N-Boc-L-高丝氨酸

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a flask containing Boc-L-homoserine (5.181 g, 23.63 mmol)) in THF (50 ml) was added sodium hydride (2.93 g, 73.3 mmol) and left stirring at 0° C. for 30 minutes. The reaction mixture was warmed to RT and left for 2 hrs. 4-bromo-benzylbromide (11.81 g, 47.3 mmol) was then added as a THF solution (15 ml) dropwise. The reaction was left at RT for 20 hrs. The reaction was quenched with MeOH and the solvent removed in vacuo. The residue was dissolved in water and washed with Et2O. The aqueous layer was acidified with 2M HCl and exhaustively extracted with EtOAc. The organic layer was washed with water and brine, dried over magnesium sulphate and concentrated in vacuo. The oily residue (11 g) was purified by column chromatography eluting with 50-100% EtOAc in hexanes and flushed with 10-50% MeOH in EtOAc. Yield=927 mg, 2.388 mmol, 10% yield as a viscous oil. m/z 386/388 [M−H]+. left The reaction mixture was warmed to RT left for 2 hrs The reaction was left at RT for 20 hrs The reaction was quenched with MeOH the solvent removed in vacuo The residue was dissolved in water washed with Et2O exhaustively extracted with EtOAc The organic layer was washed with water and brine dried over magnesium sulphate concentrated in vacuo The oily residue (11 g) was purified by column chromatography eluting with 50-100% EtOAc in hexanes flushed with 10-50% MeOH in EtOAc

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

实验步骤: N-t-Boc-L-homoserine (5.14 g, 23.45 mmol) and potassium bicarbonate (2.46 g, 24.6 mmol) was weighed out in a round bottom flask and to it was added anhydrous N,N-dimethylformamide (100 mL) and benzyl bromide (4.2 g, 24.6 mmol). The mixture was stirred at room temperature for 18 hours. The crude mixture was then diluted with ethyl acetate and washed, respectively, with brine, saturated NaHCO3 and brine, and dried over Na2SO4. The organic layer was then concentrated down on rotovap and purified on normal phase column chromatography. Yield=7.27 g (100%). washed respectively, with brine, saturated NaHCO3 and brine, and dried over Na2SO4 The organic layer was then concentrated down on rotovap purified on normal phase column chromatography

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of sodium hydride (913 mg, 22.8 mmoL) in DMF at 0° C. was added N-t-Boc-L-homoserine (2 g, 9.13 mmoL). This reaction mixture was stirred at 0° C. for 15 min, and then allyl bromide (1.38 g, 11.4 mmoL) was added. The mixture was warmed up to rt, and stirred for 2 h. It was then concentrated in vacuo. The residue was diluted with water, and sequentially washed with hexane and ether. The organic layers were discarded, and the aqueous layer was carefully adjusted to pH 3 with 1 N HCl. This acidic aqueous solution was extracted with ethyl acetate. The organic phase was dried (MgSO4), and concentrated in vacuo to yield 2.2 g (93%) of (S)-4-allyloxy-2-(tert-butoxycarbonylamino)butyric acid as a colorless oil. 1H NMR (300 MHz, CD3OD) δ 1.42 (s, 9H), 1.80–1.90 (m, 1H), 2.04–2.16 (m, 1H), 3.50–3.54 (m, 2H), 3.97 (d, J=0.39 Hz, 2H), 4.23 (dd, J=8.78, 4.39 Hz, 1H), 5.15 (d, J=10.25 Hz, 1H), 5.26 (dd, J=17.38, 1.65 Hz, 1H), 5.84–5.97 (m, 1H). This starting material was employed in the synthesis of (1R,2S)-ethyl 1-((3R,5S)-1-((S)-4-(allyloxy)-2-(tert-butoxycarbonyl)butanoyl)-3-(6-methoxyisoquinolin-1-yloxy)pyrrolidine-5-carboxamido)-2-vinylcyclopropane-carboxylate as described in example 2. The mixture was warmed up to rt stirred for 2 h It was then concentrated in vacuo The residue was diluted with water sequentially washed with hexane and ether This acidic aqueous solution was extracted with ethyl acetate The organic phase was dried (MgSO4) concentrated in vacuo

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

实验步骤: 125 mg (326 μmol) (RS)-6-{[7-(aminomethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]amino}-1,3-benzothiazol-2(3H)-one (prepared according to example 20) were transformed in analogy to example 23 using N-(tert-butoxycarbonyl)-L-homoserine to give after working up and purification 32.2 mg (16%) of the title compound. to give purification 32.2 mg (16%) of the title compound

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

实验步骤: 125 mg (326 μmol) (RS)-6-{[7-(aminomethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]amino}-1,3-benzothiazol-2(3H)-one (prepared according to example 20) were transformed in analogy to example 23 using N-(tert-butoxycarbonyl)-L-homoserine to give after working up and purification 32.2 mg (16%) of the title compound. to give purification 32.2 mg (16%) of the title compound

