tert-butyl 3-hydroxypropanoate

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: Aqueous 50% NaOH solution (6.4 g-80 mmol) is added in the course of 15 minutes to a solution, cooled to 15° C., of 3,4-bis(phenylsulphonyl)-1,2,5-oxadiazole 2-oxide (16 g-44 mmol) and tert-butyl 3-hydroxypropionate (10 g-68 mmol) in 200 ml of anhydrous THF. After stirring for 2 hours, the solvent is removed in vacuo and the residue is taken up in 100 ml of water and 100 ml of ethyl acetate. The organic phase is decanted off, washed with saturated NaCl solution, dried with sodium sulphate and evaporated. the solvent is removed in vacuo The organic phase is decanted off washed with saturated NaCl solution dried with sodium sulphate evaporated

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

実験手順: Aqueous 50% NaOH solution (6.4 g-80 mmol) is added in the course of 15 minutes to a solution, cooled to 15° C., of 3,4-bis(phenylsulphonyl)-1,2,5-oxadiazole 2-oxide (16 g-44 mmol) and tert-butyl 3-hydroxypropionate (10 g-68 mmol) in 200 ml of anhydrous THF. After stirring for 2 hours, the solvent is removed in vacuo and the residue is taken up in 100 ml of water and 100 ml of ethyl acetate. The organic phase is decanted off, washed with saturated NaCl solution, dried with sodium sulphate and evaporated. the solvent is removed in vacuo The organic phase is decanted off washed with saturated NaCl solution dried with sodium sulphate evaporated

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-[(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-4,5,2′-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-ol (60 mg) is dissolved in tetrahydrofuran (1 ml) and thereto are added tert-butyl 3-hydroxy-propionate (336 mg) and triphenylphosphine (592 mg), and thereto is added dropwise diisopropyl azodicarboxylate (447 μl) and the mixture is stirred at 60° C. overnight. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. To the resulting residue is added isopropylether and the insoluble material is filtered and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1) and NH-silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give tert-butyl 3-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-4,5,2′-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-propionate (43 mg). MS (m/z): 764 [M+H]+ the mixture is extracted with ethyl acetate The organic layer is washed with a saturated brine dried over magnesium sulfate concentrated under reduced pressure To the resulting residue is added isopropylether the insoluble material is filtered the filtrate is concentrated under reduced pressure The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1) and NH-silica gel column chromatography (hexane:ethyl acetate=9:1→4:1)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-[(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-4,5,2′-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-ol (60 mg) is dissolved in tetrahydrofuran (1 ml) and thereto are added tert-butyl 3-hydroxy-propionate (336 mg) and triphenylphosphine (592 mg), and thereto is added dropwise diisopropyl azodicarboxylate (447 μl) and the mixture is stirred at 60° C. overnight. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. To the resulting residue is added isopropylether and the insoluble material is filtered and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1) and NH-silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give tert-butyl 3-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-4,5,2′-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-propionate (43 mg). MS (m/z): 764 [M+H]+ the mixture is extracted with ethyl acetate The organic layer is washed with a saturated brine dried over magnesium sulfate concentrated under reduced pressure To the resulting residue is added isopropylether the insoluble material is filtered the filtrate is concentrated under reduced pressure The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1) and NH-silica gel column chromatography (hexane:ethyl acetate=9:1→4:1)

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

実験手順: To a solution of 957 (100 mg, 0.09 mmol), DIC (18 mg, 0.14 mmol) and DMAP (20 mg, 0.14 mmol) in DCM (2 mL) was added tert-butyl 3-hydroxypropanoate (41 mg, 0.28 mmol). The solution was stirred for 6 hours at room temperature until no BM-957 was observed by TLC. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated NaHCO3 solution (50 mL), brine (50 mL) and dried over sodium sulfate. The solvent was removed in vacuo to give crude product which was used for next step without purification. The resulting residue was dissolved in DCM (5 mL) and followed by adding TFA (2.5 mL). The solution was stirred at room temperature for 3 h until no starting material was observed by TLC. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to give the pure product 5 (salt with TFA, 75 mg, yield 70% over two steps). The gradient ran from 60% of solvent A and 40% of solvent B to 20% of solvent A and 80% of solvent B in 40 min. MS (ESI): m/z 1238.17 (M+H)+. washed with saturated NaHCO3 solution (50 mL), brine (50 mL) dried over sodium sulfate The solvent was removed in vacuo to give crude product which was used for next step without purification The resulting residue was dissolved in DCM (5 mL) by adding TFA (2.5 mL) The reaction mixture was concentrated in vacuo the residue was purified by HPLC

