Zentiva, A.s.

Stanislav Radl

Kamal Jarrah

Jan Stach

A method of manufacturing glimepiride of formula I wherein trans-4-methylcyclohexylamine pivalate of formula VII is reacted, either directly or after conversion to trans-4-methylcyclohexylamine or to its another salt, with an alkyl [4-(2-{[(3-ethyl-4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1 yl)carbonyl]amino)ethyl)phenyl]-sulfonyl carbamate of general formula IV wherein R is a C1-C5 alkyl, giving glimepiride of formula I, trans-4-Methylcyclohexylamine pivalate of formula VII 

Method of manufacturing glimepiride and the respective intermediate

A method of manufacturing an amorphous form of the hemi-calcium salt of (3R, 5R) 7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid of formula (I), in which (3R, 5R) 7-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid or its salt with a cation Mwherein Mis either a cation of an alkali metal or an ammonium cation of formula RNHwherein R is lower C&#x2013;Calkyl, n may reach values ranging between 0 and 3, is, without isolating the intermediate in the form of the hemi-calcium salt or of another salt, acid or lactone, converted, in a solution, by the treatment with the calcium salt or calcium hydroxide, or a calcium C&#x2013;Calcoholate, to the hemi-calcium salt, and the latter is precipitated with a C&#x2013;Chydrocarbon or dialkylether of formula ROR, wherein each of Rand Ris a C&#x2013;Calkyl group. The starting acid or its salt is prepared starting from (3R, 5R) tert-butyl (6-{2-[3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxane-4-yl) acetate of formula II.

Method of manufacturing an amorphous form of the hemi-calcium salt of (3R,5R) 7-3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yll-3, 5-dihydroxyheptanoic acid (actorvastatin)

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Praha, Czechia

Stanislav Radl