ethyl 7-oxoheptanoate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: rac-7-Methoxy-2,3-dip-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate K) (80 mg, 0.232 mmol) in dry DCE (4 ml) at RT under nitrogen was treated with DIPEA (0.044 ml, 0.255 mmol) followed by ethyl 7-oxoheptanoate (80 mg, 0.463 mmol). The resulting mixture was stirred at RT for 10 minutes and treated with sodium triacetoxyborohydride (245 mg, 1.158 mmol). The mixture was heated at 60° C. for 16 hours. A further portion of sodium triacetoxyborohydride (245 mg, 1.158 mmol) was added and the mixture was heated at 50° C. for 3 days. After cooling to RT, the reaction mixture was diluted with DCM (50 ml) and washed with water (×2). The organic portion was isolated using a phase separating cartridge and the solvent was removed in vacuo. Purification of the crude product by chromatography on silica eluting with 0-20% EtOAc/iso-hexane afforded the title compound. The mixture was heated at 60° C. for 16 hours the mixture was heated at 50° C. for 3 days After cooling to RT washed with water (×2) The organic portion was isolated separating cartridge the solvent was removed in vacuo Purification of the crude product by chromatography on silica eluting with 0-20% EtOAc/iso-hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2,3-dip-tolyl-5,6-dihydropyrido[2,3-b]pyrazine (Example 8.2 step 1) (3.88 g, 12.38 mmol) in DCE (70 ml) was added ethyl 7-oxoheptanoate (6.40 g, 37.1 mmol) followed by sodium triacetoxyborohydride (10.4 g, 49.1 mmol). The reaction mixture was stirred for 2 days at room temperature under an atmosphere of nitrogen. The reaction mixture was diluted with water (70 ml) and extracted with EtOAc (3×70 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with EtOAc/iso-hexane, followed by further purification using reverse phase chromatography eluting with MeCN/water (0.1% TFA) to afford the title compound; extracted with EtOAc (3×70 ml) The combined organic extracts were dried over MgSO4 filtered concentrated in vacuo The crude product was purified by chromatography on silica eluting with EtOAc/iso-hexane followed by further purification eluting with MeCN/water (0.1% TFA)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To rac-2,3-dip-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-8-yl acetate (Intermediate HF)(70 mg, 0.187 mmol) in 1,2-dichloroethane (3 ml) was added ethyl 7-oxoheptanoate (97 mg, 0.562 mmol). The reaction mixture was stirred at room temperature for 20 minutes and sodium triacetoxyborohydride (119 mg, 0.562 mmol) was added. The solution was stirred at room temperature overnight. Water (5 ml) was added and the reaction mixture was stirred vigorously for 15 minutes. The resulting mixture was extracted with DCM (×3). The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was passed through a pre-conditioned Isolute SCX-2 SPE column loading with MeOH and eluting with 1M ammonia in MeOH (20 ml). The solvent was removed in vacuo and the resulting crude was purified by chromatography on silica eluting with 0-100% EtOAc/iso-hexane to afford the title compound LC-MS Rt=1.58 mins; [M+H]+ 530.4, Method 2minLC_v003. The solution was stirred at room temperature overnight the reaction mixture was stirred vigorously for 15 minutes The resulting mixture was extracted with DCM (×3) The combined organic extracts were dried over MgSO4 filtered concentrated eluting with 1M ammonia in MeOH (20 ml) The solvent was removed in vacuo the resulting crude was purified by chromatography on silica eluting with 0-100% EtOAc/iso-hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (S)-2,3-diphenyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-8-yl acetate (Intermediate HBS) (46 mg, 0.133 mmol) in DCE (7 ml) was added ethyl 7-oxoheptanoate (68.8 mg, 0.4 mmol) followed by sodium triacetoxyborohydride (226 mg, 1.065 mmol). The reaction mixture was left to stir at room temperature overnight under an atmosphere of nitrogen. A further portion of ethyl 7-oxoheptanoate (71.8 mg, 0.417 mmol) was added. The reaction mixture was left to stir for a further 5 hours under an atmosphere of nitrogen. Water (20 ml) was added and the resulting mixture was extracted with EtOAc (3×20 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated to give a crude oil. The resulting crude product was purified by chromatography on silica eluting with 0-40% EtOAc/iso-hexane to afford an oil. The compound was passed through a pre-conditioned Isolute SCX-2 SPE column loading with MeOH and eluting with 1M ammonia in MeOH (20 ml) to afford the title compound; The reaction mixture was left The reaction mixture was left to stir for a further 5 hours under an atmosphere