(S)-叔亮氨醇

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: As described in Example 1(f) for the preparation of N-(1(S)-benzyl-2-methoxyethyl)-3(R)-(t-butoxycarbonylamino)succinamic acid benzyl ester, N-t-butoxycarbonyl-D-aspartic acid β-benzyl ester (1.00 g, 3.10 mmol) and L-t-leucinol (400 mg, 3.40 mrnol) were coupled with BOP to afford 1.20 g (90%) of 3(R)-(t-butoxycarbonylamino)-N-(1(S)-hydroxymethyl-2,2-dimethyl-propyl)succinamic acid benzyl ester as a white powder, mp 186-7° C.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Compound 66 was prepared according to the procedure described for the synthesis of compound 64 by replacing tert-leucine methylamide with tert-leucinol. LCMS (+ESI) m/z=393.3 [M+H]+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Compound 66 was prepared according to the procedure described for the synthesis of compound 64 by replacing tert-leucine methylamide with tert-leucinol. LCMS (+ESI) m/z=393.3 [M+H]+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Compound 51 was prepared according to the procedure described for the synthesis of compound 28 by replacing intermediate 16 with intermediate 18, and replacing tert-leucine methylamide with tert-leucinol. 1H NMR (CDCl3) δ 7.54-7.60 (m, 1H), 7.41-7.47 (m, 2H), 7.17-7.23 (m, 1H), 6.95 (dd, J=7.3, 3.4 Hz, 1H), 3.80-3.86 (m, 1H), 3.65-3.70 (m, 1H), 3.04 (m, 2H), 2.64 (m, 2H), 1.74-1.84 (m, 4H), 1.04 (s, 9H). LCMS (+ESI) m/z=378.3 [M+H]+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Compound 48 was prepared according to the procedure described for the synthesis of compound 37 by replacing intermediate 19 with intermediate 15, and replacing tert-leucine methylamide with tert-leucinol. 1H NMR (CDCl3) δ 7.48-7.53 (m, 1H), 7.33-7.38 (m, 2H), 7.18-7.22 (m, 1H), 3.92-3.95 (m, 1H), 3.78-3.83 (m, 1H), 3.64-3.68 (m, 1H), 3.57 (s, 2H), 3.20 (m, 2H), 2.72-2.79 (m, 2H), 2.53 (s, 3H), 1.02 (s, 9H). LCMS (+ESI) m/z=393.2 [M+H]+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Compound 48 was prepared according to the procedure described for the synthesis of compound 37 by replacing intermediate 19 with intermediate 15, and replacing tert-leucine methylamide with tert-leucinol. 1H NMR (CDCl3) δ 7.48-7.53 (m, 1H), 7.33-7.38 (m, 2H), 7.18-7.22 (m, 1H), 3.92-3.95 (m, 1H), 3.78-3.83 (m, 1H), 3.64-3.68 (m, 1H), 3.57 (s, 2H), 3.20 (m, 2H), 2.72-2.79 (m, 2H), 2.53 (s, 3H), 1.02 (s, 9H). LCMS (+ESI) m/z=393.2 [M+H]+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was made in two steps using a similar process to that described in example Z-2. 16 (41 mg, 0.09 mmol) and freebased L-tert-leucinol (59 mg, 0.50 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (3S,11aR)-3-(1,1-dimethylethyl)-N-[(4-fluorophenyl)methyl]-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (40 mg, 85%). This material was hydrogenated in a second step as described in example Z-2 to give (3S,11aR)-3-(1,1-Dimethylethyl)-N-[(4-fluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (32 mg, 97%) as a tinted white solid. 1H NMR (CDCl3) δ 11.15 (br, 1H), 10.32 (s, 1H), 8.38 (s, 1H), 7.29 (m, 2H), 6.98 (m, 2H), 5.43 (m, 1H), 4.58 (m, 2H), 4.36 (m, 2H), 4.21 (m, 1H), 3.99 (m, 1H), 3.79 (m, 1H), 1.02 (s, 9H); ES+ MS: 430 (M+1).

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 2-chloro-5,6-difluoropyridine-3-carbonitrile (6.52 g, 34.13 mmol), (2S)-2-amino-3,3-dimethyl-butan-1-ol (4.00 g, 34.13 mmol) and triethylamine (9.51 mL, 68.26 mmol) in CH3CN (50 mL) and THF (50 mL) was heated at 80° C. for 4 hours. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The crude product was purified via silica gel chromatography (0-60% EtOAc/Hexanes gradient) to afford 6.7 g of the desired product as an off white solid: 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J=9.7 Hz, 1H), 5.32 (m, 1H), 4.19-4.08 (m, 1H), 3.95-3.83 (m, 1H), 3.74-3.51 (m, 1H), 0.92 (s, 9H); LC/MS (60-90% ACN/water 5 min with 0.9% FA) m/z 272.02 (M+H), retention time 1.02 minutes. The mixture was cooled to room temperature the solvent was evaporated under reduced pressure The crude product was purified via silica gel chromatography (0-60% EtOAc/Hexanes gradient)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of (2S)-2-amino-3,3-dimethyl-butan-1-ol (5.0 g, 42.7 mmol) and 2,4-dichloro-5-fluoro-pyrimidine (5.7 g, 42.7 mmol) in DMF (50 mL) was added triethylamine (7.1 mL, 51.2 mmol). After 90 minutes, the reaction was diluted into aqueous saturated NH4Cl solution and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-10% MeOH/CH2Cl2 gradient) to afford 6.7 g of the desired product, 1, as a sticky solid: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.48 minutes (M+H) 248.32. extracted twice with EtOAc The combined organic phases were washed twice with brine dried (MgSO4) filtered concentrated in vacuo The crude residue was purified via silica gel chromatography (0-10% MeOH/CH2Cl2 gradient)

