MXPA03001470A - Processes for preparing cilostazol. - Google Patents

Abstract

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

Description

PROCESSES TO PREPARE CILOSTAZOLE FIELD OF THE INVENTION The present invention relates to processes for preparing cilostazol.

BACKGROUND OF THE INVENTION The present invention relates to processes for preparing (l-cyclohexyl-lH-tetrazol-5-yl) butoxy] -3,4-dihydro-2 (1H) -quinolinone of the formula (1) which is also known by the generic name cilostazol. Cilostazol inhibits platelet aggregation and is used to treat patients with intermittent claudication.

Cilostazol is described in U.S. Patent No. 4,277,479 (the '79 patent), which teaches a preparation wherein the phenol group of 6-hydroxy-3,4-dihydroquinolinone ("6-HQ") of the formula ( II) is alkylated with -cyclohexyl-5- (4-halobutyl) -tetrazole ("tetrazole") of the form mule (III). It is recommended to use an equimolar or surplus amount up to two molar equivalents of the formula (III) The 79 patent mentions a wide variety of bases that can be used to promote the alkylation reaction, namely, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, silver carbonate, elemental sodium, elemental potassium, sodium methylate, sodium ethylate, triethylamine, pyridine, N, N-dimethylaniline, N -methylmorpholine, 4-dimethylaminopyridine, 1,5-diaza-bicyclo [4.3.0] - ??? -5-ene, 1, 5 -diaza-bicyclo [5,4,0] -undec-7-ene ("DBU"), and 1,4-diazabicyclo [2, 2, 2] octane.

The 79 patent says that the alkylation can be carried out pure or in a solvent. The suitable solvents are said to be methanol, ethanol, propanol, butanol, ethylene glycol, dimethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, acetone, methyl ethyl ketone, benzene, toluene, xylene, methyl acetate, ethyl acetate, N, N -dimethylformamide, dimethyl sulfoxide and hexamethylphosphoryl triamide.

According to Examples 4 and 26 of the 79 patent, cilostazol was prepared using DBU as a base and ethanol as solvent.

In Nishi, T. et al. Chem. Pharm. Bull. 1983, 31, 1151-57, a cilostazol preparation is described wherein 6-HQ reacts with 1.2 molar equivalents of 5- (4-chlorobutyl) -1-cyclohexyl-1H-tetrazole ("CHCBT", tetrazole III in where X = C1) in isopropanol with potassium hydroxide as a base. Cilostazol was obtained with a yield of 74%.

One of the reasons for using an excess of tetrazol as was done in Nishi et al and as recommended by the 1479 patent, is that CHCBT is unstable to some bases. When exposed to an alkali metal hydroxide in water for a sufficient period CHCBT passes through elimination and cyclization to give byproducts (IV) and (V) t The performance reported by Nishi et al is based on the limiting reagent 6 -HQ. The yield with respect to CHCBT is 69%. In the production economy of a chemical compound on a large scale, the improvements in the yield of the chemical compound are rewarded with savings in the production cost of the chemical compound. CHCBT is an expensive compound to prepare and should not be wasted. It would be desirable to be able to note other improvements in the performance of 6-HQ alkylation with CHCBT and its analogous halogens so as to lower the cost of production of cilostazol. In other words, it would be desirable to further improve the performance of cilostazol by increasing the degree of conversion of CHCBT to cilostazol, contrary to, for example, improving the yield calculated from 6-HQ by increasing the excess of tetrazole or by manipulating the reaction conditions. so as to increase the conversion of 6-HQ into cilostazol but at the expense of a poorer conversion of CHCBT to cilostazol. Although CHCBT is unstable to the hydroxide ion, it is relatively stable in the presence of non-nucleophilic organic bases. There are advantages to using inorganic bases, however, that 1 favor their selection with respect to the organic bases. First, the 6-HQ phenolic proton is labile. Therefore, relatively caustic and non-caustic inorganic bases can be used to prepare cilostazol. In addition, inorganic bases are easier to separate from the product and less toxic to the environment when discarded than organic bases. Accordingly, it would be very desirable to use an inorganic base while improving the conversion of CHCBT to cilostazol.

