Diisopropylethylamine → 1-isobutyl-3-[2-[4-[3-[4-[[4-methyl-1-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]indol-3-yl]methyl]phenoxy]propyl]-4,9-diazaspiro[5.5]undecan-9-yl]-2-oxo-ethyl]urea

HRID 2284874Notes

Reaction equation

HRID 2284874 reaction equation
C([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12]C(=O)C)[C@H:10]([O:16]C(=O)C)[C@@H:9]([O:20]C(=O)C)[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44]OS(C)(=O)=O)=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=O)C.[CH2:50]1[C:55]2([CH2:60][CH2:59][N:58]([C:61](=[O:71])[CH2:62][NH:63][C:64]([NH:66][CH2:67][CH:68]([CH3:70])[CH3:69])=[O:65])[CH2:57][CH2:56]2)[CH2:54][NH:53][CH2:52][CH2:51]1.C(N(C(C)C)CC)(C)C.C[O-].[Na+]>CO.C(#N)C>[CH2:67]([NH:66][C:64]([NH:63][CH2:62][C:61]([N:58]1[CH2:59][CH2:60][C:55]2([CH2:50][CH2:51][CH2:52][N:53]([CH2:44][CH2:43][CH2:42][O:41][C:38]3[CH:39]=[CH:40][C:35]([CH2:34][C:26]4[C:27]5[C:32](=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])[N:24]([C@H:8]5[C@H:9]([OH:20])[C@@H:10]([OH:16])[C@H:11]([OH:12])[C@@H:6]([CH2:5][OH:4])[O:7]5)[CH:25]=4)=[CH:36][CH:37]=3)[CH2:54]2)[CH2:56][CH2:57]1)=[O:71])=[O:65])[CH:68]([CH3:69])[CH3:70]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 10942334Sodium MethoxideHCID 1180213681-[2-(3,8-Diazaspiro[5.5]undecan-3-yl)-2-oxo-ethyl]-3-isobutyl-ureaHCID 118045083[(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[4-methyl-3-[[4-(3-methylsulfonyloxypropoxy)phenyl]methyl]indol-1-yl]tetrahydropyran-2-yl]methyl acetate

Product 1

HCID 917550101-isobutyl-3-[2-[4-[3-[4-[[4-methyl-1-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]indol-3-yl]methyl]phenoxy]propyl]-4,9-diazaspiro[5.5]undecan-9-yl]-2-oxo-ethyl]urea

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
80 °C

Procedure

To a 0.25 L round bottom flask add [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[4-methyl-3-[[4-(3-methylsulfonyloxypropoxy)phenyl]methyl]indol-1-yl]tetrahydropyran-2-yl]methyl acetate (7.2 g, crude), 1-[2-(4,9-diazaspiro[5.5]undecan-9-yl)-2-oxo-ethyl]-3-isobutyl-urea (12.28 mmol), acetonitrile (100 mL), and diisopropylethylamine (40.92 mmol). Heat at 80° C. for 16 hours then concentrate under reduced pressure. Add methanol (50 mL) and sodium methoxide (20.46 mmol, 30% solution in MeOH) and stir at room temperature for 1 hour. Quench by adding a small piece of dry ice. Concentrate under reduced pressure. Purify by reverse phase flash chromatography (400 g C18 cartridge) eluting with 5-80% water (0.1% formic acid) in acetonitrile (0.1 % formic acid) in three portions. Concentrate under reduced pressure to yield the title compound as a formic acid salt containing small impurities. Dissolve the salt in 7N ammonia in methanol (20 mL) then concentrate to form the free base. Purify the free base by flash chromatography (330 g silica gel cartridge) eluting with 5% 7N ammonia in methanol/dichloromethane. Concentrate the product fractions under reduced pressure to yield the title compound (1.75 g, 22.81%): MS (m/z): 746.6 (M+H). H1 NMR (400.31 MHz, CD3OD): δ 7.28 (d, J=8.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 2H), 7.02 (s, 1H), 6.97 (t, J=8.8 Hz, 1H), 6.69 (d, J=7.2 Hz, 1H), 5.37 (d, J=9.2 Hz, 1H), 4.15 (s, 2H), 3.95 (t, J=6.0 Hz, 2H), 3.91 (d, J=1.6 Hz, 2H), 3.87-3.80 (m, 2H), 3.65 (dd, J=11.6, 5.6 Hz, 1H), 3.57-3.38 (m, 5H), 3.31 (bm, 2H), 2.90 (d, J=6.8 Hz, 2H), 2.46-2.13 (m, 8H), 1.88 (pentet, J=6.8 Hz, 2H), 1.68 (septet, J=6.8 Hz, 1H), 1.61-1.28 (m, 8H), 0.86 (d, J=6.8, 6H).

Workup

  1. concentrationthen concentrate under reduced pressure
  2. customQuench
  3. additionby adding a small piece of dry ice
  4. concentrationConcentrate under reduced pressure
  5. customPurify by reverse phase flash chromatography (400 g C18 cartridge)
  6. washeluting with 5-80% water (0.1% formic acid) in acetonitrile (0.1 % formic acid) in three portions
  7. concentrationConcentrate under reduced pressure

Sources & evidence

ORD record
ord-39b171cea227465ab2ecd92a108618da
Source dataset
uspto-grants-2015_09
Patent number
US09145437B2

Reaction notes

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