4-Methylmorpholine → (S)-2-Isopropylamino-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide monohydrochloride

HRID 990346ノート

反応式

HRID 990346 の反応式
[CH:1]([NH:4][C@@H:5]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:6]([OH:8])=O)([CH3:3])[CH3:2].CN1CCOCC1.[ClH:20].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[CH2:29][CH2:30][CH2:31][NH2:32])=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[ClH:20].[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[CH2:29][CH2:30][CH2:31][NH:32][C:6](=[O:8])[C@@H:5]([NH:4][CH:1]([CH3:2])[CH3:3])[CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:24][CH:23]=1

参加物

7

反応物 4

HCID 79724-MethylmorpholineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 15852242HCID 15852242、化合物HCID 18418679HCID 18418679、化合物

生成物 1

HCID 86758547(S)-2-Isopropylamino-4-methyl-pentanoic acid [4,4-bis-(4-fluoro-phenyl)-butyl]-amide monohydrochloride収率 35%

試薬・触媒・溶媒 2

HCID 887Methanol溶媒HCID 6228Dimethylformamide溶媒

反応条件

温度
0 °C

実験手順

A suspension of (S)-2-isopropylamino-4-methyl-pentanoic acid (433 mg, 2.50 mmol), N-methylmorpholine (0.275 mL, 2.50 mmol), and 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (750 mg, 2.52 mmol) in dry DMF (12 mL) was treated with Triton® B (2.27 mL, 4.99 mmol, 40 wt percent solution in methanol, Aldrich, Milwaukee, Wis.), a clear solution was obtained and cooled to 0° C. in an ice-water bath. Solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.940 g, 2.50 mmol) was then added. After stirring at 0° C. for 90 minutes the cooling bath was removed, and the stirring was continued at ambient temperature for 30 minutes. After this period, the reaction mixture was mixed with 100 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (100 mL), brine (100 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (EtOAc:hexanes:MeOH 50:50:5). The free amine was dissolved in 5 mL of ethyl ether and treated with ethereal HCl to afford 368 mg (35%) of the pure titled compound as a white foam: mp 100-103° C.

後処理

  1. customa clear solution was obtained
  2. customwas removed
  3. waitthe stirring was continued at ambient temperature for 30 minutes
  4. waitAfter this period
  5. additionthe reaction mixture was mixed with 100 mL of diethyl ether
  6. washthe resulting mixture was successively washed with saturated aqueous NaHCO3 solution (100 mL), brine (100 mL)
  7. dry with materialwas dried over Na2SO4
  8. concentrationThe solution was concentrated in vacuo
  9. customaffording a viscous oil
  10. customThe crude product was purified by flash chromatography (EtOAc:hexanes:MeOH 50:50:5)
  11. dissolutionThe free amine was dissolved in 5 mL of ethyl ether
  12. additiontreated with ethereal HCl

出典と根拠

ORDレコード
ord-b50349b7eb7f4eb98e2e2fa073fc138e
出典データセット
uspto-grants-2002_10
特許番号
US06458781B1

反応ノート

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