WO2001000577A2 - Preparation of substituted piperidin-4-ones - Google Patents

Preparation of substituted piperidin-4-ones Download PDF

Info

Publication number
WO2001000577A2
WO2001000577A2 PCT/US2000/015029 US0015029W WO0100577A2 WO 2001000577 A2 WO2001000577 A2 WO 2001000577A2 US 0015029 W US0015029 W US 0015029W WO 0100577 A2 WO0100577 A2 WO 0100577A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
alkyl
refers
compound
phenyl
Prior art date
Application number
PCT/US2000/015029
Other languages
French (fr)
Other versions
WO2001000577A3 (en
Inventor
John Robert Rizzo
Michael Alexander Staszak
Tony Yantao Zhang
Original Assignee
Eli Lilly And Company
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
Priority to US10/018,036 priority Critical patent/US6538136B1/en
Priority to EA200200101A priority patent/EA200200101A1/en
Priority to EP00939451A priority patent/EP1196382A2/en
Priority to BR0011996-2A priority patent/BR0011996A/en
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to JP2001506987A priority patent/JP2003522122A/en
Priority to IL14633900A priority patent/IL146339A0/en
Priority to AU54535/00A priority patent/AU770759B2/en
Priority to MXPA01012727A priority patent/MXPA01012727A/en
Priority to KR1020017016848A priority patent/KR20020015068A/en
Priority to SK1901-2001A priority patent/SK19012001A3/en
Priority to CA002370491A priority patent/CA2370491A1/en
Publication of WO2001000577A2 publication Critical patent/WO2001000577A2/en
Priority to NO20016151A priority patent/NO20016151L/en
Publication of WO2001000577A3 publication Critical patent/WO2001000577A3/en
Priority to HK02106801.4A priority patent/HK1045309A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/02—Preparation by ring-closure or hydrogenation

