Ethyl isocyanate → (S)-4-[(S)-1-Ethylcarbamoyloxymethyl-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester

HRID 655587Notes

Reaction equation

[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C@H:17]([CH2:29][OH:30])[CH2:18][CH2:19][N:20]2[CH2:27][CH2:26][C:23]3([CH2:25][CH2:24]3)[C@H:22]([OH:28])[CH2:21]2)[C:13](=[O:31])[C@@H:12]1[CH3:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C@H:17]([CH2:29][O:30][C:36](=[O:37])[NH:35][CH2:33][CH3:34])[CH2:18][CH2:19][N:20]2[CH2:27][CH2:26][C:23]3([CH2:25][CH2:24]3)[C@H:22]([OH:28])[CH2:21]2)[C:13](=[O:31])[C@@H:12]1[CH3:32])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

Conditions

Temperature: 40 °C

Procedure

To a solution of (S)-4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-hydroxymethyl-propyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (intermediate 39; 63 mg, 0.14 mmol) in acetonitrile (1 mL) was added ethyl isocyanate (11 mg, 0.14 mmol) at 0° C. The ice bath was removed, then after 16 h another portion of ethyl isocyanate (11 mg, 0.14 mmol) was added, and the reaction mixture was stirred at 40° C. for 72 h. Volatile material was removed by concentration under vacuum, and the residue was chromatographed (SiO2; dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) to afford the title compound (33 mg, 45%). Colorless gum, MS (ISP)=517.3 (M+H)+.

Workup

customThe ice bath was removed
customVolatile material was removed by concentration under vacuum
customthe residue was chromatographed (SiO2; dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25)

Sources & evidence

ORD record: ord-7b8853304df8450883a09d5a05a6b403
Source dataset: uspto-grants-2011_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08071586B2

Reaction notes

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