Download PDF
Synlett 2007(5): 0709-0712  
DOI: 10.1055/s-2007-970769
LETTER
© Georg Thieme Verlag Stuttgart · New York

Alternative Synthesis of the PDE5 Inhibitor RWJ387273 (R290629)

Sébastien Lemairea, Bert Willemsensb, István E. Markó*a
a Université Catholique de Louvain, Unité de Chimie Organique et Médicinale, Place Louis Pasteur, 1, 1348 Louvain-la-Neuve, Belgium
Fax: +32(10)472788; e-Mail: marko@chim.ucl.ac.be;
b Chemical Process Research, Johnson & Johnson Pharmaceutical Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium
Further Information

Publication History

Received 22 November 2006
Publication Date:
08 March 2007 (online)

    Permissions and Reprints All articles of this category

Abstract

An alternative synthesis of a PDE5 inhibitor is reported using a highly diastereoselective Pictet-Spengler reaction.

Key words

Pictet-Spengler reaction - β-tetrahydrocarboline oxidation - Buchwald-Hartwig coupling - PDE5 inhibitor

    References and Notes

  • 1 Corbin JD. Francis SH. J. Biol. Chem.  1999,  274:  13729 
    CrossrefGoogle Scholar
  • 2 For Viagra®(sildenafil), see: Brook G. Drugs Today  2000,  26:  125 
    Google Scholar
  • 3 For Levitra®(vardenafil), see: Sorbera LA. Martin L. Rabasseda X. Castaner J. Drugs Future  2001,  26:  141 
    CrossrefGoogle Scholar
  • 4a For Cialis®(tadalafil), see: Sorbera LA. Martin L. Leeson PA. Castaner J. Drugs Future  2001,  26:  15 
    CrossrefGoogle Scholar
  • 4b For discovery of tadalafil, see: Daugan A. Grondin P. Ruault C. Gouville A.-CLM. Coste H. Kirilovsky J. Hyafil F. Labaudinière R. J. Med. Chem.  2003,  46:  4525 
    CrossrefGoogle Scholar
  • 4c Daugan A. Grondin P. Ruault C. Gouville A.-CLM. Coste H. Kirilovsky J. Linget J.-M. Hyafil F. Labaudiniere R. J. Med. Chem.  2003,  46:  4533 
    CrossrefGoogle Scholar
  • 5a Jiang W. Alford V. Qiu Y. Bhattacharjee S. John YM. Haynes-Johnson D. Kraft PJ. Lundeen SG. Sui Z. Bioorg. Med. Chem.  2004,  12:  1505 
    CrossrefPubMedGoogle Scholar
  • 5b Lanter J. Sui Z. Macielag MJ. Fiordeliso J. Jiang W. Qiu Y. Bhattacharjee S. Kraft P. John TM. Haynes-Johnson D. Craig E. Clancy J. J. Med. Chem.  2004,  47:  656 
    CrossrefPubMedGoogle Scholar
  • 5c Jiang W, and Sui Z. inventors; WO  2004000842. 
    CrossrefPubMed
  • 5d Qiu Y. Bhattacharjee S. Kraft P. John TM. Craig E. Haynes-Johnson D. Guan J. Jiang W. Macielag M. Sui Z. Clancy J. Lundeen S. Eur. J. Pharmacol.  2003,  472:  73 
    CrossrefPubMedGoogle Scholar
  • 5e Jiang W, and Sui Z. inventors; WO  2003042213. 
    CrossrefPubMed
  • 5f Jiang W. Sui Z. Macielag M. Walsh SP. Fiordeliso JJ. Lanter JC. Guan J. Qiu Y. Kraft P. Bhattacharjee S. Craig E. Haynes-Johnson D. John TM. Clancy J. J. Med. Chem.  2003,  46:  441 
    CrossrefPubMedGoogle Scholar
  • 5g Jiang W. Sui Z. Chen X. Org. Lett.  2003,  5:  43 
    CrossrefPubMedGoogle Scholar
  • 5h Jiang W. Sui Z. Chen X. Tetrahedron Lett.  2002,  43:  8941 
    CrossrefPubMedGoogle Scholar
  • 5i Sui Z. Guan J. Macielag M. Jiang W. Zhang S. Qiu Y. Kraft P. Bhattacharjee S. John TM. Hyanes-Johnson D. Clancy J. J. Med. Chem.  2002,  456:  4094 
    CrossrefPubMedGoogle Scholar
  • 5j Sui Z, Macielag M, Guan J, Jiang W, and Lanter JC. inventors; WO  2001087882. 
    CrossrefPubMed
  • 5k Jiang W. Guan J. Macielag JM. Zhang S. Qiu Y. Kraft P. Bhattacharjee S. John TM. Haynes-Johnson D. Lundeen S. Sui Z. J. Med. Chem.  2005,  48:  2126 
    CrossrefPubMedGoogle Scholar
  • 6a Willemsens B. Vervest I. Ormerod D. Aelterman W. Fannes C. Mertens N. Markó IE. Lemaire S. Org. Process Res. Dev.  2006,  10:  1275 
    CrossrefGoogle Scholar
  • 6b Li X, Lemaire S, Markó I, and Willemsens B. inventors; WO  2006093719. 
    Crossref
  • 7 Li X. Branum S. Russel RK. Jiang W. Sui Z. Org. Process Res. Dev.  2005,  9:  640 
    CrossrefGoogle Scholar
  • 8 Jiang W. Sui Z. Chen X. Tetrahedron Lett.  2002,  43:  8941 
    CrossrefGoogle Scholar
  • 9 Cox ED. Cook JM. Chem. Rev.  1995,  95:  1797 
    CrossrefGoogle Scholar
  • For the attribution of the cis:trans ratio, see:
  • 11a Ungemach F. Soerens D. Weber R. DiPierro M. Campos O. Mokry P. Cook JM. Silverton JV. J. Am. Chem. Soc.  1980,  102:  6976 
    CrossrefGoogle Scholar
  • 11b Bailey PD. Hollinshead SP. McLay NR. Tetrahedron Lett.  1987,  5177 
    CrossrefGoogle Scholar
  • 12a Josse O. Labar D. Marchand-Brynaert J. Synthesis  1999,  404 
    CrossrefGoogle Scholar
  • 12b For the mechanism: Belleau B. Martel R. Lacasse G. Menard M. Weinberg NL. Perron YG. J. Am. Chem. Soc.  1968,  823 
    CrossrefGoogle Scholar
  • 12c Belleau B. Malek G. J. Am. Chem. Soc.  1968,  1651 
    CrossrefGoogle Scholar
  • 13 Peng S. Guo M. Winterfeldt E. Liebigs Ann. Chem.  1993,  137 
    Google Scholar
  • 14 Peng S. Zhang L. Cai M. Winterfeldt E. Liebigs Ann. Chem.  1993,  141 
    Google Scholar
10