Definitions

  • the present invention provides a novel process for the preparation of substituted piperidin-4-ones useful as intermediates in the preparation of pharmaceuticals.
  • the present invention provides a process for the preparation of a compound of formula I:
  • R is hydrogen, CrC 6 alkyl, halo(CrC 6 )alkyl, phenyl, benzyl, or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, d-C-e alkyl, C C 6 alkoxy, halo(CrC 6 )alkyI, phenyl, N0 2) and CN;
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently hydrogen, C C 6 alkyl, halo(d- C 6 )alkyl, phenyl, or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, C C 6 alkyl, CrC 6 alkoxy, -S(C C 6 alkyl), -S(phenyl), halo(C C 6 )alkyl, phenyl, N0 2 , and CN; or the
  • Halo As used herein, the terms "Halo”, “Halide” or “Hal” refers to a chlorine, bromine, iodine or fluorine atom, unless otherwise specified herein.
  • Me refers to a methyl group
  • Et refers to an ethyl group
  • Pr refers to a propyl group
  • iPr refers to an isopropyl group
  • Bu refers to a butyl group
  • Ph refers to a phenyl group
  • benzyl refers to a -CHaphenyl group.
  • C- 1 -C 4 alkyl refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like.
  • CrC 6 alkyl refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like.
  • the term “CrC 6 alkyl” includes within its scope “C 1 -C 4 alkyl”.
  • C ⁇ -C 6 alkoxy refers to a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom.
  • Typical C 1 -C 6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like.
  • the term “CrC ⁇ alkoxy” includes within its definition the term “C1-C4 alkoxy”.
  • -S(CrC 6 alkyl) refers to a straight or branched alkyl chain having from one to six carbon atoms attached to a sulfur atom such as -SCH 3 , -SCH 2 CH 3 , -SCH2CH2CH3, -SCH 2 CH 2 CH 2 CH3, and the like.
  • halo(CrC 6 )alkyl refers to a straight or branched alkyl chain having from one to six carbon atoms with 1 , 2 or 3 halogen atoms attached to it.
  • Typical halo(CrC 6 )alkyl groups include chloromethyl, 2- bromoethyl, 1 -chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl and the like.
  • halo(CrC 6 )alkyl includes within its definition the term "halo(C ⁇ -C 4 )alkyl".
  • This invention includes the hydrates and the pharmaceutically acceptable salts of the compounds of formula I.
  • a compound of this invention can possess a sufficiently basic functional group which can react with any of a number of inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to salts of the compounds of formula I which are substantially non-toxic to living organisms.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid. Such salts are also known as acid addition salts.
  • Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • salts examples include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1 ,4-dioate, hexyne-1 ,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate
  • any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. It is further understood that such salts may exist as a hydrate.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three- dimensional structures which are not interchangeable. The three-dimensional structures are called configurations.
  • enantiomer refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
  • chiral center refers to a carbon atom to which four different groups are attached.
  • diastereomers refers to stereoisomers which are not enantiomers.
  • two diastereomers which have a different configuration at only one chiral center are referred to herein as “epimers”.
  • racemate racemic mixture
  • racemic modification refer to a mixture of equal parts of enantiomers.
  • enantiomeric enrichment refers to the increase in the amount of one enantiomer as compared to the other.
  • E 1 is the amount of the first enantiomer and E 2 is the amount of the second enantiomer.
  • the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 50:30 is achieved, the ee with respect to the first enantiomer is 25%.
  • the final ratio is 90:10, the ee with respect to the first enantiomer is 80%.
  • An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred.
  • Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art.
  • the enantiomers of compounds of formula I can be resolved by one of ordinary skill in the art using standard techniques well known in the art, such as those described by J. Jacques, et al., “Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981.
  • Some of the compounds of the present invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations.
  • the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers, and diastereomers are within the scope of the present invention.
  • the terms "R” and “S” are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center.
