WO2006022488A1

WO2006022488A1 - Process for purification of cilostazol

Info

Publication number: WO2006022488A1
Application number: PCT/KR2005/002676
Authority: WO
Inventors: Tai-Au Lee; Ja-Heouk Khoo; Kyung-Chan Kwon; Doo-Byung Lee; Seong-Ho Song
Original assignee: Yuhan Corp
Current assignee: Yuhan Corp
Priority date: 2004-08-25
Filing date: 2005-08-17
Publication date: 2006-03-02
Anticipated expiration: 2007-02-25
Also published as: KR100633232B1; KR20060018571A

Abstract

The present invention provides a process for preparing high purity cilostazol. The process comprises: (a) adding crude cilostazol to an acid selected from the group consisting of oxalic acid, maleic acid, sulfuric acid, and a mixture thereof to form a cilostazol salt; and (b) recovering cilostazol through adding a base to the cilostazol salt.

Description

PROCESS FOR PREPARING CILOSTAZOL

Technical Field

[1] The present invention relates to a process for preparing high purity cilostazol.

Background Art

[2] Cilostazol, whose chemical name is 6-[4-(l-cyclohexyl-lH-tetrazol-5-yl)butoxy] -

3,4-dihydro-2(lH)-quinolinone, is known as a useful cell platelet aggregation inhibitor, thereby being used to treat patients with intermittent claudication, and is represented by the following formula (I).

[3] Known methods of preparing cilostazol are disclosed in U.S. Patent No. 4,277,479 and WO 02/014283.

[4] U.S. Patent No. 4,277,479 discloses a process for preparing cilostazol through performing alkylation of phenol group of 6-hydroxy-3,4-dihydroquinolinone with l-cyclohexyl-5-(4-halobutyl)-tetrazole in the presence of l,8-diazabicyclo[5.4.0] - undec-7-ene (DBU) as a base to obtain a crude cilostazol and then performing column chromatography or re-crystallization to purify the crude cilostazol.

[5] WO 02/014283 discloses a process for purifying cilostazol by re-crystallization, using organic solvents such as butanol, acetone, and toluene.

[6] However, the column chromatography methods disclosed in the prior art (i.e., U.S.

Patent No. 4,277,479) cannot be easily applied for industrial-scale mass production, and the re-crystallization methods also have a disadvantage in that impurities cannot be removed to a satisfactory level. The impurities include known impurities, such as 6- [4-( 1 -cyclohexyl- 1 H-tetrazol-5-yl)-butoxy] - 1 - [4-( 1 -cyclohexyl- 1 H-tetrazol-5-yl)-but yl]-3,4-dihydro-lH-quinolin-2-one (Impurity A) and

6-[4-(l-cyclohexyl-lH-tetrazol-5-yl)-butoxy]-lH-quinolin-2-one (Impurity B), and unknown impurities.

[7] Thus, there is a need for a novel process for preparing cilostazol with satisfactory purity, i.e., a process for purifying a crude cilostazol. Disclosure of Invention

Technical Problem [8] The present invention provides a process for preparing high purity cilostazol, wherein an acid is employed to form a cilostazol salt and cilostazol is then recovered from the cilostazol salt, thereby remarkably removing any known impurities (Impurities A and B) and unknown impurities.

Technical Solution

[9] According to an aspect of the present invention, there is provided a process for preparing cilostazol, the process comprising: (a) adding crude cilostazol to an acid selected from the group consisting of oxalic acid, maleic acid, sulfuric acid, and a mixture thereof to form a cilostazol salt; and (b) recovering cilostazol through adding a base to the cilostazol salt.

Best Mode

[10] A process for preparing high purity cilostazol according to an embodiment of the present invention includes purifying crude cilostazol through forming an acid addition salt of cilostazol.

[11] As used herein, 'crude cilostazol' refers to cilostzol before purification and may be prepared by known methods in the art, e.g., processes disclosed in U.S. Patent No. 4,277,479. Impurities include ό-K^l-cyclohexyl-lH-tetrazol-S-yty-butoxy] - 1 - [4-( 1 -cyclohexyl- 1 H-tetrazol-5-yl)-butyl] -3 ,4-dihydro- 1 H-quinolin-2-one (Impurity A), 6-[4-(l-cyclohexyl-lH-tetrazol-5-yl)-butoxy]-lH-quinolin-2-one (Impurity B), and/or unknown impurities.

[12] The process of the present invention includes (a) adding crude cilostazol to an acid selected from the group consisting of oxalic acid, maleic acid, sulfuric acid, and a mixture thereof to form a cilostazol salt; and (b) recovering cilostazol through adding a base to the cilostazol salt.

