KR100712234B1 - Process for manufacturing of glimepiride - Google Patents

Abstract

The present invention relates to a method for preparing glymepiride of formula (1), in particular, reacting toxic phosgene gas, diphosgene or triphosgene with amine, or pressurizing the amine under toxic carbon monoxide gas. Without the use of phenylethyl isocyanate and trans-4-methyl-cyclohexyl isocyanate, which can only be obtained, the glymepyride can be obtained in high purity and in high yield, which is economical, simple and environmentally friendly. It relates to a method for producing glymepyride that can be produced.

[Formula 1]

Glymepyride, Sulfonylurea, Isocyanate

Description

Production Method of Glymepyride {PROCESS FOR MANUFACTURING OF GLIMEPIRIDE}

The present invention relates to a method for preparing glymepiride of formula (1), in particular, reacting toxic phosgene gas, diphosgene or triphosgene with amine, or pressurizing the amine under toxic carbon monoxide gas. Without the use of phenylethyl isocyanate and trans-4-methyl-cyclohexyl isocyanate, which can only be obtained, the glymepyride can be obtained in high purity and in high yield, which is economical, simple and environmentally friendly. It relates to a method for producing glymepyride that can be produced.

[Formula 1]

Glymepyride represented by the formula (1) has a chemical name of N- [4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl ] -Benzenesulfonyl] -N'-trans-4-methylcyclohexylurea, a sulfonylurea-based diabetic agent that promotes the secretion of insulin developed by Hoechst, Germany, and in particular, has a stronger blood sugar than other sulfonylureas While it has a lowering effect, it is widely used as an oral hypoglycemic agent due to its low cardiovascular side effects.

The method for preparing glymepyride is known from German Patent No. 2951135, US Patent No. 4379785, and Korean Patent Publication No. 1984-1969. In summary, the preparation method can be seen in Scheme (1) below. As is, 3-ethyl-4-methyl-2-oxo-3-pyrroline is reacted with 2-phenylethyl-isocyanate of formula (2) to 3-ethyl-4-methyl-2- of formula (3) Oxo-3-pyrroline-1- (N-2-phenylethyl) -carboxamide is obtained, which is then reacted with chlorosulfonic acid (ClSO ₃ H) to give the desired sulfonylchloride compound. The polyvinyl chloride compound and ammonia are reacted to obtain a sulfonamide compound of formula (4). The sulfonamide compound was then reacted with cyclohexyl isocyanate of formula (5) to finally prepare glymepyride.

Scheme 1

However, as shown in Scheme (1), in this conventional preparation method, phenylethyl isocyanate is used in the first reaction step, and trans-4-methyl-cyclohexyl isocyanate is used as the reactant in the last reaction step. It is possible to obtain mepyrides, since these isocyanate compounds can be prepared by reacting the corresponding amines with the toxic phosgene gas, diphosgene or triphosgene, or by pressurizing the amine under toxic carbon monoxide gas. As a compound, there were disadvantages in terms of environment and economy.

In addition, Korean Patent Publication No. 1984-1984 discloses N- [4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonyl ] -N'-4-methylcyclohexyl-thiourea is desulfurized with mercury oxide to give N- [4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-car Copymido) -ethyl] -benzenesulfonyl] -N'-4-methylcyclohexyl-isourea methyl ether was prepared and dissolved in dioxane to add concentrated hydrochloric acid to synthesize glymepiride. The method is described.

However, this also implies the use of toxic substances such as mercury oxide that can cause poisoning.

 Meanwhile, Korean Patent Publication No. 1984-1970 discloses 4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonamide and cyclohexyl. N- [4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonyl] -N'-4 prepared from isocyanate In methylcyclohexyl-thiourea, sulfur atoms in the thiourea groups are treated with oxidizing agents such as oxides or salts of heavy metals, hydrogen peroxide, sodium peroxide, nitrous acid or permanganate, or substituted thiourea with phosgene or phosphorus pentachloride. A process for the synthesis of glymepyride by treating and desulfurizing is described.

However, there are problems in that cyclohexyl-isocyanate, which can still be produced by the highly toxic gas, in the early stage of the reaction and the use of heavy metal oxides, phosgene, etc. for desulfurization.

