Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to processes for preparing cilostazol.
• the present invention pertains to processes for preparing 6-[4-(l-cyclohexyl-lH- tetrazol-5-yl)butoxy]-3,4-dihydro-2( lH)-quinolinone of formula (I)
• Cilostazol inhibits cell platelet aggregation and is used to treat patients with intermittent claudication.
• Cilostazol is described in U.S. Patent No. 4,277,479 ("the '479 patent”), which teaches a preparation wherein the phenol group of 6-hydroxy-3,4-dihydroquinolinone ("6- ⁇ Q") of formula (II) is alkylated with a l-cyclohexyl-5-(4-halobutyl)-tetrazole (“the tetrazole”) of formula (HI). It is recommended to use an equimolar or excess amount up to two molar equivalents of the tetrazole (HI).
• the "479 patent mentions a wide variety of bases that may 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-dimethylaminopy ⁇ dine; l,5-diaza-bicyclo[4,3,0]-non-5-ene, l,5-diaza-bicyclo[5,4,0]-undec-7-ene ("DBU”), and 1 ,4-diazabicyclo[2,2,2]octane.
• bases namely, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, silver carbonate, elemental sodium, elemental potassium, sodium methylate, sodium eth
• Suitable solvents are said to be methanol, ethanol, propanol, butanol, ethylene glycol, dimethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, acetone, methylethylketone, benzene, toluene, xylene, methyl acetate, ethyl acetate, N,N-dimethylformamide, dimethylsulfoxide and hexamethylphosphoryl triamide.
• cilostazol was prepared using DBU as base and ethanol as solvent.
• CHCBT 5-(4-chlorobutyl)-l- cyclohexyl-lH-tetraazole
• Cilostazol was obtained in 74% yield.
• One reason for using an excess of tetrazole as was done in Nishi et al. and recommended by the '479 patent is that CHCBT is unstable to some bases. When exposed to an alkali metal hydroxide in water for a sufficient period, CHCBT undergoes elimination and cyclization to yield byproducts (IV) and (V).
• CHCBT is unstable to hydroxide ion, it is relatively stable in the presence of non-nucleophilic organic bases.
• inorganic bases favor their selection over organic bases.
• HQ is labile.
• relatively non-caustic and easily handled inorganic bases may be used to prepare cilostazol.
• inorganic bases are easier to separate from the product and are less toxic to the environment when disposed than organic bases are. Therefore, it would also be highly desirable to use an inorganic base while realizing an improvement in conversion of CHCBT to cilostazol.
• the present invention provides improved processes for preparing cilostazol (I) by alkylating the phenol group of 6-HQ with the ⁇ carbon of a 5-(4-halobutyl)-l-cyclohexyl- lH-tetrazole.
• the invention provides a process wherein 6-HQ and a water soluble base are dissolved in water A l-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 phase transfer catalyst to form a biphasic mixture in which the 6-HQ and tetrazole react to produce cilostazol.
• the process may be practiced by a variety of procedures taught by the present invention.
• a reaction promoter like sodium sulfate, is added to accelerate phase transfer of 6-HQ into the organic solvent.
• Another aspect of the present invention provides a preparation of cilostazol from a single phase reaction mixture of 6-HQ and a l-cyclohexyl-5-(4-halobuty ⁇ )-tetrazole and a mixture of inorganic bases.
• the base mixture comprises an alkali metal hydroxide and alkali metal carbonate. This process minimizes decomposition of the starting tetrazole and cilostazol by buffering the pH which results in improved yield calculated based upon the tetrazole, the more precious of the two organic starting materials.
• a preferred embodiment wherein the alkali metal hydroxide is added portionwise minimizes the formation of dimeric byproducts.
• the reaction mixture is dehydrated with molecular sieves before the tetrazole is added.
• the present invention provides a process for preparing cilostazol (I) by alkylating the phenol group of 6-HQ with the ⁇ carbon of a 5-(4-halobutyl)-l-cyclohexyl-lH-tetrazole
• the present invention improves upon processes previously used to perform the chemical transformation depicted in Scheme 1 which result in a greater conversion of the tetrazole starting material to cilostazol.
