KR101827744B1 - Method for preparing tolimidone on large scale - Google Patents

Abstract

The present invention relates to a method for preparing tolimidone maintaining high purity and uniform particle distribution on a large scale. According to the present invention, high-purity tolimidone can be manufactured in a short time when compared to existing technologies while keeping the moisture content and grain size distribution constant by using a tetrabutylammonium bromide catalyst and ethanol recrystallization. Therefore, the method is suitable for industrial mass production.

Description

METHOD FOR PREPARING TOLIMIDONE ON LARGE SCALE [0002]

The present invention relates to a mass production method of tolimidone which maintains a high purity and a uniform particle distribution. More specifically, by using a tetrabutylammonium bromide catalyst and ethanol recrystallization, The present invention relates to a method suitable for industrial mass production since it can be produced by keeping the water content and the particle size distribution constant.

Tolimidone of the following formula (1) shows an excellent blood glucose lowering effect in an animal model of diabetes mellitus disease through the action of lowering blood glucose by activating Lyn kinase (The Journal of Pharmacology and Experimental Therapeutics, 2012 , Vol. 342, No. 1, pp. 23-32).

 [Chemical Formula 1]

To date, the preparation of tollimidone is carried out by reacting a compound of the formula (VI) with a compound of the formula (V) as a starting material as shown in the following reaction scheme 1 to obtain an intermediate of the formula (IV) An aldehyde intermediate is obtained. Next, an intermediate of formula (3) and urea are refluxed under reflux under sodium ethoxide / ethanol to obtain a sodium salt of formula (2), followed by the addition of a 6N aqueous hydrochloric acid solution or acetic acid The sodium metal is desalted to obtain the tollimon of formula (1). (U.S. Patent No. 3,922,345; Journal of Medicinal Chemistry, 1980, Vol. 23, pp. 1026-1031)

 [Reaction Scheme 1]

However, in the case of the first reaction, meta-cresol of formula 6 and starting material of formula 5 are reacted under Dean-Stark apparauts in the presence of potassium hydroxide to obtain an intermediate of formula 4 The process of removing water at high temperature of 140 ~ 150 ℃ is not suitable for mass production process.

Next, it is not easy to completely remove the water used for washing in the filtration process during the mass production, in the step of desalting the sodium salt of formula (2) using hydrochloric acid or acetic acid to obtain the tollimidone of formula (1). In addition, the tollimon of the formula (1) obtained by the above production method has a nonuniform particle size distribution and a low reproducibility of the particle size distribution.

In general, the particle size distribution of the drug is known to affect the drug dissolution rate, bioavailability and stability (JOURNAL OF PHARMACEUTICAL SCIENCES 2010, 99 (1), 51 ~ 75; INTERNATIONAL JOURNAL OF PHARMACEUTICS 1995, 122 (1-2) , 35-47). Therefore, the uniform particle size distribution of the tollimon of formula (1) is very important to keep the dissolution and bioavailability of the clinical drug uniform.

Accordingly, it is a technical object of the present invention to provide a method suitable for mass production of high purity toluimidone while maintaining moisture content and particle size distribution constant.

In addition, another object of the present invention is to provide a pharmaceutical composition comprising the tollimidone produced by the above method.

In order to solve the above problems,

i) reacting a compound of formula 6 with a compound of formula 5 under a tetrabutylammonium bromide catalyst to produce a compound of formula 4;

ii) reacting the prepared compound of formula 4 with a compound of formula 3 via Vilsmeier reaction;

iii) refluxing the thus prepared compound of formula (III) with urea and sodium ethoxide to prepare a sodium salt compound of formula (2);

iv) desalting the sodium salt compound of formula (2) to obtain the tollimoid of formula (1), followed by recrystallization with ethanol:

[Chemical Formula 6]

[Chemical Formula 5]

[Chemical Formula 4]

(3)

(2)

[Chemical Formula 1]

The present invention also provides a pharmaceutical composition comprising the tollimidone prepared by the above method and a pharmaceutically acceptable carrier.

Hereinafter, the present invention will be described in detail.

In step (i) of the method for preparing tollimonine according to the present invention, the meta-cresol of formula 6 and the dimethyl (or ethyl) chloroacetaldehyde starting material of formula 5 are reacted with a tetrabutylammonium bromide catalyst, 4 < / RTI > The tetrabutylammonium bromide catalysis is preferably carried out in the presence of potassium hydroxide in a toluene solvent.

