Diethyl Ether → tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate

HRID 705743Notes

Reaction equation

HRID 705743 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.ClC(Cl)C.CCOCC.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)=[CH:25][C:24]=1[O:42][CH3:43].C(N(CC)CC)C>[Cl-].[Zn+2].[Cl-].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:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:33][CH2:34]3)=[CH:25][C:24]=2[O:42][CH3:43])[N:7]=1

Participants

8

Reactant 5

HCID 3283Diethyl EtherHCID 63651,1-Dichloroethane2×HCID 8471TriethylamineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 57416157Tert-butyl 4-(4-amino-3-methoxyphenyl)piperidine-1-carboxylate

Product 1

HCID 86675841tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylateYield 64%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 6386tert-ButanolSolvent2×

Procedure

A solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (981 mg, 4.52 mmol) in 1:1 tert-butanol:dichloroethane (40 mL) was cooled to 0° C. under nitrogen then 1.0 M zinc(II) chloride in ether (4.52 mL, 4.52 mmol) was added dropwise. After one hour a solution of tert-butyl 4-(4-amino-3-methoxyphenyl)piperidine-1-carboxylate (I26) (1.26 g, 4.11 mmol) and triethylamine (0.860 mL, 6.17 mmol) in 1:1 tert-butanol:dichloroethane (50 mL) was added dropwise at −10° C. then the mixture was stirred for 16 hours allowing the temperature to rise to room temperature. The mixture was concentrated, evaporated onto silica and chromatographed (120 g silica cartridge, 0-10% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I27) (1.277 g, 64% yield) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.28 (d, J=8.3 Hz, 1H), 8.01 (s, 1H), 6.86 (dd, J=8.3, 1.8 Hz, 1H), 6.76 (d, J=1.8 Hz, 1H), 4.25 (br s. 2H), 3.91 (s, 3H), 2.87-2.73 (m, 2H), 2.64 (tt, J=12.1, 3.6 Hz, 1H), 1.83 (d, J=12.5 Hz, 2H), 1.69-1.54 (m, overlaps with water), 1.49 (s, 9H). LCMS Method C: rt 7.12 min; m/z 431.0 [M-tBu+2H]+, 387.1 [M-Boc+2H]+; m/z 485.1 [M−H]−.

Workup

  1. customto rise to room temperature
  2. concentrationThe mixture was concentrated
  3. customevaporated onto silica
  4. customchromatographed (120 g silica cartridge, 0-10% ethyl acetate/petroleum benzine 40-60° C.)

Sources & evidence

ORD record
ord-c37d639600474c1eb80543c3c36982e8
Source dataset
uspto-grants-2015_11
Patent number
US09174946B2

Reaction notes

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