• the improvements may be viewed as falling into one of two aspects of the present invention: (1) a heterogeneous, or biphasic, process employing phase transfer catalysis and improvements applicable to the heterogeneous process and (2) improvements applicable to a homogeneous process.
• the present invention provides a biphasic process for preparing cilostazol by alkylating the phenol group of 6-HQ with a 5-(4-halobutyl)-l-cyclohexyl- lH-tetrazole using controlled phase transfer methodology.
• phase transfer catalysis See, Dehmlow, EN.; Dehmlow, S.S., Phase Transfer Catalysis 3rd ed. (NCH Publishers: New York 1993).
• a solution of 6-HQ, a water-soluble base and a trialkyl ammonium phase transfer catalyst in water is contacted with a solution of a 5-(4-halobutyl)-l-cyclohexyl-lH-tetrazole in a water-immiscible organic solvent for a period of time sufficient to cause the tetrazole to be substantially completely converted to cilostazol and then separating the cilostazol from the biphasic mixture.
• the biphasic reaction mixture separates the base from the base sensitive tetrazole.
• 6-HQ phenolate anion complexes with the tetra-alkyl ammonium ion which increases its solubility in the water-immiscible organic solvent.
• the complexed phenolate then enters the water-immiscible phase and reacts with the tetrazole there.
• Suitable phase transfer catalysts are ammonium salts such as tricaprylylmethylammonium chloride (Aliquat ® 336) , tetra-n-butylammonium bromide (“TBAB”), benzyltriethylammonium chloride (“TEBA”), cetyltrimethylarnmonium bromide , cetylpyridinium bromide, N-benzylquininium chloride, tetra-n-butylammonium chloride, tetra-n-butylammonium hydroxide, tetra-n-butylammonium iodide, tetra-ethylammonium chloride, benzyltributylammonium bromide, benzyltriethylammonium bromide, hexadecyltriethylammonium chloride, tetramethylammonium chloride, hexadecyltrimethyl ammoni
• phase transfer catalysts are Aliquat ® 336, TBAB, TEBA and mixtures thereof, the most preferred being Aliquat ® 336.
• the phase transfer catalyst may be used in a stoichiometric or substoichiometric amount, preferably from about 0.05 to about 0.25 equivalents with respect to the tetrazole.
• Suitable bases are soluble in water but poorly soluble or insoluble in water-immiscible organic solvents. Such bases are typically metal salts of inorganic counterions.
• Preferred inorganic bases are hydroxide and carbonate salts of alkali metals. 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)-l-cyclohexyl-lH-tetrazole may be chlorine, bromine or iodine, preferably chlorine.
• the tetrazole may be used in any amount desired, it is most desirable to use a stoichiometric amount of tetrazole or less relative to 6-HQ, more preferably about 0.9 molar equivalents.
• Preferred water-immiscible solvents are toluene, hexanes, dichloromethane and mixtures thereof. An excess of water to water-immiscible solvent is preferred, although the ratio may vary widely.
• Preferred ratios of water to water-immiscible solvent range from about 0.5: 1 to about 8: 1 (v/v), more preferably from about 1 : 1 to about 6: 1.
• the 6-HQ, water- soluble base and phase transfer catalyst are dissolved in water.
• the tetrazole is dissolved in the water-immiscible solvent and the two solutions are contacted and agitated, with optional heating, until the tetrazole is substantially consumed.
• Cilostazol may be isolated by cooling the reaction mixture to precipitate the cilostazol and then filtering or decanting the solutions.
• Cilostazol may be purified by methods shown in Table 1 or any conventional method known in the art.
• a biphasic mixture of the water-miscible organic solvent and the aqueous solution of 6-HQ, 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 may be either continuous or portionwise.
• an aqueous suspension of 6-HQ and the phase transfer catalyst are contacted with the solution of tetrazole in the water-immiscible organic solvent.
• the biphasic mixture is agitated and optionally heated, while the water- soluble base is slowly added to the mixture.
• the slow addition may be either continuous as in a concentrated aqueous solution of the base or portionwise.
• reaction promoters are salts like sodium sulfate and potassium sulfate that increase the ionic strength of aqueous solutions but do not form strongly acidic or basic aqueous solutions.
