tert-butyl N-[(2S)-2-hydroxypropyl]carbamate

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

Procedure: ((S)-2-Hydroxy-propyl)-carbamic acid tert-butyl ester (0.25 g, 1.43 mmol) was dissolved in acetonitrile (14 ml) and iodomethane (1.78 ml, 28.5 mmol), and then silver oxide (0.53 g, 2.28 mmol; prepared as in Org. Syn. Coll. Vol. VII, p. 386) were added. The reaction flask was covered to protect from light and the reaction was heated at reflux for 24 h. Additional iodomethane (1.8 ml) and silver oxide (0.26 g) were added and heating was continued until the reaction was judged to be complete by standard reverse phase LC/MS. The reaction mixture was filtered through diatomaceous earth, rinsing with ethyl acetate. After evaporation the residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 85 mg (32%) of ((S)-2-methoxy-propyl)-carbamic acid tert-butyl ester. (M+Na)+=212. the reaction was heated at reflux for 24 h heating The reaction mixture was filtered through diatomaceous earth rinsing with ethyl acetate After evaporation the residue was purified by silica gel chromatography (ethyl acetate/hexanes)

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

Procedure: ((S)-2-Hydroxy-propyl)-carbamic acid tert-butyl ester (0.25 g, 1.43 mmol) was dissolved in acetonitrile (14 ml) and iodomethane (1.78 ml, 28.5 mmol), and then silver oxide (0.53 g, 2.28 mmol; prepared as in Org. Syn. Coll. Vol. VII, p. 386) were added. The reaction flask was covered to protect from light and the reaction was heated at reflux for 24 h. Additional iodomethane (1.8 ml) and silver oxide (0.26 g) were added and heating was continued until the reaction was judged to be complete by standard reverse phase LC/MS. The reaction mixture was filtered through diatomaceous earth, rinsing with ethyl acetate. After evaporation the residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 85 mg (32%) of ((S)-2-methoxy-propyl)-carbamic acid tert-butyl ester. (M+Na)+=212. the reaction was heated at reflux for 24 h heating The reaction mixture was filtered through diatomaceous earth rinsing with ethyl acetate After evaporation the residue was purified by silica gel chromatography (ethyl acetate/hexanes)

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

Procedure: Cool a solution of tert-butyl [(2S)-2-hydroxypropyl]carbamate (870 g, 4.96 mol) in tetrahydrofuran (10 L) to 5° C. Add sodium hydride (60% dispersion, 248 g, 6.21 mol, 1.25 eq.) in portions over 8 minutes. Stir the reaction at 5° C. for 30 minutes. Add methyl iodide (387 mL, 6.21 mol, 1.25 eq.) dropwise over 5 minutes and allow the reaction to proceed at 5-10° C. for 45 minutes. Quench the reaction with water (1 L) and extract with ethyl acetate (4 L). Obtain the organic layer and concentrate it in vacuo to obtain a residue. Co-evaporate the residue with toluene (2×1 L), dilute with dichloromethane (2 L) and filter. Rinse remaining solid with additional dichloromethane (500 mL). Concentrate the combined dichloromethane liquid filtrate in vacuo to obtain a crude intermediate of tert-butyl N-[(2S)-2-methoxypropyl]carbamate (880 g, 94%). the reaction at 5° C. for 30 minutes the reaction Quench the reaction with water (1 L) extract with ethyl acetate (4 L) Obtain the organic layer concentrate it in vacuo to obtain a residue Co-evaporate the residue with toluene (2×1 L) dilute with dichloromethane (2 L) filter Rinse Concentrate the combined dichloromethane liquid filtrate in vacuo

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

Procedure: Cool a solution of tert-butyl [(2S)-2-hydroxypropyl]carbamate (870 g, 4.96 mol) in tetrahydrofuran (10 L) to 5° C. Add sodium hydride (60% dispersion, 248 g, 6.21 mol, 1.25 eq.) in portions over 8 minutes. Stir the reaction at 5° C. for 30 minutes. Add methyl iodide (387 mL, 6.21 mol, 1.25 eq.) dropwise over 5 minutes and allow the reaction to proceed at 5-10° C. for 45 minutes. Quench the reaction with water (1 L) and extract with ethyl acetate (4 L). Obtain the organic layer and concentrate it in vacuo to obtain a residue. Co-evaporate the residue with toluene (2×1 L), dilute with dichloromethane (2 L) and filter. Rinse remaining solid with additional dichloromethane (500 mL). Concentrate the combined dichloromethane liquid filtrate in vacuo to obtain a crude intermediate of tert-butyl N-[(2S)-2-methoxypropyl]carbamate (880 g, 94%). the reaction at 5° C. for 30 minutes the reaction Quench the reaction with water (1 L) extract with ethyl acetate (4 L) Obtain the organic layer concentrate it in vacuo to obtain a residue Co-evaporate the residue with toluene (2×1 L) dilute with dichloromethane (2 L) filter Rinse Concentrate the combined dichloromethane liquid filtrate in vacuo