To confirm the stereochemistry of compound 3, the two diastereoisomers trans-3 and cis-3 were prepared in a two-step sequence. Treatment of unprotected l-tryptophan methyl ester with aldehyde 2 leads to the quantitative formation of the corresponding carbolines in a 45:55 cis:trans ratio. An NMR study allowed the identification of both diastereoisomers without ambiguity. After separation by chromatography, each isomer was benzylated leading to pure compounds cis-3 and trans-3 used as references to assess the trans stereochemistry of compound 3 obtained from tryptophan derivative 1.

15

Procedure for Compound 3 (65 mmol scale).
In a round-bottomed flask charged with toluene (6 L/mol), N-benzyl-l-tryptophan methyl ester (1 equiv) and the aromatic aldehyde 2 (1.05 equiv) were added at r.t. Finally, PTSA (0.1 equiv) was added and the reaction mixture was refluxed in a Dean-Stark apparatus for 22 h. After cooling to r.t., sat. aq NaHCO3 (0.2 L/mol) was added. After 15 min of stirring and then separation of the two phases, the organic solvent was evaporated under vacuum. The obtained crude product was purified by crystallisation from t-BuOMe (3 L/mol) to afford compound 3 in 73% yield. 1H NMR (300 MHz, CDCl3): δ = 7.51-7.07 (m, 12 H), 6.72 (d, 1 H, J = 8 Hz), 5.39 (s, 1 H), 4.53 (t, 2 H, J = 9 Hz), 3.94 (m, 1 H), 3.80 (m, 2 H), 3.61 (s, 3 H), 3.19 (m, 2 H), 3.13 (t, 2 Hz, J = 9 Hz). 13C NMR (75 MHz, CDCl3): δ = 173.7, 160.0, 139.7, 136.5, 135.6, 134.0, 128.9, 128.5, 128.3, 127.7, 127.1, 127.0, 125.3, 121.5, 119.3, 118.2, 110.8, 108.9, 71.4, 60.4, 56.1, 54.2, 51.3, 29.6, 24.5. IR: 3388, 1732, 1601, 1488, 1451 cm-1. MS (EI, 70eV): m/z = 438.3, 379.4, 347.1, 184.2.