  • the term “R” (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • S sinister
  • S refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the priority of groups is based upon their atomic number (in order of decreasing atomic number).
  • a partial list of priorities and a discussion of stereochemistry is contained in "Nomenclature of Organic Compounds: Principles and Practice", (J.H. Fletcher, et al., eds., 1974) at pages 103-120.
  • the specific stereoisomers and enantiomers of compounds of formula (I) can be prepared by one of ordinary skill in the art utilizing well known techniques and processes, such as those disclosed by Eliel and Wilen, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., 1994, Chapter 7 Separation of Stereoisomers. Resolution. Racemization, and by Collet and Wilen, "Enantiomers, Racemates, and Resolutions", John Wiley & Sons, Inc., 1981.
  • the specific stereoisomers and enantiomers can be prepared by stereospecific syntheses using enantiomerically and geometrically pure, or enantiomerically or geometrically enriched starting materials.
  • the specific stereoisomers and enantiomers can be resolved and recovered by techniques such as chromatography on chiral stationary phases, enzymatic resolution or fractional recrystallization of addition salts formed by reagents used for that purpose.
  • step A the compound of formula IV is combined with the compound of formula III in a suitable organic solvent, such as ethanol and the mixture is further combined with a compound of formula II in the presence of a suitable acid.
  • a suitable acid are inorganic or organic Bronsted acids, which include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, formic acid, trifluoroacetic acid, acetic acid, chloroacetic acid, and the like.
  • Step B a suitable base is added followed by addition of about 1 equivalent of compound of formula V.
  • a suitable base examples include inorganic or organic bases well known in the art, which include but are not limited to, trialkylamines, such as triethylamine, tributylamine, diisopropylethylamine, isopropyldiethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate tribasic, and the like.
  • trialkylamines such as triethylamine, tributylamine, diisopropylethylamine, isopropyldiethylamine
  • potassium hydroxide sodium hydroxide
  • potassium carbonate sodium carbonate
  • potassium phosphate tribasic and the like.
  • the reaction is stirred at a temperature of from about 50 °C to about 80 °C, preferably reflux, for about 2 hours to about 16 hours.
  • the compound of formula I is then isolated and purified using techniques and procedures well known in the art. For example, the reaction mixture is cooled to about 5°C and treated with about one equivalent of base, such as potassium hydroxide dissolved in water. The mixture is then extracted with a suitable organic solvent, such as heptane and MTBE. The organic extracts are then combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the compound of formula I. The compound of formula I is then purified by recrystallization or flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane to provide purified compound of formula I.
  • base such as potassium hydroxide dissolved in water
  • a suitable organic solvent such as heptane and MTBE.
  • the organic extracts are then combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the compound of formula I.
  • the compound of formula I is then purified by recrystall
  • the salt of the product can be isolated using standard techniques well known in the art without treating with base.
  • the following examples represent the process of the present invention as described generally above in Scheme I. These examples are illustrative only and are not intended to limit the invention in any way.
  • the reagents and starting materials are readily available to one of ordinary skill in the art.
  • the reaction mixture is then cooled to 5°C and treated with potassium hydroxide (1 17.6 g, 2.1 mol, dissolved in 200 mL of water).
  • the reaction mixture is then extracted with heptane (2 X 500 mL) and MTBE (2 X 500 mL).
  • the organic extracts is then combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the title compound, (339.36 g after 18% by volume of the above combined organic extracts was removed prior to concentration).
  • This material was purified by chromatography on silica gel (methylene chloride/ethanol, 100:1) to provide purified title compound.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention provides a novel process for the preparation of substituted piperidin-4-ones useful as intermediates in the preparation of pharmaceuticals.

