MK-0822; Odanacatib.
603139-19-1
Formula: C25H27F4N3O3S
Mass: 525.17093
Merck Frosst Canada Ltd. phase 3
(2S)-N-(1-Cyanocyclopropyl)-4-fluoro-4-methyl-2-({(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}amino)pentanamide
(S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-(((S)-2,2,2-trifluoro-1-(4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)ethyl)amino)pentanamide
N1-(1-Cyanocyclopropyl)-4-fluoro-N2-[2,2,2-trifluoro-1(S)-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl]-L-leucinamide
synthesis.........http://newdrugapprovals.org/2014/05/09/mk-0822-odanacatib-has-been-identified-as-a-potent-and-selective-inhibitor-of-cathepsin-k/
J. Org. Chem., 2009, 74 (4), pp 1605–1610
DOI: 10.1021/jo802031
An enantioselective synthesis of the Cathepsin K inhibitor odanacatib (MK-0822) 1 is described. The key step involves the novel stereospecific SN2 triflate displacement of a chiral α-trifluoromethylbenzyl triflate 9a with (S)-γ-fluoroleucine ethyl ester 3 to generate the required α-trifluoromethylbenzyl amino stereocenter. The triflate displacement is achieved in high yield (95%) and minimal loss of stereochemistry. The overall synthesis of 1 is completed in 6 steps in 61% overall yield.
(2S)-N-(1-Cyanocyclopropyl)-4-fluoro-4-methyl-2-({(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)biphenyl-4-yl]ethyl}amino)pentanamide (1)
To a visually clean 5-necked 50-L round-bottomed flask equipped with a mechanical stirrer, a thermocouple, a dropping funnel, and a nitrogen inlet was added biaryl acid 12a (1.87 kg, 4.0 mol) and DMAc (9.3 L)…………………………………….deleted……………………………………………………. and dried under vacuum at 35 °C to yield 1 as a white solid (2.50 kg, 97% yield, 99.7 area %, 99.9% de by HPLC):
mp 223−224 °C;
1H NMR (CD3OD) δ 8.17 (br s, 1H), 8.05 (d, 2H, J = 8.5 Hz), 7.96 (d, 2H, J = 8.5 Hz), 7.80 (d, 2H, J = 8.0 Hz), 7.64 (d, 2H, J = 8.0 Hz), 4.43 (m, 1H), 3.55 (ddd, 1H, J = 5.0, 8.5, 8.0 Hz), 3.18 (s, 3H), 2.84 (br m, 1H), 2.02 (m, 2H), 1.46 (d, 3H, J = 21.5 Hz), 1.43 (d, 3H, J = 22.0 Hz), 1.36 (m, 2H), 1.07 (m, 1H), 0.94 (m, 1H);
13C NMR (125 MHz, acetone-d6) δ 175.2, 146.0, 141.2, 140.6, 136.1, 130.3, 128.9 (q,J = 282.8 Hz), 128.7, 128.6, 128.4, 120.9, 95.9 (d, J = 164.3 Hz), 63.5 (q, J = 30.0 Hz), 59.2 (d, J = 3.5 Hz), 44.8 (d, J = 23.1 Hz), 44.3, 27.5 (d, J = 23.9 Hz), 27.1 (d, J = 24.9 Hz), 20.7, 16.5;
13C NMR (125 MHz, acetone-d6) δ 175.2, 146.0, 141.2, 140.6, 136.1, 130.3, 128.9 (q,J = 282.8 Hz), 128.7, 128.6, 128.4, 120.9, 95.9 (d, J = 164.3 Hz), 63.5 (q, J = 30.0 Hz), 59.2 (d, J = 3.5 Hz), 44.8 (d, J = 23.1 Hz), 44.3, 27.5 (d, J = 23.9 Hz), 27.1 (d, J = 24.9 Hz), 20.7, 16.5;
19F NMR (CD3OD) δ −73.2, −136.8; IR (cm−1) 3331, 2244, 1687, 1304, 1152;
[α]20D + 23.3 (c 0.53, MeOH);
HRMS calcd for C25H28F4N3O3S [MH]+ 526.1782; found 526.1781;
HPLC Phenomenex Spherisorb 4.6 mm × 25 cm column; eluants (A) 0.1% aqueous H3PO4 and (B) acetonitrile; 1 mL/min; gradient A/B 60:40 to 30:70 over 30 min; λ = 265 nm; temperature 45 °C; tR(1 (major diastereoisomer)) = 15.8 min, tR(1 (minor diastereoisomer)) = 16.4 min; HPLC (chiral) Chiralpak AD 4.6 mm × 15 cm column; eluants (A) hexanes, (B) ethanol, and (C) methanol; 1 mL/min; isocratic A/B/C 80:10:10 for 60 min; λ = 265 nm; temperature 40 °C; tR((S,S)-1) = 14.5 min, tR((R,S)-1) = 11.9 min, tR((S,R)-1) = 18.2 min,tR((R,R)-1) = 25.3 min, >99.5% (S,S).
Supporting Information
Copies of 1H, 13C, and 19F NMR spectra for 1.
