1-Hydroxybenzotriazole → Ethyl 3-((3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)amino)-3-oxopropanoate

HRID 1482692Notes

Reaction equation

HRID 1482692 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:19][CH:18]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:28]([O:30][C:31](=[O:36])[CH2:32][C:33]([O-])=[O:34])[CH3:29].[K+].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.CCCCCC.C(OCC)(=O)C>[F:15][C:14]1[C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:1][C:33](=[O:34])[CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:36])[CH:7]=[CH:6][CH:5]=2)=[N:10][C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:19][CH:18]=2)=[N:12][CH:13]=1

Participants

8

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 3446434Potassium ethyl malonateHCID 59174534N4-(3-aminophenyl)-5-fluoro-N2-(4-(2-methoxyethoxy)phenyl)pyrimidine-2,4-diamine

Product 1

HCID 86724347Ethyl 3-((3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)amino)-3-oxopropanoateYield 96.8%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 21226206Ethyl acetate hexaneSolvent

Procedure

Into a 25 ml, three neck flask under nitrogen atmosphere, a solution of N4-(3-aminophenyl)-5-fluoro-N2-(4-(2-methoxyethoxy)phenyl)pyrimidine-2,4-diamine (0.15 g) in DMF (5 mL) was charged potassium 3-ethoxy-3-oxopropanoate (0.089 g), EDCI.HCl (0.117 g), HOBt (0.093 g) and TEA (0.164 g). The reaction mixture was stirred for 8 hr at room temperature. Completion of the reaction was monitored by TLC using hexane:ethyl acetate (5:5) as the mobile phase. After completion, the reaction mixture was poured into water. The product was extracted with ethyl acetate and the organic layer was washed with brine. The solvent was removed under reduced pressure at 40° C. The obtained solid was purified by triturating with diethyl ether (2×10 mL) to give 0.19 g of ethyl 3-((3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)amino)-3-oxopropanoate. 1H NMR: DMSO-d6 (400 MHz): 1.182-1.234 (q, 3H, J=6.8), 3.306 (s, 3H), 3.461 (s, 2H), 3.623-3.646 (t, 2H, J=4.8), 4.010-4.033 (t, 2H, J=4.4), 4.090-4.144 (t, 2H, J=7.2), 6.775-6.797 (d, 2H, J=8.8), 7.267-7.283 (d, 2H, J=6.4), 7.511-7.533 (d, 1H, J=8), 7.575-7.591 (d, 1H, J=6.4), 7.817 (s, 1H), 8.058-8.066 (d, 1H, J=3.2), 8.963 (s, 1H), 9.375 (s, 1H), 10.162 (s, 1H).

Workup

  1. extractionThe product was extracted with ethyl acetate
  2. washthe organic layer was washed with brine
  3. customThe solvent was removed under reduced pressure at 40° C
  4. customThe obtained solid was purified
  5. customby triturating with diethyl ether (2×10 mL)

Sources & evidence

ORD record
ord-b90be2df3acf4395a27e8988e5b1b8b5
Source dataset
uspto-grants-2016_08
Patent number
US09415049B2

Reaction notes

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