Phosphorus oxychloride → Fosamprenavir Calcium

HRID 333034Notes

Reaction equation

HRID 333034 reaction equation
[CH2:1]([C@H:8]([NH:29][C:30](=[O:37])[O:31][C@H:32]1[CH2:36][CH2:35][O:34][CH2:33]1)[C@H:9]([OH:28])[CH2:10][N:11]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:38]=[P:39](Cl)(Cl)Cl.Cl.[OH2:44].[OH2:45].C([O-])(=O)C.[Ca+2:50].C([O-])(=O)C>O.C(C(C)=O)C(C)C.N1C=CC=CC=1>[CH3:26][CH:25]([CH2:24][N:11]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:10][C@@H:9]([O:28][P:39]([O-:38])([O-:45])=[O:44])[C@@H:8]([NH:29][C:30]([O:31][C@@H:32]1[CH2:33][O:34][CH2:35][CH2:36]1)=[O:37])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:27].[Ca+2:50]

Participants

8

Reactant 4

HCID 24813Phosphorus oxychlorideHCID 82163Calcium acetate monohydrateHCID 9807180(3S)-Tetrahydro-3-furanyl N-((1S,2R)-2-hydroxy-3-((2-methylpropyl)((4-nitrophenyl)sulfonyl)amino)-1-(phenylmethyl)propyl)carbamateHCID 21885828Hydrate;hydrochloride

Product 1

HCID 131535Fosamprenavir Calcium

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1049PyridineSolventHCID 7909Methyl Isobutyl KetoneSolvent

Conditions

Temperature
5 °C

Procedure

Mixture of 100 g (0.186 mol) (3S)-tetrahydro-3-furyl N-[(1S,2R)-1-benzyl-2-hydroxy-3-(N-isobutyl-4-nitrobenzene sulphonamido)propyl]carbamate (IV) and 200 ml pyridine was cooled to 0-10° C. and 70.0 g (0.456 mol) of POCl3 was added and stirred at ambient temperature for 4 hours, 400 ml methyl isobutyl ketone was added, cooled and 1:1 conc. HCl-water was added. Mixture was heated to 50° C. for 1 hour, cooled to 25-30° C. Organic layer was separated, washed with water and partially concentrated; 500 ml water and 31.5 g sodium bicarbonate was added and stirred. The organic layer was separated and 100 ml ethylacetate, 400 ml methanol and 5.0 g Pd/C was added. The reaction mass was stirred under hydrogen pressure for 4 hours at 30° C. The mixture was filtered, catalyst washed with methanol. The filtrate was heated to 50° C. and 33.0 g (0.186 mol) calcium acetate monohydrate in 100 ml water was added and stirred for 30 minutes. Cooled to 30° C. and stirred. Solid was filtered, washed with 1:1 mixture of methanol-water and dried to obtain crude fosamprenavir calcium.

Workup

  1. temperaturecooled
  2. temperatureMixture was heated to 50° C. for 1 hour
  3. temperaturecooled to 25-30° C
  4. customOrganic layer was separated
  5. washwashed with water
  6. concentrationpartially concentrated
  7. addition500 ml water and 31.5 g sodium bicarbonate was added
  8. stirringstirred
  9. customThe organic layer was separated
  10. addition100 ml ethylacetate, 400 ml methanol and 5.0 g Pd/C was added
  11. stirringThe reaction mass was stirred under hydrogen pressure for 4 hours at 30° C
  12. filtrationThe mixture was filtered
  13. washcatalyst washed with methanol
  14. temperatureThe filtrate was heated to 50° C.
  15. stirringstirred for 30 minutes
  16. temperatureCooled to 30° C.
  17. stirringstirred
  18. filtrationSolid was filtered
  19. washwashed with 1:1 mixture of methanol-water
  20. customdried

Sources & evidence

ORD record
ord-fc0a9e4e72044735a6656153ce79f16c
Source dataset
uspto-grants-2014_11
Patent number
US08877947B2

Reaction notes

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