EP1480943A2 - Synthese von 3,5-dihydroxy-7-pyrrol-1-yl-heptansäuren - Google Patents

Synthese von 3,5-dihydroxy-7-pyrrol-1-yl-heptansäuren

Info

Publication number
EP1480943A2
EP1480943A2 EP03786885A EP03786885A EP1480943A2 EP 1480943 A2 EP1480943 A2 EP 1480943A2 EP 03786885 A EP03786885 A EP 03786885A EP 03786885 A EP03786885 A EP 03786885A EP 1480943 A2 EP1480943 A2 EP 1480943A2
Authority
EP
European Patent Office
Prior art keywords
dihydroxy
formula
phenyl
protected
ketal
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Withdrawn
Application number
EP03786885A
Other languages
English (en)
French (fr)
Inventor
Jakob Oren
Ben-Zion Dolitzky
Zvi Harel
Nurit Perlman
Ramy Lidor-Hadas
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teva Pharmaceutical Industries Ltd
Original Assignee
Teva Pharmaceutical Industries Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Teva Pharmaceutical Industries Ltd filed Critical Teva Pharmaceutical Industries Ltd
Publication of EP1480943A2 publication Critical patent/EP1480943A2/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888

Definitions

  • the present invention relates to processes for preparing 3,5-dihydroxy-7-pyrrol-l-yl heptanoic acids of a class that is effective at inhibiting the biosynthesis of cholesterol in humans, and more particularly to improved synthetic methods for preparing them from 7-amino-3,5- dihydroxy heptanoic acid and 1,4-diketo starting materials.
  • HMG-CoA 3-hy ⁇ Oxy-3-methyl-glutaryl-coenzyme A
  • the first HMG-CoA inhibitor to be described is compactin ([lS-lXR *) , 7 ⁇ , 8 ⁇ (2S * , 4S * ),8a ⁇ ]]-l,2,3,7,8,8a-hexahydro-7-methyl-8-[2-(tetrahydro-4- hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-l-naphthalenyl 2-methylbutanoate), which was isolated from cultures o ⁇ Penicillium in 1976.
  • lovastatin [lS-fl ⁇ , 7 ⁇ , 8 ⁇ (2S * , 4S * ),8a ⁇ ]]-l,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H- pyran-2-yl)ethyl]-l-naphthalenyl 2-methylbutanoiate
  • FDA Food and Drug Administration
  • atorvastatin [(phenylamino)carbonyl]- 1 H-pynole- 1 -heptanoic acid
  • Atorvastatin later received FDA approval as an adjunct to a low cholesterol diet to reduce elevated levels of total cholesterol, low density lipoprotein cholesterol, apo B and triglycerides and to increase levels of high density lipoprotein cholesterol in patients with hyperlipidemia.
  • lovastatin In contrast to compactin, lovastatin, simvastatin and pravastatin, there is no known fermentation culture that produces atorvastatin. It, and other 3,5-dihydroxy-7-pynol-l-yl hepanoic acids, must be synthesized by traditional synthetic methods.
  • the '893 patent describes a synthesis of racemic atorvastatin by a nine-step process that included building up of the heptanoic acid side chain by acetoacetic acid synthesis. The final product was a racemate containing 50% of the S,S stereoisomer.
  • the '995 patent describes a synthesis of the R,R stereoisomer of atorvastatin.
  • the '995 patent used an iterative stepwise process to elaborate the 3,5-dihydiOxy heptanoic acid side chain.
  • the C-5 stereocenter was set by stereoselective aldol-type condensation.
  • the chain was extended by another two carbon atoms and the C-3 stereocenter was set by Claisen condensation with tert-butyl acetate.
  • U.S. Patent No. 5,298,627 discloses a process for preparing atorvastatin in which the
  • 3,5-heptanoic acid side chain is incorporated in a single convergent step rather than being elaborated from a propanal side chain as in the '893 and '995 patent processes.
  • a precursor of the side chain of atorvastatin was made by Claisen condensation of NN-diphenyl acetamide and 4-cyano-3-hydroxy-butanoic acid ethyl ester. The resulting 6-cy-u ⁇ o-3,5-dihydroxy hexanoic acid amide was protected with 2,2-dimethoxypropane. The nitrile was reduced with
  • Raney-nickel and the resulting amine was reacted with 1,4-diketone 9 (structure shown in Example 3) in 2: 1 : 1 heptane: THF:toluene in the presence of pivalic acid as a catalyst.
  • the reaction of the -tmine with the 1,4-ketone is known as the Paal-Knon pyrolle synthesis (hereafter "Paal Knon reaction”). It involves addition of a primary amine to both keto groups of the 1,4-ketone and elimination of two moles of water to achieve aromaticity.
  • the product was an acetonide-protected 3,5-dihydroxy-7-pynol-l-yl hepantoic acid amide. After cleaving of the acetonide, the amide group was hydrolyzed to the carboxylic acid with sodium hydroxide to give atorvastatin as the sodium salt.
  • U.S. Patent No. 5,216,174 teaches generally that the Paal Knon reaction can be performed on an acetonide-protected 7-amino-3,5-dihydroxy heptanoic acid tert-butyl ester in an inert solvent or solvents such as, for example, hexane, toluene and the like for about 24 hours at about the reflux temperature of the solvent or solvents and that the product is not isolated but is treated directly with acid to remove the acetonide protecting group.
  • an inert solvent or solvents such as, for example, hexane, toluene and the like
  • Knon reaction is carried out in a temiary solvent mixture of toluene-heptane-tetrahydrofuran (THF) (1:4: 1) in the presence of a pivalic acid catalyst.
