1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → N-(7-((2S,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-6-methoxy-8-methyl-2-oxo-2H-chromen-3-yl)-3',6-dimethoxybiphenyl-3-carboxamide

HRID 1511237Notes

Reaction equation

HRID 1511237 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:28])[C:12]=1[O:13][C@H:14]1[C@@H:19]3[O:20]C(=O)[O:22][C@@H:18]3[C@@H:17]([O:24][CH3:25])[C:16]([CH3:27])([CH3:26])[O:15]1)[O:9][C:8](=[O:29])[C:7]([NH:30][C:31](=[O:40])OCC1C=CC=CC=1)=[CH:6]2.CCN=C=NCCCN(C)C.[CH3:52][O:53][C:54]1[CH:55]=[C:56]([C:60]2[C:65]([O:66][CH3:67])=[CH:64][CH:63]=[C:62](C(O)=O)[CH:61]=2)[CH:57]=[CH:58][CH:59]=1.C(=O)([O-])[O-]>[Pd].C1COCC1.N1C=CC=CC=1.C(Cl)Cl.CO.C(N(CC)CC)C>[OH:20][C@@H:19]1[C@H:18]([OH:22])[C@@H:17]([O:24][CH3:25])[C:16]([CH3:27])([CH3:26])[O:15][C@H:14]1[O:13][C:12]1[C:11]([CH3:28])=[C:10]2[C:5]([CH:6]=[C:7]([NH:30][C:31]([C:62]3[CH:61]=[C:60]([C:56]4[CH:57]=[CH:58][CH:59]=[C:54]([O:53][CH3:52])[CH:55]=4)[C:65]([O:66][CH3:67])=[CH:64][CH:63]=3)=[O:40])[C:8](=[O:29])[O:9]2)=[CH:4][C:3]=1[O:2][CH3:1]

Participants

10

Reactant 4

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 19660Carbonate IonHCID 25140397Benzyl 6-methoxy-7-((3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxotetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-8-methyl-2-oxo-2H-chromen-3-ylcarbamateHCID 549124263',6-Dimethoxy-(1,1'-biphenyl)-3-carboxylic acid

Product 1

HCID 25139812N-(7-((2S,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-6-methoxy-8-methyl-2-oxo-2H-chromen-3-yl)-3',6-dimethoxybiphenyl-3-carboxamideYield 3.5%

Reagents, catalysts & solvents 5

HCID 23938PalladiumCatalystHCID 887MethanolSolventHCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolventHCID 21875418Pyridine methylene chlorideSolvent

Procedure

Palladium on carbon (10%, 20.0 mg) was added to 25a (100 mg, 0.18 mmol) in anhydrous THF (5.00 mL) and the solution was placed under an atmosphere of H2. After 6.5 hours, the solution was filtered through SiO2 (1:1 CH2Cl2:Acetone) and the eluent was concentrated to afford a yellow solid, which was used without further purification (56.0 mg, 75%). EDCI (21.4 mg, 0.11 mmol) and 3′,6-dimethoxybiphenyl-3-carboxylic acid (23.1 mg, 0.089 mmol) were added to the amine (18.7 mg, 0.045 mmol) in 30% pyridine/CH2Cl2 (0.70 mL). After 12 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to afford a colorless solid, which was used without further purification (10.5 mg, 36%). Triethylamine (150 μL) was added to the carbonate (10.4 mg, 0.016 mmol) in MeOH (2.50 mL). After 12 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 20:1; CH2Cl2:MeOH) to afford 26a as a colorless amorphous solid (2.00 mg, 20%, 5% over 3 steps): 1H NMR (CDCl3, 500 MHz) 8.73 (s, 1H), 8.70 (d, J=5.4 Hz, 1H), 7.84 (td, J=6.2, 2.4 Hz, 1H), 7.82 (s, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.06 (d, J=7.8 Hz, 1H), 7.03-7.00 (m, 2H), 6.88-6.86 (m, 1H), 6.81 (s, 1H), 4.99 (d, J=6.6 Hz, 1H), 4.24 (t, J=4.2 Hz, 1H), 4.00 (dd, J=6.5, 3.7 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.83 (s, 3H), 3.80 (d, J=7.4 Hz, 1H), 3.45 (s, 3H), 3.08 (d, J=4.7 Hz, 1H), 2.67 (s, 1H), 2.42 (s, 3H), 1.28 (d, J=8.1 Hz, 3H), 1.18 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 164.6, 158.9, 158.3, 158.2, 148.2, 145.6, 142.5, 137.5, 130.1, 129.0, 128.2, 127.2, 124.9, 122.5, 122.2, 121.2, 121.0, 115.1, 144.2, 112.1, 110.0, 105.4, 101.3, 81.7, 76.8, 69.0, 68.0, 59.1, 55.3, 54.9, 54.3, 28.3, 28.2, 9.1; IR (film) νmax 2961, 2928, 1713, 1670, 1601, 1464, 1383, 1261, 1094, 1022, 798, 700 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C34H37NO11, 636.2445. found, 636.2477.

Workup

  1. filtrationthe solution was filtered through SiO2 (1:1 CH2Cl2:Acetone)
  2. concentrationthe eluent was concentrated
  3. customto afford a yellow solid, which
  4. customwas used without further purification (56.0 mg, 75%)
  5. waitAfter 12 hours
  6. concentrationthe solvent was concentrated
  7. customthe residue purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone)
  8. customto afford a colorless solid, which
  9. customwas used without further purification (10.5 mg, 36%)
  10. waitAfter 12 hours
  11. concentrationthe solvent was concentrated
  12. customthe residue purified via column chromatography (SiO2, 20:1; CH2Cl2:MeOH)

Sources & evidence

ORD record
ord-d87471e3bd4348e289fa5e9fc1e47cf8
Source dataset
uspto-grants-2012_07
Patent number
US08212011B2

Reaction notes

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