Sodium Hydroxide → HCID 66549079, compound

An orange solution of Example 56B (98 mg, 0.666 mmol), DMF (1 mL), i-Pr2NEt (0.244 mL, 1.40 mmol), and methyl 4-((2,5-dioxopyrrolidin-1-yloxy)carbonylamino)-1H-indazole-1-carboxylate (232 mg, 0.699 mmol) was stirred at ambient temperature 15 minutes, followed by the addition of MeOH (2.00 mL) and sodium hydroxide (50% in water, 0.105 mL, 2.00 mmol). After 10 minutes, water (3 mL) was added dropwise and a sticky gum was observed. The mixture was heated to reflux and a slurry persisted. The mixture was cooled slowly to ambient temperature and filtered, washing with 1:1 MeOH/water (6 mL). The white solid was dried in a vacuum oven at 50° C. to provide (1H-indazol-4-yl)-3-(3-phenylcyclobutyl)urea (144 mg, 0.470 mmol, 70.6% yield). Analytical chiral HPLC (20% IPA/hexanes isochratic method, 0.7 mL/min, AD-H column) showed two peaks (Retention times: major: 10.1 min; minor: 12.1 min) in a 2:1 ratio. The mixture was dissolved in 1:1 IPA/MeOH (20 mL) and separated on a 30×250 mm AD-H semi-prep column (10 mL/min, 2 mL/injection, 15% IPA/hexanes isochratic, 28 min runs, stack injection) to provide the title compound (55 mg, 0.18 mmol, 38% yield) and Example 57 (23 mg, 0.074 mmol, 16% yield). 1H NMR (500 MHz, DMSO-d6) 13.15 (s, 1H), 8.75 (s, 1H), 8.24 (s, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.62-7.25 (m, 6H), 7.21 (d, J=8.3 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 4.33 (dq, J=16.5, 8.2 Hz, 1H), 3.35-3.24 (m, 1H), 2.84 (ddd, J=15.6, 7.7, 2.8 Hz, 2H), 2.13 (td, J=10.4, 2.6 Hz, 2H). MS (DCI) M/Z 324 [M+NH4]+.

1. temperatureThe mixture was heated
2. temperatureto reflux
3. filtrationfiltered
4. washwashing with 1:1 MeOH/water (6 mL)
5. customThe white solid was dried in a vacuum oven at 50° C.

ORD record

ord-830d5d0566624c7a9edc47120ffdeb74

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08802711B2