The accelerated development of an optimized synthesis of 1,2,4-oxadiazoles: Application of microwave irradiation and statistical design of experiments

Tetrahedron Letters

Volumn 44, Issue 52, 2003, Pages 9337-9341

  Evans, Marc D ^a   Ring, Jessica ^a   Schoen, Adam ^a   Bell, Andrew ^b   Edwards, Paul ^b   Berthelot, Didier ^b   Nicewonger, Robb ^a   Baldino, Carmen M ^a  

^a ARQULE INC   (United States)

^b PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United Kingdom)

Author keywords

Amidoxime; Design of experiments; Microwave; Optimization; Oxadiazole

Indexed keywords

1,2,4 OXADIAZOLE DERIVATIVE;

ARTICLE; CHEMICAL REACTION; MICROWAVE IRRADIATION; SYNTHESIS;

EID: 0344010058     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2003.10.055     Document Type: Article

References (17)

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14. Characterization description: Equipment: All RP-HPLC-MS experiments were performed using a Shimadzu HPLC system consisting of two LC-10ADvp pumps, a LEAP Technologies auto-sampler, and an SCL-10A system controller, interfaced with a Waters ZQ mass spectrometer. Relative purity was assessed using an SPD-10A UV detector (@ 254nm) and a SEDEX 75 ELSD detector. The molecular weight of the compounds were confirmed using Electrospray ionization with positive ion detection. A mass spectrometer cone voltage of 20 volts was used for these experiments. HPLC columns: The Zorbax SB-C8 columns (4.6×30 mm columns, packed with 3.5 μm particles) were obtained from Mac-MOD. Chemicals: Water and acetonitrile were HPLC grade from EM Science. The trifluoroacetic acid was 99+% spectrophotometric grade from Aldrich. The HPLC eluents were prepared by adding 0.1% (vol/vol) trifluoroacetic acid to water (solvent A) and acetonitrile (solvent B).
15. Production procedure for library of 1,2,4-oxadiazoles. To a 0.25 M solution of carboxylic acid in DMF (800 μL, 0.2 mmol) was added a 0.25 M solution of HBTU in DMF (800 μL, 0.2 mmol) followed by neat N,N-diisopropylethylamine (82 μL, 0.47 mmol), and lastly a 0.25 M solution of amidoxime in DMF (800 μL, 0.2 mmol). After the mixture was irradiated in a Personal Chemistry Smith Workstation at 191°C for 2 min, the solvent was evaporated. The resulting oil was dissolved in dichloromethane (2 mL) and washed twice with water (2 mL). The solvent was evaporated to afford the crude product.
16. Purification conditions: Equipment: A Maccel semi-prep SH-C18 50×20 mm column was used. All compounds were purified using a Shimadzu HPLC system consisting of two LC-8A prep pumps, LC-10ADvp pump, SPD-10A UV detector, and an SCL-10A system controller. Two Gilson liquid handlers were used for injection and collection and a Micromass Platform LCZ mass spectrometer for detection. The Masslynx version 3.3 platform controlled the injections, tracked all data output, and interfaced with the Gilson Unipoint software to trigger the collection of fractions. Experimental conditions: Purification was done by RP-HPLC with MS trigger using a gradient of water (solvent A) and acetonitrile (solvent B) with 0.1% formic acid. Molecular weights were detected using positive electrospray ionization mode on the mass spectrometer with a cone voltage of 20 volts. These general conditions were applied across the set and not optimized for individual compounds.
17. 3): δ 2.48 (s, 3H), δ 7.39 (d, 2H, J=8 Hz), δ 8.11 (d, 2H, J=8 Hz), δ 8.17 (d, 2H, J=5 Hz), 8.85 (br, 2H).