In addition, Korean Patent Publication No. 1984-1971 discloses N- (4- [2-amino-ethyl] -benzenesulfonyl) -N'-4-methylcyclohexylurea as 3-ethyl-4-methyl-2-oxo. A method for synthesizing glymepyride by reacting with 3-pyrroline-1-carboxylic acid chloride is described.

However, the production of 3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxylic acid chloride requires toxic phosgene, which still poses similar problems to the other inventions described above. have.

As described above, in the conventional production methods, glymepyride using an isocyanate compound such as phenylethyl isocyanate and / or trans-4-methyl-cyclohexyl isocyanate, which can be produced by toxic phosgene gas or toxic carbon monoxide gas or the like. Even if it is possible to obtain or do not use such an isocyanate compound, there is still a problem that phosgene or other toxic substances or harmful substances, that is, mercury oxide, oxide of heavy metal, or the like should be used.

The use of such poisonous toxic substances or harmful substances is harmful to the human body and may cause environmental problems, and it is a fact that there is a costly problem in the installation to minimize the risk.                         

Due to the problems of the prior art, not only can be conveniently produced in high purity, high yield, but also a more environmentally friendly and economical method for producing glymepyride has been urgently required.

In order to solve the problems of the prior art, the present inventors do not use phenylethyl isocyanate prepared through toxic reaction conditions, and replace the cutisus using 3-phenylpropanoyl azide as an alternative reagent. Carbonylation reagent and trans-4-methyl-, such as N, N'-carbonyldiimidazole, without the use of expensive trans-4-methyl-cyclohexyl isocyanate, by the Curtius rearrangement reaction By reaction with cyclohexylamine, the present invention has been completed in which glymepyride can be produced without using an isocyanate compound.

Accordingly, an object of the present invention is to provide a method for producing glymepyride with high purity and high yield, which is safer, economical and environmentally friendly.

In order to achieve the above object, the present invention a) 3-phenylpropanoyl chloride (common name: hydrocinnamoyl chloride) and sodium azide by reacting 3-phenylpropanoyl azide (common name: hydrocinnamoyl) Azide) and then reacted with 3-ethyl-4-methyl-2-oxo-3-pyrroline to react 3-ethyl-4-methyl-2-oxo-3-pyrroline-1- (N- Preparing 2-phenylethyl) -carboxamide;

b) reacting the 3-ethyl-4-methyl-2-oxo-3-pyrroline-1- (N-2-phenylethyl) -carboxamide with chlorosulfonic acid to give 4- [2- (3-ethyl- 4-Methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonylchloride was synthesized and reacted with ammonia to produce 4- [2- (3-ethyl-4-methyl- Preparing 2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonamide;

c) Activated intermediates formed by reacting N, N'-carbonyldiimidazole (CDI) with trans-4-methyl-cyclohexylamine, in the presence of a base, wherein 4- [2- (3-ethyl- Provided is a method for preparing glymepyride comprising reacting with 4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonamide to obtain glymepyride.

At this time, the 3-phenylpropanoyl azide of step a) is dissolved in a non-polar solvent by reacting sodium azide dissolved in water and 3-phenylpropanoyl chloride dissolved in a non-polar solvent at a temperature of 5 ℃ ~ 35 ℃. It can be manufactured as it is. In addition, 3-ethyl-4-methyl-2-oxo-3-pyrroline-1- (N-2-phenylethyl) -carboxamide of step a) is 1.0-2.0 equivalents of 3-phenylpropanoyl. It can be prepared by adding 3-ethyl-4-methyl-2-oxo-3-pyrroline to azide and proceeding with a coupling reaction while heating and refluxing at a temperature of 40 ° C. to 120 ° C. to cause a Curtis shifting reaction. have.

4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonylchloride of step b) is a temperature of 10 ℃ ~ 60 ℃ Prepared by reacting 5-10 equivalents of chlorosulfonic acid with 3-ethyl-4-methyl-2-oxo-3-pyrroline-1- (N-2-phenylethyl) -carboxamide without solvent, or 3- Ethyl-4-methyl-2-oxo-3-pyrroline-1- (N-2-phenylethyl) -carboxamide was dissolved in dichloromethane, and 2 to 5 equivalents of chlorosulfonic acid and 1 to 2 equivalents at low temperature. The thing which mixed and added thionyl chloride can be made to react.

