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-isopropoxy-8-methyl-2-oxo-2h-chromen-3-yl)-1h-indole-2-carboxamide

HRID 2272801Notes

Reaction equation

HRID 2272801 reaction equation
[CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH3:30])[C:14]=1[O:15][C@H:16]1[C@@H:21]3[O:22]C(=O)[O:24][C@@H:20]3[C@@H:19]([O:26][CH3:27])[C:18]([CH3:29])([CH3:28])[O:17]1)[O:11][C:10](=[O:31])[C:9]([NH:32][C:33](=O)[O:34]CC1C=CC=CC=1)=[CH:8]2)([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.[NH:54]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:56]=[C:55]1C(O)=O.C(=O)([O-])[O-]>[Pd].C1COCC1.N1C=CC=CC=1.C(Cl)Cl.CO.C(Cl)Cl.C(N(CC)CC)C>[OH:22][C@@H:21]1[C@H:20]([OH:24])[C@@H:19]([O:26][CH3:27])[C:18]([CH3:29])([CH3:28])[O:17][C@H:16]1[O:15][C:14]1[C:13]([CH3:30])=[C:12]2[C:7]([CH:8]=[C:9]([NH:32][C:33]([C:55]3[NH:54][C:62]4[C:57]([CH:56]=3)=[CH:58][CH:59]=[CH:60][CH:61]=4)=[O:34])[C:10](=[O:31])[O:11]2)=[CH:6][C:5]=1[O:4][CH:1]([CH3:2])[CH3:3]

Participants

11

Reactant 4

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 19660Carbonate IonHCID 72899Indole-2-carboxylic acidHCID 25140398Benzyl 6-isopropoxy-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-ylcarbamate

Product 1

HCID 25140679n-(7-((2s,3r,4s,5r)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2h-pyran-2-yloxy)-6-isopropoxy-8-methyl-2-oxo-2h-chromen-3-yl)-1h-indole-2-carboxamideYield 32.1%

Reagents, catalysts & solvents 6

HCID 23938PalladiumCatalystHCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolventHCID 21875418Pyridine methylene chlorideSolvent

Procedure

Palladium on carbon (10%, 4 mg) was added to 25c (19.0 mg, 0.033 mmol) in anhydrous THF (220 μL) and the solution was placed under an atmosphere of H2. After 12 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 (14.5 mg, 99%). EDCI (15.6 mg, 0.081 mmol) and 1H-indole-2-carboxylic acid (10.5 mg, 0.065 mmol) was added to the amine (14.5 mg, 0.033 mmol) in 30% pyridine/CH2Cl2 (1.00 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 (10.0 mg, 50%). Triethylamine (150 μL) was added to the carbonate (10.0 mg, 0.017 mmol) in MeOH (2.5 mL) and CH2Cl2 (2.50 mL). After 12 hours, the solvent was concentrated and the residue purified via column chromatography (SiO2, 10:1 CH2Cl2:Acetone) to afford 26k as a colorless amorphous solid (6.00 mg, 46%, 23% over 3 steps): 1H NMR (CDCl3, 500 MHz) δ 8.16 (s, 1H), 7.52 (s, 1H), 7.34-7.30 (m, 5H), 6.75 (s, 1H), 4.93 (d, J=5.0 Hz, 1H), 4.56-4.51 (m, 1H), 4.23 (t, J=4.0 Hz, 1H), 3.98-3.96 (m, 1H), 3.76 (s, 1H), 3.43 (s, 3H), 3.06 (d, J=4.3 Hz, 1H), 2.65 (s, 1H), 2.38 (s, 3H), 1.33 (dd, J=11.2, 6.1 Hz, 6H), 1.29 (s, 3H), 1.27 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 157.6, 152.1, 146.6, 146.0, 142.1, 134.5, 127.7, 127.5, 127.2, 122.2, 121.3 (2C), 120.2 (2C), 115.0 (2C), 108.1 (2C), 101.2, 81.6, 71.2, 68.9, 68.1, 66.5, 59.0, 24.8, 23.6, 20.8 (2C), 9.1; IR (film) νmax cm−1 3406, 2930, 2375, 1705, 1522, 1394, 1229, 1205, 1111, 1078, 1049, 933, 793, 739, 698; HRMS (ESI+) m/z: [M+Na]+ calcd for C30H34N2O9, 589.2162. found, 589.2111.

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 (14.5 mg, 99%)
  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 (10.0 mg, 50%)
  10. waitAfter 12 hours
  11. concentrationthe solvent was concentrated
  12. customthe residue purified via column chromatography (SiO2, 10:1 CH2Cl2:Acetone)

Sources & evidence

ORD record
ord-7fc1c1b93eef4b1396e5e5fb8374342e
Source dataset
uspto-grants-2015_09
Patent number
US09120774B2

Reaction notes

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