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Hydrochloric Acid → Tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate

HRID 705727
Notes
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Reaction equation

HRID 705727 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[C:25]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:35][C:36]([O-])=[O:37])[C:24]([C:39]([F:42])([F:41])[F:40])=[CH:23][N:22]=3)=[C:16]([O:43][CH3:44])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].O[N:47]1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>O1CCCC1.CN(C)C=O>[NH2:47][C:36](=[O:37])[CH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][CH2:27][C:25]1[C:24]([C:39]([F:40])([F:42])[F:41])=[CH:23][N:22]=[C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)=[CH:15][C:16]=2[O:43][CH3:44])[N:26]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 517111Ammonium CarbonateHCID 71225535Lithium 2-(2-(2-(2-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate

Product 1

HCID 71225669Tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a stirred solution of lithium 2-(2-(2-(2-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I7) (0.352 g, 0.672 mmol), 1-hydroxybenzotriazole (0.093 g, 0.686 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide)hydrochloride (0.121 g, 0.629 mmol) in dry tetrahydrofuran (16 mL) and dimethylformamide (7 mL) was added N,N-diisopropylethylamine (0.498 mL, 2.86 mmol) under a nitrogen atmosphere. The reaction mixture was stirred for 10 minutes at room temperature then ammonium carbonate (0.263 g, 2.859 mmol) was added and the resulting suspension was stirred at room temperature for 18 hours. The reaction volatiles were evaporated in vacuo and the resulting residue was diluted with ethyl acetate (15 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×15 mL). The combined organic extracts were washed with water, brine, dried (magnesium sulfate) and concentrated in vacuo to give a yellow foam which was purified by flash column chromatography on silica gel (55-85% ethyl acetate/petroleum ether) to give the title compound (I8) (0.276 g, 87%) as a yellow foam; 1H NMR (300 MHz, CDCl3) δ 1.48 (d, 9H, J=1.1 Hz), 3.09 (d, 8H, J=3.9 Hz), 3.58 (brs, 4H), 3.66 (s, 2H), 3.88 (d, 3H, J=1.0 Hz), 5.48 (brs, 1H), 5.78 (brs, 1H), 6.54 (d, 1H, J=1.3 Hz), 6.57 (s, 1H), 7.23-7.25 (brs, 4H), 7.72 (s, 1H), 8.13 (d, 1H, J=8.6 Hz) and 8.48 (s, 1H). LCMS Method B: rt 8.52 min; m/z 615.4 [M+H]+.

Workup

  1. stirringthe resulting suspension was stirred at room temperature for 18 hours
  2. customThe reaction volatiles
  3. customwere evaporated in vacuo
  4. additionthe resulting residue was diluted with ethyl acetate (15 mL) and water (10 mL)
  5. customThe layers were separated
  6. extractionthe aqueous layer was extracted with ethyl acetate (2×15 mL)
  7. washThe combined organic extracts were washed with water, brine
  8. dry with materialdried (magnesium sulfate)
  9. concentrationconcentrated in vacuo
  10. customto give a yellow foam which
  11. customwas purified by flash column chromatography on silica gel (55-85% ethyl acetate/petroleum ether)

Sources & evidence

ORD record
ord-5f7d6558853b4d829b669bad4d7cf9cc
Source dataset
uspto-grants-2015_11
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09174946B2

Reaction notes

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