Diethyl Ether → Diethyl (4-{[4-chloro-5-(trifluoromethyl) pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate

HRID 511237Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 511237
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:33]=[CH:32][C:22]([CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[CH:21][C:20]=1[O:34][CH3:35].C(N(CC)CC)C>ClCCCl.CC(O)(C)C.[Cl-].[Cl-].[Zn+2]>[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:33]=[CH:32][C:22]([CH2:23][P:24](=[O:31])([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[CH:21][C:20]=2[O:34][CH3:35])[N:12]=1

Komponenten

8

Edukt 4

HCID 3283Diethyl EtherHCID 8471TriethylamineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 86653997Diethyl(4-amino-3-methoxybenzyl)phosphonate

Produkt 1

HCID 86654002Diethyl (4-{[4-chloro-5-(trifluoromethyl) pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonateAusbeute 70 %

Reagenzien, Katalysatoren, Lösungsmittel 3

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

Versuchsvorschrift

1.0 M Zinc dichloride in ether (4.07 mL, 4.07 mmol) was added to a solution of 2,4-dichloro-5-trifluoromethylpyrimidine (0.803 g, 3.70 mmol) in 1,2-dichloroethane (6.7 mL) and t-BuOH (6.7 mL). After 30 minutes diethyl (4-amino-3-methoxybenzyl)phosphonate (1.01 g, 3.70 mmol) was added followed by triethylamine (0.567 mL, 4.07 mmol) while keeping the temperature at ˜25° C. The reaction mixture was allowed to stir at rt overnight before quenching with sat. aq. NaHCO3 (10 mL). The resulting mixture was extracted with EtOAc (15 mL) and the organic layer was washed with brine (10 mL), dried over anhydrous NaSO4, filtered, and concentrated under reduced pressure to afford a yellow oil. This crude material was initially purified using an Isco Combiflash system eluting with 0→5% MeOH in DCM as eluent followed by preparative HPLC (MDP) to afford diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate, 1.09 g (70% yield). 1H NMR (CD3OD, 400 MHz): δ=1.28 (t, J=7.07 Hz, 6 H), 3.23-3.29 (m, 2 H), 3.90-3.95 (m, 3 H), 4.01-4.13 (m, 4 H), 6.90-6.96 (m, 1 H), 7.03 (m, J=2.00 Hz, 1 H), 8.02 (d, J=8.34 Hz, 1 H), 8.62 (s, 1 H). MS (ES+).

Aufarbeitung

  1. customat ˜25° C
  2. custombefore quenching with sat. aq. NaHCO3 (10 mL)
  3. extractionThe resulting mixture was extracted with EtOAc (15 mL)
  4. washthe organic layer was washed with brine (10 mL)
  5. dry with materialdried over anhydrous NaSO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customto afford a yellow oil
  9. customThis crude material was initially purified
  10. washeluting with 0→5% MeOH in DCM as eluent

Quellen und Nachweise

ORD-Eintrag
ord-6ed68d65c02a4807b85a75d1998a3b38
Quelldatensatz
uspto-grants-2015_08
Patentnummer
US09096624B2

Notizen zur Reaktion

Wird geladen…