Versatile monitoring tools in parallel solid-phase synthesis

Chimia

Volumn 57, Issue 5, 2003, Pages 229-236

  Felder, Eduard R ^a   Martina, Katia ^b   Scarpella, Simona ^b   Tatò, Marco ^b  

^a PFIZER INC   (United States)

^b NONE

Author keywords

Chemiluminescent nitrogen detector; Combinatorial chemistry; High throughput analytics; Magic angle spinning NMR; Solid phase analytics

Indexed keywords

FORMYL RESIN; RESIN; UNCLASSIFIED DRUG;

AMINATION; ANALYTIC METHOD; ARTICLE; AUTOMATION; CHEMOLUMINESCENCE; COMBINATORIAL CHEMISTRY; DERIVATIZATION; DRUG IDENTIFICATION; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; INFRARED SPECTROSCOPY; LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; NITROGEN DETECTOR; NUCLEAR MAGNETIC RESONANCE; SOLID; SYNTHESIS;

EID: 0037705324     PISSN: 00094293     EISSN: None     Source Type: Journal    
DOI: 10.2533/000942903777679299     Document Type: Article

References (33)

1. a) SPORE Solid Phase Organic Reactions database vers. 2003.1, MDL Molecular Design Ltd., San Leandro, USA;
2. b) A. Scannell-Lansky, C. Zechel, in 'Combinatorial Chemistry - A Practical Approach', Ed. W. Bannwarth, E.R. Felder, Wiley-VCh, Weinheim, 2000, p. 329;
3. c) B.A. Bunin, 'The Combinatorial Index', Academic Press, San Diego, 1998.
4. M.A. Fivush, T.M. Willson, Tetrahedron Lett. 1997, 38, 7151.
5. 2O 1:1 (3 × 10 ml), THF (3 × 10 ml), and DCM (3 × 10 ml). The resin was dried under vacuum to constant weight.
6. 2O 1:1 (3 × 10 ml), THF (3 × 10 ml), and DCM (3 × 10 ml). A mixture of TFA/DCM 30% was added to the resins, and the suspensions were shaken for 2 h at rt. The resins were filtered and rinsed with appropriate solvents to a combined filtrate. The obtained crude product solutions were evaporated in a vacuum centrifuge to form amorphous residues. This being a test library, variable yields and product purities were obtained.
7. H.-U. Gremlich, Biotech. and Bioeng. (Comb. Chemistry) 1999, 61, 179.
8. FTIR: KBr pellet method: The resin was finely mixed with pure, dry (spectroscopic grade) KBr (resin contents of formulation: ∼1%), and then pressed to a clear disk. The sample measurement was performed on a Perkin Elmer Spectrum 1000 FTIR spectrometer.
9. H.-U. Gremlich, in 'Ullmann's Encyclopedia of Industrial Chemistry', vol. B5, Wiley-VCh, Weinheim, 1994.
10. ATR/FTIR: Our spectra are acquired on a Thermo Nicolet Avatar 36 FTIR instrument. This attenuated total reflection spectroscopy system allows the analysis of a minimal quantity of pressed resin beads (50-100 beads) without using the KBr dilution.
11. T. Wehler, J. Westman, Tetrahedron Lett. 1996, 37, 4771.
12. a) P.A. Keifer, L. Baltusis, D.M. Rice, A.A. Tymiak, J.N. Shoolery, J. Magn. Reson., Ser. A 1996, 119, 65;
13. b) P.A. Keifer, Drug Discovery Today 1997, 2, 468;
14. c) M.J. Shapiro, J.S. Gounarides, Prog. Nucl. Magn. Reson. Spectr. 1999, 35, 153.
15. 2) and placed into the nanoprobe tube; the spinning rate was approximately 2.5 kHz for all samples.
16. a) S. Meiboom, D. Gill, Rev. Sci. Instrum. 1958, 29, 688;
17. b) R. Freeman, 'A Handbook of Nuclear Magnetic Resonance', Longman Scientific Technical, Harlow, 1987, p. 262.
18. a) W. Willker, D. Leibfritz, R. Kerssebaum, W. Bermel, Magn. Reson. Chem. 1993, 31, 287;
19. b) T.D.W. Claridge, 'High-Resolution NMR Techniques in Organic Chemistry', Tetrahedron Organic Chemistry Series Vol. 19, Pergamon, London, 1999, p. 221.
