KR19990026645A - A new method for producing 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid - Google Patents

Abstract

The present invention relates to a process for preparing 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid and its pharmaceutically acceptable salts and solvates of formula (I), designated as Aceclofenac,

2 - [(2,6-dichlorophenyl) amino] phenyl] acetamide represented by the general formula (1) can be prepared by reacting a haloethyl ester of 2- [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid represented by the general formula Acetoxyacetic acid.

The haloethyl ester of 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid used in the present invention can be obtained by reacting a 2 - [(2,6-dichlorophenyl) amino] phenylacetic acid named diclofenac Can be obtained by reacting an alkali metal salt with haloethyl acetate.

The present invention relates to a process for producing 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid and a pharmaceutically acceptable salt thereof in a high purity and a high yield, can do.

Description

A new method for producing 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid

The present invention relates to 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid and its pharmaceutically acceptable salts and solvates of formula (I), designated as Aceclofenac, , 6-dichlorophenyl) amino] phenylacetoxyacetic acid. ≪ / RTI >

(In the above formula, R means a methyl group containing 1 to 3 halogens.)

In the formula (1) of the present invention Aceclofenac is known to be active as an anti-inflammatory and analgesic agent (ES 520,813).

ES 2,020,146, ES 2,046,141 (corresponding to Korean Patent Application No. 93-173), CA 2,111,169 (Korean Patent Application No. 93-27,558), and ES 2, CH 682,747 are known. These preparations typically use 2 - [(2,6-dichlorophenyl) amino] phenylacetic acid sodium salt, known as diclofenac sodium salt, with 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid , And the two ester groups present in the molecule of the specific ester are selectively reacted using the difference in sensitivity of the reaction conditions or a non-saponificative method differentiated by selective reaction ), And then selectively reacting them. The basic skeleton is summarized as follows.

1) Patent document ES 520,813 (Korean Patent Application No. 88-14,523)

This method involves hydrolyzing benzyl ester of 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid of structural formula 3 to obtain aceclofenac 1 .

However, a major disadvantage of this method is the need for special equipment for handling compressed gas, and the risks associated with industrial use of hydrogen and catalyst. In addition, this method is limited to the use of aceclofenac esters, especially benzyl esters, which can be hydrolyzed, thus decreasing industrial utility value.

2) Patent document ES 2,020,146

This method involves reacting a benzyl or tertiary butyl ester of 2- [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid of structural formula 4 with chlorotrimethyl silane (TMS-Cl) and sodium iodide in an acetonitrile solvent To obtain aceclofenac- 1 . However, this method has the disadvantage that chlorotrimethylsilane is very expensive and therefore not economical.

3) Patent Document ES 2,046,141 (Korean Patent Application No. 93-173)

The above process involves selectively reacting the 2-tetrahydrofuranyl ester of 2- [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid of formula 5 with acetic acid in a solvent mixture, Aceclofenac is obtained in yield (60-72%).

4) Patent literature CH 682,747

The method of the structural formula of Scheme 3 is very similar to the scheme 3 in the patent document ES 2,046,141 5 2 - [(2,6- dichlorophenyl) amino] phenyl-2-acetoxy-2-acetic acid of the tetrahydrofuranyl ester instead of Structural Formula 6 -Tetrahydropyranyl ester, which is treated with an acid in a heterogeneous solvent system of toluene and water to obtain aceclofenac.

5) Patent document CA 2,111,169 (corresponding to Korean Patent Application No. 93-27,558)

The above method is a method for obtaining aceclofenac by reacting a tertiary alkyl ester of 2- [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid of structural formula 7 with anhydrous triflu or acetic anhydride, The disadvantage of the method is the use of anhydrous trifluoroacetic acid or anhydrous formic acid, which is expensive and industrially difficult to handle.

The present inventors have studied to prepare 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid, named aceclofenac, and pharmaceutically acceptable salts and solvates thereof by a convenient process at high purity and yield The present invention has been completed.

It is an object of the present invention to provide a process for preparing 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid and its pharmaceutically acceptable salts, solvates, designated as aceclofenac, .

In order to attain the above object, the present invention provides a method for producing 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid represented by the following formula Aceclofenac and a pharmaceutically acceptable salt or solvate thereof The present invention provides a process for producing high purity and high yield by an industrially convenient production process.

Formula 1

The production method of the present invention is characterized in that a haloethyl ester of 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid represented by the general formula (2) Amino] phenylacetoxyacetic acid. ≪ / RTI >

(2)

(In the above formula, R means a methyl group containing 1 to 3 halogens.)

