Synthesis and solid-phase purification of anthranilic sulfonamides as CCK-2 ligands

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 24, 2007, Pages 6905-6909

  Woods, Craig R ^a   Hack, Michael D ^a   Allison, Brett D ^a   Phuong, Victor K ^a   Rosen, Mark D ^a   Morton, Magda F ^a   Prendergast, Clodagh E ^b   Barrett, Terrance D ^a   Shankley, Nigel P ^a   Rabinowitz, Michael H ^a  

^a JOHNSON AND JOHNSON PHARMACEUTICAL RESEARCH AND DEVELOPMENT   (United States)

^b UNIVERSITY OF LIVERPOOL   (United Kingdom)

Author keywords

Anthranilic sulfonamides; CCK; CCK 2; Cholecystokinin; Resin capture purification; Solid phase purification; Sulfonamide synthesis; TBD Me; TBD PS; Trisamine PS

Indexed keywords

ANTHRANILIC ACID DERIVATIVE; CHOLECYSTOKININ B RECEPTOR; LIGAND; SULFONAMIDE;

ARTICLE; DRUG PURIFICATION; DRUG STABILITY; DRUG SYNTHESIS; HUMAN; LIVER MICROSOME; NONHUMAN; RAT; REACTION ANALYSIS; SOLID PHASE EXTRACTION;

ANIMALS; ANTHRANILIC ACIDS; CHOLECYSTOKININ; COMBINATORIAL CHEMISTRY TECHNIQUES; DRUG DESIGN; HUMANS; LIGANDS; MICROSOMES, LIVER; MOLECULAR STRUCTURE; RATS; RECEPTOR, CHOLECYSTOKININ B; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES;

EID: 35848958793     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.09.087     Document Type: Article

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33. a of the primary amine of the trisamine-PS resin was calculated to be 9.6 based on the N1-(2-Amino-ethyl)-N1-[2-(4-methyl-benzyl-amino)-ethyl]-ethane-1,2-diamine fragment of the resin.
34. a of TBD-PS to be 13.5 based on the 1-(4-methyl-benzyl)-1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine fragment of the resin.
35. Typical procedure for sulfonamide synthesis: To a 20 mL reaction vial were added amine 3 (50.0 mg, 0.18 mmol, 1 equiv), dichloromethane (10 mL) and pyridine (100 μL, 0.88 mmol, 5 equiv). Sulfonyl chloride (0.36 mmol, 2 equiv) was then added and contents agitated on a shaker plate for one hour or until reaction was complete by HPLC. Excess sulfonyl chloride was then removed by the addition of trisamine-PS resin (tris-(2-aminoethyl)aminoethyl polystyrene resin, 200 mg, 0.88 mmol, Aldrich, 4.4 mmol/g loading), shaking for 1 h, followed by filtration, and rinsing of the resin with dichloromethane. Purification of desired compound was carried out in a two-step 'catch and release' method by addition of TBD-PS resin (1,5,7-triazabicyclo[4.4.0]dec-5-ene polystyrene resin, 325 mg, 0.88 mmol, 5 equiv, Novabiochem, 2.7 mmol/g loading), shaking for 1 h, then collecting the resin containing the sequestered product via filtration and rinsing with dichloromethane. The desired product was released by shaking the resin with a 10% trifluoroacetic acid solution in dichloromethane (10 mL) for 30 min followed by filtration and removal of solvent under reduced pressure to yield the desired product as the trifluoroacetate salt. In several cases, the product obtained was an amber oil, but could easily be crystallized by the addition and subsequent trituration with diethyl ether.
36. Relative microsomal stability was assed by testing 2, 4a-t with the same batch of human and rat liver microsomes for thirty minutes under an identical protocol, followed by determination of the amount of parent remaining via LCMS analysis.
37. Rosen, M. D.; Hack, M. D.; Allison, B. D.; Phuong, V. K.; Woods, C. R.; Morton, M. F.; Prendergast, C. E.; Barrett, T. D.; Schubert, C.; Li, L.; Wu, X.; Freedman, J. M.; Wu, J.; Shankley, N. P.; Rabinowitz, M. H., manuscript in preparation.