tert-butyl N-sulfamoylcarbamate

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

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

Procedure: N-t-butoxycarbonylsulfamide is prepared in the same manner as in the paragraph (a) in Step A-6 in Preparative Example 7-A. (2S,4R)-4-Acetylthio-1-t-butoxycarbonylpyrrolidine-2-methanol (i.e., a substrate) is allowed to react with N-t-butoxycarbonylsulfamide in the similar manner as in the paragraph (b) in Step A-6 in Production Example 7-A under a condition for Step C-8 shown in Table 2 to give (2S,4R)-4-acetylthio-1-t-butoxycarbonyl-2-(N-t-butoxycarbonyl-N-sulfamoylamino) methylpyrrolidine. NMR δ(CDCl3) ppm: 1.41(s, 9H), 1.55(s, 9H), 1.9 to 2.0 (m, 2H), 2.35(s, 3H), 3.32(dd, J=11.4 Hz, J=8.2 Hz, 1H), 3.6 to 3.9(m, 3H), 3.9 to 4.1(m, 1H), 4.5(m, 1H), 6.15(s, 2H). IR ν (KBr) cm-1 : 3420, 3320, 1706, 1686, 1666.

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

Procedure: N-t-butoxycarbonylsulfamide is prepared in the same manner as in the paragraph (a) in Step A-6 in Preparative Example 7-A. (2S,4R)-4-Acetylthio-1-t-butoxycarbonylpyrrolidine-2-methanol (i.e., a substrate) is allowed to react with N-t-butoxycarbonylsulfamide in the similar manner as in the paragraph (b) in Step A-6 in Production Example 7-A under a condition for Step C-8 shown in Table 2 to give (2S,4R)-4-acetylthio-1-t-butoxycarbonyl-2-(N-t-butoxycarbonyl-N-sulfamoylamino) methylpyrrolidine. NMR δ(CDCl3) ppm: 1.41(s, 9H), 1.55(s, 9H), 1.9 to 2.0 (m, 2H), 2.35(s, 3H), 3.32(dd, J=11.4 Hz, J=8.2 Hz, 1H), 3.6 to 3.9(m, 3H), 3.9 to 4.1(m, 1H), 4.5(m, 1H), 6.15(s, 2H). IR ν (KBr) cm-1 : 3420, 3320, 1706, 1686, 1666.

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

Procedure: N-t-butoxycarbonylsulfamide is prepared in the same manner as in the paragraph (a) of Step A-6 in Preparative Example 7-A. (2R,4R)-4-acetylthio-1-t-butoxycarbonylpyrrolidine-2-methanol (i.e., a substrate) is allowed to react with the obtained N-t-butoxycarbonylsulfamide in the similar manner as in paragraph (b) of Step A-6 in Preparative Example 7-A under a condition for Step B-6 shown in Table 2 to give (2R,4R)-4-acetylthio-1-t-butoxycarbonyl-2-(N-t-butoxycarbonyl-N-sulfamoylamino)methylpyrrolidine. NMR δ(CDCl3) ppm: 1.43(s, 9H), 1.53(s, 9H), 2.34(s, 3H), 2.5(m, 1H), 3.15(dd, J=12.2 Hz, J=6.2 Hz, 1H), 3.58(dd, J=14.8 Hz, J=3.2 Hz, 1H), 3.8 to 4.1(m, 2H), 4.16(dd, J=12.2 Hz, J=7.8 Hz, 1H), 4.4 to 4.7 (m, 1H), 6.11(s, 2H). IR ν (CHCl3) cm-1 : 3360, 3200, 1710, 1688.

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

Procedure: Preparation of a sulfamide compound To a solution of (2R,4S)-4-acetylthio-1-t-butoxycarbonylpyrrolidine-2-methanol (i.e., a substrate) in tetrahydrofuran (THF), triphenylphosphine (PPh3), N-t-butoxycarbonylsulfamide (BSMD), and azodicarboxylic acid diethyl ester (DEAD) are successively added under ice cooling. The conditions for this reaction are shown in Table 2, Step A-6. The reaction mixture is diluted with toluene, concentrated, diluted with toluene, and the formed crystals are filtered off. The filtrate is concentrated. The residue is purified by silica gel column chromatography to give (2R,4S)-4-acetylthio-1-t-butoxycarbonyl-2-(N-t-butoxycarbonyl-N-sulfamoylamino)methylpyrrolidine. NMR δ(CDCl3) ppm: 1.41(s, 9H), 1.55(s, 9H), 1.19 to 2.0(m, 2H), 2.35(s, 3H), 3.32(dd, J=11.4 Hz, J=8.2 Hz, 1H), 3.6 to 3.9(m, 3H), 3.9 to 4.1(m, 1H), 4.5(m, 1H), 6.15(s, 2H). IR ν (KBr) cm-1 : 3420, 3320, 1706, 1686, 1666. concentrated diluted with toluene the formed crystals are filtered off The filtrate is concentrated The residue is purified by silica gel column chromatography

