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Diethyl Ether → tert-Butyl 4-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate

HRID 1779004
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Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 1779004
CCOCC.Cl[C:7]1[N:12]=[C:11]([Cl:13])[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[N:23][CH:24]=1.CCN(CC)CC>[Cl-].[Cl-].[Zn+2].ClCCCl.CC(O)(C)C>[Cl:13][C:11]1[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=[C:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[N:23][CH:24]=2)[N:12]=1
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Komponenten

8

Edukt 4

HCID 3283Diethyl EtherHCID 8471TriethylamineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 59128562tert-Butyl 4-(5-aminopyridin-2-yl)piperidine-1-carboxylate

Produkt 1

HCID 86712273tert-Butyl 4-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate

Reagenzien, Katalysatoren, Lösungsmittel

3
HCID 3007855ZincchlorideKatalysatorHCID 111,2-DichloroethaneLösungsmittelHCID 6386tert-ButanolLösungsmittel

Versuchsvorschrift

A 1.0 M ZnCl2 solution in Et2O (2.16 mL, 2.16 mmol) was added cautiously to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (411 mg, 1.89 mmol) in 1:1 t-BuOH:DCE (100 mL) at room temperature and the resulting mixture stirred at room temperature for 20 minutes. tert-Butyl 4-(5-aminopyridin-2-yl)piperidine-1-carboxylate (K4) (500 mg, 1.80 mmol) was added followed by Et3N (0.30 mL, 2.16 mmol) then stirring was continued for 44 hours at room temperature. The volatiles were removed in vacuo and the residue was suspended in water (250 mL). The resulting suspension was sonicated for 10 minutes then filtered, washing the filter cake with water (2×100 mL). The filter cake was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A44 as an off white solid (346 mg, 42%); 1H NMR (400 MHz, d6-DMSO) δ 10.74 (s, 1H), 8.81 (s, 1H), 8.73 (d, J=2.4 Hz, 1H), 8.00 (dd, J=8.5, 2.5 Hz, 1H), 7.30 (d, J=8.5 Hz, 1H), 4.05 (d, J=11.8 Hz, 2H), 2.82 (m, 3H), 1.81 (d, J=11.1 Hz, 2H), 1.55 (m, 2H), 1.41 (s, 9H). LCMS-A: rt 5.949 min; m/z 458 [M+H]+.

Aufarbeitung

  1. customThe volatiles were removed in vacuo
  2. customThe resulting suspension was sonicated for 10 minutes
  3. filtrationthen filtered
  4. washwashing the filter cake with water (2×100 mL)
  5. custompurified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.)

Quellen und Nachweise

ORD-Eintrag
ord-f99558afdfc54f87b79d3e475dc36974
Quelldatensatz
uspto-grants-2016_02
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US09266864B2

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