Dimethylformamide → HCID 58700146, compound

HRID 2215629Notes

Reaction equation

HRID 2215629 reaction equation
[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH:23]1[CH:24]=[CH:25][C:26]2N(O)N=[N:29][C:27]=2[CH:28]=1.[CH3:33][CH:34](C)[N:35]=C=NC(C)C.CN([CH:45]=[O:46])C>CCOC(C)=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([NH:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[C:10](=[O:12])[NH:35][CH2:34][CH2:33][NH:29][C:27]2[CH:28]=[CH:23][C:24]([O:46][CH3:45])=[CH:25][CH:26]=2)=[CH:6][CH:7]=1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 12734DiisopropylcarbodiimideHCID 757711-HydroxybenzotriazoleHCID 21950690HCID 21950690, compound

Product 1

HCID 58700146HCID 58700146, compoundYield 68%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Procedure

L-p-Iodo-phenylalanine (3.00 g, 10 mmol) was dissolved in H2O (25 mL) containing equimolar amounts of NaOH (0.40 g, 10 mmol). The solution was cooled to 0° C., then m-toluoyl chloride (1.32 mL, 10 mmol) was added dropwise under vigorous stirring. The mixture was allowed to warm to room temperature and stirred for approx. 2 h. After neutralization with 0.5 M HCl, the product was extracted from the reaction mixture three times with EtOAc. The combined organic layers were dried (MgSO4), filtered and the solvent was removed in vacuo to yield (S)-(3-(4-Iodo-phenyl)-2-(3-methyl-benzoylamino)-propionic acid 2 (3.36 g, 82%): 1H-NMR (400 MHz, CD3OD) δ=7.62–7.05 (m, 8H), 4.82 (dd, J=5.0, J=9.7, 1H), 3.32–3.26 (m, 1H), 3.08–3.03 (m, 1H), 2.36 (s, 3H). MS calcd. for C17H17INO3 (M+H+) 410.22. found 410.2. Step B: (S)-(3-(4-Iodo-phenyl)-2-(3-methyl-benzoylamino)-propionic acid 2 (3.36 g, 8.2 mmol) was dissolved in DMF (40 mL), HOBt (1.20 g, 9 mmol) and DIC (1.38 ml, 8.9 mmol) were added and the solution was stirred for 10 min at room temperature. N-(4-Mthoxyphenyl)-ethane-1,2-diamine (1.48 g, 8.9 mmol) was added and the solution was stirred for 4 h at room temperature. The reaction mixture was then diluted with EtOAc and washed with H2O three times. The organic solvent was partially removed, upon which the product precipitated. The precipitate was collected by filtration, recrystallized from EtOAc and dried under high vacuum to yield (S)-N-{2-(4-Iodo-phenyl)-1-[2-(4-methoxy-phenylamino)-ethylcarbamoyl]-ethyl}-3-methyl-benzamide 3 (3.03 g, 68%): 1H-NMR (400 MHz, CD3OD) δ=7.59–7.6.60 (m, 12H), 4.71 (dd, J=7.0, J=8.2, 1H), 3.69 (s, 3H), 3.38–2.97 (m, 6H), 2.37 (s, 3H). MS calcd. for C26H29IN3O3 (M+H+) 558.12. found 558.1. Step C: (S)-N-{2-(4-Iodo-phenyl)-1-[2-(4-methoxy-phenylamino)-ethylcarbamoyl]-ethyl}-3-methyl-benzamide 3 (20 mg, 0.04 mmol) was suspended in a 2:1 mixture of dioxane and water (3 mL) together with phenyl-boronic acid (13 mg, 0.12 mmol), Na2CO3 (15 mg, 0.16 mmol) and Pd(PPh3)4 (4 mg, 0.004 mmol). The mixture was heated to 150° C. (microwave-assisted) for 5 min and filtered. The filtrate was subjected to reverse phase HPLC, the fractions containing the product were combined and lyophilized to yield the title compound as a white solid (9 mg, 44%): 1H-NMR (400 MHz, CD3OD) δ=7.57–6.74 (m, 17H), 4.83 (m, 1H), 3.74 (s, 3H), 3.72–3.23 (m, 4H), 2.36 (s, 3H). MS calcd. for C32H34N3O3 (M+H+) 508.26. found 508.2.

Workup

  1. stirringthe solution was stirred for 4 h at room temperature
  2. washwashed with H2O three times
  3. customThe organic solvent was partially removed, upon which the product
  4. customprecipitated
  5. filtrationThe precipitate was collected by filtration
  6. customrecrystallized from EtOAc
  7. customdried under high vacuum

Sources & evidence

ORD record
ord-d6f122e019a6418997cfadc2b2596c97
Source dataset
uspto-grants-2006_09
Patent number
US07109243B2

Reaction notes

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