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

HRID 511237ノート

反応式

HRID 511237 の反応式
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

参加物

8

反応物 4

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

生成物 1

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

試薬・触媒・溶媒 3

HCID 3007855Zincchloride触媒HCID 111,2-Dichloroethane溶媒HCID 6386tert-Butanol溶媒

実験手順

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+).

後処理

  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

出典と根拠

ORDレコード
ord-6ed68d65c02a4807b85a75d1998a3b38
出典データセット
uspto-grants-2015_08
特許番号
US09096624B2

反応ノート

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