反应详情

To a stirred solution of K2CO3 (17.2 g, 124 mmol) in H2O (62 mL) at room temperature was added dioxane (490 mL), 3-bromo-4-(2-hydroxyethoxy)-5-iodobenzoic acid ethyl ester (17.2 g, 41.4 mmol), 3-chlorophenylboronic acid (7.77 g, 49.7 mmol), and [1,1′bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with CH2Cl2 (0.676 g, 0.828 mmol). This mixture was stirred at room temperature for 4 h, and it appeared to be in progress but not done by TLC and HPLC. Another 0.1 eq. of 3-chlorophenylboronic acid (0.647 g) was added, and the reaction stirred an additional 24 h. Over the next 4 days, 0.1 eq. of the boronic acid was added at one a day intervals until the reaction was almost completely done by HPLC (60% bis-arylated, 25.4% mono-arylated, and 12.6% SM). The reaction was diluted with HCl (1187 mL, 0.17 M) and the resulting solution was extracted with EtOAc (1×300 mL and 3×200 mL). The combined organic layers were washed wtih 0.1 N HCl (2×90 mL), H2O (2×90 mL), and brine (2×90 mL) and then dried (Na2SO4). After concentration, the residue was first purified by flash chromatography (0 to 50% EtOAc/hexane gradient) and then HPLC [60% CH2Cl2 (6% MTBE):40% hexane] to afford the bis-arylated product (6.16 g, 35%) as a viscous faint yellow oil (for mono-arylated product, see step 1 of Example 33); 1H NMR (DMSO-d6) δ1.31 (t, J=7.0 Hz, 3H), 3.12 (q, J=5.5 Hz, 2H), 3.28 (t, J=5.7 Hz, 2H), 4.32 (dd, J=7.0, 14.1 Hz, 2H), 4.45 (t, J=5.5 Hz, 1H), 7.45-7.53 (m, 4H), 7.53-7.58 (m, 2H), 7.67-7.69 (m, 2H), 7.91 (s, 2H); IR (film) 3440, 3090, 2990, 2930, 2860, 1720, 1610, 1570, 1475, 1425, 1390, 1360, 1340, 1310, 1245, 1160, 1120, 1100, 1090, 1065, 1025, 770, 710, and 500 cm−1; mass spectrum [(+) APCI], m/z 431/433 (M+H)+, 448/450 (M+NH4)+.

1. stirringthe reaction stirred an additional 24 h
2. extractionthe resulting solution was extracted with EtOAc (1×300 mL and 3×200 mL)
3. washThe combined organic layers were washed wtih 0.1 N HCl (2×90 mL), H2O (2×90 mL), and brine (2×90 mL)
4. dry with materialdried (Na2SO4)
5. concentrationAfter concentration
6. customthe residue was first purified by flash chromatography (0 to 50% EtOAc/hexane gradient)