids were collected on a Buchner funnel, washed with water (4 x 100 mL) and dried under reduced pressure. The product of two runs was combined for purification. The crude product (52 g) was triturated with 50% methanol in chloroform (500 mL) for 1 hour. The product was collected on a Buchner funnel and washed with 50% methanol in chloroform (2 x 50 mL) and methanol (2 x 50 mL). The solid was dried under reduced pressure to give the title compound (34.1 g) as a powder. |
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With N-Bromosuccinimide; In chloroform; |
(1) 293 mg of 5-acetyl-8-benzyloxycarbostyril are dissolved in 15 ml of chloroform, and 200 mg of N-bromosuccinimide are added thereto. The mixture is refluxed for 2 hours under stirring. 300 mg of N-bromosuccinimide are added to the mixture and 4 hours after the commencement of the reaction, 100 mg of N-bromosuccinimide are further added thereto. Six hours after the reaction is started, the mixture is cooled and is allowed to stand at 20 C. for 2 days. Precipitated crystals are collected by filtration. Then, the crystals are washed with methanol and ether and then dried. 110 mg of 5-bromoacetyl-8-benzyloxycarbostyril are thereby obtained as colorless crystals. |
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5-Acetyl-8-benzyloxy-2(1H)-quinolinone (EE) (20.0 g, 68.2 mmol) was dissolved in dichloromethane (200 mL) and cooled to 0 C. Boron trifluoride diethyl etherate (10.4 mL, 82.0 mmol) was added via syringe and the mixture was warmed to room temperature to give a thick suspension. The suspension was heated at 45 C. (oil bath) and a solution of bromine (11.5 g, 72.0 mmol) in dichloromethane (100 mL) was added over 40 minutes. The mixture was kept 45 C. for an additional 15 minutes and then cooled to room temperature. The mixture was concentrated under reduced pressure and then triturated with 10% aqueous sodium carbonate (200 mL) for 1 hour. The solids were collected on a Buchner funnel, washed with water (4×100 mL) and dried under reduced pressure. The product of two runs was combined for purification. The crude product (52 g) was triturated with 50% methanol in chloroform (500 mL) for 1 hour. The product was collected on a Buchner funnel and washed with 50% methanol in chloroform (2×50 mL) and methanol (2×50 mL). The solid was dried under reduced pressure to give 5-(2-bromo-1-oxy)ethyl-8-benzyloxy-2(1H)-quinolinone (R) (34.1 g) as an off white powder. |
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With boron trifluoride diethyl etherate; bromine; In dichloromethane; at 0 - 45℃; for 0.916667h; |
The product from step (c) (20.0 g, 68.2 mmol) was dissolved in dichloromethane (200 mL) and cooled to 0 C. Boron trifluoride diethyl etherate (10.4 mL, 82. 0 mmol) was added via syringe and the mixture was warmed to room temperature to give a thick suspension. The suspension was heated at 45 C (oil bath) and a solution of bromine (11.5 g, 72.0 mmol) in dichloromethane (100 mL) was added over 40 min. The mixture was kept at 45 C for an additional 15 min and then cooled to room temperature. The mixture was concentrated under reduced pressure and then triturated with 10% aqueous sodium carbonate (200 mL) for 1 hour. The solids were collected on a Buchner funnel, washed with water (4 x 100 mL) and dried under reduced pressure. The product of two runs was combined for purification. The crude product (52 g) was triturated with 50% methanol in CHLOROFORM (500 mL) for 1 hour. The product was collected on a Buchner funnel and washed with 50% methanol in chloroform (2 x 50 mL) and methanol (2 x 50 mL). The solid was dried under reduced pressure to give the title compound (34.1 g) as a powder. |
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Preparation 4 8-Benzyloxy-5-(2-Bromoacetyl)-1H-quinolin-2-one The product of Preparation 3 (20.0 g, 68.2 mmol) was dissolved in dichloromethane (200 mL) and cooled to 0 C. Boron trifluoride diethyl etherate (10.4 mL, 82.0 mmol) was added via syringe and the mixture was warmed to room temperature to give a thick suspension. The suspension was heated at 45 C. (oil bath) and a solution of bromine (11.5 g, 72.0 mmol) in dichloromethane (100 mL) was added over 40 min. The mixture was kept at 45 C. for an additional 15 min and then cooled to room temperature. The mixture was concentrated under reduced pressure and then triturated with 10% aqueous sodium carbonate (200 mL) for 1 hour. The solids were collected on a Buchner funnel, washed with water (4*100 mL) and dried under reduced pressure. The product of two runs was combined for purification. The crude product (52 g) was triturated with 50% methanol in chloroform (500 mL) for 1 hour. The product was collected on a Buchner funnel and washed with 50% methanol in chloroform (2*50 mL) and methanol (2*50 mL). The solid was dried under reduced pressure to give the title compound (34.1 g) as a powder. |
