Citric Acid → (3-Chloro-4-cyano-2-methylphenyl)-D-threonine

HRID 470733

Reaction equation

HRID 470733 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:19])=[O:18])[C@H:14]([CH3:16])[OH: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@@H:14]([OH:15])[CH3:16])[C:17]([OH:19])=[O:18])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]

Participants

6

Reactant 4

HCID 311Citric AcidHCID 11430Potassium CarbonateHCID 69435D-ThreonineHCID 445509712-Chloro-4-fluoro-3-methylbenzonitrile

Product 1

HCID 57908671(3-Chloro-4-cyano-2-methylphenyl)-D-threonine

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
75 °C

Procedure

2-chloro-4-fluoro-3-methylbenzonitrile (CAS 796600-15-2, 45 g, 265.4 mmol) was mixed together with H-D-Thr-OH (37.92 g, 318.4 mmol) in DMSO (250 mL). K2CO3 (73.35 g, 530.7 mmol) was added to the reaction mixture and the reaction mixture stirred at 75° C. for 24 h. The reaction mixture was cooled 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 on silica gel with a gradient of hexanes/EtOAc and then with EtOAc, 100% to get the purified final product (39.0 g, 54%) 1H NMR (500 MHz, Acetone-d6, δ in ppm) 7.49 (d, 9 Hz, 1H), 6.70 (d, J=9 Hz, 1H), 5.38 (d, J=10 Hz, 1H), 4.47 (d, J=6 Hz, 1H), 4.25 (m, 1H), 2.34 (s, 3H), 1.33 (d, J=6 Hz, 3H).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. stirringstirred for 10 min at room temperature
  3. extractionThe solution was extracted with EtOAc several times
  4. customto get the crude product
  5. customThe crude product was chromatographed on silica gel with a gradient of hexanes/EtOAc
  6. customwith EtOAc, 100% to get the
  7. custompurified final product (39.0 g, 54%) 1H NMR (500 MHz, Acetone-d6, δ in ppm) 7.49 (d, 9 Hz, 1H), 6.70 (d, J=9 Hz, 1H), 5.38 (d, J=10 Hz, 1H), 4.47 (d, J=6 Hz, 1H), 4.25 (m, 1H), 2.34 (s, 3H), 1.33 (d, J=6 Hz, 3H)

Sources & evidence

ORD record
ord-0996d674fb3d4ce791bf780f0a387e78
Source dataset
uspto-grants-2014_01
Patent number
US08629167B2

Linked notes

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