Formic Acid → Amitiza

HRID 1627941Notes

Reaction equation

HRID 1627941 reaction equation
[CH3:1][CH2:2][CH2:3][CH2:4][C:5]([F:27])([F:26])[C@:6]1([OH:25])[O:11][C@@H:10]2[CH2:12][C:13]([C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C@H:9]2[CH2:8][CH2:7]1)=[O:14].C(N)(C)(C)C.C(O)=O>C(OCC)(=O)C.O>[CH3:1][CH2:2][CH2:3][CH2:4][C:5]([F:27])([F:26])[C@:6]1([OH:25])[O:11][C@@H:10]2[CH2:12][C:13]([C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C@H:9]2[CH2:8][CH2:7]1)=[O:14]

Participants

5

Reactant 2

HCID 284Formic AcidHCID 53246203HCID 53246203, compound

Product 1

HCID 157920Amitiza

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of compound 10 (150 g) in dichloromethane (15 volumes), was added 10% palladium on carbon (35% wt) and the suspension was hydrogenated at 2 PSI for 15 hours. After the completion of the reaction, the mixture was filtered through Celite®, concentrated to near dryness and purified by column chromatography (ethyl acetate in hexanes) to give crude Lubiprostone. To a solution of crude Lubiprostone in ethyl acetate (10 vol) was added tert-butylamine (1.05 eq) at room temperature. The mixture was stirred at room temperature until precipitation of the amine salt occurred. The amine salt was isolated by filtration and dried to give Lubiprostone tert-butylamine salt (20 g). The amine salt was suspended in ethyl acetate (6 volumes) and water (3 volumes). The resulting bi-phasic mixture was adjusted to about pH 5 with formic acid. The organic layer was separated and concentrated to obtain Lubiprostone as a syrup. Upon crystallization using ethyl acetate/petroleum ether (1:9 volumes), the syrup produced Lubiprostone (1, 12 g) in approximately 70% recovery. The Lubiprostone filtrate was concentrated to near-dryness. HRMS (ESI+) [M+NH4]+ of (1): Formula: C20H36F2NO5: cal m/z: 408.25561 amu. found: 408.25626 amu.

Workup

  1. customThe organic layer was separated
  2. concentrationconcentrated

Sources & evidence

ORD record
ord-52fa1f42fb6e4e4dafeb5ea2b00eeab5
Source dataset
uspto-grants-2014_07
Patent number
US08785663B2

Reaction notes

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