Citric Acid → (R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoic acid

HRID 563204Notes

Reaction equation

[Cl:1][C:2]1[C:9]([CH3:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][C@H:13]([C:17]([OH:20])([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].C([O-])([O-])=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:12][C@H:13]([C:17]([OH:20])([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]

Participants

Conditions

Temperature: 75 °C

Procedure

2-chloro-4-fluoro-3-methylbenzonitrile (1.06 g, 6.26 mmol) was mixed together with (R)-2-amino-3-hydroxy-3-methylbutanoic acid (1.00 g, 7.51 mmol) in DMSO (25 mL). K2CO3 (1.73 g, 12.52 mmol) was added to the reaction mixture and stirred at 75° C. for 24 h. Then the reaction mixture was cool down to room temperature and poured slowly in to a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed with a gradient of hexane/EtOAc (4:6) and then with EtOAc, 100% to get the title compound (1.40 g). 1H NMR (500 MHz, acetone-d6, δ in ppm) 7.51 (d, J=9 Hz, 1H), 6.72 (d, J=9 Hz, 1H), 5.48 (d, J=9 Hz, 1H), 4.16 (d, J=9 Hz, 1H), 2.34 (s, 3H), 1.43 (s, 3H), 1.41 (s, 3H).

Workup

temperatureThen the reaction mixture was cool down to room temperature
stirringstirred for 10 min at room temperature
extractionThe solution was extracted with EtOAc several times
customto get the crude product
customThe crude product was chromatographed with a gradient of hexane/EtOAc (4:6)

Sources & evidence

ORD record: ord-f8992d24a108486db801044533e5ad6c
Source dataset: uspto-grants-2011_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08067448B2

Reaction notes

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