tert-butyl N-[(2R)-1-oxopropan-2-yl]carbamate

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

Procedure: Sodium cyanoborohydride (1.1 g) and acetic acid (0.75 mL) were added to a mixture of methyl (S)-2-amino-3-phenylpropanoate (2.72 g) and (R)-tert-butyl 1-oxopropan-2-ylcarbamate (1.97 g) in methanol to perform reductive amination (2.37 g, 46%). Next, deprotection and conversion to hydrochloride were performed (1.0 g, 45%) using trifluoroacetic acid and a 4 M hydrochloric acid-1,4-dioxane solution, followed by subjecting to condensation with isoquinoline-6-sulfonyl chloride prepared in Reference Example 1 (1.04 g, 75%). 28 mg of the title compound was obtained as a white solid (29%) with reference to the method of Step 3 of Example 1 using 80 mg of the obtained product.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Boc-D-alanine is dissolved in tetrahydrofuran and stirred at 0° C. under argon. Bis(N-methylpiperazinyl)aluminum hydride is added and the reaction mixture is heated to reflux overnight. Ether is then added, and the excess hydride is quenched with saturated NaCl. The aqueous phase is separated and extracted with ether. The combined organic phases are washed with 2M NaOH, 2M HCl and saturated NaCl. The solution is dried over Na2SO4 and evaporated to yield N-Boc-D-alaninal. the reaction mixture is heated to reflux overnight the excess hydride is quenched with saturated NaCl The aqueous phase is separated extracted with ether The combined organic phases are washed with 2M NaOH, 2M HCl and saturated NaCl The solution is dried over Na2SO4 evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Boc-D-alanine is dissolved in tetrahydrofuran and stirred at 0° C. under argon. Bis(N-methylpiperazinyl)aluminum hydride is added and the reaction mixture is heated to reflux overnight. Ether is then added, and the excess hydride is quenched with saturated NaCl. The aqueous phase is separated and extracted with ether. The combined organic phases are washed with 2M NaOH, 2M HCl and saturated NaCl. The solution is dried over Na2SO4 and evaporated to yield N-Boc-D-alaninal. the reaction mixture is heated to reflux overnight the excess hydride is quenched with saturated NaCl The aqueous phase is separated extracted with ether The combined organic phases are washed with 2M NaOH, 2M HCl and saturated NaCl The solution is dried over Na2SO4 evaporated

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

Procedure: In a 20 mL scintillation vial, ((R)-1-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (2.5 g, 14.4 mmol) and (triphenylphosphoranylidene)acetonitrile (6.52 g, 21.7 mmol) were mixed in dichloromethane (20 mL) and stirred at room temperature for 16 h. The solvent was evaporated to give the crude material, which was purified by column chromatography (silica gel, gradient n-hexanes ethyl acetate) to provide 1.8 g (63%) of ((R)-3-cyano-1-methyl-allyl)-carbamic acid tert-butyl ester in a 3:1 diastereoselectivity (E:Z) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ ppm 6.38-6.79 (m, 1H), 5.47 (dd, J=16.24, 1.89 Hz, 1H), 4.48 (bs, 1H), 4.47 (bs, 1H), 1.45 (s, 1H), 1.28 (d, J=7.18 Hz, 9H). The solvent was evaporated to give the crude material, which was purified by column chromatography (silica gel, gradient n-hexanes ethyl acetate)

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

Procedure: In a 20 mL scintillation vial, ((R)-1-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (2.5 g, 14.4 mmol) and (triphenylphosphoranylidene)acetonitrile (6.52 g, 21.7 mmol) were mixed in dichloromethane (20 mL) and stirred at room temperature for 16 h. The solvent was evaporated to give the crude material, which was purified by column chromatography (silica gel, gradient n-hexanes ethyl acetate) to provide 1.8 g (63%) of ((R)-3-cyano-1-methyl-allyl)-carbamic acid tert-butyl ester in a 3:1 diastereoselectivity (E:Z) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ ppm 6.38-6.79 (m, 1H), 5.47 (dd, J=16.24, 1.89 Hz, 1H), 4.48 (bs, 1H), 4.47 (bs, 1H), 1.45 (s, 1H), 1.28 (d, J=7.18 Hz, 9H). The solvent was evaporated to give the crude material, which was purified by column chromatography (silica gel, gradient n-hexanes ethyl acetate)

