4-氧丁酸甲基酯

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

实验步骤: The title compound was prepared from 2,3-diphenyl-5,6,7,8-tetrahydropyrido[3,2-b]pyrazine (Ex. 4.1 step 1) and methyl 4-oxobutanoate analogously to Example 10, step 1;

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

实验步骤: Diacetoneamine hydrogen oxalate (4.25 g) and methyl 4-oxobutanoate (2 g) were suspended in methanol (20 ml). The reaction mixture were stirred at 100° C. for three hours and then at room temperature overnight. It was then evaporated and the residue was purified by Combiflash chromatography (2.0 M ammonia methanol in dichloromethane=0-30%) to give methyl 3-(6,6-dimethyl-4-oxopiperidin-2-yl)propanoate (1.35 g, 37%). at room temperature overnight It was then evaporated the residue was purified by Combiflash chromatography (2.0 M ammonia methanol in dichloromethane=0-30%)

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

实验步骤: Diacetoneamine hydrogen oxalate (4.25 g) and methyl 4-oxobutanoate (2 g) were suspended in methanol (20 ml). The reaction mixture were stirred at 100° C. for three hours and then at room temperature overnight. It was then evaporated and the residue was purified by Combiflash chromatography (2.0 M ammonia methanol in dichloromethane=0-30%) to give methyl 3-(6,6-dimethyl-4-oxopiperidin-2-yl)propanoate (1.35 g, 37%). at room temperature overnight It was then evaporated the residue was purified by Combiflash chromatography (2.0 M ammonia methanol in dichloromethane=0-30%)

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

实验步骤: A solution of commercially available methyl 4-oxobutanoate (4.454 g; 38.36 mmol) in DCM (90 ml) was treated with 2-methylpropane-2-sulfinamide (4.650 g; 38.36 mmol) and with anh. CuSO4 (12.246 g; 76.73 mmol). The resulting heterogeneous mixture was further stirred at rt, under nitrogen, for 12 h. The resulting grey mixture was then filtered over a short pad of celite, and the separated solids were further washed with DCM. The obtained orange filtrate was concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded methyl 4-((tert-butylsulfinyl)imino)-butanoate as a yellow oil. LC-MS (conditions A): tR=0.56 min.; [M+H]+: 220.40 g/mol. The resulting grey mixture was then filtered over a short pad of celite the separated solids were further washed with DCM The obtained orange filtrate was concentrated to dryness under reduced pressure Purification by FC (DCM/MeOH=25/1)

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

实验步骤: (S)-Proline (14.9 mg, 0.13 mmol) was added to a stirred solution of 16 (150 mg, 1.29 mmol) in THF (650 μl). The reaction mixture was stirred at r.t. for 14 h. The reaction mixture was purified directly by column chromatography, eluting with petrol/EtOAc (2:1), to give the aldehydes 17 and SI-3 (as a 3.6:1 mixture of anti:syn diastereoisomers, 91 mg, 61%) as a clear colourless oil. The reaction was also conducted on a 244 mg scale of aldehyde 16 in DMF which gave a 2:1 ratio of anti:syn diastereoisomers (100 mg, 41%). as a 3.6:1 mixture of anti gave a 2:1 ratio of anti

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

实验步骤: (S)-Proline (14.9 mg, 0.13 mmol) was added to a stirred solution of 16 (150 mg, 1.29 mmol) in THF (650 μl). The reaction mixture was stirred at r.t. for 14 h. The reaction mixture was purified directly by column chromatography, eluting with petrol/EtOAc (2:1), to give the aldehydes 17 and SI-3 (as a 3.6:1 mixture of anti:syn diastereoisomers, 91 mg, 61%) as a clear colourless oil. The reaction was also conducted on a 244 mg scale of aldehyde 16 in DMF which gave a 2:1 ratio of anti:syn diastereoisomers (100 mg, 41%). as a 3.6:1 mixture of anti gave a 2:1 ratio of anti

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

实验步骤: To a solution of 3-[(R)-2-amino-2-(2-hydroxy-phenyl)-ethyl]-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-5-[4-(5-trifluoromethyl-furan-2-ylmethyl)-piperazin-1-yl]-1H-pyrimidine-2,4-dione (15-1) (67 mg, 0.100 mmol) in 1,2-dicholoroethane (2 mL) were 4-oxo-butyric acid methyl ester (17 mg, 0.150 mmol) and sodium triacetoxyborohydride (42 mg, 0.200 mmol) in the order, followed by stirring at room temperature for 1.5 hrs. The solution was neutralized with an aqueous saturated sodium bicarbonate solution to separate an organic layer. After concentration of the organic layer, the residue was purified using silica gel chromatography(eluent: dichloromethane/methanol, 30/1) and dried in a vacuum to afford 40 mg of the compound as a colorless oil (yield 53%). 1H NMR (300 MHz, CDCl3) δ 1.79 (2H, m), 2.20-2.33 (4H, m), 2.32 (3H, s), 2.48 (2H, m), 2.60 (2H, t), 2.80 (2H, m), 3.58 (2H, m), 3.61 (2H, s), 3.63 (3H, s), 4.06-4.15 (2H, m), 4.42 (1H, dd), 5.42 (2H, dd), 6.30 (1H, d), 6.72-6.78 (3H, m), 7.06-7.15 (2H, m), 7.26 (1H, m), 7.41 (1H, m), 7.55 (1H, d) to separate an organic layer After concentration of the organic layer, the residue was purified dichloromethane/methanol, 30/1) and dried in a vacuum

