Lithium Chloride → HCID 86713888, compound

HRID 521963

Reaction equation

Br[C:2]1[S:3][C:4]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][C:46]=1[Sn](CCCC)(CCCC)CCCC.[Cl-].[Li+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:25]([O:24][C:22]([NH:21][C@H:18]1[C@@H:17]([F:29])[CH2:16][O:15][C@H:14]([C:13]2[N:12]([CH3:30])[N:11]=[CH:10][C:9]=2[NH:8][C:7]([C:5]2[N:6]=[C:2]([C:46]3[CH:45]=[CH:44][N:43]=[CH:42][C:41]=3[F:40])[S:3][C:4]=2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])[CH2:20][CH2:19]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]

Participants

Conditions

Temperature: 135 °C

Procedure

A mixture of tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (100 mg, 0.16 mmol, intermediate 88), 3-fluoro-4-tri-n-butylstannyl pyridine (93 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium(0) (9.3 mg, 0.008 mmol), copper (I) iodide (9 mg, 0.047 mmol) and lithium chloride (21 mg, 0.48 mmol) in dioxane (1.5 mL) was degassed by bubbling nitrogen gas through it for 5 min. The mixture was heated at 135° C. under microwave irradiation for 45 min. After cooling to room temperature, more 3-fluoro-4-tri-n-butylstannyl pyridine (93 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium(0) (9.3 mg, 0.008 mmol), copper (I) iodide (9 mg, 0.047 mmol) and lithium chloride (21 mg, 0.48 mmol) were added and the mixture was degassed by bubbling nitrogen gas through it for 5 min. The mixture was heated at 135° C. for 45 min, cooled to room temperature, filtered through celite and the filtrate concentrated under reduced pressure. Purification via silica gel column chromatography (0-80% EtOAc/isohexane) gave tert-butyl N-[4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]-2-(3-fluoro-4-pyridyl)thiazol-5-yl]carbamate as a pale brown solid. This solid was stirred in a solution of HCl (4.0 M in dioxane, 3 mL) and MeOH (0.5 mL) at room temperature for 18 hr. The solvents were removed under reduced pressure. Purification via preparative HPLC gave 182 as the formate salt as a pale pink solid (26 mg, 33%). 1H NMR (400 MHz, d6-DMSO) δ 9.27 (s, 1H), 8.43 (d, J=2.8 Hz, 1H), 8.28-8.23 (m, 1H), 8.00 (s, 1H), 7.78-7.72 (m, 1H), 7.47 (s, 1H), 7.42 (br s, 2H), 4.78-4.58 (m, 2H), 3.99-3.85 (m, 1H), 3.79-3.67 (m, 1H), 3.49 (s, 3H), 3.17-3.02 (m, 1H), 1.90-1.80 (m, 1H), 1.67-1.51 (m, 2H), 1.41 (d, J=13.1 Hz, 1H). Alkyl NH2 not observed. LCMS (ES+) m/z 450 (M+1).

Workup

customwas degassed
customby bubbling nitrogen gas through it for 5 min
temperatureAfter cooling to room temperature
customthe mixture was degassed
customby bubbling nitrogen gas through it for 5 min
temperatureThe mixture was heated at 135° C. for 45 min
temperaturecooled to room temperature
filtrationfiltered through celite
concentrationthe filtrate concentrated under reduced pressure
customPurification via silica gel column chromatography (0-80% EtOAc/isohexane)

Sources & evidence

ORD record: ord-447be63c7eaa4a6d89877e42b133e3af
Source dataset: uspto-grants-2016_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09328106B2

Linked notes

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