EP1311485A1 - Processes for preparing cilostazol - Google Patents
Processes for preparing cilostazolInfo
- Publication number
- EP1311485A1 EP1311485A1 EP01963979A EP01963979A EP1311485A1 EP 1311485 A1 EP1311485 A1 EP 1311485A1 EP 01963979 A EP01963979 A EP 01963979A EP 01963979 A EP01963979 A EP 01963979A EP 1311485 A1 EP1311485 A1 EP 1311485A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- tetrazole
- cilostazol
- alkali metal
- cyclohexyl
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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 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).
- 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.
- 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.
- 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.
- 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.
- 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
- 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.
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US22536200P | 2000-08-14 | 2000-08-14 | |
US225362P | 2000-08-14 | ||
PCT/US2001/025398 WO2002014283A1 (en) | 2000-08-14 | 2001-08-14 | Processes for preparing cilostazol |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1311485A1 true EP1311485A1 (en) | 2003-05-21 |
EP1311485A4 EP1311485A4 (en) | 2004-05-12 |
Family
ID=22844569
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP01963979A Withdrawn EP1311485A4 (en) | 2000-08-14 | 2001-08-14 | Processes for preparing cilostazol |
Country Status (17)
Country | Link |
---|---|
EP (1) | EP1311485A4 (en) |
JP (2) | JP3845059B2 (en) |
KR (1) | KR20030024865A (en) |
CN (1) | CN1469864A (en) |
AU (1) | AU2001284887A1 (en) |
CA (1) | CA2419181A1 (en) |
CZ (1) | CZ2003667A3 (en) |
HK (1) | HK1053116A1 (en) |
HU (1) | HUP0302688A2 (en) |
IL (1) | IL154458A0 (en) |
IS (1) | IS6716A (en) |
MX (1) | MXPA03001470A (en) |
NO (1) | NO20030699L (en) |
NZ (1) | NZ524363A (en) |
PL (1) | PL365672A1 (en) |
SK (1) | SK2992003A3 (en) |
WO (1) | WO2002014283A1 (en) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030045547A1 (en) | 2001-05-02 | 2003-03-06 | Shinji Aki | Process for producing carbostyril derivatives |
US7399864B2 (en) | 2001-05-02 | 2008-07-15 | Otsuka Pharmaceutical Co., Ltd. | Process for producing carbostyril derivatives |
US20050101631A1 (en) | 2002-08-01 | 2005-05-12 | Otsuka Pharmaceuticals Company | Process for producing carbostyril derivatives |
DK1489080T3 (en) * | 2002-09-10 | 2011-04-04 | Otsuka Pharma Co Ltd | Process for producing cilostazole |
CN1914175A (en) * | 2004-02-05 | 2007-02-14 | 特瓦制药工业有限公司 | Method of making 7-(4-bromobutoxy)-3,4-dihydrocarbostyril |
KR100633232B1 (en) * | 2004-08-25 | 2006-10-11 | 주식회사유한양행 | A novel method for purification of 6-[4-1-cyclohexyl-1h-tetrazol-5-ylbutoxy-3,4-dihydro-21h-quinolinone having high purity |
US20070270590A1 (en) * | 2006-04-20 | 2007-11-22 | Marioara Mendelovici | Methods for preparing eszopiclone crystalline form a, substantially pure eszopiclone and optically enriched eszopiclone |
TW200848041A (en) | 2007-03-30 | 2008-12-16 | Otsuka Pharma Co Ltd | A medicament for treating schizophrenia comprising cilostazol |
WO2008133949A1 (en) | 2007-04-25 | 2008-11-06 | Concert Pharmaceuticals, Inc. | Analogues of cilostazol |
CN101434598B (en) * | 2008-12-19 | 2012-11-07 | 重庆康乐制药有限公司 | Preparation of cilostazol |
CN102086190B (en) * | 2011-01-28 | 2013-07-10 | 海南美兰史克制药有限公司 | Cilostazol compound and novel preparation method thereof |
