tert-butyl (2S)-2-[[2-(4-bromophenyl)-2-oxoethyl]carbamoyl]pyrrolidine-1-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the product of Step 1 (1.00 g, 2.43 mmol), PPh3 (1.00 g, 3.71 mmol) and diisopropylethylamine (1.3 mL, 7.28 mmol) in CH3CN (30 mL) was added hexachloroethane (0.812 g, 3.43 mmol) as a solid, portion-wise. The mixture was allowed to stir for 12 hours. TLC (3:1 hexanes:ethyl acetate) indicated the presence of starting material. Therefore, additional PPh3 (0.65 g, 2.43 mmol) and hexachloroethane (0.575 g, 2.43 mmol) were added and stirring continued for 4 hours. The solvent was removed in vacuo, the residue diluted with ethyl acetate-H2O and the layers separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed (H2O, brine), dried (Na2SO4), and filtered. The solvent was removed in vacuo and the residue purified by flash column chromatography (3:1 hexanes:ethyl acetate) to provide (S)-tert-butyl 2-(5-(4-bromophenyl)oxazol-2-yl)pyrrolidine-1-carboxylate (0.605 g, 63%). 1HNMR (400 MHz, DMSO-d6) δ 7.60-7.68 (m, 5H), 4.80-4.91 (m, 1H), 3.46-3.51 (m, 1H), 3.33-3.39 (m, 1H), 2.18-2.31 (m, 1H), 1.84-1.99 (m, 3H), 1.36 (s, 4H), 1.15 (s, 5H). LCMS: Anal. Calcd. for C18H21BrN2O3: 392. found: 393 (M+H)+. stirring continued for 4 hours The solvent was removed in vacuo the residue diluted with ethyl acetate-H2O the layers separated The aqueous phase was extracted twice with ethyl acetate the combined organic layers were washed (H2O, brine) dried (Na2SO4) filtered The solvent was removed in vacuo the residue purified by flash column chromatography (3:1 hexanes:ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-amino-1-(4-bromophenyl)ethanone hydrochloride salt (1.10 g, 4.39 mmol), (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.02 g, 4.73 mmol), and diisopropylethylamine (3.10 mL, 17.4 mmol) in DMF (20 mL) was added 3-(diethoxyphosphoryloxy)-(1,2,3)-benzotriazin-4(3H)-one (DEPBT, 2.0 g, 6.68 mmol) and the solution was allowed to stir for 2 hours. The mixture was poured into H2O-ethyl acetate and the layers were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed (H2O×2, brine), dried (Na2SO4), and filtered. The solvent was removed in vacuo and the residue purified by flash column chromatography (1:1 hexanes:ethyl acetate) to provide (S)-tert-butyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)pyrrolidine-1-carboxylate (1.02 g, 56%) as a colorless foam. 1HNMR (400 MHz, DMSO-d6) δ 8.16-8.21 (m, 1H), 7.90-7.92 (m, 2H), 7.73-7.75 (m, 2H), 4.59 (dd, J=5.7, 18.4 Hz, 1H), 4.51 (dd, J=5.7, 18.4 Hz, 1H), 4.13-4.19 (m, 1H), 3.24-3.27 (m, 2H, partially obscured by H2O), 2.05-2.12 (m, 1H), 1.74-1.81 (m, 3H), 1.39 (s, 3H), 1.33 (3, 6H); LCMS: Anal. Calcd. for C18H23BrN2O4: 410. found: 411 (M+H)+. the layers were separated The aqueous phase was extracted twice with ethyl acetate the combined organic layers were washed (H2O×2, brine) dried (Na2SO4) filtered The solvent was removed in vacuo the residue purified by flash column chromatography (1:1 hexanes:ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the product of Step 1 (1.00 g, 2.43 mmol), PPh3 (1.00 g, 3.71 mmol) and diisopropylethylamine (1.3 mL, 7.28 mmol) in CH3CN (30 mL) was added hexachloroethane (0.812 g, 3.43 mmol) as a solid, portion-wise. The mixture was allowed to stir for 12 hours. TLC (3:1 hexanes:ethyl acetate) indicated the presence of starting material. Therefore, additional PPh3 (0.65 g, 2.43 mmol) and hexachloroethane (0.575 g, 2.43 mmol) were added and stirring continued for 4 hours. The solvent was removed in vacuo, the residue diluted with ethyl acetate-H2O and the layers separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed (H2O, brine), dried (Na2SO4), and filtered. The solvent was removed in vacuo and the residue purified by flash column chromatography (3:1 hexanes:ethyl acetate) to provide (S)-tert-butyl 2-(5-(4-bromophenyl)oxazol-2-yl)pyrrolidine-1-carboxylate (0.605 g, 63%). 