Propanoic acid, 2-[(tetrahydro-2H-pyran-2-yl)oxy]-, (2R)- synthesis

Yield:95586-53-1 85%

Reaction Conditions:

Stage #1: (2R)-2-(tetrahydro-2H-pyran-2-yloxy)propanoic acid methyl esterwith lithium hydroxide in tetrahydrofuran;water at 0; for 5 h;
Stage #2: with hydrogenchloride in tetrahydrofuran;water; pH=3;

Steps:

4.2.4. (2R)-2-(Tetrahydro-2H-pyran-2-yloxy)-propanoic acid (15)

A solution of methyl ester 14 (2.07 g, 11.00 mmol) was stirred in 1 M THF/LiOH (5:3 aq, 50 mL) for 5 h at 0 °C. Then the reaction mixture was acidified to pH 3 with 10% hydrochloric acid and extracted four times with ethyl acetate. The combined extracts were washed with a saturated NaCl solution (1×), dried with MgSO₄, and filtered. A clear liquid (1.64 g, 9.40 mmol, 85%) of THP protected lactic acid 15 was obtained after evaporation of the solvent and drying in high vacuum. Further purification was not necessary. IR (film): 1735, 3103 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ=1.45 (d, J=7.0 Hz, 1H, C_βH₃), 1.50 (d, J=7.0 Hz, 2H, C_βH₃), 1.55 (m, 2H, CH_2, THP-H ^{[3], [4] and [5]}), 1.70 (m, 2H, CH_2, THP-H ^{[3], [4] and [5]}), 1.83 (m, 2H, CH_2, THP-H ^{[3], [4] and [5]}), 3.52 and 3.86 (2m, 2H, CH_2, THP-H⁶), 4.25 and 4.43 (2q, J=7.0 Hz, 1H, C_αH), 4.65 and 4.73 (2m, 1H, CH, THP-H²), 9.76 (s, 1H, CO₂H) ppm; ¹³C NMR (100 MHz, CDCl₃): δ=19.1, 19.6, 25.3, 30.3, 62.8, 70.1, 98.0, 178.1 ppm; MS (ESI): m/z (%)=89 (15), 101 (11), 173 ([M-H]^-, 100), 174 (11); HRMS (ESI): M⁺+Na, found 197.0785; C₈H₁₄NaO₄ requires 197.0790.

References:

Lüttenberg, Sebastian;Sondermann, Frank;Scherkenbeck, Jürgen [Tetrahedron,2012,vol. 68,# 8,p. 2068 - 2073] Location in patent:experimental part