The glymepyride of step c) is 4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl]-at a temperature of 50 ° C. to 120 ° C. To the salt solution formed by reacting benzenesulfonamide with a base in the presence of a solvent, 1.0 to 2.0 equivalents of the above-mentioned activated intermediate is added to the reaction mixture, followed by purification, wherein the base is potassium carbonate 1.5-. It is preferable to use 2.5 equivalents or 1.0 to 1.5 equivalents of sodium hydride.

This preparation method of the present invention is as shown in the following scheme (2).

Scheme 2

Hereinafter, the preparation method of the glymepyride of the present invention will be described in detail for each step.

(One) 3-Ethyl-4-methyl-2-oxo-3-pyrroline-1- (N-2-phenylethyl) -carboxamide 3) Manufacture

 In the production method according to the present invention, in step a) of preparing 3-ethyl-4-methyl-2-oxo-3-pyrroline-1- (N-2-phenylethyl) -carboxamide, , 3-phenylpropanoyl chloride and sodium azide were reacted to synthesize 3-phenylpropanoyl azide, and then purified. Instead, 3-ethyl-propaneyl azide was reacted with 3-ethylpropane rearrangement reaction. 3-ethyl-4-methyl-2-oxo-3-pyrroline-1- (N-2-phenylethyl)-of the formula (3) by reacting with 4-methyl-2-oxo-3-pyrroline Carboxamide can be obtained.

Specific synthesis method of the 3-phenylpropanoyl azide is as follows. That is, 3-phenylpropanoyl azide dissolved in a non-polar solvent is synthesized by dropwise addition of 3-phenylpropanoyl chloride dissolved in a non-polar solvent that is not mixed with water at low temperature to sodium azide dissolved in water. can do. Non-polar solvents used in this case are aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as ethyl ether and isopropyl ether, acetates such as ethyl acetate, ketones such as methyl ethyl ketone and methyl isobutyl ketone, and hexane Aliphatic hydrocarbons such as pentane and octane, haloalkanes such as chloroform, dichloromethane and dichloroethane are preferred, but among them, aliphatic hydrocarbons are most preferred. The reaction temperature is appropriately 5 ° C to 35 ° C, and at 40 ° C or higher, the Curtis repositioning reaction proceeds, so care should be taken not to exceed the temperature. Since the reaction is to react on a two-phase surface with an organic solvent that does not mix with water, a phase-transfer-catalysis may be added if necessary.

3-ethyl-4-methyl-2-oxo-3-pyrroline was added to 3-phenylpropanoyl azide dissolved in the non-polar solvent obtained above, and the coupling reaction was carried out while carrying out the Curtis shifting reaction. 3-ethyl-4-methyl-2-oxo-3-pyrroline-1- (N-2-phenylethyl) -carboxamide of formula (3) can be obtained. At this time, 3-phenylpropanoyl azide was 3-ethyl-4-methyl of formula (3) using 1.0-2.0 equivalents to 3-ethyl-4-methyl-2-oxo-3-pyrroline. 2-oxo-3-pyrroline-1- (N-2-phenylethyl) -carboxamide can be prepared. In order for the Curtis shifting reaction to proceed, the reaction temperature may be from 40 ° C. to 120 ° C., but it is preferable to reflux at a temperature of 80 ° C. or higher. At this temperature, the Curtis repositioning reaction can take place best, resulting in a high yield of the desired compound.

 The reaction solution obtained in the reaction was concentrated under reduced pressure, etherified or aliphatic hydrocarbons were added for solidification, followed by filtration and drying to obtain 3-ethyl-4-methyl-2-oxo-3-pyrroline-1 of formula (3). -(N-2-phenylethyl) -carboxamide can be obtained. If necessary, it may be purified by recrystallization.

According to the present invention, without using phenylethyl isocyanate, and by the Curtis shifting reaction using 3-phenylpropanoyl azide as an alternative reagent, it is toxic such as phosgene gas, diphosgene or triphosgene or carbon monoxide. In addition to avoiding the use of gas, it is possible to produce glymepyride without using an expensive isocyanate compound, that is, the phenylethyl isocyanate.

(2) Preparation of 4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonamide (Formula 4)

Further, in the production method of the present invention, 4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzene of the formula (4) In the step b) of preparing sulfonamide, first, 3-ethyl-4-methyl-2-oxo-3-pyrroline-1- (N-2-phenylethyl) -carboxamide of formula (3) Reacted with chlorosulfonic acid and then separated to synthesize 4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonylchloride, It was reacted with ammonia without purification and recrystallized to yield 4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl of formula (4). ] -Benzenesulfonamide can be obtained.