CN107382970A (en) * | 2017-07-26 | 2017-11-24 | 浙江金立源药业有限公司 | A kind of synthetic method of Cilostazol |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01265051A (en) * | 1988-04-14 | 1989-10-23 | Fuji Photo Film Co Ltd | Production of diaryloxyalkane |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5535019A (en) * | 1978-09-01 | 1980-03-11 | Otsuka Pharmaceut Co Ltd | Carbostyryl derivative |
-
2001
- 2001-08-14 JP JP2002519426A patent/JP3845059B2/en not_active Expired - Fee Related
- 2001-08-14 MX MXPA03001470A patent/MXPA03001470A/en unknown
- 2001-08-14 SK SK299-2003A patent/SK2992003A3/en unknown
- 2001-08-14 CA CA002419181A patent/CA2419181A1/en not_active Abandoned
- 2001-08-14 EP EP01963979A patent/EP1311485A4/en not_active Withdrawn
- 2001-08-14 WO PCT/US2001/025398 patent/WO2002014283A1/en not_active Application Discontinuation
- 2001-08-14 AU AU2001284887A patent/AU2001284887A1/en not_active Abandoned
- 2001-08-14 NZ NZ524363A patent/NZ524363A/en unknown
- 2001-08-14 PL PL01365672A patent/PL365672A1/en unknown
- 2001-08-14 IL IL15445801A patent/IL154458A0/en unknown
- 2001-08-14 KR KR10-2003-7002140A patent/KR20030024865A/en not_active Application Discontinuation
- 2001-08-14 CZ CZ2003667A patent/CZ2003667A3/en unknown
- 2001-08-14 HU HU0302688A patent/HUP0302688A2/en unknown
- 2001-08-14 CN CNA018172083A patent/CN1469864A/en active Pending
-
2003
- 2003-02-13 IS IS6716A patent/IS6716A/en unknown
- 2003-02-13 NO NO20030699A patent/NO20030699L/en not_active Application Discontinuation
- 2003-07-25 HK HK03105399.3A patent/HK1053116A1/en unknown
-
2005
- 2005-06-21 JP JP2005181031A patent/JP2005350474A/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01265051A (en) * | 1988-04-14 | 1989-10-23 | Fuji Photo Film Co Ltd | Production of diaryloxyalkane |
Non-Patent Citations (5)
Title |
---|
DUENO E E ET AL: "Cesium Promoted O-Alkylation of Alcohols for the Efficient Ether Synthesis" TETRAHEDRON LETTERS, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 40, no. 10, 5 March 1999 (1999-03-05), pages 1843-1846, XP004155978 ISSN: 0040-4039 * |
FREEDMAN H H ET AL: "AN IMPROVED WILLIAMSON ETHER SYNTHESIS USING PHASE TRANSFER CATALYSIS" TETRAHEDRON LETTERS, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, no. 38, 1975, pages 3251-3254, XP002056609 ISSN: 0040-4039 * |
PATENT ABSTRACTS OF JAPAN vol. 014, no. 024 (C-677), 18 January 1990 (1990-01-18) & JP 01 265051 A (FUJI PHOTO FILM CO LTD), 23 October 1989 (1989-10-23) * |
See also references of WO0214283A1 * |
SHIMIZU T ET AL: "PHYSICO-CHEMICAL PROPERTIES AND STABILITY OF CILOSTAZOL" ARZNEIMITTEL FORSCHUNG. DRUG RESEARCH, EDITIO CANTOR. AULENDORF, DE, vol. 35, no. 7A, 1985, pages 1117-1123, XP000938507 ISSN: 0004-4172 * |
Also Published As
Publication number | Publication date |
---|---|
JP2005350474A (en) | 2005-12-22 |
IL154458A0 (en) | 2003-09-17 |
JP2004506043A (en) | 2004-02-26 |
NO20030699L (en) | 2003-04-10 |
JP3845059B2 (en) | 2006-11-15 |
PL365672A1 (en) | 2005-01-10 |
WO2002014283A1 (en) | 2002-02-21 |
NZ524363A (en) | 2004-03-26 |
MXPA03001470A (en) | 2005-06-30 |
SK2992003A3 (en) | 2003-10-07 |
CN1469864A (en) | 2004-01-21 |
EP1311485A4 (en) | 2004-05-12 |
CZ2003667A3 (en) | 2003-08-13 |
AU2001284887A1 (en) | 2002-02-25 |
HUP0302688A2 (en) | 2003-12-29 |
HK1053116A1 (en) | 2003-10-10 |
CA2419181A1 (en) | 2002-02-21 |
NO20030699D0 (en) | 2003-02-13 |
KR20030024865A (en) | 2003-03-26 |
IS6716A (en) | 2003-02-13 |
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RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: PILARKSI, GIDEON Inventor name: FINKELSTEIN, NINA Inventor name: MENDELOVICHI, MARIOARA |
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