Potassium Iodide → [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[[4-[3-[9-[2-(isobutylcarbamoylamino)acetyl]-4,9-diazaspiro[5.5]undecan-4-yl]propoxy]phenyl]methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate

HRID 2284878Notes

Reaction equation

HRID 2284878 reaction equation
[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[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]Cl)=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2].[CH2:46]1[C:51]2([CH2:56][CH2:55][CH2:54][NH:53][CH2:52]2)[CH2:50][CH2:49][N:48]([C:57](=[O:67])[CH2:58][NH:59][C:60]([NH:62][CH2:63][CH:64]([CH3:66])[CH3:65])=[O:61])[CH2:47]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C(OC(=O)C)(=O)C>C(#N)C.CN(C)C1C=CN=CC=1.C(OC[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](OC(=O)C)[C@H](N2C3C(=C(C)C=CC=3)C(CC3C=CC(OCCCCl)=CC=3)=C2)O1)(=O)C.C(N(CC)CC)C.CO.CCOC(C)=O>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[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][N:53]4[CH2:52][C:51]5([CH2:50][CH2:49][N:48]([C:57](=[O:67])[CH2:58][NH:59][C:60](=[O:61])[NH:62][CH2:63][CH:64]([CH3:65])[CH3:66])[CH2:47][CH2:46]5)[CH2:56][CH2:55][CH2:54]4)=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2]

Participants

12

Reactant 5

HCID 4875Potassium IodideHCID 7918Acetic AnhydrideHCID 11430Potassium CarbonateHCID 1180213681-[2-(3,8-Diazaspiro[5.5]undecan-3-yl)-2-oxo-ethyl]-3-isobutyl-ureaHCID 118045123[(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[[4-(3-chloropropoxy)phenyl]methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate

Product 1

HCID 118045058[(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[[4-[3-[9-[2-(isobutylcarbamoylamino)acetyl]-4,9-diazaspiro[5.5]undecan-4-yl]propoxy]phenyl]methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetateYield 51.8%

Reagents, catalysts & solvents 6

HCID 142844-(Dimethylamino)pyridineCatalystHCID 118045123[(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[[4-(3-chloropropoxy)phenyl]methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetateCatalystHCID 887MethanolSolventHCID 6342AcetonitrileSolventHCID 8471TriethylamineSolvent2×HCID 8857Ethyl AcetateSolvent2×

Procedure

To a stirred solution of [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[[4-(3-chloropropoxy)phenyl]methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (143.38 mmoles; 118.40 g) in acetonitrile (829 mL) add 1-[2-(3,8-diazaspiro[5.5]undecan-3-yl)-2-oxo-ethyl]-3-isobutyl-urea (143.38 mmoles; 47.35 g), potassium carbonate (286.75 mmoles; 39.63 g), and potassium iodide (143.38 mmoles; 23.80 g). Heat the mixture at reflux under nitrogen overnight. Cool the reaction mixture to room temperature and add acetic acid anhydride (1.43 moles; 135.53 mL) and N,N-dimethyl-4-pyridinamine (14.34 mmoles; 1.75 g). Stir the mixture for 1 hour. Concentrate the mixture under reduced pressure and partition the residue between water and EtOAc. Separate the organic layer and wash with brine, dry over MgSO4, filter, and concentrate under reduced pressure. The residue is combined with another lot prepared in a similar manner starting from [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[[4-(3-chloropropoxy)phenyl]methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (6.2 mmol). Purify by flash column chromatography on silica gel (1.5 kg) eluting with 99:1 EtOAc:triethylamine (1cv), EtOAc (3cv's) and 190:10:1 EtOAc:MeOH:triethylamine (5cv's) to afford the title compound (68.2 g; 49% yield) mass spectrum (m/z): 918.6 (M+1).

Workup

  1. temperatureHeat the mixture
  2. temperatureat reflux under nitrogen overnight
  3. concentrationConcentrate the mixture under reduced pressure
  4. custompartition the residue between water and EtOAc
  5. customSeparate the organic layer
  6. washwash with brine
  7. dry with materialdry over MgSO4
  8. filtrationfilter
  9. concentrationconcentrate under reduced pressure
  10. customprepared in a similar manner
  11. customPurify by flash column chromatography on silica gel (1.5 kg)
  12. washeluting with 99:1 EtOAc

Sources & evidence

ORD record
ord-ebf8b3a2485f43f4899aaa3691166736
Source dataset
uspto-grants-2015_09
Patent number
US09145437B2

Reaction notes

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