Citric Acid → (2R,3S)-2-(3-chloro-4-cyanophenylamino)-3-hydroxybutanoic acid

HRID 470755Notes

Reaction equation

[Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C@@H:12]([C:16]([OH:18])=[O:17])[C@H:13]([CH3:15])[OH:14].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[CH:9]=[C:8]([NH:11][C@H:12]([C@@H:13]([OH:14])[CH3:15])[C:16]([OH:18])=[O:17])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]

Participants

Conditions

Temperature: 75 °C

Procedure

2-chloro-4-fluorobenzonitrile (60702-69-4) (2.0 g, 12.86 mmol) was mixed together with H-D-Thr-OH (1.84 g, 15.43 mmol) in DMSO (30 mL). K2CO3 (3.73 g, 27.0 mmol) was added to the reaction mixture and stirred at 75° C. for 24 h. The reaction mixture was cooled down to room temperature and poured slowly into 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 and then with EtOAc, 100% to get the pure final product 1.8 g): 1H NMR (500 MHz, acetone-d6, δ in ppm) 7.51 (d, J=9 Hz, 1H), 6.95 (s, 1H), 6.82 (d, J=9 Hz, 1H), 5.17 (d, J=9 Hz, 1H), 4.42 (m, 1H), 4.22 (d, J=6 Hz, 1H), 2.34 (s, 3H), 1.28 (d, J=6 Hz, 3H).

Workup

temperatureThe reaction mixture was cooled 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

Sources & evidence

ORD record: ord-88382b334e3f4ce2b33f635e6e76605b
Source dataset: uspto-grants-2014_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08629167B2

Reaction notes

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