S-EMCA synthesis

Yield:1199796-29-6 41%

Reaction Conditions:

Stage #1:methyl 3α,7α,12α-trimethoxymethyloxy-6α-ethyl-5β-cholan-24-oate with n-butyllithium;diisopropylamine in tetrahydrofuran;hexane at -78;Inert atmosphere;
Stage #2:methyl iodide in tetrahydrofuran;hexane at -78 - 20;

Steps:

6
23(S)-methyl-3α,7α,12α-trihydroxy-6α-ethyl-5β-cholan-24-oic acid (Ih3e); To a solution of diisopropylamine (0.56 ml, 4.026 mmol) in freshly distilled THF (15 ml) cooled at -78° C. and under N₂ atmosphere, ¹¹BuLi 2.5N in hexane (1.53 ml, 3.840 mmol) was added dropwise. The reaction was stirred at -78° C. for 30' and then a solution of 3 (350 mg, 0.601 mmol) dissolved in freshly distilled THF (7 ml) was added dropwise. The resulting solution was stirred at -78° for 90'. Iodomethane (0.56 ml, 9.015 mmol) was added, the reaction mixture was stirred at -78° C. for 60', and then slowly warmed to room temperature overnight. The mixture was then concentrated under reduced pressure, and the resulting residue was diluted with H₂O (30 ml) and extracted with AcOEt (3×30 ml). The collected organic layers were washed with brine (30 ml), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was then treated with a solution of MeOH/HCl 37% (20 ml, 20:1 vol/vol) at 45° for 8 h. The mixture was concentrated under reduced pressure, and the resulting residue was diluted with H₂O (30 ml) and extracted with AcOEt (3×30 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous Na₂SO₄, and concentrate under reduced pressure. The resulting residue was treated with a solution of NaOH 10% in MeOH (15 ml) at 45° C. for 24 h. The mixture was then concentrated under reduced pressure, and the resulting residue was diluted with H₂O (20 ml), washed with ⁱPr₂O (3×15 ml), acidify with HCl 3N, and finally extracted with CHCl₃ (3×20 ml). The organic layers were washed with brine (100 ml), dried over anhydrous Na₂SO₄, and concentrated. The resulting residue was purified by medium pressure chromatography (column: “RP-1 8 Lobar B”, MeOH/H₂O from 5:5 to 6:4, 50 psi) to give 4 (47 mg, 41%).Mp: 195-197° C.¹H-NMR (CDCl₃+CD₃OD) δ: 0.63 (3H, s, 18-CH₃), 0.84-0.88 (6H, m, 19-CH₃+CH₃CH₂), 0.98 (3H, d, J=6.60 Hz, 21-CH₃), 1.10 (3H, d, J=6.80 Hz, CH(CH₃)COOH), 2.61 (m, 1H, CH(CH₃)COOH), 3.35 (1H, m. 3-CH), 3.65 (1H, m, 7-CH), 3.92 (1H, m, 12-CH).¹³C-NMR (CDCl₃+CD₃OD) δ: 11.51, 12.34, 17.52, 19.19, 22.09, 22.67, 23.11, 26.65, 27.40, 28.05, 29.83, 33.31, 34.56, 35.06, 35.40, 38.67, 39.90, 41.11, 41.39, 41.69, 45.10, 46.39, 47.32, 70.65, 71.79, 72.90, 182.07.

References:

Intercept Pharmaceuticals, Inc. US2010/152151, 2010, A1 Location in patent:Page/Page column 28

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