EXTRACT OF THE INVENTION The present invention provides improved processes for preparing cilostazol (I) by alkylating the phenol group of 6-HQ with the carbon d of a 5- (4-halobutyl) -1-cyclohexyl-1H-tetrazole.

In a first aspect, the invention provides a process wherein 6 -HQ and a water soluble base are dissolved in water. A 1-cyclohexyl-5- (5-halobutyl) -tetrazole is dissolved in an organic solvent immiscible with water. The two solutions are combined in the presence of a quaternary ammonium salt phase transfer catalyst to form a biphasic mixture in which 6-HQ and tetrazole react to produce cilostazol. The t. The process can be practiced by a variety of methods taught by the present invention. In one variation, a reaction promoter, such as sodium sulfate, is added to accelerate the transfer of 6-HQ phase into the organic solvent.

Another aspect of the present invention provides a cilostazol preparation from a mixture of the single-phase reaction of 6-HQ and a 1-cyclohexyl-5- (4-halobutyl) -tetrazole and a mixture of inorganic bases. The base mixture comprises an alkali metal hydroxide and an alkali metal carbonate. This process minimizes the decomposition of tetrazole and initial cilostazol is regulating the pH which results in an improved yield calculated based on tetrazole, the most precious of the two initial organic materials. A preferred embodiment wherein the alkali metal hydroxide is added in portions minimizes the formation of money byproducts. In another preferred embodiment of the homogeneous process, the reaction mixture is dehydrated with molecular sieves before adding the tetrazole.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a process for preparing cilostazol (I) by alkylation of the phenol group of 6-HQ with the carbon d of a 5- (5-halobutyl) -1-cyclohexyl-1H-tetrazole ("tetrazole"). "). The transformation itself, illustrated in Scheme 1, is known.

Scheme 1 The present invention improves processes previously used to perform the chemical transformation illustrated in Scheme 1 that result in a greater conversion of the initial tetrazole material into cilostazol. It can be seen that the improvements are in one of the two aspects of the present invention: (1) a heterogeneous, or two-phase process, which employs phase transfer catalysts and improvements applicable to the heterogeneous process and (2) improvements applicable to a process homogeneous.

In a first aspect, the present invention provides a biphasic process for preparing cilostazol by alkylation of the phenol group of 6-HQ with a 5- (4-butylbutyl) -1-cyclohexyl-1H-tetrazole using the phase transfer methodology controlled For a discussion of the theory and general application of phase transfer catalysts, see Dehmlow, E.V. Dehmlow, S.S., Phase Transfer Catalysts 3rd edition. (VCH Publishers: New York 1993).

According to the process of the present invention, a 6-HQ solution, a water-soluble base and a trialkyl ammonium phase transfer catalyst in water is contacted with a solution of 5- (4-halobutyl) - 1-cyclohexyl-lH-tetrazole in an organic solvent immiscible with water for a period of time sufficient to cause the tetrazole to become substantially complete in cilostazol and then the cilostazol is separated from the biphasic mixture.

The biphasic reaction mixture separates the base form of the tetrazole sensitive to the base. Although we do not intend to tie ourselves to any particular theory, we believe that the 6-HQ phenolate anion forms a complex with the tetra-alkyl ammonium ion that increases its solubility in the water-immiscible organic solvent. The phenolate that formed the complex then enters the phase immiscible with water and reacts with the tetrazole that is there.

Suitable phase transfer catalysts are ammonium salts such as tricaprylmethylammonium chloride (Aliquat ® 336), tetra-n-butylammonium bromide ("TBAB"), benzyltriethylammonium chloride ("????"), cetyltrimethylammonium bromide, cetylpyridinium bromide, N -benzylquininium chloride, tetra-n-butylammonium chloride, hydroxide of tetra-n-butylammonium, tetra-n-butylammonium iodide, tetra-ethyl ammonium chloride, benzyltributylammonium bromide, benzyltriethylammonium bromide, hexadecyltriethylammonium chloride, tetramethylammonium chloride, hexadecyltrimethyl ammonium chloride, and octyltrimethylammonium chloride. More preferred phase transfer catalysts are Aliquat® 336, TBAB, TEBA, and mixtures thereof, the most preferred is Aliquat® 336. The phase transfer catalyst can be used in a stoichiometric or substoichiometric amount, preferably 0.05. at 0.25 equivalent with respect to tetrazole.

