Preparation of 2-[[2-[(1R,5R)-2-oxo-5-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl]ethyl]thio]-1,3-thiazole-4-carboxylic acid 4-piperidinemethanol salt and crystal polymorphs thereof.

Abstract

There is provided 2-[[2-[(1R,5R)-2-oxo-5-[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl]ethyl]thio]-1,3-thiazole-4-carboxylic acid (I; R = H) 4-piperidinemethanol salt that can serve as a drug for the treatment of underactive bladder related to incomplete bladder emptying, which can be administered orally and poses little risk of side effects. There are also provided crystals of the compd. I 4-piperidinemethanol salt that are advantageous as the bulk drug of a pharmaceutical in terms of stability, long-term storage, ease of handling, ease of formulation, and the like. Salts of the compd. I, or a mixt. of diastereomers thereof, and 4-piperidinemethanol are extremely chem. stable crystals and therefore permit long-term storage and are very useful as the bulk drug of a pharmaceutical. Thus, a soln. of 1.13 g 1-phenyl-5-([6,7,7-trifluoro-3-methyl-3-[(trimethylsilyl)oxy]-6-hepten-1-yl]sulfonyl)-1H-tetrazole in 8.0 mL 1,2-dimethoxyethane was treated dropwise slowly with 4.8 mL 0.65 M potassium hexmethyldisilazide/toluene soln. at -78°, stirred at the same temp. for 30 min, treated slowly dropwise with a soln. of 461 mg Et 2-([2-[(1R,2S,5S)-2-(acetyloxy)-5-formylcyclopentyl]ethyl]thio)-1,3-thiazole-4-carboxylate in 5.0 mL 1,2-dimethoxyethane at -78°, stirred at the same temp. for 30 min, warmed to room temp., and treated with aq. satd. NaHCO3 soln. to give, after workup and silica gel chromatog., 703 mg Et 2-[[2-((1R,2S,5R)-2-(acetyloxy)-5-[(1E)-7,8,8-trifluoro-4-methyl-4-[(trimethylsilyl)oxy]-1,7-octadien-1-yl]cyclopentyl)ethyl]thio]-1,3-thiazole-4-carboxylate (II; R = Me, R1 = acetyl, R2 = trimethylsilyl). A soln. of 703 mg II (R = Me, R1 = acetyl, R2 = trimethylsilyl) in 6.0 mL ethanol was treated with 2 N aq. NaOH soln. under ice-cooling, stirred overnight at room temp., treated with 1 N aq. HCl soln. at the same temp., and stirred for 30 min to give, after workup, 538 mg II (R = R1 = R2 = H). A soln. of 538 mg II (R = R1 = R2 = H) in 6.0 mL pyridine was treated with 0.33 mL acetic anhydride, stirred overnight at room temp., poured into 1 N aq. HCl soln. to give, after workup, 589 mg II (R = R2 = H, R1 = acetyl). A soln. of 589 mg II (R = R2 = H, R1 = acetyl) in 58 mL toluene was treated with 567 mg 4-dimethylaminopyridine, heated to 100°, treated with 0.37 mL 2,4,6-trichlorobenzoyl chloride, stirred for 15 min, and cooled to room temp. to give, after workup and silica gel chromatog., 200 mg cyclic lactone (III) and its epimer (IV). A soln. of 200 mg cyclic lactone III in 1.0 mL methanol and 2.0 mL THF was treated with 0.62 mL 2 N aq. NaOH soln., stirred overnight at room temp., and poured into 1 N aq. HCl soln. to give, after workup, 190 mg 2-[(2-[(1R,2S,5R)-2-Hydroxy-5[(1E,4S)-7,8,8-trifluoro-4-hydroxy-4-methyl-1,7-octadien-1-yl]cyclopentyl]ethyl)thio]-1,3-thiazole-4-carboxylic acid (V; R = H). A soln. of 190 mg V (R = H) in 2.1 mL DMF was treated with 340 mg K2CO3 and 0.09 mL MeI, stirred overnight at room temp. to give, after workup, 196 mg V (R = Me). A soln. of 196 mg V (R = Me) in 1.4 mL DMSO and 2.8 mL EtOAc was treated with 0.43 mL diisopropylethylamine and 196 mg SO3-pyridine complex under ice-cooling, stirred for 15 min to give, after workup and silica gel chromatog., 152 mg I (R = Me). A soln. of 152 mg I (R = Me) in 2.0 mL 1,2-dimethoxyethane and 1.0 mL H2O, treated with 16.0 mg LiOH under ice-cooling, stirred at room temp. for 2 h, poured into 5% aq. KHSO4 soln. to give, after workup and silica gel chromatog., 127 mg I (R = H) as a viscous oil. I (R = H) (7.0 g) was dissolved in 245 mL EtOAc, treated with 1.744 g 4-piperidinemethanol and stirred overnight, followed by filtering off the pptd. white crystals and vacuum-drying to give 8.7 g crude I (R = H) 4-piperidinemethanol salt as a ∼9:1 mixt. of diastereomers. The latter crude compd. (60 mg) was dissolved in 300 μL tert-Bu Me ether and 300 μL isopropanol at 40°, stirred for 60 min, and treated with 900 μL tert-Bu Me ether at room temp. for 6 h. The resulting slurry was stirred overnight at 55° and filtered, followed by vacuum-drying at room temp. to give, 30 mg I (R = H) 4-piperidinemethanol salt (crystal form A). The crystal form A was very stable and showed 98.6, 99.6, and 92.0% residual ratio when it was stored at 60° for 1 mo, at 40° for 1 mo, and at 40° and 75% RH for 1 mo, resp., as compared to 60.4, 76.0, and 58.6%, resp., for noncryst. compd. I (R = H). The compd. I (R = H) 4-piperidinemethanol salt in vitro increased the contractility of rat's detrusor muscles by 5.97, 54.35, 177.91, and 245.91% at 1 nmol/L, 10 nmol/L, 100 nmol/L, and 1 μmol/L, resp. A tablet contg. I (R = H) 4-piperidinemethanol salt (crystal C form) and a vial contg. I (R = H) 4-piperidinemethanol salt (crystal A form) were described. [on SciFinder(R)]