Description

PREPARATION OF SUBSTITUTED PIPERIDIN-4-ONES
The present invention provides a novel process for the preparation of substituted piperidin-4-ones useful as intermediates in the preparation of pharmaceuticals.
G.T. Katvalyan and E.A. Mistryukov, Izv. Akad. Nauk SSSR, Ser. Khim., H. 2575 (2436 transl.) (1968) disclose a multistep synthesis of 1-methyl-3,3- dimethyl-piperidin-4-one starting with methylamine and isobutyraldehyde. In addition, I.V. Micovic, et al., J. Chem. Soc, Perkin Trans., 1, 2041 (1996) disclose a multistep synthesis of 1-benzyl-3,3-gem-dimethyl-piperdine-4-one starting with benzylamine and methyl acrylate.
It has now been discovered that 3-substituted piperidones can be prepared simply and efficiently following the one-pot procedure of the present invention, thus obviating the traditionally lengthy syntheses such as those requiring a Dieckmann condensation.
The present invention provides a process for the preparation of a compound of formula I:
formula I
Figure imgf000002_0001
wherein R is hydrogen, CrC6 alkyl, halo(CrC6 )alkyl, phenyl, benzyl, or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, d-C-e alkyl, C C6 alkoxy, halo(CrC6)alkyI, phenyl, N02) and CN; R1, R2, R3, R4, R5 and R6 are each independently hydrogen, C C6 alkyl, halo(d- C6 )alkyl, phenyl, or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, C C6 alkyl, CrC6 alkoxy, -S(C C6 alkyl), -S(phenyl), halo(C C6)alkyl, phenyl, N02, and CN; or the pharmaceutically acceptable salt thereof; comprising combining a compound of formula II:
formula II
Figure imgf000003_0001
wherein R1, R2, R3, and R4 are defined as above, a compound of formula
O nδ/'X formula III
wherein R° is defined as above, and a compound of formula IV:
R-NH "„2 formula IV wherein R is defined as above, in the presence of a suitable acid; followed by addition of a suitable base and a compound of formula V:
formula V
Figure imgf000003_0002
wherein R6 is defined as above.
As used herein, the terms "Halo", "Halide" or "Hal" refers to a chlorine, bromine, iodine or fluorine atom, unless otherwise specified herein.
As used herein, the term "Me" refers to a methyl group, the term "Et" refers to an ethyl group, the term "Pr" refers to a propyl group, the term "iPr" refers to an isopropyl group, the term "Bu" refers to a butyl group, the term "Ph" refers to a phenyl group, the term "benzyl" refers to a -CHaphenyl group.
As used herein the term "C-1-C4 alkyl" refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like.
As used herein the term "CrC6 alkyl" refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like. The term "CrC6 alkyl" includes within its scope "C1-C4 alkyl".
As used herein the term "Cι-C6 alkoxy" refers to a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Typical C1-C6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term "CrCβ alkoxy" includes within its definition the term "C1-C4 alkoxy".
As used herein the term "-S(CrC6 alkyl)" refers to a straight or branched alkyl chain having from one to six carbon atoms attached to a sulfur atom such as -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2CH2CH2CH3, and the like.
As used herein the term "halo(CrC6)alkyl" refers to a straight or branched alkyl chain having from one to six carbon atoms with 1 , 2 or 3 halogen atoms attached to it. Typical halo(CrC6)alkyl groups include chloromethyl, 2- bromoethyl, 1 -chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl and the like. The term "halo(CrC6)alkyl" includes within its definition the term "halo(Cι-C4)alkyl".
This invention includes the hydrates and the pharmaceutically acceptable salts of the compounds of formula I. A compound of this invention can possess a sufficiently basic functional group which can react with any of a number of inorganic and organic acids, to form a pharmaceutically acceptable salt.
The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds of formula I which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid. Such salts are also known as acid addition salts.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1 ,4-dioate, hexyne-1 ,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, g-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1 -sulfonate, napththalene-2- sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid, oxalic acid and methanesulfonic acid.
It should be recognized that the particular counte on forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. It is further understood that such salts may exist as a hydrate.
The designation " -^^ " refers to a bond that protrudes forward out of the plane of the page.
The designation ' "'"i " refers to a bond that protrudes backward out of the plane of the page.