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of Boc-L-HomoSer-OH (10.0 g, 45.6 mmol) in DMF was added sodium hydride (2.74 g, 114 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 15 mins, and then allyl bromide (6.90 g, 57.0 mmol) was added. The mixture was warmed to 20° C. and stirred for 2 hrs. The mixture was quenched with saturated NH4Cl solution and then concentrated in vacuum. The residue was diluted with water, and sequentially washed with hexane and ether. The organic layers were discarded, and the aqueous layer was carefully adjusted to pH=3 with 1 N HCl. The acidic aqueous solution was extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated in vacuum to give Boc-L-HomoSer(O-allyl)-OH (8.00 g, 67.8%). The mixture was warmed to 20° C. stirred for 2 hrs The mixture was quenched with saturated NH4Cl solution concentrated in vacuum The residue was diluted with water sequentially washed with hexane and ether The acidic aqueous solution was extracted with ethyl acetate The organic phase was dried over MgSO4 concentrated in vacuum

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of sodium hydride (913 mg, 22.8 mmoL) in DMF at 0° C. was added N-t-Boc-L-homoserine (2 g, 9.13 mmoL). This reaction mixture was stirred at 0° C. for 15 min, and then allyl bromide (1.38 g, 11.4 mmoL) was added. The mixture was warmed up to rt, and stirred for 2 h. It was then concentrated in vacuo. The residue was diluted with water, and sequentially washed with hexane and ether. The organic layers were discarded, and the aqueous layer was carefully adjusted to pH 3 with 1 N HCl. This acidic aqueous solution was extracted with ethyl acetate. The organic phase was dried (MgSO4), and concentrated in vacuo to yield 2.2 g (93%) of (S)-4-allyloxy-2-(tert-butoxycarbonylamino)butyric acid as a colorless oil. 1H NMR (300 MHz, CD3OD) δ 1.42 (s, 9H), 1.80-1.90 (m, 1H), 2.04-2.16 (m, 1H), 3.50-3.54 (m, 2H), 3.97 (d, J=4.39Hz, 2H), 4.23 (dd, J=8.78, 4.39Hz, 1H), 5.15 (d, J=10.25Hz, 1H), 5.26 (dd, J=17.38, 1.65Hz, 1H), 5.84-5.97 (m, 1H). The mixture was warmed up to rt stirred for 2 h It was then concentrated in vacuo The residue was diluted with water sequentially washed with hexane and ether This acidic aqueous solution was extracted with ethyl acetate The organic phase was dried (MgSO4) concentrated in vacuo

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

实验步骤: To a solution of N-Boc-L-Homoserine (16 mg, 0.075 mmol, 1.5 eq) and HOBT hydrate (12 mg, 0.085 mmol, 1.7 eq) in DMF (2 mL) was added PS-carbodiimide (also known as N-Cyclohexylcarbodiimide-N′-propoxymethyl polystyrene, purchased from Biotage) (80 mg, 1.25 mmol/g resin, 0.1 mmol, 2.0 eq). After 10 minutes, a solution of tert-butyl 4-(3-(5-aminopent-1-ynyl)phenoxy)piperidine-1-carboxylate (0.25 mL of a 0.2 M solution in DCM, 0.05 mmol, 1.0 eq) was added and the resulting solution stirred overnight. To the resulting solution was then added MP-carbonate resin (95 mg, 2.64 mmol/g resin, 0.25 mmols, 5 eq), the suspension stirred 2 hrs, filtered, the resin washed with DCM and the filtrate concentrated by rotovap. The residue was taken up in 20% TFA/DCM (2 mL) and stirred 1 hr, methanol (1 mL) was added, and the resulting solution concentrated by rotovap. The resulting residue was purified by HPLC to yield (S)-2-amino-4-hydroxy-N-(5-(3-(piperidin-4-yloxy)phenyl)pent-4-ynyl)butanamide as a gum. ESI-MS (m/z): Calculated for C20H29N3O3: 360.2 (M+1); Measured: 360.2. filtered the resin washed with DCM the filtrate concentrated by rotovap stirred 1 hr methanol (1 mL) was added the resulting solution concentrated by rotovap The resulting residue was purified by HPLC

