N'-Hydroxybenzenecarboximidamide → 2-chloro-4-((1R,2R)-2-hydroxy-1-(3-phenyl-1,2,4-oxadiazol-5-yl)propylamino)-3-methylbenzonitrile

HRID 470764

反応式

HRID 470764 の反応式
[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].F[B-](F)(F)F.CN(C)C(O)=[N+](C)C.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[C:51](=[N:59]O)([NH2:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>[Cl-].[Na+].O.CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@@H:11]([C:12]2[O:14][N:59]=[C:51]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[N:58]=2)[C@H:15]([OH:17])[CH3:16])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]

参加物

8

反応物 5

HCID 69186N'-HydroxybenzenecarboximidamideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 13074157Tetramethyluronium tetrafluoroborateHCID 57908625(2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid2 回

生成物 1

HCID 670062032-chloro-4-((1R,2R)-2-hydroxy-1-(3-phenyl-1,2,4-oxadiazol-5-yl)propylamino)-3-methylbenzonitrile収率 4%

試薬・触媒・溶媒 2

HCID 6228Dimethylformamide溶媒HCID 57417360Sodium chloride; water溶媒

反応条件

温度
100 °C

実験手順

To a 25 mL round bottom flask charged with (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (413 mg, 1.5 mmol) (intermediate 3a) and anhydrous DMF (15 mL) was added O-(benztriazol-1-yl)N,N,N′,N′)-tetramethyluronium tetrafluorborate (743 mg, 2.3 mmol), diisopropylethylamine (1.3 mL, 7.5 mmol), and HOBt (42 mg, 0.31 mmol). This mixture was let stir for a period of 10 min, to this mixture was added benzamidoxime (312 mg, 2.3 mmol). This mixture was allowed to stir for a period of 16 h. The reaction was then heated to 100° C. for a period of 5 h then cooled to room temperature. To the reaction was added brine (25 mL) and this was extracted with EtOAc (2×25 mL). The combined organic extracts were then washed with water (20 mL) and brine (25 mL) then dried over sodium sulphate. Filtration and concentration gave a dark oil. This was purified via silica gel chromatography eluted with 50% EtOAc/hexanes. A second column was run, eluting with 30% EtOAc/hexanes to provide product (21 mg, 4%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.04 (m, 2H), 7.49 (m, 3H), 7.34 (d, J=8.6 Hz, 1H), 6.60 (d, J=8.7 Hz, 1H), 5.40 (d, J=8.7 Hz, 1H), 4.87 (dd, J=3.9, 8.7 Hz, 1H), 4.42 (br s, 1H), 2.77 (br s, 1H), 2.33 (s, 3H), 1.33 (d, J=6.5 Hz, 3H).

後処理

  1. stirringto stir for a period of 16 h
  2. temperaturethen cooled to room temperature
  3. extractionthis was extracted with EtOAc (2×25 mL)
  4. washThe combined organic extracts were then washed with water (20 mL) and brine (25 mL)
  5. dry with materialthen dried over sodium sulphate
  6. filtrationFiltration and concentration
  7. customgave a dark oil
  8. customThis was purified via silica gel chromatography
  9. washeluted with 50% EtOAc/hexanes
  10. washeluting with 30% EtOAc/hexanes

出典と根拠

ORDレコード
ord-1560ec176830497faac9a5812a4c4205
出典データセット
uspto-grants-2014_01
特許番号
US08629167B2

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