Sk Corporation

Sk Holdings Co., Ltd.

Jong-Ho Lim

Hee-Jun Hwang

Ki-Nam Uhm

Sang-Chul Lim

Byong-Sung Kwak

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 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.

Method of preparing optically pure (R)- or (S)- tetrahydrofuranyl ketone

Disclosed is a method for optically resolving a racemic &agr;-substituted heterocyclic carboxylic acid (&agr;-HCCA) by taking advantage of enantioselectivity of enzymes. &agr;-HCCA is reacted with alcohol to give a racemic &agr;-HCCA ester, which is then reacted with an enzyme with enantioselectivity, whereby either R-form or S-form of the racemate is hydrolyzed. Extraction with an organic solvent can obtain enantiomers of the &agr;-HCCA ester. The extracted enantiomeric &agr;-HCCA ester is converted to enantiomeric &agr;-HCCA by catalytic hydrogenation in an organic solution or by enzymatic hydrolysis in an aqueous solution. Thus, a racemic mixture of &agr;-HCCA can be optically resolved with high optical purity at high yields as well as at low cost.

Method for optically resolving a racemic &agr;-substituted heterocyclic carboxylic acid using enzyme

Disclosed is a method for preparing an R- or S-forms of &agr;-substituted heterocyclic carboxylic acid (&agr;-HCCA) and a counter enantiomeric form of &agr;-substituted heterocyclic carboxylic acid ester thereto by use of an enzyme. A racemic &agr;-HCCA is reacted with alcohol to give a racemic &agr;-HCCA ester, which is then brought into contact with an enzyme with enantioselectivity, whereby either R-form or S-form of the racemate is hydrolyzed. Extraction with an organic solvent can obtain enantiomers of the &agr;-HCCA ester. Thus, a certain enantiomeric form of &agr;-HCCA and a counter enantiomeric form of &agr;-HCCA ester thereto, respectively can be prepared with high optical purity at high yields as well as at low cost.

Method for preparing an R- or S-form of &agr;-substituted heterocyclic carboxylic acid and a counter enantiomeric form of &agr;-substituted heterocyclic carboxylic acid ester thereto using enzyme

Growing community of inventors

Daejeon, South Korea

Jong-Ho Lim