(1S,2S)-2-amino-1-phenylpropane-1,3-diol

反応条件: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (1S,2S)-2-Amino-1-phenylpropane-1,3-diol (20.0 g, 120 mmol), diethyl carbonate (29.7 mL, 245 mmol), and K2CO3 (1.65 g, 12.0 mmol) were charged into a flask with mechanical stirrer and a vigreux-column. This suspension was heated in an oil bath at 135° C., to give a yellow solution. The accrued EtOH was distilled off over the vigreux column. The reaction was stirred over a period of 3 h, until no more EtOH could be distilled off. The reaction mixture was then cooled to 50° C., diluted with EtOAc and aqueous NaHCO3. The organic layers were separated, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (550 g SiO2) using EtOAc in heptane from 33% to 100% in order to give the title compound as a beige oil (7.50 g, 33%). 1H NMR (400 MHz, DMSO-d5): 7.87 (br s, 1H), 7.50-7.30 (m, 5H), 5.37 (d, 1H), 5.23-5.17 (m, 1H), 3.70-3.60 (m, 1H), 3.60-3.50 (m, 2H). to give a yellow solution The accrued EtOH was distilled off over the vigreux column could be distilled off The reaction mixture was then cooled to 50° C. diluted with EtOAc and aqueous NaHCO3 The organic layers were separated washed with brine dried over MgSO4 filtered concentrated The residue was purified by column chromatography (550 g SiO2)

反応条件: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (1S,2S)-2-Amino-1-phenylpropane-1,3-diol (20.0 g, 120 mmol), diethyl carbonate (29.7 mL, 245 mmol), and K2CO3 (1.65 g, 12.0 mmol) were charged into a flask with mechanical stirrer and a vigreux-column. This suspension was heated in an oil bath at 135° C., to give a yellow solution. The accrued EtOH was distilled off over the vigreux column. The reaction was stirred over a period of 3 h, until no more EtOH could be distilled off. The reaction mixture was then cooled to 50° C., diluted with EtOAc and aqueous NaHCO3. The organic layers were separated, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (550 g SiO2) using EtOAc in heptane from 33% to 100% in order to give the title compound as a beige oil (7.50 g, 33%). 1H NMR (400 MHz, DMSO-d5): 7.87 (br s, 1H), 7.50-7.30 (m, 5H), 5.37 (d, 1H), 5.23-5.17 (m, 1H), 3.70-3.60 (m, 1H), 3.60-3.50 (m, 2H). to give a yellow solution The accrued EtOH was distilled off over the vigreux column could be distilled off The reaction mixture was then cooled to 50° C. diluted with EtOAc and aqueous NaHCO3 The organic layers were separated washed with brine dried over MgSO4 filtered concentrated The residue was purified by column chromatography (550 g SiO2)

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

実験手順: To a solution of (1S,2S)-2-amino-1-phenyl-1,3-propanediol (2.07 g, 12.4 mmol) in DMF (10 mL) was added imidazole (1.0 g, 14.7 mmol) and tert-butyldimethylsilyl chloride (2.30 g, 15.3 mmol). After stirring at rt for 12 h the mixture was added to diluted brine (150 mL, water/brine:1/1). Extraction with ethyl acetate (4×30 mL), washing of the combined extracts with brine (30 mL) and drying (MgSO4) gave after concentration a residue which was purified by flash chromatography on silica gel (eluent: ethyl acetate). The title compound was obtained as colourless oil. δH (CDCl3): 0.24, 0.26 (6H, 2s), 1.12 (9H, s), 2.50–2.78 (3H, br s), 3.16 (1H, ddd), 3.78 (1H, dd), 3.85 (1H, dd), 4.84 (1H, d), 7.49–7.55 (5H, m); m/z (ES+)=282.32 [M+H]+; RT=2.87 min. Extraction with ethyl acetate (4×30 mL) washing of the combined extracts with brine (30 mL) drying (MgSO4) gave after concentration a residue which was purified by flash chromatography on silica gel (eluent: ethyl acetate)

