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 585395Notes

Reaction equation

HRID 585395 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-dione

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
20 °C

Procedure

To a stirred suspension of epothilone F (10 g, 19.1 mmol) in tetrahydrofuran (200 ml) under argon, chilled in an ice bath to 5° C. or below, was added diphenylphosphoryl azide (6.20 ml, 7.90 g, 28.6 mmol, 1.5 equivalents). The mixture was stirred for approximately 10 min. 1,8-diazabicyclo[5.4.0]undec-7-ene (3.43 ml, 3.53 g, 22.8 mmol, 1.2 equivalents) was then added gradually at a rate that maintained the temperature of the mixture below 8° C. The mixture was stirred for 30 min., then allowed to warm to 20° C. and stirred for 18 hours. To the reaction mixture was added a solution of 1.0 M trimethylphosphine in tetrahydrofuran (21 ml, 18.3 g, 21 mmol, 1.1 equivalents), which generated a mild exotherm with gas evolution. The mixture was allowed to stir at 20° C. for 30 minutes, and water (52 ml) was added. After 30 minutes, 28% aqueous NH4OH (26.5 ml) was added. After stirring at 25° C. for another 30 minutes, water (100 ml) was added, and the mixture was extracted with methylene chloride (3×100 ml). The combined organic extracts were washed with 1.0 M aqueous ammonium hydroxide (2×100 ml), and then with half-saturated aqueous sodium chloride (100 ml). The solvents were removed on a rotary evaporator, and the residue dried in vacuo for 18 hours.

Workup

  1. temperaturechilled in an ice bath to 5° C. or below
  2. temperaturethat maintained the temperature of the mixture below 8° C
  3. stirringThe mixture was stirred for 30 min.
  4. stirringstirred for 18 hours
  5. stirringto stir at 20° C. for 30 minutes
  6. waitAfter 30 minutes
  7. stirringAfter stirring at 25° C. for another 30 minutes
  8. extractionthe mixture was extracted with methylene chloride (3×100 ml)
  9. washThe combined organic extracts were washed with 1.0 M aqueous ammonium hydroxide (2×100 ml)
  10. customThe solvents were removed on a rotary evaporator
  11. customthe residue dried in vacuo for 18 hours

Sources & evidence

ORD record
ord-6cce2c2c2a9b4a5cab3beb223e15db93
Source dataset
uspto-grants-2005_08
Patent number
US06930187B2

Reaction notes

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