LETTER
Synthetic Optimization of PF-00868554
799
coupling,13 dihydropyrone 19 reacted with aldehyde 12 in tion of PF-00868554 (1) in a 27% overall yield without
the presence of pyridine–borane complex in methanol at 0 the requirement of column purification, which has provid-
°C to provide crude compound 1. Because the carbon- ed multigram quantities of material which supported pre-
linked dihydropyrone 1 is mildly acidic, it can be effec- clinical studies.
tively extracted into a basic aqueous solution. After wash-
ing the aqueous layers with diethyl ether and acidification
with AcOH, the crude product was extracted into EtOAc
Acknowledgment
The authors would like to thank Drs. Robert Scott and Cristina
Lewis for their help when carrying out this work. We would also
like to thank Drs. Peter Dragovich and Siegfried Reich for their sup-
port and Dr. Robert Kania for helpful discussion during the prepa-
ration of this manuscript.
and further crystallized to provide the desired product in
75% yield with over 95% purity.
O
OH
O
O
O
ii
i
HO
OH
+
22
References and Notes
O
N
iii
O
25
24
(1) Sarbah, S. A.; Younossi, Z. M. J. Clin. Gastroenterol. 2000,
30, 125.
23
O
O
O
(2) Hayashi, N.; Takehara, T. J. Gastroenterol. 2006, 41, 17.
(3) Lohmann, V.; Korner, F.; Koch, J.; Herian, U.; Theilmann,
L.; Bartenschlager, R. Science 1999, 285, 110.
OBn
Br
iv
OH
N
(4) Li, H.; Tatlock, J.; Linton, A.; Gonzalez, J.; Jewell, T.; Patel,
L.; Ludlum, S.; Drowns, M.; Rahavendran, S. V.; Skor, H.;
Hunter, R.; Shi, S. T.; Herlihy, K. J.; Parge, H.; Hickey, M.;
Yu, X.; Chau, F.; Nonomiya, J.; Lewis, C. J. Med. Chem.
2009, 52, 1255.
N
7
17
OEt
O
O
v
(5) Li, H.; Tatlock, J.; Linton, A.; Gonzalez, J.; Borchardt, A.;
Dragovich, P.; Jewell, T.; Prins, T.; Zhou, R.; Blazel, J.;
Parge, H.; Love, R.; Hickey, M.; Doan, C.; Shi, S.; Duggal,
R.; Lewis, C.; Fuhrman, S. Bioorg. Med. Chem. Lett. 2006,
16, 4834.
O
OH
vi
OH
OH
N
N
(6) Li, H.; Linton, A.; Tatlock, J.; Gonzalez, J.; Borchardt, A.;
Abreo, M.; Jewell, T.; Patel, L.; Drowns, M.; Ludlum, S.;
Goble, M.; Yang, M.; Blazel, J.; Rahavendran, R.; Skor, H.;
Shi, S.; Lewis, C.; Fuhrman, S. J. Med. Chem. 2007, 50,
3969.
(7) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467.
(8) Camp, D.; Matthews, C. F.; Neville, S. T.; Rouns, M.; Scott,
R. W.; Truong, Y. Org. Process Res. Dev. 2006, 10, 814.
(9) Jeffery, T. J. Chem. Soc., Chem. Commun. 1984, 1287.
(10) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100,
3009.
(11) Deshapande, S. S. J. Indian Chem. Soc. 1932, 9, 303.
(12) Experimental Conditions of Optimized Heck Coupling
and Product Characterization
26
1
27
vii
O
viii
O
O
N
19
Scheme 3 Optimized synthesis of PF-00868544. Reagents and con-
ditions: (i) 1. H2SO4, 100 °C; 2. Na2SO4, 100 °C; 3. HCl, 100 °C; (ii)
NH4OH, 50 °C, 80% over 4 steps; (iii) POBr3, DMF, 120 °C, 88%;
(iv) 15, Pd(OAc)2, Bu4NCl, dicyclohexylmethylamine, DMAC, 90
°C; (v) H2, Pd/C, EtOH, 65% over 2 steps; (vi) CDI, ethyl magnesium
malonate, 1 N HCl, MTBE; (vii) K2CO3, MeOH, 80% over 2 steps;
(viii) 12, pyridine·BH3, MeOH, 0 °C, 75%.
To a solution of benzyl ester 15 (1.30 g, 4.74 mmol) in
DMAC (11 mL) in a two-neck round-bottomed flask was
added 4-bromo-2,6-diethylpyridine (7, 1.22 g, 5.69 mmol),
followed by TBACl (1.30 g, 4.74 mmol), and Pd(OAc)2. The
resulting solution was degassed by house vacuum followed
by argon back filling (3×). Dicyclohexylmethylamine (2.0
mL, 9.50 mmol) was added, and the reaction vessel was
lowered into a pre-heated oil bath at 90 °C. The reaction was
stirred at this temperature under argon until all benzyl ester
15 was consumed (about 5 h). The solution was cooled to r.t.,
diluted with H2O (60 mL) and then extracted with MTBE
(2 × 50 mL). The combined organic layers were washed with
H2O (2 × 50 mL), sat. NaHCO3 (50 mL), 5% aq AcOH (50
mL), then brine (sat., 50 mL). The yellow solution was dried
(MgSO4), filtered, and concentrated to provide a crude
amber oil (2.1 g). 1H NMR (300 MHz, CDCl3): d = 1.26–
1.32 (m, 6 H), 1.48–1.64 (m, 8 H), 2.71–2.74 (m, 2 H), 2.75–
2.84 (m, 5 H), 5.02–5.07 (m, 1 H), 5.10–5.12 (m, 1 H), 6.35–
6.42 (m, 1 H), 6.51–6.59 (m, 1 H), 6.89 (s, 2 H), 7.22–7.26
(m, 5 H). MS (APCI): m/z = 408.20 [M + H]+.
In conclusion, an optimized synthetic route to prepare
gram quantities of PF-00868554 (1) has been developed.
By using a precedented pyridine synthesis through a py-
rone intermediate, the use of a potentially dangerous high-
energy N-oxide 5 was eliminated, and the overall yield of
pyridine 7 was improved from 14% to 70%. The late-stage
chiral separation was replaced by an early introduction of
an optically pure Heck coupling partner 15. Substitution
of LiCl with Bu4NCl effectively suppressed the formation
of the undesired retro-aldol side product in the Heck reac-
tion and provided olefin 17 in high yields. Finally, utiliza-
tion of milder base (pyridine–borane) under lower
reaction temperature successfully improved the reductive
condensation between dihydropyrone 19 and aldehyde 12
to 75% yield. The new synthetic sequence led to prepara-
Synlett 2010, No. 5, 796–800 © Thieme Stuttgart · New York