SK2992003A3 - Processes for preparing cilostazol - Google Patents

Abstract

The present invention provides processes for preparing cilostazol and processes for purifying cilostazol by recystallization.

Description

Technical field

The present invention relates to processes for the preparation of cilostazol.

BACKGROUND OF THE INVENTION

The present invention relates to processes for the preparation of 6- (4- (1-cyclohexyl-1H-tetrazol-5-yl) butoxy] -3,4-dihydro-2 (1H) quinolinone of formula (I)

also known under the generic name cilostazol. Cilostazol prevents platelet aggregation and is used to treat patients with intermittent curvature (intermittent claudication).

Cilostazol is described in U.S. Patent 4,277,479 ("Patent 479), which describes a preparation wherein the phenol group of 6-hydroxy-3,4-dihydroquinolinone (" 6-HQ) of formula (II) is alkylated with 1-cyclohexyl- 5- (4-halobutyl) -tetrazole ("tetrazole) of formula (III). It is recommended to use an equimolar amount or an amount exceeding two molar equivalents of tetrazole (III).

"Patent 479 discloses a wide variety of bases that can be used to support the alkylation reaction, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, silver carbonate, atomic sodium, atomic potassium, sodium methylate, sodium ethylate, triethylamine, pyridine, Ν, Ν-dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, 1,5-diazobicyclo [4.3.0] non-5-ene, 1,5-diazebicyclo [5, 4,0] -undec-7-ene (DBU) and 1,4-diazabicyclo [2.2.2] octane.

"Patent 479 discloses that alkylation can be conducted as pure or in a solvent. Suitable solvents include methanol, ethanol, propanol, butanol, ethylene glycol, dimethyl ether, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, benzene, toluene, xylene, methyl acetate, ethyl acetate, Ν, Ν-dimethylformamide, dimethylsulfoxide and hexamethylphosphoryl triamide.

According to Examples 4 and 26 of "Patent 479, cilostazol was prepared using DBU as the base and ethanol as the solvent.

In Nishi T. et al. Chem. Parm. Bull. 1983, 31, 1151-57 describes the preparation of cilostazol in which 6-HQ is reacted with 1,2 molar 5- (4-chlorobutyl) -1-cyclohexyl-1H-tetrazole ("CHCBT, tetrazole III, wherein X = C1") ) in isopropanol with sodium hydroxide as the base. The yield of cilostazol was 74%.

One reason for using excess tetrazole, as was the case with Nishi et al. and as recommended in the '479 patent, the CHCBT is unstable in some principles. When exposed to an alkali metal hydroxide for a sufficient period of time, CHCBT undergoes elimination and cyclization to produce by-products (IV) and (V).

The yield reported by Nishi et al. is based on the 6-HQ limiting reagent. The yield with respect to CHCBT is 69%. From an economic point of view, chemical production on a large scale results in improvements in chemical yield resulting in cost savings in chemical production. CHCBT is an expensive compound and should not be wasted. It is therefore highly desirable to make further improvements in the yield of alkylation of 6-HQ by CHCBT and its halogen analogs so as to reduce the cost of manufacturing cilostazol. In other words, it would be desirable to further improve the yield of cilostazol by increasing the degree of conversion of CHCBT to cilostazole as opposed to, for example, improving yield calculated on the basis of 6-HQ by increasing excess tetrazole or manipulating reaction conditions by increasing the conversion of 6-HQ to cilostazol. at the expense of impaired conversion of CHCBT to cilostazol.

Although CHCBT is unstable in the presence of hydroxyl ions, it is relatively stable in the presence of non-nucleophilic organic bases. This is an advantage over the use of inorganic bases, but the choice nevertheless tends to be inorganic bases. In particular, the phenol proton in 6-HQ is labile. Thus, they can be used to prepare cilostazol; relatively incoherent and easy to use inorganic bases. Furthermore, inorganic bases are easier to separate from products and are less toxic to the environment than organic bases. Therefore, it would also be highly desirable to use an inorganic principle to improve the conversion of CHCBT to cilostazol.

SUMMARY OF THE INVENTION

The present invention provides improved processes for the preparation of cilostazol (I) by alkylation of the 6-HQ δ phenol group with carbon

5- (4-halobutyl) -1-cyclohexyl-lH-tetrazole.

