(2R)-2-amino-3-phenylpropan-1-ol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 9.0 g (49 mmol) of (R)-2-amino-3-phenylpropionitrile.HCl-salt (97.5% e.e.) in 280 mL of methanol-water 1:1 was added 2.2 equiv. of conc. HCl solution and 2.0 g of 5% Pd/C. The solution was hydrogenated for 19 h at 35° C. and 0.9 MPa of hydrogen pressure. Then additional 2 g of Pd/C was added and hydrogenation was continued for 24 h at 3.0 MPa. According to chiral HPLC 91% of (R)-2-amino-3-phenyl-1-propanol was formed together with 6% of (R)-3-phenyl-1,2-diaminopropane The reaction mixture was filtered and partially evaporated. The solution was basified to pH 10 using diluted NaOH solution and extracted with CH2CL2. The organic solution was dried over Na2SO4 and evaporated. hydrogenation was continued for 24 h at 3.0 MPa

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared in a similar manner as described in example 4 from 3-(4-methoxy-phenyl)-acrylic acid and D-phenylalaninol. MS (M+H, 312.3). Prepared in a similar manner

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: First, 2.81 g of 1-phenyl-4,6-dichloropyrazolo[3,4-d]pyrimidine was suspended in 60 ml of ethanol, then 3.2 g of (R)-(+)-2-amino-3-phenyl-1-propanol was added with stirring. After 48 hours the solvent was removed under vacuum and the oil was flash chromatographed (2-5-7% MeOH/CHCl3) to yield 3.80 g of (R)-β-[(1-phenyl-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]benzenepropanol (95%). After 48 hours the solvent was removed under vacuum chromatographed (2-5-7% MeOH/CHCl3)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: First, 2.81 g of 1-phenyl-4,6-dichloropyrazolo[3,4-d]pyrimidine was suspended in 60 ml of ethanol, then 3.2 g of (R)-(+)-2-amino-3-phenyl-1-propanol was added with stirring. After 48 hours the solvent was removed under vacuum and the oil was flash chromatographed (2-5-7% MeOH/CHCl3) to yield 3.80 g of (R)-β-[(1-phenyl-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]benzenepropanol (95%). After 48 hours the solvent was removed under vacuum chromatographed (2-5-7% MeOH/CHCl3)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3 g of (R)-(+)-2-amino-3-phenylpropanol and 1.8 g of ethylene carbonate in 50 ml toluene in a round bottom flask equipped with a Dean-Stark trap was refluxed for 24 hrs. The reaction mixture was poured into ethyl acetate/water mixture and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water, followed by brine, dried and concentrated. Kugelrohr distillation at 150°-160° C./0.5 mm Hg provided 2.75 g (75%) of an oil. was refluxed for 24 hrs the aqueous layer was extracted with ethyl acetate The combined organic extracts were washed with water dried concentrated Kugelrohr distillation at 150°-160° C./0.5 mm Hg

