(1R,2R,3S,5R)-(2-TERT-BUTOXYCARBONYLAMINO)-6,6-DIMETHYLBICYCLO[3.1.1]HEPTAN-3-CARBOXYLIC ACID synthesis

Yield:1027343-59-4 61%

Reaction Conditions:

Stage #1: (1R,2R,5S,7R)-2-amino-6,6-dimethylbicyclo[3.3.1]heptane-3-carboxylic acid hydrochloridewith sodium hydroxide;water at 0; pH=8;
Stage #2: di-tert-butyl dicarbonate in 1,4-dioxane at 0 - 20; pH=8; for 6 h;

Steps:

9

Example 9(lR,2R,3S,5R)-(2-tert-Butoxycarbonylamino)-6,6-dimethylbicyclo[3.1.1]heptan- 3-carboxylic acid (compound 16) (Scheme 4)0.66 g (3 mmol) of (li?,2i?,35^l,5i?)-2-amino-6,6-dimethylbicyclo[3.1.1]heρtan-3- carboxylic acid hydrochloride 6, prepared according to Example 5, was dissolved in 5 ml of distilled water at 0 °C and the pH of the solution was adjusted to pH = 8 with 3% sodium hydroxide solution in the presence of bromothymol blue indicator (the amfoter form of amino acid is precipitated off). 5 ml of dioxane and 0.72 g (3.3 mmol) of Boc₂O was than added to the mixture. The reaction mixture was stirred at room temperature maintaining the pH = 8 with 3% sodium hydroxide solution. After 6 h stirring at room temperature, the solution was cooled to 0 °C and acidified with 5% hydrochloric acid solution to pH = 5, then the solution was extracted with chloroform (3x50 ml). The combined organic layer was dried (Na₂SO₄) and evaporated, and the white crystalline product obtained was recrystallized from ?-hexane. The NMR measurement of the resulted product showed the present of approx. 12% isomer impurity (probably the trans compound) despite of the recrystallization process was repeated several times.Isolated compound: 0.52 g (61%); mp: 151-153 ⁰C; [α]∞ = +46.0 (c = 0.5, MeOH);IR= 3255, 2914, 1711, 1654, 1407, 1171 cm^'1. Anal. Calcd. for C₁₅H₂₅NO₄ (283.36): C, 63.58; H, 8.89; N, 4.94; Found: C, 63.79; H, 8.41; N, 5.19. ¹H NMR (CDCl₃) δ (ppm): 0.88 (3H, s, Me-6), 1.24 (3H, s, Me-6), 1.47 (9H, s, CMe₃), 1.75 (IH, d, H-4, J =10.6 Hz), 1.84-1.99 (3H, m), 2.20-2.31 (2H, m), 3.21 (IH, dt, J= 2.5, 10.1 Hz), 4.31 (IH, t, J= 10.1 Hz), 7.33 (IH₅ d, J= 10.1 Hz), 11.30 (IH, br s). ¹³C NMR (CDCl₃) δ (ppm): 20.6 (Me), 24.5 (CH₂), 26.5 (Me), 27.5 (CH2), 28.6 (CMe₅), 39.0 (CH), 39.3 (C_q), 39.6 (CH), 46.7 (CH), 50.5 (CH), 81.4 (CMe₃), 155.8 (NC=O), 179.8 (C=O).

References:

WO2008/59299,2008,A1 Location in patent:Page/Page column 13-14