In a first embodiment, the present invention provides a process wherein 6-HQ and a water-soluble base are dissolved in water. 1-Cyclohexyl-5- (4-halobutyl) -tetrazole is dissolved in a water-immiscible organic solvent. The two solutions are combined in the presence of a quaternary ammonium salt as a phase transfer catalyst to form a biphasic mixture in which 6-HQ and tetrazole react to form cilostazol. The process may be carried out by the various processes set forth in this invention. In one variation, an activator, such as sodium sulfate, is added to accelerate the phase transfer of 6-HQ to the organic solvent.

A further embodiment of the present invention provides the preparation of cilostazol from a one-phase reaction mixture of 6-HQ and 1-cyclohexyl-5- (4-halobutyl) -tetrazole and a mixture of inorganic bases. The base mixture comprises alkali metal hydroxides and carbonates. This procedure minimizes the decomposition of both the starting tetrazole and cilostazol by pH buffering, resulting in an improvement in the yield calculated on the basis of tetrazole, the more expensive of the two organic starting materials. A preferred arrangement in which alkali metal hydroxide is added in portions minimizes the formation of dimeric by-products. In another preferred embodiment according to a homogeneous process, the reaction mixture is dehydrated on a molecular sieve prior to the addition of tetrazole.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for the preparation of cilostazol (I) by alkylation of the phenol group 6-HQ δ with carbon of 5- (4-halobutyl) 1-cyclohexyl-1H-tetrazole ("tetrazole). The transformation itself described in Scheme 1 is known.

Scheme 1

The present invention improves from all processes previously used for the chemical transformation described in Scheme 1, those which lead to a greater conversion of the starting tetrazole to cilostazol. These improvements can be viewed in terms of two main aspects (embodiments) of the present invention: (1) a heterogeneous or biphasic process utilizing phase transfer catalysis and enhancements applicable to a heterogeneous process; and (2) enhancements applicable to a homogeneous process.

In a first embodiment, the present invention provides a process for preparing cilostazol by alkylating the phenol group 6-HQ with 5- (4-halobutyl) -1-cyclohexyl-1H-tetrazole in two phases using a controlled phase transfer methodology. Regarding the discussion of theory and general use of phase catalysis i

transmission, see Dehmlow E.V., Dehmlow S.S., Phase Transfer Catalysis (VCH Publishers: New York 1993).

According to the method of the invention, a solution of 6-HQ, a water-soluble base and a trialkyl ammonium phase transfer catalyst in water is in contact with a solution of 5- (4-halobutyl) -1-cyclohexyl-ΙΗ-tetrazole in a water-immiscible organic solvent for sufficient time to that tetrazole is substantially completely converted to cilostazol and then cilostazol is separated from the biphasic mixture.

The biphasic reaction mixture separates the base from tetrazole, which is sensitive to the base. Although not supported by any particular theory, it is believed that the phenol anion 6-HQ forms a complex with the tetraalkyl ammonium ion, which increases its solubility in a water-immiscible solvent. The complex phenolate then enters the water-immiscible phase and reacts here with tetrazole.

Suitable phase transfer catalysts are ammonium salts such as tricycrylmethylammonium chloride (Alquat ^e 336), tetra-n-butylammonium bromide ("TBAB"), benzyltriethylammonium chloride ("TEBA"), cetyltrimethylammonium bromide, tetraethylpyridinium bromide, tetra-n-butylammonium iodide, tetraethylammonium chloride, benzyltributylammonium bromide, benzyltriethylammonium bromide, hexadecyltriethylammonium chloride and octyltrimethylammonium chloride. More preferred phase transfer catalysts are Aliquat 336, TBAB, TEBA and mixtures thereof, most preferred is Aliquat ® 336. Phase transfer catalysts may be used in a stoichiometric or substoichiometric amount, preferably from about 0.05 to about 0.25 eq. calculated by tetrazole.

Suitable bases are water soluble and not well soluble or insoluble in water-immiscible organic solvents. These bases are usually metal salts of inorganic counterions. Preferred inorganic bases are alkali metal hydroxides and carbonates. More preferred inorganic bases are NaOH, KOH, K ₂ CO ₃ , Na ₂ CO _3, and NaHCO ₃ . The most preferred inorganic base in heterogeneous processes is NaOH.

