O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate → N,N,N',N'-Tetramethylazodicarboxamide

Neat CDI (49 mg, 0.302 mmol) was added to stirred solution of mono acid (92 mg, 0.200 mmol) in an. THF (1 ml) and the mixture was heated at 50° C. for 30 min and then allowed to cool to rt. Then N-cyclopropyl-N-methylsulfamide (45.1 mg, 0.300 mmol) and DBU (0.060 ml, 0.400 mmol) were added consecutively. The mixture sonicated for 1-2 hand then stirred overnight at rt. Reaction was quenched with MeOH (0.5 ml) and then acidified with 1N HCl and extracted with EtOAc (2×25 mL), washed with water, brine and dried (Na2SO4). Crude product (123 mg) was purified by silica gel flash chromatography (5% MeOH in DCM) to afford amide-ester as an off-white solid (101 mg). 1N NaOH (2 mL, 2.000 mmol) was added to stirred solution of the amide ester (98 mg, 0.166 mmol) in THF-MeOH under nitrogen. The mixture was stirred at rt for 2 h and then acidified with 1N HCl (3 ml), extracted with EtOAc (2×25 ml), washed with water, brine and dried (MgSO4). Evaporation of solvents afforded amide-acid as an off-white solid (94 mg). Neat 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (53.5 mg, 0.167 mmol) was added to a stirred mixture of the amide-acid (74 mg, 0.128 mmol), 3-methyl-3,8-diazabicyclo[3.2.1]octane, 2HCl (26.4 mg, 0.128 mmol) and TEA (0.071 ml, 0.512 mmol) in DCM (2 ml) under nitrogen. The mixture was stirred at rt for 1 h and quenched with MeOH (0.5 ml) and then evaporated to dryness and purified by reverse-phase HPLC to afford diamide and isolated in mono TFA salt form (61.3 mg) as a beige solid. LC/MS: Retention time: 1.857 min; m/e 686 (MH+). The product was observed to exist as inter-converting rotamers by 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.72-0.84 (m, J=1.83 Hz, 2H), 0.85-0.96 (m, J=2.44 Hz, 2H), 1.19-1.31 (m, 1H), 1.33-1.48 (m, 2H), 1.50-1.62 (m, 1H), 1.69-1.89 (m, 8H), 1.92-2.23 (m, 10H), 2.56-2.69 (m, 2H), 2.77-2.90 (m, 1H), 2.90-3.02 (m, 1H), 3.04-3.14 (m, 4H), 3.11-3.54 (m, 1H), 3.60-3.71 (m, J=15.26 Hz, 1H), 3.82-3.96 (m, 3H), 5.06-5.22 (m, 1H), 6.92-7.01 (m, J=8.55, 2.44 Hz, 1H), 7.07-7.14 (m, J=2.14 Hz, 1H), 7.27-7.33 (m, J=8.55 Hz, 1H), 7.40-7.49 (m, 1H), 7.86-7.94 (m, J=8.24 Hz, 1H), 7.98-8.06 (m, 1H).

1. customquenched with MeOH (0.5 ml)
2. customevaporated to dryness
3. custompurified by reverse-phase HPLC

ORD record

ord-719e487b65824e43b69c1095b5214d1f

Source dataset

uspto-grants-2009_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07521443B2