The haloethyl ester of 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid of Formula 2 is prepared by reacting the alkali metal salt of 2- [(2,6-dichlorophenyl) amino] phenylacetic acid, named diclofenac, Ethyl < / RTI > haloacetate.

As described above, aceclofenac converts a sodium salt of 2 - [(2,6-dichlorophenyl) amino] phenylacetic acid to a specific ester of 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid, The two ester groups present in the molecule of a specific ester can be selectively reacted using the sensitivity difference of the reaction conditions or can be removed by a specific ester which can be removed by a non-saponificative method which is differentiated by selective reaction And then selectively reacting the resulting product.

Meanwhile, Woodward (RB Woodward) group used trichloroethyl groups as protecting groups for carboxy groups in the entire synthesis of Cephalosporin C (RB Woodward, et al ., J. Amer. Chem. Soc 1956, 88, 852) and J. Grimshaw used the iodoethyl group as a protective group in the peptide synthesis (J. Grimshaw, J. Chem. Soc., 1965, 7136).

The present invention relates to a process for the preparation of 2 - [(2,6-dichlorophenyl) amino] phenylacetic acid, which is a diclofenac alkali metal salt, such as the trichloroethyl group used as the protecting group of the carboxy group and the iodoethyl group used as the protecting group Aceclofenac is prepared by selectively removing a haloethyl group from 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid halide prepared by introducing a haloethyl group.

In the present invention, the removal of the haloethyl group is accomplished by attacking the halogen by an electron source and concerted elimination process as shown in the figure, so that the haloethyl group is selectively removed from the ester of aceclofenac of the present invention And the haloethyl group can be used also in the presence of a? -Lactam ring highly susceptible to hydrolysis. Therefore, the present invention can provide a high purity aceclofenac at a high yield with a high yield .

In the present invention, 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid is prepared according to the following reaction scheme 6.

Wherein M is an alkali metal cation, preferably a sodium salt or potassium salt, and R means a methyl group containing 1 to 3 halogens.

Hereinafter, the production method of the present invention will be described in detail with reference to the reaction formula (6).

Ⅰ. Haloethyl 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetate (formula

2) (the first step)

In the present invention, the esterification of alkali metal carboxylates such as 2 - [(2,6-dichlorophenyl) amino] phenylacetic acid sodium salt or potassium salt is carried out in two phases by a phase transfer catalyst, Or by reacting the carboxylic acid metal salt with a haloethyl acetate in an aprotic solvent which can not dissociate a polar protons such as dimethylformamide, dimethylsulfoxide and acetone, By the above esterification reaction, a haloethyl ester of 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid of Formula 2 can be obtained. Depending on the reactivity of the haloethyl acetate used, a catalytic amount or equivalent of sodium iodide may be added to the reaction solution. As the haloethyl acetate used in the present invention, it is preferable to use trichloroethyl haloacetate or iodoethyl haloacetate. The reaction temperature is preferably from 0 ° C to 150 ° C, more preferably from room temperature to 80 ° C. This reaction may also be used directly in the second step reaction, described below, without a special purification step such as recrystallization or silica gel chromatography after a simple workup.

Ⅱ. Preparation of 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid (Formula 1) (Step 2)

A mixture of the haloethyl ester of 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid of formula (2) Zinc is reacted in a solvent to obtain 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid. As the solvent, tetrahydrofuran and KH₂PO₄An aqueous solution of acetic acid, an aqueous solution of hydrochloric acid, an aqueous solution of formic acid, dimethylformamide and the like can be used, and in particular, tetrahydrofuran and KH₂PO₄It is preferable to use a mixed solution with an aqueous solution or an aqueous acetic acid solution. The reaction temperature is preferably from 0 ° C to 50 ° C, particularly preferably at room temperature. In the present invention, the reaction takes place in a very short time and a high purity aceclofenac can be obtained at a high yield.

In the present invention, the molecular structure was confirmed by comparing infrared spectroscopy, ultraviolet visible light spectroscopy, nuclear magnetic resonance spectrum, mass spectrometry and elemental analytical calculated and measured values of representative compounds.

Hereinafter, the present invention will be described in more detail by way of examples. However, the following examples are intended to illustrate the contents of the present invention and are not intended to limit the scope of the present invention. Haloethyl haloacetate, which is used as a raw material in the present invention, can be produced by a known method (for example, D. Seebach, et al., Justus Liebigs Ann. Chem., 1978, 2044; W. Steglich, et al., Angew. Chem. Int. Ed. Engl., 1969, 8, 981, A. Takeda, et al., Chem. Lett., 1982, 1909).

