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Stage #1: (tert-butoxy)-N-{4-(N,N-dipropylcarbamoyl)-8-[4-(pyrrolidinylcarbonyl)phenyl](3H-benzo[f]azepin-2-yl)}carboxamide With trifluoroacetic acid In dichloromethane at -25 - 20℃;
Stage #2: With sodium hydrogencarbonate In water
11
Example 11; N-BOC deprotection of HG3 to afford target HG4; [000134] Removal of the N-BOC protecting group was accomplished using trifiuoroacetic acid (TFA, 10 equiv) in DCM (15 volumes, -25 to 25 0C, 24 hours) according to the following procedure. A solution of TFA was prepared in an equal volume of DCM and added to a cold (-25 0C) solution of HG3 over a period of 1 hour, while maintaining the batch temperature < 20 0C. Upon completion of the addition, the temperature of the batch was allowed to rise to 20-25 0C. The completed reaction mixture was diluted into cold (0-5 0C) water. After a phase separation and back extraction of the aqueous layer, the pH of the batch was adjusted with 10% NaHCOs solution to remove the excess TFA. The organic phase was further washed with brine, dried (MgSO4), filtered and concentrated to a light yellow slurry. The slurry was triturated in EtOAc (11.6 volumes, 2 hours, 20-250C) and filtered to afford a light pink solid. The cake was washed with EtOAc (2 portions of 1.5 volume each) and final wash with heptanes (2 portions of 1.5 volume each). The final compound was dried in a vacuum oven (40 0C, 48 hours). [000135] The deprotection of HG3 was performed using this procedure. The reaction progress was monitored using HPLC. A representative deprotection was performed on HG3 (560 mg, 1 mmol, 74.9% a/a). From this trial was isolated 320 mg (92.3% yield) of HG4 (98.6% a/a). [000136] For these experiments, the batch volume was reduced to approximately 1 volume of DCM with respect to HGl, prior to the addition of ethyl acetate to precipitate the HG4 product.
{2-amino-8-[4-(pyrrolidinylcarbonyl)phenyl]-(3H-benzo[f]azepin-4-yl)}-N,N-dipropylcarboxamide[ No CAS ]
C36H40N4O5S2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50.05%
With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; for 16h;
To a solution of compound 3 (230.52 mg, 654.17 umol) in DMF (2 mL) was added Motohmod (0.15 g, 327.09 umol), DIEA (126.82 mg, 981.26 umol, 170.92 uL) and HOBt (53.04 mg, 392.50 umol). The mixture was stirred at 25 C for 16 hr. LC-MS indicated compound 3 was consumed completely and a peak with desired mass (m/z: 672.1([M+H+])) was detected. The reaction mixture was purified by prep-HPLC (A: H20, B: ACN). Compound 4 (0.11 g, 163.72 umol, 50.05% yield) was obtained as a white solid. Calculated MW: 671.8 observed m/z: 672.1([M+H+])