Ammonia → Atorvastatin calcium

HRID 1641622Notes

Reaction equation

HRID 1641622 reaction equation
CC(C(CCC[CH2:15][N:16]1[C:20]([CH:21]([CH3:23])[CH3:22])=[C:19]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])[C:18]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:17]1[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)C(O)(O)C([O-])=O)(C)C.[OH-:46].[Na+].[C:48]([O-:51])(=[O:50])[CH3:49].[Ca+2:52].[C:53]([O-:56])(=[O:55])[CH3:54].N.[C:58](#N)[CH3:59]>O.C1CCCCC1.C(OCC)(=O)C>[CH3:23][CH:21]([C:20]1[N:16]([CH2:15][CH2:59][C@@H:58]([OH:46])[CH2:54][C@@H:53]([OH:56])[CH2:49][C:48]([O-:51])=[O:50])[C:17]([C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)=[C:18]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:19]=1[C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25])[CH3:22].[CH3:23][CH:21]([C:20]1[N:16]([CH2:15][CH2:54][C@@H:53]([OH:55])[CH2:58][C@@H:59]([OH:46])[CH2:49][C:48]([O-:51])=[O:50])[C:17]([C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)=[C:18]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:19]=1[C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25])[CH3:22].[Ca+2:52]

Participants

9

Reactant 5

HCID 222AmmoniaHCID 6116Calcium AcetateHCID 6342AcetonitrileHCID 14798Sodium HydroxideHCID 86643743HCID 86643743, compound

Product 1

HCID 60822Atorvastatin calcium

Reagents, catalysts & solvents 3

HCID 962WaterSolvent3×HCID 8078CyclohexaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

20 gm of R—(R*,R*)]-1,1-dimethylethyl-2-(4-fluorophenyl)-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoate was taken in 400 mL of acetonitrile to obtain clear solution at 40° C. to 45° C. The reaction mixture was cooled to 25° C. to 30° C. and 2.60 gm of NaOH solution in 100 mL of water was added within 15 min and stirred for 30 min. Acetonitrile was distilled under vacuum to obtain white slurry or solid. The compound thus obtained was further cooled at 10° C. to 15° C. 400 mL of water (with pH≈8.0 adjusted by liquor ammonia) was added followed by slow addition of 400 mL of ethyl acetate to dissolve the solution. 3.48 gm of calcium acetate solution in 80 mL of water was added to obtain hazzy solution at 10° C. to 15° C. followed by addition of liquor ammonia to adjust the pH≈8.0. The reaction mixture was stirred for 2 hrs at 35° C. to 40° C. and cooled to 30° C. to 35° C. The organic layer was separated and washed with water and filtered through hyflow bed followed by washing with ethyl acetate. The organic phase was distilled to remove ethyl acetate completely till powder or lump of material was obtained. The solid thus obtained was treated with 100 mL of cyclohexane and stirred for 30 min. The product was filtered, washed with cyclohexane and dried at 30° C. to 35° C. to obtain amorphous atorvastatin calcium.

Workup

  1. customto obtain clear solution at 40° C. to 45° C
  2. temperatureThe reaction mixture was cooled to 25° C. to 30° C.
  3. distillationAcetonitrile was distilled under vacuum
  4. customto obtain white slurry or solid
  5. customThe compound thus obtained
  6. temperaturewas further cooled at 10° C. to 15° C
  7. dissolutionto dissolve the solution
  8. customto obtain hazzy solution at 10° C. to 15° C.
  9. stirringThe reaction mixture was stirred for 2 hrs at 35° C. to 40° C.
  10. temperaturecooled to 30° C. to 35° C
  11. customThe organic layer was separated
  12. washwashed with water
  13. filtrationfiltered through hyflow bed
  14. washby washing with ethyl acetate
  15. distillationThe organic phase was distilled
  16. customto remove ethyl acetate completely till powder or lump of material
  17. customwas obtained
  18. customThe solid thus obtained
  19. stirringstirred for 30 min
  20. filtrationThe product was filtered
  21. washwashed with cyclohexane
  22. customdried at 30° C. to 35° C.

Sources & evidence

ORD record
ord-266131fe3bd747b1a11f93993c1040da
Source dataset
uspto-grants-2012_02
Patent number
US08115015B2

Reaction notes

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