As used herein, the term "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three- dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term "enantiomer" refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another. The term "chiral center" refers to a carbon atom to which four different groups are attached. As used herein, the term "diastereomers" refers to stereoisomers which are not enantiomers. In addition, two diastereomers which have a different configuration at only one chiral center are referred to herein as "epimers". The terms "racemate", "racemic mixture" or "racemic modification" refer to a mixture of equal parts of enantiomers.
The term "enantiomeric enrichment" as used herein refers to the increase in the amount of one enantiomer as compared to the other. A convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or "ee", which is found using the following equation: ee = E1 - E2 X 100
E^ F
wherein E1 is the amount of the first enantiomer and E2 is the amount of the second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 50:30 is achieved, the ee with respect to the first enantiomer is 25%. However, if the final ratio is 90:10, the ee with respect to the first enantiomer is 80%. An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art. In addition, the enantiomers of compounds of formula I can be resolved by one of ordinary skill in the art using standard techniques well known in the art, such as those described by J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981. Some of the compounds of the present invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers, and diastereomers are within the scope of the present invention. The terms "R" and "S" are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term "R" (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term "S" (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in "Nomenclature of Organic Compounds: Principles and Practice", (J.H. Fletcher, et al., eds., 1974) at pages 103-120.
The specific stereoisomers and enantiomers of compounds of formula (I) can be prepared by one of ordinary skill in the art utilizing well known techniques and processes, such as those disclosed by Eliel and Wilen, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., 1994, Chapter 7 Separation of Stereoisomers. Resolution. Racemization, and by Collet and Wilen, "Enantiomers, Racemates, and Resolutions", John Wiley & Sons, Inc., 1981. For example, the specific stereoisomers and enantiomers can be prepared by stereospecific syntheses using enantiomerically and geometrically pure, or enantiomerically or geometrically enriched starting materials. In addition, the specific stereoisomers and enantiomers can be resolved and recovered by techniques such as chromatography on chiral stationary phases, enzymatic resolution or fractional recrystallization of addition salts formed by reagents used for that purpose.
Compounds of formula I can be prepared by following the procedures as set forth in Scheme I. This scheme is not intended to limit the scope of the invention in any way. All substituents, unless otherwise indicated, are previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art.
Scheme I
formula I
Figure imgf000008_0001
formula V
R-NH. formula IV
In Scheme I, step A, the compound of formula IV is combined with the compound of formula III in a suitable organic solvent, such as ethanol and the mixture is further combined with a compound of formula II in the presence of a suitable acid. Examples of a suitable acid are inorganic or organic Bronsted acids, which include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, formic acid, trifluoroacetic acid, acetic acid, chloroacetic acid, and the like.
For example, about 2.25 equivalents of a compound of formula III is combined with a compound of formula IV in ethanol. This solution is slowly added to a solution of about 1.05 equivalents of compound of formula II in ethanol with about 1.0 to 1.2 equivalents of hydrochloric acid at a temperature of from about 50 °C to about 90 °C, preferably at reflux. After 8 hours to about 24 hours, preferably about 18 hours, in Step B, a suitable base is added followed by addition of about 1 equivalent of compound of formula V. Examples of a suitable base are inorganic or organic bases well known in the art, which include but are not limited to, trialkylamines, such as triethylamine, tributylamine, diisopropylethylamine, isopropyldiethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate tribasic, and the like. Alternatively, when R5 = R6, all of the aldehyde can be added in one portion. The reaction is stirred at a temperature of from about 50 °C to about 80 °C, preferably reflux, for about 2 hours to about 16 hours.