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (S)-tert-leucinol (0.937 g, 7.99 mmol) and (3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one (1 g, 2.66 mmol; Example 261, Step F) were combined in a reaction flask and heated to 100° C. After 2 d, the reaction mixture was cooled to RT and dissolved in ethyl acetate. The organic phase was washed with 3×10 mL 1N HCl and 1×10 mL brine, dried over MgSO4, filtered and concentrated to afford the title compound. the reaction mixture was cooled to RT The organic phase was washed with 3×10 mL 1N HCl and 1×10 mL brine dried over MgSO4 filtered concentrated

反应条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2,6-difluoro-5-iodonicotinic acid (4 g, 14.04 mmol, 1 equiv.) in toluene (30 mL) was added thionyl chloride (5.12 mL, 70.18 mmol, 5 equiv.) followed by DMF (0.5 mL). The reaction was stirred at 110° C. for 1 h. The reaction was concentrated. The residue was re-suspended in THF (15 mL) and added dropwise to a solution of ethyl-3-(dimethylamine)acrylate (2.1 mL, 14.04, 1.1 equiv.) and triethylamine (2.15 mL, 15.44 mmol, 1.1 equiv.) in THF (15 mL). The reaction was stirred at 67° C. for 2 h and cooled to 23° C. (S)-2-amino-3,3-dimethylbutan-1-ol (1.81 g, 15.44 mmol, 1.1 equiv.) was subsequently added and stirred at 23° C. for 30 min. The reaction was quenched with water (40 mL) and ethyl acetate (40 mL). The aqueous layer was extracted with ethyl acetate (2×40 mL), and the organics were dried and concentrated. The compound was purified via silica gel chromatography and concentrated to provide (S)-ethyl 2-(2,6-difluoro-5-iodonicotinoyl)-3-(1-hydroxy-3,3-dimethylbutan-2-ylamino)acrylate Intermediate 80 (4.49 g, 66%). Calcd for C17H21F2IN2O4 [M+H]+: 482.9. The reaction was concentrated The reaction was stirred at 67° C. for 2 h was subsequently added stirred at 23° C. for 30 min The reaction was quenched with water (40 mL) and ethyl acetate (40 mL) The aqueous layer was extracted with ethyl acetate (2×40 mL) the organics were dried concentrated The compound was purified via silica gel chromatography concentrated

反应条件: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 2,6-difluoro-5-iodonicotinic acid (4 g, 14.04 mmol, 1 equiv.) in toluene (30 mL) was added thionyl chloride (5.12 mL, 70.18 mmol, 5 equiv.) followed by DMF (0.5 mL). The reaction was stirred at 110° C. for 1 h. The reaction was concentrated. The residue was re-suspended in THF (15 mL) and added dropwise to a solution of ethyl-3-(dimethylamine)acrylate (2.1 mL, 14.04, 1.1 equiv.) and triethylamine (2.15 mL, 15.44 mmol, 1.1 equiv.) in THF (15 mL). The reaction was stirred at 67° C. for 2 h and cooled to 23° C. (S)-2-amino-3,3-dimethylbutan-1-ol (1.81 g, 15.44 mmol, 1.1 equiv.) was subsequently added and stirred at 23° C. for 30 min. The reaction was quenched with water (40 mL) and ethyl acetate (40 mL). The aqueous layer was extracted with ethyl acetate (2×40 mL), and the organics were dried and concentrated. The compound was purified via silica gel chromatography and concentrated to provide (S)-ethyl 2-(2,6-difluoro-5-iodonicotinoyl)-3-(1-hydroxy-3,3-dimethylbutan-2-ylamino)acrylate Intermediate 80 (4.49 g, 66%). Calcd for C17H21F2IN2O4 [M+H]+: 482.9. The reaction was concentrated The reaction was stirred at 67° C. for 2 h was subsequently added stirred at 23° C. for 30 min The reaction was quenched with water (40 mL) and ethyl acetate (40 mL) The aqueous layer was extracted with ethyl acetate (2×40 mL) the organics were dried concentrated The compound was purified via silica gel chromatography concentrated