The halogen atom in 5- (4-halobutyl) -1-cyclohexyl-1H-tetrazole (X in formula III) may be chlorine, bromine or iodine, preferably chlorine. Although tetrazole can be used in any amount, it is desirable to use a stoichiometric amount or less with respect to 6-HQ, preferably about 0.9 mol.

Preferred water-immiscible solvents are toluene, hexanes, dichloromethane and mixtures thereof. The ratio of water to water-immiscible solvent may vary, but an excess of water is preferred, that is, the ratio of water to water-immiscible solvent ranges from about 0.5: 1 to about 8: 1 (v / v), more preferably from about 1: 1. : 1 to about 6: 1.

According to one preferred method for the preparation of cilostazole, the 6-HQ, the water-soluble base and the phase transfer catalyst are dissolved in water. Tetrazole is dissolved in a water-insoluble solvent and the two solutions are in contact, mixed, and can be heated until the tetrazole is substantially consumed. Cilostazol can be isolated by cooling the reaction mixture, precipitating cilostazol and then filtering or decanting the solutions. Cilostazol can be purified by the methods listed in Table 1 or by any conventional methods known in the art.

Alternatively, the biphasic mixture of an organic solvent and an aqueous solution of 6-HQ, a water-soluble base and a phase transfer catalyst is mixed and may be heated while tetrazole is slowly added to the stirred mixture. The slow addition of tetrazole may be either continuous or in portions.

In another alternative method, the aqueous suspension of 6-HQ and the phase transfer catalyst is in contact with a solution of tetrazole in an organic solvent with water immiscible. The biphasic mixture is stirred and may be heated while the water-soluble base is slowly added. This slow addition can again be either continuous or in portions.

Each of these preferred methods can be changed to be further improved, for example by adding a reaction activator to the aqueous phase. Reaction activators are salts, such as sodium sulfate and potassium sulfate, which increase the ionic strength of aqueous solutions but do not form strongly acidic or strongly basic aqueous solutions. Reactive activators reduce the solubility of 6-HQ in the aqueous phase and improve the efficiency of phase transfer into the organic phase. A preferred reaction activator is sodium sulfate. Preferably, the reaction activators are added in an amount of about 12 to 16% (w / v) based on the aqueous phase.

In a second embodiment, the present invention provides a process for preparing cilostazole by alkylating the phenol group with 6-HQ with 5- (4-halobutyl) -1-cyclohexyl-1H-tetrazole in one liquid phase reaction mixture. 6-HQ and tetrazole can be used in any amount, although it is preferred that the limiting reagent be tetrazole, preferably used in an amount of from about 0.9 to about 0.99 eq. with respect to 6-HQ. Suitable solvents for the formation of a single liquid phase reaction mixture in this embodiment of the invention are non-aqueous hydroxyl solvents, including 1-butanol, isopropanol, 2-butanol and amyl alcohol.

In this process, two inorganic bases are used to catalyze the reaction. One is an alkali metal hydroxide such as sodium or potassium hydroxide. The second base is an alkali metal carbonate such as sodium or potassium carbonate. The most preferred alkali metal is potassium. Thus, a preferred mixture of bases is a mixture of potassium hydroxide and potassium carbonate. The alkali metal hydroxide is preferably used in an amount of from about 0.9 to about 1.2 eq. relative to 6-HQ and the alkali metal carbonate is preferably used in an amount of from about 0.1 to about 0.2 eq. with respect to 6-HQ.

The 6-HQ, tetrazole, alkali metal hydroxide and carbonate may be added to the non-aqueous solvent in any desired order and in any desired amount.

In one suitable method, 6-HQ, tetrazole and an alkali metal carbonate are added to the hydroxyl solvent along with a portion, for example a quarter, of the alkali metal hydroxide. The remaining alkali metal hydroxide is then added portionwise to the reaction mixture. It has been found that the addition of alkali metal hydroxide in portions suppresses by-products that are formed by halogen substitution in tetrazole with 6-HQ lactam nitrogen.

Molecular sieves may be used to remove water from the liquid phase of the reaction mixture prior to the addition of tetrazole. Three and four angstrom sieves are preferred, most preferably three angstrom sieves. The molecular sieves may be mixed with the solution to remove the water formed by deprotonation with 6-HQ potassium hydroxide or accidentally formed water. Preferably, the molecular sieve is placed in a soxlet extraction funnel, a dropping funnel container, or other suitable apparatus mounted on the reaction vessel that allows the water lip to circulate through the molecular sieve and return condensate to the reaction vessel. The solution is then heated under reflux to allow water vapor to circulate through the molecular sieve. After the 6-HQ solution is dewatered, tetrazole is added to the solution to react with the 6-HQ phenolate to form cilostazol.

