1-Naphthoic acid → (2R)-3-[[3-(4-fluoro-3-methylphenoxy) phenyl][[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

HRID 1265194노트

반응식

HRID 1265194 반응식
[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:17]1[CH:18]=[C:19]([N:23]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:42])([F:41])[F:40])[CH:33]=2)[CH2:24][C@@H:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:20]=[CH:21][CH:22]=1.C1(C(O)=O)C2C(=CC=CC=2)C=CC=1>CN(C)C(=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:21]2[CH:20]=[C:19]([N:23]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:40])([F:41])[F:42])[CH:33]=3)[CH2:24][C@@H:25]([OH:30])[C:26]([F:27])([F:28])[F:29])[CH:18]=[CH:17][CH:22]=2)=[CH:4][C:3]=1[CH3:9]

참가 물질

7

반응물 4

HCID 68471-Naphthoic acidHCID 10796Cesium carbonate2회HCID 27373944-Fluoro-3-methylphenolHCID 86586491(2R)-3-[[(3-bromophenyl)] [[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol

생성물 1

HCID 57109777(2R)-3-[[3-(4-fluoro-3-methylphenoxy) phenyl][[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol수율 23%

시약·촉매·용매 2

HCID 1140Toluene용매HCID 31374Dimethylacetamide용매

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온도
105 °C

실험 절차

A suspension of 4-fluoro-3-methylphenol (98.0 μL, 0.88 mmol) and cesium carbonate (319.5 mg, 0.98 mrnol) in 1 mL of N,N-dimethylacetamide was preheated at 60° C. for 5 minutes. To this solution was added 4 mL of a stock solution containing (2R)-3-[[(3-bromophenyl)][[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (200 mg, 0.437 mmol) from EX-33B, 1-naphthoic acid (164 mg, 0.95 mmol), copper(I) trifluoromethansulfonate benzene complex (21.8 mg, 0.0434 mmol), 4 Å sieves (105 mg), and 4 mL of toluene. The reaction mixture was stirred at 105° C. for 3 weeks and 2 days. During that time, additional cesium carbonate and catalyst were added (a spatula tip of each) to the reaction three different times. The reaction was cooled to room temperature, filtered through celite, and the solvent was evaporated. The residue was purified by reverse phase HPLC eluting with 35% to 90% acetonitrile in water to afford 50.5 mg (23%) of the desired (2R)-3-[[3-(4-fluoro-3-methylphenoxy)phenyl][[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd. for C24H20F7NO3: 504.1410 [M+H]+, found: 504.1389. 1H NMR (acetone-d6) δ 7.44 (t, 1H), 7.24 (d, 1H), 7.08-7.21 (m, 3H), 6.98 (t, 1H), 6.75-6.85 (m, 1H), 6.68-6.74 (m, 1H), 6.53 (d, 1H), 6.21-6.34 (m, 2H), 4.79 (t, 2H), 4.464.53 (m, 1H), 3.95 (dd, 1H), 2.61-2.72 (m, 1H), 2.20 (s, 3H).

후처리

  1. customto the reaction three different times
  2. temperatureThe reaction was cooled to room temperature
  3. filtrationfiltered through celite
  4. customthe solvent was evaporated
  5. customThe residue was purified by reverse phase HPLC
  6. washeluting with 35% to 90% acetonitrile in water

출처 및 근거

ORD 기록
ord-815208241e834dddb3c51d0f2eee112f
출처 데이터셋
uspto-grants-2003_04
특허 번호
US06544974B2

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