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

HRID 2279767Notes

Reaction equation

HRID 2279767 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([Cl:12])[N:3]=1.CCOCC.[CH2:18]([O:20][P:21]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([F: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:12][C:4]1[C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:7]=[C:2]([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[F:34])[N:3]=1

Participants

8

Reactant 4

HCID 3283Diethyl EtherHCID 81531DiisopropylethylamineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 86697720(4-Amino-3-fluorobenzyl)phosphonic acid diethyl ester2×

Product 1

HCID 86697719Diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-fluorobenzyl)phosphonateYield 111.2%

Reagents, catalysts & solvents 3

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

Procedure

A solution of 2,6-Dichloro-5-trifluoromethylpyrimidine (4.76 gm, 22 mmol) in 20 mL of dichloroethane and t-butanol (1:1) was treated with a 1M solution of zinc chloride in ether (22 mL, 22 mmol) and allowed to stir at RT for 30 minutes. The mixture was subsequently cooled to 0° C. and treated with a solution of (4-amino-3-fluorobenzyl)phosphonic acid diethyl ester (Compound 22D, 3.3 g, 7.94 mmol) in dichloroethane and t-butanol (10 mL, 1:1) over 10 min through an addition funnel. After 1 hr, diisopropylethylamine (2.2 mL, 12.6 mmol) was added and the mixture was allowed to stir for 24 hours at RT. The solvents were evaporated and the residue was purified using flash column chromatography (9:1 DCM:EtOAc) to afford 3.9 g of the title compound (71%). 1H NMR (600 MHz, CDCl3): δ=1.23-1.28 (m, 6H), 3.1 (d, J=22 Hz, 2H), 4.02-4.09 (m, 4H), 7.09-7.25 (m, 2H), 7.63 (s, 1H), 8.24-8.27 (m, 1H), 8.58 (s, 1H).

Workup

  1. temperatureThe mixture was subsequently cooled to 0° C.
  2. waitAfter 1 hr
  3. stirringto stir for 24 hours at RT
  4. customThe solvents were evaporated
  5. customthe residue was purified

Sources & evidence

ORD record
ord-8a08f26cd1b34620a04bb5cedf8305e7
Source dataset
uspto-grants-2015_09
Patent number
US09133224B2

Reaction notes

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