Water → tert-butyl 4-[(E)-4-[4-[[4-methyl-1-[(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydropyran-2-yl]indol-3-yl]methyl]phenyl]but-3-enyl]-4,9-diazaspiro[5.5]undecane-9-carboxylate

HRID 2284540Notes

Reaction equation

HRID 2284540 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](Br)=[CH:37][CH:36]=3)=[CH:25]2)O1)(=[O:3])[CH3:2].CC1(C)C(C)(C)OB(/[CH:50]=[CH:51]/[CH2:52][CH2:53][N:54]2[CH2:71][CH2:70][CH2:69][C:56]3([CH2:61][CH2:60][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:58][CH2:57]3)[CH2:55]2)O1.C(=O)([O-])[O-].[K+].[K+].[OH2:79]>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH3:33][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:27]=1[C:26]([CH2:34][C:35]1[CH:40]=[CH:39][C:38](/[CH:50]=[CH:51]/[CH2:52][CH2:53][N:54]3[CH2:55][C:56]4([CH2:57][CH2:58][N:59]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:60][CH2:61]4)[CH2:69][CH2:70][CH2:71]3)=[CH:37][CH:36]=1)=[CH:25][N:24]2[C@H:8]1[C@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:79]1

Participants

8

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 671974083-(4-bromophenylmethyl)-4-methyl-1-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)indoleHCID 86701860tert-butyl 4-[(E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyl]-4,9-diazaspiro[5.5]undecane-9-carboxylate2×

Product 1

HCID 118021687tert-butyl 4-[(E)-4-[4-[[4-methyl-1-[(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-(acetoxymethyl)tetrahydropyran-2-yl]indol-3-yl]methyl]phenyl]but-3-enyl]-4,9-diazaspiro[5.5]undecane-9-carboxylateYield 62%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalyst2×HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylCatalyst2×HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
65 °C

Procedure

To a 20 L temperature controlled reactor charge [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[(4-bromophenyl)methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (1.37 moles; 1.18 kg; 73% purity), tert-butyl 8-[(E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyl]-3,8-diazaspiro[5.5]undecane-3-carboxylate (1.79 moles; 776.46 g), potassium carbonate (3.85 moles; 532.03 g), THF (11.80 L) and water (1.18 L). Degas the mixture by subsurface nitrogen purge for 30 minutes and then add Pd(OAc)2 (54.99 mmoles; 12.35 g) and XPhos (54.99 mmoles; 26.22 g). Heat the mixture to 65° C. and stir overnight. Charge additional XPhos (13.75 mmoles; 6.55 g) and Pd(OAc)2 (13.75 mmoles; 3.09 g) and continue to stir at 65° C. for about 1 hour. Prepare a solution of tert-butyl 8-[(E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-enyl]-3,8-diazaspiro[5.5]undecane-3-carboxylate (343.71 mmoles; 149.32 g) in THF (500 mL) and degas by subsurface purge with nitrogen for 5 mins. Add this solution to the main reaction mixture and continue stirring at 65° C. for about 3 hours. Cool the reaction mixture to room temperature and pump into a 50 L vessel equipped with a bottom outlet valve. Dilute the mixture with iso-hexane (11.80 L) and wash with brine (11.80 L). Separate the layers and filter the organic phase through a pad of silica gel (2.95 kg). Wash the pad twice with a mixture of THF (5.90 L) and iso-hexane (5.90 L). Concentrate the filtrate under reduced pressure to give the title compound (1.695 Kg; 62% purity as judged by quantative NMR; 88% yield), mass spectrum (m/z): 858.4 (M+1).

Workup

  1. customDegas the mixture by subsurface nitrogen
  2. custompurge for 30 minutes
  3. stirringto stir at 65° C. for about 1 hour
  4. customdegas by subsurface
  5. custompurge with nitrogen for 5 mins
  6. additionAdd this solution to the main reaction mixture
  7. stirringcontinue stirring at 65° C. for about 3 hours
  8. temperatureCool the reaction mixture to room temperature
  9. custompump into a 50 L vessel
  10. customequipped with a bottom outlet valve
  11. additionDilute the mixture with iso-hexane (11.80 L)
  12. washwash with brine (11.80 L)
  13. customSeparate the layers
  14. filtrationfilter the organic phase through a pad of silica gel (2.95 kg)
  15. washWash the pad
  16. additiontwice with a mixture of THF (5.90 L) and iso-hexane (5.90 L)
  17. concentrationConcentrate the filtrate under reduced pressure

Sources & evidence

ORD record
ord-2989cadcb8a94ce8992490ad0eaca0ac
Source dataset
uspto-grants-2015_09
Patent number
US09145435B2

Reaction notes

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