20. M. Rance, O.W. Sorensen, G. Bodenhausen, G. Wagner, R.R. Ernst, K. Wüthrich, Biochem. Biophys. Res. Commun. 1983, 117, 479.
21. 3 functions, nor from the aromatic and aliphatic protons of the resin (e.g. compare the region from 6.5 to 7.5 ppm of Fig. 3 vs. Fig. 4).
22. The Vnmr Varian software allows the deconvolution of observed spectra into individual Lorentzian and/or Gaussian lines using the Levenberg-Marquart method for curve fitting; see 'Modeling of Data' (Chapter 14, p. 542) in W.H. Press, B.P. Flannery, S.A. Teukolsky, W.T. Vetterling, 'Numerical Recipes in C, The Art of Scientific Computing', Cambridge University Press, 1988. Up to 2048 data points from an expansion of an experimental spectrum can be deconvoluted at one time, and up to 25 lines can be fit to this section of the observed spectrum. For each line it is possible to have a quite precise value of the relative integral.
23. V. Pinciroli, R. Biancardi, N. Colombo, M. Colombo, V. Rizzo, J. Comb. Chem. 2001, 3, 434.
24. 6 directly in the NMR tube. The concentration ratio of silane to analyte species is 1:18, which exactly compensates for the 18 protons of the trimethylsilyl groups present in the reference signal.
25. 2O (P.A. Keifer et al., see above). 64 scans + 8 dummy scans, and a repetition rate of 6 s were used for each spectrum, all adding up to an NMR measurement time of 7.2 min per sample (total recycle time ∼10 min). Exponential line broadening (1 Hz) zero filling was applied to all spectra.
26. 2O (P.A. Keifer et al., see above). 64 scans + 8 dummy scans, and a repetition rate of 6 s were used for each spectrum, all adding up to an NMR measurement time of 7.2 min per sample (total recycle time ∼10 min). Exponential line broadening (1 Hz) zero filling was applied to all spectra.
27. 2O/acetonitrile 5:95; the gradient runs from 10 to 90% B in 8 min, then holds 90% B for 2 min. The injection volume is 10 μl. The mass spectrometer is operated in positive and in negative ion mode, with the capillary voltage set to 2.5 KV; the source temperature is 120°C; the cone is 10 V; full scan, mass range set from 100 to 800 amu.
28. J.N. Kyranos, J.C. Hogan, Anal. Chem. 1998, 70, 389A.
29. a) E.W. Taylor, M.G. Qian, G.D. Dollinger, Anal. Chem. 1998, 70, 3339;
30. b) N. Shah, M. Gao, K. Tsutsui, A. Lu, J. Davis, R. Scheuerman, W. Fitch, R. Wilgus, J. Comb. Chem. 2000, 2, 453;
31. c) D. Yurek, D.L. Branch, M.-S. Kuo, J. Comb. Chem. 2002, 4, 138.
32. Our HPLC-CLND system consists of a Waters 2790 Alliance Separation Module interfaced with a UV detector with dual wavelength (set to 220 nm) and with a Micromass ZQ single quadrupole mass detector with ESI interface. The flow rate is set to 1 ml/min and split after the column in order to have a flow of 100 μl/min into the nitrogen detector and 100 μl/min into the mass detector. The chemiluminescent nitrogen detector is an Antek 8060. The furnace temperature is 1050°C, the argon flow is 65 ml/min with an oxygen flow of 273 ml/min. The reaction chamber pressure is maintained at 25 Torr by the vacuum pump and the ozone flow is 30ml/min. Zorbax SB C8 (4.6 × 50 mm, 5 μm) analytical columns are used and the injection volume is 10 μl. The column is eluted with a linear gradient from 5 to 95% buffer B in 10 min. Buffer A is 0.01% (v/v) formic acid (FA) in water; buffer B is 0.01% (v/v) FA in MeOH.
33. The CLND was calibrated using a caffeine standard (99% from Aldrich) at different concentrations (100, 200, 400 and 800 μM). Each standard soln. was run at least in triplicates.