1146699-70-8

122-51-0

1146699-66-2

步驟C. 將(R)-2-(4-氯-N-(2-氟-4-(N'-羥基甲脒基)芐基)-苯磺酰氨基)-5,5,5-三氟戊酰胺（246g）加入反應(yīng)器中，隨后加入干燥的乙腈（509mL）、原甲酸三乙酯（120mL）和三氟乙酸（7mL）。將反應(yīng)混合物加熱至40-50℃，并通過HPLC監(jiān)測反應(yīng)進(jìn)度，直至起始原料的相對面積百分比（AP）低于0.15。反應(yīng)完成后，一次性加入甲醇（1.48L），然后加入水（1.034L），保持反應(yīng)體系溫度在45-50℃。隨后將反應(yīng)混合物冷卻至15-20℃，過濾收集固體。用乙腈:甲醇:水（2:6:5，v/v/v）的混合溶劑洗滌濾餅，并在50-60℃下真空干燥，得到(2R)-2-[N-[(4-氯苯基)磺?；鵠-N-[2-氟-4-(1,2,4-惡二唑-3-基)芐基]氨基]-5,5,5-三氟戊酰胺，為白色固體（228g，收率90%）。 1H NMR (CDCl3, 300MHz) δ: 1.40-1.58 (m, 1H), 1.75-1.90 (m, 1H), 1.92-2.07 (m, 1H), 2.10-2.26 (m, 1H), 4.37 (dd, J = 8.67, 6.22Hz, 1H), 4.48 (d, J = 15.64Hz, 1H), 4.64 (d, J = 15.82Hz, 1H), 5.54 (s, 1H), 6.33 (s, 1H), 7.44-7.54 (m, 2H), 7.62 (t, J = 7.72Hz, 1H), 7.68-7.76 (m, 3H), 7.85 (dd, J = 7.91, 1.51Hz, 1H), 8.76 (s, 1H). 13C NMR (DMSO-d6, 75MHz) δ: 170.34, 167.75, 165.80, 159.64 (d, J = 244.5Hz, 1C), 138.19, 137.64, 131.25 (d, J = 3.75Hz, 1C), 129.31, 129.23, 129.05 (d, J = 14.25Hz, 1C), 126.74 (q, J = 274.5Hz, 1C), 126.91, 126.80, 123.12 (d, J = 3.75Hz, 1C), 113.7 (d, J = 24.0Hz, 1C), 57.92, 41.38 (d, J = 4.5Hz, 1C), 30.04 (d, J = 30.0Hz, 1C), 22.90. 19F NMR (CDCl3, 282MHz) δ: -116.3, -66.5. IR (KBr): 3454, 334, 3286, 2952, 1705, 1432, 1325, 1260, 1167, 1084, 828 cm-1. 元素分析: 計(jì)算值 C20H17ClF4N4O4S: C, 46.11; H, 3.29; N, 10.71; S, 6.15; F, 14.58; Cl, 6.80. 實(shí)測值: C, 46.06; H, 3.24; N, 10.71; S, 6.25; F, 14.60; Cl, 6.88.

參考文獻(xiàn)：

[1] Patent: US2009/111858, 2009, A1. Location in patent: Page/Page column 23

[2] Patent: US2009/111858, 2009, A1. Location in patent: Page/Page column 19-20

[3] ACS Medicinal Chemistry Letters, 2010, vol. 1, # 3, p. 120 - 124

BMS-708163 抑制Notch 過程時顯示出低選擇性。