of nitrogen the resulting mixture was extracted with EtOAc (3×20 ml) The combined organic extracts were dried over MgSO4 filtered concentrated to give a crude oil The resulting crude product was purified by chromatography on silica eluting with 0-40% EtOAc/iso-hexane to afford an oil eluting with 1M ammonia in MeOH (20 ml)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (R)-2,3-diphenyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-8-yl acetate (Intermediate HBR) in DCE (7 ml) was added ethyl 7-oxoheptanoate (71.8 mg, 0.417 mmol) followed by sodium triacetoxyborohydride (236 mg, 1.112 mmol). The reaction mixture was left to stir at room temperature overnight under an atmosphere of nitrogen. A further portion of ethyl 7-oxoheptanoate (6 equivalents) was added and the reaction mixture was left to stir at RT for 4 days. The mixture was diluted with water (20 ml) and extracted with EtOAc (3×20 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The resulting crude product was purified by chromatography on silica eluting with 0-40% EtOAc/iso-hexane to afford the title compound; The reaction mixture was left the reaction mixture was left to stir at RT for 4 days extracted with EtOAc (3×20 ml) The combined organic extracts were dried over MgSO4 filtered concentrated in vacuo The resulting crude product was purified by chromatography on silica eluting with 0-40% EtOAc/iso-hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of rac-2,3-diphenyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine-7,8-diyl diacetate (Intermediate I) (69 mg, 0.171 mmol) in DCE (3 ml) was added ethyl 7-oxoheptanoate (88 mg, 0.513 mmol) followed by sodium triacetoxyborohydride (109 mg, 0.513 mmol). The reaction was left to stir overnight at room temperature under an atmosphere of nitrogen. To the reaction mixture was added further ethyl 7-oxoheptanoate (88 mg, 0.513 mmol) followed by sodium triacetoxyborohydride (109 mg, 0.513 mmol). The reaction mixture was left to stir at RT under an atmosphere of nitrogen for 4 days. The mixture was diluted with water and extracted with EtOAc (3×20 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The resulting crude product was purified by chromatography on silica eluting with 0-70% EtOAc/iso-hexane to afford the title compound; The reaction was left The reaction mixture was left to stir at RT under an atmosphere of nitrogen for 4 days extracted with EtOAc (3×20 ml) The combined organic extracts were dried over MgSO4 filtered concentrated in vacuo The resulting crude product was purified by chromatography on silica eluting with 0-70% EtOAc/iso-hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of rac-8-ethyl-2,3-diphenyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate HC)(13 mg, 0.041 mmol) in DCE (2 ml) was added ethyl 7-oxoheptanoate (24.84 mg, 0.144 mmol) followed by sodium triacetoxyborohydride (69.9 mg, 0.330 mmol). The reaction mixture was left to stir at room temperature under an atmosphere of nitrogen. Water (10 ml) was added and the resulting mixture was extracted with EtOAc (3×10 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The crude product was passed through a pre-conditioned Isolute SCX-2 SPE column loading with MeOH and eluting with 1M ammonia in MeOH (10 ml) to afford the title product; The reaction mixture was left the resulting mixture was extracted with EtOAc (3×10 ml) The combined organic extracts were dried over MgSO4 filtered concentrated in vacuo eluting with 1M ammonia in MeOH (10 ml)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2,3-bis(3-Fluoro-4-methylphenyl)-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate G)(256 mg, 0.729 mmol) in DCE (10 ml) was treated with ethyl 7-oxoheptanoate (125 mg, 0.729 mmol) and triethylamine (0.112 ml, 0.801 mmol) and stirred at RT for 15 mins. Sodium triacetoxyborohydride (772 mg, 3.64 mmol) was added and stirring continued at 60° C. for 18 h. The reaction mixture was diluted with water and DCM and the organic portion was separated. The aqueous portion was extracted with DCM and the combined organic extracts were dried (sodium sulphate), filtered and concentrated in vacuo to give a yellow gum. The crude product was purified by chromatography on silica eluting with 0-20% EtOAc in iso-hexane to afford the title compound; stirring continued at 60° C. for 18 h the organic portion was separated The aqueous portion was extracted with DCM the combined organic extracts were dried (sodium sulphate) filtered concentrated in vacuo to give a yellow gum The crude product was purified by chromatography on silica eluting with 0-20% EtOAc in iso-hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-m-Tolyl-3-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate FB)(61 mg, 0.193 mmol) in dry DCE (1 ml) at RT was treated with DIPEA (0.037 ml, 0.213 mmol) followed by ethyl 7-oxoheptanoate (66.6 mg, 0.387 mmol). The reaction mixture was stirred at RT for 10 minutes and sodium triacetoxyborohydride (205 mg, 0.967 mmol) was added. The resulting mixture was stirred at 60° C. overnight. After cooling to RT, the mixture was slowly added to water (50 ml) and extracted with DCM (3×). The combined organic extracts were passed through a phase separating column and concentrated in vacuo. The resulting crude product was purified by chromatography on silica eluting with 0-5% EtOAc/iso-hexane to afford the title compound; LCMS Rt 1.61 mins MS m/z 473.4 [ M+H]+; Method 2minLC_v003 The resulting mixture was stirred at 60° C. overnight After cooling to RT extracted with DCM (3×) separating column concentrated in vacuo The resulting crude product was purified by chromatography on silica eluting with 0-5% EtOAc/iso-hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-phenyl-3-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate FA) (1.03 g, 3.42 mmol) in 1,2-dichloroethane (15 ml) was treated with ethyl 7-oxoheptanoate (1.776 g, 10.25 mmol) followed by sodium triacetoxyborohydride (3.62 g, 17.09 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with saturated NaHCO3 (70 ml) and was extracted with DCM (×3). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The resulting crude product was purified by chromatography on silica eluting with 0-60% EtOAc/iso-hexane to give an oil. The product was loaded onto an Isolute™ SCX-2 cartridge, washed with MeOH and eluted with 2M NH3 in MeOH. The methanolic ammonia fractions were concentrated in vacuo to afford the title compound; was extracted with DCM (×3) The combined organics were dried (MgSO4) filtered concentrated in vacuo The resulting crude product was purified by chromatography on silica eluting with 0-60% EtOAc/iso-hexane to give an oil washed with MeOH eluted with 2M NH3 in MeOH The methanolic ammonia fractions were concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Phenyl-2-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate F) (162 mg, 0.538 mmol) in dry DCE (1 ml) was treated with DIPEA (0.103 ml, 0.591 mmol) followed by ethyl 7-oxoheptanoate (185 mg, 1.075 mmol). The reaction mixture was stirred at RT for 10 minutes and sodium triacetoxyborohydride (570 mg, 2.69 mmol) was added. The resulting mixture was stirred at 60° C. for 16 hours. After cooling to RT, the mixture was slowly added to water (50 ml) and extracted with DCM (3×). The combined organic extracts were passed through a phase separating column and concentrated in vacuo. The resulting crude product was purified by chromatography on silica eluting with 0-10% EtOAc/iso-hexane to afford the title compound; LCMS; Rt 1.38 mins MS m/z 458 [ M+H]+; Method 2minLC_v003 The resulting mixture was stirred at 60° C. for 16 hours After cooling to RT extracted with DCM (3×) separating column concentrated in vacuo The resulting crude product was purified by chromatography on silica eluting with 0-10% EtOAc/iso-hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2,3-Dip-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate E) (10 g, 31.7 mmol) in DCE (300 ml) was added DIPEA (6.09 ml, 34.9 mmol) followed by ethyl 7-oxoheptanoate (10.92 g, 63.4 mmol). The mixture was stirred at RT for 10 minutes and sodium triacetoxyborohydride (16.80 g, 79 mmol) was added portionwise. The reaction mixture was heated at 40° C. overnight and then added slowly to water (500 ml) and stirred at RT for 10 minutes. The organic layer was separated and the aqueous layer extracted with dichloromethane (2×200 ml). The combined organics were washed with brine (200 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give a pale yellow oil. Isolute Separtis SCX-2 (capture/release super cation exchange resin) (222 g, 127 mmol) was added to a column and the product was loaded with MeOH (50 ml). The column was flushed with MeOH (750 L) followed by 2 N NH3/MeOH (1000 ml, prepared from 280 ml 7 N+720 ml MeOH) to afford the title compound. No further purification was carried out; HPLC (Agilent 1200) Rt 6.38 min, Method B The reaction mixture was heated at 40° C. overnight stirred at RT for 10 minutes The organic layer was separated the aqueous layer extracted with dichloromethane (2×200 ml) The combined organics were washed with brine (200 ml) dried over anhydrous sodium sulfate concentrated in vacuo to give a pale yellow oil Isolute Separtis SCX-2 (capture/release super cation exchange resin) (222 g, 127 mmol) was added to a column The column was flushed with MeOH (750 L)