In the procedure of Nishi et al. it was necessary to separate unreacted starting materials and organic bases by column chromatography. On an operating scale, it is desirable to avoid chromatography and co-production of solid waste. We have further discovered that cilostazol prepared according to the invention or by other methods can selectively crystallize from certain solvents in high purity without the need for "purification by chromatography to remove, for example, unreacted starting materials.

acetone, methyl t-butyl ether, aqueous dimethylacetamide, THF, methanol, isopropanol, benzyl alcohol, 2-pyrrolidone, acetonitrile, Cellosolve, isobutyl acetate, sec-butanol, tert-butanol, DMF, chloroform, diethyl ether and mixtures thereof.

Suitable recrystallization toluene, methyl ethyl ketone, solvents are 1-butanol, dichloromethane, ethyl acetate,

The invention will be further illustrated by the following examples.

EXAMPLES

Example 1

Preparation of Cilostazol Using Phase Transfer Catalyst

The L reactor was charged with 6-HQ (16.5 g, 0.1011 mol) and NaOH (1 eq.) In water (90 mL). To this solution was added toluene (15 mL) and CHCBT (22.22 g, 0.0915 mol), Na ₂ SO ₄ (17 g), and catalyst (1.9 g) (aliquat 336). The mixture was heated to reflux for 5 h. After cooling to room temperature, the solid was filtered and washed with water and methanol to give the crude product (29 g, yield 88%; purity by HPLC -99%).

Example 2

Preparation of Cilostazol with Addition of CHCBT Suddenly

6-HQ (10 g, 0.0613 mol), KOH (4.05 g, 0.0722 mol), K ₂ CO ₃ (1.5 g, 0.011 mol), CHCBT (18 g, 0.0742 mol) and n-BuOH (130 mL) was heated at reflux for about 5 hours. After cooling the reaction mixture to room temperature, the solid was filtered and washed with n-BuOH and water. The crude product (19.7 g, 85% yield) was recrystallized from n-BuOH (10 vol.) To give cilostazole crystals (94% yield).

Example 3

Preparation of Cilostazol with Addition of CHCBT in Portions

6-HQ (10 g, 0.0613 mol), KOH (1.01 g, 0.018 mol), K ₂ CO ₃ (1.5 g, 0.011 mol), CHCBT (13.4 g, 0.0752 mol) and n-BuOH (130 mL) was heated at reflux for about 1 hour. After 1 hour a second 1.1 g portion of KOH was added and reflux was continued. The procedure was repeated with another two 1.1 g portions of KOH. After all KOH was added, the reaction was continued for an additional hour. The reaction mixture was cooled to room temperature, the solid was filtered, washed with nBuOH and dried to give the product (15.6 g, 56% yield).

s

Example 4

Preparation of Cilostazol Using Molecular Networks as a

Dehydrating Agent

A 3-necked flask equipped with a condenser and a soxlet extraction funnel containing 3A molecular sieves (28 g) was charged with 6HQ (10 g, 0.0613 mol), KOH (4.05 g, 0.0722 mol) and K ₂ CO ₃ (1.5 g, 0.011 mol) and 130 ml of n-BuOH. The mixture was heated to reflux and the reflux of the solvent was passed through a molecular sieve. After 30 minutes, CHCBT (18 g, 0.0742 mol, 1.2 eq) was added and heating was continued for about 5 h. Then the reaction mixture was cooled and the product was filtered and washed with n-BuOH. The yield after drying was 14.4 g (62%).

Example 5

Preparation of Cilostazol Using Excess 6-HQ

6-HQ (10 g, 0.0613 mol), KOH (4.05 g, 0.0722 mol), K ₂ CO ₃ (1.5 g, 0.011 mol), CHCBT (13.4 g, 0.0555) mol) and 130 ml of n-BuOH were heated under reflux for 5 hours. After cooling the reaction mixture to room temperature, the solid was filtered and washed with n-BuOH and water and dried to give the product cilostazole (15.93 g, 76.2% yield).

