Organic Process Research & Development
Article
(8) No literature reference was found for preparation of N-amino-
2,3-pyrrole dicarboxylates. A few methods are reported to prepare N-
alkyl-2,3-pyrrole dicarboxylates. For an approach utilizing dipolar
cycloaddition, see: Katritzky, A. R.; Yao, J.; Bao, W.; Qi, W.; Steel, P. J.
J. Org. Chem. 1999, 64, 346−350. For preparation from functionalized
diazoacetates and enol ether, see: Hoffmann, M. G.; Wenkert, E.
Tetrahedron 1993, 49, 1057−1062. For other miscellaneous methods,
AUTHOR INFORMATION
Corresponding Author
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
see: Roder, E.; Wiedenfeld, H.; Bourauel, T. Liebigs Ann. Chem. 1987,
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1117−1119. Chadwick, D. J.; Hodgson, S. T. J. Chem. Soc., Perkin
We thank Dr. Su Pan for developing the HPLC analytical
methods and Dr. Simon Leung for the chemical safety
evaluation of compound 20. We also acknowledge Drs.
Thomas Razler, Ian Young, Adrian Ortiz, and Jaan Pesti for
helpful discussions, together with Chemical Development
senior management for support during the preparation of the
manuscript.
Trans. 1 1982, 1833−1836.
(9) (a) Migliara, O.; Petruso, S.; Sprio, V. J. Heterocycl. Chem. 1979,
16, 833−834. (b) Migliara, O.; Petruso, S.; Sprio, V. J. Heterocycl.
Chem. 1979, 16, 1105−1107.
(10) Dastrup, D. M.; Yap, A. H.; Weinreb, S. M.; Henry, J. R.;
Lechleiter, A. J. Tetrahedron 2004, 60, 901−906.
(11) Compound 20 is Ames positive, an eye irritant, and a sensitizer
and should be handled with caution.
REFERENCES
(12) It has been reported that protic solvents favored C-alkylation,
and O-alkylated products were the major product in polar aprotic
solvents for the alkyation of cyclopentan-1,3-diones. See: Schick, H.;
Schwarz, H.; Finger, A.; Schwarz, S. Tetrahedron 1982, 38, 1279−1283.
In our case, the protic solvents provided slightly higher (∼20:1)
selectivity of the desired C-alkylation over O-alkylation, but product
21 was formed in lower yield due to the increased formation of the
bisalkyl impurity (Table 1, entries 1 and 2).
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(1) (a) Schroeder, G. M.; Chen, X.-T.; Williams, D. K.; Nirschl, D. S.;
Cai, Z.-W.; Wei, D.; Tokarski, J. S.; An, Y.; Sack, J.; Chen, Z.; Huynh,
T.; Vaccaro, W.; Poss, M.; Wautlet, B.; Gullo-Brown, J.; Kellar, K.;
Manne, V.; Hunt, J. T.; Wong, T. W.; Lombardo, L. J.; Fargnoli, J.;
Borzilleri, R. M. Bioorg. Med. Chem. Lett. 2008, 18, 1945−1951 and
references therein. (b) Fink, B. E.; Gavai, A. V.; Vite, G. D.; Chen, P.;
Mastalerz, H.; Norris, D. J.; Tokarski, J. S.; Zhao, Y.; Han, W.-C. WO/
2005/066176, 2005. (c) Gavai, A. V.; Chen, P.; Norris, D.; Fink, B. E.;
Mastalerz, H.; Zhao, Y.; Han, W.-C.; Zhang, G.; Johnson, W.;
Ruediger, E.; Dextraze, P.; Daris, J.-P.; Kim, S.-H.; Leavitt, K.; Kim, K.;
Lu, S.; Zheng, P.; Mathur, A.; Vyas, D.; Tokarski, J. S.; Yu, C.;
Oppenheimer, S.; Zhang, H.; Lee, F.; Wong, T. W.; Vite, G. D.
Abstracts of Papers of 233rd National Meeting of the American Chemical
Society; American Chemical Society: Washington, DC, March 2007;
MEDI-017. (d) Gavai, A. V.; Han, W.-C.; Chen, P.; Ruediger, E. H.;
Mastalerz, H.; Fink, B. E.; Norris, D. J. U.S. Pat. 7,064,203, 2006.
(2) (a) Hunt, J. T.; Mitt, T.; Borzilleri, R.; Gullo-Brown, J.; Fargnoli,
J.; Fink, B.; Han, W.-C.; Mortillo, S.; Vite, G.; Wautlet, B.; Wong, T.;
Yu, C.; Zheng, X.; Bhide, R. J. Med. Chem. 2004, 47, 4054−4059.
(b) Mastalerz, H.; Chang, M.; Gavai, A.; Johnson, W.; Langley, D.;
Lee, F. Y.; Marathe, P.; Mathur, A.; Oppenheimer, S.; Tarrant, J.;
Tokarski, J. S.; Vite, G.; Vyas, D. M.; Wong, H.; Wong, T. W.; Zhang,
H.; Zhang, G. Bioorg. Med. Chem. Lett. 2007, 17, 2828−2833.
(13) Per the Sigma-Aldrich product label.