  • THF toluene-heptane-tetrahydrofuran
  • Another similar condensation between a diketone and amine is described in U.S. Patent No. 5,397,792 where the condensation is carried out in a 6: 10:5 toluene eptane/tetrahydrofuran solvent mixture in the presence of pivalic acid as catalyst.
  • U.S. Patents Nos. 5,003,080; 5,097,045; 5,124,482; 5,149,837; 5,216,174; 5,245,047 and 5,280,126 disclose methods of making atorvastatin free acid and lactone and/or stereoisomers thereof.
  • Roth, B.D. et al. J. Med. Chem. 1991, 34, 357-66 discloses preparations of atorvastatin lactone and other pynol-1-yl ethylmevalonolactones with variable substituents on the pyrrole ring.
  • the present invention provides processes for preparing 3,5-dihydroxy-7- pynol-1-yl heptanoic acids.
  • a 3,5-dihydiOxy-7-pvnol-l-yl heptanoic acid is made by oxidizing a 3,5-dihydroxy-7-pynol-l-yl heptanol precursor compound.
  • the oxidation can be done directly or with isolation of the intermediate aldehyde.
  • the heptanol starting materials are a novel class of compounds. They can be made by reacting a ketal-protected 7- ammo-3,5-dihydroxy-l -heptanol with certain 1,4-diketones under acid catalyst conditions, preferably at elevated temperature and with removal of water.
  • the 7-amino-3,5 ⁇ dihydroxy ⁇ l- heptanols also are novel compounds.
  • valuable intermediates for preparing HMG-CoA inhibitory compounds are prepared by reaction of silylether-diprotected 7-amino-3,5-dihydroxy heptanoic acid esters with certain 1,4-diketones.
  • One route to the heptanoic acid starting material involves subjecting a ketal-protected 7-amino-3,5-dihydiOxy heptanoic acid ester to ketal cleaving conditions followed by silylation of the deprotected hydroxy groups.
  • a known synthetic pathway for making atorvastatin is improved by conducting the Paal Knon reaction step in a low boiling point ether rather than in the solvent systems used in the past. In a low boiling point ether, the reaction goes in high yield and produces few side products.
  • FIG. 1 depicts a prefened reaction sequence of the present invention.
  • M is an alkali metal
  • i is 1.
  • M is an alkaline earth metal
  • FIG. 2 depicts a second prefened reaction sequence of the present invention.
  • z is 1.
  • M is an alkaline earth metal
  • z is 2.
  • FIG. 3 depicts a third prefened reaction sequence of the present invention.
  • the chemical nomenclature used in this disclosure follows the system for naming compounds of the International Union of Pure and Applied Chemistry (IUPAC).
  • IUPAC International Union of Pure and Applied Chemistry
  • the IUPAC system assigns a number to every atom in a compound.
  • This disclosure also uses relative numbering where it is the clearest way to describe the invention to those skilled in the art.
  • the absolute numbering assigned by the IUPAC system is to be distinguished from relative numbering commonly used to express bonding relationships between functional groups.
  • the hydroxy groups of 3,5-dihydroxy heptanoic acid are in a 1,3 relationship to each other, because they are separated by three carbon atoms including those to which they are attached.
  • the keto groups of a 1,4-diketone of a particular compound will not necessarily be numbered 1 and 4 under the IUPAC system.
  • alkyl includes straight chained and branched alkyl groups containing from 1 to 6 atoms
  • lower alkyl includes straight chained and branched alkyl groups containing from 1 to 4 carbon atoms
  • substituted phenyl includes phenyl substituted with 1-3 groups of alkyls or halogens or alkoxides.
  • compounds used in or obtained by practice of the present invention include any salts, solvates or crystalline forms of the compounds. However, when a salt or solvate is specifically indicated, only that salt or solvate (in any crystalline or amorphous form) is meant.
  • the compounds depicted in formulae in this disclosure include all stereoisomers except where indicated in a formula by solid or hatched wedge-shaped bonds or by the description in the accompanying text.
  • the present invention provides processes for synthesizing 3,5-dihydiOxy-7-pynol-l-yl heptanoic acids of Formula (I)
  • Ri is selected from the group consisting of: 1-naphthyl, 2-naphthyl, cyclohexyl, cyclohexylmefhyl, norbomenyl, phenyl, phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, alkoxy of from one to four carbon atoms, or alkanoyloxy of from two to eight carbon atoms, benzyl,
  • R 2 or R 3 are independently selected from the group consisting of: hydrogen, alkyl of from one to six carbon atoms, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, phenyl substituted with fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, alkyl of from one to four carbon atoms, or alkoxy of from one to four carbon atoms, cyano, trifluoromethyl, or
  • R 5 and Rg are independently hydrogen, alkyl of from one to six carbon atoms, phenyl, phenyl substituted with fluorine, chlorine, bromine, cyano, or trifluoromethyl;
  • R 4 is selected from the group consisting of: alkyl of from one to six carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and trifluoromethyl.