Ⅰ. Haloethyl 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetate (formula

2)

Example 1 Preparation of trichloroethyl 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetate

(50 ml) of 2 - [(2,6-dichlorophenyl) amino] phenylacetic acid sodium salt (5.0 g, 15.7 mmol) and trichloroethyl chloroacetate (4.26 g, 18.8 nmol) Heated to 50 < 0 > C and reacted for 3 hours. The reaction solution was cooled to room temperature, ethyl acetate was added thereto, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate: hexane (1: 7) to obtain 7.42 g (97%) of the title compound as a white solid.

_{^{1 H-NMR (CDCl 3:}} δ): 3.94 (s, 2H), 4.77 (s, 2H), 4.81 (s, 2H), 6.54 (d,

1H, J = 8 Hz), 6.64 (br s, 1H), 6.52-7.34 (m, 6H)

IR (KBr): 3331, 1778, 1732, 1578, 1508, 1451, 1412, 1389, 1150, 770,

748, 729 cm ^-1

Example 2 Preparation of trichloroethyl 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetate

A mixture of the sodium salt of 2 - [(2,6-dichlorophenyl) amino] phenylacetic acid (3.8 g, 11.96 mmol), trichloroethyl chloroacetate (3.24 g, 14.35 nmol) and sodium iodide (0.89 g, 5.98 mmol) Amide solution (38 ml) was reacted at room temperature for 5 hours while stirring well. Ethyl acetate was added to the reaction solution, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate: hexane (1: 7) to obtain 5.48 g (94%) of the title compound as a white solid.

This material was confirmed to be identical to the product of Example 1 by thin layer chromatography and NMR.

Example 3 Preparation of trichloroethyl 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetate

A solution of sodium acetate (3.32 g, 22.14 mmol) and an acetone solution of 2 - [(2,6-dichlorophenyl) amino] phenylacetic acid sodium salt (7.04 g, 22.14 mmol), trichloroethyl chloroacetate (5 g, 22.14 nmol) and sodium iodide (44 ml) were reacted at room temperature for 22 hours while stirring well. Ether was added to the reaction solution, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate: hexane (1: 10) to obtain 8.69 g (81%) of the title compound as a white solid.

This material was confirmed to be identical to the product of Example 1 by thin layer chromatography and NMR.

Example 4 Preparation of trichloroethyl 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetate

(7.0 g, 22.14 mmol), trichloroethyl chloroacetate (5 g, 22.14 nmol) and trimethylbenzylammonium chloride (4.11 g, 22.14 mmol) were added to a solution of 2 - [(2,6- dichlorophenyl) amino] phenylacetic acid sodium salt And sodium iodide (3.32 g, 22.14 mmol) were reacted at room temperature for 22 hours while stirring well in a mixed solution of dichloromethane (22 ml) and water (22 ml). Ether was added to the reaction solution, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate: hexane (1: 10) to obtain 7.43 g (69%) of the title compound as a white solid.

This material was confirmed to be identical to the product of Example 1 by thin layer chromatography and NMR.

Example 5 Preparation of ethyl iodide 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetate

(70 ml) solution of 2 - [(2,6-dichlorophenyl) amino] phenylacetic acid sodium salt (2.19 g, 6.88 mmol) and iodoethyl chloroacetate (2.84 g, 8.93 nmol) The reaction was carried out at room temperature for 3 hours. Ethyl acetate was added thereto, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate: hexane (1: 10) to obtain 2.1 g (60%) of the title compound as a white solid.

_{^{1 H-NMR (CDCl 3:}} δ): 3.17 (t, 2H, J = 6.8 Hz) 3.92 (s, 2H), 4.35 (t, 2H,

J = 6.8 Hz), 4.67 (s, 2H), 6.54 (d, 1H, J =

6.67 (br s, 1 H), 6.92-7.34 (m, 6 H)

Ⅱ. Preparation of 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid (1)

Example 6 Preparation of 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid

Zinc (13.46 g) was added thereto while stirring a tetrahydrofuran solution (68 ml) of trichloroethyl 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetate (10 g, 20.6 mmol) Then, 1M aqueous potassium dihydrogenphosphate (KH ₂ PO ₄ ) solution (14 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The pH of the reaction mixture is adjusted to 7 with a saturated solution of saturated sodium bicarbonate solution, then the zinc is removed by filtration and the filtrate is concentrated under reduced pressure to remove tetrahydrofuran. Dichloromethane was added to the concentrate, and a 10% hydrochloric acid aqueous solution was added. After stirring well, the organic layer was separated. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was recrystallized from toluene to obtain 6.64 g (91%) of the title compound as white crystals. Melting point 149-150 DEG C

