Cesium carbonate → 5-(4-((1R,2S)-2-amino-3-fluoro-1-hydroxypropyl)-phenyl)picolinonitrile

HRID 525574Notes

Reaction equation

CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)O1.[NH2:18][C@H:19]([CH2:29][F:30])[C@@H:20]([C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1)[OH:21].C([O-])([O-])=O.[Cs+].[Cs+]>C(COC)OC.O.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>[NH2:18][C@H:19]([CH2:29][F:30])[C@@H:20]([C:22]1[CH:23]=[CH:24][C:25]([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)=[CH:26][CH:27]=1)[OH:21]

Participants

Conditions

Temperature: 90 °C

Procedure

To a solution of 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl) -pyridine-2-carbonitrile (0.5 g, 2.17 mmol) in dimethoxyethane (10 mL) and water (3 mL) is added (1R,2S)-2-Amino-3-fluoro-1-(4-iodo-phenyl)-propan-1-ol (0.65 g, 2.20 mmol) and Cs2CO3 (2.15 g, 6.59 mmol), and degassed with nitrogen followed by addition of Pd(PPh3)4 (0.25 g, 0.21 mmol) and heated the reaction mixture to 90° C. for 1.5 hours. Solvent is evaporated in vacuo, to get crude material purified by column chromatography eluting in 2.5 to 3% methanol in CH2Cl2 to afford the title compound (0.3 g) as impure. 1H NMR (400 MHz, DMSO-d6) δ: 3.09-3.18 (m, 1H), 3.48 (s, 1H), 4.24-4.28 (m, 0.5H), 4.36-4.41 (m, 1H), 4.49-4.52 (m, 0.5H), 4.64 (d, J=6.16 Hz, 1H), 7.53 (d, J=8.16 Hz, 2H), 7.59 (d, J=8.24 Hz, 2H), 7.76 (d, J=8.2, 1H), 8.0 (dd, J1=8.16 Hz, J2=2.32 Hz, 1H), 8.93 (d, J=1.76 Hz, 1H). LC-MS (m/z): [M+H]=272.00.

Workup

customdegassed with nitrogen
customSolvent is evaporated in vacuo
customto get crude material
custompurified by column chromatography
washeluting in 2.5 to 3% methanol in CH2Cl2

Sources & evidence

ORD record: ord-c6a411f4da3c41ec9c80a95e24fd65c0
Source dataset: uspto-grants-2016_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09340564B2

Reaction notes

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