The compound of formula I is then isolated and purified using techniques and procedures well known in the art. For example, the reaction mixture is cooled to about 5°C and treated with about one equivalent of base, such as potassium hydroxide dissolved in water. The mixture is then extracted with a suitable organic solvent, such as heptane and MTBE. The organic extracts are then combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the compound of formula I. The compound of formula I is then purified by recrystallization or flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane to provide purified compound of formula I. Alternatively, the salt of the product can be isolated using standard techniques well known in the art without treating with base. The following examples represent the process of the present invention as described generally above in Scheme I. These examples are illustrative only and are not intended to limit the invention in any way. The reagents and starting materials are readily available to one of ordinary skill in the art. As used herein, the following terms have the meanings indicated: "eq" or "equiv." refers to equivalents; "g" refers to grams; "mg" refers to milligrams; "L" refers to liters; "ml_" refers to milliliters; "μl_" refers to microliters; "mol" refers to moles; "mmol" refers to millimoles; "psi" refers to pounds per square inch; "mm Hg" refers to millimeters of mercury; "min" refers to minutes; "h" or "hr" refers to hours; "°C" refers to degrees Celsius; "TLC" refers to thin layer chromatography; "HPLC" refers to high performance liquid chromatography; "Rf" refers to retention factor; "Rt" refers to retention time; "δ'Yefers to part per million down-field from tetramethylsilane; "THF" refers to tetrahydrofuran; "DMF" refers to N,N- dimethylformamide; "DMSO" refers to methyl sulfoxide; "LDA" refers to lithium diisopropylamide; "aq" refers to aqueous; "EtOAc" refers to ethyl acetate; "iPrOAc" refers to isopropyl acetate; "MeOH" refers to methanol; "MTBE" refers to tert-butyl methyl ether; "TMEDA" refers to N,N,N',N'- tetramethylethylenediamine, and "RT" refers to room temperature. Example 1 Preparation of N-Benzyl-3,3-dimethyl-piperidin-4-one.
Figure imgf000010_0001
Scheme I: Benzylamine (214 g, 2 mol) is combined with formaldehyde
(37% in water, 375 g, 4.5 mol) in ethanol (1 L) with occasional cooling. This biphasic mixture is added over a period of 90 minutes to a refluxing solution of 2- methyl-3-butanone (182 g, 2.11 mol) in anhydrous ethanol (1 L) and hydrochloric acid (209 g of 37% solution, 2.1 mol). The brownish solution is heated at reflux for an additional 18 hours. Then triethylamine (310 mL, 223.8 g, 2.21 mol) and formaldehyde (50 g, 36%, 0.6 mol) are added sequentially and the reaction mixture is heated at reflux for 24 hours. The reaction mixture is then cooled to 5°C and treated with potassium hydroxide (1 17.6 g, 2.1 mol, dissolved in 200 mL of water). The reaction mixture is then extracted with heptane (2 X 500 mL) and MTBE (2 X 500 mL). The organic extracts is then combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the title compound, (339.36 g after 18% by volume of the above combined organic extracts was removed prior to concentration). This material was purified by chromatography on silica gel (methylene chloride/ethanol, 100:1) to provide purified title compound.
1H NMR (CDCI3) δ 1.14 (s, 6H), 2.41 (s,2H), 2.52 (t, 2H), 2.72 (t, 2H), 3.57 (s, 2H), 7.2-7.4 (m, 5H). Example 2 Alternative Preparation of N-Benzyl-3,3-dimethyl-piperidin-4-one.
In a 1 liter 3-necked flask equipped with mechanical stirring, addition funnel and a calcium chloride drying tube is added a 37% weight solution of formaldehyde (168.5 mL, 2.25 mole) dissolved in 500 mL of absolute ethanol. The resulting solution is cooled in an ice-water bath to 10°C, and benzylamine (109 mL, 1 mole) is added dropwise over a one hour period. In a separate 3 liter 3-necked flask equipped with mechanical stirring, addition funnel and two condensers is added 3-methyl-2-butanone (113 mL, 1.06mole) dissolved in 500ml of absolute ethanol and concentrated hydrogen chloride (92 mL, 1.11 mole). The resulting solution is brought to reflux and the formaldehyde/benzylamine solution is added dropwise over a 2 hour period. This solution is refluxed overnight, and then cooled to ambient temperature. Diisopropylethylamine (142.2 g, 1.1 mole) and formaldehyde (22.46 mL,
0.3mole) are added and the resulting solution is heated to reflux for six hours, and then cooled to ambient temperature. The solution is quenched with potassium hydroxide (61.6 g, 1.1 mole) in 200 mL of water, and then extracted with 500 mL ethyl acetate three times. The organics are concentrated under vacuum to give 225 g of red oil. The crude oil is dissolved in 1 liter of methylene chloride. This solution is carefully poured over 1 kg of silica gel on a sintered glass filter. The silica gel is washed with 4 L of methylene chloride. The methylene chloride is concentrated under vacuum to provide 142 g of a yellow oil which crystallizes in the freezer overnight. Yield=65.4%. While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood by one of the ordinary skill in the art, that the practice of the invention encompasses all of the usual variations, adaptations, or modifications, as come within the scope of the following claims and its equivalents.