1HNMR (400 MHz, DMSO-d6) δ 7.60-7.68 (m, 5H), 4.80-4.91 (m, 1H), 3.46-3.51 (m, 1H), 3.33-3.39 (m, 1H), 2.18-2.31 (m, 1H), 1.84-1.99 (m, 3H), 1.36 (s, 4H), 1.15 (s, 5H). LCMS: Anal. Calcd. for C18H21BrN2O3: 392. found: 393 (M+H)+. stirring continued for 4 hours The solvent was removed in vacuo the residue diluted with ethyl acetate-H2O the layers separated The aqueous phase was extracted twice with ethyl acetate the combined organic layers were washed (H2O, brine) dried (Na2SO4) filtered The solvent was removed in vacuo the residue purified by flash column chromatography (3:1 hexanes:ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-amino-1-(4-bromophenyl)ethanone hydrochloride salt (1.10 g, 4.39 mmol), (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.02 g, 4.73 mmol), and diisopropylethylamine (3.10 mL, 17.4 mmol) in DMF (20 mL) was added 3-(diethoxyphosphoryloxy)-(1,2,3)-benzotriazin-4(3H)-one (DEPBT, 2.0 g, 6.68 mmol) and the solution was allowed to stir for 2 hours. The mixture was poured into H2O-ethyl acetate and the layers were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed (H2O×2, brine), dried (Na2SO4), and filtered. The solvent was removed in vacuo and the residue purified by flash column chromatography (1:1 hexanes:ethyl acetate) to provide (S)-tert-butyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)pyrrolidine-1-carboxylate (1.02 g, 56%) as a colorless foam. 1HNMR (400 MHz, DMSO-d6) δ 8.16-8.21 (m, 1H), 7.90-7.92 (m, 2H), 7.73-7.75 (m, 2H), 4.59 (dd, J=5.7, 18.4 Hz, 1H), 4.51 (dd, J=5.7, 18.4 Hz, 1H), 4.13-4.19 (m, 1H), 3.24-3.27 (m, 2H, partially obscured by H2O), 2.05-2.12 (m, 1H), 1.74-1.81 (m, 3H), 1.39 (s, 3H), 1.33 (3, 6H); LCMS: Anal. Calcd. for C18H23BrN2O4: 410. found: 411 (M+H)+. the layers were separated The aqueous phase was extracted twice with ethyl acetate the combined organic layers were washed (H2O×2, brine) dried (Na2SO4) filtered The solvent was removed in vacuo the residue purified by flash column chromatography (1:1 hexanes:ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture J.6 (S)-tert-butyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-pyrrolidine-1-carboxylate (12.8 g, 31.12 mmol) and ammonium acetate (12.0 g, 155.7 mmol) in xylenes (155 mL) was heated in a sealed tube at 140° C. for 2 hours. The volatile component was removed in vacuo, and the residue was partitioned carefully between ethyl acetate and water, whereby enough saturated NaHCO3 solution was added so as to make the pH of the aqueous phase slightly basic after the shaking of the biphasic system. The layers were separated, and the aqueous layer was extracted with an additional ethyl acetate. The combined organic phase was washed with brine, dried (MgSO4), filtered, and concentrated. The resulting material was recrystallized from ethyl acetate/hexanes to provide two crops of J.7 (S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate, 5.85 g. The mother liquor was concentrated in vacuo and submitted to a flash chromatography (silica gel; 30% ethyl acetate/hexanes) to provide an additional 2.23 g. 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): δ 12.17/11.92/11.86 (m, 1H), 7.72-7.46/7.28 (m, 5H), 4.86-4.70 (m, 1H), 3.52 (app br s, 1H), 3.36 (m, 1H), 2.30-1.75 (m, 4H), 1.40/1.15 (app br s, 9H). LC (Cond.