tert-butyl N-[1-(hydroxymethyl)cyclopropyl]carbamate

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a solution of tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate (Bioorg. Med. Chem. Lett., 2008, 18(6), 2188) (135 mg, 0.72 mmoles) in DCM (8 mL) was added Dess-Martin periodinane (277 mg, 0.65 mmole). After stirring 1 hr, the reaction was filtered through celite and concentrated to a yellow oil which was further purified by Isolera (7%-70% ethyl acetate/hexanes) to provide 84 mg (87%) of tert-butyl (1-formylcyclopropyl)-carbamate as a white solid. the reaction was filtered through celite concentrated to a yellow oil which was further purified by Isolera (7%-70% ethyl acetate/hexanes)

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: N-Boc-1-amino-1-hydroxymethylcyclopropane is dissolved in triethylamine under argon at 0° C. Methanesulfonyl chloride is added with a syringe and the contents stirred at room temperature overnight. The solution is poured into 10% aqueous citric acid and extracted with ethyl acetate. The organic layer is dried over MgSO4 filtered and evaporated to give N-Boc-1-amino-1-hydroxymethylcyclopropane mesylate. extracted with ethyl acetate The organic layer is dried over MgSO4 filtered evaporated

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

Procedure: N-Boc-1-amino-1-hydroxymethylcyclopropane is dissolved in triethylamine under argon at 0° C. Methanesulfonyl chloride is added with a syringe and the contents stirred at room temperature overnight. The solution is poured into 10% aqueous citric acid and extracted with ethyl acetate. The organic layer is dried over MgSO4 filtered and evaporated to give N-Boc-1-amino-1-hydroxymethylcyclopropane mesylate. extracted with ethyl acetate The organic layer is dried over MgSO4 filtered evaporated

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

Procedure: To a stirred solution of PPh3 (15.52 g, 59.2 mmol) in THF (80.0 mL) cooled to 0° C. was added DIAD (11.50 mL, 59.2 mmol) and the resulting solution stirred at 0° C. for 0.5 h. Intermediate 104C (8.00 g, 23.66 mmol) was added as a solution in THF (20 mL) at 0° C. and stirred at RT for 45 min. A solution of tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate (5.32 g, 28.4 mmol) in THF (10 mL) at was added at 0° C. and the reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was diluted with water (250 mL) and extracted with EtOAc (2×200 mL). The combined organic layer was washed with brine dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (220 g REDISEP® column, eluting with 20% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 350A as a pale yellow liquid (10 g, 85%). MS(ES): m/z=508 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ ppm 4.45 (s, 2H), 4.41-4.25 (m, 4H), 1.46 (s, 9H), 1.40-1.30 (m, 4H), 1.24 (s, 3H), 1.03-0.94 (m, 2H), 0.90-0.78 (m, 2H). stirred at RT for 45 min to stir at RT for 16 h extracted with EtOAc (2×200 mL) The combined organic layer was washed with brine dried over Na2SO4 filtered concentrated The crude product was purified by silica gel chromatography (220 g REDISEP® column, eluting with 20% EtOAc in hexane) Fractions containing the product evaporated

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

Procedure: To a stirred solution of PPh3 (15.52 g, 59.2 mmol) in THF (80.0 mL) cooled to 0° C. was added DIAD (11.50 mL, 59.2 mmol) and the resulting solution stirred at 0° C. for 0.5 h. Intermediate 104C (8.00 g, 23.66 mmol) was added as a solution in THF (20 mL) at 0° C. and stirred at RT for 45 min. A solution of tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate (5.32 g, 28.4 mmol) in THF (10 mL) at was added at 0° C. and the reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was diluted with water (250 mL) and extracted with EtOAc (2×200 mL). The combined organic layer was washed with brine dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (220 g REDISEP® column, eluting with 20% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 350A as a pale yellow liquid (10 g, 85%). MS(ES): m/z=508 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ ppm 4.45 (s, 2H), 4.41-4.25 (m, 4H), 1.46 (s, 9H), 1.40-1.30 (m, 4H), 1.24 (s, 3H), 1.03-0.94 (m, 2H), 0.90-0.78 (m, 2H). stirred at RT for 45 min to stir at RT for 16 h extracted with EtOAc (2×200 mL) The combined organic layer was washed with brine dried over Na2SO4 filtered concentrated The crude product was purified by silica gel chromatography (220 g REDISEP® column, eluting with 20% EtOAc in hexane) Fractions containing the product evaporated

