Acetoacetic Acid → N-{(2S)-2-(4-fluorophenyl)-4-[3-(4-hydroxypiperidin-1-yl)azetidin-1-yl]butyl}-N-methyl-3,5-bis(trifluoromethyl)benzamide

HRID 749412ノート

反応式

HRID 749412 の反応式
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8](CC=O)[CH2:9][N:10]([CH3:27])[C:11](=[O:26])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)=[CH:4][CH:3]=1.[C:31]([OH:34])(=O)[CH3:32].[C:35](O)(=O)[CH3:36].N1CC(N2CCC(O)CC2)C1.CC(CC(O)=O)=O.[CH3:57][N:58]1[CH2:63][CH2:62][N:61]([CH:64](C2C=CC=CC=2)C2C=CC=CC=2)[CH2:60][CH2:59]1.Cl.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH2:63][CH2:62][N:61]2[CH2:60][CH:59]([N:58]3[CH2:57][CH2:32][CH:31]([OH:34])[CH2:36][CH2:35]3)[CH2:64]2)[CH2:9][N:10]([CH3:27])[C:11](=[O:26])[C:12]2[CH:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:15]=[C:14]([C:22]([F:23])([F:25])[F:24])[CH:13]=2)=[CH:6][CH:7]=1

参加物

8

反応物 6

HCID 96Acetoacetic AcidHCID 81531DiisopropylethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 6420019Cyclizine HydrochlorideHCID 58683524N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-3,5-bis(trifluoromethyl)benzamideHCID 866068721-Azetidin-3-ylpiperidin-4-ol diacetate

生成物 1

HCID 11455933N-{(2S)-2-(4-fluorophenyl)-4-[3-(4-hydroxypiperidin-1-yl)azetidin-1-yl]butyl}-N-methyl-3,5-bis(trifluoromethyl)benzamide収率 60%

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒

実験手順

N-[(2S)-2-(4-Fluorophenyl)-4-oxobutyl]-N-methyl-3,5-bis(trifluoromethyl)benzamide (see Method 20; 0.40 g, 0.91 mmol) was dissolved in CH2Cl2 (10 mL) and to the resultant solution were added 1-azetidin-3-ylpiperidin-4-ol diacetate (see Method 15 with the exception that the diacetate was used rather than the corresponding dihydrochlorid; 0.28 g, 1.0 mmol) and DIPEA (0.76 g, 5.8 mmol). The mixture was stirred for a few minutes at RT and then sodium triacetoxyborohydride (0.43 g, 2.0 mmol) was added. The solution was stirred at RT overnight and then the solvent was removed by evaporation. The residue was partitioned between ethyl acetate and saturated NaHCO3 (aq). The phases were separated and the aqueous solution was extracted twice with ethyl acetate. The combined organic solutions were washed with water, dried over Na2SO4 and then the solvent was removed by evaporation. The residue was purified by flash chromatography using a mixture of methanol and CH2Cl2 as eluent. The product was dissolved in a mixture of water and acetonitrile and the solution was then freeze-dried. There was obtained 0.32 g (60%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 1.4-3.8 (cm, 24H), 6.8-7.5 (cm, 6H), 7.9 (s, 1H); LCMS: m/z 576 (M+1)+.

後処理

  1. stirringThe solution was stirred at RT overnight
  2. customthe solvent was removed by evaporation
  3. customThe residue was partitioned between ethyl acetate and saturated NaHCO3 (aq)
  4. customThe phases were separated
  5. extractionthe aqueous solution was extracted twice with ethyl acetate
  6. washThe combined organic solutions were washed with water
  7. dry with materialdried over Na2SO4
  8. customthe solvent was removed by evaporation
  9. customThe residue was purified by flash chromatography
  10. additiona mixture of methanol and CH2Cl2 as eluent
  11. dissolutionThe product was dissolved in a mixture of water and acetonitrile
  12. customthe solution was then freeze-dried

出典と根拠

ORDレコード
ord-3d4feb42f0604bd48beba742d0f65308
出典データセット
uspto-grants-2008_07
特許番号
US07402581B2

反応ノート

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