16

Procedure for Compound 4 (46 mmol scale).
Compound 3 (1 equiv) was dissolved in MeOH-THF (6 L/mol; 1:1) at r.t. Then, aq NaOH (3 L/mol, 15% w/w) was added in one portion. After 28 h of stirring at r.t., the organic mixture was acidified to pH 6-7 and extracted by CH2Cl2 (5 L/mol). 1H NMR (300 MHz, CDCl3): δ = 8.20 (br s, 1 H), 7.60 (s, 1 H), 7.43 (d, 1 H, J = 8 Hz), 7.21-6.94 (m, 10 H), 6.58 (d, 1 H, J = 14 Hz), 5.22 (s, 1 H), 4.40 (t, 2 H, J = 9 Hz), 3.88 (m, 1 H), 3.85 (AB, 1 H, J = 14 Hz), 3.74 (AB, 1 H, J = 14 Hz), 3.13 (d, 2 H, J = 5 Hz), 3.00 (t, 2 H, J = 9 Hz).
Then, at r.t., (NH4)2CO3 (3 equiv) and EEDQ (1.1 equiv) were added to the CH2Cl2 phase. After a 16 h stirring period, the organic phase was filtered over dicalite. Then the organic layer was washed with H2O (3 L/mol) and the organic solvent was evaporated under reduced pressure. 1H NMR (200 MHz, CDCl3): δ = 7.72-7.64 (m, 2 H), 7.40-7.15 (m, 8 H), 6.90-6.64 (m, 4 H), 5.60 (br s, 1 H), 4.90 (s, 1 H), 4.52 (t, 2 H, J = 9 Hz), 3.90 (m, 1 H), 3.88 (AB, 1 H, J = 4 Hz), 3.66 (AB, 1 H, J = 4 Hz), 3.15 (m, 2 H), 3.07 (t, 2 H, J = 9 Hz). The obtained primary amide (1 equiv) was dissolved in dry DMF (10 L/mol) at 0 °C. After addition of pyridine (0.7 L/mol), POCl3 (1.2 equiv) was added dropwise to the reaction mixture. After a 2 h stirring period at 0 °C, the reaction mixture was quenched with a CuSO4 aq solution and extracted with CH2Cl2. After evaporation of the organic solvent, the obtained solid was purified by crystallization from t-BuOMe to afford compound 4 in 50% yield. 1H NMR (200 MHz, CDCl3): δ = 7.62-7.58 (m, 1 H), 7.47-7.16 (m, 11 H), 6.84 (d, 1 H, J = 11 Hz), 4.96 (s, 1 H), 4.76 (t, 2 H, J = 11 Hz), 4.19 (AB, 1 H, J = 18 Hz), 3.60 (AB, 1 H, J = 18 Hz), 3.46-3.20 (m, 2 H). 13C NMR (50 MHz, CDCl3): δ = 160.4, 137.4, 136.4, 134.3, 131.4, 129.0, 128.6, 128.5, 128.1, 127.7, 126.6, 125.3, 121.9, 119.5, 118.1, 117.2, 110.9, 109.3, 104.8, 71.4, 61.9, 55.4, 48.4, 29.4,25.5. IR: 3388, 2848, 2219, 1612, 1489, 1467, 1453, 1302, 1234 cm-1. MS (EI, 70 eV): m/z = 404.4, 260.1, 233.1, 169.1, 91.5.