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

実験手順: To a solution of (1S,2S)-2-amino-1-phenyl-1,3-propanediol (2.07 g, 12.4 mmol) in DMF (10 mL) was added imidazole (1.0 g, 14.7 mmol) and tert-butyldimethylsilyl chloride (2.30 g, 15.3 mmol). After stirring at rt for 12 h the mixture was added to diluted brine (150 mL, water/brine:1/1). Extraction with ethyl acetate (4×30 mL), washing of the combined extracts with brine (30 mL) and drying (MgSO4) gave after concentration a residue which was purified by flash chromatography on silica gel (eluent: ethyl acetate). The title compound was obtained as colourless oil. δH (CDCl3): 0.24, 0.26 (6H, 2s), 1.12 (9H, s), 2.50–2.78 (3H, br s), 3.16 (1H, ddd), 3.78 (1H, dd), 3.85 (1H, dd), 4.84 (1H, d), 7.49–7.55 (5H, m); m/z (ES+)=282.32 [M+H]+; RT=2.87 min. Extraction with ethyl acetate (4×30 mL) washing of the combined extracts with brine (30 mL) drying (MgSO4) gave after concentration a residue which was purified by flash chromatography on silica gel (eluent: ethyl acetate)

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

実験手順: In 15 mL of THF was suspended 0.5 g of a racemic mixture, 1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxylic acid (content 99.5%; trans compound 88.1%, cis compound 11.4%). To the suspension was added 0.3 g (1 equivalent) of (1S,2S)-2-amino-1-phenyl-1,3-propanediol, which was made into a solution, followed by crystallization. The crystals were then aged for 30 minutes at room temperature (25° C.). The crystals were collected by filtration using, for example, glass filter, washed with 5 mL of THF, followed by drying overnight at room temperature under reduced pressure to afford 0.37 g of substantially pure (2R,4S)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-benzothiepin-2-carboxylic acid.(1S,2S)-2-amino-1-phenyl-1,3-propanediol salt as colorless crystals [HPLC area percentage; (2R,4R):(2S,4S):(2S,4R):(2R,4S)=0.6%:0.6%:8.3%:85.6%]. followed by crystallization (25° C.) The crystals were collected by filtration filter washed with 5 mL of THF by drying overnight at room temperature under reduced pressure

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

実験手順: This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using (1S,2S)-2-amino-1-phenyl-1,3-propanediol instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 409 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (1H, br. s.) 9.67 (1H, s) 7.99 (1H, d, J=5.37 Hz) 7.76 (1H, d, J=5.32 Hz) 7.45 (1H, d, J=8.64 Hz) 7.33 (1H, d, J=5.37 Hz) 7.27 (1H, dd, J=3.54, 2.22 Hz) 7.21-7.25 (2H, m) 7.10-7.21 (3H, m) 6.62 (1H, d, J=5.42 Hz) 6.36 (1H, dd, J=3.54, 1.73 Hz) 5.55 (1H, d, J=4.73 Hz) 4.90 (1H, dd, J=4.83, 3.17 Hz) 4.84 (1H, t, J=5.64 Hz) 4.07 (1H, dt, J=7.80, 5.30 Hz) 3.50 (1H, dt, J=10.58, 6.96 Hz) 3.40 (1H, dt, J=10.55, 5.34 Hz)

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

実験手順: (The compound of the general formula (II)—wherein R1 is a hydroxy-methyl group, R2 is a phenyl group, R3 is a hydroxy group) Racemic 2-hydroxy-2-(2-chlorophenyl)acetic acid (20.0 g 107 mmol) was dissolved in 60 cm3 of ethylacetate saturated with water and (1S, 2S)-(+)-1-phenyl-2-amino-1,3-propane-diol (18.0 g 107.5 mmol) was added thereto and then the mixture was seed by a salt formed from (S)-(+)-2-hydroxy-2-(2-chlorophenyl)acetate and (1S, 2S)-(+)-1-phenyl 2-amino-1,3-propane-diol at room temperature. was added