-J1): RT=1.71 min; LC/MS: Anal. Calcd. For [M+H]+ C18H23BrN3O2: 392.10; found 391.96. HRMS: Anal. Calcd. For [M+H]+ C18H23BrN3O2: 392.0974; found 392.0959. The volatile component was removed in vacuo the residue was partitioned carefully between ethyl acetate and water, whereby enough saturated NaHCO3 solution was added so as The layers were separated the aqueous layer was extracted with an additional ethyl acetate The combined organic phase was washed with brine dried (MgSO4) filtered concentrated The resulting material was recrystallized from ethyl acetate/hexanes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture J.6 (S)-tert-butyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-pyrrolidine-1-carboxylate (12.8 g, 31.12 mmol) and ammonium acetate (12.0 g, 155.7 mmol) in xylenes (155 mL) was heated in a sealed tube at 140° C. for 2 hours. The volatile component was removed in vacuo, and the residue was partitioned carefully between ethyl acetate and water, whereby enough saturated NaHCO3 solution was added so as to make the pH of the aqueous phase slightly basic after the shaking of the biphasic system. The layers were separated, and the aqueous layer was extracted with an additional ethyl acetate. The combined organic phase was washed with brine, dried (MgSO4), filtered, and concentrated. The resulting material was recrystallized from ethyl acetate/hexanes to provide two crops of J.7 (S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate, 5.85 g. The mother liquor was concentrated in vacuo and submitted to a flash chromatography (silica gel; 30% ethyl acetate/hexanes) to provide an additional 2.23 g. 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): δ 12.17/11.92/11.86 (m, 1H), 7.72-7.46/7.28 (m, 5H), 4.86-4.70 (m, 1H), 3.52 (app br s, 1H), 3.36 (m, 1H), 2.30-1.75 (m, 4H), 1.40/1.15 (app br s, 9H). LC (Cond.-J1): RT=1.71 min; LC/MS: Anal. Calcd. For [M+H]+ C18H23BrN3O2: 392.10; found 391.96. HRMS: Anal. Calcd. For [M+H]+ C18H23BrN3O2: 392.0974; found 392.0959. The volatile component was removed in vacuo the residue was partitioned carefully between ethyl acetate and water, whereby enough saturated NaHCO3 solution was added so as The layers were separated the aqueous layer was extracted with an additional ethyl acetate The combined organic phase was washed with brine dried (MgSO4) filtered concentrated The resulting material was recrystallized from ethyl acetate/hexanes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N,N-Diisopropylethylamine (18 mL, 103.3 mmol) was added dropwise, over 15 minutes, to a heterogeneous mixture of N-Boc-L-proline (7.139 g, 33.17 mmol), HATU (13.324 g, 35.04 mmol), the HCl salt of 2-amino-1-(4-bromo-phenyl)ethanone (8.127 g, 32.44 mmol), in dimethylformamide (105 mL) and stirred at ambient condition for 55 minutes. Dimethylformamide was removed in vacuo, and the resulting residue was partitioned between ethyl acetate (300 mL) and water (200 mL). The organic layer was washed with water (200 mL) and brine, dried (MgSO4), filtered, and concentrated. A silica gel mesh was prepared from the residue and submitted to flash chromatography (silica gel; 50-60% ethyl acetate/hexanes) to provide J.6 (S)-tert-butyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)pyrrolidine-1-carboxylate as a white solid (12.8 g). NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): δ8.25-8.14 (m, 1H), 7.92 (br d, J=8.0, 2H), 7.75 (br d, J=8.6, 2H), 4.61 (dd, J=18.3, 5.7, 1H), 4.53 (dd, J=18.1, 5.6, 1H), 4.22-4.12 (m, 1H), 3.43-3.35 (m, 1H), 3.30-3.23 (m, 1H), 2.18-2.20 (m, 1H), 1.90-1.70 (m, 3H), 1.40/1.34 (two app br s, 9H). LC (Cond.-31): RT=1.70 min; LCMS: Anal. Calcd. For [M+Na]+ C18H23BrN2NaO4: 433.07; found 433.09. Dimethylformamide was removed in vacuo the resulting residue was partitioned between ethyl acetate (300 mL) and water (200 mL) The organic layer was washed with water (200 mL) and brine dried (MgSO4) filtered concentrated A silica gel mesh was prepared from the residue

