Especially, among Ureido-TiBA derivatives synthesized from the compounds of formula (II), 2-(4-{2-[3-cyclohexyl-1-(4-cyclohexylbutyl)ureido]ethyl}phenylthio)-2-methylpropionic acid (hereinafter, called to “GW7647”) and 2-(4-{2-[1-heptyl-3-(2,4-difluorophenyl)ureido]ethyl}phenylthio)-2-methyl propionic acid (hereinafter, called to “GW9578”) are known as remedies for heart diseases caused by hypertension, high-cholesterol and an excess of fat (J. Med. Chem. 1999, 42, 3785; PCT publication WO 00/23407; Bioorg Med. Chem. Lett. 2001, 11, 1225). These articles disclosed the compounds of formula (II) for preparing Ureido-TiBA derivatives and the process for preparing the same.

As above, tert-butyl 2-[4-(2-aminoethyl)phenylthio]-2-methylpropionate was obtained in 86% yield by reacting 4-bromothiophenol (1) as a starting material with tert-butyl 2-bromoisobutyrate to obtain tert-butyl 2-(4-bromophenylthio)-2-methylpropionate (2) in 80% yield, reacting it with N-vinyl phthalimide in presence of palladium catalyst for 24 hours to obtain tert-butyl 2-[4-(2-phthalimidoethenyl)phenylthio]-2-methylpropionate (3) in 84% yield, reducing the resulted compound (3) under Wilkinson catalyst to obtain tert-butyl 2-[4-(2-phthalimidoethyl)phenylthio]-2-methylpropionate (4) in 91% yield and then reacting the resulted compound (4) with hydrazine.
Although the above compound (II) has known to be an excellent efficacy, the manufacturing method thereof was not satisfactory, thereby being not cost-effective. That is to say,                1) The manufacturing method according to the reaction scheme consists of 4 steps, and the total yield thereof is as low as 53%. So, it is not proper to be applied to the industry.        2) The manufacturing process according to the reaction scheme includes two steps for more than 10 hours, which takes long time to obtain the final product.        3) Palladium (Pd) and rhodium (Rh) used in the reaction scheme are expensive to increase manufacturing cost and may lead to pollution of environment.        
Under the circumstance, the novel process for preparing the above compound with easiness and low cost has been demanded in the art.
USPTO Backgrounds
USPTO Backgrounds