  • the 3- and 5- carbon atoms have an R configuration.
  • Ri is 4-fluorophenyl and R 3 is a radical of formula -CONR 5 R ⁇ 5 .
  • 3,5-dihydroxy-7-pynol-l-yl heptanoic acids are those wherein R, is 4-fluorophenyl, R 3 is a radical of formula -CONR 5 R- 5 and _j is alkyl or trifluoromethyl, with isopropyl being especially prefened.
  • 5-dihydroxy-7-pynol- 1 -yl heptanoic acids are those having the prefened R l3 R 3 and R 4 substitutents wherein R 2 is phenyl.
  • An especially prefened specific 3,5-dihydroxy-7-pynol-l-yl heptanoic acid is atorvastatin.
  • the 3,5-dihydroxy-7-pynol-l- yl heptanoic acid of Formula (I) is synthesized by oxidizing a ketal-protected 3,5-dihydroxy-7- pynol-l-yl-1 -heptanol of Formula (II)
  • Substitutents R 7 and R 8 are each independently selected from the group consisting of hydrogen, alkyl, substituted or unsubstituted phenyl, or R 7 and R 8 together with the carbon to which they are attached form a C 5 -C 7 carbo cycle, except that R 7 and R 8 are not both hydrogen.
  • Prefened alkyl groups are methyl and tert-butyl.
  • Prefened substituted phenyl groups are /?-C 6 H 4 OCH 3 , j?-C 6 H 3 (OCH 3 ) 2 , o,t)-C 6 H 3 (OCH 3 ) 2 , /?-C 6 IL,NO 2 and -C 6 H 4 NO 2
  • R 7 -C-R 8 carbenyl fragments are isopropylidene, ethylidene, tert-butylmethylidene, 1-tert-butylethylidene, 1- phenylethylidene, l-(4-methoxyphenyl) ethylidene, cyclopenylidene, cyclohexylidene, cycloheptylidene, 4-methoxybenzylidene, 2,4-dimethyxybenzylidene, 3,4- dimethoxybenzylidene, 2-nitrobenzylidene, 4-nitrobenzylidene,
  • the primary alcohol of the Formula (II) compound can be oxidized directly to the acid (without intermediate isolation of the aldehyde) using known strong oxidizers such as MnO 2 ,
  • the oxidation can be performed following the methodology of Lehel, Sz. et al. J. of Labelled Cpd, And Radiopharm. 2000, 43, 807-815; Takano, S. et al. Heterocycles 1988, 27, 2413-2415; Singh, A. et al. Tet. lett. 1992, 33, 2307-2310 or Sano, H. et al.
  • oxidation of the primary alcohol of compounds of Formula (II) can be conducted in two steps with isolation of the intermediate aldehyde, a 4-(2-oxoethy ⁇ )-6-(2- (py ⁇ ol-l-yl)ethyl)-l,3-dioxane of Formula (IN)
  • Mild oxidizing conditions must be used in order to be able to isolate the aldehyde.
  • Suitably mild oxidizing agents include (COCl) 2 /DMSO (Swern) (Org Syn Coll. Vol. 7, 1990, 258), pyridinium dichromate, pyridinium chlorochromate, ⁇ aOCl/TEMPO and pentavalent iodine reagents such as Dess-Martin periodinane (J. Org. Chem., 1983, 48, 4155). Dess-Martin periodinane is a prefened mild oxidizing agent because of its selectvity.
  • the isolated aldehyde of Formula (IV) is then oxidized to the carboxylic acid using suitable oxidizing agent such as ⁇ aClO 2 or AgNO 3 , with NaClO 2 being prefened.
  • the ketal protecting group is cleaved by conventional techniques employing acidic conditions which are well known in the art.
  • the ketal protecting group can be hydrolyzed with an acid catalyst in an alcohol, ether or hydrocarbon solvent.
  • the acid catalyst may be a mineral acid, a sulfonic acid or a carboxylic acid.
  • Exemplary acid catalysts include, but are not limited to hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, methanesulfonic acid, perchloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, toluenesulfonic acid and the like.
  • a prefened acid catalyst is hydrochloric acid (HC1).
  • the ketal can be cleaved in an alcohol solvent including but not limited to C ⁇ -C 6 alcohols including methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl- 2-propanol, pentanol, hexanol, cyclohexanol, ethylene glycol and diethylene glycol.
  • a prefened alcoholic solvent is ethanol.
  • Ethereal solvents that can be used include but are not limited to dioxane, THF and DME.
  • a prefened ethereal solvent is THF.
  • the ketal can be cleaved in an hydrocarbon solvent such as toluene, hexane, and heptane.
  • Deprotection yields the 3,5-dihydroxy-7-pynol-l-yl heptanoic acid of Formula (I), which may then be converted, if so desired, to a metal salt by contacting it with a source of the metal cation.
  • Pharmaceutically acceptable metal salts which are prefened, include sodium, potassium, calcium, magnesium, aluminum, iron and zinc salts.
  • the heptanoic acid and a source of the metal cation are dissolved in a solvent. Then, the desired metal salt of the Formula (I) compound is precipitated from the solution.
  • the source of the metal cation contains the metal ion and a counterion.
  • the solvent is selected with the consideration that the protonated counterion be highly soluble in the solvent so that the source of metal ion does not precipitate from the solution in competition with the desired salt.
  • water and ethanol are good solvents when the source of the metal cation is NaOH, Ca(OH) 2 or Ca(OAc) 2 .
  • the heptanol of Formula (II) used in the process can be prepared from readily available and/or commercially available starting material. According to one prefened synthetic route to the heptanol of Formula (II) shown in FIG. 1, a ketal-protected 6-cyano-3,5-dihydroxyl hexanoic acid ester of Formula (V)