Suitable bases are soluble in water but poorly soluble or insoluble in organic solvents that are impervious to water. Such bases are typically metal salts of inorganic counter ions. Preferred inorganic bases are alkali metal hydroxide and carbonate salts. More preferred inorganic bases are NaOH, KOH, K 2 CO 3, Na 2 CO 3 and NaHCO 3. The most preferred inorganic base in the heterogeneous process is NaOH.

The halogen atom of 5- (4-halobutyl) -1-cyclohexyl-1H-tetrazole (X in formula III) can be chlorine, bromine or iodine, preferably chlorine. Although tetrazole can be used in any desired amount, it is most desirable to use a stoichiometric amount of tetrazole or less in relation to 6-HQ, more preferably 0.9-molar equivalent.

Preferred water-immiscible solvents are toluene, hexanes, dichloromethane and mixtures thereof. An excess of water is preferred to the solvent immiscible in water, although the ratio can vary greatly. Preferred water ratios to water-immiscible solvents are in the range of 0.5: 1 to 8: 1 (v / v), more preferably 1: 1 to 6: 1.

According to a preferred process for preparing cilostazol, the 6-HQ, the water-soluble base and the phase transfer catalyst are dissolved in water. The tetrazole is dissolved in the solvent immiscible with water and the two solutions are placed in contact and stirred, with optional heating, until the tetrazole is substantially consumed. The cilostazol can be isolated by cooling the reaction mixture to precipitate the cilostazol and then filtering or decanting the solutions. The cilostazol can be purified by the methods shown in Table 1 or by any conventional method known in the art.

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

In yet another alternative procedure, an aqueous suspension of 6-HQ and the phase transfer catalyst are brought into contact with the tetrazole solution in the water-immiscible organic solvent. The biphasic mixture is stirred and optionally heated, while the water-soluble base is slowly added to the mixture. The slow aggregate can be continuous as in a concentrated aqueous solution of the base or in portions.

Each of these preferred processes can be modified to take advantage of another improvement, which is to add a promoter of the reaction to the aqueous phase. The promoters of the reaction are salts such as sodium sulfate and potassium sulfate which increase the ionic strength of the aqueous solutions but do not form strongly acidic or basic aqueous solutions. The promoters of the reaction decrease the solubility of 6-HQ in the aqueous phase and improve the efficiency of the phase transfer to the organic phase. The preferred reaction promoter is sodium sulfate. Preferably, the reaction promoter is added in the amount of 12% -16% (w / v) with respect to the aqueous phase.

In a second aspect, the present invention provides a process for preparing cilostazol by alkylation of the phenol group of 6-HQ with a 5- (4-halobutyl) -1-cyclohexyl-1H-tetrazole in a reaction mixture of a single liquid phase. 6 '-HQ and tetrazole can be used in any amount, although it is preferred that the tetrazole is the limiting reagent, preferably used from 0.9 to 0.99 equivalent with respect to 6-HQ. Suitable solvents for forming the liquid single phase reaction mixture of this aspect 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 of the bases is an alkali metal hydroxide such as sodium or potassium hydroxide. The other base is an alkali metal carbonate such as sodium or potassium carbonate. The most preferred alkali metal is potassium. Thus, the mixtures of preferred bases are mixtures of potassium hydroxide and potassium carbonate. The alkali metal hydroxide is preferably used in an amount of 0.9 to 1.2 equivalents with respect to the 6-HQ and the alkali metal carbonate is preferably used in an amount of 0.1 to 0.2 equivalent with respect to the 6-HQ.

The 6-HQ, the tetrazole, the alkali metal hydroxide and the alkaline meta-1 carbonate can be added to the non-aqueous solvent in any desired order and at any desired speed.

In a preferred process, 6HQ, tetrazole and alkali metal carbonate are added to the hydroxyl solvent together with a portion, eg. a one-quarter portion of the alkali metal hydroxide. Then, the rest of the alkali metal hydroxide is added in portions to the reaction mixture. It has been found that the portionwise addition of the alkali metal hydroxide removes a byproduct that is formed by the substitution of the halogen of the tetrazole with the nitrogen of the 6-lactam lactate.

