Trimethylsilylacetylene → {4-Fluoro-7-[5-(4-fluoro-benzyl)-[1,2,3]triazol-1-yl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}-acetic acid

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Reaction Steps

The title compound was prepared using analogous procedures described in EXAMPLE 3 from propyl (7-azido-4-fluoro-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate (EXAMPLE 7, Step 6) and 1-fluoro-4-prop-2-yn-1-ylbenzene obtained according to the following procedure (Gazz. Chim. Ital. 1990, 120, 783). To a mixture of ethynyltrimethylsilane (1 eq) in THF (0.6M) at room temperature was added ethylmagnesium bromide (1 eq). The mixture was stirred at room temperature for 30 min then copper bromide (I) (0.1 eq) was added. After stirring for 30 min, a 1M solution of 4-fluorobenzyl bromide (1 eq) in THF was added and the mixture was heated to reflux overnight. The reaction mixture was quenched by addition to a cold solution of NH4Cl sat, stirred for 30 min then extracted with Et2O, washed with brine, dried and evaporated. Purification by Combi-flash using a gradient of 0-100% EA/Hex afforded the desired TMS alkyne. The TMS alkyne was directly mixed with potassium fluoride (1.2 eq) in DMF (0.2M containing 1% water). The mixture was stirred at room temperature overnight then quenched by addition of HCl 3N, stirred for 1 h then extracted with pentanes, washed with NaHCO3 sat, brine, dried and evaporated. Crude alkyne compound was used directly for click chemistry described in EXAMPLE 3. The resulting racemic esters were resolved by HPLC using a 4.6×250 mm Chiralpak AS column eluting with 60% EtOH, 39.75% Hexanes and 0.25% Et3N at 0.8 mL/min and 254 nm. The resulting chiral esters (retention times=10.3 and 13.3 min) were hydrolyzed to afford EXAMPLE 8.1 and 8.2 respectively. 11-1 NMR of EXAMPLE 8.1: 1H NMR (400 MHz, DMSO-d6): δ 12.20 (s, 1 H), 7.55 (s, 1 H), 7.33 (dd, 2 H), 7.27 (d, 1 H), 7.17 (t, 2 H), 6.96 (td, 1 H), 6.85 (dd, 1 H), 5.23-5.09 (m, 1 H), 4.58 (dd, 1 H), 4.44 (dd, 1 H), 4.25 (s, 2 H), 3.65-3.52 (m, 2 H), 3.12-3.02 (m, 1 H), 2.89 (ddd, 1 H), 2.32-2.19 (m, 1 H), 2.14-2.02 (m, 1 H). MS (+ESI) m/z: 423.1.

Provenance & Evidence