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

实验步骤: To a solution of 3-[(R)-2-amino-2-(2-hydroxy-phenyl)-ethyl]-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-5-[4-(5-trifluoromethyl-furan-2-ylmethyl)-piperazin-1-yl]-1H-pyrimidine-2,4-dione (15-1) (67 mg, 0.100 mmol) in 1,2-dicholoroethane (2 mL) were 4-oxo-butyric acid methyl ester (17 mg, 0.150 mmol) and sodium triacetoxyborohydride (42 mg, 0.200 mmol) in the order, followed by stirring at room temperature for 1.5 hrs. The solution was neutralized with an aqueous saturated sodium bicarbonate solution to separate an organic layer. After concentration of the organic layer, the residue was purified using silica gel chromatography(eluent: dichloromethane/methanol, 30/1) and dried in a vacuum to afford 40 mg of the compound as a colorless oil (yield 53%). 1H NMR (300 MHz, CDCl3) δ 1.79 (2H, m), 2.20-2.33 (4H, m), 2.32 (3H, s), 2.48 (2H, m), 2.60 (2H, t), 2.80 (2H, m), 3.58 (2H, m), 3.61 (2H, s), 3.63 (3H, s), 4.06-4.15 (2H, m), 4.42 (1H, dd), 5.42 (2H, dd), 6.30 (1H, d), 6.72-6.78 (3H, m), 7.06-7.15 (2H, m), 7.26 (1H, m), 7.41 (1H, m), 7.55 (1H, d) to separate an organic layer After concentration of the organic layer, the residue was purified dichloromethane/methanol, 30/1) and dried in a vacuum

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

实验步骤: To a solution of the product of Example 112, step a (794 mg, 3.8 mmol) in DCE (10 mL) was added methyl-4-oxobutanoate (0.891 mL, 7.7 mmol) followed by Na(OAc)3BH (1.6 g, 7.7 mmol). The mixture was stirred at room temperature overnight and then quenched by the addition of saturated aqueous NaHCO3 solution. The layers were separated and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography on SiO2 column eluting with EtOAc/Hex afforded the desired compound as a colorless liquid (1.11 g, 95%). MS (ESI) mass calcd. C17H25NO4, 307.2. m/z found 308.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.35-7.20 (m, 5H), 4.22-4.12 (m, 2H), 3.86-3.80 (m, 1H), 3.67-3.60 (m, 4H), 3.52-3.45 (m, 1H), 2.69-2.56 (m, 2H), 2.41-2.26 (m, 2H), 1.80-1.71 (m, 2H), 1.33-1.24 (m, 6H). quenched by the addition of saturated aqueous NaHCO3 solution The layers were separated the combined organic layers were dried over Na2SO4 filtered concentrated in vacuo Chromatography on SiO2 column eluting with EtOAc/Hex

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

实验步骤: To a solution of the product of Example 112, step a (794 mg, 3.8 mmol) in DCE (10 mL) was added methyl-4-oxobutanoate (0.891 mL, 7.7 mmol) followed by Na(OAc)3BH (1.6 g, 7.7 mmol). The mixture was stirred at room temperature overnight and then quenched by the addition of saturated aqueous NaHCO3 solution. The layers were separated and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography on SiO2 column eluting with EtOAc/Hex afforded the desired compound as a colorless liquid (1.11 g, 95%). MS (ESI) mass calcd. C17H25NO4, 307.2. m/z found 308.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.35-7.20 (m, 5H), 4.22-4.12 (m, 2H), 3.86-3.80 (m, 1H), 3.67-3.60 (m, 4H), 3.52-3.45 (m, 1H), 2.69-2.56 (m, 2H), 2.41-2.26 (m, 2H), 1.80-1.71 (m, 2H), 1.33-1.24 (m, 6H). quenched by the addition of saturated aqueous NaHCO3 solution The layers were separated the combined organic layers were dried over Na2SO4 filtered concentrated in vacuo Chromatography on SiO2 column eluting with EtOAc/Hex

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

实验步骤: The title compound was prepared from 2,3-diphenyl-5,6,7,8-tetrahydropyrido[3,2-b]pyrazine (Ex. 4.1 step 1) and methyl 4-oxobutanoate analogously to Example 10, step 1;

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

实验步骤: Into an apparatus similar to that in Example 1, were charged 104.2 g (1 mole) of N-hydroxyethylethylenediamine and 116.1 g (1 mole) of methyl 3-formylpropionate. At 130° C., 18 g of water and 32 g of methanol were distilled off. After adding 340.5 g (1 mole) of behenic acid, esterification was carried out at 210° to 220° C. to obtain 4-behenoyloxyethyl-2,3,6,7-tetrahydro-1,4-diazocin-5-one. At 130° C., 18 g of water and 32 g of methanol were distilled off was carried out at 210° to 220° C.