Molecular sieves can be used to remove water from the single-phase liquid reaction mixture before adding the tetrazole. Three and four angstrom molecular sieves are preferred, with three angstrom sieves being most preferred. Molecular sieves can be stirred with the solution to remove the water formed by deprotonation of 6-HQ by KOH or adventitious water. Preferably, the molecular sieves are placed in a soxlet extraction funnel, the deposit of a drip funnel, or another suitable apparatus mounted in the reaction vessel that allows the circulation of vapor through the molecular sieves and the regio of the condensate to the reaction vessel. The solution is then refluxed to circulate water vapor over the molecular sieves. After the 6-HQ phenolate solution has been dehydrated, the tetrazole is added to the solution to react with the 6-HQ phenolate to produce cilostazol.

In the Nishi et al process, it was necessary to separate the initial materials that did not react and the organic base by column chromatography. In a large-scale process it is desirable to avoid chromatography and concomitant production of solid phase. We have further discovered that the cilostazol prepared according to the teachings of the present invention or by other methods can be crystallized selectively from certain solvents with high purity without the need for "cleaning" chromatography to remove, for example, the initial materials that did not react . Suitable recrystallization solvents are 1-butanol, acetone, toluene, methyl ethyl ketone, dichloromethane, ethyl acetate, methyl t-butyl ether, mixtures of dimethyl acetamide and water, THF, methanol, isopropanol, benzyl alcohol, 2-pyrrolidone, acetonitrile , Cellosolve, monoglime, isobutyl acetate, sec -butanol, tere -butanol, DMF, chloroform, diethyl ether and mixtures thereof. invention is now illustrated with the following examples EXAMPLES Example 1 Preparation of Cilostazol Using a Phase Transfer Catalyst A 1 liter reactor was charged with 6-HQ (16.5 g, 0.1011 mol) and NaOH (1 equivalent) in water (90 m 1). 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 refluxed for 8 hours. After this period of time, the mixture was cooled to room temperature, the solid was filtered and washed with water and methanol to obtain the crude product (29 g, yield 88%, purity by HPLC 99%).

Example 2 Preparation of Cilostazol with Aggregate of CHCBT in One Portion 6-HQ (10 g, 0.0613 mol), KOH (5.05 g, 0.0722 mol is), K2C03 (1.5 g, 0.011 mol), CHCBT (18 g, 0.0742 mol) and n -BuOH (130 mL) were heated to reflux for 5 hours. After cooling the reaction mixture to room temperature, the solid was filtered, washed with n -BuOH and water. The crude product (19.7 g, 85% yield) was recrystallized from n -BuOH (10 vol.) To give cilostazol crystals (94% yield).

EXAMPLE 3 Preparation of Cilostazol by the Aggregate of the Base in Servings 6-HQ (10 g, 0.0613 mol), KOH (1.01 g, 0.013 mol), K2C03 (1.5 g, 0.011 mol), CHCBT (13.4 g, 0.0552 mol) and 130 ml of n -BuOH were heated to reflux for 1 hour. After 1 hour, a second portion of 1.1 g of KOH was added and the reflux continued. The procedure was repeated with two additional 1.1 g portions of KOH. After adding all the KOH the reaction continued for another hour. The reaction mixture was cooled to room temperature, the solid was filtered and washed with n -BuOH and dried to give the product (15.6 g, 56% yield).

