KR100633232B1 - A novel method for purification of 6-[4-1-cyclohexyl-1h-tetrazol-5-ylbutoxy-3,4-dihydro-21h-quinolinone having high purity - Google Patents

Abstract

The present invention is directed to 6- [4- (1-cyclohexyl-1H-tetrazol-5-yl) butoxy] -3,4-dihydro-2 (1H) -quinolinone having inhibitory effect on cell platelet aggregation. A novel purification method of cilostazol).

Cilostazol, purification method, platelet aggregation, intermittent claudication

Description

Novel 6- [4- (1-cyclohexyl-1H-tetrazol-5-yl) butoxy] -3,4-dihydro-2 (1H) -quinolinone purification method {A NOVEL METHOD FOR PURIFICATION OF 6- [4- (1-CYCLOHEXYL-1H-TETRAZOL-5-YL) BUTOXY-3,4-DIHYDRO-2 (1H) -QUINOLINONE HAVING HIGH PURITY}

The present invention provides a compound of formula 1, 6- [4- (1-cyclohexyl-1H-tetrazol-5-yl) butoxy] -3,4-dihydro-2 (1H), having a cell platelet aggregation inhibitory effect A novel purification method of) -quinolinone (hereinafter referred to as "cilostazol").

The compound of formula 1 is used to treat patients with intermittent claudication, which has a cell platelet aggregation inhibitory action. In addition, methods for producing the same are known from US Pat. No. 4,277,479 and WO 02/014283.

U.S. Patent No. 4,277,479 discloses 1-5-diaza-bicyclo [5,4,0] -undec-7-ene (DBU) as a base as a phenol group of 6-hydroxy-3,4-dihydroquinolinone. The cilostazol is prepared by alkylation with 1-cyclohexyl-5- (4-halobutyl) -tetrazole in the presence, and the resulting cilostazol is separated using column chromatography or recrystallized by an organic solvent such as ethanol. It discloses a method for purifying through. WO 02/014283 also discloses a method for purifying cilostazol by recrystallizing the cilostazol obtained from an organic solvent such as butanol, acetone or toluene.

However, the cilostazol purification method using the column chromatography of the prior art can effectively remove impurities, but is not suitable for mass production, and the method of recrystallization from organic solvents is present in crude cilostazol. There is a problem that impurities cannot be removed effectively.

Accordingly, the present inventors have conducted a number of studies to solve the problems of the prior art, as a result, can produce cilostazol with high purity, and developed a novel purification method that is easy to industrialize.

Accordingly, an object of the present invention is to provide a high purity purification method of the compound of formula (1).

The present invention provides a method for purifying a high purity of a compound of the following Chemical Formula 1 (cilostazol).

The high purity cilostazol purification method of the present invention comprises the steps of i) mixing the crude cilostazol with a single organic solvent or a mixed solvent thereof in the presence of an acid to prepare a cilostazol salt; And ii) converting the cilostazol salt prepared in step i) to cilostazol.

In the present invention, "Crude Cilostazol" means cilostazol without undergoing a purification step.

Crude cilostazol in the present invention can be easily prepared according to the following method disclosed in the prior art. A mixed solution of 6-hydroxy-3,4-dihydroquinolinone (10.0 g), ethanol (300 ml) and DBU (10.4 ml) was heated to reflux, and 1-cyclohexyl-5- (4 -Chlorobutyl) -tetrazole (15 g) and ethanol (30 ml) mixed solution was added dropwise for 90 minutes, and then reacted and separated for 5 hours at the same temperature to prepare crude cilostazol. (U.S. Patent No. 4,277,479)

In step i) of the purification process of the invention, the crude cilostazol is mixed with an organic solvent in the presence of an acid. The inventors have found that in the case of oxalic acid, maleic acid or sulfuric acid, the present inventors selectively form salts with cilostazol in an organic solvent and hardly form salts with cilostazol impurities. Therefore, the acid used in the purification method of the present invention is preferably oxalic acid, maleic acid or sulfuric acid. The amount of acid used at this time is preferably 1 to 3 equivalents based on the crude cilostazol. In addition, tetrahydrofuran, ketones, esters or a mixed solvent thereof may be used as the organic solvent, and among them, acetone, methyl ether ketone or 2-pentanone may be used as the ketone, and ethyl acetate may be used as the ester. , Methyl acetate or isopropyl acetate can be used.

In the purification method of the present invention, the reaction of step i) can be preferably carried out at 0 ~ 50 ℃, more preferably at room temperature.