Examples 6-28

Table 1 provides data for the selective crystallization of cilostazole from mixtures containing minor amounts of 6-HQ and CHCBT. The obtained cilostazol has small particle sizes and a narrow particle size distribution. '

Table 1

Example Solvent Volume * Recommended Procedure

6 7 8 n-BuOH n-BuOH acetone 10 20 20 Suspension. ** reflux. Cool to 9 toluene 20 t .m. dissolve at re fluxe . cool 10 Methyl ethyl ketone 11 na t.m. dissolve at reflux . cool 11 CH ₂ Cl ₂ 4 na t.m. dissolve at reflux . cool 12 ethyl acetate 10 na t.m. suspension at reflux lh.

Cool to r.t.

13 MTBE 10 Suspension at reflux 1h. Cool to r.t. 14 2: 1 DMA-H2O 10 Dissolve in DMA at 70-80 ° C. Add water. Cool to r.t. Precipitate at 65 ° C. 15 THF 13 Dissolve at reflux. cool na t.m. 16 methanol 3 Dissolve at reflux. cool na t.m. 17 acetone 2.5 Suspension at reflux 1h. Cool to r.t. 18 ethanol 12.5 Dissolve at reflux. cool na t.m. 19 isopropanol 19 Dissolve at reflux. cool na t.m. 20 acetone 33 Dissolve at reflux. cool at 40 ° C. 21 benzyl alcohol 2 Dissolve at 55 ° C. Cool to

t .m. 22 2-pyrrolidone 3.5 Dissolve at 65 ° C. Cool to t .m. 23 acetonitrile 6.5 Dissolve at reflux. cool at 30 ° C. 24 2-BuOH 5 Dissolve at ~ 90 ° C. Cool to t .m. 25 cellosolve 3 Dissolve at -100 ° C. Cool to t .m. 26 monoglyme 13 Dissolve at reflux. cool na t. m. 27 isobutyl 23 Dissolve at reflux (115 ° C). Cool to r.t. 28 n-BuOH 20 Dissolve at reflux. process with bleaches, (SX1 active coal and tonsil silicate). cool on r.t. '

based on the volume of cilostazol

Reflux - Heating (reflux)

It should be understood that some changes and replacements are envisaged and expected by those skilled in the art without departing from the scope of the invention. In this regard, it is well within the scope of the following claims to be conceived in a broader manner and in a manner consistent with the spirit and scope of the invention.

Cellosolve (2-ethoxyethanol)

Monoglyme (ethylene glycol dimethyl ether)

Claims (30)

