1-Ethyl-3,5-dimethyl-1H-pyrazole-4-carbaldehyde → 6-[2-(3-chloro-4-isopropoxyphenyl)ethyl]-6-cyclopentyl-3-[(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one

Participants

Reaction Conditions

Reaction Steps

A solution of 6-[2-(3-chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione (379 mg; 1.0 mmol from step 1 below) and 1-ethyl-3,5-dimethyl-1H-pyrazole-4-carbaldehyde (152 mg; 1.1 mmol) in methanol was heated at 40° C. overnight. The reaction mixture was treated with (CH3)2NHBH3 (65 mg, 1.1 equiv), and heated at 40° C. overnight again. The reaction was partitioned between EtOAc and H2O. The EtOAc layer was dried with Na2SO4, concentrated, and purified by reverse phase HPLC using 0.1% HOAc in H2O and CH3CN. (Column: Water's Bondapak, C18, particle size: 37-55 micron column size: 47×300 mm; Flow rate: 70 ml/min; Detector: was set at 254 nm; Buffer A: 0.1% HOAc in H2O; Buffer B: 0.1% HOAc in CH3CN. The column was equilibrated in A for 20 minutes. The sample was dissolved in 5 ml of DMSO, filtered, and injected onto the column. The gradient was held at 75% A/25% for 5 minutes and then increased linearly to 55% A/45% B in 15 minutes and then continued isocratically at 45% B for another 25 minutes. The desired product eluted at 28 minutes.) The product-containing fractions were lyophilized to afford the title compound as a powder (196.2 mg, 40%). 1H NMR (400 MHz, DMSO-d6): δ 1.13 (t, 3H), 1.26 (d, m overlap, 8H), 1.35-1.63 (m, 6H), 1.75 (m, 2H), 2.02 (s, 3H), 2.10 (s, 3H), 2.21 (m, 1H), 2.39 (m, overlap, 3H), 2.61 (d, J=16.4 Hz, 1H), 3.1 (m, 2H, overlap with H2O peak), 3.81 (q, 2H), 4.56 (7 line pattern, 1H), 6.90 (d, J=8.8 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 7.11 (s, 1H). LC-MS (APCI) calcd for C29H39ClN2O4: 514.26, found (M+H+): 515.3 m/z.

Provenance & Evidence