The cilostazol salt prepared in step i) of the present invention can be converted to high purity cilostazol in the presence of a base according to conventional methods. For example, in step ii) of the present invention, triethylamine, sodium hydroxide or potassium hydroxide may be used as the base, and sodium hydroxide, which is inexpensive and generally usable, may be preferably used. In addition, the reaction of step ii) of the present invention may be carried out in the presence of an organic solvent, wherein ethyl acetate, methylene chloride, chloroform may be used as the organic solvent, and chloroform may be easily used. It is more preferable because it can melt | dissolve.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are illustrative of the invention and do not limit the scope of the invention.

Example

Preparation Example 1

6-hydroxy-3,4-dihydroquinolinone (10.0 g) with ethanol (300 ml), DBU (10.4 ml), 1-cyclohexyl-5- (4-chlorobutyl) -tetrazole (15 g ) Was added to the reaction vessel and the reaction temperature was heated to 75 ℃ ~ 80 ℃ and then reacted overnight and separated to prepare a crude cilostazol (20 g, 89%).

Example 1

Crude cilostazol (50 g) was added to acetone (300 mL) at 20 ° C. to 25 ° C., and oxalic acid (14.6 g) was added to the mixed solution, followed by stirring at 20 ° C. to 25 ° C. for 3 hours. The resulting solid was filtered under reduced pressure, washed with acetone (40 mL), and dried in vacuo at 40 ° C to 45 ° C to prepare cilostazol oxalic acid salt (60.3 g, 97%).

The obtained cilostazol oxalic acid salt (60.3 g) was added to a mixed solution of chloroform (700 mL) and distilled water (175 mL), and sodium hydroxide (10.6 g) was added thereto. The organic layer was separated, concentrated under reduced pressure to remove the organic solvent, ethanol (250 mL) was added to the concentrated residue, stirred for 1 to 2 hours, filtered, and dried in vacuo at 40 ° C to 45 ° C to obtain high purity cilostazol (47.5 g). ) Was prepared.

Example 2

Crude cilostazol (50 g) was added to acetone (250 mL) at 20 ° C to 25 ° C, and maleic acid (18.9 g) was added to the mixed solution, followed by stirring at 20 ° C to 25 ° C for 3 hours. . The resulting solid was filtered under reduced pressure, washed with acetone (40 mL), and dried in vacuo at 40 ° C to 45 ° C to prepare cilostazol maleic acid salt (59.1 g, 90%).

The obtained cilostazol maleic acid salt (59.1 g) was added to a mixed solution of chloroform (700 mL) and distilled water (175 mL), and sodium hydroxide (9.8 g) was added thereto. The organic layer was separated, concentrated under reduced pressure to remove the organic solvent, ethanol (250 mL) was added to the concentrated residue, stirred for 1 to 2 hours, filtered, and then vacuum dried at 40 ° C to 45 ° C to obtain high purity cilostazol (44 g). ) Was prepared.

Example 3

Crude cilostazol (50 g) was added to acetone (250 mL) at 20 ° C. to 25 ° C., and sulfuric acid (15.9 g) was added to the mixed solution, followed by stirring at 20 ° C. to 25 ° C. for 3 hours. The resulting solid was filtered under reduced pressure, washed with acetone (40 mL), and dried in vacuo at 40 ° C to 45 ° C to prepare cilostazol sulfate (58.2 g, 92%).

The obtained cilostazol sulfate (58.2 g) was added to a mixed solution of chloroform (700 mL) and distilled water (175 mL), and sodium hydroxide (10.0 g) was added thereto. The organic layer was separated, concentrated under reduced pressure to remove the organic solvent, ethanol (250 mL) was added to the concentrated residue, stirred for 1 to 2 hours, filtered, and dried in vacuo at 40 ° C. to 45 ° C. (45.5 g). ) Was prepared.

Example 4

Acetone: Ethyl acetate (= 2: 1) To a mixed solvent (200 mL) was added crude cilostazol (50 g) at 20 ° C to 25 ° C, and sulfuric acid (15.9 g) was added to the mixed solution at 20 ° C. Stir at ˜25 ° C. for 3 hours. The resulting solid was filtered under reduced pressure, washed with acetone (40 mL), and then vacuum dried at 40 ° C. to 45 ° C. to prepare cilostazol sulfate (56.9 g, 90%).