Example 4 Preparation of Cilostazol Using Molecular Sieves as Dehydration Agent A three-necked flask equipped with a condenser and a soxlet extraction funnel containing 3A molecular sieves (28 g) was charged with 6-HQ (10 g, 0.0613 moles), KOH (4.05 g, , 0722 moles) and K 2 CO 3 (1.5 g, 0.011 moles) and 130 ml yn -BuOH. The mixture was heated to reflux and the reflux was maintained by passing the solvent over the molecular sieves. After 30 minutes, CHCBT (18 g, 0.0742 moles, 1.2 equivalents) was added and the reflux continued for 5 hours. 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 an Excess of 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, 0.0552 mol) and 130 ml of n-BuOH were heated to reflux for 5 hours. After cooling the reaction mixture to room temperature, the solid was filtered and washed with n -BuOH and water, the material was dried to give the product cilostazol (15.93 g, 75.2% yield). Examples 6-28 Table 1 provides the conditions for selectively crystallizing cilostazol from mixtures containing minor amounts of 6-HQ and CHCBT. Cilostazol is obtained with a small particle size and a narrow particle size distribution. Table 1 Example Solvent Volume * Recommended Procedure 6 n-BuOH 10 7 n-BuOH 20 8 Acetone 20 Suspension, Reflux, Cool to room temperature Toluene 20 Dissolve at reflux, Cool to room temperature 10 Methyl ethyl 11 Dissolve at reflux, cool ketone at room temperature 11 C¾C12 Dissolve at reflux, Cool at room temperature 12 Acetate 10 Suspension at reflux lh, Cool at temperature Example Solvent Volume * Recommended procedure ambient 13 MTBE 10 Reflux suspension lh, Cool to room temperature 14 2: 1 DMA-H20 10 Dissolve in DMA at 70 ° C-80 ° C Add water. Cool to room temperature. Precipitate at 65 ° C 15 THF 13 Dissolve at reflux. Cool at room temperature 16 Methanol 3 Dissolve at reflux. Cool to room temperature. Precipitate at 55 ° C 17 Acetone 2.5 Suspension at reflux for 1 h. Cool to room temperature 18 Ethanol 12.5 Dissolve at reflux. Cool at room temperature 19 Isopropanol 19 Dissolve at reflux. Cool at room temperature Solvent Volume * Recommended Procedure Acetone 33 Dissolve at reflux. Cool to 40 ° C Alcohol 2 Dissolve at 55 ° C. Cool to benzyl at room temperature 2-Pyrrolidone 3.5 Dissolve at 65 ° C. Cool to room temperature Acetonitrile 6.5 Dissolve at reflux. Cool at 30 ° C 2-BuOH 5 Dissolve at 90 ° C. Cool to room temperature Cellosolve 3 Dissolve at 100 ° C. Cool to room temperature Monoglime 13 Dissolve at reflux. Cool to room temperature iso-Butyl-23 Dissolve at reflux (115 ° C). acetate Cool to room temperature n-BuOH 20 Dissolve at reflux. Treat with bleaching agents, (SSl activated carbon and tonsil silicate). Cool at temperature Example Solvent Volume * Recommended procedure environment. * In relation to the volume of cilostazol It should be understood that some modification, alteration and substitution of the experts in the art is anticipated and expected without departing from the teachings of the invention. Accordingly, it is appropriate that the following claims be interpreted broadly and in a manner consistent with the scope and spirit of the invention.

Claims (30)

