Methanone, (3,4-dihydro-2(1H)-isoquinolinyl)[2-[(4-methoxyphenyl)amino]-4-thiazolyl]- synthesis

Yield:736945-96-3 88%

Reaction Conditions:

with (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate in N,N-dimethyl-formamide at 23; for 0.5 h;

Steps:

Example 3: 4-(3,4-dihydro-2(1H)-isoquinolinylcarbonyl)-N-[4-(methyloxy)phenyl]-1,3-thiazol-2-amine

General procedure: To a stirring solution of 2-{[4-(methyloxy)phenyl]amino}-1,3-thiazole-4-carboxylic acid (95 mg, 0.380 mmol) and BOP (201 mg, 0.456 mmol) in N,N-Dimethylformamide (DMF) (2 mL) stirred at room temperature was added 1,2,3,4-tetrahydroisoquinoline (0.15 mL, 1.183 mmol). The reaction mixture was stirred at 23 °C (room temperature) for 30 minutes. The reaction mixture was taken up in methanol (1 mL) and purified by Prep HPLC (Gilson) using a Sunfire Prep C18 column (5 uM, 30 x 75 mm, i.d.) eluting with water (+ 0.1% TFA) / acetonitrile (+ 0.1% TFA) (20% → 60%, 50 mL/min) over a 12-minute gradient. The appropriate fractions (Ret time = 10.7 mins) were combined and freeze dried to give 4-(3,4-dihydro-2(1H)-isoquinolinylcarbonyl)-N-[4-(methyloxy)phenyl]-1,3-thiazol-2-amine (125 mg, 0.335 mmol, 88 % yield) as an off-white solid. 1H NMR (400 MHz, METHANOL-d4) 7.49 (d, J = 8.53 Hz, 2H), 7.17 - 7.30 (m, 4H), 7.03 - 7.17 (m, 1H), 6.93 (br. s., 2H), 5.10 (br. s., 1H), 4.83 (br. s., 1H), 4.08 (br. s., 1H), 3.89 - 4.01 (m, 1H), 3.81 (s, 3H), 3.01 (br. s., 2H). MS (ES) m/e 366.1 [M+H]⁺

References:

Washburn, David G.;Holt, Dennis A.;Dodson, Jason;McAtee, Jeff J.;Terrell, Lamont R.;Barton, Linda;Manns, Sharada;Waszkiewicz, Anna;Pritchard, Christina;Gillie, Dan J.;Morrow, Dwight M.;Davenport, Elizabeth A.;Lozinskaya, Irina M.;Guss, Jeffrey;Basilla, Jonathan B.;Negron, Lorena Kallal;Klein, Michael;Willette, Robert N.;Fries, Rusty E.;Jensen, Timothy C.;Xu, Xiaoping;Schnackenberg, Christine G.;Marino Jr., Joseph P. [Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,# 17,p. 4979 - 4984] Location in patent:supporting information