Triethylamine → HCID 131720947, compound

Participants

Reaction Steps

To a stirred mixture of (S)-N-[[3-[3-fluoro-4(-1-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide hydrochloride (EXAMPLE 7, 16.2 kg, 43.5 moles), tetrahydrofuran (205 kg) and triethylamine (10.1 kg, 100 moles) is added acetoxyacetyl chloride (6.5 kg, 47.8 moles) in tetrahydrofuran (11.1 kg) over 35 minutes keeping the temperature at 22°-23°. After 40 minutes, at which time TLC and HPLC analysis indicated complete formation of the acetoxyacetamide intermediate, the mixture is concentrated under reduced pressure to 30 l, diluted with methanol (100 l) and concentrated to 30 l. To the residue is added methanol (25 l) and an aqueous solution of potassium carbonate (5.6 kg in 56 l). The resulting mixture is stirred 20 hr at 22°-25° at which time TLC and HPLC analysis indicates the reaction is complete. The pH is adjusted to 7-7.5 with hydrochloric acid (4N, 14.3 l). The mixture is stirred 18 hr at 15°-22° then 3 hrs at 2°-5°. The solids are collected on a filter, washed with water (68 l) and dried at 20°-25° with recycled nitrogen to give the desired product. The crude product is dissolved in water (225 l) at 60°-70°, clarified through a 0.6 micron filter, diluted with water rinse (55 l) and stirred 17 hrs. at 15°. The solids are collected on a filter, washed with water at 15° and dried at 45° with recycled nitrogen to a water content of 0.33%. These solids are dissolved in a solution of ethyl acetate (143 l), methanol (65 l) and water (1.95 l) at 60°-65°. The solution is cooled to 15°-25° and stirred 16 hrs for crystallization. The solids are collected on a filter, washed with ethyl acetate (75 l) and dried with 45° nitrogen to give the desired product. The product is recrystallized two more times from water (147 1 then 133 l) at 60°-70°, clarified each time through a 0.6 micron filter and rinsed with water (40 1 and 30 l). The solids are dried on the filter at 30° with recycled nitrogen to give, after deagglomeration through a mill, the title compound as the sesquihydrate (6.45% water), TLC (silica gel; methanol/methylene chloride, 5/95) Rf =0.45; [α]D =-20° (c=1.0, ethanol).

Provenance & Evidence