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

HRID 470759Notes

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-b51ac99178b74770833b77083d9f50f8
Source dataset: uspto-grants-2014_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08629167B2

Reaction notes

Loading…