Ammonia → Simvastatin ammonium salt

HRID 1271613Notes

Reaction equation

HRID 1271613 reaction equation
COCC[NH:5][C:6](=[O:35])[CH2:7][C@H:8]([OH:34])[CH2:9][C@H:10]([OH:33])[CH2:11][CH2:12][C@@H:13]1[C@@H:22]2[C:17](=[CH:18][C@H:19]([CH3:31])[CH2:20][C@@H:21]2[O:23][C:24](=[O:30])[C:25]([CH3:29])([CH3:28])[CH2:26][CH3:27])[CH:16]=[CH:15][C@@H:14]1[CH3:32].[OH-:36].[Na+].N>CO.O>[CH3:27][CH2:26][C:25]([C:24]([O:23][C@@H:21]1[C@@H:22]2[C@@H:13]([CH2:12][CH2:11][C@@H:10]([OH:33])[CH2:9][C@@H:8]([OH:34])[CH2:7][C:6]([O-:36])=[O:35])[C@@H:14]([CH3:32])[CH:15]=[CH:16][C:17]2=[CH:18][C@H:19]([CH3:31])[CH2:20]1)=[O:30])([CH3:28])[CH3:29].[NH4+:5]

Participants

6

Reactant 3

HCID 222AmmoniaHCID 14798Sodium HydroxideHCID 18454787HCID 18454787, compound

Product 1

HCID 10961424Simvastatin ammonium salt

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 962WaterSolvent

Conditions

Temperature
75 °C

Procedure

To the concentrate obtained in step 2 is added methanol (840 ml), water (550 ml) and sodium hydroxide (45 gm) at 25° C. The contents are heated to 75° C. and maintained for 7 hours at about 75° C. Then the solvent is distilled off at reduced pressure, cooled to 20° C. and water (400 ml) is added. Then the pH of the reaction mass is adjusted to 5 with 2N hydrochloric acid at 25° C., ethyl acetate (400 ml) is added and the pH is again adjusted to 3.5 with 2N hydrochloric acid solution. The layers are separated and the aqueous layer is washed with ethyl acetate (200 ml). The combined organic layer is dried on sodium sulfate. Ammonia solution, prepared by mixing aqueous ammonia (20 ml) and methanol (20 ml), is added to the reaction mass for 15 minutes at about 25° C., stirred for 1 hour at 25° C. and again for 1 hour at 0° C.–5° C. Then the separated solid is filtered and washed with chilled ethyl acetate (50 ml) to give 28 gm of simvastatin ammonium salt (HPLC Purity 97.5%).

Workup

  1. temperaturemaintained for 7 hours at about 75° C
  2. distillationThen the solvent is distilled off at reduced pressure
  3. temperaturecooled to 20° C.
  4. additionwater (400 ml) is added
  5. customis adjusted to 5 with 2N hydrochloric acid at 25° C.
  6. additionethyl acetate (400 ml) is added
  7. customThe layers are separated
  8. washthe aqueous layer is washed with ethyl acetate (200 ml)
  9. customThe combined organic layer is dried on sodium sulfate
  10. customAmmonia solution, prepared
  11. additionis added to the reaction mass for 15 minutes at about 25° C.
  12. filtrationThen the separated solid is filtered
  13. washwashed with chilled ethyl acetate (50 ml)

Sources & evidence

ORD record
ord-d6f92f8cef864b2892f8a2e944a735b3
Source dataset
uspto-grants-2007_04
Patent number
US07205415B2

Reaction notes

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