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

実験手順: The product from Example 35, Step A, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenyl isothiocyanate (0.316 g, 1.0 mmol) was reacted with (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol (0.167 g, 1.0 mmol) according to the procedure for Example 23, Step B to give the product after trituration with hexanes/ethyl acetate, 1/1, v/v and filtration through silica gel using hexanes/ethyl acetate, 1/1, v/v as eluant The resulting orange oil/foam was triturated with hexanes/ether to give the product as an orange solid (0.155 g), mp (slow decomposition). to give the product after trituration with hexanes/ethyl acetate, 1/1, v/v and filtration through silica gel was triturated with hexanes/ether

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

実験手順: (The compound of the general formula (II)—wherein R1 is a hydroxy-methyl group, R2 is a phenyl group, R3 is a hydroxy group) Racemic 2-hydroxy-2-(2-chlorophenyl)acetic acid (20.0 g 107 mmol) was dissolved in 60 cm3 of ethylacetate saturated with water and (1S, 2S)-(+)-1-phenyl-2-amino-1,3-propane-diol (18.0 g 107.5 mmol) was added thereto and then the mixture was seed by a salt formed from (S)-(+)-2-hydroxy-2-(2-chlorophenyl)acetate and (1S, 2S)-(+)-1-phenyl 2-amino-1,3-propane-diol at room temperature. was added

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

実験手順: The product from Example 35, Step A, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenyl isothiocyanate (0.316 g, 1.0 mmol) was reacted with (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol (0.167 g, 1.0 mmol) according to the procedure for Example 23, Step B to give the product after trituration with hexanes/ethyl acetate, 1/1, v/v and filtration through silica gel using hexanes/ethyl acetate, 1/1, v/v as eluant The resulting orange oil/foam was triturated with hexanes/ether to give the product as an orange solid (0.155 g), mp (slow decomposition). to give the product after trituration with hexanes/ethyl acetate, 1/1, v/v and filtration through silica gel was triturated with hexanes/ether

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

実験手順: 100 g N-acetyl-indoline-2-carboxylic acid (purity 96.5%) was dissolved in 835 ml of a mixture containing 90% ethanol (EtOH), 5% water and 5% methanol (MeOH), with heating to 60° C., and with mechanical stirring. 54.4 g/0.69 eq. (1S,2S)-1-phenyl-2-amino-1,3-propanediol ([α]20D =+25.7° (c=1, MeOH)) was dosed in portions in 30 min. at 60° C. At the end spontaneous crystallization of the salt took place. After 30 minutes' subsequent stirring at 60-66° C., cooling to 15° C. took place, followed by another 30 minutes' stirring. After filtration over a P4 glass filter, three washings with 120 ml EtOH took place. After air-drying, 68.9 g off-white (S)-N-acetyl-indoline-2-carboxylic acid-(1S,2S)-1-phenyl-2-amino-1,3-propanediol salt was obtained, corresponding to a yield of 37.8%. Enantiomeric excess=96.3% (chiral HPLC). At the end spontaneous crystallization of the salt cooling to 15° C. followed by another 30 minutes ' stirring After filtration over a P4 glass filter three washings with 120 ml EtOH After air-drying

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

実験手順: Following a procedure similar to that described in Example 6, but using 5.7 g of (1S, 2S)-(+)-2-amino-1-phenyl-1,3-propanediol, 5 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 250 ml of benzene, 250 ml of absolute methanol and 4.34 g of sodium cyanoborohydride, 1.54 g of the title compound were obtained having an Rf=0.27 (thin layer chromatography over silica gel, using a 2:1 by volume mixture of ethyl acetate and hexane as the developing solvent).