Claims

WHAT IS CLAIMED IS:
1. A process for the preparation of a compound of formula I:
formula I
Figure imgf000012_0001
wherein R is hydrogen, CrC6 alkyl, halo(Cι-C6 )alkyl, phenyl, benzyl, or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, Cι-C6 alkyl, C C6 alkoxy, halo(C C6)alkyl, phenyl, N02, and CN; R1, R2, R3, R4, R5 and R6 are each independently hydrogen, C C6 alkyl, halo(C Cβjalkyl, phenyl, or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, d-C6 alkyl, CrC6 alkoxy, -S(C C6 alkyl), -S(phenyl), halo(C C6)alkyl, phenyl, N02, and CN; or the pharmaceutically acceptable salt thereof; comprising combining a compound of formula II:
formula II
Figure imgf000012_0002
wherein R1, R2, R3, and R4 are defined as above, a compound of formula III:
O
R5/\H formula i-i wherein R5 is defined as above, and a compound of formula IV:
R-NH2 formula IV wherein R is defined as above, in the presence of a suitable acid; followed by addition of a suitable base and a compound of formula V:
O R6/\|_| formula V
wherein R6 is defined as above.
2. The process according to claim 1 wherein the suitable base is diisopropylethylamine.
3. The process according to claim 2 wherein the suitable acid is HCI.
4. The process according to claim 3 wherein R1, R2, R3, R4, R5 and R6 are each independently hydrogen, C-i-Cβ alkyl, phenyl or benzyl.
5. The process according to claim 4 wherein R3 and R4 are CrC6 alkyl.
6. The process according to claim 4 wherein R5 is Cι-C6 alkyl and R6 is hydrogen.
The process according to claim 5 wherein R3 and R4 are methyl.
8. The process according to 6 wherein R5 is methyl.
9. The process according to claim 7 wherein R5 and R6 are hydrogen.
10. The process according to claim 9 wherein R1 and R2 are hydrogen.
11. The process according to claim 10 wherein R is hydrogen.
12. The process according to claim 10 wherein R is benzyl.
13. A process for the preparation of a compound of formula
formula
Figure imgf000014_0001
wherein R is hydrogen, C C6 alkyl, halo(CrC6 )alkyl, phenyl, benzyl, or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, CrC6 alkyl, C C6 alkoxy, halo(C C6)alkyl, phenyl, N02, and CN; R1, R2, R3, R4, R5 and R6 are each independently hydrogen, C C6 alkyl, halo(d- C6 )alkyl, phenyl, or phenyl substituted with from 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, CrC6 alkyl, C Cβ alkoxy, -S(Cι-C6 alkyl), -S(phenyl), halo(C C6)alkyl, phenyl, N02, and CN; or the pharmaceutically acceptable salt thereof; comprising combining a compound of formula II:
formula II
Figure imgf000014_0002
wherein R1, R2, R3, and R4 are defined as above, a compound of formula III:
Figure imgf000014_0003
formula III wherein R5 is defined as above, an excess of a compound of formula V:
formula V
Figure imgf000014_0004
wherein R6 is defined as above and R6 is the same as R5, and a compound of formula IV:
R-NH2 formula IV wherein R is defined as above, in the presence of a suitable acid; followed by addition of a suitable base.
PCT/US2000/015029 1999-06-29 2000-06-13 Preparation of substituted piperidin-4-ones WO2001000577A2 (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
IL14633900A IL146339A0 (en) 1999-06-29 2000-06-13 Preparation of substituted piperidin-4-ones
EP00939451A EP1196382A2 (en) 1999-06-29 2000-06-13 Preparation of substituted piperidin-4-ones
BR0011996-2A BR0011996A (en) 1999-06-29 2000-06-13 Preparation of substituted piperidin-4-ones
MXPA01012727A MXPA01012727A (en) 1999-06-29 2000-06-13 Preparation of substituted piperidin-4-ones.
JP2001506987A JP2003522122A (en) 1999-06-29 2000-06-13 Production of substituted piperidin-4-ones
EA200200101A EA200200101A1 (en) 1999-06-29 2000-06-13 RECEPTION OF SUBSTITUTED PIPERIDIN-4-ONES
AU54535/00A AU770759B2 (en) 1999-06-29 2000-06-13 Preparation of substituted piperidin-4-ones
US10/018,036 US6538136B1 (en) 1999-06-29 2000-06-13 Preparation of substituted piperidin-4-ones
KR1020017016848A KR20020015068A (en) 1999-06-29 2000-06-13 Preparation of Substituted Piperidin-4-Ones
SK1901-2001A SK19012001A3 (en) 1999-06-29 2000-06-13 Preparation of substituted piperidin-4-ones
CA002370491A CA2370491A1 (en) 1999-06-29 2000-06-13 Preparation of substituted piperidin-4-ones
NO20016151A NO20016151L (en) 1999-06-29 2001-12-17 Preparation of substituted piperidin-4-ones
HK02106801.4A HK1045309A1 (en) 1999-06-29 2002-09-17 Preparation of substituted piperidin-4-ones

