Telaprevir synthesis

Yield:402957-28-2 80%

Reaction Conditions:

Stage #1:C₃₈H₅₇N₇O₇ with methanol;potassium carbonate at 20; for 0.5 h;
Stage #2: with Dess-Martin periodane in dichloromethane at 20;

Steps:

30
250 μ of saturated K₂C0₃ was added to a solution of 14 (0.514 g, 0.75 mmol) in MeOH (20 ml) at room temperature. The reaction mixture was stirred for 30 minutes at room temperature resulting in a pale yellow suspension. After full conversion (as judged by TLC analysis), the reaction mixture was washed with 20 ml brine, the aqueous layer was washed again with 10 ml CH₂C1₂ (2x). The organic layers were collected, dried with MgS0₄ and concentrated in vacuo, to yield a pale yellow solid. The yellow solid was dissolved in CH₂CI₂ (10 ml) and Dess-Martin periodinane (0.650 g, 1.532 mmol) was added at room temperature. The reaction mixture was stirred overnight before adding saturated NaHC0₃ solution (10 ml) and saturated Na₂S₂0₃ solution (10 ml). This mixture was stirred for 10 minutes, separated and the aqueous layers were washed with EtOAc (2 x 10 ml). The organic layers were collected, dried with MgSC^ and concentrated in vacuo to give the crude product as an 83: 13:4 mixture of diastereomers. After silica gel flash chromatography (1% MeOH in CH₂C1₂), 1 (0.412 mg, 0.61 mmol, 80%) was obtained as a white solid. ^lU NMR (500.23 MHz, DMSO-i¾: 5 = 9.19 (d, J= 1.4 Hz, 1H), 8.91 (d, J= 24.5 Hz, 1H), 8.76 (dd, J = 1.5, 2.5 Hz, 1H), 8.71 (d, J= 5.3 Hz, 1H), 8.49 (d, J= 9.2 Hz, 1H), 8.25 (d, J = 6.8 Hz, 1H), 8.21 (d, J = 8.9 Hz, 1H), 4.94 (m, 1H), 4.68 (dd, J= 6.5, 9.0 Hz, 1H), 4.53 (d, J = 9.0 Hz, 1H), 4.27 (d, J = 3.5 Hz, 1H), 3.74 (dd, J = 8.0, 10 Hz, 1H), 2.74 (m, 1H), 3.64 (d, J = 3.5 Hz, 1H), 0.92 (s, 9H), 0.87 (t, 3H), 0.84-1.40 (m, 23H), 0.65 (m, 2H), 0.56 (m, 2H); ¹³C NMR (125.78 MHz, CDC1₃): δ = 197.0 (C), 171.8 (C), 170.4 (C), 169.0 (C), 162.1 (C), 161.9 (C), 147.9 (CH), 144.0 (C), 143.4 (CH), 56.4 (CH), 56.3 (CH), 54.2 (CH), 53.4 (CH), 42.3 (CH), 41.3 (CH), 32.1 (CH), 31.8 (CH), 31.6 (CH), 29.1 (CH), 28.0 (CH), 26.4 (CH₃); (cm⁴): 3302 (m), 2928 (m), 2858 (w), 1658 (s), 1620 (s), 1561 (s), 1442 (m); HRMS (ESI, 4500 V): m/z calcd. for C₃6H₅3N₇0₆Na⁺ ([M + Na]⁺) 702.3950, found 702.3941.

References:

VERENIGING VOOR CHRISTELIJK HOGER ONDERWIJS, WETENSCHAPPELIJK ONDERZOEK EN PATIËNTENZORG;RUIJTER, Eelco;ORRU, Romano;ZNABET, Anass;POLAK, Marloes;TURNER, Nicholas WO2011/103932, 2011, A1 Location in patent:Page/Page column 50; 51

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