Solid phase synthesis of sulfonamides using a carbamate linker

Tetrahedron Letters

Volumn 38, Issue 19, 1997, Pages 3373-3376

  Raju, B ^a   Kogan, Timothy P ^a  

^a TEXAS BIOTECHNOLOGY CORPORATION   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

SULFONAMIDE;

ARTICLE; DRUG PURITY; DRUG SYNTHESIS; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; IN VITRO STUDY; INFRARED SPECTROPHOTOMETRY; REACTION ANALYSIS; TECHNIQUE;

EID: 0030907666     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(97)00652-7     Document Type: Article

References (50)

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29. 2, 1:1) of the resin bound sulfonamide 3a gave the sulfonamide and benzylamine as a 1:1 mixture, as determined by NMR, suggesting incomplete deprotonation using NaH. Cleavage under basic conditions avoided possible contamination resulting from unreacted urethane.
30. 2 (5 mL), and MeOH (10 mL). The resin was dried under vacuum and the IR spectrum recorded (NaCl);
31. 2 (5 mL), and MeOH (10 mL). The resin was dried under vacuum and the IR spectrum recorded (NaCl);
32. (c) Carbamate 3 (LHMDS): To a stirred suspension of resin 2 (200 mg, 0.92 mmol/g, 0.184 mmol) in dry THF (2 mL) at -70 °C was added LHMDS (1.1 mL of l M solution, 6 equiv.) dropwise and stirred for 45 min. To this was added the THF solution of p-toluenesulfonyl chloride (209 mg, 1.104 mmol) and the reaction mixture was slowly allowed attain rt and stirring continued for 8 h. The remainder of the procedure and workup were as in (10b);
33. (d) Cleavage using LiOH/water/THF: To a suspension of resin 3 (100 mg, 0.74 mmol/g) in water/THF (ratio 1:2, 4 mL) was added a saturated solution of LiOH in water (2 mL). After being vortexed for 54 h the mixture was filtered and the resin was washed with water (1 mL) and methanol (2 mL). The filtrate was concentrated under reduced pressure. The residue was neutralized with HCl to pH 2-3 and was extracted with ethyl acetate (8 mL). The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure to afford the sulfonamides 4;
34. (e) Cleavage using NaOMe/THF: To a suspension of resin 3 (200 mg, 0.74 mmol/g) in THF (2 mL) was added freshly prepared sodium methoxide in methanol (2 mL, 3M, prepared using sodium granules and 95% methanol) which was vortexed for 16 h. The remainder of the procedure and workup were same as in (10d);
35. 12 in toluene (2 M, 55.6 mL, 111 mmol, 10 equiv.) and the mixture was stirred at rt for 6 h. The resin was filtered, washed with dry THF (200 mL), and dried under vacuum in a desiccator;
36. (g) Carbamate 2k-z and 2a1, 2b1, 2c1: To a suspension of the resin 1b (700 mg, 0.74 mmol/g, 0.518 mmol) in dry THF (7 mL) was added 10 equivalent of an aniline and DIEA (135 mL, 0.777 mmol, 1.5 equiv.) and the mixture was stirred rt for 8 h. The remainder of the procedure was as in (10a).
37. (a) DIEA was distilled over ninhydrin and then over calcium hydride,
38. (b) Using triethylamine as a base instead of DIEA failed to yield the carbamates from methyl anthranillate (2u), o-aminobenzonitrile (2x), and the three regioisomeric nitroanilines (2aa, 2bb, and 2cc).
39. (c) The purity of the sulfonamides derived from anilines using LHMDS as a base was significantly lower than that obtained using NaH as a base.
40. (d). The purity of the sulfonamides obtained by using the LiOH cleavage protocol was superior.
41. Commercial 1.93 M solution in toluene was used. WARNING: Phosgene is highly toxic and should only be handled in a hood with appropriate safety equipments.
42. All the sulfonamides gave satisfactory high resolution PMR spectra and Fab mass spectra on a sub set of samples.
43. 2, 24 h, rt;
44. 2Cl; (h) 3 M NaOMe in methanol, THF, 16 h, rt.; Method B (for anilines):
45. 12 in toluene, dry THF, 8h, rt;
46. 2, DIEA, THF, 8 h, rt;
47. 2Cl;
48. (g) LiOH, water/THF, 54 h, rt.
49. Backes, B. J.; Virgilio, A. A.; Ellman, J. A. J. Am. Chem. Soc. 1996, 118, 3055 and references cited therein.
50. Use of acid labile Wang or related linkers to synthesize sulfonamides and related analogs is under progress and will be reported in the near future.