  • Substituent R 9 is a substituted or unsubstituted Ci- lower alkyl radical, preferably tert-butyl.
  • An especially prefened compound of Formula (V) is ( ⁇ R-c ⁇ )-6-cyanomethyl-2,2-dimethyl-l,3-dioxane-4-acetic acid tert-butyl ester 2 .
  • Compound 2 is readily available in high yield by known processes. Brower, P.L. et al. Tet Lett.
  • Formula (V) include alkali metal and alkaline earth metal borohydrides, borane, dialkylboranes (such as di-isoamylborane), alkali metal aluminum hydrides (preferably lithium aluminum hydride), alkali metal (trialkoxy)aluminum hydrides, or dialkyl aluminum hydrides (such as di- isobutylalurninum hydride).
  • the prefened reducing agent is lithium aluminum hydride.
  • the reduced product is a 6-(2-aminoethyl)-4-(2-hydroxyethyl)- 1 ,3-dioxane of Formula
  • the Paal-Knon reaction of a Formula (VI) compound with a Formula (VII) compound is carried out in a solvent, with an acid catalyst under reflux and with evaporative removal of water, for example, by using a Dean-Stark trap.
  • Suitable solvents include any that do not inhibit the reaction or decompose or otherwise divert the starting material from the desired product.
  • Non-limiting examples of such solvents are pentane, n-hexane, n-heptane, cyclohexane, benzene, isopropyl benzene, chlorobenzene, dichlorobenzene, dichloromethane, dichloroethane, chloroform, tetrachloroform, tetrachloromethane, toluene, xylene, mesitylene, MTBE, THF, dioxane and the like.
  • Prefened solvents are mixtures of heptane and THF and toluene, with toluene being especially prefened.
  • Suitable acid catalysts include, but are not limited to, carboxylic acids such as acetic acid, butyric acid, pivalic acid, benzoic acid and trichloro acetic acid, phenols and cresols.
  • the reaction takes about twenty hours to go to completion. If a water-immiscible solvent is used, the reaction mixture can then be washed with water and after phase separation the 3,5-dihydroxy- 7-pynOl-l-yl-l -heptanol of Formula (II) is obtained in the organic phase. Otherwise, the reaction mixture can be concentrated, taken up in a water-immiscible solvent, washed with water, after which the Formula (II) compound is obtained in the organic phase.
  • An especially prefened technique for conducting the Paal-Knon reaction using amines of Formula (VI) has been developed.
  • the amine of Formula (VI) is brought into contact with the 1,4-diketone (VII) as an acid addition salt with pivalic acid.
  • This technique therefore delivers one molar equivalent of an acid catalyst to the Paal-Knon reaction mixture simultaneously with the amine of Formula (VI).
  • the pivalic acid salt of an amine of Formula (VI) can be generated by dissolving the amine in a suitable solvent and adding pivalic acid to the solution.
  • Suitable solvents are preferably aprotic, moderately polar organic liquids like lower alkyl ethers and lower alkyl ketones that are sufficiently polar to dissolve the amine, but are sufficiently non-polar that the salt, once formed, is poorly soluble and precipitates in good yield.
  • Methyl tert-butyl ether (“MTBE”) has been found to be a suitable solvent for compound 3.
  • the present invention provides a process for preparing compounds of Formula (I) by application of the Paul-Knon reaction to a silylether-diprotected 7-arnino- 3,5-dihydroxy heptanoic acid ester and a 1,4-diketone of Formula (VII) followed by deprotection of the hydroxy groups and hydrolysis of the ester.
  • silylether-diprotected 7-am o-3,5-dihydroxy heptanoic acid esters useful in the process are those having the molecular Formula (VIII) or (IX)
  • R 9 is as previously defined and R 10 , R ⁇ , R 12 , R 13 and R 14 are independently selected from the group consisting of C C 6 linear, branched and cyclic, substituted and unsubstituted hydrocarbyl radicals and phenyl.
  • Compounds of Formula (IX) have not been prepared before and constitute an aspect of the invention.
  • An especially prefened compound of Formula (IX) is 6-(2-aminoethyl)-2,2- diisopropyl-l,3-dioxa-2-silacyclohexane-4-acetic acid tert-butyl ester 4, whose preparation is set forth in Example 11, below.
  • Compounds of Formulae (VIII) and (IX) can be prepared by either of two other processes described below or any other way. Referring now to FIG. 2, compounds of Formulae (VIII) and (IX) can be prepared from compounds of Formula (V), such as compound 2.
  • the ketal protecting group of a Formula (V) compound is cleaved under acidic conditions to yield a 6-cyano-3,5-dihydroxy hexanoic acid ester of
  • the hydiOxy groups of the product are then reprotected as silylethers and the silylated product is subjected to nitrile reduction to yield the desired starting material for the Paal-Knon reaction.
  • Formula (X) are protected as silylethers using any reagent known to those skilled in the art to be useful for silylating secondary hydroxy groups.
  • exemplary monofunctional silylating agents include, but are not limited to, those that introduce: a trimethyl silyl group, such as, chlorotrimethylsilane, bromotrimethylsilane, trimethylsilyl trichloroacetate, 3- trimethylsilyloxazolidinone, trimethylsilyltrifluoromethanesulfonate, N-methyl-N-
