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Potassium Acetate → tert-butyl 4-((1R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-4-pyrimidinyl)-6-fluoro-3-pyridinyl)ethyl)-1-piperazinecarboxylate

HRID 1621877
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 1621877
Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C@@H:41]([C:43]2[CH:44]=[C:45](B(O)O)[C:46]([F:49])=[N:47][CH:48]=2)[CH3:42])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].CC([O-])=O.[K+]>O1CCOCC1.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:45]3[CH:44]=[C:43]([C@H:41]([N:38]4[CH2:37][CH2:36][N:35]([C:33]([O:32][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:34])[CH2:40][CH2:39]4)[CH3:42])[CH:48]=[N:47][C:46]=3[F:49])[CH:3]=2)=[CH:12][CH:13]=1
KomponentenReaktionsbedingungenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

6

Edukt 3

HCID 517044Potassium AcetateHCID 595484046-chloro-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amineHCID 66600472(R)-5-(1-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid

Produkt 1

HCID 66600507tert-butyl 4-((1R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-4-pyrimidinyl)-6-fluoro-3-pyridinyl)ethyl)-1-piperazinecarboxylateAusbeute 43,5 %

Reagenzien, Katalysatoren, Lösungsmittel

2
HCID 962WaterLösungsmittelHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

6-chloro-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amine (Example 177) (0.766 g, 1.996 mmol), (5-((1R)-1-(4-(tert-butoxycarbonyl)-1-piperazinyl)ethyl)-2-fluoro-3-pyridinyl)boronic acid (Example 146, Step 4)(0.705 g, 1.996 mmol), PdCl2AmPhos (0.071 g, 0.100 mmol), and KOAc (0.588 g, 5.99 mmol) in a mixture of dioxane (16.6 mL) and water (3.3 mL) was sparged with nitrogen and then heated at 100° C. for 2.5 h. The yellow reaction mixture was subsequently partitioned between CH2Cl2 (60 mL) and water (50 mL). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were then dried over Na2SO4 and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (80 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide tert-butyl 4-((1R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-4-pyrimidinyl)-6-fluoro-3-pyridinyl)ethyl)-1-piperazinecarboxylate (0.570 g, 0.868 mmol, 43.5% yield) as light-yellow foam. m/z (ESI, +ve) 657.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=8.22 Hz, 1H); 8.18 (s, 1H); 7.18 (d, J=7.24 Hz, 4H); 6.82-6.89 (m, 5H); 4.75 (br. s., 4H); 3.79 (s, 6H); 3.60 (d, J=7.04 Hz, 1H); 3.43 (br. s., 4H); 2.63 (s, 3H); 2.30-2.53 (m, 4H); 1.44 (s, 12H).

Aufarbeitung

  1. customwas sparged with nitrogen
  2. customThe yellow reaction mixture was subsequently partitioned between CH2Cl2 (60 mL) and water (50 mL)
  3. customThe organic layer was separated
  4. extractionthe aqueous layer was extracted with CH2Cl2 (2×50 mL)
  5. dry with materialThe combined organic extracts were then dried over Na2SO4
  6. concentrationconcentrated
  7. custompurified by chromatography through a silica gel column (80 g)
  8. washeluting with a gradient of 0% to 100% EtOAc in hexane

Quellen und Nachweise

ORD-Eintrag
ord-021bbf308b9841b18097ec27fa8f29b0
Quelldatensatz
uspto-grants-2014_07
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08772480B2

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