In a known method, the compound of the formula (6) and the compound of the formula (5) are reacted at a high temperature of 140 to 150 DEG C for a long period of time, for example, about 160 g of the compound of the formula Of the compound of formula (5) is reacted for 12 to 16 hours while the reaction material of formula (4) separated in the Dean-Stark apparatus is fed back into the reactor at a high temperature, so that it is not suitable for mass production .

In the present invention, the reaction is carried out in the presence of tetrabutylammonium bromide catalyst, preferably at a temperature of 100 to 120 DEG C, more preferably at a temperature of about 105 to 110 DEG C, It is suitable for mass production because the reaction can be completed in time.

In step (ii) of the method for preparing tollimonine according to the present invention, the compound of formula (IV) is prepared through the reaction of the compound of formula (IV) with Vilsmeier. The aldehyde intermediate of formula (3) may be obtained by reacting the compound of formula (4) with N, N-dimethylformamide and phosphryl chloride.

In step (iii) of the method for preparing tollimonine according to the present invention, the compound of formula (3) is refluxed with urea and sodium ethoxide to prepare a sodium salt compound of formula (2).

In step (iv) of the method for preparing tollimonine according to the present invention, the tolumidon sodium salt of formula (2) is desalted to obtain the tollimoid of formula (1), followed by recrystallization from ethanol.

In the present invention, the sodium salt of the tolrimidon of formula (2) is desalted, preferably using hydrochloric acid or acetic acid. After desalting, washing with water is required. In the reaction using 15 g of the compound of formula (3), the residual water amount during vacuum drying for 14 hours at 65 ° C Less than 0.1% water removal is easy.

However, in the mass production of tollimidone, for example in the production of tens to hundreds of kilograms, complete water removal is difficult. In the case of active pharmaceutical ingredients (API), maintaining a constant water content is very important for quality control.

In the present invention, after desalting the sodium salt of tolumidon and washing it with water, the water can be easily removed by recrystallization with refluxing stirring in ethanol without completely drying it.

On the other hand, the tollimidone prepared by a known method includes an impurity and needs a purification process, but in the present invention, most impurities can be removed through ethanol recrystallization. In addition, in the case of tollimone prepared by a known method, the particle size distribution is uneven and the reproducibility of the particle size distribution is also lowered, so that there may be a problem in maintaining the dissolution rate and bioavailability uniformly in the manufacture of the drug. However, The particle size distribution can be made uniform through recrystallization. The particle size distribution of the tollimon in accordance with the present invention is preferably d (0.5) of 5 to 30 mu m.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a tollimoid and a pharmaceutically acceptable carrier prepared by the above method.

In the present invention, pharmaceutically acceptable carriers include hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinylacetate phthalate, cellulose acetate phthalate, poly (methacrylic acid, methyl Methacrylate) copolymers and poly (methacrylic acid, ethyl acrylate) copolymers, shellac, and mixtures thereof may be used, but are not limited thereto. Among the above-mentioned pharmaceutically acceptable carriers, for the purpose of sustained release, a hydrophobic substance or a hydrophilic polymer may be used. The hydrophobic substance is pharmaceutically acceptable and includes polyvinyl acetate, ethyl cellulose and cellulose acetate, a poly (methacrylate) copolymer, a poly (ethyl acrylate, methyl methacrylate) copolymer as a polymethacrylate copolymer, (Trimethylaminoethyl methacrylate) copolymer, fatty acid and fatty acid esters, fatty acid alcohols, waxes, and the like can be used, but the present invention is not limited thereto. More specifically, examples of fatty acid and fatty acid esters include glyceryl palmitostearate, glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl monooleate and stearic acid, fatty acid alcohols such as cetostearyl alcohol, Cetyl alcohol and stearyl alcohol, and waxes such as carnauba wax, bees wax and microcrystalline wax may be selected and used, but the present invention is not limited thereto. The hydrophilic polymer may be selected from saccharides, cellulose derivatives, gums, polyvinyl derivatives, polymethacrylate copolymers, polyethylene derivatives and carboxyvinyl polymers. Specific examples of the hydrophilic polymer include dextrin, polydextrin, dextran, pectin and pectin Hydroxypropyl starch, amylose, amylopectin and the like can be selected from among cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, Hydroxypropylmethylcellulose acetate succinate, hydroxyethylmethylcellulose, and the like can be selected. As the gums, guar gum, locust bean gum, sword Acacia gum, gum arabic, gellan gum, xanthan gum, and the like can be selected. As the polyvinyl derivative, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl acetal diethylaminoacetate and the like can be selectively used Poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) copolymer, etc. may be selected as the polymethacrylate copolymer, and polyethylene oxide and the like may be used as the polyethylene derivative And carbomers may be used as the carboxyvinyl polymer, but the present invention is not limited thereto. In addition, the pharmaceutical composition according to the present invention may further comprise, for example, a diluent, a binder, a disintegrant, a fluidizing agent, a pH adjusting agent and the like, if necessary.

