KR100554108B1 - A process for preparing erdosteine - Google Patents

Abstract

The present invention relates to a generic name Erdosteine, ie, [(2-oxo-3-tetrahydrothienylcarbamoyl) -methylthio] acetic acid of the formula (I), used as a therapeutic agent for acute and chronic respiratory diseases. A method for preparing the compound, wherein D, L-homocysteine thiolactone hydrochloride of the following formula (II) is reacted with chloroacetyl chloride of the formula (III) to form 3-chloroacetamido-2-oxo- of the following formula (IV) A method for producing erthostein, comprising the steps of preparing tetrahydrothiophene, and reacting a compound of formula (IV) with thioglyconic acid of formula (V) to produce erdostein of formula (I) , The reaction of all the steps is characterized in that by reacting the reactants of each step in a two-phase solution consisting of a basic aqueous solution and an organic solvent for 2 to 3 hours at a temperature of -10 ~ 20 ℃.

Erdosteine, respiratory disease medication, two-phase solution

Description

       Production method of erdosstein {A PROCESS FOR PREPARING ERDOSTEINE}

The present invention relates to a process for producing erdostein, in particular, by performing all the reaction process in a two-phase solution consisting of a basic aqueous solution and an organic solvent, it is possible to produce a high purity target material in high yield compared to the prior art The present invention relates to a new process for producing erdostein.

[(2-oxo-3-tetrahydrothienylcarbamoyl) -methylthio] acetic acid of the following structural formula (I), well known by the common name Erdosteine, is a known medicament used for treating acute and chronic respiratory diseases. As a substance, it is also marketed under the trade name 'ERDOR' in Korea.

Conventional U. S. Patent No. 4,411, 909 introduces an erdostein method, which comprises the following steps. First, this preparation method is carried out by the D, L-homocysteine thiolactone hydrochloride of the following formula (II) and the following formula (III) Chloroacetyl chloride was reacted under basic conditions to prepare 3-chloroacetamido-2-oxo-tetrahydrothiophene of formula (IV), followed by the compound of formula (IV) and thioglycolic acid of formula (V) Is reacted under basic conditions to prepare erdosteine of formula (I).

However, the production method introduced in the U.S. patent produces reaction by-products in which the lactone ring is decomposed in the reaction process because the entire reaction process proceeds under strong basic conditions, thereby yielding a first stage reaction for preparing the compound of formula (IV). The yield of the second stage reaction to produce 72% silver, the final target material was 48% and the total yield was only 35%, making it a commercially uneconomical process.

As a more advanced method, Korean Patent No. 278119 discloses that thiodiglyconic acid of the following formula (VI) is activated by reaction with ethylchloroformate in the presence of an organic base such as triethylamine, and then D of the following formula (II) A method for preparing a compound of formula (I) as a target substance by reacting with, L-homocysteine thiolactone hydrochloride is presented.

However, the method introduced in this domestic patent, when reacting thiodiglyconic acid of the formula (VI) and ethyl chloroformate, not only the carboxyl group of one portion but also the activation of both carboxyl groups are likely to occur by-products In addition, by using an organic solvent, such as triethylamine, there is a disadvantage (by yield 70-75%) that a by-product is generated and undergoes a purification process, in particular, expensive such as thiodiglyconic acid of formula (VI) Because of the use of the compound, it was economically inefficient.

In addition, according to Korean Patent Publication No. 2002-0068140, the thiodiglyconic anhydride of the following formula (VII) is added to the D, L-homocysteine thiolactone hydrochloride of the following formula (II) in the presence of an organic base such as triethylamine. A method of producing the desired compound (I) by reaction with is introduced.

    However, the thiodiglyconic anhydride of the formula (VII) used as a reactant in this method is only to activate the thiodiglyconic acid of the formula (VI), and ultimately to use a expensive compound (VI) In addition, by using an organic base such as triethylamine, by-products are generated, and thus must be purified. This method is also an economically inefficient synthesis method.

Therefore, the present inventors have been researched to improve the problems of the prior art, as a result, to prepare the ersteine basically the same process as the US Patent No. 4,411,909, the entire reaction process with a basic aqueous solution and an organic solvent By proceeding in a two-phase solution, it has been developed a method of suppressing the formation of by-products and producing safe and economically high purity erdossteine.

Erdostein preparation method of the present invention for achieving this object is the reaction of D, L-homocysteine thiolactone hydrochloride of the formula (II) with chloroacetyl chloride of the formula (III) 3- Preparing chloroacetamido-2-oxo-tetrahydrothiophene, and reacting a compound of formula (IV) with thioglyconic acid of formula (V) to prepare erdostein of formula (I) In the method of preparing the erdostein consisting of, the reaction of all the steps in the two-phase solution consisting of a basic aqueous solution and an organic solvent to react the reactants of each step at a temperature of -10 ~ 20 ℃ for 2 to 3 hours It is characterized by proceeding by.

 Hereinafter, the present invention will be described in detail.

The present invention basically prepares erdostein in the same process as US Pat. No. 4,411,909, but all the reaction processes are characterized in that the reaction in a two-phase solution consisting of a basic aqueous solution and an organic solvent. As the base usable in the basic aqueous solution according to the present invention, any form of inorganic salt may be used. Preferably, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate are used. The organic solvent is preferably a polar solvent, more preferably an aprotic solvent, and examples thereof include acetone, ethyl acetate, dichloromethane and chloroform.