In this process, there are two methods for preparing 4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonyl chloride. Do. First, 3-ethyl-4-methyl-2-oxo-3-pyrroline-1- (N-2-phenylethyl) -carboxamide of formula (3) was added to excess chlorosulfonic acid without solvent. The desired compound can be prepared by filtration. In this case, the equivalent amount of chlorosulfonic acid is preferably 5-10 equivalents, but most preferably 6 equivalents, and the reaction temperature is preferably 10 ° C.-60 ° C., but 40 ° C. is an optimum condition. You can get it.                     

Second, it can be prepared by applying the method disclosed in the Republic of Korea Patent Publication No. 2002-0083568. 3-ethyl-4-methyl-2-oxo-3-pyrroline-1- (N-2-phenylethyl) -carboxamide of formula (3) was dissolved in haloalkanes such as dichloromethane and dichloroethane. After adding an appropriate amount of chlorosulfonic acid and thionyl chloride (SOCl ₂ ) at a low temperature, the mixture was heated to reflux, ice water was added after completion of the reaction, the organic solvent was extracted, and concentrated under reduced pressure to obtain 4- [2- (3-ethyl- 4-Methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonylchloride can be prepared. The chlorosulfonic acid used at this time is preferably 2 to 5 equivalents, most preferably 3 equivalents. Thionyl chloride is preferably 1 to 2 equivalents, but most preferably 1.2 equivalents.

4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonylchloride prepared in the above formula (4) ) 4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonamide can be obtained. In the reaction with ammonia, the reaction may be carried out by directly passing ammonia gas through a suitable solvent, or may be reacted using an aqueous ammonia solution. Among them, a solid produced by heating using an aqueous ammonia solution and then cooling after completion of the reaction is filtered to yield 4- [2- (3-ethyl-4-methyl-2-oxo-3 of formula (4). -Pyrroline-1-carboxamido) -ethyl] -benzenesulfonamide can be obtained. Since the target compound of formula (4) obtained at this time contains water and may affect the next reaction, a process of dehydration and purification through recrystallization is required. Preferred recrystallization solvents include methanol, ethanol, alcohols such as isopropanol, ketones, and the like.

(3) Preparation of Glymepyride

4- [2- (3-) of formula (4) without purification of the activated intermediate obtained after reacting N, N'-carbonyldiimidazole (CDI) with trans-4-methyl-cyclohexylamine Glymepyride can be prepared by reacting in the presence of a base using 1.0-2.0 equivalents to ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonamide. have.

 By not reacting with such expensive trans-4-methyl-cyclohexyl isocyanate, but by reacting a transyl-4-yl-cyclohexylamine with a carbonylation reagent such as N, N'-carbonyldiimidazole This makes it possible to obtain the target compound more conveniently and safely at a relatively low cost.

 The activated intermediate can be seen to consist of a mixture of a compound of formula (7) and trans-4-methyl-cyclohexyl isocyanate as shown in Scheme (3) below. This mixture is no longer purified and is used directly in the next reaction.

Scheme 3

In preparing the activated intermediates, solvents that can be used include nitriles such as acetonitrile, ethers such as ethyl ether, tetrahydrofuran and dioxane, amides such as dimethylformamide and dimethylacetamide and ethyl acetate Acetates, aromatic hydrocarbons, halo alkanes, ketones, sulfoxides such as dimethyl sulfoxide or mixed solvents thereof are possible, of which ethers are preferred.

 4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonamide of formula (4) is reacted with a suitable base in a suitable solvent. Glymepyride may be prepared by adding the purified crude intermediate prepared above to the reaction solution in the salt state, and purifying it. Suitable bases used at this time include inorganic bases and organic bases. As the organic base, it is possible to use organic bases composed of tertiary amines such as triethylamine and 1,8-diazabicyclo [5.4.0] unde-7ene (DBU).

 As the inorganic base, an inorganic base containing an alkali metal or an inorganic base containing an alkaline earth metal may be used. Alkali metal inorganic bases include inorganic bases containing potassium metal, such as sodium bicarbonate, sodium carbonate, sodium hydroxide, sodium alkoxide and sodium hydride (NaH), potassium carbonate, potassium hydroxide There may be inorganic bases containing potassium metals such as siloxanes, potassium alkoxides, inorganic bases containing lithium metals such as lithium hydroxides, and inorganic bases containing cesium metals such as cesium carbonates. Potassium carbonate and sodium hydride base are preferable, and potassium carbonate used here is preferably 1.5 to 2.5 equivalents, and sodium hydride 1.0 to 1.5 equivalents. As the alkaline earth metal base, calcium bases such as calcium carbonate and calcium hydroxide are possible.