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

实验步骤: To a solution of N-Boc-L-Homoserine (16 mg, 0.075 mmol, 1.5 eq) and HOBT hydrate (12 mg, 0.085 mmol, 1.7 eq) in DMF (2 mL) was added PS-carbodiimide (also known as N-Cyclohexylcarbodiimide-N′-propoxymethyl polystyrene, purchased from Biotage) (80 mg, 1.25 mmol/g resin, 0.1 mmol, 2.0 eq). After 10 minutes, a solution of tert-butyl 4-(3-(5-aminopent-1-ynyl)phenoxy)piperidine-1-carboxylate (0.25 mL of a 0.2 M solution in DCM, 0.05 mmol, 1.0 eq) was added and the resulting solution stirred overnight. To the resulting solution was then added MP-carbonate resin (95 mg, 2.64 mmol/g resin, 0.25 mmols, 5 eq), the suspension stirred 2 hrs, filtered, the resin washed with DCM and the filtrate concentrated by rotovap. The residue was taken up in 20% TFA/DCM (2 mL) and stirred 1 hr, methanol (1 mL) was added, and the resulting solution concentrated by rotovap. The resulting residue was purified by HPLC to yield (S)-2-amino-4-hydroxy-N-(5-(3-(piperidin-4-yloxy)phenyl)pent-4-ynyl)butanamide as a gum. ESI-MS (m/z): Calculated for C20H29N3O3: 360.2 (M+1); Measured: 360.2. filtered the resin washed with DCM the filtrate concentrated by rotovap stirred 1 hr methanol (1 mL) was added the resulting solution concentrated by rotovap The resulting residue was purified by HPLC

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a flask containing Boc-L-homoserine (5.181 g, 23.63 mmol)) in THF (50 ml) was added sodium hydride (2.93 g, 73.3 mmol) and left stirring at 0° C. for 30 minutes. The reaction mixture was warmed to RT and left for 2 hrs. 4-bromo-benzylbromide (11.81 g, 47.3 mmol) was then added as a THF solution (15 ml) dropwise. The reaction was left at RT for 20 hrs. The reaction was quenched with MeOH and the solvent removed in vacuo. The residue was dissolved in water and washed with Et2O. The aqueous layer was acidified with 2M HCl and exhaustively extracted with EtOAc. The organic layer was washed with water and brine, dried over magnesium sulphate and concentrated in vacuo. The oily residue (11 g) was purified by column chromatography eluting with 50-100% EtOAc in hexanes and flushed with 10-50% MeOH in EtOAc. Yield=927 mg, 2.388 mmol, 10% yield as a viscous oil. m/z 386/388 [M−H]+. left The reaction mixture was warmed to RT left for 2 hrs The reaction was left at RT for 20 hrs The reaction was quenched with MeOH the solvent removed in vacuo The residue was dissolved in water washed with Et2O exhaustively extracted with EtOAc The organic layer was washed with water and brine dried over magnesium sulphate concentrated in vacuo The oily residue (11 g) was purified by column chromatography eluting with 50-100% EtOAc in hexanes flushed with 10-50% MeOH in EtOAc

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a flask containing Boc-L-homoserine (5.181 g, 23.63 mmol)) in THF (50 ml) was added sodium hydride (2.93 g, 73.3 mmol) and left stirring at 0° C. for 30 minutes. The reaction mixture was warmed to RT and left for 2 hrs. 4-bromo-benzylbromide (11.81 g, 47.3 mmol) was then added as a THF solution (15 ml) dropwise. The reaction was left at RT for 20 hrs. The reaction was quenched with MeOH and the solvent removed in vacuo. The residue was dissolved in water and washed with Et2O. The aqueous layer was acidified with 2M HCl and exhaustively extracted with EtOAc. The organic layer was washed with water and brine, dried over magnesium sulphate and concentrated in vacuo. The oily residue (11 g) was purified by column chromatography eluting with 50-100% EtOAc in hexanes and flushed with 10-50% MeOH in EtOAc. Yield=927 mg, 2.388 mmol, 10% yield as a viscous oil. m/z 386/388 [M−H]+. left The reaction mixture was warmed to RT left for 2 hrs The reaction was left at RT for 20 hrs The reaction was quenched with MeOH the solvent removed in vacuo The residue was dissolved in water washed with Et2O exhaustively extracted with EtOAc The organic layer was washed with water and brine dried over magnesium sulphate concentrated in vacuo The oily residue (11 g) was purified by column chromatography eluting with 50-100% EtOAc in hexanes flushed with 10-50% MeOH in EtOAc

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

实验步骤: N-t-Boc-L-homoserine (5.14 g, 23.45 mmol) and potassium bicarbonate (2.46 g, 24.6 mmol) was weighed out in a round bottom flask and to it was added anhydrous N,N-dimethylformamide (100 mL) and benzyl bromide (4.2 g, 24.6 mmol). The mixture was stirred at room temperature for 18 hours. The crude mixture was then diluted with ethyl acetate and washed, respectively, with brine, saturated NaHCO3 and brine, and dried over Na2SO4. The organic layer was then concentrated down on rotovap and purified on normal phase column chromatography. Yield=7.27 g (100%). washed respectively, with brine, saturated NaHCO3 and brine, and dried over Na2SO4 The organic layer was then concentrated down on rotovap purified on normal phase column chromatography