Another feature of the present invention is to react within 2 to 3 hours at a temperature range of -20 to 50 ° C, preferably -10 to 20 ° C. At this time, if the reaction temperature is -10 ℃ or less, there is a disadvantage that the reaction time is long due to the decrease in the reactivity, on the contrary, when the temperature is 20 ℃ or more, a large amount of decomposition products of the lactone ring by the base is generated a problem that the yield is greatly reduced . In addition, if the reaction time is 2 hours or less, the reaction has not been sufficiently progressed yet, and after 3 hours, the lactone ring is very unstable under the basic conditions, causing a problem in that the lactone ring is decomposed.

According to the present invention, unlike the prior art, it is possible to reduce the decomposition products of the lactone ring by the base to 0.5% or less (HPLC purity), so that no separate purification process is required, and the yield is a high yield of 75% of the overall yield. Compounds can be prepared simply.

      Hereinafter, examples of the present invention will be described. However, the following examples do not limit the scope of the invention.

Example 1  ; Synthesis of 3-chloroacetamido-2-oxo-tetrahydrothiophene

195 g of sodium hydroxide was dissolved in 750 ml of purified water, 310 ml of acetone was added to form a two-phase solution, and then cooled to 10 ° C., and 750 g of D, L-homocysteine thiolactone hydrochloride was added thereto. The ideal solution was stirred for about 30 minutes, cooled to -5 ° C, and a solution containing 195 g of sodium hydroxide in 750 ml of purified water and 405 g of chloroacetyl chloride in 600 ml of acetone were added dropwise at the same time. After raising the temperature of the solution to room temperature, 2250 ml of purified water was added, and acetone was evaporated under reduced pressure. The resulting solid was filtered, washed with 1500 ml of purified water, and dried at 80 ° C. for 5 hours to obtain 850 g (90%) of the title compound. It was.

Melting Point: 137 ~ 138 ℃

IR (KBr) υcm ^-1 3290, 1708, 1648

NMR (CDCl ₃ ) 1.9-2.1 (m, 2H), 2.85-2.95 (m, 2H), 4.0 (s, 2H),

                                4.5-4.6 (m, 1 H), 7.1 (d, 1 H)

HPLC purity: 99.9%

Example 2  ; Synthesis of 3-chloroacetamido-2-oxo-tetrahydrothiophene

      870 g (92%) of the title compound were obtained in the same manner as in Example 1, except that methylene chloride was used instead of acetone.

      The spectral data is the same as in Example 1.

      HPLC purity: 100%

Example 3  ; Synthesis of [(2-oxo-3-tetrahydrothienylcarbamoyl) -methylthio] acetic acid

      338 g of sodium hydroxide was dissolved in 750 ml of purified water, and 2250 ml of ethyl acetate was added thereto to form a two-phase solution, which was then cooled to 10 ° C and 398 g of thioglycolic acid was added thereto. The resulting ideal solution was stirred for 30 minutes, and then 825 g of 3-chloroacetamido-2-oxo-tetrahydrothiophene was added dropwise and stirred at 20 ° C for 2 hours. The mixture was adjusted to pH 3.2 using 300 ml of hydrochloric acid, and then stirred for 1 hour. The resulting solid was filtered, washed with 1500 ml of purified water, and dried at 80 ° C. for 5 hours to obtain 900 g (85%) of the title compound.

Melting Point: 158-160 ℃

IR (KBr) υcm ^-1 3285, 1740, 1685, 1665

NMR (DMSO-d ₆ ) 2.1-2.3 (m, 2H), 2.9-3.2 (m, 2H), 3.8-3.9 (m, 4H),

                          5.1 (m, 1H), 9.4 (d, 1H)

HPLC purity: 99.7%

Example 4  ; Synthesis of [(2-oxo-3-tetrahydrothienylcarbamoyl) -methylthio] acetic acid

      880 g (83%) of the title compound was obtained in the same manner as in Example 3, except that methylene chloride was used instead of ethyl acetate.

      The spectral data is the same as in Example 3.

      HPLC purity: 99.6%

According to the present invention, it is possible to produce a target substance having a purity of 99.5% or more in high yield of 75% or more in overall yield by minimizing the decomposition of lactone ring in the production of erdostein, and in a more economical way than in the prior art. Dostain can be prepared.

Claims (3)

3-chloroacetamido-2-oxo-tetrahydrothiophene of formula (IV) was prepared by reacting D, L-homocysteine thiolactone hydrochloride of formula (II) with chloroacetyl chloride of formula (III). In the manufacturing method of the erodostein consisting of the step of reacting the compound of formula (IV) with thioglyconic acid of formula (V) to produce the erdostain of the following formula (I), The reaction of all the above steps is a two-phase solution consisting of a basic aqueous solution consisting of an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, and an organic solvent of acetone, ethyl acetate, methylene chloride or chloroform. Method of producing erdostein, characterized in that the reaction proceeds by reacting the reaction of each step at a temperature of -10 ~ 20 ℃ for 2 to 3 hours.

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