  • trimethylsilyl trifluoiOacetamide, N-trimethylsilyldiethylamine, and N-trimethylsilylimidazole and hexamethyldisilazane
  • a triethyl silyl group such as chlorotriethylsilane, N-methyl-N- triethylsilyltrMuoroacetamide, allyltriethylsilane, N-triethylsilylacetamide, triethylsilyldiethylamine,
  • a triisopropylsilyl group such as, trisopropylsilane and triisopropylsilyltrifluoromethylsulfonate
  • a dimethyl-zso-propylsilyl group such as c loxo-iso- propyldimethylsilane and di(z ' 5 , -propyldimethylsilyl)- ⁇ n ⁇ e
  • a diethyl-wo-propylsilyl group such as chlorodiethyl-wo-propylsilane, and diethyl-wo-propylsilyl triflate
  • a dimethylthexyl group such as chlorodimethylthexylsilane and dimtheylthexyls
  • difunctional silylating reagents can be used to protect the 1,3-diol of the 7- anrno-3,5-dihydiOxy heptanoic acid ester.
  • difunctional silylating reagents include those that introduce a di-tert-butylsilyl group, such as di-tert-butyldichlorosilane and di-tert- butyldi(trifluoroacetyl)silane; a di- ⁇ o-propylsilyl group, such as di-fso-propyldichlorosilane and di-wo-propyldi(trifluoroacetyl)silane; a dimethylsilyl group, such as dimethyldichlorosilane; a diethylsilyl group, such as diethyldichlorosilane; and a diphenylsilyl group, such a dichlorodiphenyl
  • Difunction silylating reagents are prefened because they tend to be more stable to a subsequent hydrogenation step.
  • Especially prefened silylating agents are dichlorodi-wo- propylsilane, dichlorodiphenylsilane and di-tert-butyldichlorosilane.
  • Acid scavengers are well-known and include but are not limited, to non-nucleophilic amine bases such as N,N- diisopropylethylamine, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-lutidine, triethylamine, 2-, 3-, or 4- picoline, N-methyl morpholine, imidazole, pyridine and pyrimidine.
  • a prefened acid scavenger is triethylamine. With a particular silylating agent, it also may be beneficial to add an activator such as
  • HOBT N-hydroxybenzotriazole
  • imidazole imidazole
  • DMAP N-hydroxybenzotriazole
  • the silylating agent is dichlorodi-wo- propylsilane
  • the acid scavenger is triethyl amine
  • the solvent is THF, CH 2 C1 2 or toluene
  • the silylether-diprotected product is isolated by filtering off Et 3 N»HCl, the filtrate is washed with water, and the solvent is evaporated.
  • silylation may yield some silyl monoprotected products:
  • the monoprotected products can be carried forward in mixture with the diprotected products in the Paal-Knon reaction.
  • Compounds of Formula (XII) have not been prepared before and constitute an aspect of the invention.
  • An especially prefened compound of Formula (XII) is 6-cyanomethyl-2,2- diisopropyl-l,3-dioxa-2-silacyclohexane-4-acetic acid tert-butyl ester 5, whose preparation is set forth in Example 10, below.
  • the nitrile group of the silylether-diprotected 6-cyano-3,5-dihydroxy hexanoic acid ester is selectively reduced to give the silylether-diprotected 7-arnino-3,5- dihydroxy heptanoic acid ester of Formula (NIII) or (IX).
  • the selective reduction can be performed with Raney-nickel in an alcohol solution with ⁇ H 3 under 4.0-4.5 atm hydrogen pressure.
  • the crude product can then be used in the Paal-Knon reaction with or without purification or it can be purified and converted to its pivalate salt by the technique previously described for generating the pivalate salt of compounds of Formula (VI).
  • Prefened solvents in which to generate the pivalate salt of the silylether-diprotected 7-- ⁇ rnino- ⁇ - ⁇ -dihydroxy heptanoic acid ester are heptane, THF and toluene.
  • a second alternative process for preparing silylether- diprotected 7-amino-3,5-dihydiOxy heptanoic acid esters of Formulae (VIII) and (IX) begins with compounds of Formula (XIII)
  • Compounds of Formula (XIII) can be prepared by selective nitrile reduction of compounds of Formula (V) with a molybdenum doped Raney nickel catalyst in a mixture of ammonia and methanol under 50 psig H 2 at room temperature as described in Baumann, K.L. et al. Tet. Lett. 1992, 33, 2283-2284.
  • the compounds of Formula (XIII) are converted to compounds of Formulae (VIII) and
  • the ketal protecting group of compounds of Formula (XIII) can be cleaved under acidic conditions like those previously described for deprotecting compounds of Formula (III).
  • the ketal is cleaved in a solution containing approximately one molar equivalent of HCl with respect to the compound of Formula (XIII), the 7-amino-3,5-dihydroxy heptanoic acid ester is isolated as its hydrochloride salt (XTV)
  • One exemplary and prefened reaction mixture for ketal deprotection is prepared by dissolving the compound of Formula (XIII) in an alcohol or ether, preferably ethanol or THF, and slowly adding one equivalent of aqueous hydrochloric acid to the solution.
  • an alcohol or ether preferably ethanol or THF
  • aqueous hydrochloric acid preferably ethanol or THF
