Sodium Hydroxide → CI-1029

HRID 844833Notes

Reaction equation

HRID 844833 reaction equation
[C:1]([C:5]1[CH:10]=[C:9]([CH2:11][OH:12])[C:8]([CH3:13])=[CH:7][C:6]=1[S:14][C:15]1[C:20](=[O:21])[O:19][C@:18]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH:33]C(=O)C)=[CH:29][CH:28]=2)([CH:22]([CH3:24])[CH3:23])[CH2:17][C:16]=1[OH:37])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(O)(O)=O)(=O)O.[C]>C(O)(=O)C.O.C(O)C>[NH2:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][C@:18]2([CH:22]([CH3:24])[CH3:23])[O:19][C:20](=[O:21])[C:15]([S:14][C:6]3[CH:7]=[C:8]([CH3:13])[C:9]([CH2:11][OH:12])=[CH:10][C:5]=3[C:1]([CH3:2])([CH3:3])[CH3:4])=[C:16]([OH:37])[CH2:17]2)=[CH:28][CH:29]=1

Participants

7

Reactant 3

HCID 14798Sodium HydroxideHCID 70150021HCID 70150021, compoundHCID 178508643HCID 178508643, compound

Product 1

HCID 54687772CI-1029Yield 82%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 702EthanolSolventHCID 962WaterSolvent2×

Conditions

Temperature
108 °C

Procedure

(S)-N-(4-{2-[5-(2-tert-Butyl-4-hydroxymethyl-5-methylphenylsulfanyl)-4-hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl}phenyl)acetamide (27b) (8.90 Kg, 16.4 mol correcting for HPLC purity of 96.8%), water (43 L) and cold ethyl alcohol (76 L) were added to a reactor under an inert atmosphere. Sodium hydroxide, 50% aqueous solution (31 Kg) and water (27 L) were added and the vessel sealed. The mixture was stirred and heated to 108° C. Stirring was continued at 108-112° C. for 2.5 hours. The mixture was cooled to 65° C. and the pH adjusted to 6.9 by addition of 23.7 Kg glacial acetic acid over 40 minutes while maintaining the batch temperature between 65 and 69° C. The solution was transferred to a second reactor containing 3 Kg ADP carbon. The first reactor was rinsed with ethyl alcohol (5 L) and the rinse transferred to the second reactor. The resulting mixture was stirred at 65-67° C. for 15 minutes and then filtered with the aid of Supercel Hyflo (5 Kg) into a still. The second reactor and the filter were rinsed with a solution of water (5 L) in ethyl alcohol (25 L) and the rinse combined with the product solution in the still which was then concentrated under vacuum at 40-46° C. to remove 18-20 L solvent. Seed crystals were added to the remaining solution in the still and the mixture stirred and cooled to 0° C. and filtered. The product was washed with water (40 L) and vacuum dried overnight at 61° C. to give (S)-6-[2-(4-aminophenyl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methylphenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydropyran-2-one (27) (7.00 Kg, 13.4 mol, 82% yield correcting for HPLC purity, ethanol and water content): mp: 140° C. (dec); Assay (HPLC): 99.2 area%; Chiral assay (HPLC): 99.7 area % (S) isomer; Ethanol (GC): 6.7 w/w %; Water (KF): 0.32 w/w %. This material is suitable for use in the preparation of pharmaceutically acceptable salts.

Workup

  1. customthe vessel sealed
  2. stirringStirring
  3. temperatureThe mixture was cooled to 65° C.
  4. temperaturewhile maintaining the batch temperature between 65 and 69° C
  5. customThe solution was transferred to a second reactor
  6. washThe first reactor was rinsed with ethyl alcohol (5 L)
  7. stirringThe resulting mixture was stirred at 65-67° C. for 15 minutes
  8. filtrationfiltered with the aid of Supercel Hyflo (5 Kg) into a still
  9. washThe second reactor and the filter were rinsed with a solution of water (5 L) in ethyl alcohol (25 L)
  10. concentrationwas then concentrated under vacuum at 40-46° C.
  11. customto remove 18-20 L solvent
  12. additionSeed crystals were added to the remaining solution in the still and the mixture
  13. stirringstirred
  14. temperaturecooled to 0° C.
  15. filtrationfiltered
  16. washThe product was washed with water (40 L) and vacuum
  17. customdried overnight at 61° C.

Sources & evidence

ORD record
ord-faf177decd864147bd8fb4638d03ef56
Source dataset
uspto-grants-2002_04
Patent number
US06380400B1

Reaction notes

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