N-methyl-2-pyrrolidone → HCID 86677689, compound

HRID 1499758Notes

Reaction equation

[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:14]([C:16]3[C:17]([O:32][CH3:33])=[C:18]([CH:24]4[CH2:27][N:26]([CH2:28][C@@H:29]([OH:31])[CH3:30])[CH2:25]4)[C:19]([F:23])=[C:20](Cl)[CH:21]=3)[CH3:15])[N:9]=[C:10]([CH:11]([F:13])[F:12])[C:3]=12.[CH3:34][N:35]1CCCC1=O>[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.[C-]#N.[Zn+2].[C-]#N>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:14]([C:16]3[C:17]([O:32][CH3:33])=[C:18]([CH:24]4[CH2:27][N:26]([CH2:28][C@@H:29]([OH:31])[CH3:30])[CH2:25]4)[C:19]([F:23])=[C:20]([CH:21]=3)[C:34]#[N:35])[CH3:15])[N:9]=[C:10]([CH:11]([F:13])[F:12])[C:3]=12

Participants

Conditions

Temperature: 130 °C

Procedure

To a microwave vial containing (2S)-1-[3-(3-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-6-fluoro-2-methoxyphenyl)azetidin-1-yl]propan-2-ol (16 mg, 0.032 mmol, from Example 76) was added zinc (1.0 mg, 0.016 mmol), bis(tri-t-butylphosphine)palladium (6.5 mg, 0.013 mmol) and N-methylpyrrolidinone (0.20 mL, 2.0 mmol). The mixture was degassed with N2 for a few minutes before adding zinc cyanide (7.5 mg, 0.064 mmol). The resulting mixture was stirred at 130° C. overnight and then cooled and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1.8 mg, 11.2%). The product was isolated as a racemic mixture. LCMS calculated for C22H25F3N7O2 (M+H)+: m/z=476.2; Found: 476.2

Workup

customThe mixture was degassed with N2 for a few minutes
temperaturecooled
custompurified on RP-HPLC (XBridge C18 column
washeluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min)

Sources & evidence

ORD record: ord-4056fd6d4bf04a3d8c1289d0c3c8b2ac
Source dataset: uspto-grants-2015_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09199982B2

Reaction notes

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