(14) We discovered that the source and quality of sodium
diethyloxalacetate had an impact on the impurity profile and reaction
yield. To distinguish between different lots, the pH of an aqueous
solution (1.0 g of the salt in 25 mL of water) of sodium
diethyloxalacetate was measured. Batches of sodium diethyloxalacetate
that produced an aqueous solution with pH > 9.5 led to higher levels
of the bisalkyl impurity and lower yields. These batches required
additional acetic acid (>0.12 equiv) to produce levels of the bisalkyl
impurity and yields similar to batches of diethyloxalacetate that
provided aqueous solutions with a pH < 9.5.
(15) The proton NMR analysis of 21 (after chromatographic
purification) clearly reveals that it is a keto form, not an enol, as a
double doublet pattern of the α-proton of the ketone 21 at δ 3.1 ppm
(see the Experimental Section). In addition, only one peak was
observed for 21 in the HPLC chromatogram.
(16) Less than 1% potency loss of 21 was observed after holding the
reaction stream for 48 h at room temperature. No potency loss of 22
in the toluene stream after aqueous workup was observed after one
week at ambient temperature. However, the reaction stream of 22
without aqueous workup shows about 1% loss of product potency after
19 h at ambient temperature and 6% loss after 4 days.
(17) Upon scaling this protocol, an emulsion layer was observed
which needed to be set aside and further processed to recover the
product pyrrole. Additional lab development work on this step
determined that replacing toluene with isopropyl acetate as the solvent
in the telescoped sequence eliminated the formation of the emulsion.
(18) When utilizing 22 in the isopropyl acetate stream, we found that
water content played an important role. When the KF was >3 wt %,
the hydrogenolysis was complete within 2 h with no impact on the
impurity profile. The use of isopropyl acetate removed the periodic
venting that was necessary with toluene. Once complete, the solution
was filtered, concentrated, and azetropically dried to obtain a water
concentration of <1 wt %. This was crucial for the crystallization of
MSA salt of 23 as with >1.5 wt % water oiling occurred which fouled
the isolation.
(3) For references regarding the preparation of trisubstituted pyrrole
4, see: (a) Selic,
̌
L.; Stanovnik, B. Synthesis 1999, 479−482. (b) Svete,
J.; Aljaz-Rozic, M.; Stanovnik, B. J. Heterocycl. Chem. 1997, 34, 177−
̌
̌
̌
193. (c) Hamamoto, I. Jpn. Kokai Tokkyo Koho (1996), JP 08059611 A
19960305 Heisei. For amination of pyrrole 4 to 5, see: (d) Parlanti,
L.; Discordia, R. P.; Hynes, J., Jr.; Miller, M. M.; O’Grady, H. R.; Shi,
Z. Org. Lett. 2007, 9, 3821−3824. (e) Hynes, J., Jr.; Doubleday, W. W.;
Dyckman, A. J.; Godfrey, J. D., Jr.; Grosso, J. A.; Kiau, S.; Leftheris, K.
J. Org. Chem. 2004, 69, 1368−1371.
(4) Fink, B. E.; Vite, G. D.; Mastalerz, H.; Kadow, J. F.; Kim, S.-H.;
Leavitt, K. J.; Du, K.; Crews, D.; Mitt, T.; Wong, T. W.; Hunt, J. T.;
Vyas, D. M.; Tokarski, J. S. Bioorg. Med. Chem. Lett. 2005, 15, 4774−
4779.
(5) Hynes, J., Jr.; Dyckman, A. J.; Lin, S.; Wrobleski, S. T.; Wu, H.;
Gillooly, K. M.; Kanner, S. B.; Lonial, H.; Loo, D.; McIntyre, K. W.;
Pitt, S.; Shen, D. R.; Shuster, D. J.; Yang, X.; Zhang, R.; Behnia, K.;
Zhang, H.; Marathe, P. H.; Doweyko, A. M.; Tokarski, J. S.; Sack, J. S.;
Pokross, M.; Kiefer, S. E.; Newitt, J. A.; Barrish, J. C.; Dodd, J.;
Schieven, G. L.; Leftheris, K. J. Med. Chem. 2008, 51, 4−16 and
references therein.
(6) Cai, Z.-w.; Wei, D.; Borzilleri, R. M.; Qian, L.; Kamath, A.;
Mortillo, S.; Wautlet, B.; Henley, B. J.; Jeyaseelan, R., Sr.; Tokarski, J.;
Hunt, J. T.; Bhide, R. S.; Fargnoli, J.; Lombardo, L. J. Bioorg. Med.
Chem. Lett. 2008, 18, 1354−1358.
(7) Kim, M.; Vedejs, E. J. Org. Chem. 2004, 69, 7262−7265. For
reductions of pyrrole 3-carboxylates with DIBALH, see: Kinugawa,
M.; Masuda, Y.; Arai, H.; Nishikawa, H.; Ogasa, T.; Tomioka, S.; Kasai,
M. Synthesis 1996, 633−636.
(19) Charles, I.; Latham, D. W. S.; Hartley, D.; Oxford, A. W.;
Scopes, D. I. C. J. Chem. Soc., Perkin Trans. 1 1980, 1139−1146.
(20) Addition of 1 equiv of TEA, which fully neutralized the MSA,
slowed the acid-catalyzed annulation.
(21) During a stress test of the reaction in isopropanol, the isopropyl
derivative of 12, resulting from the ester exchange, was observed at
<0.1 HPLC AP after holding the mixture at 80 °C for 12 h. For a
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