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Stage #1: With triethylamine; isobutyl chloroformate In tetrahydrofuran at -20 - -10℃; for 0.25 h; Stage #2: With ammonium hydroxide In tetrahydrofuran at -20 - 20℃; for 1 h;
1-[(tert-butoxy)carbonyl]azetidine-3-carboxylic acid (4.96 g, 24.65 mmol) and TEA (5.84 ml, 42.0 mmol) were dissolved in THF (60 ml) and cooled to -20°C. Isobutyl chloroformate (4.8 ml, 37.0 mmol) was added slowly and the reaction mixture stirred at ^10°C for 15 min. 28percent aqueous ammonia (7.46 ml, 394 mmol) was added and the mixture allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched with sat. NaHC<(aq) and extracted with DCM (3 x 100 ml). The combined organic extracts were dried (Na2S04), filtered and evaporated in vacuo. Purification by flash chromatography using a gradient elution of 20-100percent EtOAc / heptane followed by 1-4percent MeOH / EtOAc afforded the title compound (3.99 g, 81 percent) as a white solid. 1 H-NMR (CDCI3, 250 MHz): d[ppm]= 5.47 (s, 2H), 4.22 - 4.01 (m, 4H), 3.34 - 3.15 (m, 1 H), 1 .46 (s, 9H) HPLCMS (Method A): [m/z]: 222.95 [M+Na]+
63%
With ammonium acetate; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃;
To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (from Activate Scientific. 0.25 g, 1.2 mmol), ammonium acetate (0.14 g, 1.9 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.71 g, 1.9 mmol) in N,N-dimethylformamide (4 mL) was added N,N-diisopropylethylamine (0.43 mL, 2.5 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with MeOH and purified on prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1percent ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.156 g, 63percent). LCMS calculated for C9H16N2O3Na (M+Na)+: m/z=223.1. Found: 223.0
Reference：
[1] Patent: WO2017/68089, 2017, A2, . Location in patent: Page/Page column 234; 235
[2] Patent: US2014/121198, 2014, A1, . Location in patent: Paragraph 0688; 0689
[3] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 5, p. 757 - 761
[4] Patent: WO2010/60952, 2010, A1, . Location in patent: Page/Page column 81
[5] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 3037 - 3040
2
[ 24424-99-5 ]
[ 486415-29-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 5, p. 757 - 761
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