The pharmaceutical composition according to the present invention can be effectively used for prevention or treatment of diabetes due to its excellent blood glucose lowering effect.

The method for producing tollimonine of the present invention is suitable for mass production of tollimidone by efficiently shortening the reaction time at a high temperature at a lower temperature for a long time. According to the present invention, high purity toluimidone can be produced while maintaining a low water content and a uniform particle size distribution.

Fig. 1 shows the results of analyzing the particle size distribution of tollimone before and after ethanol recrystallization.
2 shows the results of HPLC analysis for measuring the purity of the tollimidone prepared in Comparative Example 3. Fig.
Fig. 3 shows the result of HPLC analysis for measuring purity of tollimidone after ethanol recrystallization prepared in Example 4. Fig.

Hereinafter, the present invention will be described more specifically by way of examples. However, the following examples are given to aid understanding of the present invention, and the scope of the present invention is not limited thereto.

Example  One- 1: 1 - (2,2- Dimethoxyethoxy ) -3-methylbenzene in a small amount ( Tetrabutylammonium  Bromide catalyst reaction)

Meta-cresol (165 g, 1.53 mol) and 330 mL of toluene were placed in a 1,500 mL reaction flask, and tetrabutylammonium bromide (49.5 g) was added thereto. Potassium hydroxide (85%, 100.7 g) was then slowly added thereto, and chloroacetaldehyde dimethylacetal (302.1 g) was added thereto. The reaction temperature was elevated to 110 ° C and reaction completion was confirmed by TLC for 6 hours while stirring under reflux. After the reaction temperature was cooled to room temperature, the toluene layer was separated, washed with 300 mL of 5% sodium hydroxide aqueous solution, and then washed with 300 mL of brine. Subsequently, 30 g of magnesium sulfate was added to the organic layer to remove moisture, followed by filtration. The organic solvent was distilled under reduced pressure to obtain the desired compound (278.4 g, 93%).

^{1 H-NMR 500 MHz (CDCl} 3): 7.15 (m, 1H), 6.75 (m, 3H), 4.68 (t, 1H), 3.97 (d, 2H), 3.40 (s, 6H), 2.29 (s, 3H)

Example  One- 2: 1 - (2,2- Dimethoxyethoxy ) -3-methylbenzene < / RTI > ( Tetrabutylammonium  Bromide catalyst reaction)

Meta-cresol (72.5 kg) was added to the reactor and potassium hydroxide (125.43 kg) was added with stirring. Tetrabutylammonium bromide (21.75 kg) and toluene (145 L) were then added. Chloroacetaldehyde dimethylacetal (135.58 kg) was added thereto, and the mixture was refluxed for 22 hours while keeping the temperature at 105 ° C or higher (reaction confirmed after 6 hours). The internal temperature of the reactor was lowered to 15 to 25 ° C. and purified water (363 L) was added. After stirring for 30 minutes, the lower aqueous layer was transferred to another reactor. Toluene (145 L) was added to the reactor in which the water layer was transferred, and the organic layers were combined after extraction. Sodium sulfate (72.5 kg) and silica gel (72.5 kg) were added and stirred for 1 hour or more. After filtration through a filter, the filtrate was transferred to a reactor. While maintaining the internal temperature of the reactor at 65 캜 or lower, the reaction mixture was concentrated under reduced pressure to obtain 118 kg of the target compound.

Comparative Example 1: 1 - (2,2- Dimethoxyethoxy ) -3-methylbenzene (using a Dean-Stark apparatus)

Potassium hydroxide (85%, 107.4 g) was slowly added with stirring to a meta-cresol (160 g, 1.48 mol) in a 1,000 mL reaction flask and stirred at 100 to 130 ° C for 1 hour to completely dissolve potassium hydroxide. Aldehyde dimethylacetal (298.8 g) was slowly added dropwise. The temperature of the reaction solution was maintained at 140 to 150 ° C., and the reaction was carried out for 16 hours. The water layer was removed using a Dean-Stark apparatus and the organic layer was added to the reaction solution again. The completion of the reaction was confirmed by TLC, and after cooling the reaction temperature to room temperature, 300 mL of toluene and 400 mL of purified water were added. The organic layer was separated, washed with 200 mL of 5% aqueous sodium hydroxide solution, and then the organic layer was washed with 200 mL of brine. Subsequently, 30 g of magnesium sulfate was added to the organic layer to remove moisture, followed by filtration. The organic solvent was distilled under reduced pressure to obtain the desired compound (272 g, 94%).

