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

HRID 511237笔记

反应方程式

HRID 511237 反应方程式
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

参与物

8

反应物 4

HCID 3283乙醚HCID 8471三乙胺HCID 27827742,4-二氯-5-三氟甲基嘧啶HCID 86653997Diethyl(4-amino-3-methoxybenzyl)phosphonate

产物 1

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

试剂、催化剂与溶剂 3

HCID 3007855氯化锌催化剂HCID 111,2-二氯乙烷溶剂HCID 6386叔丁醇溶剂

实验过程

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+).

后处理

  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

来源与证据

ORD记录
ord-6ed68d65c02a4807b85a75d1998a3b38
来源数据集
uspto-grants-2015_08
专利号
US09096624B2

反应笔记

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