tert-butyl N-(1,3-dihydroxypropan-2-yl)carbamate

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

実験手順: Finely ground K2CO3 (4.32 g, 31.2 mmol, 4 equiv.) was added to N-Boc-serinol (1.45 g, 7.8 mmol, 1 equiv.) in 20 mL DMSO under argon; then 3-nitrophthalonitrile (3.38 g, 19.5 mmol, 2.5 equiv.) was added. The reaction mixture first turned pink, and then orange upon addition of the 3-nitrophthalonitrile. The reaction mixture was stirred at room temperature and monitored periodically by TLC (9:1 benzene:CH3CN). After 72 h, the reaction mixture was partitioned between EtOAc and water. The two layers were separated, and the aqueous layer was extracted 3 times with 50 mL EtOAc. The organic layer from the original partitioning was added to the organic extract. This mixture was then washed twice with 50 mL of saturated NaHCO3, and twice with 50 mL of water, and was then dried over Na2SO4. The solvent was removed at reduced pressure, and the resulting crude orange solid was recrystallized from methanol/water to give 2.43 g (70% yield) of a slightly pink/tan solid. [Rf: 0.25 (9:1 benzene:CH3CN); melting point 167-169° C.; 1H NMR (200 MHz, CD3CN) δ 7.85-7.4 (m, 6H, ArH), 5.76 (br s, 1H, NH), 4.39 (s, 5H, (—CH2)2CH—), 1.42 (s, 9H, C(CH3)3).] the reaction mixture was partitioned between EtOAc and water The two layers were separated the aqueous layer was extracted 3 times with 50 mL EtOAc The organic layer from the original partitioning was added to the organic extract This mixture was then washed twice with 50 mL of saturated NaHCO3 twice with 50 mL of water, and was then dried over Na2SO4 The solvent was removed at reduced pressure the resulting crude orange solid was recrystallized from methanol/water to give 2.43 g (70% yield) of a slightly pink/tan solid

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: Finely ground K2CO3 (4.32 g, 31.2 mmol, 4 equiv.) was added to N-Boc-serinol (1.45 g, 7.8 mmol, 1 equiv.) in 20 mL DMSO under argon; then 3-nitrophthalonitrile (3.38 g, 19.5 mmol, 2.5 equiv.) was added. The reaction mixture first turned pink, and then orange upon addition of the 3-nitrophthalonitrile. The reaction mixture was stirred at room temperature and monitored periodically by TLC (9:1 benzene:CH3CN). After 72 h, the reaction mixture was partitioned between EtOAc and water. The two layers were separated, and the aqueous layer was extracted 3 times with 50 mL EtOAc. The organic layer from the original partitioning was added to the organic extract. This mixture was then washed twice with 50 mL of saturated NaHCO3, and twice with 50 mL of water, and was then dried over Na2SO4. The solvent was removed at reduced pressure, and the resulting crude orange solid was recrystallized from methanol/water to give 2.43 g (70% yield) of a slightly pink/tan solid. [Rf: 0.25 (9:1 benzene:CH3CN); melting point 167-169° C.; 1H NMR (200 MHz, CD3CN) δ 7.85-7.4 (m, 6H, ArH), 5.76 (br s, 1H, NH), 4.39 (s, 5H, (—CH2)2CH—), 1.42 (s, 9H, C(CH3)3).] the reaction mixture was partitioned between EtOAc and water The two layers were separated the aqueous layer was extracted 3 times with 50 mL EtOAc The organic layer from the original partitioning was added to the organic extract This mixture was then washed twice with 50 mL of saturated NaHCO3 twice with 50 mL of water, and was then dried over Na2SO4 The solvent was removed at reduced pressure the resulting crude orange solid was recrystallized from methanol/water to give 2.43 g (70% yield) of a slightly pink/tan solid

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

実験手順: Finely ground K2CO3 (4.32 g, 31.2 mmol, 4 equiv.) was added to N-Boc-serinol (1.45 g, 7.8 mmol, 1 equiv.) in 20 mL DMSO under argon; then 3-nitrophthalonitrile (3.38 g, 19.5 mmol, 2.5 equiv.) was added. The reaction mixture first turned pink, and then orange upon addition of the 3-nitrophthalonitrile. The reaction mixture was stirred at room temperature and monitored periodically by TLC (9:1 benzene:CH3CN). After 72 h, the reaction mixture was partitioned between EtOAc and water. The two layers were separated, and the aqueous layer was extracted 3 times with 50 mL EtOAc. The organic layer from the original partitioning was added to the organic extract. This mixture was then washed twice with 50 mL of saturated NaHCO3, and twice with 50 mL of water, and was then dried over Na2SO4. The solvent was removed at reduced pressure, and the resulting crude orange solid was recrystallized from methanol/water to give 2.43 g (70% yield) of a slightly pink/tan solid. [Rf: 0.25 (9:1 benzene:CH3CN); melting point 167-169° C.; 1H NMR (200 MHz, CD3CN) δ 7.85-7.4 (m, 6H, ArH), 5.76 (br s, 1H, NH), 4.39 (s, 5H, (—CH2)2CH—), 1.42 (s, 9H, C(CH3)3).] the reaction mixture was partitioned between EtOAc and water The two layers were separated the aqueous layer was extracted 3 times with 50 mL EtOAc The organic layer from the original partitioning was added to the organic extract This mixture was then washed twice with 50 mL of saturated NaHCO3 twice with 50 mL of water, and was then dried over Na2SO4 The solvent was removed at reduced pressure the resulting crude orange solid was recrystallized from methanol/water to give 2.43 g (70% yield) of a slightly pink/tan solid