_{^{1 H-NMR (CDCl 3:}} δ): 3.92 (s, 2H), 4.70 (s, 2H), 6.54 (d, 1H, J = 8 Hz),

6.62 (br s, 1 H), 6.91-7.33 (m, 6 H)

IR (KBr): 3320, 1773 , 1717, 1439, 1256, 1150, 1055, 750 cm -1

Elemental analysis:

Found (%): C; 54.03 H; 3.57 N; 3.91

Theoretical (%): C; 54.26 H; 3.70 N; 3.95

Example 7 Preparation of 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid

Zinc (7 g) was added thereto while stirring well in a 90% acetic acid solution (82 ml) of trichloroethyl 2- [(2,6-dichlorophenyl) amino] phenylacetoxyacetate (2 g, 4.1 mmol) The mixture was stirred at room temperature for 1 hour. The zinc was removed by filtration

And concentrated under reduced pressure. Dichloromethane was added to the concentrate, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was recrystallized with toluene to obtain 1.32 g (90%) of the desired compound.

This material was confirmed to be identical to the product of Example 6 by thin layer chromatography and NMR.

Example 8 Preparation of 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid

Zinc (271 mg) was added thereto while stirring a tetrahydrofuran solution (5 ml) of iodoethyl 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetate (210 mg, 0.41 mmol) Then, 1M aqueous potassium dihydrogen phosphate solution (1.2 ml) was added, and the mixture was stirred at room temperature for 1 hour. The pH of the reaction solution was adjusted to 7 with a saturated sodium hydrogencarbonate solution, the zinc was removed by filtration, and the filtrate was concentrated under reduced pressure to almost remove tetrahydrofuran. Dichloromethane was added to the concentrate, and a 10% hydrochloric acid aqueous solution was added. After stirring well, the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was recrystallized from toluene to obtain 117 mg (80%) of the title compound as white crystals.

This material was confirmed to be identical to the product of Example 6 by thin layer chromatography and NMR.

The compound of formula (I) may be used in the form of a general pharmaceutical preparation, and may be administered in various oral or parenteral formulations in actual clinical administration. In the case of formulation, diluents or excipients such as fillers, weighing agents, binders, wetting agents, disintegrants, surfactants and the like which are usually used are used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, It is prepared by mixing sucrose, lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral administration include suspensions, solutions, emulsions, and syrups. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are simple diluents commonly used . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, and freeze-drying agents. Propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.

The present invention relates to a process for the preparation of 2 - [(2,6-dichlorophenyl) amino] phenylacetoxy (2-methylphenyl) amino] phenylacetoxyacetic acid by reacting a haloethyl ester of 2- [ Acetic acid and a pharmaceutically acceptable salt thereof,

The selectivity of the reaction is excellent, the reaction conditions are mild, the production process is convenient, and a high purity aceclofenac can be produced at a high yield.

Claims (6)

2 - [(2,6-dichlorophenyl) amino] phenyl] acetamide represented by the general formula (1) can be prepared by reacting a haloethyl ester of 2- [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid represented by the general formula 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid, or a pharmaceutically acceptable salt or solvate thereof, which produces acetoxyacetic acid. Scheme 6 2. The compound according to claim 1, wherein the haloethyl ester of 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid is trichloroethyl ester or iodoethyl ester. Dichlorophenyl) amino] phenylacetoxyacetic acid or a pharmaceutically acceptable salt or solvate thereof. [2] The method according to claim 1, wherein the solvent used is 2 - [(2,6-dichlorophenyl) amino] propionic acid which is a mixed solution of tetrahydrofuran and KH ₂ PO ₄ aqueous solution, aqueous acetic acid solution, aqueous hydrochloric acid solution or dimethylformamide ] Phenylacetoxyacetic acid or a pharmaceutically acceptable salt or solvate thereof. The method according to claim 1, wherein the alkali metal salt of 2- [(2,6-dichlorophenyl) amino] phenylacetic acid is reacted in a solvent in which polar protons can not be dissociated or in an adverse reaction using a phase transfer catalyst 2 - [(2, 3-dihydroxyphenyl) amino] phenylacetoxyacetic acid of formula (2) , 6-dichlorophenyl) amino] phenylacetoxyacetic acid or a pharmaceutically acceptable salt or solvate thereof. The method according to claim 4, wherein 2 - [(2,6-dichlorophenyl) amino] phenylacetoxyacetic acid or a pharmaceutically acceptable salt thereof or a solvent thereof is added to the reaction solution in an amount of catalytic to an equivalent amount of sodium iodide Method of manufacturing cargo. 5. A compound according to claim 4, wherein the haloethyl acetate is trichloroethyl haloacetate or iodoethyl haloacetate, or a pharmaceutically acceptable salt thereof. ≪ / RTI >