  • dropwise addition of a 5.7% solution of HCl in ethanol is especially prefened while, when the solvent is THF, dropwise addition of 37% HCl in water is prefened.
  • Hydrolysis should go substantially to completion after about three hours at ambient temperature (the temperature of the solution increases by about 5°C to about 10°C due to exothermicity of the reaction).
  • the solvent is evaporated leaving the hydrochloride salt as a residue. Care should be taken to evaporate the solvent without excessive heating because the salt starts to decompose above about 60 °C.
  • the salt also is hygroscopic. When aqueous acid is used as the acid catalyst, rotary evaporation at mild temperatures will not remove all of the water. It is desirable to further dry the salt before silylating the hydroxy groups in the next reaction. To further dry the salt, it can be taken up in THF and stirred over 4A molecular sieves. Drying over molecular sieves was found to reduce the water content of the salt from about 2% to about 0.8% (Karl Fischer).
  • drying agents like MgSO 4 and CaCl 2 can be used, they were found to be less effective at drying the hydrochloride salt.
  • the dried salt can be used conveniently as the starting material in the silylation step that follows.
  • the 7-ammo-3,5-dihydroxy heptanoic acid ester can be silylated under the same conditions as the 6-cyano-3,5-dihydroxy heptanoic acid esters of Formula (X).
  • silylating compounds of Formula (XTV) which are functionalized with a nucleophilic amine group, it is preferable to use a monofunctional silylating agent.
  • the silylating agent will bond to the amine as well as the hydroxyl groups.
  • an excess of the monofunctional silylating agent and acid scavenger yet more preferably from about three to about five molar equivalents of a monofunctional silylating agent with respect to the compound of Formula (XTV) and from about four to about six molar equivalents of the acid scavenger. It is acceptable that some monofunctional silyating agent react with the amine to form tri-silylated compounds of Formula (NUT):
  • the acid scavenger is triethyl -irnine
  • the solvent is THF or toluene
  • silylether-diprotected 7-amino-3,5-dihydroxy heptanoic acid ester in either free base or pivalate salt form can be used as starting material for the Paal-Knon synthesis of silylether-diprotected 3,5-dihydroxy-7-pynol-l-yl heptanoic acid esters of Formulae (XV) and (XVI)
  • the Paal-Knon reaction is preferably carried out at elevated temperature, with an added acid catalyst if the amine starting material is not a pivalate salt, and with evaporative removal of water employing generally the conditions previously described for reacting compounds of Formulae (VI) and (VII).
  • the product is desilylated, hydrolyzed to the free acid (or lactone) and optionally salif ⁇ ed.
  • the silyl protecting group(s) can be removed conventionally using reagents that generate fluoride anion, such as tetrabutylammonium fluoride ("TBAF"), HF/pyridine, HF/Et 3 N, BF 3 'H 2 O and LiBF 4 .
  • TBAF tetrabutylammonium fluoride
  • HF/pyridine HF/pyridine
  • HF/Et 3 N HF/Et 3 N
  • BF 3 'H 2 O LiBF 4 .
  • silyl protecting group of compounds of Formulae (XV) and (XVI) can be removed concurrently with hydrolysis of the ester group using an alkali metal hydroxide, alkoxide or carbonate such as sodium hydroxide, potassium hydroxide, and potassium carbonate. It will be appreciated that changing a protecting group ordinarily introduces two additional steps to a synthesis: deprotection of the original protecting group and addition of the new group. However, replacement of the ketal protecting group of compounds of Formulae (V) and (XIII) with silyl protecting groups introduces only one additional step to the synthesis of compounds of Formula (I) because the silyl group is removed under the same conditions employed in hydrolyzing the ester.
  • Silyl groups with aryl substituents like SiPh 2 are more susceptible to removal by a strong base.
  • Suitable solvents for base-induced desilylation include but are not limited to the alcohol solvents listed above in the acetonide deprotecting step.
  • the Formula (XV) or (XVI) compound is concunently desilylated and hydrolyzed with sodium hydroxide in methanol and the compound of Formula (I) is recovered as its sodium salt.
  • the present invention provides a process for preparing atorvastatin by contacting a ketal-protected 7-amino-3R,5R-dihydroxy heptanoic acid ester of Formula (Xffl')
  • One undesired side product of the Paal-Knon reaction is a compound of Formula (XVIII):
  • Another impurity that is found in the product mixture is the desfluoro compound of Formula (XTV), which may be derived from unfluorinated diketo starting material.
  • the compounds are carried forward when the acetonide and ester groups are removed to form the conesponding tetrahydroxy compound 10 and desfluoiOatorvastatin 11
  • the Paal-Knon reaction is carried out in a single component solvent system of a low boiling point ether that is at least of technical grade purity and with pivalic acid as the acid catalyst.
  • the solvent is tetrahydrofuran.
