Alternative synthesis of the PDE5 inhibitor RWJ387273 (R290629)

Synlett

Volumn , Issue 5, 2007, Pages 709-712

  Lemaire, Sébastien ^a   Willemsens, Bert ^b   Markó, István E ^a  

^a UNIVERSITÉ CATHOLIQUE DE LOUVAIN   (Belgium)

^b JANSSEN RESEARCH AND DEVELOPMENT   (Belgium)

Author keywords

tetrahydrocarboline oxidation; Buchwald Hartwig coupling; PDE5 inhibitor; Pictet Spengler reaction

Indexed keywords

BETA TETRAHYDROCARBOLINE; CARBOLINE DERIVATIVE; PHOSPHODIESTERASE V INHIBITOR; RWJ 387273; UNCLASSIFIED DRUG;

ARTICLE; DRUG STRUCTURE; OXIDATION; PICTET SPENGLER REACTION;

EID: 33947733051     PISSN: 09365214     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-2007-970769     Document Type: Article

References (40)

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31. -1. MS (EI, 70eV): m/z = 438.3, 379.4, 347.1, 184.2.
32. -1. MS (EI, 70 eV): m/z = 404.4, 260.1, 233.1, 169.1, 91.5.
33. -1.
34. 3): δ = 7.63-7.52 (m, 2 H), 7.25-7.02 (m, 5 Hz), 6.73 (d, 1 H, J = 8 Hz), 5.08 (s, 1 H), 4.55 (t, 2 H, J = 8 Hz), 3.35 (m, 1 H), 3.12 (t, 2 H, J = 8 Hz), 3.08 (m, 1 H), 2.85 (m, 2 H), 1.80 (s, 1 H).
35. 3): δ = -68.64.
36. 6): δ = 202.2, 168.4, 159.5, 137.9, 136.4, 132.5, 128.0, 127.6, 127.0, 126.7, 126.3, 125.4, 123.9, 108.6, 71.2, 61.8, 44.0, 43.3, 39.8, 39.6, 39.3, 3.09, 29.1.
37. 13C NMR (100 MHz, DMSO): δ = 173.5, 159.3, 153.9, 140.7, 134.5, 131.0, 127.6, 127.4, 125.2, 124.7, 124.3, 122.7, 118.4, 118.0, 108.6, 71.0, 66.3, 48.9, 29.0.
38. 2O (2 L/mol) and seeding with compound 9, the reaction mixture was stirred for 16 h at r.t. The desired compound 9 was obtained by filtration with an er >99.5:0.5 in 59% yield.
39. 3OD): δ = 8.30 (d, 1 H, J = 9.3 Hz), 8.02 (m, 1 H), 7.35 (m, 4 H), 7.10 (m, 3 H), 6.55 (m, 2 H), 4.85 (d, 1 H, J = 22.0 Hz), 4.54 (d, 1 H, J = 22.0 Hz), 4.40 (t, 2 H, J = 9.5 Hz), 2.92 (t, 2 H, J = 9.5 Hz).
40. 2O) for 3 min. Optical purities were measured by Capillary Electrophoresis employing (Method B: CEO 01/211/01/01) a 57 cm uncoated fused silica column (75 μm I.D., 375 μm O.D., UV wavelength of 200 nm) at 20°C. The mobile phase consisted of a 50 mM phosphate buffer, at pH 3.0; the chiral selector of 10 mM DM-β-CD. Each run lasted 30 min.