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N,N-Diisopropylethylamine (18 mL, 103.3 mmol) was added dropwise, over 15 minutes, to a heterogeneous mixture of N-Boc-L-proline (7.139 g, 33.17 mmol), HATU (13.324 g, 35.04 mmol), the HCl salt of 2-amino-1-(4-bromo-phenyl)ethanone (8.127 g, 32.44 mmol), in dimethylformamide (105 mL) and stirred at ambient condition for 55 minutes. Dimethylformamide was removed in vacuo, and the resulting residue was partitioned between ethyl acetate (300 mL) and water (200 mL). The organic layer was washed with water (200 mL) and brine, dried (MgSO4), filtered, and concentrated. A silica gel mesh was prepared from the residue and submitted to flash chromatography (silica gel; 50-60% ethyl acetate/hexanes) to provide J.6 (S)-tert-butyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)pyrrolidine-1-carboxylate as a white solid (12.8 g). NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): δ8.25-8.14 (m, 1H), 7.92 (br d, J=8.0, 2H), 7.75 (br d, J=8.6, 2H), 4.61 (dd, J=18.3, 5.7, 1H), 4.53 (dd, J=18.1, 5.6, 1H), 4.22-4.12 (m, 1H), 3.43-3.35 (m, 1H), 3.30-3.23 (m, 1H), 2.18-2.20 (m, 1H), 1.90-1.70 (m, 3H), 1.40/1.34 (two app br s, 9H). LC (Cond.-31): RT=1.70 min; LCMS: Anal. Calcd. For [M+Na]+ C18H23BrN2NaO4: 433.07; found 433.09. Dimethylformamide was removed in vacuo the resulting residue was partitioned between ethyl acetate (300 mL) and water (200 mL) The organic layer was washed with water (200 mL) and brine dried (MgSO4) filtered concentrated A silica gel mesh was prepared from the residue

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the solution of (S)-tert-butyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)pyrrolidine-1-carboxylate (compound 18a, 5.0 g, 12.2 mmol) in xylene (75 ml) were added ammonium acetate (23.4 g, 304 mmol) and acetic acid (5 ml) at room temperature. The reaction mixture was placed in an oil bath and heated to 160° C. with water being azeotroped into a Dean-Stark trap. After 3 hours, the resulting mixture was cooled to room temperature and then extracted with ethyl acetate and distillated water. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give a crude product, which was purified with column chromatography (100% ethyl acetate) to yield the pure product 19a (4.4 g). The reaction mixture was placed in an oil bath azeotroped into a Dean-Stark trap extracted with ethyl acetate and distillated water The organic layer was dried over MgSO4 filtered concentrated under reduced pressure to give a crude product, which was purified with column chromatography (100% ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 2-amino-4′-bromoacetophenone hydrochloride 17 (5.0 g, 20.0 mmol) in DCM (150 mL) was added DIPEA (2.6 g, 20 mmol) at room temperature. After stirred for 10 minutes, the suspension became yellow solution. To another flask charged with a DCM (100 mL) solution of N-Boc-L-Proline (5.2 g, 24.0 mmol) was added HOBt.H2O (3.7 g, 24.0 mmol) at room temperature. EDC.HCl (4.6 g, 24.0 mmol) was added to the proline mixture and the mixture was continually stirred at room temperature for 30 minutes. The above-mentioned yellow solution was added to the proline mixture and stirred at room temperature overnight. The resulting mixture was filtered