2,3-Difluoro-4-methoxybenzeneboronic acid → 4-(((2',3'-Difluoro-4'-methoxy-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine

HRID 391467노트

반응식

HRID 391467 반응식
Br[C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:5][O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.[F:34][C:35]1[C:40]([F:41])=[C:39]([O:42][CH3:43])[CH:38]=[CH:37][C:36]=1B(O)O>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:34][C:35]1[C:40]([F:41])=[C:39]([O:42][CH3:43])[CH:38]=[CH:37][C:36]=1[C:2]1[CH:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[C:4]([CH2:5][O:6][CH2:7][C:8]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:3]=1

참가 물질

5

반응물 2

HCID 250672722,3-Difluoro-4-methoxybenzeneboronic acidHCID 58993603tert-Butyl 4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate

생성물 1

HCID 589935254-(((2',3'-Difluoro-4'-methoxy-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine

시약·촉매·용매 2

HCID 11979704Tetrakis(triphenylphosphine)palladium촉매HCID 8028Tetrahydrofuran용매

반응 조건

온도
120 °C

실험 절차

tert-Butyl 4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (150 mg, 0.28 mmol), 2,3-difluoro-4-methoxyphenylboronic acid (139 mg, 0.84 mmol), and tetrakis(triphenylphosphine) palladium(0) (33 mg, 0.03 mmol) were combined in dry tetrahydrofuran (3 mL) in a microwave tube and sealed. After flushing with nitrogen, 1.0 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated and treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol and concentrated to afford 45 mg (33%). 1H-NMR (CDCl3, 500 MHz) δ 7.57 (s, 1H), 7.26-7.38 (m, 6H), 7.13-7.17 (m, 1H), 7.00-7.06 (m, 1H), 6.77-6.83 (m, 1H), 4.41 (s, 2H), 3.93 (s, 3H), 3.44 (s, 2H), 2.84-2.92 (m, 2H), 2.68-2.77 (m, 2H), 2.13-2.18 (m, 2H), 1.83-1.92 (m, 2H). Mass spec.: 492.01 (MH)+. Accurate mass spec.: m/z 492.1978 [MH]+, Δ=3.3 ppm.

후처리

  1. customsealed
  2. customAfter flushing with nitrogen, 1.0 mL of a 1 N potassium hydroxide aqueous solution
  3. additionwas introduced
  4. temperatureAfter cooling to room temperature
  5. concentrationthe reaction mixture was concentrated
  6. additiontreated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h
  7. customThe solvent was removed in vacuo
  8. washAfter washing the column with several volumes of methanol
  9. washthe product was eluted
  10. washby washing the column with 2 M ammonia in methanol
  11. concentrationconcentrated
  12. customto afford 45 mg (33%)

출처 및 근거

ORD 기록
ord-ebace3218e7c42d0a0f727aa7772e207
출처 데이터셋
uspto-grants-2013_02
특허 번호
US08383821B2

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