Nitrogen → tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate

HRID 705723Notes

Reaction equation

HRID 705723 reaction equation
Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.N#N.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:18][C:17]=1[O:35][CH3:36].C(N(CC)CC)C>[Cl-].[Zn+2].[Cl-].ClC(Cl)C.C(O)(C)(C)C>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:24][CH2:23]3)=[CH:18][C:17]=2[O:35][CH3:36])[N:7]=1

Participants

7

Reactant 4

HCID 947NitrogenHCID 8471TriethylamineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 67128946Tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate

Product 1

HCID 86704320tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylateYield 69%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 86704321Dichloroethane t-butanolSolvent3×

Conditions

Temperature
0 °C

Procedure

To a stirred chilled solution (0° C.) of 2,4-dichloro-5-(trifluromethyl)pyrimidine (0.800 g, 3.68 mmol) under a stream of dry N2 gas in 1:1 dichloroethane/tert-butanol (50 mL) was added a solution of zinc chloride (1 M in diethyl ether; 4.42 mL, 4.42 mmol). After 1 hour of stirring at 0° C., a solution of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate (I2) in 1:1 dichloroethane/tert-butanol (15 mL) (1.13 g, 3.68 mmol, 1 eq.) was added drop wise over 30 minutes followed by the drop wise addition of a solution of triethylamine (0.565 mL, 0.410 mmol, 1.1 eq.) in 1:1 dichloroethane/tert-butanol (5 mL) over 30 minutes. The resulting mixture was then stirred vigorously at room temperature for 18 hours. The volatiles were evaporated under reduced pressure and the residue then dried under high vacuum. Ethyl acetate and water were added and the aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water, brine, dried (magnesium sulfate), filtered and evaporated to give the crude product as a dark yellow foam. The crude product was purified by flash column chromatography on silica gel (0-20% ethyl acetate/petroleum ether) to yield the title compound (I3) (1.25 g, 69%) as a yellow solid; 1H NMR (300 MHz, CDCl3) δ 1.48 (s, 9H), 3.11 (t, 4H, J=5.2 Hz), 3.59 (t, 4H, J=5.0 Hz), 3.88 (s, 3H), 6.54 (s, 1H), 6.57 (d, 1H, J=9.4 Hz), 7.83 (s, 1H), 8.17 (d, 1H, J=8.5 Hz) and 8.53 (s, 1H). LCMS Method B: rt 9.24 min; m/z 488.3 [M+H]+.

Workup

  1. stirringThe resulting mixture was then stirred vigorously at room temperature for 18 hours
  2. customThe volatiles were evaporated under reduced pressure
  3. customthe residue then dried under high vacuum
  4. additionEthyl acetate and water were added
  5. extractionthe aqueous layer was extracted with ethyl acetate (3×30 mL)
  6. washThe combined organic extracts were washed with water, brine
  7. dry with materialdried (magnesium sulfate)
  8. filtrationfiltered
  9. customevaporated
  10. customto give the crude product as a dark yellow foam
  11. customThe crude product was purified by flash column chromatography on silica gel (0-20% ethyl acetate/petroleum ether)

Sources & evidence

ORD record
ord-78f2e7b2e61c40f988366b7bbd1ce9d1
Source dataset
uspto-grants-2015_11
Patent number
US09174946B2

Reaction notes

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