through Celite® to remove the precipitate. The filtrate was extracted with H2O/DCM, and the organic layer was washed with brine, dried over MgSO4, and filtered. After being concentrated under reduced pressure, the crude product was purified by column chromatography (ethyl acetate: n-hexane=2:5) to yield pure product 18a as a yellow gel (7.4 g). at room temperature the mixture was continually stirred at room temperature for 30 minutes stirred at room temperature overnight The resulting mixture was filtered through Celite® to remove the precipitate The filtrate was extracted with H2O/DCM the organic layer was washed with brine dried over MgSO4 filtered After being concentrated under reduced pressure the crude product was purified by column chromatography (ethyl acetate: n-hexane=2:5)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of N-Boc-L-Proline (5.16 g, 24.0 mmol) and HOBt.H2O (3.67 g, 24.0 mmol) was stirred at room temperature for 10 min and then treated with N-ethyl-N′-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl, 4.60 g, 24.0 mmol). The resulting mixture was stirred at room temperature for 30 min and then treated with a yellow solution formed by stirring 2-amino-4′-bromoacetophenone hydrochloride (5.0 g, 20.0 mmol) and N,N-diisopropylethylamine (DIPEA, 2.58 g, 20 mmol) in dichloromethane (DCM, 150 ml) at room temperature for 10 min. The resulting mixture was stirred at room temperature overnight and then filtered through Celite® to remove the precipitate. The filtrate was extracted with DCM and H2O. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified with column chromatography (ethyl acetate:hexanes=2:5) to yield pure product 1a as a yellow gel (7.39 g, 90%). treated with a yellow solution formed The resulting mixture was stirred at room temperature overnight filtered through Celite® to remove the precipitate The filtrate was extracted with DCM and H2O The organic layer was washed with brine dried over MgSO4 filtered concentrated The residue was purified with column chromatography (ethyl acetate:hexanes=2:5)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N,N-Diisopropylethylamine (18 mL, 103.3 mmol) was added dropwise, over 15 minutes, to a heterogeneous mixture of N-Boc-L-proline (7.139 g, 33.17 mmol), HATU (13.324 g, 35.04 mmol), the HCl salt of 2-amino-1-(4-bromo-phenyl)ethanone (8.127 g, 32.44 mmol), in dimethylformamide (105 mL) and stirred at ambient condition for 55 minutes. Dimethylformamide was removed in vacuo, and the resulting residue was partitioned between ethyl acetate (300 mL) and water (200 mL). The organic layer was washed with water (200 mL) and brine, dried (MgSO4), filtered, and concentrated. A silica gel mesh was prepared from the residue and submitted to flash chromatography (silica gel; 50-60% ethyl acetate/hexanes) to provide J.6 (S)-tert-butyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)pyrrolidine-1-carboxylate as a white solid (12.8 g). 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): δ 8.25-8.14 (m, 1H), 7.92 (br d, J=8.0, 2H), 7.75 (br d, J=8.6, 2H), 4.61 (dd, J=18.3, 5.7, 1H), 4.53 (dd, J=18.1, 5.6, 1H), 4.22-4.12 (m, 1H), 3.43-3.35 (m, 1H), 3.30-3.23 (m, 1H), 2.18-2.20 (m, 1H), 1.90-1.70 (m, 3H), 1.40/1.34 (two app br s, 9H). LC (Cond.-J1): RT=1.70 min; LCMS: Anal. Calcd. For [M+Na]+ C18H23BrN2NaO4: 433.07; found 433.09. Dimethylformamide was removed in vacuo the resulting residue was partitioned between ethyl acetate (300 mL) and water (200 mL) The organic layer was washed with water (200 mL) and brine dried (MgSO4) filtered concentrated A silica gel mesh was prepared from the residue