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Ammonium Chloride → tert-Butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate

HRID 1473117
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Reaktionsgleichung von HRID 1473117
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:27]=[C:26]([CH2:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH2:36][C:37]([O-])=[O:38])[C:25]([C:40]([F:43])([F:42])[F:41])=[CH:24][N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].[NH4+].C[N:48](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:48][C:37](=[O:38])[CH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][CH2:28][C:26]1[C:25]([C:40]([F:42])([F:43])[F:41])=[CH:24][N:23]=[C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)=[CH:16][CH:17]=2)[N:27]=1
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Komponenten

6

Edukt 4

HCID 25517Ammonium ChlorideHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 68282975Lithium 2-(2-(2-(2-((4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate

Produkt 1

HCID 71229653
tert-Butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate
Ausbeute 29 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6228DimethylformamideLösungsmittel

Versuchsvorschrift

The crude lithium 2-(2-(2-(2-((4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I97) was dissolved in DMF (2 mL) and ammonium chloride (210 mg, 3.92 mmol), HATU (149 mg, 0.392 mmol) and DIPEA (68.0 μL, 0.392 mmol) were added. The resulting mixture was stirred at room temperature for 18 hours, then concentrated. The residue was partitioned between saturated sodium bicarbonate (50 mL) and ethyl acetate (50 mL); the aqueous phase was extracted with further ethyl acetate (2×50 mL) and the combined ethyl acetate phases washed with brine (3×50 mL), dried over sodium sulfate and evaporated. The residue was chromatographed (4 g silica cartridge, 20-100% gradient of 1% isopropylamine in ethyl acetate/petroleum benzine 40-60° C., then 0-5% gradient methanol/1% isopropylamine in ethyl acetate) to give a residue which was chromatographed (12 g silica cartridge, 80-100% gradient of 1% isopropylamine in ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I98) (34 mg, 29% yield over two steps from ester) as a white foam; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.62 (s, 1H), 7.57 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 7.29-7.20 (m, 8H), 5.38 (s, 2H), 3.73 (s, 2H), 3.49 (s, 2H), 3.46-3.39 (m, 4H), 3.16-3.04 (m, 4H), 2.44-2.34 (m, 4H), 1.45 (s, 9H). LCMS Method C: rt 5.08 min; m/z 599.1 [M+H]+, 499.1 [M-Boc+2H]+; m/z 597.2 [M−H]−.

Aufarbeitung

  1. concentrationconcentrated
  2. customThe residue was partitioned between saturated sodium bicarbonate (50 mL) and ethyl acetate (50 mL)
  3. extractionthe aqueous phase was extracted with further ethyl acetate (2×50 mL)
  4. washthe combined ethyl acetate phases washed with brine (3×50 mL)
  5. dry with materialdried over sodium sulfate
  6. customevaporated
  7. customThe residue was chromatographed (4 g silica cartridge, 20-100% gradient of 1% isopropylamine in ethyl acetate/petroleum benzine 40-60° C.
  8. custom0-5% gradient methanol/1% isopropylamine in ethyl acetate) to give a residue which
  9. customwas chromatographed (12 g silica cartridge, 80-100% gradient of 1% isopropylamine in ethyl acetate/petroleum benzine 40-60° C.)

Quellen und Nachweise

ORD-Eintrag
ord-4e53dce41fac45c39b106caf3e59f9fe
Quelldatensatz
uspto-grants-2015_04
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US09012461B2

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