[13] In the step (a), the acid is selected from the group consisting of oxalic acid, maleic acid, sulfuric acid, and a mixture thereof, which can selectively react with crude cilostazol (i.e., not with its impurities) to form a cilostazol salt. The amount of the acid may be in the range of about 1 ~ 3 eq. to 1 eq. of crude cilostazol.

[14] The step (a) may be carried out in an organic solvent, such as tetrahydrofuran, ketones, esters, or mixtures thereof. The ketones include acetone, methyl ethyl ketone, and/or 2-pentanone, and the esters include ethyl acetate, methyl acetate, and/or isopropyl acetate. The step (a) may be performed at 0 ~ 50 °C, preferably at room temperature.

[15] In the step (b), the cilostazol salt is converted into a purified cilostazol through adding a base to the cilostazol salt. The base neutralizes the cilostazol salt (i.e., acid addition salt) to form a free form of cilostazol. Although conventional bases may be used in the step (b), an organic base such as triethylamine or an inorganic base such as sodium hydroxide or potassium hydroxide may be used. Further, the step (b) may be carried out in an organic solvent, e.g., ethyl acetate, methylene chloride, and chloroform, or in a mixed solvent of water and the organic solvent, e.g., a mixed solvent of water and chloroform. Among them, a mixed solvent of water and chloroform may be preferably used, because it can easily dissolve cilostazol.

[16] When the process of the present invention is performed, high purity ( > 99.80%) cilostazol may be obtained. As confirmed in the following examples, all known impurities, i.e., Impurities A and B, and unknown impurities are remarkably removed by the process of the present invention.

[17] The present invention is further illustrated and described by the following examples, which should not be taken to limit the scope of the invention.

[18] Preparation Example

[19] 10.0 g of 6-hydroxy-3,4-dihydro-lH-quinolin-2-one, 300 ml of ethanol, 10.4 ml of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 15 g of

5-(4-chlorobutyl)-l-cyclohexyl-lH-tetrazole were mixed. The reaction mixture was heated to 75 °C ~ 80 °C and stirred overnight. Then, the reaction mixture was cooled to room temperature and filtered. The resulting precipitate was washed with ethanol. The obtained wet cake was dried to give 20 g of crude cilostazol (yield: 89%).

[20] M.P. 158 ~ 162 °C

[21] ¹H-NMR (CDCl , δ , ppm) 1.10-2.10 (m, 14H, methylene protons of cyclohexyl ring, -OCH CH CH CH -), 2.90-2.95 (m, 4H, -NHCOCH CH -), 2.61 (t, 2Η, J=8Hz, -OCH 2 CH2 CH2 CH2 -), 3.98 (t, 2Η, J=6Ηz, -OCH 2 CH2 CH2 CH2 -), 4.11-4.15

(m, IH, methine protons of cyclohexyl ring), 6.66-6.71 (m, 3H, aromatic protons), 7.84 (s, IH, NH)

[22] Example 1

[23] 14.6 g of oxalic acid was added to the solution of 50 g of crude cilostazol in 300 ml of acetone. The reaction mixture was stirred at 20°C ~ 25°C for 3 hours and then filtered under reduced pressure. The resulting wet cake was washed with 40 ml of acetone and dried at 40°C ~ 45°C under reduced pressure to give 60.3 g of cilostazol oxalate (yield: 97%).

[24] 60.3 g of cilostazol oxalate and 10.6 g of sodium hydroxide were added under stirring to the mixed solvent of 700 ml of chloroform and 175 ml of water. The organic layer was separated and concentrated under reduced pressure to remove an organic solvent. 250 ml of ethanol was added to the resulting residue, which was stirred for about 2 hours, filtered, and then dried at 40°C ~ 45°C under reduced pressure to give 47.5 g of cilostazol (yield: 97.9%).

[25] Example 2

[26] 18.9 g of maleic acid was added to the solution of 50 g of crude cilostazol in 250 ml of acetone. The reaction mixture was stirred at 20°C ~ 25°C for 3 hours and then filtered under reduced pressure. The resulting wet cake was washed with 40 ml of acetone and dried at 40°C ~ 45°C under reduced pressure to give 59.1 g of cilostazol malate (yield: 90%).

[27] 59.1 g of cilostazol malate and 9.8 g of sodium hydroxide were added under stirring to the mixed solvent of 700 ml of chloroform and 175 ml of water. The organic layer was separated and concentrated under reduced pressure to remove an organic solvent. 250 ml of ethanol was added to the resulting residue, which was stirred for about 2 hours, filtered, and then dried at 40°C ~ 45°C under reduced pressure to give 44 g of cilostazol (yield: 97.8%).

