Microwave-enhanced nucleophilic fluorination in the synthesis of fluoropyridyl derivatives of [3,2-c]pyrazolo-corticosteroids, potential glucocorticoid receptor-mediated imaging agents

Bioorganic and Medicinal Chemistry Letters

Volumn 16, Issue 13, 2006, Pages 3454-3458

  Kahn, Michael G C ^a   Konde, Emmanuel ^a   Dossou, Francis ^a   Labaree, David C ^b   Hochberg, Richard B ^b   Hoyte, Robert M ^a,b  

^a STATE UNIVERSITY OF NEW YORK   (United States)

^b YALE CANCER CENTER   (United States)

Author keywords

Glucocorticoid imaging agents; Microwave enhancement; Nucleophilic fluorination; Steroid pyrazoles

Indexed keywords

2' (2 FLUORO 4 PYRIDYL) 11BETA,17,21 TRIHYDROXY 16ALPHA METHYL 20 OXO PREGN 4 ENO [3,2 C] PYRAZOLE; [3,2 C]PYRAZOLO CORTICOSTEROID DERIVATIVE; CHLOROPYRIDYL; FLUORINE 18; FLUOROPYRIDYL DERIVATIVE; GLUCOCORTICOID; GLUCOCORTICOID RECEPTOR; HALOGEN; ISOTOPE; PYRAZOLE DERIVATIVE; PYRIDINE DERIVATIVE; STEROID; UNCLASSIFIED DRUG;

ARTICLE; BIOLOGICAL ACTIVITY; CHEMICAL STRUCTURE; DRUG SYNTHESIS; FLUORINATION; HEATING; IMAGING; MICROWAVE RADIATION; POSITRON EMISSION TOMOGRAPHY; SYNTHESIS;

ADRENAL CORTEX HORMONES; FLUORINE; GLUCOCORTICOIDS; KINETICS; MICROWAVES; MOLECULAR STRUCTURE; POSITRON-EMISSION TOMOGRAPHY; PREGNENES; PYRAZOLES; PYRIDINES; RECEPTORS, GLUCOCORTICOID; SENSITIVITY AND SPECIFICITY; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33646842866     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.04.008     Document Type: Article

References (11)

1. Hoyte R.M., Zhang J., Lerum R., Oluyemi A., Persaud P., O'Connor C., Labaree D.C., and Hochberg R.B. J. Med. Chem. 45 (2002) 5397
2. Kilbourn M.R. Flourine-18 labelling of radiopharmaceuticals (1990), National Academy Press, Washington, DC 22-35
3. Liveris M., and Miller J. J. Chem. Soc. (1963) 3486
4. Kappe C.O. Angew. Chem., Int. Ed. 43 (2004) 6250
5. Dolce F., Dolle F., Jubeau S., Vaufrey F., and Crouzel C. J. Labelled Compd. Radiopharm. 42 (1999) 975
6. Dolle F., Dolce F., Valette H., Hinnen F., Vaufrey F., Guenther I., Fuseau C., Coulon C., Bottlaender M., and Crouzel C. J. Med. Chem. 42 (1999) 2251
7. Kumar P., Wiebe L.I., Asikoglu M., Tandon M., and McEwan A.J. Appl. Radiat. Isot. 57 (2002) 697
8. 4: 495.2606, found: 495.2602.
9. Wust F., Carlson K.E., and Katzenellenbogen J.A. Steroids 68 (2003) 177
10. Fluorination reactions were carried out using 5 mg (0.009 mmol) of chloropyridyl compound, 10 mg (0.027 mmol) kryptofix-222, and 5.4 mg (0.093 mmol) KF in 0.5 mL DMSO. In reactions studied using conventional heating the reactants were mixed in a screw-capped test tube that was closed and then heated with stirring in an oil bath at the indicated temperature (Table 2). Reaction progress was monitored by withdrawing small aliquots, which were diluted in methanol and analyzed for fluorinated product by high-performance liquid chromatography (HPLC): Beckman System Gold (Model 126 modular pumps and Model 168 diode-array detector) with 32Karat Software using a 25 cm × 4.4 mm Ultrasphere-ODS column eluted at 1 mL/min with 70% or 85% methanol-water. UV detection was at 270 nm. In reactions studied using microwave heating the reactants were mixed in a 10 mL conical flask fitted with a condenser and mounted in the cavity of a CEM Discover microwave reactor. The reactor was operated with stirring in open-vessel mode under constant temperature conditions. The temperature was maintained by a combination of compressed air cooling and applied microwave power. For example, to maintain a temperature of 130 °C, typically required about 80 W with compressed air at 40 psi. Reaction progress was monitored by withdrawing small aliquots by syringe through narrow bore Teflon tubing extending through the top of the condenser into the reaction vessel. The aliquots were diluted with methanol and analyzed by HPLC as described above. Kinetic data for these reactions were obtained from concentrations of fluorinated products computed at various time points using integration data from the HPLC analyses above.
11. Snyder S.E., and Kilburn M.R. In: Welch M.J., and Redvanly C.S. (Eds). Handbook of Radiopharmaceuticals: Radiochemistry and Applications (2003), Wiley, West Sussex, UK 195-227