Ammonium Hydroxide → 21-Aminoepothilone B

HRID 585401Notes

Reaction equation

HRID 585401 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.C(C([O-])=O)(F)(F)F.[NH4+].[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 68983TrimethylphosphineHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 199401P,P-Diphenylphosphinic azideHCID 2724268Ammonium trifluoroacetateHCID 9914741Epothilone F

Product 1

HCID 982813821-Aminoepothilone BYield 87%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
35 °C

Procedure

To a stirred suspension of epothilone F (5.0 g, 9.55 mmol, 86.2% potency) in tetrahydrofuran (50 ml) was added diphenylphosphoryl azide (2.28 ml, 2.89 g, 10.5 mmol, 1.1 equivalents) at room temperature. 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.73 ml, 1.74 g, 11.46 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 20° C., and a mixture of aqueous solution of CF3COONH4 (4M, 10 ml) and NH4OH (4M, 10 ml) was added. After the mixture was stirred for 5 min, trimethylphosphine (1M in tetrahydrofuran, 10.03 ml, 10.03 mmol, 1.05 equivalents) was added over 10 min at 20° C. The mixture was allowed to stir at 35° C. for 2 hours and then at 5° C. for 14 hours. EtOAc (200 ml) and aqueous NH4OH (1 M, 10 ml) were added. The organic layer was washed with aqueous NH4OH (1 M, 30 ml). The combined aqueous layers were extracted with EtOAc (2×30 ml). The combined organic layers were washed with a mixture of brine (20 ml) and H2O (20 ml). The solvents were removed to yield ˜60 ml on a rotary evaporator, and EtOAc (60 ml) was added. The solvent was removed again to ˜65 ml, and the resulting slurry was crystallized from EtOAc/heptane to give 21-amino epothilone B (3.75 g, 87% yield corrected for input potency) as a white solid.

Workup

  1. stirringstirred for 6.5 hours
  2. temperatureThe mixture was cooled to 20° C.
  3. additionwas added
  4. stirringAfter the mixture was stirred for 5 min
  5. stirringto stir at 35° C. for 2 hours
  6. waitat 5° C. for 14 hours
  7. washThe organic layer was washed with aqueous NH4OH (1 M, 30 ml)
  8. extractionThe combined aqueous layers were extracted with EtOAc (2×30 ml)
  9. washThe combined organic layers were washed with a mixture of brine (20 ml) and H2O (20 ml)
  10. customThe solvents were removed
  11. customto yield ˜60 ml
  12. customon a rotary evaporator, and EtOAc (60 ml)
  13. additionwas added
  14. customThe solvent was removed again to ˜65 ml
  15. customthe resulting slurry was crystallized from EtOAc/heptane

Sources & evidence

ORD record
ord-a2e34cacfc3b4101abc8d32e303baad2
Source dataset
uspto-grants-2005_08
Patent number
US06930187B2

Reaction notes

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