[28] Example 3

[29] 15.9 g of sulfuric acid was added to the solution of 50 g of crude cilostazol in 250 ml of acetone. The reaction mixture was stirred at 20°C ~ 25°C for 3 hours and then filtered under reduced pressure. The resulting wet cake was washed with 40 ml of acetone and dried at 40°C ~ 45°C under reduced pressure to give 58.2 g of cilostazol sulfate (yield: 92%).

[30] 58.2 g of cilostazol sulfate and 10.0 g of sodium hydroxide were added under stirring to the mixed solvent of 700 ml of chloroform and 175 ml of water. The organic layer was separated and concentrated under reduced pressure to remove an organic solvent. 250 ml of ethanol was added to the resulting residue, which was stirred for about 2 hours, filtered, and then dried at 40°C ~ 45°C under reduced pressure to give 45.5 g of cilostazol (yield: 98.9%).

[31] Example 4

[32] 15.9 g of sulfuric acid was added to the solution of 50 g of crude cilostazol in 200 ml of a mixed solvent of acetone and ethyl acetate (2: 1, v/v). The reaction mixture was stirred at 20°C ~ 25°C for 3 hours and then filtered under reduced pressure. The resulting wet cake was washed with 40 ml of acetone and dried at 40°C ~ 45°C under reduced pressure to give 56.9 g of cilostazol sulfate (yield: 90%).

[33] 56.9 g of cilostazol sulfate and 9.8 g of sodium hydroxide were added under stirring to the mixed solvent of 700 ml of chloroform and 175 ml of water. The organic layer was separated and concentrated under reduced pressure to remove an organic solvent. 250 ml of ethanol was added to the resulting residue, which was stirred for about 2 hours, filtered, and then dried at 40°C ~ 45°C under reduced pressure to give 44.5g of cilostazol (yield: 98.9%).

[34] Example 5

[35] 15.9 g of sulfuric acid was added to the solution of 50 g of crude cilostazol in 350 ml of ethyl acetate. The reaction mixture was stirred at 20°C ~ 25°C for 3 hours and then filtered under reduced pressure. The resulting wet cake was washed with 40 ml of ethyl acetate and dried at 40°C ~ 45°C under reduced pressure to give 56.9 g of cilostazol sulfate (yield: 90%).

[36] 56.9 g of cilostazol sulfate and 9.8 g of sodium hydroxide were added under stirring to the mixed solvent of 700 ml of chloroform and 175 ml of water. The organic layer w as separated and concentrated under reduced pressure to remove an organic solvent. 250 ml of ethanol was added to the resulting residue, which was stirred for about 2 hours, filtered, and then dried at 40°C ~ 45°C under reduced pressure to give 45g of cilostazol (yield: 100%).

[37] Example 6

[38] 15.9 g of sulfuric acid was added to the solution of 50 g of crude cilostazol in 250 ml of methyl ethyl ketone. The reaction mixture was stirred at 20°C ~ 25°C for 3 hours and then filtered under reduced pressure. The resulting wet cake was washed with 40 ml of methyl ethyl ketone and dried at 40°C ~ 45°C under reduced pressure to give 57 g of cilostazol sulfate (yield: 91%).

[39] 57 g of cilostazol sulfate and 9.8 g of sodium hydroxide were added under stirring to the mixed solvent of 700 ml of chloroform and 175 ml of water. The organic layer was separated and concentrated under reduced pressure to remove an organic solvent. 250 ml of ethanol was added to the resulting residue, which was stirred for about 2 hours, filtered, and then dried at 40°C ~ 45°C under reduced pressure to give 45g of cilostazol (yield: 100%).

[40] Example 7

[41] 15.9 g of sulfuric acid was added to the solution of 50 g of crude cilostazol in 300 ml of methyl acetate. The reaction mixture was stirred at 20°C ~ 25°C for 3 hours and then filtered under reduced pressure. The resulting wet cake was washed with 40 ml of methyl acetate and dried at 40°C ~ 45°C under reduced pressure to give 57 g of cilostazol sulfate (yield: 91%).

[42] 57 g of cilostazol sulfate and 9.8 g of sodium hydroxide were added under stirring to the mixed solvent of 700 ml of chloroform and 175 ml of water. The organic layer was separated and concentrated under reduced pressure to remove an organic solvent. 250 ml of ethanol was added to the resulting residue, which was stirred for about 2 hours, filtered, and then dried at 40°C ~ 45°C under reduced pressure to give 45g of cilostazol (yield: 100%).