17

Procedure for Compound 5 (1.23 mmol scale).
Compound 4 (1 equiv) was dissolved in EtOH-pyridine (5 L/mol, 2:1) at r.t. Then, NaBH4 (5 equiv) was added and the reaction mixture was heated to 70 °C for 12 h. A second portion of NaBH4 (5 equiv) was added and the reaction mixture was stirred for additional 12 h at 70 °C. After completion, aq NH4Cl (5 L/mol) and CH2Cl2 (5 L/mol) were added. The organic layers were separated and the organic solvent was evaporated under reduced pressure to afford compound 5 in 97% yield; er 95.7:4.3. 1H NMR (200 MHz, CDCl3): δ = 7.56-7.03 (m, 11 H), 6.81 (d, 1 H, J = 8 Hz), 4.64 (t, 3 H, J = 9 Hz), 3.92 (AB, 1 H, J = 14 Hz), 3.42 (AB, 1 H, J = 14 Hz), 3.35-3.19 (m, 3 H), 3.00-2.61 (m, 3 H). MS (EI, 70 eV): m/z = 380.1, 355.1, 261.2, 260.1, 184.1, 91.0, 73.1. IR: 3406, 1614, 1488, 1307, 1241, 981 cm-1.

18

Procedure for Compound 6 (2.95 mmol scale).
See ref. 5f and 6b: 1H NMR (200 MHz, CDCl3): 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).

19

Procedure for Compound 7 (69 mmol scale).
Compound 6 (1 equiv) was partially dissolved in CH2Cl2 (5 L/mol) at r.t. After cooling at 0 °C, Et3N (1.5 equiv) was added followed by the dropwise addition over 10 min of (CF3CO)O (1.2 equiv) in CH2Cl2 (1 L/mol). After a 0.5 h stirring period, the reaction mixture was quenched with sat. NaHCO3. The organic layer was evaporated under reduced pressure to afford compound 7 in >95% yield.1H NMR (300 MHz, CDCl3): δ = 7.90 (br s, 1 H), 7.54 (d, 1 H, J = 7 Hz), 7.32-7.02 (m, 5 H), 6.82 (s, 1 H), 6.69 (d, 1 H, J = 8 Hz), 4.55 (t, 2 H, J = 9 Hz), 4.08 (m, 1 H), 3.55 (m, 1 H), 3.13 (t, 2 H, J = 9 Hz), 2.98 (m, 2 H). 13C NMR (150 MHz, CDCl3): δ = 160.5, 136.3, 130.4, 130.3, 128.9, 127.8, 126.2, 125.6, 122.5, 119.9, 118.2, 111.2, 109.4, 109.2, 71.5, 53.6, 45.9, 29.4, 22.2. 19F NMR (300 MHz, CDCl3): δ = -68.64.

20

Procedure for Compound 8 (44 mmol scale).
Confer ref. 6a, mixture of tautomers: 1H NMR (600 MHz, DMSO-d 6): δ = 10.94 (s, 1 H, 90%), 10.68 (s, 1 H, 10%), 7.62 (m, 1 H), 7.43 (m, 2 H), 7.30 (m, 1 H), 7.06 (s, 1 H), 6.89 (d, 1 H, J = 8 Hz), 6.73 (m, 1 H), 6.13 (s, 1 H, 90%), 6.02 (s, 1 H, 10%), 4.51 (t, 2 H, J = 9 Hz), 4.42 (m, 1 H), 3.55 (m, 1 H), 3.16 (m, 2 H), 3.02 (m, 1 H), 2.93 (m, 1 H). 13C NMR (150 MHz, DMSO-d 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.

21

Procedure for Compound 9 (12 mmol scale).
Compound 8 (1 equiv) was dissolved in EtOH (10 L/mol) at r.t. Then, KOH (2 equiv) dissolved in H2O was added to the reaction mixture. After a 16 h stirring period at r.t., sat. NH4Cl was added and the reaction mixture was extracted with EtOAc. The evaporation of the organic layer under reduced pressure afforded compound 9 in 90% yield. 1H NMR (400 MHz, DMSO): δ = 11.58 (s, 1 H), 8.13 (d, 1 H, J = 7.81 Hz), 7.61-7.53 (m, 2 H), 7.29 (ddd, 1 H, J = 8.12, 5.85, 2.14 Hz), 7.17 (s, 1 H), 7.07 (dd, 1 H, J = 8.31, 1.76 Hz), 6.73 (d, 1 H, J = 8.31 Hz), 5.38 (br s, 1 H), 4.50 (t, 2 H, J = 9.06 Hz), 4.18 (dd, 1 H, J = 12.97, 2.90 Hz), 4.02 (dd, 1 H, J = 12.97, 1.38 Hz), 3.60 (br s, 1 H), 3.13 (t, 2 H, J = 8.69 Hz). 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.