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

Procedure: 2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile (0.91 g, 3.80 mmol) was reacted with N-Boc-(S)-1-amino-2-propanol (1.00 g, 5.71 mmol) in the presence of triphenylphosphine and DIAD using the method of Example 99. After Boc-deprotection 0.30 g (30%) of the title compound was obtained. 1H-NMR (400 MHz; d6-DMSO): δ 1.43 (d, 3H), 2.91-3.40 (m, 1H), 4.29-4.39 (m, 1H), 4.71-4.85 (m, 1H), 7.97 (d, 1H), 7.89 (d, 1H), 7.96 (d, 1H), 7.97 (d, 1H), 8.11 (dd, 1H). m/z [260.7+1].

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

Procedure: ((S)-2-Hydroxy-propyl)-carbamic acid tert-butyl ester (0.25 g, 1.43 mmol) was dissolved in acetonitrile (14 ml) and iodomethane (1.78 ml, 28.5 mmol), and then silver oxide (0.53 g, 2.28 mmol; prepared as in Org. Syn. Coll. Vol. VII, p. 386) were added. The reaction flask was covered to protect from light and the reaction was heated at reflux for 24 h. Additional iodomethane (1.8 ml) and silver oxide (0.26 g) were added and heating was continued until the reaction was judged to be complete by standard reverse phase LC/MS. The reaction mixture was filtered through diatomaceous earth, rinsing with ethyl acetate. After evaporation the residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 85 mg (32%) of ((S)-2-methoxy-propyl)-carbamic acid tert-butyl ester. (M+Na)+=212. the reaction was heated at reflux for 24 h heating The reaction mixture was filtered through diatomaceous earth rinsing with ethyl acetate After evaporation the residue was purified by silica gel chromatography (ethyl acetate/hexanes)

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

Procedure: Cool a solution of tert-butyl [(2S)-2-hydroxypropyl]carbamate (870 g, 4.96 mol) in tetrahydrofuran (10 L) to 5° C. Add sodium hydride (60% dispersion, 248 g, 6.21 mol, 1.25 eq.) in portions over 8 minutes. Stir the reaction at 5° C. for 30 minutes. Add methyl iodide (387 mL, 6.21 mol, 1.25 eq.) dropwise over 5 minutes and allow the reaction to proceed at 5-10° C. for 45 minutes. Quench the reaction with water (1 L) and extract with ethyl acetate (4 L). Obtain the organic layer and concentrate it in vacuo to obtain a residue. Co-evaporate the residue with toluene (2×1 L), dilute with dichloromethane (2 L) and filter. Rinse remaining solid with additional dichloromethane (500 mL). Concentrate the combined dichloromethane liquid filtrate in vacuo to obtain a crude intermediate of tert-butyl N-[(2S)-2-methoxypropyl]carbamate (880 g, 94%). the reaction at 5° C. for 30 minutes the reaction Quench the reaction with water (1 L) extract with ethyl acetate (4 L) Obtain the organic layer concentrate it in vacuo to obtain a residue Co-evaporate the residue with toluene (2×1 L) dilute with dichloromethane (2 L) filter Rinse Concentrate the combined dichloromethane liquid filtrate in vacuo

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

Procedure: Cool a solution of tert-butyl[(2S)-2-hydroxypropyl]carbamate (870 g, 4.96 mol) in tetrahydrofuran (10 L) to 5° C. Add sodium hydride (60% dispersion, 248 g, 6.21 mol, 1.25 eq.) in portions over 8 minutes. Stir the reaction at 5° C. for 30 minutes. Add methyl iodide (387 mL, 6.21 mol, 1.25 eq.) dropwise over 5 minutes and allow the reaction to proceed at 5-10° C. for 45 minutes. Quench the reaction with water (1 L) and extract with ethyl acetate (4 L). Obtain the organic layer and concentrate it in vacuo to obtain a residue. Co-evaporate the residue with toluene (2×1 L), dilute with dichloromethane (2 L) and filter. Rinse remaining solid with additional dichloromethane (500 mL). Concentrate the combined dichloromethane liquid filtrate in vacuo to obtain a crude intermediate of tert-butyl N-[(2S)-2-methoxypropyl]carbamate (880 g, 94%). the reaction at 5° C. for 30 minutes the reaction Quench the reaction with water (1 L) extract with ethyl acetate (4 L) Obtain the organic layer concentrate it in vacuo to obtain a residue Co-evaporate the residue with toluene (2×1 L) dilute with dichloromethane (2 L) filter Rinse Concentrate the combined dichloromethane liquid filtrate in vacuo