Suitable solvents used in the reaction may be ketones, ethers, amides, nitriles, acetates, sulfoxides or mixed solvents thereof, among which the use of ethers and ketones or mixed solvents thereof may be used. desirable.

The reaction temperature is 4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonamide and the base salt of formula (4). Although more than the temperature for forming is needed, 50 degreeC-120 degreeC is preferable, and 70 degreeC-110 degreeC is more preferable in it. The reaction rate was checked using thin layer chromatography or HPLC while the reaction was carried out under the above reaction conditions. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, dissolved in water, and diluted with hydrochloric acid. The resulting solid can be filtered and purified by recrystallization or the like to prepare glymepyride, the final target compound, in powder or crystalline form. Filtration and purification under the same conditions as described above can produce a higher purity glymepyride than the conventional method.

Reagents used in the present invention can be easily prepared or purchased by known methods as known compounds.

Hereinafter, the present invention will be described in detail with reference to preferred embodiments of the present invention. However, the scope of the present invention is not limited thereto, but is presented as an example.

Example 1 (step a)

; Preparation of 3-ethyl-4-methyl-2-oxo-3-pyrroline-1- (N-2-phenylethyl) -carboxamide

12 g of sodium azide (NaN₃) was dissolved in 100 ml of water, and cooled to 5 ° C to 10 ° C. 40 ml of toluene was added to the solution. Then, a solution of 20.6 ml of 3-phenylpropanoyl chloride in 50 ml of toluene was slowly added dropwise for 30 minutes. After completion of the dropwise addition, the reaction was stirred at the same temperature for 1 hour. The water layer was removed, the toluene solution was dried over anhydrous magnesium sulfate, filtered and washed with 10 ml of toluene. 13.5 g of 3-ethyl-4-methyl-2-oxo-3-pyrroline was added to the filtered toluene solution, and the mixture was heated with gentle stirring. In particular, since nitrogen was generated between 40 ° C and 60 ° C, the temperature was gradually raised. After nitrogen was exhausted, the mixture was heated to reflux for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and then cooled. The resulting solid was triturated with isopropyl ether, filtered and the 3-ethyl-4-methyl-2-oxo-3-pyrroline-1- 26.4 g of (N-2-phenylethyl) -carboxamide was obtained. (Yield 90%)

Melting Point: 107 ℃

Example 2 (step b)

Preparation of 4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonamide

(Method 1)

13 g of 3-ethyl-4-methyl-2-oxo-3-pyrroline-1- (N-2-phenylethyl) -carboxamide were slowly added for 30 minutes while stirring 20 ml of chlorosulfonic acid at 5 ° C. After the addition, the reaction was stirred for 3 hours while maintaining the reaction temperature at 30 ° C to 40 ° C. After the reaction was completed, the reaction solution was added dropwise to 200 g of ice water. The resulting white solid was filtered and washed with water to obtain 4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonylchloride . Immediately without purification, 150 ml of aqueous ammonia solution was added to the flask and heated to reflux for 1 hour. Further 50 ml of aqueous ammonia solution was added during the reflux. After the reaction was completed, the reaction solution was cooled to 5 ° C ~ 10 ° C and the resulting white solid was filtered and washed with water. The obtained solid was recrystallized from isopropanol to give 13.3 g of 4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonamide. (Yield = 79%)

Melting Point: 181 ~ 182 ℃

¹H-NMR (DMSO-d6, 400 MHz)

8.36 (1H, t), 7.75 (2H, d), 7.47 (2H, d), 7.29 (2H, s), 4.15 (2H, s),

3.47 ~ 3.50 (2H, m), 2.86 ~ 2.90 (2H, m), 2.17 ~ 2.20 (2H, q),

2.01 (3H, s), 0.97 (3H, t)

FAB-MS m / e: 352 (M + 1), 374, 307, 219, 181, 154, 126

(Method 2)

