1,8-Diazabicyclo(5.4.0)undec-7-ene → 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 585402Notes

Reaction equation

HRID 585402 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([O-])(=O)C.[NH4+].CP(C)C.O1CCCC1>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 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 199401P,P-Diphenylphosphinic azideHCID 517165Ammonium AcetateHCID 9914741Epothilone FHCID 86589763trimethylphosphine THF

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-dione

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
32.5 °C

Procedure

To a suspension of epothilone F (5.0 g, 9.55 mmol, 86.2% potency) and diphenylphosphoryl azide (2.27 ml, 10.5 mmol, 1.1 eq) in tetrahydrofuran (40 ml) was added gradually 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.71 ml, 11.46 mmol, 1.2 eq) and the reaction subsequently stirred at 25-40° C. for 4-6 hrs. To the reaction mixture was then added a 6.0 M solution of ammonium acetate (7.96 ml, 47.7 mmol, 5 eq) followed by 1.0 M trimethylphosphine/tetrahydrofuran solution (1.5 eq). The reaction mixture was diluted with water and the aqueous phase extracted with three portions of ethyl acetate (40 ml each). The organic phase was then washed with three portions of diluted ammonium hydroxide (40 ml each). The combined aqueous washes are then extracted with two portions of ethyl acetate (40 ml each). The combined ethyl acetate phases are washed with two portions of water (20 ml each) then concentrated and azeotropically dried under reduced pressure to a final volume of 60 ml. The resulting solution was heated at 65-75° C. and 70 ml n-heptane was added slowly. The mixture was allowed to cool slowly and stirred at a final temperature of 15-20° C. The resulting solid (3.34 g, 78% corrected for input potency) was isolated by filtration followed by vacuum drying to afford crystalline product.

Workup

  1. customthe reaction
  2. extractionthe aqueous phase extracted with three portions of ethyl acetate (40 ml each)
  3. washThe organic phase was then washed with three portions of diluted ammonium hydroxide (40 ml each)
  4. extractionThe combined aqueous washes are then extracted with two portions of ethyl acetate (40 ml each)
  5. washThe combined ethyl acetate phases are washed with two portions of water (20 ml each)
  6. concentrationthen concentrated
  7. customazeotropically dried under reduced pressure to a final volume of 60 ml
  8. temperatureThe resulting solution was heated at 65-75° C.
  9. addition70 ml n-heptane was added slowly
  10. temperatureto cool slowly
  11. stirringstirred at a final temperature of 15-20° C
  12. customThe resulting solid (3.34 g, 78% corrected for input potency) was isolated by filtration
  13. customdrying
  14. customto afford crystalline product

Sources & evidence

ORD record
ord-0501e210912949a7831ac2f5b65f2009
Source dataset
uspto-grants-2005_08
Patent number
US06930187B2

Reaction notes

Loading…