• the reaction promoters decrease the solubility of 6-HQ in the aqueous phase and improve the efficiency of phase transfer to the organic phase.
• the preferred reaction promoter is sodium sulfate.
• the reaction promoter is added in the amount of about 12-16% (w/v) with respect to the aqueous phase.
• the present invention provides a process for preparing cilostazol by alkylating the phenol group of 6-HQ with a 5-(4-halobutyl)-l-cyclohexyl-lH-tetrazole in a single liquid phase reaction mixture.
• 6-HQ and the tetrazole may be used in any amount, though it is preferred that the tetrazole be the limiting reagent, preferably used in from about 0.9 to about 0.99 equivalents with respect to the 6-HQ.
• Suitable solvents for forming the single liquid phase reaction mixture of this aspect of the invention are non- aqueous hydroxylic solvents, which include 1-butanol, isopropanol, 2-butanol and amyl alcohol.
• 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.
• preferred base mixtures are mixtures 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 equivalents with respect to the 6-HQ and the alkali metal carbonate is preferably used in an amount of about 0.1 to about 0.2 equivalents with respect to the 6-HQ.
• the 6-HQ, tetrazole, alkali metal hydroxide and alkali metal carbonate may be added to the non-aqueous solvent in any order desired and at any rate desired.
• 6-HQ, the tetrazole and the alkali metal carbonate are added to the hydroxylic solvent along with a portion, e.g. about a one-fourth portion, of the alkali metal hydroxide. Thereafter, the remainder of the alkali metal hydroxide is added portionwise to the reaction mixture. It has been found that portionwise addition of the alkali metal hydroxide suppresses a byproduct that forms by the substitution of the halogen of the tetrazole by the 6-HQ lactam nitrogen.
• Molecular sieves may be used to remove water from the single liquid phase reaction mixture before the tetrazole is added. Three and four angstrom molecular sieves are preferred, with three angstrom sieves being most preferred.
• the molecular sieves may be stirred with the solution to remove water formed by deprotonation of 6-HQ by KOH or adventitious water.
• the molecular sieves are placed in a soxlet extraction funnel, the reservoir of a dropping funnel, or other suitable apparatus mounted on the reaction vessel that will allow circulation of vapor through the molecular sieves and return of the condensate to the reaction vessel.
• the solution is then refluxed to circulate water vapor over the molecular sieves.
• the tetrazole is added to the solution to react with the 6-HQ phenolate to produce cilostazol.
• Suitable recrystallization solvents are 1-butanol, acetone, toluene, methyl ethyl ketone, dichloromethane, ethyl acetate, methyl t-butyl ether, dimethyl acetamide-water mixtures, THF, methanol, isopropanol, benzyl alcohol, 2-pyrrolidone, acetonitrile, Cellosolve, monoglyme, isobutyl acetate, sec-butanol, tert-butanol, DMF, chloroform, diethyl ether and mixtures thereof.
• the invention will now be further illustrated with the following examples. EXAMPLES
• 6-HQ (10 g, 0.0613 moles), KOH (4.05 g, 0.0722 moles), K 2 CO 3 (1.5 g, 0.011 mole), CHCBT (13.4 g, 0.0552 moles) and 130 ml n-BuOH were heated at reflux for 5 hours.
• Table 1 provides conditions for selectively crystallizing cilostazol from mixtures containing minor amounts of 6-HQ and CHCBT. Cilostazol is obtained with small particle size and narrow particle size distribution.
• Methyl ethyl etone 11 Dissolve at reflux. Cool to r.t.

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• 2001
  • 2001-08-14 KR KR10-2003-7002140A patent/KR20030024865A/ko not_active Application Discontinuation
  • 2001-08-14 SK SK299-2003A patent/SK2992003A3/sk unknown
  • 2001-08-14 PL PL01365672A patent/PL365672A1/xx unknown
  • 2001-08-14 WO PCT/US2001/025398 patent/WO2002014283A1/en not_active Application Discontinuation
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  • 2001-08-14 JP JP2002519426A patent/JP3845059B2/ja not_active Expired - Fee Related
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