30 ml of dichloromethane was added to 10 g of 3-ethyl-4-methyl-2-oxo-3-pyrroline-1- (N-2-phenylethyl) -carboxamide to dissolve it, and after cooling to 5 ° C to 10 ° C, 8.6 ml of sulfonic acid and 3.2 ml of thionyl chloride were added sequentially. After completion of the dropwise addition, the reaction solution was heated to reflux for 3 hours. The reaction solution was cooled to 10 ° C, diluted with 70 ml of dichloromethane, and the reaction solution was slowly added dropwise to ice water, followed by stirring for 30 minutes. The organic layer was extracted, washed with cooled aqueous sodium carbonate solution, followed by washing with saturated brine, and the reaction solution was concentrated under reduced pressure. 4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonylchloride precipitated during concentration. When the concentration was completed, 100ml of ammonia aqueous solution was added and heated to reflux. Further 50 ml of aqueous ammonia solution was added during the reflux. After the reaction was completed, the reaction solution was cooled to 5 ° C ~ 10 ° C and the resulting white solid was filtered and washed with water. The obtained solid was recrystallized from isopropanol to give 10.5 g of 4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonamide. Yield = 81.4%)

Example 3 (step c)

; N- [4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonyl] -N'-trans-4-methylcyclo Preparation of hexyl urea (glymepyride)

(Method 1)

In flask 1, 7.0 g of N, N'-carbonyldiimidazole (CDI) was added to 50 ml of dioxane, cooled to 5 ° C. under nitrogen, and 5 g of trans-4-methyl-cyclohexylamine was added to the reaction solution for 10 minutes. Was added slowly, followed by reaction for 2 hours. Grinded finely with 10 g of 4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonamide prepared in Example 2 in Flask 2. To 6.0 g of potassium carbonate (K 2 CO 3), 150 ml of dioxane was added, and the mixture was slowly heated to reflux for 2 hours and cooled to 25 ° C. The activated intermediate, previously synthesized in solution in Flask 1, was added to Flask 2 at once and slowly heated to reflux for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 200 ml of a 1% aqueous ammonia solution, activated carbon was added, the mixture was stirred for 30 minutes, and then filtered under reduced pressure. The filtered mother liquor was cooled to 5 ° C to 10 ° C, adjusted to pH 3-4 with 6N hydrochloric acid, and the resulting solid was filtered, washed with water and dried to give N- [4- [2- (3-ethyl-4- 12.5 g of methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonyl] -N'-trans-4-methyl cyclohexyl urea was obtained (yield = 89.5%). The glymepyride could be recrystallized from acetone or alcohol depending on the purity.

¹H-NMR (DMSO-d6, 400 MHz)

10.29 (1H, s), 8.37 (1H, t), 7.81 (2H, d), 7.46 (2H, d), 6.25 (1H, d),

4.16 (2H, s), 3.46-3.51 (2H, m), 2.88-2.92 (2H, m), 2.16-2.20 (2H, q),

2.01 (3H, s), 0.97 (3H, t), 0.82 (3H, d), 0.70 ~ 1.70 (10H, m)

FAB-MS m / e: 491 (M + 1), 378, 352, 253, 181, 152, 126

(Method 2)

In Flask 1, 3.5 g of N, N'-carbonyldiimidazole (CDI) was added to 30 ml of tetrahydrofuran, cooled to 5 ° C under nitrogen, and 2.5 g of trans-4-methyl-cyclohexylamine was added to the reaction solution. After slowly adding for 10 minutes, the reaction was carried out for 2 hours. 5.0 g of 4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonamide prepared in Example 2 in Flask 2 and sodium hydroxide 80 ml of tetrahydrofuran was added to 0.68 g of a lide (NaH, 60%) and reacted at 25 ° C. for 2 hours. The activated intermediate, previously synthesized in solution in Flask 1, was slowly added to Flask 2 for 10 minutes and slowly heated to reflux for 3 hours. After the reaction was completed, N- [4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonyl ] -N'-trans-4-methylcyclohexylurea 5.8 g was obtained. (Yield = 83%)

As described above, according to the present invention, the glymepyride can be obtained in high purity and high yield without using phenylethyl isocyanate and trans-4-methyl-cyclohexyl isocyanate, which are produced through a poisonous gas which is expensive and harmful to human body. It is economical, and the manufacturing process is simple and environmentally friendly to produce glymepyride.

