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To a solution of(Z)-7-[(1 R,2R,3R)-2-((E)-4,4-difluoro-3-oxo-1 -octenyl)-3-(phenylmethoxy)-5-ox ocyclopentyl]-5-heptenoic acid (10, R1 is phenyl, R2 and R3 are H, R6 is H, and the S/D bond between the carbon at position 9b 1 and the carbon at position 9b2 is a double bond, 50 mg) in ethyl acetate (5 ml_), was added 10percent palladium on carbon (5 mg) and the suspension was hydrogenated at atmospheric pressure for 10 hours. After the completion of the reaction, the mixture was filtered through Celite.(R). and the crude material was re-crystallized using ethyl acetate/heptanes to yield Lubiprostone as a crystalline material in 70percent yield.HRMS (ESI+) [M + NH4]+ Formula: C20H36F2NO5: cal m/z: 408.25561 amu, found: 408.25626 amu
With hydrogen;palladium 10% on activated carbon; In ethyl acetate; for 10.0h;
To a solution of(Z)-7-[(1 R,2R,3R)-2-((E)-4,4-difluoro-3-oxo-1 -octenyl)-3-(phenylmethoxy)-5-ox ocyclopentyl]-5-heptenoic acid (10, R1 is phenyl, R2 and R3 are H, R6 is H, and the S/D bond between the carbon at position 9b 1 and the carbon at position 9b2 is a double bond, 50 mg) in ethyl acetate (5 ml_), was added 10% palladium on carbon (5 mg) and the suspension was hydrogenated at atmospheric pressure for 10 hours. After the completion of the reaction, the mixture was filtered through Celite and the crude material was re-crystallized using ethyl acetate/heptanes to yield Lubiprostone as a crystalline material in 70% yield.HRMS (ESI+) [M + NH4]+ Formula: C20H36F2NO5: cal m/z: 408.25561 amu, found: 408.25626 amu
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 .
With hydrogen;palladium 10% on activated carbon; In dichloromethane; under 103.432 Torr; for 15.0h;
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 .
4-methoxybenzyl 7-[(2R,4aR,5R,7aR)-2-(1,1-difluoro-pentyl)-octahydro-2-hydroxy-6-oxocyclopenta[b]pyran-5-yl]heptanoate[ No CAS ]
[ 136790-76-6 ]
Yield
Reaction Conditions
Operation in experiment
40 g
With 5%-palladium/activated carbon; hydrogen; In ethyl acetate; for 3.0h;
Preparation of Crude Lubiprostone (0090) 4-Methoxybenzyl 7-[ (2R, 4aR, 5R, 7aR)-2-(1,1-difluoro-pentyl)-octahydro-2-hydroxy-6-oxocyclopenta[b]pyran-5-yl)heptanoate (60 g, 117.5 mmol, enantiomeric purity ?99%) was dissolved in 600 ml ethyl acetate and followed by addition of 5% palladium on charcoal under hydrogen for 3 hours. Then, the reaction mixture was filtered with celite pad. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent to obtain 40 g oily Lubiprostone. HPLC analysis of the product showed that 1.1% impurity A was found.