(2S,5R)-5-[(tert-Butoxycarbonyl)aMino]tetrahydro-2H-pyran-2-carboxylic Acid Chemical Properties

Boiling point:

413.9±45.0 °C(Predicted)

Density 

1.19±0.1 g/cm3(Predicted)

storage temp. 

2-8°C

pka

3.57±0.40(Predicted)

Appearance

White to off-white Solid

optical activity

-16.5° (C=0.01 g/ml, CHCL3)

(2S,5R)-5-[(tert-Butoxycarbonyl)aMino]tetrahydro-2H-pyran-2-carboxylic Acid Usage And Synthesis

Uses

(2S,5R)-5-[(tert-Butoxycarbonyl)amino]tetrahydro-2H-pyran-2-carboxylic Acid is aids in the synthesis of novel tetrahydropyran-based, topoisomerase inhibitors with anti-gram-positive activity. Also used in the synthesis of novel tetrahydropyran-based dipeptide isoster compounds.

Synthesis

General procedure for the synthesis of (2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid from tert-butyl (3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate: tert-butyl (3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)carbamate was added to the reactor (1700 g 1 eq. for preparation see Kriek et al. Eur. J. Org. Chem. 2003, 13, 2418-2427), NaHCO3 (1241 g, 2 eq.), KBr (87 g, 0.1 eq.), TEMPO (17.6 g, 0.015 eq.), Aliquat 336 (17 mL, 0.005 eq. ) and iPrOAc (17 L). The suspension was cooled to 0°C and 10% NaOCl solution (10.2 L, 2.33 eq.) was added slowly, controlling the internal temperature below 5°C. The reaction mixture was stirred at 10°C for 90 min and complete consumption of the raw materials was confirmed by TLC (ninhydrin staining assay). A 40% NaHSO3 solution (1.5 L) was added at 12°C to quench the reaction, followed by the addition of 25% HCl (2.5 L) at 15°C. The mixture was warmed up to 20°C and the aqueous and organic phases were separated. The aqueous phase was extracted with iPrOAc (8.5 L) and the organic phase was combined and washed with deionized water (15 L). The organic phase was concentrated at a jacket temperature of 100°C and under reduced pressure to remove 18 L of solvent. The residue was cooled to 65 °C, heptane (14 L) was added and the resulting suspension was cooled to -6 °C and filtered. The product was dried over a rotary evaporator (20 L) to afford (2S,5R)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylic acid as a white solid (1406 g, 78% yield).1H-NMR (d6-DMSO): δ=12.64 (m, 1H), 6.85 (m, 1H), 3.84 (m, 1H), 3.76 (m, 1H), 3.32 (m, 1H), 3.01 (t, J=10.5 Hz, 1H), 1.92 (m, 2H), 1.53 (m, 2H), 1.39 (s, 9H).GC-MS: tR=3.49 min; [M+1]+=246.

References

[1] Patent: WO2012/164498, 2012, A1. Location in patent: Page/Page column 31
[2] European Journal of Organic Chemistry, 2003, # 13, p. 2418 - 2427
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 18, p. 7396 - 7415