[43] Example 8

[44] 15.9 g of sulfuric acid was added to the solution of 50 g of crude cilostazol in 400 ml of isopropyl acetate. The reaction mixture was stirred at 20°C ~ 25°C for 3 hours and then filtered under reduced pressure. The resulting wet cake was washed with 40 ml of isopropyl acetate and dried at 40°C ~ 45°C under reduced pressure to give 59.5 g of cilostazol sulfate (yield: 94%). [45] 59.5 g of cilostazol sulfate and 10.2 g of sodium hydroxide were added under stirring to the mixed solvent of 700 ml of chloroform and 175 ml of water. The organic layer was separated and concentrated under reduced pressure to remove an organic solvent. 250 ml of ethanol was added to the resulting residue, which was stirred for about 2 hours, filtered, and then dried at 40°C ~ 45°C under reduced pressure to give 46.5 g of cilostazol (yield: 98.7%).

[46] Example 9

[47] 15.9 g of sulfuric acid was added to the solution of 50 g of crude cilostazol in 250 ml of 2-pentanone. The reaction mixture was stirred at 20°C ~ 25°C for 3 hours and then filtered under reduced pressure. The resulting wet cake was washed with 40 ml of 2-pentanone and dried at 40°C ~ 45°C under reduced pressure to give 56.9 g of cilostazol sulfate (yield: 90%).

[48] 56.9 g of cilostazol sulfate and 9.8 g of sodium hydroxide were added under stirring to the mixed solvent of 700 ml of chloroform and 175 ml of water. The organic layer was separated and concentrated under reduced pressure to remove an organic solvent. 250 ml of ethanol was added to the resulting residue, which was stirred for about 2 hours, filtered, and then dried at 40°C ~ 45°C under reduced pressure to give 45 g of cilostazol (yield: 100%).

[49] Example 10

[50] 15.9 g of sulfuric acid was added to the solution of 50 g of crude cilostazol in 200 ml of tetrahydrofuran. The reaction mixture was stirred at 20°C ~ 25°C for 3 hours and then filtered under reduced pressure. The resulting wet cake was washed with 40 ml of tetrahydrofuran and dried at 40°C ~ 45°C under reduced pressure to give 56.9 g of cilostazol sulfate (yield: 90%).

[51] 56.9 g of cilostazol sulfate and 9.8 g of sodium hydroxide were added under stirring to the mixed solvent of 700 ml of chloroform and 175 ml of water. The organic layer was separated and concentrated under reduced pressure to remove an organic solvent. 250 ml of ethanol was added to the resulting residue, which was stirred for about 2 hours, filtered, and then dried at 40°C ~ 45°C under reduced pressure to give 44.5 g of cilostazol (yield: 98.9%).

[52] Comparative Example

[53] 10 g of crude cilostazol was dissolved in 150 ml of 95% ethanol at 20°C ~ 25°C.

The reaction mixture were slowly cooled and filtered under reduced pressure. The resulting precipitate was washed with 20 ml of ethanol and then dried at 40°C ~ 45°C under reduced pressure to give 8.8 g of cilostazol.

[54] Test Example

[55] The cilostazols prepared according to Preparation Example, Examples 1 - 10 and

Comparative Example were analyzed by HPLC to determine the contents of impurities, i.e., 6-[4-(l-cyclohexyl-lH-tetrazol-5-yl)-butoxy] -

1 - [4-( 1 -cyclohexyl- 1 H-tetrazol-5-yl)-butyl] -3 ,4-dihydro- 1 H-quinolin-2-one (Impurity A), 6-[4-(l-cyclohexyl-lH-tetrazol-5-yl)-butoxy]-lH-quinolin-2-one (Impurity B), and unknown impurities. The results of HPLC analysis are summarized in Table 1.

[56] Table 1

[57] - : not detected [58] As shown above, according to the process of the present invention, cilostazol of high purity (> 99.80%) can be obtained.

Claims

[1] A process for preparing cilostazol, the process comprising:

(a) adding crude cilostazol to an acid selected from the group consisting of oxalic acid, maleic acid, sulfuric acid, and a mixture thereof to form a cilostazol salt; and

(b) recovering cilostazol through adding a base to the cilostazol salt.

[2] The process of claim 1, wherein the step (a) is carried out in an organic solvent selected from the group consisting of tetrahydrofuran, acetone, methyl ethyl ketone, 2-pentanone, ethyl acetate, methyl acetate, isopropyl acetate, and a mixture thereof.

[3] The process of claim 1, wherein the amount of the acid is about 1 ~ 3 eq. to 1 eq. of the crude cilostazol.

[4] The process of claim 1, wherein the base is triethylamine, sodium hydroxide, or potassium hydroxide.