HOAt → 2-(3-ethynyl-quinolin-6-yloxy)-N-(2-hydroxy-1-methyl-1-prop-2-ynyloxymethyl-ethyl)-2-methylsulfanyl-acetamide

Beteiligte Stoffe

Reaktionsschritte

1-hydroxy-7-azabenzotriazole (0.717 g), O-(1H benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.692 g) and 2-amino-2-methyl-3-prop-2-ynyloxy-propan-1-ol hydrochloric salt (0.947 g) were added at room temperature to a solution of triethylamine (2.14 ml) and (3-ethynyl-quinolin-6-yloxy)-methylsulfanyl-acetic acid (1.20 g) in 43 ml of dry DMF. The reaction mixture was stirred 16 hrs at R.T and then poured onto a mixture of ethyl acetate and brine. The two layers were separated and the aqueous layer was extracted thrice with ethyl acetate. The organic layers were combined, washed with sat. sodium hydrogeno carbonate (1×), with water (1×), with brine(1×) and then dried over sodium sulphate. After filtration and concentration under reduced pressure 2.01 g of a crude mixture were isolated as a dark orange oil. The crude mixture was purified by flash chromatography on silica gel (hexane/ethyl acetate) to give 1.22 g of 2-(3-ethynyl-quinolin-6-yloxy)-N-(2-hydroxy-1-methyl-1-prop-2-ynyloxymethyl-ethyl)-2-methylsulfanylacetamide in mixture with (3-ethynyl-quinolin-6-yloxy)-methylsulfanyl-acetic acid 2-[2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-acetylamino]-2-methyl-3-prop-2-ynyloxy-propyl ester resulting from the homo coupling process. This residue was dissolved in 24 ml of THF/H2O (1/1) and treated with 42 mg of LiOH monohydrate at room temperature for 1 h 45. The crude mixture was extracted pH=11) thrice with ethyl acetate. The organic layers were combined, washed with water (1×) and with brine (1×) and then, dried over sodium sulphate. After filtration and concentration under reduced pressure, crude 2-(3-Ethynyl-quinolin-6-yloxy)-N-(2-hydroxy-1-methyl-1-prop-2-ynyloxymethyl-ethyl)-2-methylsulfanyl-acetamide (0.944 g) was obtained as a yellow oil and used in the next step without any further purification.

Herkunft & Nachweise