Amlodipine Impurity 48 synthesis

Yield:39562-06-6 26%

Reaction Conditions:

in ethanol;acetic acid at 20 - 95; for 3 h;

Steps:

56

Ethyl acetoacetate (638 μL, 99%, 5.00 mmol), 2-chlorobenzaldehyde (562 μL, 99%, 5.00 mmol) and methyl-3-aminocrotonate (593 mg, 97%, 5.00 mmol) were taken up in EtOH (3.25 mL) at rt. AcOH (217 μL) was added and the mixture was heated to 95 ⁰C. After 3h, the reaction mixture was cooled to ambient temperature, diluted with EtOAc (20 mL), dried over Na₂SO₄ and crystallized from EtOAc/hexane (1 :9) to afford 451 mg (26%) of 3-ethyl 5-methyl 4-(2-chlorophenyl)-l,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate as a white solid: MP 125-127 ⁰C; ¹H NMR (500 MHz, CDCl₃) δ 1.20 (t, J= 7.0 Hz, 6H), 2.30 (s, 3H), 2.31 (s, 3H), 3.61-3.62 (m, 3H), 4.05-4.10 (m, 4H), 5.40 (s, IH), 5.70-5.74 (m, IH), 7.02-7.06 (m, IH), 7.10-7.15 (m, IH), 7.22-7.25 (m, IH), 7.35-7.39 (m, IH); ¹³C NMR (125 MHz, CDCl₃) δ 14.3, 19.4, 19.5, 19.6, 37.2, 37.3, 37.6, 50.8, 50.9, 59.8, 103.8, 103.9, 104.1,126.7, 126.8, 126.9, 127.3, 129.3, 131.2, 131.4, 131.6, 132.4, 143.9, 144.0, 144.1, 145.6,145.8, 145.9, 167.6, 167.7, 168.0, 168.1; MS (ES) m/z 372 (M+Na)⁺, 350 (M+H)⁺, 318, 304, 272, 238; m/z 350.098 (calcd for Ci₈H₂iClNO₄ (M+H)⁺: 350.115).

References:

WO2008/6070,2008,A2 Location in patent:Page/Page column 150-151