1,1'-Carbonyldiimidazole → 13-Cyclohexyl-N-((dimethylamino)sulfonyl)-3-methoxy-6-(5-(3-(4-morpholinyl)-3-oxopropyl)-1,3-oxazol-2-yl)-6,7-dihydro-5H-indolo[2,1-a] [2]benzazepine-10-carboxamide

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13-Cyclohexyl-3-methoxy-6-(5-(3-(4-morpholinyl)-3-oxopropyl)-1,3-oxazol-2-yl)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (Peak2-Chiral Isomer B) (100 mg, 0.17 mMol) was dissolved in 1.9 ml of anhydrous THF and carbonyldiimidazole (37.1 mg, 0.23 mMol) added. The reaction was stirred under a nitrogen atmosphere at room temperature for 1 hr and heated at reflux for 1 hr under nitrogen. The reaction was cooled under nitrogen and dimethyl sulfamide (145 mg, 1.17 mMol) and DBU (27.5 uL, 0.18 mMol) added to the reaction. The reaction was heated to 50 C under a nitrogen atmosphere for 4 hrs, then cooled to room temperature and analyzed by HPLC for progress. The reaction was heated for an additional 2.5 hrs at 50 C and again monitored by HPLC. Dimethyl sulfamide (100 mg) and DBU (27 uL) were added to the reaction and the reaction heated to reflux for 3 hrs under nitrogen. Heat was removed and the reaction cooled to room temperature and stirred overnight. The reaction was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and the aqueous phase extracted with ethyl acetate. The organic phases were combined and washed sequentially with 1N aqueous hydrochloric acid, brine then dried over magnesium sulfate. Removal of volatiles in vacuuo left 209 mg of crude product which was purified by reverse phase HPLC under the following conditions: Shimadzu prep. HPLC using Discovery VP software: % A=10% methanol, 90% water, 0.1% TFA; % B=90% methanol, 10% water, 0.1% TFA; Initial % B=50; Final % B=100; Gradient=15 min; Runtime=15 min; Flow rate=45 ml/min; Column=Waters Sunfire 30 mm×100 mm; Peak collection 8.2 min to 9.1 min.; The title compound was isolated as a colorless solid, 71.2 mg (60%). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.25 (q, J=12.82 Hz, 1.2 H) 1.31-1.53 (m, 2.1 H) 1.58-1.85 (m, 3.2 H) 1.86-2.12 (m, 4.2 H) 2.54-2.76 (m, 2.1 H) 2.81-2.99 (m, 3.3 H) 2.99-3.12(m, 7.3 H) 3.14-3.24(m, 1 H) 3.34-3.61 (m, 3.1 H) 3.60-3.73 (m, 5.3H) 3.72-3.82 (m, 0.9 H) 3.84 (s, 0.6 H) 3.90 (s, 2.5 H) 4.02 (dd, J=14.95, 6.10 Hz, 0.9 H) 4.77-4.92 (m, 1.3 H) 6.78-6.87 (m, 1 H) 6.88-7.05 (m, 2 H) 7.30-7.51 (m, 1.2 H) 7.64 (dd, J=8.39, 1.37 Hz, 0.8 H) 7.81-7.95 (m, 1.0 H) 8.01-8.21 (m, 1 H) 8.67 (s, 0.2 H) 9.86 (s, 0.8 H). HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: % A=10% methanol, 90% water, 0.1% trifluoroacetic acid; % B=90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial % B=50; Final % B=100; Gradient=5 min; Runtime=6 min; Flow rate=5 ml/min; Wavelength=220 nm; Column=Phenomenex Luna 3.0 mm×50 mm S10. Retention Time=3.03 min, purity 99%. Flow injection Mass Spectrometry: MS m/z 704(MH+), 726(M+Na)+, m/z 702(M-H)−. Chiral Purity: Column: Chiralacel OJ-H analytical column 4.6 mm×250 mm; Mobile Phase: 12% methanol in carbon dioxide; Temp: 35° C.; Flow rate: 2.0 ml/min for 40 min; UV monitoring=213 nm; Injection: 5 uL of approximately 1 mg/mL solution in ethanol; Retention time: 32.5 min, purity=100% EE=99.9%.

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