Trifluoroacetic acid → N-[4-(2-amino-4,4,4-trifluoro-butoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide trifluoroacetate

HRID 1685941노트

반응식

HRID 1685941 반응식
[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:26])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[F:24])[CH:10]=[CH:11][C:12]=1[OH:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC1C=NN(C)C=1C1C=C(NC(=O)C2C=CC(OC)=CC=2F)C=CC=1O.C1COCC1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:91][C:92]([F:106])([F:105])[CH2:93][CH:94]([NH:97]C(=O)OC(C)(C)C)[CH2:95]O.[C:107]([OH:113])([C:109]([F:112])([F:111])[F:110])=[O:108]>C1COCC1>[F:110][C:109]([F:112])([F:111])[C:107]([OH:113])=[O:108].[NH2:97][CH:94]([CH2:93][C:92]([F:106])([F:105])[F:91])[CH2:95][O:13][C:12]1[CH:11]=[CH:10][C:9]([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[F:24])=[CH:8][C:7]=1[C:6]1[N:5]([CH3:26])[N:4]=[CH:3][C:2]=1[Cl:1]

참가 물질

8

반응물 6

HCID 6422Trifluoroacetic acidHCID 11776TriphenylphosphineHCID 5363146Diisopropyl azodicarboxylateHCID 23237059Tert-butyl (4,4,4-trifluoro-1-hydroxybutan-2-yl)carbamateHCID 136388017N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamideHCID 136388019N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide THF

생성물 1

HCID 86633181N-[4-(2-amino-4,4,4-trifluoro-butoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide trifluoroacetate수율 24.5%

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매4회

실험 절차

N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide (20.0 mg, 53.2 μmol) was dissolved in anhydrous THF (0.3 mL). Triphenylphosphine (15.4 mg, 58.5 μmol), pre-dissolved in anhydrous THF (0.1 mL) was added to the N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-2-fluoro-4-methoxybenzamide/THF solution. The reaction was stirred for 5 minutes and then DIAD (16.6 μl, 85.2 μmol), pre-dissolved in anhydrous THF (0.1 mL) was added to the reaction. The mixture was stirred at r.t. for 5 more minutes and then tert-butyl 4,4,4-trifluoro-1-hydroxybutan-2-ylcarbamate (16.2 mg, 66.5 μmol), pre-dissolved in anhydrous THF (0.1 mL) was added. The reaction was then stirred for 4 hours and checked by LC/MS. While the reaction had not gone to completion, pushing the reaction by heating or extending the reaction time did not seem to improve the yield. Thus, the solvent was evaporated, the resulting oil re-suspended in CH2Cl2 (0.5 mL) and TFA (20.5 μl, 266 μmol) was added (to remove the Boc-protecting group from the amine). The reaction was stirred overnight at room temperature. The next day, the solvent was removed and the resulting oil was re-dissolved in DMSO (1 mL). The product was purified by Prep LC/MS (0-50% B, 30 min) to yield N-[4-(2-amino-4,4,4-trifluoro-butoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-2-fluoro-4-methoxy-benzamide trifluoroacetate (8.1 mg, 13.0 μmol, 24.5%) as a colorless oil. LCMS m/z 501.3 (M+H); 1H NMR (400 MHz, MeOH-d4) δ ppm 2.48-2.86 (m, 2 H), 3.75 (d, J=2.78 Hz, 3 H), 3.87-3.97 (m, 1 H), 3.89 (s, 3 H), 4.10-4.43 (m, 2 H), 6.85 (dd, J=12.88, 2.27 Hz, t H), 6.91 (dd, J=8.72, 2.40 Hz, 1 H), 7.30 (dd, J=9.09, 2.27 Hz, 1 H), 7.61 (d, J=2.53 Hz, 1 H), 7.65-7.69 (m, 1 H), 7.76 (t, J=8.59 Hz, 1 H), 7.90 (dd, J=8.97, 2.65 Hz, 1 H).

후처리

  1. additionwas added to the reaction
  2. stirringThe mixture was stirred at r.t. for 5 more minutes
  3. additionwas added
  4. stirringThe reaction was then stirred for 4 hours
  5. customthe reaction
  6. temperatureby heating
  7. customThus, the solvent was evaporated
  8. customto remove the Boc-
  9. stirringThe reaction was stirred overnight at room temperature
  10. customThe next day, the solvent was removed
  11. dissolutionthe resulting oil was re-dissolved in DMSO (1 mL)
  12. customThe product was purified by Prep LC/MS (0-50% B, 30 min)

출처 및 근거

ORD 기록
ord-9c80ebff6b5c46109390ee70ba716799
출처 데이터셋
uspto-grants-2012_04
특허 번호
US08148417B2

반응 노트

불러오는 중…