  • the pivalic acid may be added to the reaction mixture either separately or as a pivalate salt of the ketal-protected 7- amino-3R,5R-dihydroxy heptanoic acid ester.
  • the solution is heated to reflux. Under these conditions, the reaction goes to completion in from about 24 to about 72 hours.
  • the reaction mixture is concentrated, either on a rotary evaporator or by distillation.
  • the residue of evaporation is dissolved in a lower alkyl alcohol such as methanol, ethanol, or isopropanol and then heated until it dissolves. Water is then added. The mixture is cooled and stirred at ambient temperature for 1 to 24 hours to precipitate the product, which is then separated from the reaction mixture, e.g. by filtering or decanting.
  • a lower alkyl alcohol such as methanol, ethanol, or isopropanol
  • the 3,5-dihydroxy-7-pynol-l-yl heptanoic acid ester of Formula (XVLT) can be converted to atorvastatin by contacting it with an acid like aqueous HCl to remove the acetonide protecting group followed by contacting with Ca(OH) 2 to hydrolyze the ester and form the calcium salt as taught in commonly-assigned U.S. Patent No. 6,528,661, which is hereby incorporated by reference in its entirety.
  • the ketal of the Formula (XVII') compound may be cleaved with an acid and the ester group hydrolyzed with an alkali metal hydroxide, alkoxide or carbonate, such as sodium hydroxide, resulting in an alkali metal salt of atorvastatin.
  • the alkali metal salt may then be transposed, if so desired, with calcium chloride to atorvastatin hemi-calcium as described in Example 10 of U.S. Patent No. 5,273,995, with calcium acetate as described in U.S. Patent No. 5,298,627 or by other means known to one of skill in the art.
  • Compounds of Formula (I) are known to be useful in plasma cholesterol reduction therapy. Accordingly, the products of the present inventive processes, including their pharmaceutially acceptable salts, find use in treatment of hypercholesterolemia and hyperlipidemia.
  • Triflate Trifluoromethanesulfonate Method A Synthesis by Oxidation of A Ketal-Protected 3.5-Dihvdro ⁇ y-7-Pvnol-l-yl-l- Heptanol to A Ketal-Protected 3,5-Dihvdroxy-7-Pvnol-l-yl Heptanoic Acid
  • pivalate salt 3 (0.67 g, 2.2 mmol) prepared as described in Example 2, 4-fluoro- ⁇ -(2-methyl-l-oxopropyl- ⁇ -oxo-N, ⁇ - diphenylbenzenebutana ide 9 (0.76 g, 1.83 mmole) and toluene (10 ml).
  • the stirred mixture was refluxed for 27 hours and washed twice with water (15 ml)(ethyl acetate and NaCl were added to assist in the separation).
  • the organic phase was dried over MgSO and evaporated, leaving a residue ofthe title compound (0.86 g, 80.1%).
  • the solvent was stripped on a rotary evaporator at 20 mm Hg vacuum at 50°C.
  • the 10 residue (112 g, quant.) was dissolved in THF (335 g) and dried over molecular sieves (33 g).
  • Example 7 The product residue of Example 7 was dissolved in toluene (300 g). To a 3 -necked, round-bottom flask equipped with a mechanical stiner, a thermometer and a Dean-Stark apparatus was added toluene (20 g), a portion of the toluenic solution of compound 17 (47 g solution, 9.2 g, 20 mmol), 1,4-diketone 9 (3 g, 7 mmol) and pivalic acid (0.5 g, 5 mmol). The mixture was heated to reflux and allowed to reflux through the Dean Stark apparatus for 17 h.
  • reaction mixture was washed with water (50 g) to give a toluene solution (60 g) contain crude compound 18.
  • 6-cyano-3,5-dihydroxy heptanoic acid tert-butyl ester 11.19 g, 48.8 mmol
  • dichloromethane 60 ml
  • HOBT HOBT
  • Et 3 N 21 ml
  • a solution of dichlorodiisopropylsilane (10 ml) in dichloromethane 35 ml was added dropwise to the flask over 25 min. while the temperature was monitored so as to not exceed 30°C. The mixture was stirred at reflux for 4 h and then cooled to room temperature.
  • a solution of compound 5 (7.82 g, 22.9 mmol) prepared as described in Example 10 was dissolved in a solution of 12% NH 3 in methanol (100 ml) and added to a Pan shaker containing Raney nickel that had been washed with absolute ethanol before use. The solution was shaken under 65-73 psi. hydrogen pressure for 7.75 hr. The Raney nickel was removed by filtering through a pad of celite under nitrogen stream to avoid ignition of the Raney nickel and washed with methanol. The filtrate was concentrated at reduced pressure to yield 7.14 g (90.2%) of the title compound as a green oil.
  • Example 17 To a 500 ml 3-necked round bottom flask equipped with thermometer, condenser and magnetic stiner, were added compound 16 (30 g, 0.109 mole), pivalic acid (5.17 g, 50 mmol), 1,4 diketone 9 (35.2 g, 85 mmol) and THF (180 ml). The mixture was refluxed for 72 h and cooled to 25 °C. The brown oil residue was dissolved in 260 ml ethanol by heating to 65 °C. Water (100 ml) was added dropwise over 45 min. The mixture was cooled slowly to room temperature and stirred overnight. The precipitated solid was filtered, washed with 5:2 ethanol: water and dried at 60 °C overnight to give the title compound as an off-white solid (41.5 g, 75.1% yield).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP03786885A 2002-11-15 2003-11-17 Synthese von 3,5-dihydroxy-7-pyrrol-1-yl-heptansäuren Withdrawn EP1480943A2 (de)

