Citric Acid → (2r,3s)-2-(4-Cyano-2-methyl-3-(trifluoromethyl)phenylamino)-3-hydroxybutanoic acid

HRID 470804Notes

Reaction equation

F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14].C1[C:20]([CH2:21][C@@H:22]([NH2:26])[C:23]([OH:25])=[O:24])=CC=C(OC2C=CC(O)=CC=2)C=1.C([O-])([O-])=[O:36].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:26][C@H:22]([C@@H:21]([OH:36])[CH3:20])[C:23]([OH:25])=[O:24])=[C:3]([CH3:14])[C:4]=1[C:10]([F:13])([F:12])[F:11])#[N:7]

Participants

Conditions

Temperature: 75 °C

Procedure

4-fluoro-3-methyl-2-(trifluoromethyl)benzonitrile (1.0 g, 4.92 mmol) and D-theronine (703 mg, 90 mmol) were added to DMSO (15 mL). K2CO3 (3.26 g) was added to the reaction mixture and stirred at 75° C. for 24 h. The reaction mixture was cooled 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 give the crude product. The crude product was chromatographed with a gradient of hexanes/EtOAc and then with EtOAc, 100% to give the final product (400 mg). 1H NMR (500 MHz, acetone-d6, δ in ppm) 7.62 (d, J=9 Hz, 1H), 6.98 (d, J=9 Hz, 1H), 5.52 (d, J=9 Hz, 1H), 4.52 (m, 1H), 4.32 (m, 1H), 2.35 (s, 3H), 1.35 (d, J=6 Hz, 3H).

Workup

temperatureThe reaction mixture was cooled to room temperature
stirringstirred for 10 min at room temperature
extractionThe solution was extracted with EtOAc several times
customto give the crude product
customThe crude product was chromatographed with a gradient of hexanes/EtOAc

Sources & evidence

ORD record: ord-eda7f568cf45452aa739ab28d2460750
Source dataset: uspto-grants-2014_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08629167B2

Reaction notes

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