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Sodium Hydroxide → HCID 68157525, Verbindung

HRID 1892770
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 1892770
[CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25](OC)=[O:26])=[CH:23][N:22]=1)[C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[N:12]2)=[CH:9][CH:10]=1.[OH-].[Na+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:68][CH2:69][CH2:70][C:71]([O:73][CH3:74])=[O:72]>CO.[Cl-].[Na+].O>[CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:68][CH2:69][CH2:70][C:71]([O:73][CH3:74])=[O:72])=[O:26])=[CH:23][N:22]=1)[C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[N:12]2)=[CH:9][CH:10]=1
KomponentenReaktionsbedingungenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

8

Edukt 5

HCID 14798Sodium HydroxideHCID 81531DiisopropylethylamineHCID 2734767Methyl 3-aminopropanoate hydrochlorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 68178642HCID 68178642, Verbindung

Produkt 1

HCID 68157525
HCID 68157525, Verbindung
Ausbeute 91,1 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 887MethanolLösungsmittelHCID 57417360Sodium chloride; waterLösungsmittel

Reaktionsbedingungen

Temperatur
20 °C

Versuchsvorschrift

To a solution of (+\−)-methyl 6-(3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butylamino)nicotinate (800 mg, 1.85 mmol) in methanol (5 mL) was added 2N aqueous sodium hydroxide (9.2 mL, 18.4 mmol). The resulting mixture was stirred at 20° C. for 2 h. Methanol was removed under reduced pressure and the residue was acidified by addition of 1N aqueous HCl to pH 3-4 and extracted with dichloromethane (30 mL×2). The combined organic layers were concentrated under reduced pressure. The residue was dissolved in DMF (10 mL). HATU (1.36 mg, 3.58 mmol) and N,N-di-iso-propylethylamine (1.15 mg, 8.95 mmol) were added. Methyl 3-aminopropanoate hydrochloride (370 mg, 2.68 mmol) was added. The resulting mixture was stirred at 30° C. for 1 h. The mixture was poured into brine (30 mL) and extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with 1N aqueous HCl (30 mL), dried over anhydrous Na2SO4 and concentrated to dryness. The crude residue was purified silica gel chromatography to give (+\−)-methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butylamino)nicotinamido)propanoate (850 mg) as an oil. 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.37 (d, J=12.0 Hz, 2H), 7.87 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.76-7.70 (m, 2H), 6.52 (s, 1H), 6.22 (d, J=8.4 Hz, 1H), 5.07 (d, J=4.0 Hz, 1H), 4.86 (d, J=9.2 Hz, 1H), 3.62-3.58 (m, 5H), 2.54 (t, J=5.6 Hz, 2H), 1.77-1.59 (m, 3H), 1.75-1.63 (m, 2H), 0.95 (d, J=6.0 Hz, 3H), 0.91 (d, J=6.0 Hz, 3H). (+\−)-methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butylamino)nicotinamido)propanoate was resolved by SFC (column: Chiralpak AD-3, 50×4.6 mm×3 μm; mobile phase: 40% methanol in CO2; modifier: 0.05% diethylamine; flow rate: 4 mL/min) to give methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butylamino)nicotinamido)propanoate, Isomer 1 (450 mg, retention time: 0.62 min) and methyl 3-(6-(3-methyl-1-(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)butylamino)nicotinamido)propanoate, isomer 2 (400 mg, retention time: 1.30 min).

Aufarbeitung

  1. customMethanol was removed under reduced pressure
  2. additionthe residue was acidified by addition of 1N aqueous HCl to pH 3-4
  3. extractionextracted with dichloromethane (30 mL×2)
  4. concentrationThe combined organic layers were concentrated under reduced pressure
  5. dissolutionThe residue was dissolved in DMF (10 mL)
  6. stirringThe resulting mixture was stirred at 30° C. for 1 h
  7. extractionextracted with ethyl acetate (30 mL×2)
  8. washThe combined organic layers were washed with 1N aqueous HCl (30 mL)
  9. dry with materialdried over anhydrous Na2SO4
  10. concentrationconcentrated to dryness
  11. customThe crude residue was purified silica gel chromatography

Quellen und Nachweise

ORD-Eintrag
ord-9f8492a057184e87a3d353fb9e09d8e1
Quelldatensatz
uspto-grants-2013_08
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08507533B2

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