Sodium Carbonate → HCID 23648330, compound

HRID 2215630Notes

Reaction equation

I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:24][C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)[C:10](=[O:23])[NH:11][CH2:12][CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.O1CCOCC1.[C:40]1(B(O)O)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:2]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:24][C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)[C:10](=[O:23])[NH:11][CH2:12][CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1

Participants

Conditions

Temperature: 150 °C

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

filtrationfiltered
additionthe fractions containing the product

Sources & evidence

ORD record: ord-03c3b105e16844b897f76f5e66b0cde5
Source dataset: uspto-grants-2006_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07109243B2

Reaction notes

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