Efficient Synthesis of the Immunomodulating Compound KRP-203

Abstract

A practical and concise synthesis of KRP-203 (1) was achieved by utilizing a palladium coupling reaction mediated by XantPhos and Pd₂(dba)₃ as the key step. The coupling reaction of aryl bromide 5 with 3-hydroxythiophenol (6) proceeded chemoselectively to give phenol 7 in spite of the presence of a chlorine substituent on 5 and a hydroxyl group on 6. Phenol 7 was converted into KRP-203 by benzylation and removal of the protecting groups in high yield.

Key words

palladium - cross-coupling - synthesis - KRP-203 - FTY720

References

• 1a Liu G. Link JT. Pei Z. Reilly EB. Leitza S. Nguyen B. Marsh KC. Okasinski GF. von Geldern TW. Ormes M. Fowler K. Gallatin M. J. Med. Chem.  2000,  43:  4025 
• 1b Wang Y. Chackalamannil S. Chang W. Greenlee W. Ruperto V. Duffy RA. McQuade R. Lachowicz JE. Bioorg. Med. Chem. Lett.  2001,  11:  891 
• 1c Bonnet B. Soullez D. Girault S. Maes L. Landry V. Davioud-Charvet E. Sergheraert C. Bioorg. Med. Chem.  2000,  8:  95 
• 2 Pinchart A. Dallaire C. Gingras M. Tetrahedron Lett.  1998,  39:  543 
• 3a Herradura PS. Pendola KA. Guy RK. Org. Lett.  2000,  2:  2019 
• 3b Savarin C. Srogl J. Liebeskind LS. Org. Lett.  2002,  4:  4309 
• 3c Bates CG. Gujadhur RK. Venkataraman D. Org. Lett.  2002,  4:  2803 
• 3d Paloma C. Oiarbide M. López R. Gómez-Bengoa E. Tetrahedron Lett.  2000,  41:  1283 
• 3e Kwong FY. Buchwald SL. Org. Lett.  2002,  4:  3517 
• 3f Schopfer U. Schlapbach A. Tetrahedron  2001,  57:  3069 
• 4 Shimizu H. Takahashi M. Kaneko T. Murakami T. Hakamata Y. Kudou S. Kishi T. Fukuchi K. Iwanami S. Kuriyama K. Yasue T. Enosawa S. Matsumoto K. Takeyoshi I. Morishita Y. Kobayashi E. Circulation  2005,  111:  222 
• 5 Kiuchi M. Adachi K. Kohara T. Minoguchi M. Hanano T. Aoki Y. Mishina T. Arita M. Nakao N. Ohtsuki M. Hoshino Y. Teshima K. Chiba K. Sasaki S. Fujita T. J. Med. Chem.  2000,  43:  2946 
• 6a Kahan BD. Karlix JL. Ferguson RM. Leichtman AB. Mulgaonkar S. Gonwa TA. Skerjanec A. Schmouder RL. Chodoff L. Transplantation  2003,  76:  1079 
• 6b Tedesco-Silva H. Mourad G. Kahan BD. Boira JG. Weimar W. Mulgaonkar S. Nashan B. Madsen S. Charpentier B. Pellet P. Vanrenterghem Y. Transplantation  2004,  77:  1826 
• 6c Kappos L. Antel J. Comi G. Montalban X. O’Connor P. Polman CH. Haas T. Korn AA. Karlsson G. Radue EW. N. Engl. J. Med.  2006,  355:  1124 
• 7a Mandala S. Hadju R. Bergstrom J. Quackenbush E. Xie J. Milligan J. Thornton R. Shei G. Card D. Keohane C. Rosenbach M. Hale J. Lynch CL. Rupprecht K. Parsons W. Rosen H. Science  2002,  296:  346 
• 7b Brinkmann V. Davis MD. Heise CE. Albert R. Cottens S. Hof R. Bruns C. Prieschl E. Baumruker T. Hiestand P. Foster CA. Zollinger M. Lynch KR. J. Biol. Chem.  2002,  277:  21453 
• 8 Sanna MG. Liao J. Jo E. Alfonso C. Ahn M. Peterson MS. Webb B. Lefebvre S. Chun J. Gray N. Rosen H. J. Biol. Chem.  2004,  279:  13839 
• 9 Fujishiro J. Kudou S. Iwai S. Takahashi M. Hakamata Y. Kinoshita M. Iwanami S. Izawa S. Yasue T. Hashizume K. Murakami T. Kobayashi E. Transplantation  2006,  82:  804 
• 10a Konishi Y, Ando N, Kuriyama K, Iwanami S, and Kudou S. inventors; PCT Int. Appl. WO  03/029205.  ; Chem. Abstr. 2003, 138, 304049
• 10b Tsubuki T, Kobayashi K, and Komatsu H. inventors; PCT Int. Appl. WO  2006/041019.  ; Chem. Abstr. 2006, 144, 412416
• 11a Fan Y, Gao W, Gray N, Terding K, Lefebvre S, Mi Y, Nussbaumer P, Pan S, Wang W, Zecri F, Perez LB, La Montagne KR, and Ettmayer P. inventors; PCT Int. Appl. WO  03/099192.  ; Chem. Abstr. 2003, 140, 4842
• 11b Kiuchi M, Kobayashi N, Sugahara K, and Nakamura M. inventors; PCT Int. Appl. WO  2006/129688.  ; Chem. Abstr. 2006, 146, 45290
• 12 Itoh T. Mase T. Org. Lett.  2004,  6:  4587