A convenient 'catch and release' synthesis of fused 2-alkylthio-pyrimidinones mediated by polymer-bound BEMP

Tetrahedron Letters

Volumn 44, Issue 27, 2003, Pages 5041-5045

  Adams, Gregory L ^a   Graybill, Todd L ^a   Sanchez, Robert M ^a   Magaard, Victoria W ^a   Burton, George ^a   Rivero, Ralph A ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

2 tert butylimino 2 diethylamino 1,3 dimethyl perhydro 1,3,2 diazaphosphorine; Parallel synthesis; Quinazolin 4 one; Quinazolinone; Solid supported reagents; Thienopyrimidinone

Indexed keywords

2 TERT BUTYLIMINO 2 DIETHYLAMINO 1,3 DIMETHYLPERHYDRO 1,3,2 DIAZAPHOPHORINE; BASE; POLYMER; POLYSTYRENE; PYRIMIDINONE DERIVATIVE; REAGENT; RESIN; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL BOND; CHEMICAL ENGINEERING; CHEMICAL REACTION KINETICS; METHODOLOGY; REACTION ANALYSIS; SUBSTITUTION REACTION; SYNTHESIS;

EID: 0037505221     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(03)01188-2     Document Type: Article

References (30)

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18. To our knowledge, DMSO has never been reported as a preferred solvent for quinazolinone ring formation.
19. Advantages include clean and reliable conversion, excellent solubility of reagents and intermediates, minimal evaporative solvent loss during long periods of heating, and compatibility with the 'release' and purification steps.
20. In our previous work with P-BEMP sequestered 3-thio-1,2,4-triazoles, ACN was an optimal solvent when employing alkyl halides and ethanol was optimal for nucleophilic epoxide ring opening. To our surprise, use of ACN for preparation of 9 frequently is problematic owing to poor product solubility in ACN. Further, epoxide ring opening in ethanol provides products 10 with low purity (<40%). In contrast, S-alkylation of ion-pair 4 in DMSO is reliable with both alkyl halides and epoxides. While use of DMSO in the 'release' step (for both epoxides and alkylating agents) does require introduction of a purification step, a single, robust, production protocol (with fewer product solubility issues and high success rates) is very convenient.
21. Although not emphasized in this report, the corresponding 2-thioxo-2,3-dihydro-1H-quinazolin-4-ones 3 are also obtained in excellent purity (70-100%) after treatment of 4 with dilute AcOH/ACN solution.
22. 2O containing 0.02% TFA (3.6 min gradient) and monitored at 214 nm using a UV detector and by a SEDEX 75 evaporative light scattering detector (ELSD) operating at 42°C. LCMS M+H signals were consistent with expected MW for all reported products.
23. Purification was carried out using a semipreparative YMC Combiprep ODS-A reversed-phase column (20 mm×50 mm, particle size S-5 μm, 750 μL injection volume) via use of a 10-95% gradient of water/acetonitrile (4 min gradient, 25 mL/min flow rate) on a Gilson HPLC system.
24. The generic protocols reported here were developed to maximize scope and product diversity. In cases where specific individual compounds (or a more narrow scope) are desired, significantly improved purity and yield are typically achieved by straightforward tuning of the sequence (variation of temperature/time).
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30. When the purified yield data for this manuscript was collected in our laboratory, it was customary to experience a significant loss (∼50%) owing to cumulative losses during purification and the post-synthesis processing (transfers, fractionation, fraction combination etc.). Further, additional yield loss was expected here as the maximum injection volume allowed by the HPLC purification system (0.75 mL) limited the volume of DMSO used to wash resin after product release.