Triethylamine → N1-(2-(2-hydroxyethoxy)ethyl)-N3-(4-(piperidin-1-yl)-2-(6-((3-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)phenyl)isophthalamide

HRID 1408121Notes

Reaction equation

HRID 1408121 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[N:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:15]=1.[OH:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][NH:38][C:39]([C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](O)=[O:45])=[O:40].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[OH:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][NH:38][C:39](=[O:40])[C:41]1[CH:49]=[CH:48][CH:47]=[C:43]([C:44]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)=[CH:4][C:3]=2[C:14]2[CH:15]=[C:16]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[N:17]=[CH:18][N:19]=2)=[O:45])[CH:42]=1

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 665867546-(2-amino-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)-pyrimidin-4-amineHCID 665867923-((2-(2-Hydroxyethoxy)ethyl)carbamoyl)benzoic acid

Product 1

HCID 86705958N1-(2-(2-hydroxyethoxy)ethyl)-N3-(4-(piperidin-1-yl)-2-(6-((3-(trifluoromethyl)benzyl)amino)pyrimidin-4-yl)phenyl)isophthalamideYield 18%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Into a 100-mL round bottom flask, was placed a solution of 6-(2-amino-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)pyrimidin-4-amine (300 mg, 0.70 mmol, 1.00 equiv) in N,N-dimethylformamide (6 mL). This was followed by the addition of 3-(2-(2-hydroxyethoxy)ethylcarbamoyl)benzoic acid (302.2 mg, 1.19 mmol, 1.70 equiv) at room temperature. To this was added triethylamine (156 mg, 1.54 mmol, 2.20 equiv). To the mixture was added EDC.HCl (148.2 mg, 0.78 mmol, 1.10 equiv) at room temperature, followed by HOBT (104.4 mg, 0.77 mmol, 1.10 equiv) at room temperature. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 83.6 mg (15%) of a yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.76 (s, 1H), 8.40 (s, 1H), 8.039 (t, J=8.1 Hz, 2H), 7.74 (s, 1H), 7.63˜7.57 (m, 3H), 7.53˜7.50 (m, 2H), 7.47˜7.40 (m, 2H), 6.93 (s, 1H), 4.81 (s, 2H), 3.71˜3.58 (m, 8H), 3.43˜3.39 (m, 4H), 1.84˜1.81 (m, 6H). MS (ES, m/z): 663 [M+H]+.

Workup

  1. customInto a 100-mL round bottom flask, was placed
  2. concentrationThe resulting mixture was concentrated under vacuum
  3. customThe crude product was purified by reverse phase HPLC
  4. washeluting with a water/CH3CN gradient
  5. additioncontaining 0.05% TFA

Sources & evidence

ORD record
ord-268544cc837046a095e0e6cd5097091f
Source dataset
uspto-grants-2014_12
Patent number
US08916569B2

Reaction notes

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