PATENT 1. A process for the preparation of cilostazol comprising: (a) dissolving 6-hydroxy-3,4-dihydroquinoline and a water-soluble base in water to form an aqueous phase; b) dissolving 1-cyclohexyl-5- (4-halobutyl) -tetrazole in a water-immiscible solvent to form an organic phase, c) forming a biphasic mixture by combining the aqueous phase and the organic phase in the presence of quaternary ammonium as a phase transfer catalyst, d) isolating cilostazol from the biphasic mixture. 2. The process of claim 1 wherein the molar amount of 6-hydroxy-3,4-dihydroquinoline is greater than the molar amount of 1-cyclohexyl-5- (4-halobutyl) tetrazole. The solvent-containing process according to claim 1, characterized by being immiscible with water, is selected from toluene, hexane, dichloromethane and from the group of mixtures thereof. The process according to claim 1, wherein the quaternary ammonium phase transfer catalyst is selected from the group consisting of tricycrylmethylammonium chloride, tetra-butylammonium bromide, benzyltriethylammonium chloride, cetyltrimethylammonium bromide, cetylpyridinium bromide, nbenzamide, nbenzamide, butylammonium iodide, tetraethylammonium chloride, benzyltributylammonium bromide, benzyltriethylammonium bromide, hexadecyltriethylammonium chloride, tetramethylammonium chloride, hexadecyltrimethylammonium chloride and octyltrimethylammonium chloride. The process according to claim 4, wherein the quaternary ammonium phase transfer catalyst is selected from the group consisting of tricycrylmethylammonium chloride, tetrabutylammonium bromide, triethylbenzylammonium bromide and mixtures thereof. The process according to claim 5, characterized in that the quaternary ammonium phase transfer catalyst is tricycrylmethylammonium chloride. 7. The process of claim 1 wherein the water-soluble base is an alkali metal hydroxide, carbonate or bicarbonate. The process according to claim 7, wherein the water-soluble base is selected from the group consisting of NaOH, KOH, K ₂ CO ₃ , Na ₂ CO ₃ and NaHCO ₃ . The method of claim 7, wherein the water-soluble base is NaOH. 10. The process of claim 1 further comprising dissolving a reactive activator selected from the group consisting of potassium carbonate and sodium sulfate in water. 11. The process of claim 1 wherein 1-cyclohexyl-5- (4-halobutyl) -tetrazole is 1-cyclohexyl-5- (4-chlorobutyl) -tetrazole. 12. A process for the preparation of cilostazol comprising: a) adding 6-hydroxy-3,4-dihydroquinoline, 1-cyclohexyl-5- (4-halobutyl) -tetrazole, about 0.9 to about 1.2 equivalents relative to the alkali metal dihydroquinoline dihydroquinoline, and about 0.1 to about 0, 2 equivalents relative to an alkali metal carbonate dihydroquinoline to a non-aqueous hydroxyl solvent to form a reaction mixture; and b) isolating cilostazol from the reaction mixture. The method of claim 12, wherein about 0.9 to about 1.2 equivalents of the alkali metal hydroxide is added at once. 14. The process of claim 12, wherein a first portion of the alkali metal hydroxide is added and, after the addition of 6-hydroxy-3,4-dihydroquinoline, 1-cyclohexyl-5- (4-halobutyl) tetrazole and the alkali metal carbonate, a second portion alkali metal hydroxide. 15. The method of claim 14, further comprising adding a third portion of the alkali metal hydroxide after the second portion. 16. The process of claim 12 wherein the non-aqueous hydroxyl solvent is selected from the group consisting of 1-butanol, 2-butanol and amyl alcohol. 17. The process of claim 16 wherein the non-aqueous hydroxyl solvent is 1-butanol. The process of claim 12, wherein the alkali metal hydroxide is potassium hydroxide and the alkali metal carbonate is potassium carbonate. 19. The process of claim 12 wherein the molar amount of 6-hydroxy-3,4-dihydroquinoline is greater than the molar amount of 1-cyclohexyl-5- (4-halobutyl) tetrazole. 20. The process of claim 12 wherein the molar amount of 1-cyclohexyl-5- (4-halobutyl) tetrazole is greater than the molar amount of 6-hydroxy-3,4-dihydroquinoline. 21. The method of claim 12, further comprising removing the water resulting from the combination of 6-hydroxy-3,4-dihydroquinoline and the alkali metal in the hydroxyl solvent by molecular sieves. 22. The process of claim 12 wherein the 1-cyclohexyl-5- (4-halobutyl) tetrazole is 1-cyclohexyl-5- (4-chlorobutyl) tetrazole. 23. A process for preparing cilostazol comprising dissolving 6-hydroxy-3,4-dihydroquinoline in a non-aqueous solvent, activating the phenol group of 6-hydroxy-3,4-dihydroquinoline with an alkali metal hydroxide to form the 6-hydroxy-3,4-dihydroquinoline phenolate removing the water formed as a byproduct of phenol activation from the solution by molecular sieves followed by the addition of 1-cyclohexyl-5- (4-halobutyl) tetrazole and isolating cilostazol from the reaction mixture. The method of claim 23, wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide. 25. The method of claim 23 wherein the non-aqueous solvent is selected from the group consisting of butanol, toluene, hexane, dichloromethane, and mixtures thereof. 26. The process of claim 12 wherein the 1-cyclohexyl-5- (4-halobutyl) -tetrazole is 1-cyclohexyl-5- (4-chlorobutyl) -tetrazole. A method of purifying cilostazol by recrystallization from a solvent selected from the group consisting of 1-butanol, acetone, toluene, methyl ethyl ketone, dichloromethane, ethyl acetate, methyl t-butyl ether, an aqueous mixture. dimethylacetamide, THF, methanol, isopropanol, benzyl alcohol, 2-pyrrolidone, acetonitrile, 2-ethoxyethanol, ethylene glycol dimethyl ether, isobutyl acetate, sec-butanol, tert-butanol, DMF, chloroform, diethyl ether and mixtures thereof. 28. Very pure cilostazol characterized in that it is free of impurities. 29. Micronized cilostazol characterized by a small particle size and a narrow particle size distribution. A very pure cilostazol characterized in that it is prepared by a process according to any one of claims 1, 12 and 23.