1. CLAIMS 1. A process for preparing cilostazol comprising: a) dissolving 6-hydroxy-3, -dihydroquinolinone and a water-soluble base in water to form an aqueous phase; b) dissolving a 1-cyclohexyl-5- (4-halobutyl) -tetrazole in a solvent immiscible with water to form an organic phase, c) forming a biphasic mixture by contacting the aqueous phase and the organic phase in the presence of a Quaternary ammonium phase transfer catalyst, d) and recover cilostazol from the biphasic mixture. 2. The process of claim 1, wherein the molar amount of 6-hydroxy-3,4-dihydroquinolinone is greater than the molar amount of l-cyclohexyl-5- (4-halobutyl) -tetrazole. 3. The process of claim 1, wherein the solvent immiscible with water is selected from the group consisting of toluene, hexane, dichloromethane and mixtures thereof. 4. The process of claim 1, wherein the quaternary ammonium phase transfer catalyst is selected from the group consisting of tricaprylylmethylammonium chloride, tetra-n-butylammonium bromide, benzyltriethallyl chloride, bromide 2 cetyltrimethylammonium, cetylpyridinium bromide, N-benzylquininium chloride, tetra-n-butylammonium chloride, tetra-n-butylammonium hydroxide, tert-butylammonium iodide, tetraethylammonium chloride, benzyltributylammonium bromide, benzyltriethylammonium bromide, hexadecyltriethylammonium chloride, tetramethylammonium chloride, exadecyltrimethyl ammonium chloride, and octyltrimethylammonium chloride. 5. The process of claim 4, wherein the quaternary ammonium phase transfer catalyst is selected from the group consisting of tricaprylmethyl ammonium chloride, tetrabutylammonium bromide, triethylbenzylammonium bromide, and mixtures thereof. 6. The process of claim 5, wherein the quaternary ammonium phase transfer catalyst is tricaprylmethyl ammonium chloride. 7. The process of claim 1, wherein the water-soluble base is an alkali metal hydroxide, carbonate or bicarbonate. 8. The process of 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. 3 9. The process of claim 7, wherein the water-soluble base is NaOH. 10. The process of claim 1, further comprising dissolving a reaction promoter 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 preparing cilostazol comprising: a) adding 6-hydroxy-3,4-dihydroquinolinone, a 1-cyclohexyl-5- (4-halobutyl) -tetrazole, from 0.9 to 1.2 equivalents of a metal hydroxide alkaline with respect to the dihydroquinolinone, and from 0.1 to 0.2 equivalents of an alkali metal carbonate with respect to the dihydroquinolinone to a nonaqueous hydroxylic solvent to form a reaction mixture, and b) recovering cilostazol from the mixture of the reaction. 13. The process of claim 12, wherein from 0.9 to 1.2 equivalents of the alkali metal hydroxide are added in one portion. 4 14. The process of claim 13, wherein the alkali metal hydroxide is added by adding a first portion of the alkali metal hydroxide and after the addition of the 6-hydroxy-3,4-dihydroquinolinone, the 1-cyclohexyl-5- (4- halobutyl) -tetrazole, and the alkali metal carbonate, add a second portion of the alkali metal hydroxide. 15. The process of claim 14, further comprising 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, isopropanol, 2-butanol and amyl alcohol. 17. The process of claim 16, wherein the non-aqueous hydroxyl solvent is 1-butanol. 18. The process of claim 12, wherein the alkali metal hydroxide is potassium hydroxide and the alkali metal carbonate is potassium carbonate. The process of claim 12, wherein the molar amount of S-hydroxy-3,4-dihydroquinolinone is greater than the molar amount of l-cyclohexyl-5- (4-halobutyl) -tetrazole. 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-dihydroquinolinone. 21. The process of claim 12, further comprising removing the water that is formed by the combination of 6-hydroxy-3,4-dihydroquinolinone and the alkali metal and the hydroxylic solvent with molecular sieves. 22. The process of claim 12, wherein 1-cyclohexyl-5- (4-halobutyl) -tetrazole is 1-cyclohexyl-4- (4-chlorobutyl) -tetrazole. 23. A process for preparing cilostazol comprising dissolving 6-hydroxy-3, 4-dihydroquinolinone in a non-aqueous solvent, activating the phenol group of 6-hydroxy-3,4-dihydroquinolinone with an alkali metal hydroxide to form phenol ate of 6 -hydroxy-3, 4-dihydroquinolinone, purify water formed as a by-product of the activation of phenol from the solvent by dragging on molecular sieves, and then add a 1-cyclohexyl-5- (4-halobutyl) -tetrazole and recover cilostazol d of the solvent. 24. The process of claim 23, wherein the alkali metal hydroxide is sodium hydroxide or potassium hydroxide. 25. The process of claim 23, wherein the non-aqueous solvent is selected from the group consisting of 1-butanol, toluene, hexane, dichloromethane, and mixtures thereof. 26. The process of claim 23, wherein 1-cyclohexyl-5- (4-halobutyl) -tetrazole is 1-cyclohexyl-5- (4-chlorobutyl) -tetrazole. 27. A process for 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, mixtures of dimethyl acetamide and water, THF, methanol, isopropanol, benzyl alcohol, 2-pyrrolidone, acetonitrile, Cellosolve, monoglyme, isobutyl acetate, sec-butanol, tert-butanol, DMF, chloroform, diethyl ether and mixtures thereof. Highly pure Cilostazol free of impure 7 29. Micronized cilostazol of small particle size and narrow particle size distribution. 30. Substantially pure Cilostazol prepared by the process of any of claims 1, 12 and 23.