The obtained cilostazol sulfate (56.9 g) was added to a mixed solution of chloroform (700 mL) and distilled water (175 mL), and sodium hydroxide (9.8 g) was added thereto. The organic layer was separated, concentrated under reduced pressure to remove the organic solvent, ethanol (250 mL) was added to the concentrated residue, stirred for 1 to 2 hours, filtered, and dried in vacuo at 40 ° C. to 45 ° C. (44.5 g). ) Was prepared.

Example 5

Crude cilostazol (50 g) was added to ethyl acetate (350 mL) at 20 ° C to 25 ° C, and sulfuric acid (15.9g) was added to the mixed solution, followed by stirring at 20 ° C to 25 ° C for 3 hours. The resulting solid was filtered under reduced pressure, washed with ethyl acetate (40 mL), and dried in vacuo at 40 ° C. to 45 ° C. to prepare cilostazol sulfate (56.9 g, 90%).

The obtained cilostazol sulfate (56.9 g) was added to a mixed solution of chloroform (700 mL) and distilled water (175 mL), and sodium hydroxide (9.8 g) was added thereto. The organic layer was separated, concentrated under reduced pressure to remove the organic solvent, ethanol (250 mL) was added to the concentrated residue, stirred for 1 to 2 hours, filtered, and dried in vacuo at 40 ° C. to 45 ° C. (45 g). ) Was prepared.

Example 6

Crude cilostazol (50 g) was added to methyl ethyl ketone (250 mL) at 20 ° C to 25 ° C, sulfuric acid (15.9g) was added to the mixed solution, and the mixture was stirred at 20 ° C to 25 ° C for 3 hours. . The resulting solid was filtered under reduced pressure, washed with methyl ethyl ketone (40 mL), and dried in vacuo at 40 ° C. to 45 ° C. to prepare cilostazol sulfate (57 g, 91%).

The obtained cilostazol sulfate (57 g) was added to a mixed solution of chloroform (700 mL) and distilled water (175 mL), and sodium hydroxide (9.8 g) was added thereto. The organic layer was separated, concentrated under reduced pressure to remove the organic solvent, ethanol (250 mL) was added to the concentrated residue, stirred for 1 to 2 hours, filtered, and dried in vacuo at 40 ° C. to 45 ° C. (45 g). ) Was prepared.

Example 7

Crude cilostazol (50 g) was added to methyl acetate (300 mL) at 20 ° C. to 25 ° C., and sulfuric acid (15.9 g) was added to the mixed solution, followed by stirring at 20 ° C. to 25 ° C. for 3 hours. The resulting solid was filtered under reduced pressure, washed with methyl acetate (40 mL), and then vacuum dried at 40 ° C. to 45 ° C. to prepare cilostazol sulfate (57 g, 91%).

The obtained cilostazol sulfate (57 g) was added to a mixed solution of chloroform (700 mL) and distilled water (175 mL), and sodium hydroxide (9.8 g) was added thereto. The organic layer was separated, concentrated under reduced pressure to remove the organic solvent, ethanol (250 mL) was added to the concentrated residue, stirred for 1 to 2 hours, filtered, and dried in vacuo at 40 ° C. to 45 ° C. (45 g). ) Was prepared.

Example 8

Crude cilostazol (50 g) was added to isopropyl acetate (400 mL) at 20 ° C to 25 ° C, sulfuric acid (15.9g) was added to the mixed solution, and the mixture was stirred at 20 ° C to 25 ° C for 3 hours. . The resulting solid was filtered under reduced pressure, washed with isopropyl acetate (40 mL), and then vacuum dried at 40 ° C. to 45 ° C. to prepare cilostazol sulfate (59.5 g, 94%).

The obtained cilostazol sulfate (59.5 g) was added to a mixed solution of chloroform (700 mL) and distilled water (175 mL), and sodium hydroxide (10.2 g) was added thereto. The organic layer was separated, concentrated under reduced pressure to remove the organic solvent, ethanol (250 mL) was added to the concentrated residue, stirred for 1 to 2 hours, filtered, and dried in vacuo at 40 ° C. to 45 ° C. (46.5 g). ) Was prepared.

Example 9

Crude cilostazol (50 g) was added to 2-pentanone (250 mL) at 20 ° C to 25 ° C, and sulfuric acid (15.9 g) was added to the mixed solution, followed by stirring at 20 ° C to 25 ° C for 3 hours. It was. The resulting solid was filtered under reduced pressure, washed with 2-pentanone (40 mL), and dried in vacuo at 40 ° C. to 45 ° C. to prepare cilostazol sulfate (56.9 g, 90%).