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

実験手順: 3-Hydroxy-propionic acid tert-butyl ester is dissolved in acetonitrile and carbon tetrabromide and triphenylphosphine is added. The mixture is stirred at room temperature overnight. After this time the mixture is concentrated in vacuo. The gummy solid is triturated with hexanes and the liquid decanted, passed through pad of silica to remove any triphenylphosphine oxide, and concentrated in vacuo. 1H NMR (400 MHz, CHLOROFORM-d) ppm 1.3 (9H, s), 2.06-2.27 (2H, m), 4.07-4.25 (2H, m). After this time the mixture is concentrated in vacuo The gummy solid is triturated with hexanes the liquid decanted to remove any triphenylphosphine oxide concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of tert-butyl 3-hydroxypropanoate (2 g, 13.68 mmol) in dry DCM (50 ml), pyridine (3.32 ml, 41.0 mmol) was added. The solution was cooled to 5° C., and (chloromethanetriyl)tribenzene (3.81 g, 13.68 mmol) was added portion-wise; the ice cooling was removed and stirring was continued for 20 hours. The solvent was evaporated and the residue was portioned between EtOAc and water; the organic layer was washed with a 3% aqueous solution of citric acid, with brine and dried over Na2SO4. The solvent was removed and the residue was purified by flash chromatography on silica gel column (petroleum ether:EtOAc=95:5) affording tert-butyl 3-(trityloxy)propanoate (3.5 g, 9.01 mmol, 65.8% yield, MS/ESI+ 411.3 [MNa]+). the ice cooling was removed The solvent was evaporated the organic layer was washed with a 3% aqueous solution of citric acid, with brine dried over Na2SO4 The solvent was removed the residue was purified by flash chromatography on silica gel column (petroleum ether:EtOAc=95:5)

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

実験手順: A solution of N,N′-dicyclohexylcarbodiimide (DCC, 3.34 g; 16.2 mmol) in dry dichloromethane (20 mL) was added using a syringe to a stirred mixture of 5-(Boc-amino)-4-oxopentanoic acid (3.70 g; 16.0 mmol), t-butyl 3-hydroxypropanoate (2.31 g; 15.8 mmol), and 4-dimethylaminopyridine (DMAP, 50 mg) in dichloromethane (40 mL) at ambient temperature under argon. The mild exothermic reaction was moderated with an ice-water bath. After stirring 2 days at ambient temperature, the mixture was suction-filtered on a glass-sinter filter. The residue was washed with dichloromethane (3×20 mL). The combined filtrates were evaporated and the residue was purified by flash chromatography on a 45×55 mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (500 mL), collecting 7×50 ml fractions. After evaporation of fractions 2-4, 5.45 g (96%) product was obtained (pale yellow oil). The mild exothermic reaction was moderated with an ice-water bath the mixture was suction-filtered on a glass-sinter filter The residue was washed with dichloromethane (3×20 mL) The combined filtrates were evaporated the residue was purified by flash chromatography on a 45×55 mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (500 mL) collecting 7×50 ml fractions After evaporation of fractions 2-4

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

実験手順: Aqueous 50% NaOH solution (6.4 g-80 mmol) is added in the course of 15 minutes to a solution, cooled to 15° C., of 3,4-bis(phenylsulphonyl)-1,2,5-oxadiazole 2-oxide (16 g-44 mmol) and tert-butyl 3-hydroxypropionate (10 g-68 mmol) in 200 ml of anhydrous THF. After stirring for 2 hours, the solvent is removed in vacuo and the residue is taken up in 100 ml of water and 100 ml of ethyl acetate. The organic phase is decanted off, washed with saturated NaCl solution, dried with sodium sulphate and evaporated. the solvent is removed in vacuo The organic phase is decanted off washed with saturated NaCl solution dried with sodium sulphate evaporated

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-[(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-4,5,2′-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-ol (60 mg) is dissolved in tetrahydrofuran (1 ml) and thereto are added tert-butyl 3-hydroxy-propionate (336 mg) and triphenylphosphine (592 mg), and thereto is added dropwise diisopropyl azodicarboxylate (447 μl) and the mixture is stirred at 60° C. overnight. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. To the resulting residue is added isopropylether and the insoluble material is filtered and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1) and NH-silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give tert-butyl 3-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-4,5,2′-trimethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-propionate (43 mg). MS (m/z): 764 [M+H]+ the mixture is extracted with ethyl acetate The organic layer is washed with a saturated brine dried over magnesium sulfate concentrated under reduced pressure To the resulting residue is added isopropylether the insoluble material is filtered the filtrate is concentrated under reduced pressure The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→2:1) and NH-silica gel column chromatography (hexane:ethyl acetate=9:1→4:1)