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
US42634202P 2002-11-15 2002-11-15
US426342P 2002-11-15
US46611403P 2003-04-29 2003-04-29
US466114P 2003-04-29
US48044003P 2003-06-23 2003-06-23
US480440P 2003-06-23
US48338103P 2003-06-27 2003-06-27
US483381P 2003-06-27
PCT/US2003/037026 WO2004046105A2 (en) 2002-11-15 2003-11-17 Synthesis of 3,5-dihydroxy-7-pyrrol-1-yl heptanoic acids

Publications (1)

Publication Number Publication Date
EP1480943A2 true EP1480943A2 (de) 2004-12-01

Family

ID=32330042

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03786885A Withdrawn EP1480943A2 (de) 2002-11-15 2003-11-17 Synthese von 3,5-dihydroxy-7-pyrrol-1-yl-heptansäuren

Country Status (3)

Country Link
EP (1) EP1480943A2 (de)
AU (1) AU2003295684A1 (de)
WO (1) WO2004046105A2 (de)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008533128A (ja) * 2005-03-14 2008-08-21 ファイザー・サイエンス・アンド・テクノロジー・アイルランド・リミテッド Ｐａａｌ−Ｋｎｏｒｒ縮合を用いた、アトルバスタチン中間体の製造
GB2424880A (en) * 2005-04-06 2006-10-11 Generics Crystalline forms of atorvastatin sodium, processes for their preparation and their use in inhibiting HMG-CoA reductase
SI22255A (sl) * 2006-04-14 2007-10-31 Krka, Tovarna Zdravil, D.D., Novo Mesto Novi polimorfi statinovih soli in njihova uporabav farmacevtskih formulacijah
US20090081801A1 (en) * 2007-08-15 2009-03-26 Vinod Kumar Kansal Process for synthesis of pyrrole derivative, an intermediate for atorvastatin
KR100850558B1 (ko) * 2008-01-02 2008-08-06 조동옥 아토르바스타틴의 효율적인 제조방법
CN103184248B (zh) * 2011-12-29 2016-02-10 杭州师范大学 一种酶催化合成n-取代的吡咯环类衍生物的方法
CN102796036B (zh) * 2012-09-12 2014-06-04 江苏阿尔法药业有限公司 一种阿托伐他汀钙的制备方法
CN111788196A (zh) * 2018-01-09 2020-10-16 配体药物公司 缩醛化合物及其治疗用途
CN109232353A (zh) * 2018-10-09 2019-01-18 河南师范大学 一种阿托伐他汀钙缩合物的制备方法
CN109232354A (zh) * 2018-10-09 2019-01-18 河南师范大学 一种高纯度阿托伐他汀钙原料药的制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5003080A (en) * 1988-02-22 1991-03-26 Warner-Lambert Company Process for trans-6-(2-(substituted-pyrrol-1-yl)alkyl)pryan-2-one inhibitors of cholesterol synthesis
IT1237792B (it) * 1989-12-21 1993-06-17 Zambon Spa Composti attivi come inibitori dell'enzima hmg-coa reduttasi
US6476235B2 (en) * 2001-01-09 2002-11-05 Warner-Lambert Company Process for the synthesis of 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide
CA2448917A1 (en) * 2001-07-06 2003-01-16 Reinhold Ohrlein Process for the preparation of intermediates useful in the synthesis of statin derivatives especially 7-amino 3,5-dihydroxy heptanoic acid derivatives, and intermediates thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004046105A3 *

Also Published As

Publication number Publication date
WO2004046105A2 (en) 2004-06-03
AU2003295684A1 (en) 2004-06-15
AU2003295684A8 (en) 2004-06-15
WO2004046105A3 (en) 2004-10-07

Similar Documents

Publication Publication Date Title
US5216174A (en) Process for trans-6-[12-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
EP0330172B1 (de) Verfahren zur Herstellung von Trans-6-[2-(substituierte pyrol-1-yl)alkyl]pyran-2-on als Cholesterolsynthesehemmer
US5280126A (en) Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5124482A (en) Process for trans-6-(2-substituted-pyrrol-1-yl)alkyl)pyran-2-one inhibitors of cholesterol synthesis
US5149837A (en) Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5097045A (en) Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
JP4524111B2 (ja) ＨＭＧ−ＣｏＡ還元酵素阻害剤の製造法
US5550152A (en) Benzopyran and related LTB4 antagonists
SK282909B6 (sk) Amidy kyseliny dihydroxyheptánovej a spôsob ich prípravy
EP1480943A2 (de) Synthese von 3,5-dihydroxy-7-pyrrol-1-yl-heptansäuren
JP5150501B2 (ja) ＨＭＧ−ＣｏＡ還元酵素阻害薬を合成する方法
US6278001B1 (en) Method for preparing (+) compactin and (+) mevinolin analog compounds having a β-hydroxy-δ-lactone grouping
JP2007513077A (ja) スタチン類の製造方法
US4611068A (en) Process for the preparation of HMG-CoA reductase inhibitors and intermediate compounds employed therein
SK12582000A3 (sk) Spôsob prípravy simvastatínu a jeho derivátov
US5049578A (en) 1-aroyl or 1-acyl-2-2pyrrolidinyl-3,5-dihydroxy alkanoic and alkenoic acids, salts, esters and lactones
US7528265B2 (en) Process for the preparation of simvastatin
JP3802481B2 (ja) スタチンの製造における新しいラクトン化方法
KR100322630B1 (ko) 심바스타틴및 이의 중간체 화합물을 제조하는 방법
KR20160126700A (ko) 스타틴의 중간체, 이의 제조방법 및 이를 이용한 로수바스타틴의 제조방법
US6291696B2 (en) Preparation of tris (trimethylsilyl) silylethyl esters
WO2002024675A1 (en) Process for manufacturing simvastatin and the novel intermediates
KR0137884B1 (ko) 콜레스테롤 합성 억제제인 트란스-6-[2-(치환-피롤-1-일)알킬] 피란-2-온의 개량된 제조 방법
PL208279B1 (pl) Sposób wytwarzania 4-oksytetrahydropiran-2-onów
AU3349689A (en) Improved process for trans-6-(2-(substituted-pyrrol-1-yl) alkyl)pyran-2-one inhibitors of cholesterol synthesis

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20040715

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20060531