Sarecycline Hydrochloride synthesis

Yield:-

Reaction Conditions:

with hydrogenchloride in ethanol;water; pH=1.3 - 1.6 at 5;

Steps:

Crude (4S,4aS,5aR,12aS)-4-dimethylamino-3, 10,12,12a-tetrahydroxy-7- [(methoxy(methyl)amino)-methyl]-l ,ll-dioxo-l,4,4a,5,5a,6,l l ,12a-octahydro-naphthacene- 2-carboxylic acid amide (lOOg, app. 35% assay) was purified on preparative column chromatography. The desired fractions (8-10 liters) were combined and the pH was adjusted to 7.0-7.5 using ammonium hydroxide. This aqueous solution was extracted 3 times with dichloromethane (4 liters each time). The dichloromethane layers were combined and concentrated under reduced pressure. The residue was suspended in ethanol (800 ml) and 20 ml water was added. The pH was gradually adjusted to pH 1.6-1.3 using 1.25M hydrochloric acid in methanol and the mixture was stirred for 20-60 minutes at which point the free base was completely dissolved. The solution was concentrated under reduced pressure to 200-250 ml and was seeded with (4S,4aS,5aR,12aS)-4-dimethylamino- 3,10, 12, 12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]- 1, 11-dioxo- l,4,4a,5,5a,6,l l,12a-octahydro-naphthacene-2-carboxylic acid amide mono HQ crystals (100-200 mg). The stirring was continued for 2-18 hours while the slurry was kept at <5°C. The resulting crystals were filtered, washed with ethanol (50 mL) and dried under reduced pressure to a constant weight. 20g crystalline (4S,4aS,5aR,12aS)-4-dimethylamino- 3,10, 12, 12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]- 1, 11-dioxo- l,4,4a,5,5a,6,l l,12a-octahydro-naphthacene-2-carboxylic acid amide mono hydrochloride was isolated in > 90% purity and > 90% assay.

References:

PARATEK PHARMACEUTICALS, INC.;WARNER CHILCOTT COMPANY, LLC;COULTER, Catherine;JOHNSTON, Sean, M.;SEYEDI, Farzaneh WO2012/155146, 2012, A1 Location in patent:Page/Page column 27-28

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