Preparing water-soluble probucol derivative, useful as cholesterol reducing agent, comprises reacting probucol compound with aliphatic saturated dicarboxylic acid, maleic acid or phthalic acid, in presence of a magnesium compound

摘要

#CMT# #/CMT# Preparation of water soluble probucol derivative (I) or its salt comprises reacting a probucol compound (II) with anhydrides of aliphatic saturated dicarboxylic acid (IIIa), maleic acid or phthalic acid, in the presence of a magnesium compound (IV). #CMT# : #/CMT# Preparation of water soluble probucol compound of formula (I) comprises reacting a probucol compound of formula (II) with anhydrides of aliphatic dicarboxylic acid of formula HO-(O)C-(CH2)n-C(O)-OH (IIIa), maleic acid or phthalic acid, in the presence of a magnesium compound of formula R7-Mg-Hal (IV). R1-R41-4C alkyl such as methyl or tert.butyl (preferred); R5, R61-8C alkenyl, phenyl or preferably 1-8C alkyl such as methyl; A : a group of aliphatic carboxylic acid (IIa) of formula -C(O)-(CH2)n-C(O)-OH, unsaturated carboxylic acid (IIb) of formula -C(O)-CH=CH-C(O)-OH or ortho substituted aromatic carboxylic acid (IIc) of formula (-C(O)-C6H4(ortho)-C(O)OH); Bx : H or A; n : 1-6 (preferably 2); R71-12C alkyl or phenyl; and Hal : halo. #CMT#[Image]#/CMT# #CMT#USE : #/CMT# (I) Is useful as cholesterol reducing agent. #CMT#ADVANTAGE : #/CMT# (I) Is soluble in water (claimed), which hydrolyzes the probucol in the body fluid and releases the active agent in such a manner. The process provides (I) with improved purity and high yield. #CMT#ORGANIC CHEMISTRY : #/CMT# Preferred Components: The magnesium compound is a Grignard reagent. The anhydride of (IIIa) is succinic acid anhydride (when n is 2) (preferred), glutaric acid anhydride (when n is 3), adipic acid anhydride (when n is 4) or pimelic acid anhydride (when n is 5). #CMT#DEFINITIONS : #/CMT# Preferred Definitions: R71-8C alkyl, preferably methyl, hexyl or tert.butyl; Hal : Cl (preferred), Br or I; and Bx : H. #CMT#EXAMPLE : #/CMT# Magnesium chips (12.3 g) in tetrahydrofuran (100 g) was mixed with iodine (0.3 g) and refluxed under tert-butylchloride (46 g) for 30 minutes. The reaction mixture was cooled and a solution of probucol (100 g) and tetrahydrofuran (100 g) were added. To the obtained suspension, succinic acid anhydride (21 g) and tetrahydrofuran (60 g) were added approximately at 45[deg]C. Toluene (100 g) and a mixture of water (250 g) and acetic acid (35 g) were added to the reaction mixture after 1 hour. The organic phase was separated and washed with water (400 g). The obtained residue comprised a mixture of probucol (27 %), succinic acid mono-{2,6-di-tert-butyl-4-[1-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-1-methyl-ethylsulfanyl]-phenyl} ester (A) (56 %) and succinic acid mono-(2,6-di-tert-butyl-4-{1-[3,5-di-tert-butyl-4-(3-carboxy-propionyloxy)-phenylsulfanyl]-1-methyl-ethylsulfanyl}-phenyl) ester (16%). The mixture was crystallized by using sodium salt of heptane and tert-butylmethylether to isolate (A). (A) was further crystallized with free acid to provide (A) with 99% purity (54 g).