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

Procedure: A solution of 1-(N-tert-butoxycarbonylamino)cyclopropanecarboxylic acid (5 g) in tetrahydrofuran was cooled to −20° C. Isobutyl chloroformate (3.24 ml) and N-methylmorpholine (2.74 ml) were added thereto, and the mixture was stirred at the same temperature as above for 20 minutes. Then, sodium borohydride (1.12 g) and water (1 ml) were added thereto, and the mixture was further stirred at room temperature for 40 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (4.24 g). the mixture was further stirred at room temperature for 40 minutes followed by extraction with ethyl acetate The extract was washed with water and saturated saline in this order dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl [1-(hydroxymethyl)cyclopropyl]carbamate (1 g, 5.3 mmol) in N,N-dimethylformamide (20 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.22 g, 8.0 mmol) and diphenylphosphoryl azide (2.33 g, 8.00 mmol). After the mixture was stirred at 80° C. for 3 hours, another batch of 1,8-diazabicyclo[5.4.0]undec-7-ene (1.22 g, 8.0 mmol) and diphenylphosphoryl azide (2.33 g, 8.00 mmol) was introduced and the mixture was stirred at 80° C. for another 2 hours. The resulting mixture was then diluted with water (20 mL) and extracted with ethyl acetate (30 mL×2). The combined organic layers were used for next step directly. the mixture was stirred at 80° C. for another 2 hours extracted with ethyl acetate (30 mL×2)

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

Procedure: To a cooled solution of methyl 1-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylate (1.2 g, 5.6 mmol) in tetrahydrofuran (10 mL) at 0° C. was added dropwise a solution of lithium borohydride (244 mg, 11.2 mmol) in tetrahydrofuran (10 mL) The reaction mixture was allowed to warm to room temperature and stirred at this temperature overnight. The reaction was quenched by addition of water (10 mL) and the resulting mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 0.8 g of the product (yield was 76.2%). The reaction was quenched by addition of water (10 mL) the resulting mixture was extracted with dichloromethane The organic layer was dried over sodium sulfate concentrated in vacuo

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

Procedure: To a solution of tert-butyl (1-(hydroxymethyl)cyclopropyl)carbamate (Bioorg. Med. Chem. Lett., 2008, 18(6), 2188) (135 mg, 0.72 mmoles) in DCM (8 mL) was added Dess-Martin periodinane (277 mg, 0.65 mmole). After stirring 1 hr, the reaction was filtered through celite and concentrated to a yellow oil which was further purified by Isolera (7%-70% ethyl acetate/hexanes) to provide 84 mg (87%) of tert-butyl (1-formylcyclopropyl)-carbamate as a white solid. the reaction was filtered through celite concentrated to a yellow oil which was further purified by Isolera (7%-70% ethyl acetate/hexanes)

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

Procedure: N-Boc-1-amino-1-hydroxymethylcyclopropane is dissolved in triethylamine under argon at 0° C. Methanesulfonyl chloride is added with a syringe and the contents stirred at room temperature overnight. The solution is poured into 10% aqueous citric acid and extracted with ethyl acetate. The organic layer is dried over MgSO4 filtered and evaporated to give N-Boc-1-amino-1-hydroxymethylcyclopropane mesylate. extracted with ethyl acetate The organic layer is dried over MgSO4 filtered evaporated