Example  2: ( E ) -3- ( Dimethylamino )-2-( Meta - Tolyloxy ) Mass production of acrylic aldehyde

246.5 kg of chloroform was added to the reactor, and 131.95 kg of N, N-dimethylformamide was added thereto. Phosphoryl chloride (277.68 kg) was slowly added dropwise while maintaining the temperature of the reaction solution at 30 ° C or lower. After completion of dropwise addition, the temperature of the reaction solution was stirred at 55 캜 for 2 hours. 1- (2,2-dimethoxyethoxy) -3-methylbenzene obtained in Example 1-2 was slowly added dropwise to the reaction solution, and the mixture was refluxed and stirred for 2 hours while maintaining the temperature of the reaction solution at 65 to 70 ° C. 145 L of toluene was then added, and the temperature of the reaction solution was cooled to 10 캜 or lower. 580 L of purified water was added to another reactor in which the internal temperature was kept at 10 캜 or lower, and the reaction solution was gradually added dropwise. At this time, the internal temperature was maintained at 50 캜 or lower. 435 L of toluene was further added to the reactor, and an aqueous potassium hydroxide solution (836.65 kg of potassium hydroxide dissolved in 1,367 liters of purified water) was gradually added dropwise. After stirring for 1 hour, the organic layer was separated and washed with 500 L of 10% brine. Sodium sulfate (72.5 kg) and silica gel (72.5 kg) were added to the organic layer and stirred for 1 hour and then filtered. The filtrate was distilled under reduced pressure to remove the organic solvent, and 136 L of ethyl acetate was added to the concentrated residue. Subsequently, heptane (29.73 kg) was added and stirred at an internal temperature of 15 to 25 ° C for 2 hours or more. The reaction mixture was cooled to 0 ° C and stirred for 1 hour, and the resulting solid was filtered and vacuum dried to obtain the desired compound (80.9 kg).

¹ H-NMR 500 MHz (Acetond-d 6): 8.79 (s, 1 H), 7.12 (m, 1 H), 6.92 (s, 3 H)

Example  3: Tolimidon  Mass production of sodium salts

To the reactor was charged 126 kg of ( E ) -3- (dimethylamino) -2- (meta-tolyloxy) acrylaldehyde, 110.9 kg of urea and 99.5 kg of ethanol (99.5% The mixture was stirred for 10 minutes or more. Sodium ethoxide (21% in ethanol) (688 kg) was added while maintaining the internal temperature of the reactor at 15 to 25 ° C. The internal temperature of the reactor was raised to 70 캜 and refluxed and stirred for 4 hours. 16.4 L of purified water was then added and stirred for 3 hours. The internal temperature of the reactor was lowered to 15 to 25 ° C, and the resulting solid was filtered and vacuum-dried at 65 ° C for 14 hours to obtain sodium salt of tollimidone (78.13 kg, 56.8%).

Comparative Example  2: Tolimidon  Small amounts of sodium salts

After adding urea (8.78 g, 0.146 mol) to the reactor, slowly add sodium ethoxide (21% in ethanol, 54.6 mL, 0.146 mol). Then, ( E ) -3- (dimethylamino) -2- (meta-tolyloxy) acrylaldehyde (15.0 g, 0.073 mol) was slowly added thereto and the mixture was refluxed at 77 ° C for 2 hours. To the reaction solution was added 2.65 mL of purified water and further stirred at 77 DEG C for 2 hours. The mixture was gradually cooled to room temperature, and the solid formed was filtered to obtain a toluimidon sodium salt (9.84 g, 60%).

Example  4: Tolimidon  Mass production

The toluimidon sodium salt (78.13 kg) was added to 1,659 L of purified water, and the mixture was heated to 60 DEG C to dissolve, and then acetic acid (26.5 kg) was gradually administered. After cooling the internal temperature to 15-25 ° C., the resulting solid was filtered and washed with 630 L of purified water. Subsequently, the water content of the obtained tollimidone (57.23 kg) was 4% even after vacuum drying at 65 ° C for 32 hours. Then, the dried tollimon was added to the reactor, 994 L of ethanol (99.5%) was added, and the temperature was raised to 70 ° C to dissolve. The temperature was gradually lowered to 15 to 25 占 폚, followed by stirring for 2 hours to perform recrystallization. The temperature of the reaction solution was lowered to 0 캜, stirred for 1 hour, and then filtered. And vacuum dried in an oven at 65 ° C for 14 hours to obtain the final compound (44.7 kg, 63%).

