Acetic Acid → (s)-4-[4-((s)-4-Hydroxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester

HRID 655543Notes

Reaction equation

[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH:20]=O)[C:13](=[O:22])[C@@H:12]1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:25]1[C:27]2([CH2:32][CH2:31][NH:30][CH2:29][C@H:28]2[OH:33])[CH2:26]1.C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].N>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][N:30]2[CH2:31][CH2:32][C:27]3([CH2:25][CH2:26]3)[C@H:28]([OH:33])[CH2:29]2)[C:13](=[O:22])[C@@H:12]1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

Conditions

Temperature: 0 °C

Procedure

To a solution of (S)-4-(4-hydroxy-butyl)-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (1.67 g, 5.21 mmol) in dichloromethane (18 mL) were added at room temperature trichloroisocyanuric acid (1.28 g, 5.21 mmol) and 2,2,6,6-tetramethylpiperidin-1-oxyl (8 mg, 0.05 mmol), upon which an exothermic reaction (Tmax=36° C.) under gas evolution started. The reaction mixture was stirred for 5 min, then insoluble material was removed by filtration. The filtrate was washed with 1 M aq. sodium thiosulfate solution and brine, dried (MgSO4), filtered, and evaporated to afford (S)-4-(4-oxo-butyl)-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (1.56 g). This aldehyde (MS (ISP)=319.1 (M+H)+) was taken up in dichloromethane (9 mL) and added at room temperature to a suspension of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2; 853 mg, 5.21 mmol), triethylamine (527 mg, 5.21 mmol), acetic acid (626 mg, 10.4 mmol), and sodium triacetoxyborohydride (1.21 g, 5.73 mmol) in dichloromethane (9 mL). The reaction mixture was stirred for 30 min, then cooled to 0° C. and treated with 25% aq. ammonia solution (1.07 mL), then allowed to reach room temperature and concentrated in vacuo. Chromatography (SiO2; dichloromethane→dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) afforded the title compound (1.26 g, 56%). Colorless gum, MS (ISP)=430.3 (M+H)+.

Workup

customto reach room temperature
concentrationconcentrated in vacuo

Sources & evidence

ORD record: ord-930ff55adfaa4483bbe2e4d9f9dbed35
Source dataset: uspto-grants-2011_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08071586B2

Reaction notes

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