Claims (17)

a) reacting 3-phenylpropanoyl chloride (HCC) dissolved in toluene or xylene and sodium azide dissolved in water to synthesize 3-phenylpropanoyl azide dissolved in toluene or xylene 3-ethyl-4-methyl-2-oxo-3-pyrroline-1- (N-2) of formula (3) by reacting this with 3-ethyl-4-methyl-2-oxo-3-pyrroline -Phenylethyl) -carboxamide; b) The 3-ethyl-4-methyl-2-oxo-3-pyrroline-1- (N-2-phenylethyl) -carboxamide is reacted with chlorosulfonic acid to give 4- [2- (3-ethyl- 4-Methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonylchloride was synthesized and reacted with ammonia to produce 4- [2- (3- Preparing ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonamide; c) Activated intermediates formed by reacting N, N'-carbonyldiimidazole (CDI) with trans-4-methyl-cyclohexylamine of the following formula (6) in the presence of a base; -(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonamide to give glymepyride to the following scheme (2) Method for preparing glymepiride represented. Scheme 2

delete delete The method of claim 1, The reaction of 3-phenylpropanoyl chloride (HCC) and sodium azide of step a) proceeds at a temperature of 5 ℃ ~ 35 ℃. The method of claim 1, The 3-phenylpropanoyl azide is used in the preparation of glymepyride in an amount of 1.0 to 2.0 equivalents relative to 3-ethyl-4-methyl-2-oxo-3-pyrroline. The method of claim 1, The 3-phenylpropanoyl azide is a method for producing glymepyride is reacted with the 3-ethyl-4-methyl-2-oxo-3-pyrroline at a temperature of 40 ℃ ~ 120 ℃. The method of claim 1, 4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonylchloride of step b) was added with excess chlorosulfonic acid without solvent. A process for producing glymepyride, which is prepared by reacting 3-ethyl-4-methyl-2-oxo-3-pyrroline-1- (N-2-phenylethyl) -carboxamide. The method of claim 7, wherein The reaction is a method for producing glymepyride proceeds at a temperature of 10 ℃ ~ 60 ℃. The method of claim 1, 4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonylchloride of step b) is 3-ethyl-4- Preparation of glymepyride, which is prepared by reacting methyl-2-oxo-3-pyrroline-1- (N-2-phenylethyl) -carboxamide with chlorosulfonic acid and thionyl chloride in dichloromethane solvent Way. The method of claim 9, The chlorosulfonic acid is used in an amount of 2 to 5 equivalents relative to 3-ethyl-4-methyl-2-oxo-3-pyrroline-1- (N-2-phenylethyl) -carboxamide, the thionyl Chloride is used in an amount of 1 to 2 equivalents. The method of claim 1, After proceeding to step b), dehydration and purification of the 4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonamide Method for producing glymepyride further comprising the step of. The method of claim 11, The dehydration and purification step is a method for producing glymepyride proceeding using methanol, ethanol or isopropanol as the recrystallization solvent. The method of claim 1, Solvents used to prepare the activated intermediate of step c) include a nitrile solvent of acetonitrile; Ether solvents of ethyl ether, tetrahydrofuran or dioxane; Amide solvents of dimethylformamide or dimethylacetamide; Acetate solvents of ethyl acetate; Aromatic hydrocarbon solvents of benzene, toluene or xylene; Haloalkane solvents of chloroform, dichloromethane or dichloroethane; Ketone solvents of methyl ethyl ketone or methyl isobutyl ketone; A method for producing glymepyride using at least one solvent selected from the group consisting of a sulfoxide solvent of dimethyl sulfoxide and a mixed solvent thereof. The method of claim 1, In step c), the activated intermediate is 1.0 to 4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) -ethyl] -benzenesulfonamide. A method for producing glymepyride, used in an amount of 2.0 equivalents. The method of claim 1, In step c), the base is an alkaline earth metal inorganic base or an alkali metal inorganic base, a method for producing glymepyride. The method of claim 15, Method for producing glymepyride using calcium carbonate or calcium hydroxide as the alkaline earth metal base. The method of claim 15, Examples of the alkali metal inorganic base include sodium salts of sodium bicarbonate, sodium carbonate, sodium hydroxide, sodium alkoxide or sodium hydride (NaH); Potassium salts of potassium carbonate, potassium hydroxide or potassium alkoxide; Lithium salts of lithium hydroxide; And one or more bases selected from the group consisting of cesium salts of cesium carbonate.