Organic Process Research & Development
Article
warm to room temperature; the stirring was continued for 2 h.
For work up the reaction had been quenched/neutralized by
addition of aqueous 2 N HCl (1.4 equiv). The reaction mixture
was reduced in volume under reduced pressure, and the residue
was taken up in ethyl acetate. The organic layer was washed twice
with water. The solvent was removed under high vacuum, and
the residue was crystallized from ethanol to yield 8 (50 g, 65%) as
a colorless solid.
Table 1. List of Compounds Prepared
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
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S
1H and 13C NMR spectra of compound 8, 13, 15, 17, 19,
and 21 and general procedure for the synthesis (PDF)
AUTHOR INFORMATION
Corresponding Author
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Mario Conde and Tizian Mueller for experimental
support during their internship.
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REFERENCES
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S.; Dedio, J.; Shimshock, S.; Lanter, C. Inhibitors of CXCR2.
WO2008000407, 2008. Hachtel, S.; Dedio, J.; Pernerstorfer, J.;
Shimshock, S.; Lanter, C.; Kosley. R. W. CXCR2 Antagonists
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Grueneberg, S.; Heitsch, H.; Bock, W.; Chen, C.; Kosley. R.; Kung,
C.-Y.; Patek, M.; Sher, R.; Shimshock, S.; Weichsel, A. New CXCR2
Inhibitors. WO2008000409, 2008. (d) Hachtel, S.; Dedio, J.;
Pernerstorfer, J.; Shimshock, S.; Lanter, C. CXCR2 Inhibitors.-
WO2008000410, 2008.
constitutes a rapid access to methyl-1-hydroxy-2-naphthoate
derivatives and heterocyclic analogues. The chemistry is both
short and efficient, but at the same time also highly variable, thus
allowing the preparation of analogues. We believe that this type
of work is a good example for the importance of synthetic
chemistry in the drug discovery process, enabling both a rapid
access to chemical space and the preparation of larger amounts of
material, enabling the full assessment of the resulting compounds
as suitable drug candidates. This concept is certainly not limited
to the given examples and should prove valuable for the
preparation of further analogues.
(2) Ding, W.; Pu, J.; Zhang, C. Synthesis 1992, 1992, 635−637.
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EXPERIMENTAL SECTION
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Synthesis of 6-Fluoro-2-(methoxycarbonyl)-1-hydrox-
ynaphthalene (8). Methyl 2-bromo-4-fluorobenzoate 9 (81 g,
0.35 mol), methyl 3-butenoate 10 (52.2 g, 1.5 equiv, 0.52 mol),
and N,N-dicyclohexylmethylamine (150 g, 160 mL, 2.2 equiv,
0.76 mol) were dissolved in dioxane (800 mL), and the solution
was thoroughly degassed with argon. Fluoroboric acid tri-tert-
butylphosphine adduct (0.03 equiv., 2.8 g, 10 mmol) were added,
and the solution was heated to 50 °C. After 10 min
tris(dibenzylideneacetone)dipalladium(0) (3.18 g, 0.01 eq.,
3.48 mmol) was added, and the reaction mixture was stirred
overnight at 110 °C. For workup dioxane was removed under
reduced pressure, and the residue was taken up in ethyl acetate.
The solution was then filtered through a small glass frit with silica
gel, and the silica gel was washed with ethyl acetate. The
combined organic phase was washed twice with 1 N HCl,
saturated NaHCO3, and water. The solvent was then removed
under reduced pressure, and the residue was dried under high
vacuum to yield the crude Heck product 11a/b.
́ ́
(6) (a) Esteban, G.; Lopez-Sanchez, M. A.; Martinez, M. E.; Plumet, J.
Tetrahedron 1998, 54, 197−212. (b) Alcock, S. G.; Baldwin, J. E.;
Bohlmann, R.; Harwood, L. M.; Seeman, J. I. J. Org. Chem. 1985, 50,
3526−3535.
(7) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989−7000.
(8) We are aware that dioxane is not an ideal solvent for large-scale
work and is generally easily replaced by performing the reaction with,
e.g., THF under a slight pressure, but the convenience of the high boiling
point of dioxane outweighed the disadvantages for this stage of
development.
The residue was taken up in anhydrous THF (800 mL), and
the solution was cooled to 5 °C. Potassium tert-butoxide (54 g,
485 mmol, 1.4 equiv) was added, and the solution was allowed to
C
Org. Process Res. Dev. XXXX, XXX, XXX−XXX