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

HRID 1254653Notes

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-ca119f127cec4d01ba7cddf93be64f92
Source dataset: uspto-grants-2013_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08455525B2

Reaction notes

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