1,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride → N1-Methyl-N1-(2-morpholinoethyl)-N3-(4-(piperidin-1-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)carbamoyl)phenyl)isophthalamide

HRID 2409862Notes

Reaction equation

HRID 2409862 reaction equation
[NH2:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)=[O:5].[CH3:32][N:33]([CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)[C:34]([C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39](O)=[O:40])=[O:35].CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH3:32][N:33]([CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)[C:34](=[O:35])[C:36]1[CH:44]=[CH:43][CH:42]=[C:38]([C:39]([NH:1][C:2]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][C:3]=2[C:4](=[O:5])[NH:6][C:7]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[N:8]=2)=[O:40])[CH:37]=1

Participants

6

Reactant 3

HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 665869413-(Methyl(2-morpholinoethyl)carbamoyl)benzoic acidHCID 665874172-amino-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide

Product 1

HCID 56643932N1-Methyl-N1-(2-morpholinoethyl)-N3-(4-(piperidin-1-yl)-2-((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)carbamoyl)phenyl)isophthalamideYield 67.1%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

Into a 50-mL round bottom flask, was placed 2-amino-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide 8d (100 mg, 0.23 mmol, 1.00 equiv), 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid (130 mg, 0.45 mmol, 1.91 equiv), EDC.HCl (67 mg, 0.35 mmol, 1.50 equiv), 4-dimethylaminopyridine (43 mg, 0.35 mmol, 1.51 equiv), and dichloromethane (5 mL). The resulting solution was stirred for 4 h at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was washed with 3×10 mL of water and 3×10 mL of aqueous NH4Cl. The mixture was dried over anhydrous sodium sulfate and 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 108.6 mg (66%) of a white solid. 1H-NMR (400 MHz, CD3OD, ppm): δ 8.66-8.64 (d, J=8.8 Hz, 1H), 8.39 (s, 1H), 8.16 (s, 3H), 8.07-8.05 (d, J=7.6 Hz, 1H), 7.99 (s, 1H), 7.79 (s, 1H), 7.16-7.68 (m, 3H), 7.61 (s, 1H), 7.07 (s, 1H), 4.11-4.10 (d, J=3.2 Hz, 2H), 3.98 (s, 3H), 3.80-3.77 (m, 4H), 3.59-3.54 (m, 6H), 3.14 (m, 4H), 1.99-1.79 (m, 6H). MS (ES, m/z): 704 [M+H]+.

Workup

  1. customInto a 50-mL round bottom flask, was placed
  2. washThe resulting mixture was washed with 3×10 mL of water and 3×10 mL of aqueous NH4Cl
  3. dry with materialThe mixture was dried over anhydrous sodium sulfate
  4. concentrationconcentrated under vacuum
  5. customThe crude product was purified by reverse phase HPLC
  6. washeluting with a water/CH3CN gradient
  7. additioncontaining 0.05% TFA

Sources & evidence

ORD record
ord-f1cf6d6953cf46d0911a32c94b777a61
Source dataset
uspto-grants-2014_08
Patent number
US08815910B2

Reaction notes

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