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

Procedure: The title compound was synthesized by using the method analogous to the synthesis of Intermediate 277 starting with tert-butyl [(2S)-2-hydroxypropyl]carbamate and alkylating it with methyl iodide.

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

Procedure: A stirred solution of thionyl chloride (4.8 mL, 66.3 mmol) in acetonitrile (30 mL) is cooled down to −45° C. and a solution of tert-butyl [(2S)-2-hydroxypropyl]carbamate (5.1 g, 26.6 mmol) in acetonitrile (40 mL) is added by an addition funnel over about 20 min, keeping the internal temperature below −40° C. Then 4-dimethylaminopyridine (324 mg, 2.6 mmol) is added followed by the dropwise addition of pyridine (10.7 mL, 133.7 mmol), keeping the temperature below −40° C. The addition takes 1.5 h. Ethyl acetate (100 mL) is added to the suspension. The mixture is filtered at −35° C. to remove the solid and the solid is washed with EtOAc before it is discarded. Saturated Na2HPO4 solution (40 mL) is added to the filtrate and the mixture is stirred vigorously for 30 min. The organic layer is separated, washed with 1M NaHSO4 to remove residual pyridine, dried (Na2SO4) and concentrated to afford a clear oil. The residue was taken up in diethyl ether, a small amount of insoluble material was removed and the filtrate was concentrated to afford the title compound (5.7 g, crude) as an oil. the internal temperature below −40° C the temperature below −40° C The addition The mixture is filtered at −35° C. to remove the solid the solid is washed with EtOAc before it Saturated Na2HPO4 solution (40 mL) is added to the filtrate The organic layer is separated washed with 1M NaHSO4 to remove residual pyridine dried (Na2SO4) concentrated to afford a clear oil a small amount of insoluble material was removed the filtrate was concentrated

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

Procedure: A stirred solution of thionyl chloride (4.8 mL, 66.3 mmol) in acetonitrile (30 mL) is cooled down to −45° C. and a solution of tert-butyl [(2S)-2-hydroxypropyl]carbamate (5.1 g, 26.6 mmol) in acetonitrile (40 mL) is added by an addition funnel over 20 min, keeping the internal temperature below −40° C. DMAP (324 mg, 2.6 mmol) is added followed by the dropwise addition of pyridine (10.7 mL, 133.7 mmol), keeping the temperature below −40° C. The addition takes 1.5 h. Ethyl acetate (100 mL) is added to the suspension. The mixture is filtered at −35° C. to remove the solid and the solid is washed with EtOAc before it is discarded. Then the filtrates are combined, and sat. Na2HPO4 solution (40 mL) is added. Again the mixture is stirred vigorously for 30 min. Then the organic layer is separated, washed with 1M aqueous NaHSO4 to remove residual pyridine, dried (Na2SO4) and concentrated to afford a clear oil. The residue was taken up in diethyl ether, a small amount of insoluble material was removed and the filtrate was concentrated to afford the title compound (5.7 g, 97%) as an oil which was used in the next step without purification. the internal temperature below −40° C the temperature below −40° C The addition The mixture is filtered at −35° C. to remove the solid the solid is washed with EtOAc before it sat. Na2HPO4 solution (40 mL) is added Then the organic layer is separated washed with 1M aqueous NaHSO4 to remove residual pyridine dried (Na2SO4) concentrated to afford a clear oil a small amount of insoluble material was removed the filtrate was concentrated

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

Procedure: The title compound was prepared using the procedure described in Example 3(g) starting from 2-chloro-6-fluoro-4-(1H-pyrazol-3-yl)benzonitrile (14.9 mmol, 3.3 g) and (S)-tert-butyl (2-hydroxypropyl)carbamate (29.8 mmol, 5.23 g). Yield 2.2 g. 1H-NMR (400 MHz; CDCl3): δ 1.53 (d, 3H), 3.44-3.61 (m, 2H), 4.48-4.54 (m, 1H), 6.59 (d, 1H), 7.48 (d, 1H), 7.55 (d, 1H), 7.75 (s, 1H). LC-MS: [M+1]=279.12.