Triethylamine → (2S)-1-[1-(4-chlorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]propan-1-one

HRID 710678ノート

反応式

HRID 710678 の反応式
[CH3:1][C:2]1[N:3]([C@@H:11]([CH3:15])[C:12]([OH:14])=O)[CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C(Cl)(=O)C(Cl)=O.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:37]3[CH2:36][CH2:35][CH2:34][NH:33][C:32]=3[CH:31]=[N:30]2)=[CH:25][CH:24]=1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[C:37]3[CH2:36][CH2:35][CH2:34][N:33]([C:12](=[O:14])[C@@H:11]([N:3]4[CH:4]=[C:5]([C:7]([F:8])([F:9])[F:10])[N:6]=[C:2]4[CH3:1])[CH3:15])[C:32]=3[CH:31]=[N:30]2)=[CH:27][CH:28]=1

参加物

7

反応物 4

HCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 680410521-(4-chlorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridineHCID 86711686(2S)-2-[2-methyl-4-(trifluoromethyl)imidazole-1-yl]propanoic acid

生成物 1

HCID 73336209(2S)-1-[1-(4-chlorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]propan-1-one収率 55.8%

試薬・触媒・溶媒 2

HCID 6228Dimethylformamide触媒HCID 6344Dichloromethane溶媒2 回

実験手順

To a solution of (2S)-2-[2-methyl-4-(trifluoromethyl)imidazole-1-yl]propanoic acid (0.020 g, 0.09 mmol) in CH2Cl2 (1.5 mL) was added oxalyl chloride (0.050 mL, 0.58 mmol) and DMF (1 drop). After 20 min at room temperature, the mixture was concentrated in vacuo and the residue was added to another flask containing 1-(4-chlorophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-b]pyridine (0.028 g, 0.13 mmol) and NEt3 (0.050 mL, 0.35 mmol) in CH2Cl2 (1 mL). The resulting mixture was stirred at room temperature for 20 min, quenched with saturated aqueous NaHCO3 solution (30 mL), and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (SiO2, 0-6% MeOH/EtOAc) to afford the titled compound (0.022 g, 32%, TFA salt) as a white solid. 1H NMR (free form) (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.44 (m, 4H), 7.42 (dd, J=9.2, 8.8 Hz, 2H), 7.37 (d, J=1.2 Hz, 1H), 5.21 (q, J=7.2 Hz, 1H), 3.75 (m, 1H), 3.53 (m, 1H), 2.86 (dd, J=6.4, 6.4 Hz, 2H), 2.46 (s, 3H), 1.72 (d, J=6.8 Hz, 3H); MS: (ES) m/z calculated for C20H19ClF3N5O [M+H]+ (free form) 438.1, found 438.1; The titled compounds were analyzed by chiral normal phase chromatography (RegisPack, 25 cm×4.6 mm, 5 micron, cat#793104, 0.1% DEA/IPA, 0.7 mL/min). The (S)-enantiomer (major) had a retention time of 8.4 min and the (R)-enantiomer (minor) had a retention time of 6.4 min (isolated in 18:1 er).

後処理

  1. concentrationthe mixture was concentrated in vacuo
  2. additionthe residue was added to another flask
  3. customquenched with saturated aqueous NaHCO3 solution (30 mL)
  4. extractionextracted with ethyl acetate (50 mL)
  5. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  6. concentrationconcentrated in vacuo
  7. custompurified by flash chromatography (SiO2, 0-6% MeOH/EtOAc)

出典と根拠

ORDレコード
ord-cd93550f21b8418aa786f07d3d426ba4
出典データセット
uspto-grants-2015_11
特許番号
US09181241B2

反応ノート

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