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

Procedure: A mixture of (R)-tert-butyl 1-oxopropan-2-ylcarbamate (28.0 g, 81.0 mmol), hydroxylamine hydrochloride (11.2 g, 81.0 mmol), pyridine (60 mL), MeOH (100 mL) was stirred at rt overnight. The solvent was then evaporated. To the residue was added water (100 mL) and the mixture was extracted with DCM (3×200 mL). The combined organic phases were dried (Na2SO4) and concentrated. The crude residue was purified by flash column chromatography (petroleum ether:EtOAc, 4:1) to give (R)-tert-butyl 1-(hydroxyimino)propan-2-ylcarbamate (24.0 g, 79%). 1H NMR (DMSO-d6, 400 MHz) δ 10.63 (s, 1H), 7.20 (d, J=5.2 Hz, 1H), 4.12 (m, 1H), 1.38 (s, 9H), 1.15 (d, J=6.8 Hz, 3H). The solvent was then evaporated To the residue was added water (100 mL) the mixture was extracted with DCM (3×200 mL) The combined organic phases were dried (Na2SO4) concentrated The crude residue was purified by flash column chromatography (petroleum ether:EtOAc, 4:1)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled solution of (R)-methyl 2-(tert-butoxycarbonylamino)propanoate (40.0 g, 98.0 mmol) in DCM (200 mL) at −78° C. was added diisobutylaluminum hydride (208 mL, 1.0 M in THF) dropwise over 30 min. The reaction mixture was stirred at −78° C. for 1.5 h then quenched with water (50 mL). After warmed to rt, the white precipitate was removed by filtration over Celite. The organic layer was then washed with brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography (petroleum ether:EtOAc, 10:1) to give (R)-tert-butyl 1-oxopropan-2-ylcarbamate (28.0 g, 82%). 1H NMR (DMSO-d6, 400 MHz) δ 9.43 (s, 1H), 7.33 (d, J=6.0 Hz, 1H), 3.85 (m, 1H), 1.39 (s, 9H), 1.12 (d, J=7.2 Hz, 3H). then quenched with water (50 mL) After warmed to rt the white precipitate was removed by filtration over Celite The organic layer was then washed with brine dried (Na2SO4) concentrated The crude residue was purified by flash chromatography (petroleum ether:EtOAc, 10:1)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled solution of (R)-methyl 2-(tert-butoxycarbonylamino)propanoate (40.0 g, 98.0 mmol) in DCM (200 mL) at −78° C. was added diisobutylaluminum hydride (208 mL, 1.0 M in THF) dropwise over 30 min. The reaction mixture was stirred at −78° C. for 1.5 h then quenched with water (50 mL). After warmed to rt, the white precipitate was removed by filtration over Celite. The organic layer was then washed with brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography (petroleum ether:EtOAc, 10:1) to give (R)-tert-butyl 1-oxopropan-2-ylcarbamate (28.0 g, 82%). 1H NMR (DMSO-d6, 400 MHz) δ 9.43 (s, 1H), 7.33 (d, J=6.0 Hz, 1H), 3.85 (m, 1H), 1.39 (s, 9H), 1.12 (d, J=7.2 Hz, 3H). then quenched with water (50 mL) After warmed to rt the white precipitate was removed by filtration over Celite The organic layer was then washed with brine dried (Na2SO4) concentrated The crude residue was purified by flash chromatography (petroleum ether:EtOAc, 10:1)

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

Procedure: A solution of 2,2,5,5-Tetramethyl-1-cyclopentylmethyl bromide in ether is added slowly to magnesium turnings until the Grignard reagent begins to form. The remainder of the alkyl bromide is then added and the mixture stirred until all the magnesium has dissolved. At 0° C. a solution of N-Boc-D-alaninal is then added and the mixture is stirred overnight. The reaction is quenched with 1M HCl, extracted with ether and the extracts are evaporated. The residue is dissolved in dioxane and 2M H2SO4 is added. The mixture is heated until the alcohol is dehydrated, as shown by thin layer chromatography. Water is added and the mixture is extracted with ether. The organic layer is dried over MgSO4 and evaporated to give N-Boc-2-amino-4-(2,2,5,5-tetramethyl-1-cyclopentyl)-3-butene. to form has dissolved The reaction is quenched with 1M HCl extracted with ether the extracts are evaporated The residue is dissolved in dioxane 2M H2SO4 is added The mixture is heated until the alcohol Water is added the mixture is extracted with ether The organic layer is dried over MgSO4 evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Boc-D-alanine is dissolved in tetrahydrofuran and stirred at 0° C. under argon. Bis(N-methylpiperazinyl)aluminum hydride is added and the reaction mixture is heated to reflux overnight. Ether is then added, and the excess hydride is quenched with saturated NaCl. The aqueous phase is separated and extracted with ether. The combined organic phases are washed with 2M NaOH, 2M HCl and saturated NaCl. The solution is dried over Na2SO4 and evaporated to yield N-Boc-D-alaninal. the reaction mixture is heated to reflux overnight the excess hydride is quenched with saturated NaCl The aqueous phase is separated extracted with ether The combined organic phases are washed with 2M NaOH, 2M HCl and saturated NaCl The solution is dried over Na2SO4 evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-Boc-D-alanine is dissolved in tetrahydrofuran and stirred at 0° C. under argon. Bis(N-methylpiperazinyl)aluminum hydride is added and the reaction mixture is heated to reflux overnight. Ether is then added, and the excess hydride is quenched with saturated NaCl. The aqueous phase is separated and extracted with ether. The combined organic phases are washed with 2M NaOH, 2M HCl and saturated NaCl. The solution is dried over Na2SO4 and evaporated to yield N-Boc-D-alaninal. the reaction mixture is heated to reflux overnight the excess hydride is quenched with saturated NaCl The aqueous phase is separated extracted with ether The combined organic phases are washed with 2M NaOH, 2M HCl and saturated NaCl The solution is dried over Na2SO4 evaporated

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

Procedure: A mixture of (R)-tert-butyl 1-oxopropan-2-ylcarbamate (28.0 g, 81.0 mmol), hydroxylamine hydrochloride (11.2 g, 81.0 mmol), pyridine (60 mL), MeOH (100 mL) was stirred at rt overnight. The solvent was then evaporated. To the residue was added water (100 mL) and the mixture was extracted with DCM (3×200 mL). The combined organic phases were dried (Na2SO4) and concentrated. The crude residue was purified by flash column chromatography (petroleum ether: EtOAc, 4:1) to give (R)-tert-butyl 1-(hydroxyimino)propan-2-ylcarbamate (24.0 g, 79%). 1H NMR (DMSO-d6, 400 MHz) δ 10.63 (s, 1H), 7.20 (d, J=5.2 Hz, 1H), 4.12 (m, 1H), 1.38 (s, 9H), 1.15 (d, J=6.8 Hz, 3H). The solvent was then evaporated To the residue was added water (100 mL) the mixture was extracted with DCM (3×200 mL) The combined organic phases were dried (Na2SO4) concentrated The crude residue was purified by flash column chromatography (petroleum ether: EtOAc, 4:1)