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: Boc—Ser(Bzl)-ol (300 mg, 1.07 mmol) was dissolved in DMF (2 ml), and NaH (50% oil suspension; 77.3 mg, 1.61 mmol) was added under ice-cooling thereto followed by stirring for 30 minutes. After addition of benzyl bromide (165 μl, 1.39 mmol), the mixture was stirred for 10 minutes under ice-cooling, and stirred for 1 hour at room temperature. Aqueous solution of 10% citric acid was added to the reaction mixture, and ethyl acetate added for extraction. The ethyl acetate layer was washed with saturated aqueous solution of sodium hydrogen carbonate, then saturated aqueous solution of NaCl, dried over magnesium sulfate, and concentrated under reduced pressure, yielding the dibenzyl derivative of Boc—Ser-ol. The Boc group of this compound was removed and sequentially coupled to Boc—Val—OH and then to Boc—Ala—OH. The Boc group of the product was removed. The product (9.5 mg, 16.9 μmol) obtained was coupled to the compound (5.7 mg, 11.1 μmol) obtained in the step 1) of the synthesis of compound (4), and the protecting groups were removed by an ordinary method, yielding compound (8) (0.5 mg) shown in Table 1 as colorless oil. cooling the mixture was stirred for 10 minutes under ice- cooling stirred for 1 hour at room temperature added for extraction The ethyl acetate layer was washed with saturated aqueous solution of sodium hydrogen carbonate saturated aqueous solution of NaCl, dried over magnesium sulfate concentrated under reduced pressure

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

実験手順: A solution of dimercaptoacetyl boc-serinol (4.1 mmol) in EtOH (20 ml) was treated with 10 ml of aqueous 1 N NaOH at room temperature for 1 h. The mixture was diluted with CH2Cl2 (100 ml) and then an aqueous solution of 0.1 M iodine (4.5 mmol) is added dropwise. The reaction mixture was stirred for 2 hours at room temperature and 1 mmol of Na2S2O3 (1 M aqueous solution) was added to the reaction mixture. The organic phase was separated, washed with water (3×200 mL), dried with magnesium sulfate, and evaporated at room temperature. The crude product was chromatographed on silica gel (200 mL) using a solvent mixture of hexane and ethyl acetate (40:20) as eluent to give 1,2-dithiolane of boc-serinol. The organic phase was separated washed with water (3×200 mL) dried with magnesium sulfate evaporated at room temperature The crude product was chromatographed on silica gel (200 mL) a solvent mixture of hexane and ethyl acetate (40:20) as eluent

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methanesulfonyl chloride (130 mmol) was added at 5° C. to a stirred solution of boc-serinol (40 mol) and triethylamine (25 ml) in dichloromethane (100 ml). The mixture was stirred at 5° C. for 5 h and at 20° C. for 20 h. Dichloromethane (200 ml) was added and the mixture was washed with an aqueous solution of sodium hydrogen carbonate (50 mM), dried (Na2SO4) and concentrated to dryness under vacuum. Chromatography of the residue on silicagel (1.2 L) eluting with hexane/ethyl:acetate (50:50) gave bis-(methanesulfonic acid ester) of boc-serinol. the mixture was washed with an aqueous solution of sodium hydrogen carbonate (50 mM) dried (Na2SO4) concentrated to dryness under vacuum Chromatography of the residue on silicagel (1.2 L) eluting with hexane/ethyl

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

実験手順: Ketoprofen (1.11 mmol) (manufactured by Tokyo Kasei Kogyo) was dissolved in dichloromethane (3 ml), and triethylamine (1.11 mmol) and dichloromethane solution (2 ml) of dimethylphosphinothioyl chloride (Mpt-Cl) (1.11 mmol) were added thereto in this order, followed by stirring for 25 minutes. Triethylamine (0.36 mmol) was further added thereto, followed by stirring for 20 minutes. The reaction solution was ice-cooled, and triethylamine (1.11 mmol), DMAP (0.19 mmol) and the Boc-serinol obtained in Reference Example 2 (0.50 mmol) were added thereto in this order, followed by stirring overnight by returning to room temperature. The reaction solution was again ice-cooled, and 25% aqueous ammonia (2 ml) and dioxane (10 ml) were added thereto in this order, followed by stirring for 20 minutes. The reaction solution was concentrated to 5 ml, and ethyl acetate was added thereto. Separation by washing with water, 5% aqueous citric acid solution, 5% aqueous sodium hydrogen carbonate solution and saturated brine consecutively was carried out, and after dehydration drying with sodium sulfate the solvent was evaporated under reduced pressure. The precipitate was purified by silica gel column chromatography (hexane:ethyl acetate=2:1, 0.5% triethylamine) to give the titled compound (287.3 mg, yield 87%). The structure was identified by 1H-NMR (CDCl3). by stirring for 20 minutes cooled were added by stirring overnight by returning to room temperature cooled by stirring for 20 minutes The reaction solution was concentrated to 5 ml, and ethyl acetate was added Separation by washing with water, 5% aqueous citric acid solution, 5% aqueous sodium hydrogen carbonate solution and saturated brine after dehydration drying with sodium sulfate the solvent was evaporated under reduced pressure The precipitate was purified by silica gel column chromatography (hexane:ethyl acetate=2:1, 0.5% triethylamine)