¹ H-NMR 500 MHz (DMSO-d ₆ ): 12.01 (s, 1 H), 8.30 (m, 2H), 6.79-7.25

Comparative Example  3: Tolimidon  Small quantity production

The tollimidonoside salt obtained in Comparative Example 2 was dissolved in purified water (150 mL) while stirring at 60 占 폚. After complete dissolution, acetic acid was added dropwise to precipitate crystals at about pH 6.0. The reaction solution was slowly cooled to room temperature, and the precipitated crystals were filtered and washed with 130 mL of purified water. Subsequently, the obtained crystals were vacuum-dried in an oven at 65 ° C for 14 hours to obtain 7.6 g of tolymidon (yield: 85.6%).

Comparative Example  4: Comparative Example  The same repeated test of 2 and 3

The same procedure as in Comparative Examples 2 and 3 was repeated to obtain 7.4 g (yield: 50.1%) of tolymidon.

Example  5: Ethanol recrystallization

5.0 g of the toluimidon obtained in the above Comparative Examples 3 and 4 was dissolved by refluxing in 40 mL of ethanol with stirring and then slowly cooled to room temperature. The mixture was stirred for 2 hours and filtered to obtain the desired compound (4.2 g, 4.3 g).

Experimental Example  1: Moisture content measurement

Tolimidon prepared in a small amount (Comparative Example 3) and large amount (Example 4) and tollimidone after ethanol recrystallization were dried in an oven at 65 ° C., and the moisture content was measured. The results are shown in Table 1 below.

As can be seen from the above Table 1, water used in the desalting process can be easily removed at the time of preparation of the tollimon in a small amount, but it is not easy to completely remove the water through the drying process at the time of mass production. However, it was found that ethanol recrystallization can easily remove moisture even in mass production.

Experimental Example  2: Particle size analysis

The particle size distributions of the tollimidone prepared in Comparative Examples 3 and 4 and the tollimidone after ethanol recrystallization in Example 5 were dry-measured under the following conditions using a particle size analyzer (Malvern, AWM2000 (MAL140253)), Table 2 and Fig.

Measurement:

- Measurement time: 3 seconds

- Measurement snaps: 3000

- Background time: 5 seconds

- Background snaps: 5000

Measurement cycles (Repeats):

- Aliquots: 1 per SOP

- Measurements: 3 per aliquot

- Delay: 5 seconds

As can be seen from the above Table 2 and FIG. 1, the toluimidon produced in Comparative Examples 3 and 4 had uneven particle size distributions and showed large particle sizes depending on the batch, and the reproducibility of the particle size distribution was also decreased , And after ethanol recrystallization, the particle size distribution was uniform. In the case of tollimidon after ethanol recrystallization prepared in Example 4, particle sizes similar to those of B-1 and B-2 were shown.

Experimental Example 3: Purity measurement

The tollimidone prepared in Comparative Example 3 and the tollimon after ethanol recrystallization prepared in Example 4 were subjected to HPLC analysis under the following conditions, and the results are shown in FIGS. 2 and 3, respectively.

Column: Agilent ZORBAX Eclipse Plus C18 (4.6 x 250 mm, 5 탆)

- Detection wavelength: 274 nm

- Column temperature: 30 ° C

- Flow rate: 2 mL / min

- mobile phase solvent: 0.1% phosphoric acid-distilled water for solvent A and 100% acetonitrile for B solvent

As can be seen from FIGS. 2 and 3, the toluimidon prepared in Comparative Example 3 contains impurities, but most impurities are removed by ethanol recrystallization.

Claims (5)

i) reacting a compound of formula 6 with a compound of formula 5 under a tetrabutylammonium bromide catalyst to produce a compound of formula 4;
ii) reacting the prepared compound of formula 4 with a compound of formula 3 via Vilsmeier reaction;
iii) refluxing the thus prepared compound of formula (III) with urea and sodium ethoxide to prepare a sodium salt compound of formula (2);
iv) desalting the sodium salt compound of formula (2) to obtain the tollimon of formula (1), followed by recrystallization from ethanol.
[Chemical Formula 6]

[Chemical Formula 5]

[Chemical Formula 4]

(3)

(2)

[Chemical Formula 1]

The process according to claim 1, wherein the tetrabutylammonium bromide catalysis in step (i) is carried out in a toluene solvent in the presence of potassium hydroxide. The process according to claim 1, wherein the tetrabutylammonium bromide catalysis in step (i) is carried out at a temperature of 100 to 120 ° C. The production method according to claim 1, wherein the particle size distribution d (0.5) of the produced tollimon is from 5 to 30 탆. delete

Images