Citric Acid → (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid

HRID 470736

反応式

HRID 470736 の反応式
[NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].C(=O)([O-])[O-].[K+].[K+].[Cl:15][C:16]1[C:23]([CH3:24])=[C:22](F)[CH:21]=[CH:20][C:17]=1[C:18]#[N:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:15][C:16]1[C:23]([CH3:24])=[C:22]([NH:1][C@H:2]([C@H:3]([OH:4])[CH3:5])[C:6]([OH:8])=[O:7])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]

参加物

7

反応物 5

HCID 311Citric AcidHCID 11430Potassium CarbonateHCID 222302-Hydroxy-1,2,3-propanetricarboxylic acid hydrate (1:1)HCID 90624D-AllothreonineHCID 445509712-Chloro-4-fluoro-3-methylbenzonitrile

生成物 1

HCID 57908625(2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid収率 48%

試薬・触媒・溶媒 1

HCID 679Dimethyl Sulfoxide溶媒

実験手順

To a three-necked, 500 mL, round-bottomed flask fitted with a nitrogen inlet, mechanical stirring apparatus, and septum was added D-allo-threonine (24.98 g, 210 mmol) followed by anhydrous DMSO (250 mL) and potassium carbonate (63.7 g, 460 mmol). This mixture was stirred under nitrogen at room temperature for a period of 30 min. To this mixture was then added 2-chloro-4-fluoro-3-methylbenzonitrile (35.51 g, 210 mmol) followed by heating of the reaction mixture to 70° C. in an oil bath for a period of 48 hs. The reaction was then allowed to cool to room temperature followed by subsequent cooling to 0° C. and a 5% citric acid/water solution (1.5 Liters) was slowly added followed by careful addition of solid citric acid until evolution of gas was no longer observed. This solution was then extracted with EtOAc (5×μL). The combined organic extracts were then dried over Na2SO4 and decanted away from the drying agent. The solvent was then removed under reduced pressure using rotary evaporation to reveal a red oil that was purified by silica gel chromatography by first eluting with hexanes/EtOAc, 1/1 (2 L) followed by methanol/EtOAc 1/7 (5 L) to afford of (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid as a light red oil/solid (27.05 g, 48%). 1H NMR (500 MHz, CD3OD, δ in ppm) 7.42 (d, J=8.7 Hz, 1H), 6.65 (d, J=8.7 Hz, 1H), 4.24 (m, 1H), 4.17 (m, 1H), 2.32 (s, 3H), 1.35 (d, J=6.6 Hz, 3H); 13C NMR (125.6 MHz, CD3OD) δ 174.2, 151.9, 137.16, 134.0, 122.6, 119.1, 110.1, 101.2, 69.1, 63.2, 20.0, 14.0.

後処理

  1. customTo a three-necked, 500 mL, round-bottomed flask fitted with a nitrogen inlet
  2. temperatureto cool to room temperature
  3. temperatureby subsequent cooling to 0° C.
  4. extractionThis solution was then extracted with EtOAc (5×μL)
  5. dry with materialThe combined organic extracts were then dried over Na2SO4
  6. customdecanted away from the drying agent
  7. customThe solvent was then removed under reduced pressure
  8. customevaporation
  9. customwas purified by silica gel chromatography
  10. washby first eluting with hexanes/EtOAc, 1/1 (2 L)

出典と根拠

ORDレコード
ord-9ae30b78449747008d9885ebd0a94bac
出典データセット
uspto-grants-2014_01
特許番号
US08629167B2

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