Triethylamine → HCID 24901496, Verbindung

HRID 1394922Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1394922
[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14](OC(C)(C)C)=[O:15])[C@H:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1.C(N(CC)CC)C.C(OC([NH:41][C@H:42](C(O)=O)[C:43]([CH3:46])([CH3:45])[CH3:44])=O)(C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl.FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([C@@H:42]([NH2:41])[C:43]([CH3:46])([CH3:45])[CH3:44])=[O:15])[C@H:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1

Komponenten

7

Edukt 4

HCID 8471TriethylamineHCID 2724699PyBOPHCID 2734668(S)-2-((tert-Butoxycarbonyl)amino)-3,3-dimethylbutanoic acidHCID 58641236HCID 58641236, Verbindung

Produkt 1

HCID 24901496HCID 24901496, Verbindung

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6344DichloromethaneLösungsmittel2×HCID 6422Trifluoroacetic acidLösungsmittel2×

Versuchsvorschrift

A solution of tert-butyl (2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (5-5, 400 mg, 1.12 mmol, 1 equiv) in a 4:1 mixture of dichloromethane and trifluoroacetic acid (20 mL) was stirred for 30 minutes, then concentrated. The residue was dried via toluene azeotrope (2×10 mL), then dissolved in DMF (5 mL). Triethylamine (0.780 mL, 5.60 mmol, 5.00 equiv), N-(tert-butoxycarbonyl)-3-methyl-L-valine (388 mg, 1.68 mmol, 1.50 equiv), and PYBOP (874 mg, 1.68 mmol, 1.50 equiv) were added, and the resulting mixture was stirred at 23° C. for 24 hours. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (hexanes initially, grading to 40% ethyl acetate in hexanes) to yield the desired coupled, N-Boc-protected intermediate, which was dissolved in a 2:1 mixture of dichloromethane and trifluoroacetic acid. The resulting solution was allowed to stand for 30 minutes, then concentrated. The residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present). The desired fractions were partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (2×50 mL), then the combined organic layers were dried over sodium sulfate and concentrated to provide (1S)-1-{[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-2,2-dimethylpropylamine (16-1) as a white solid. 1H NMR (500 MD, CDCl3) major rotamer: δ 7.40 (t, 2H, J=7.6 Hz), 7.31 (m, 1H), 7.26 (d, 2H, J=7.8 Hz), 7.11-6.93 (m, 3H), 6.38 (s, 1H), 5.81 (m, 1H), 4.88 (m, 2H), 3.03 (s, 1H), 1.00 (s, 9H). LRMS m/z (M+H) 371.0 found, 371.2 required.

Aufarbeitung

  1. concentrationconcentrated
  2. dry with materialThe residue was dried via toluene
  3. dissolutiondissolved in DMF (5 mL)
  4. stirringthe resulting mixture was stirred at 23° C. for 24 hours
  5. customThe reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (2×50 mL)
  6. dry with materialThe combined organic layers were dried over sodium sulfate
  7. concentrationconcentrated
  8. customThe residue was purified by flash column chromatography (hexanes initially
  9. customto yield the
  10. waitto stand for 30 minutes
  11. concentrationconcentrated
  12. customThe residue was purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present)
  13. customThe desired fractions were partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (2×50 mL)
  14. dry with materialthe combined organic layers were dried over sodium sulfate
  15. concentrationconcentrated

Quellen und Nachweise

ORD-Eintrag
ord-27a4f949b5f74b87b112e4217ac6bb40
Quelldatensatz
uspto-grants-2008_03
Patentnummer
US07348440B2

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