Phosphonoacetic Acid → N-[1-benzyloxycarbonyl-2-(1H-indol-3-yl)-ethyl]-3-[2-(diethoxy-phosphoryl)4-phenyl-butyrylamino]-succinamic acid benzyl ester

HRID 902954Notes

Reaction equation

HRID 902954 reaction equation
[CH2:1]([O:8][C:9](=[O:37])[CH2:10][CH:11]([NH2:36])[C:12]([NH:14][CH:15]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:38]([CH2:42][C:43](O)=O)([OH:41])([OH:40])=[O:39].[CH:46]1[CH:47]=[CH:48][C:49]2N(O)N=N[C:50]=2[CH:51]=1.[CH2:56]1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)C[CH2:57]1.F[P-](F)(F)(F)(F)F.[CH3:89][CH2:90]N(C(C)C)C(C)C.[C:98]([O-:101])(O)=O.[Na+].[CH3:103]N(C=O)C>C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC>[CH2:1]([O:8][C:9](=[O:37])[CH2:10][CH:11]([NH:36][C:98](=[O:101])[CH:42]([P:38]([O:41][CH2:89][CH3:90])([O:40][CH2:56][CH3:57])=[O:39])[CH2:43][CH2:103][C:50]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:51]=1)[C:12]([NH:14][CH:15]([C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

10

Reactant 7

HCID 546Phosphonoacetic AcidHCID 6228DimethylformamideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 2724699PyBOPHCID 692134763-Amino-n-[1-benzyloxycarbonyl-2-(1h-indol-3-yl)-ethyl]-succinamic acid benzyl ester

Product 1

HCID 87735201N-[1-benzyloxycarbonyl-2-(1H-indol-3-yl)-ethyl]-3-[2-(diethoxy-phosphoryl)4-phenyl-butyrylamino]-succinamic acid benzyl esterYield 71%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 21226206Ethyl acetate hexaneSolvent

Procedure

To a stirred solution of the peptide of Example 83 (536 mg, 1.00 mmol) in DMF (3 mL) was sequentially added phosphonoacetic acid 79 (1.00 mmol), HOBt (135 mg, 1.00 mmol) and PYBOP (520 mg, 1.00 mmol) at room temperature. DIPEA (523 μL, 3.00 mmol) was then added and the mixture was stirred at room temperature for 18 h. The reaction mixture was poured onto an aqueous solution of NaHCO3 (5%) and extracted several times with ethyl acetate. The combined organic extracts were washed with NaHCO3 (5%), H2O, KHSO4 (5%) and H2O. Drying (Na2SO4) and evaporation gave the crude product (780 mg) as a light oil. Flash chromatography (SiO2, ethyl acetate:hexane (2:1) to 100% ethyl acetate) gave a separable pair of diastereoisomers in a combined yield of 71%. The less polar diastereoisomer had the following spectroscopic data: 1H NMR (CDCl3, 400 MHz) □ 8.03 (br d, 2H), 7.61 (br d, 1H), 7.40-7.11 (m, 19H), 6.82 (d, 1H), 5.15-4.82 (m, 5H), 4.87 (dd, 1H), 4.01 (m, 4H), 3.31 (d, 2H), 3.08 (dd, 1H), 2.78-2.43 (m, 4H), 2.35 (m, 1H), 2.00 (m, 1H), 1.26 (dt, 6H); 31P NMR (CDCl3) δ 25.1; MS (Pos. FAB) 780.8 (M+).

Workup

  1. customat room temperature
  2. extractionextracted several times with ethyl acetate
  3. washThe combined organic extracts were washed with NaHCO3 (5%), H2O, KHSO4 (5%) and H2O
  4. customDrying
  5. custom(Na2SO4) and evaporation
  6. customgave the crude product (780 mg) as a light oil

Sources & evidence

ORD record
ord-596fde1e30e540afb316719f51d4cd97
Source dataset
uspto-grants-2008_04
Patent number
US07365091B2

Reaction notes

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