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

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

Procedure: To (6-chloro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methanol (9.5 mg, 0.042 mmol), PPh3 (17 mg, 0.066 mmol) and N-(t-butoxycarbonyl)sulfamide (16 mg, 0.083 mmol) in Ethyl acetate (0.5 mL) was added diisopropyl azodicarboxylate (DIAD, 0.013 mL, 0.066 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 h (monitored with TLC 40% ethyl acetate-heptane and LC-MS) and then concentrated to a residue. The residue loaded onto a 12 g ISCO silica column in CH2Cl2 and eluted with 0-30% ethyl acetate/heptane to yield the title compound as a gum, which was used in the next step without further purification. concentrated to a residue eluted with 0-30% ethyl acetate/heptane

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

Procedure: To (6-chloro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methanol (9.5 mg, 0.042 mmol), PPh3 (17 mg, 0.066 mmol) and N-(t-butoxycarbonyl)sulfamide (16 mg, 0.083 mmol) in Ethyl acetate (0.5 mL) was added diisopropyl azodicarboxylate (DIAD, 0.013 mL, 0.066 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 h (monitored with TLC 40% ethyl acetate-heptane and LC-MS) and then concentrated to a residue. The residue loaded onto a 12 g ISCO silica column in CH2Cl2 and eluted with 0-30% ethyl acetate/heptane to yield the title compound as a gum, which was used in the next step without further purification. concentrated to a residue eluted with 0-30% ethyl acetate/heptane

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

Procedure: To chlorosulfonyl isocyanate (2.45 mL, 28 mmol) in toluene (38 mL) at −10° C. (ice/methanol bath) was added t-butyl alcohol (2.66 mL, 28 mmol) dropwise. The resulting solution was stirred at 0° C. (ice bath) for 20 min. Pyridine (5.0 mL, 62 mmol) was added dropwise with the ice/methanol bath at −15° C. to −10° C. The resulting mixture was stirred with ice bath at 0° C. for 40 min. Ammonium hydroxide (28%, 10 mL, 163 mmol) was then added dropwise with the ice/methanol bath at −10° C., followed by H2O (3 mL). The resulting mixture resulting was stirred with ice bath at 0° C. for 2.5 h. The resulting two layers were separated. The aqueous layer was washed with toluene (15 mL). The combined toluene layers were extracted with H2O (13 mL). The combined aqueous layers were acidified with 24% H2SO4 to pH 2. The resulting precipitate was filtered, washed with H2O (2×13 mL) and dried to yield the title compound as a white solid. The resulting mixture was stirred with ice bath at 0° C. for 40 min The resulting mixture resulting was stirred with ice bath at 0° C. for 2.5 h The resulting two layers were separated The aqueous layer was washed with toluene (15 mL) The combined toluene layers were extracted with H2O (13 mL) The resulting precipitate was filtered washed with H2O (2×13 mL) dried

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

Procedure: To chlorosulfonyl isocyanate (2.45 mL, 28 mmol) in toluene (38 mL) at −10° C. (ice/methanol bath) was added t-butyl alcohol (2.66 mL, 28 mmol) dropwise. The resulting solution was stirred at 0° C. (ice bath) for 20 min. Pyridine (5.0 mL, 62 mmol) was added dropwise with the ice/methanol bath at −15° C. to −10° C. The resulting mixture was stirred with ice bath at 0° C. for 40 min. Ammonium hydroxide (28%, 10 mL, 163 mmol) was then added dropwise with the ice/methanol bath at −10° C., followed by H2O (3 mL). The resulting mixture resulting was stirred with ice bath at 0° C. for 2.5 h. The resulting two layers were separated. The aqueous layer was washed with toluene (15 mL). The combined toluene layers were extracted with H2O (13 mL). The combined aqueous layers were acidified with 24% H2SO4 to pH 2. The resulting precipitate was filtered, washed with H2O (2×13 mL) and dried to yield the title compound as a white solid. The resulting mixture was stirred with ice bath at 0° C. for 40 min The resulting mixture resulting was stirred with ice bath at 0° C. for 2.5 h The resulting two layers were separated The aqueous layer was washed with toluene (15 mL) The combined toluene layers were extracted with H2O (13 mL) The resulting precipitate was filtered washed with H2O (2×13 mL) dried

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

Procedure: N-t-butoxycarbonylsulfamide is prepared in the same manner as in the paragraph (a) in Step A-6 in Preparative Example 7-A. (2S,4R)-4-Acetylthio-1-t-butoxycarbonylpyrrolidine-2-methanol (i.e., a substrate) is allowed to react with N-t-butoxycarbonylsulfamide in the similar manner as in the paragraph (b) in Step A-6 in Production Example 7-A under a condition for Step C-8 shown in Table 2 to give (2S,4R)-4-acetylthio-1-t-butoxycarbonyl-2-(N-t-butoxycarbonyl-N-sulfamoylamino) methylpyrrolidine.

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

Procedure: N-t-butoxycarbonylsulfamide is prepared in the same manner as in the paragraph (a) of Step A-6 in preparative Example 7-A. (2R,4R)-4-acetylthio-1-t-butoxycarbonylpyrrolidine-2-methanol (i.e., a substrate) is allowed to react with the obtained N-t-butoxycarbonylsulfamide in the similar manner as in paragraph (b) of Step A-6 in Preparative Example 7-A under a condition for Step B-6 shown in Table 2 to give (2R,4R)-4-acetylthio-1-t-butoxycarbonyl-2-(N-t-butoxycarbonyl-N-sulfamoylamino)methylpyrrolidine.