Ammonium Chloride → HCID 68358605, compound

Temperature

75 °C

To a stirred solution of (1S,3R)-3-(3-carbamoyl-6-phenylpyrrolo[1,2-b]pyridazin-4-ylamino)-1,2,2-trimethylcyclopentanecarboxylic acid (30 mg, 0.074 mmol) in DMF (492 μl) were added Hunig's base (97 μl, 0.554 mmol) and HATU (42.1 mg, 0.111 mmol). After 15 minutes, ammonium chloride (19.74 mg, 0.369 mmol) was added. The reaction was heated at 75° C. for 24 hrs. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed successively with water, (sat.) ammonium chloride and (sat.) sodium chloride. The ethyl acetate extract was dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding a yellow oil. The crude product was chromatographed using reverse-phase HPLC (Column: LUNA 5u C18 21×100). The collected fractions were combined and concentrated under reduced pressure. The product was taken up in ethyl acetate and neutralized with (sat.) sodium carbonate. The ethyl acetate extract was dried with sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (12.7 mg, 0.030 mmol, 40.3% yield) as a white solid. LC/MS found [M+H]+=406.2. 1H NMR (400 MHz, MeOD) δ ppm 8.13-8.17 (1 H, m), 7.92-7.96 (1 H, m), 7.64-7.70 (2 H, m), 7.35-7.44 (2 H, m), 7.23-7.30 (1 H, m), 7.15-7.20 (1 H, m), 4.68-4.77 (1 H, m), 2.54-2.67 (1 H, m), 2.41-2.54 (1 H, m), 1.70-1.80 (1 H, m), 1.60-1.69 (1 H, m), 1.35-1.42 (3 H, m), 1.13-1.19 (3 H, m), 1.06-1.13 (3H, m). HPLC Retention Time=3.058 (HPLC conditions: column. Phenominex Synergy, 4.6×50 mm, Mobile phase A: 90:10 water/methanol with 0.2% H3PO4; Mobile Phase B: 90:10 methanol/water with 0.2% H3PO4; Wavelength: 220 nm; Gradient: 0-100% B over 4 minutes, then a 1-minute hold at 100% B; Flow: 4 mL/min.)

1. temperatureThe reaction mixture was cooled to room temperature
2. washThe solution was washed successively with water, (sat.) ammonium chloride and (sat.) sodium chloride
3. extractionThe ethyl acetate extract
4. dry with materialwas dried with sodium sulfate
5. filtrationfiltered
6. concentrationconcentrated under reduced pressure
7. customyielding a yellow oil
8. customThe crude product was chromatographed
9. concentrationconcentrated under reduced pressure
10. extractionThe ethyl acetate extract
11. dry with materialwas dried with sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated under reduced pressure

ORD record

ord-65504deb6ae5494085149370c5d46abd

Source dataset

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08921368B2