Sk Corporation

Sk Holdings Co., Ltd.

Hee-Jun Hwang

Byong-Sung Kwak

Jong-Ho Lim

Ki-Nam Chung

Ki-Ho Koh

Sang-Il Lee

Disclosed is a process for the preparation of 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine. In the process, low-priced 2,2'-dithiosalicylic acid as starting material is subjected to bond formation reaction with 1-chloro-2-nitrobenzene in a basic aqueous solution, a nitro group reduction reaction is conducted, cyclization and chlorination reactions are simultaneously carried out in the presence of a equivalent amount of halogenating agent, a reaction with piperazine is continuously conducted without separation, and a reaction with 2-haloethoxyethanol is conducted, thereby it is possible to economically producing Quetiapine, that is, 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine, in an environmentally friendly manner. Particularly, the process is advantageous in that economic efficiency is assured because of use of the low-priced starting material, use of an organic solvent is minimized because a reaction is conducted in an aqueous solution, and it is possible to achieve the environmentally friendly and economical process having high commercial usefulness because the number of reaction steps of the process is reduced and because generation of acidic waste is minimized.

Process for the preparation of 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)dibenzo[b,f][1,4]thiazepine

Disclosed is a method of preparing 10H-dibenzo[b,f][1,4]thiazepin-11-one, including reacting dithiosalicylic acid with 1-chloro-2-nitrobenzene in a basic aqueous solution in the presence or absence of a reducing agent, to prepare 2-(2-nitrophenylsulfuryl)benzoic acid; subjecting the 2-(2-nitrophenylsulfuryl)benzoic acid to nitro group reduction in the presence of hydrogen, a solvent and a heterogeneous metal catalyst, to prepare 2-(2-aminophenylsulfuryl)benzoic acid; and directly cyclizing the 2-(2-aminophenylsulfuryl)benzoic acid in an organic solvent in the presence or absence of an acid catalyst. The method according to the present invention is economical due to the use of the inexpensive starting material, and also environmentally friendly and efficient by minimizing the use of the organic solvent and performing direct cyclization without the activation of carboxylic acid.

Method of preparing 10H-dibenzo[b,f][11,4]thiazepin-11-one

Disclosed is a method of preparing an optically pure (R)- or (S)-tetrahydrofuranyl ketone. By such a method, (R)- or (S)-2-tetrahydrofuran amide is converted to (R)- or (S)-2-tetrahydrofuran nitrile through dehydration in the presence of a dehydrating agent and an amine base. Then, thus prepared (R)- or (S)-2-tetrahydrofuran nitrile is nucelophilic addition-reacted with a nucleophile, followed by hydrolyzing, thereby produce (R)- or (S)-tetrahydrofuranyl ketone having high optical purity, while minimizing production of other by-products.

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Daejeon, South Korea

Hee-Jun Hwang