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: First, 1.13 g of the starting material 4-chloro-1-phenylpyrazolo[3,4-d]pyrimidine was combined with 0.67 ml Et3N, 0.74 g of (R)-(+)-2-amino-3-phenyl-1-propanol in 60 ml absolute ethanol and heated in a steam bath for four hours. The solvent was then removed under vacuum and the residue was purified by flash chromatography (10-20% isopropyl alcohol/hexane) to yield 1.24 g of (R)-β-[1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]benzenepropanol (74% yield). heated in a steam bath for four hours The solvent was then removed under vacuum the residue was purified by flash chromatography (10-20% isopropyl alcohol/hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 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 (R)-phenylalaninol instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 392 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (1H, br. s.) 10.14 (1H, s) 7.98 (1H, d, J=5.47 Hz) 7.72-7.82 (2H, m) 7.40 (1H, d, J=5.37 Hz) 7.28 (1H, dd, J=3.54, 2.22 Hz) 7.14-7.22 (4H, m) 7.10 (1H, ddd, J=6.20, 2.98, 2.73 Hz) 6.73 (1H, d, J=5.52 Hz) 6.39 (1H, dd, J=3.51, 1.66 Hz) 4.82 (1H, t, J=5.56 Hz) 4.13 (1H, ddd, J=14.04, 5.58, 2.98 Hz) 3.42-3.49 (1H, m) 3.38 (1H, t, J=5.78 Hz) 2.84-2.93 (1H, m) 2.73 (1H, dd, J=13.67, 8.93 Hz)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 2-amino-4-methylthiazole-5-carboxylate (1.86 g, 10.0 mmol) in tetrahydrofuran (50 mL) was added 1,1′-carbonyldiimidazole (1.95 g, 12.0 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 17 hours, followed by the addition of (R)-(+)-2-amino-3-phenyl-1-propanol (2.00 g, 13.2 mmol). The reaction mixture was kept stirring at ambient temperature for 50 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (200 mL) and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford the title compound in 88% (3.20 g): MS (ES+) m/z 364.4 (M+1). The resulting reaction mixture The reaction mixture was kept stirring at ambient temperature for 50 hours The solvent was removed in vacuo The residue was dissolved in ethyl acetate (200 mL) washed with water and brine The organic solution was dried over anhydrous sodium sulfate filtered The filtrate was concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of ethyl 2-amino-4-methylthiazole-5-carboxylate (1.86 g, 10.0 mmol) in tetrahydrofuran (50 mL) was added 1,1′-carbonyldiimidazole (1.95 g, 12.0 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 17 hours, followed by the addition of (R)-(+)-2-amino-3-phenyl-1-propanol (2.00 g, 13.2 mmol). The reaction mixture was kept stirring at ambient temperature for 50 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (200 mL) and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford the title compound in 88% (3.20 g): MS (ES+) m/z 364.4 (M+1). The resulting reaction mixture The reaction mixture was kept stirring at ambient temperature for 50 hours The solvent was removed in vacuo The residue was dissolved in ethyl acetate (200 mL) washed with water and brine The organic solution was dried over anhydrous sodium sulfate filtered The filtrate was concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Intermediate 45 was prepared from Intermediate 17 and (2R)-2-amino-3-phenyl-1-propanol (commercially available from Aldrich) using an analagous method to that for Intermediate 42. LCMS showed MH+=424; TRET=2.59 min. TRET=2.59 min.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 9.0 g (49 mmol) of (R)-2-amino-3-phenylpropionitrile.HCl-salt (97.5% e.e.) in 280 mL of methanol-water 1:1 was added 2.2 equiv. of conc. HCl solution and 2.0 g of 5% Pd/C. The solution was hydrogenated for 19 h at 35° C. and 0.9 MPa of hydrogen pressure. Then additional 2 g of Pd/C was added and hydrogenation was continued for 24 h at 3.0 MPa. According to chiral HPLC 91% of (R)-2-amino-3-phenyl-1-propanol was formed together with 6% of (R)-3-phenyl-1,2-diaminopropane The reaction mixture was filtered and partially evaporated. The solution was basified to pH 10 using diluted NaOH solution and extracted with CH2CL2. The organic solution was dried over Na2SO4 and evaporated. hydrogenation was continued for 24 h at 3.0 MPa

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 9.0 g (49 mmol) of (R)-2-amino-3-phenylpropionitrile.HCl-salt (97.5% e.e.) in 280 mL of methanol-water 1:1 was added 2.2 equiv. of conc. HCl solution and 2.0 g of 5% Pd/C. The solution was hydrogenated for 19 h at 35° C. and 0.9 MPa of hydrogen pressure. Then additional 2 g of Pd/C was added and hydrogenation was continued for 24 h at 3.0 MPa. According to chiral HPLC 91% of (R)-2-amino-3-phenyl-1-propanol was formed together with 6% of (R)-3-phenyl-1,2-diaminopropane The reaction mixture was filtered and partially evaporated. The solution was basified to pH 10 using diluted NaOH solution and extracted with CH2CL2. The organic solution was dried over Na2SO4 and evaporated. hydrogenation was continued for 24 h at 3.0 MPa