Ammonium Hydroxide → 21-Aminoepothilone B

HRID 585400Notes

Reaction equation

HRID 585400 reaction equation
[CH3:1][C@@H:2]1[C@H:20]([OH:21])[C@@H:19]([CH3:22])[C:17](=[O:18])[C:16]([CH3:24])([CH3:23])[C@@H:15]([OH:25])[CH2:14][C:12](=[O:13])[O:11][C@H:10](/[C:26](/[CH3:35])=[CH:27]/[C:28]2[N:32]=[C:31]([CH2:33]O)[S:30][CH:29]=2)[CH2:9][C@@H:7]2[O:8][C@:6]2([CH3:36])[CH2:5][CH2:4][CH2:3]1.C1(P([N:51]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[NH4+].[Br-].[NH4+].[OH-].CP(C)C>O1CCCC1.CCOC(C)=O>[CH3:1][C@@H:2]1[C@H:20]([OH:21])[C@@H:19]([CH3:22])[C:17](=[O:18])[C:16]([CH3:24])([CH3:23])[C@@H:15]([OH:25])[CH2:14][C:12](=[O:13])[O:11][C@H:10](/[C:26](/[CH3:35])=[CH:27]/[C:28]2[N:32]=[C:31]([CH2:33][NH2:51])[S:30][CH:29]=2)[CH2:9][C@@H:7]2[O:8][C@:6]2([CH3:36])[CH2:5][CH2:4][CH2:3]1

Participants

9

Reactant 6

HCID 14923Ammonium Hydroxide2×HCID 25514Ammonium BromideHCID 68983TrimethylphosphineHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 199401P,P-Diphenylphosphinic azideHCID 9914741Epothilone F

Product 1

HCID 982813821-Aminoepothilone BYield 100.3%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
35 °C

Procedure

To a stirred suspension of epothilone F (2.5 g, 4.77 mmol, 86.2% potency) in tetrahydrofuran (25 ml) was added diphenylphosphoryl azide (1.14 ml, 1.45 g, 5.25 mmol, 1.1 equivalents) at room temperature. The mixture was stirred for approximately 5 min. 1,8-diazabicyclo[5.4.0]undec-7-ene (0.86 ml, 0.87 g, 5.73 mmol, 1.2 equivalents) was then added over 10 min. The mixture was stirred for 10 min. and then allowed to warm to 35° C. and stirred for 6.5 hours. The mixture was cooled to 10° C., and a mixture of aqueous solution of NH4Br (2M, 5 ml) and NH4OH (2M, 5 ml) was added. After the mixture was stirred for 5 min, trimethylphosphine (1M in tetrahydrofuran, 5.01 ml, 5.01 mmol, 1.05 equivalents) was added over 10 min at 10° C. The mixture was allowed to stir at 35° C. for 4 hours and then cooled to room temperature. EtOAc (80 ml) and aqueous NH4OH (1 M, 10 ml) were added. The organic layer was washed with aqueous NH4OH (1 M, 20 ml). The combined aqueous layers were extracted with EtOAc (20 ml). The combined organic layers were washed with H2O (20 ml) and dried over MgSO4. The solvents were removed on a rotary evaporator, and the residue dried in vacuo to provide the crude 21-amino epothilone B (2.5 g) as an off-white solid. The crude 21-amino epothilone B (2.45 g) was crystallized from EtOAc/heptane to give 21-amino epothilone B (1.95 g, 90% yield corrected for input potency) as a white solid.

Workup

  1. stirringThe mixture was stirred for 10 min.
  2. stirringstirred for 6.5 hours
  3. temperatureThe mixture was cooled to 10° C.
  4. additionwas added
  5. stirringAfter the mixture was stirred for 5 min
  6. stirringto stir at 35° C. for 4 hours
  7. temperaturecooled to room temperature
  8. washThe organic layer was washed with aqueous NH4OH (1 M, 20 ml)
  9. extractionThe combined aqueous layers were extracted with EtOAc (20 ml)
  10. washThe combined organic layers were washed with H2O (20 ml)
  11. dry with materialdried over MgSO4
  12. customThe solvents were removed on a rotary evaporator
  13. customthe residue dried in vacuo

Sources & evidence

ORD record
ord-1bb080e0a7304548bdec2cd3a7268fe8
Source dataset
uspto-grants-2005_08
Patent number
US06930187B2

Reaction notes

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