The obtained cilostazol sulfate (56.9 g) was added to a mixed solution of chloroform (700 mL) and distilled water (175 mL), and sodium hydroxide (9.8 g) was added thereto. The organic layer was separated, concentrated under reduced pressure to remove the organic solvent, ethanol (250 mL) was added to the concentrated residue, stirred for 1 to 2 hours, filtered, and dried in vacuo at 40 ° C. to 45 ° C. (45 g). ) Was prepared.

Example 10

Crude cilostazol (50 g) was added to tetrahydrofuran (200 mL) at 20 ° C to 25 ° C, sulfuric acid (15.9g) was added to the mixed solution, and the mixture was stirred at 20 ° C to 25 ° C for 3 hours. . The resulting solid was filtered under reduced pressure, washed with tetrahydrofuran (40 mL), and dried in vacuo at 40 ° C to 45 ° C to prepare cilostazol sulfate (56.9 g, 90%).

The obtained cilostazol sulfate (56.9 g) was added to a mixed solution of chloroform (700 mL) and distilled water (175 mL), and sodium hydroxide (9.8 g) was added thereto. The organic layer was separated, concentrated under reduced pressure to remove the organic solvent, ethanol (250 mL) was added to the concentrated residue, stirred for 1 to 2 hours, filtered, and dried in vacuo at 40 ° C. to 45 ° C. (44.5 g). ) Was prepared.

Comparative Example 1

Crude cilostazol (10 g) was added to 95% ethanol (150 mL) at 20 ° C to 25 ° C, dissolved by heating, and then slowly cooled to crystallize. The resulting solid was filtered under reduced pressure, washed with ethanol (20 mL), and dried in vacuo at 40 ° C to 45 ° C to prepare cilostazol (8.8 g).

Test Example 1

Assays of the cilostazol prepared according to Examples 1 to 10 and Comparative Example 1 are shown in Table 1 below, and expressed in HPLC purity. As shown in Table 1, purity and impurity content of cilostazol (purity of 99.80% or more) purified according to the purification method of the present invention is higher than that of cilostazol (purity of 99.54%) purified according to the purification method of the prior art. It was confirmed that this was significantly improved. In Table 1, Impurity A is 6- [4- (1-cyclohexyl-1H-tetrazol-5-yl) butoxy] -1- [4- (1-cyclohexyl-1H-tetrazol-5-yl ) Butyl] -3,4-dihydro-2 (1H) -quinolinone, Impurity B is 1- [4- (1- (cyclohexyl-1H-tetrazol-5-yl) butoxy] -6 -Hydroxy-3,4-dihydro-2 (1H) -quinolinone.

division Purity and Impurity Composition (%) water Imp A Imp B  Imp 1 (Unknown)  Imp 2 (Unknown) Preparation Example 1 98.28 0.78 0.09 0.31 0.54 Example 1 99.98 0.01 0.01 - - Example 2 99.96 0.02 0.01 - 0.01 Example 3 99.97 - 0.01 0.01 0.01 Example 4 99.97 - 0.01 - 0.02 Example 5 99.89 0.06 0.01 - 0.04 Example 6 99.95 0.03 0.02 - - Example 7 99.85 0.08 0.01 - 0.06 Example 8 99.80 0.11 - 0.02 0.07 Example 9 99.87 0.08 0.02 0.01 0.02 Example 10 99.98 0.01 0.01 - - Comparative Example 1 99.54 0.15 0.07 0.04 0.20

As described above, 6- [4- (1-cyclohexyl-1H-tetrazol-5-yl) butoxy] -3,4-dihydro-2 (1H) -quine according to the purification method of the present invention. Nolinone (cilostazol) can be produced in high purity, and industrial mass production is easy.

Claims (9)

i) a solvent selected from the group consisting of tetrahydrofuran, acetone, methylethylketone, 2-pentanone, ethyl acetate, methyl acetate, isopropyl acetate and mixtures thereof in the presence of oxalic acid, maleic acid or sulfuric acid Adding to prepare a cilostazol salt; And ii) A method for purifying cilostazol having a purity of 99.8% or more, comprising converting the cilostazol salt prepared in step i) to cilostazol in the presence of triethylamine, sodium hydroxide, or potassium hydroxide. delete delete delete A process according to claim 1, wherein the amount of acid used in step i) is 1-3 equivalents to the crude cilostazol. The process of claim 1, wherein the reaction temperature of step i) is between 0 ° C and 50 ° C. delete The process according to claim 1, wherein the reaction of step ii) is carried out in a solvent selected from ethyl acetate, methylene chloride and chloroform. delete