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

HRID 2279808Notes

Reaction equation

HRID 2279808 reaction equation
CCOCC.Cl[C:7]1[N:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([Cl:17])[N:8]=1.[CH2:18]([O:20][P:21]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([CH3:34])[CH:28]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:19].C(N(C(C)C)CC)(C)C>ClC(Cl)C.C(O)(C)(C)C.[Cl-].[Zn+2].[Cl-]>[Cl:17][C:9]1[C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:12]=[C:7]([NH:33][C:30]2[CH:31]=[CH:32][C:27]([CH2:26][P:21](=[O:25])([O:20][CH2:18][CH3:19])[O:22][CH2:23][CH3:24])=[CH:28][C:29]=2[CH3:34])[N:8]=1

Participants

8

Reactant 4

HCID 3283Diethyl EtherHCID 81531DiisopropylethylamineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 22221360(4-Amino-3-methyl benzyl)phosphonic acid diethyl ester2×

Product 1

HCID 86697748Diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methylbenzyl)phosphonate

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 63651,1-DichloroethaneSolvent2×HCID 6386tert-ButanolSolvent2×

Procedure

A 1M solution of zinc chloride in ether (12.8 mL, 12.8 mmol) was added to a solution of 2,6-dichloro-5-trifluoromethylpyrimidine (2.76 gm, 12.8 mmol) in 20 mL of dichloroethane and t-butanol (1:1) under an atmosphere of nitrogen. The reaction mixture was stirred at rt for 30 min, cooled to 0° C. and then treated with a solution of (4-amino-3-methyl benzyl)phosphonic acid diethyl ester (Compound 33D, 2.2 gm, 8.5 mmol) in dichloroethane and t-butanol (10 mL, 1:1) slowly over 10 min through an addition funnel. After 1 hour, diisopropylethylamine (2.2 mL, 12.6 mmol) was added and then reaction gradually warmed up to rt over 4 hrs. The reaction mixture was refrigerated overnight causing the desired product to precipitate out of solution. This was collected by filtration to afford 2.7 g of the title compound (73%). 1H NMR (300 MHz, CDCl3): δ 1.21-1.26 (m, 6H), 2.3 (s, 3H), 3.15 (d, J=22.0 Hz, 2H), 3.99-4.09 (m, 4H), 7.17 (m, 3H), 7.72 (d, J=7.5 Hz, 1H), 8.52 (s, 1H).

Workup

  1. temperaturecooled to 0° C.
  2. waitAfter 1 hour
  3. customreaction
  4. temperaturegradually warmed up to rt over 4 hrs
  5. waitThe reaction mixture was refrigerated overnight

Sources & evidence

ORD record
ord-40d3bd38bac24f81a29191917c5bdb9a
Source dataset
uspto-grants-2015_09
Patent number
US09133224B2

Reaction notes

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