22

Enantioselective Enrichment of Compound 9 (33.35 mol scale).
Compound 9 (1 equiv) was dissolved in H2O (2 L/mol) at r.t. Then, aq HCl 34.5% w/w (0.09 L/mol) was dropwise added to the heterogeneous mixture. Afterwards, the reaction mixture was heated at 60 °C and 2-PrOH (0.54 L/mol) was added dropwise. After 30 min, the reaction mixture was cooled down to r.t. and stirred overnight. The reaction mixture was filtered and dried under reduced pressure. The obtained HCl salt was dissolved in EtOH (4 L/mol) at r.t. and aq NH3 50.5% w/w (0.1 L/mol) was added dropwise. After addition of H2O (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.

23

Procedure for RWJ387273 (2.5 mol scale).
In degassed THF (10 L/mol) under inert atmosphere, Pd2(dba)3 (0.04 equiv) was added followed by the addition of (±)-BINAP (0.09 equiv) at r.t. After stirring for 30 min, 2-bromopyridine (1.2 equiv) was added over 10 min. Finally, pyrroloquinolone 1 (1 equiv) and t-BuONa (2.5 equiv) were added and the mixture was allowed to warm up to 60 °C and kept at that temperature for 5 h. After cooling to r.t., dicalite (20 g/mol) was added and the mixture was filtered. The cake was washed with THF (2 L/mol). Then, H2O (8 L/mol) was added to the organic mixture, followed by aq HCl 34.5% w/w (0.275 L/mol). After stirring for 30 min at r.t., EtOAc (4.3 L/mol) was added and the mixture was stirred for another 15 min. The two layers were separated and the organic layer was discarded. Then, EtOAc (5.4 L/mol) was added to the aqueous layer, followed by the addition of aq NH3 50% w/w (0.26 L/mol). After stirring for 30 min, the aqueous layer was removed and the organic phase was evaporated to dryness. The desired pyrroloquinolone 2 (yield = 135%) was obtained with a quality of 66.1%, corresponding to an active yield of 89.2%. The ee of the R-enantiomer was 99%. The product contained 2530 ppm of residual Pd.
The obtained pyrroloquinolone was dissolved in MeOH (80 L/mol) at r.t. After heating to 60 °C, the mixture was stirred for 1 h at this temperature. Then, Norit A Supra (35 g/mol) and dicalite (3.5 g/mol) were added. The mixture was stirred for another 20 min and thereafter filtered. The cake was washed with MeOH (1.7 L/mol). The solvent was reduced to 10%, at 50 °C. Subsequently, MsOH (1.02 equiv), dissolved in MeOH (0.3 L/mol) was added over 10 min to the mixture. Finally, the solution was cooled down to 20 °C and stirred for 20 h. The mixture was filtered and the cake was washed with MeOH (0.5 L/mol). After drying for 45 h, R290629 were obtained (yield 80.5%) with a HPLC quality of 100% and >99.5:0.5 er. The amount of residual Pd was below 10 ppm.
Free base: 1H NMR (400 MHz, CD3OD): 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).

24

Analytical Method.
The progress of the reaction and the purity of the products were measured by HPLC, employing (Method A: LCC01/209/01/01) a 10 cm Hypersil BDS column (4.0 mm I.D., 3 µm spherical material, UV wavelength of 254 nm) at r.t. The elution gradient was 5% MeCN/95% NH4OAc (0.5% in H2O) ramping to 95% MeCN/5% NH4OAc (0.5% in H2O) over 16 min, at a flow rate of 1.2 mL/min, then kept 95% MeCN/5% NH4OAc (0.5% in H2O) 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.