Ammonium Hydroxide → 3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

HRID 585397Notes

Reaction equation

HRID 585397 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.CP(C)C.[NH4+].[OH-]>O1CCCC1.O>[NH2:51][CH2:33][C:31]1[S:30][CH:29]=[C:28]([CH:27]=[C:26]([CH:10]2[O:11][C:12](=[O:13])[CH2:14][CH:15]([OH:25])[C:16]([CH3:24])([CH3:23])[C:17](=[O:18])[CH:19]([CH3:22])[CH:20]([OH:21])[CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]3([CH3:36])[CH:7]([O:8]3)[CH2:9]2)[CH3:35])[N:32]=1

Participants

8

Reactant 5

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

Product 1

HCID 541863353-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dioneYield 120.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent2×

Procedure

To a stirred suspension of epothilone F (47.12 g, 90.0 mmol) in tetrahydrofuran (942 ml, previously dried over 3A molecular sieves) under argon, was added diphenylphosphoryl azide (29.2 ml, 37.3 g, 135.5 mmol, 1.5 equivalents). The mixture was stirred for about 10 min. 1,8-diazabicyclo[5.4.0]undec-7-ene (24.5 ml, 24.94 g, 163.8 mmol, 1.8 equivalents) was then added gradually, at a rate that maintained the temperature of the mixture below 30° C. The mixture was stirred for 22 hours. To the reaction mixture was added a solution of trimethylphosphine in tetrahydrofuran (1.0 M, 99.0 ml, 86.3 g, 99.0 mmol, 1.1 equivalents), at a rate that maintained the temperature of the mixture below 30° C. The mixture was stirred at room temperature for 30 minutes, and water (244 ml) was added. After 30 minutes, 28% aqueous NH4OH (125.0 ml) was added, and the mixture stirred for 30 minutes. Water (470 ml) was added, and the mixture was extracted with methylene chloride (3×100 ml). The combined organic extracts were washed with aqueous ammonium hydroxide (1.0 M, 3×470 ml). NMR analysis was used to determine the presence of residual diphenylphosphate in the organic phase. The organic phase was then washed with half-saturated aqueous sodium chloride (470 ml), the solvents were removed on a rotary evaporator, and the residual solid was dried in vacuo for 18 hours to afford the crude product (56.72 g, 120.6% yield).

Workup

  1. dry with materialpreviously dried over 3A molecular sieves) under argon
  2. temperaturemaintained the temperature of the mixture below 30° C
  3. stirringThe mixture was stirred for 22 hours
  4. temperatureat a rate that maintained the temperature of the mixture below 30° C
  5. stirringThe mixture was stirred at room temperature for 30 minutes
  6. waitAfter 30 minutes
  7. stirringthe mixture stirred for 30 minutes
  8. extractionthe mixture was extracted with methylene chloride (3×100 ml)
  9. washThe combined organic extracts were washed with aqueous ammonium hydroxide (1.0 M, 3×470 ml)
  10. washThe organic phase was then washed with half-saturated aqueous sodium chloride (470 ml)
  11. customthe solvents were removed on a rotary evaporator
  12. customthe residual solid was dried in vacuo for 18 hours

Sources & evidence

ORD record
ord-8b3978a99ef04e0b899fb48513dedadd
Source dataset
uspto-grants-2005_08
Patent number
US06930187B2

Reaction notes

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