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

HRID 710677노트

반응식

HRID 710677 반응식
[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.[F: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>[F: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

참가 물질

7

반응물 4

HCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 679846101-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridineHCID 86711686(2S)-2-[2-methyl-4-(trifluoromethyl)imidazole-1-yl]propanoic acid

생성물 1

HCID 73336210(2S)-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]propan-1-one수율 79.1%

시약·촉매·용매 2

HCID 6228Dimethylformamide촉매HCID 6344Dichloromethane용매2회

실험 절차

To a solution of (2S)-2-[2-methyl-4-(trifluoromethyl)imidazole-1-yl]propanoic acid (0.020 g, 0.09 mmol) in CH2Cl2 (3 mL) was added oxalyl chloride (0.040 mL, 0.46 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-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-b]pyridine (0.028 g, 0.13 mmol) and NEt3 (0.060 mL, 0.43 mmol) in CH2Cl2 (3 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, 0-8% MeOH/EtOAc) to afford the titled compound (0.030 g, 44%, TFA salt) as a white solid. 1H NMR (TFA salt) (400 MHz, CDCl3) δ 9.70 (s, 1H), 8.43 (s, 1H), 7.78 (d, J=0.8 Hz, 1H), 7.42 (dd, J=9.2, 8.8 Hz, 2H), 7.20 (dd, J=8.8, 8.4 Hz, 2H), 5.61 (q, J=7.2 Hz, 1H), 3.89 (m, 2H), 2.84 (dd, J=6.2, 6.2 Hz, 2H), 2.65 (s, 3H), 2.15 (m, 2H), 1.84 (d, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C20H19F4N5O [M+H]+ (free form) 422.1, found 422.1; 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 7.2 min and the (R)-enantiomer (minor) had a retention time of 6.2 min (isolated in 19:1 er).

후처리

  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, 0-8% MeOH/EtOAc)

출처 및 근거

ORD 기록
ord-b82f79c1c61a4eb18020fbd9cdec95a2
출처 데이터셋
uspto-grants-2015_11
특허 번호
US09181241B2

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