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With pyridinium hydrobromide perbromide; In tetrahydrofuran; at 0℃;Reflux; |
5-Acetyl-8-benzyloxy-1H-quinolin-2-one (372 g, 1.27 mol) was dissolved in tetrahydrofuran (3.6 L) and the solution was cooled to 0 C. Pyridinium tribromide (453 g, 1.27 mol) was added thereto in portions, and the mixture was heated under reflux for 3 hours. Thereafter, tetrahydrofuran (3.1 L) was added and the mixture was heated under reflux overnight. The precipitate was collected by filtration and washed with tetrahydrofuran. The solid was suspension-washed with tetrahydrofuran (2.3 L) and, thereafter, washed with purified water (3 L). Separately, the tetrahydrofuran filtrate and the washings were mixed, concentrated under reduced pressure, and the residue was suspension-washed with tetrahydrofuran (1 L). The solids were combined and dried under reduced pressure to obtain 8-benzyloxy-5-(2-bromoacetyl)-1H-quinolin-2-one (387 g). 1H-NMR(400 MHz, DMSO-d6) delta 11.1(s, 1H), 8.49(d, J=9.0 Hz, 1H), 7.86(d, J=9.0 Hz, 1H), 7.58(d, J=8.0 Hz, 2H), 7.25-7.45(m, 5H), 6.67(d, J=9.0 Hz, 1H), 7.86(d, 5.42(s, 2H), 4.91(s, 2H) |
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Boron trifluoride-diethyletherate (29 ml) was slowly added to a solution of <strong>[93609-84-8]5-acetyl-8-phenylmethoxy-(1H)-quinolin-2-one</strong> (50 g) in dichloromethane (500 ml) at 0 C. and stirred for 10 minutes at the same temperature to get a thick precipitate. The reaction mass was heated to reflux temperature and bromine solution was added (29 g in 190 ml dichloromethane) slowly over a period of 2 hours under reflux (the HBr fumes coming from the condenser was scrubbed). Thereafter, the reaction mass was refluxed for further 45 minutes. The solvent was distilled out completely under vacuum and the mass was triturated with 10% aqueous sodium carbonate solution (100 ml). The suspension was filtered, washed with water and the crude product was taken for the next stage reaction. |
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Example 2; I0 8-Hydroxy-5-{(li?)-l-hydroxy-2-[(ftfl«s-4-[2-(2- phenylethoxy)ethyl]amino}cyclohexyl)amino]ethyl}quinolin-2(li3)-one; i) 8-(Benzyloxy)-5-(bromoacetyl)quinolin-2(lJ)-one;To a solution of 5-acetyl-8-(benzyloxy)quinolin-2(lH)-one (WO 2005/123684) (18.05g) in is DCM (200 niL) at O0C was added boron trifluoride etherate complex (9.2 mL) dropwise over 15 min and then the mixture allowed to warm to room temperature forming a thick yellow suspension. The mixture was heated at 400C and a solution of bromine (3.4 mL) in DCM (100 mL) added slowly over 40 min. After a further 15 min the mixture was allowed to reach room temperature before removing the volatiles on a rotary evaporator. The 0 residue was triturated with excess 10% aqueous sodium carbonate for Ih. The gummy solid collected by filtration and further washed with H2O and drying the solid in vacuo at 4O0C overnight. Purification was by further washing the solid with 1 : 1 DCM/methanol solutions and filtration followed by drying in vacuo at 4O0C to give the sub-title compound as a off white solid. Yield: 14.5g 5 MS APCI+ 372/374 [M+H]+ |
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Example 5 Preparation of delta-Bromoacetyl-delta-benzyloxycarbostyril (compound (If); Ri = benzyl)A dry 3 liter, 4-necked round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel and refluxing condenser was charged with of 5-Acetyl-8- benzyloxycarbostyril (50 gms/0.17 moles) and dry dichloromethane (1 liter) under argon. To this solution was added boron trifluoride etharate (25.7ml/0.204moles). The reaction mass was heated to reflux. To this reaction mass was added slowly solution of bromine (8.4 ml/0.17 moles) in dichloromethane (100 ml) at reflux in 4 hours. The mixture was refluxed for additional 30 minutes. The mass was cooled to 300C and adjusted to pH 8-9 using 10%, aqueous potassium carbonate solution (470 ml).The solvent was partially distilled under vacuum at 35C, chilled to 0-5C and stirred for 10-15 minutes. The resulting crude 5-Bromoacetyl-8-benzyloxycarbostyril was isolated by filtration, washed with diisopropyl ether (100 ml) and dried under vacuum at 50-550C for 14 hours. Yield 56.58 gmsPurification of crude 5-Bromoacetyl-8-benzyloxycarbostyril (compound (If); Ri = benzyl) The crude delta-Bromoacetyl-delta-benzyloxycarbostyril (56gms) was charged along with chloroform (280 ml) in a round bottom flask. The reaction mass was heated to reflux for 30 minutes, cooled to 25-300C in 2-3 hours. The reaction mass was further chilled to 0-50C and stirred for 30 minutes. The resulting solid was isolated by filtration, washed with <n="41"/>chloroform (55ml) and dried under vacuum at 55-600C for 4-5 hours to yield 41 gms of 5- Bromoacetyl-8-benzyloxycarbostyril. |
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