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14147899P 1999-06-29 1999-06-29
US60/141,478 1999-06-29

Publications (2)

Publication Number Publication Date
WO2001000577A2 true WO2001000577A2 (en) 2001-01-04
WO2001000577A3 WO2001000577A3 (en) 2002-01-24

Family

ID=22495854

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/015029 WO2001000577A2 (en) 1999-06-29 2000-06-13 Preparation of substituted piperidin-4-ones

Country Status (23)

Country Link
US (1) US6538136B1 (en)
EP (1) EP1196382A2 (en)
JP (1) JP2003522122A (en)
KR (1) KR20020015068A (en)
CN (1) CN1356982A (en)
AU (1) AU770759B2 (en)
BR (1) BR0011996A (en)
CA (1) CA2370491A1 (en)
CO (1) CO5200762A1 (en)
CZ (1) CZ20014548A3 (en)
EA (1) EA200200101A1 (en)
EG (1) EG22530A (en)
HK (1) HK1045309A1 (en)
HU (1) HUP0201642A3 (en)
IL (1) IL146339A0 (en)
MX (1) MXPA01012727A (en)
NO (1) NO20016151L (en)
PE (1) PE20010300A1 (en)
PL (1) PL364868A1 (en)
SK (1) SK19012001A3 (en)
SV (1) SV2002000111A (en)
WO (1) WO2001000577A2 (en)
ZA (1) ZA200109206B (en)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7608630B2 (en) 2004-01-30 2009-10-27 Hainan Yangpu New Special Pharmaceutical Co., Ltd. Marasmius androsaceus L.es Fr extract, piperidone derivative, and their use for the preparation of hypertensives
US8049573B2 (en) 2004-06-03 2011-11-01 Silicon Laboratories Inc. Bidirectional multiplexed RF isolator
US7738568B2 (en) 2004-06-03 2010-06-15 Silicon Laboratories Inc. Multiplexed RF isolator
US8198951B2 (en) 2004-06-03 2012-06-12 Silicon Laboratories Inc. Capacitive isolation circuitry
US7902627B2 (en) 2004-06-03 2011-03-08 Silicon Laboratories Inc. Capacitive isolation circuitry with improved common mode detector
US7821428B2 (en) 2004-06-03 2010-10-26 Silicon Laboratories Inc. MCU with integrated voltage isolator and integrated galvanically isolated asynchronous serial data link
US7447492B2 (en) 2004-06-03 2008-11-04 Silicon Laboratories Inc. On chip transformer isolator
US7302247B2 (en) * 2004-06-03 2007-11-27 Silicon Laboratories Inc. Spread spectrum isolator
US8441325B2 (en) 2004-06-03 2013-05-14 Silicon Laboratories Inc. Isolator with complementary configurable memory
US8451032B2 (en) 2010-12-22 2013-05-28 Silicon Laboratories Inc. Capacitive isolator with schmitt trigger
US10290608B2 (en) 2016-09-13 2019-05-14 Allegro Microsystems, Llc Signal isolator having bidirectional diagnostic signal exchange
US11115244B2 (en) 2019-09-17 2021-09-07 Allegro Microsystems, Llc Signal isolator with three state data transmission

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE510184C (en) * 1927-06-03 1930-10-16 Carl Mannich Dr Process for the preparation of 2,6-dimethyl-4-ketopiperidine-3,5-dicarboxylic acid esters
US2883387A (en) * 1959-04-21 Chjch
US5846980A (en) * 1994-03-25 1998-12-08 Cooperation Pharmaceutique Francaise N-(benzhydryloxyalkyl)-4-(carboxy/carbamoyl methyl)-piperidine derivatives as antidepressants
EP0982304A1 (en) * 1998-06-30 2000-03-01 Eli Lilly And Company Piperidine derivatives having effects on serotonin related systems

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2883387A (en) * 1959-04-21 Chjch
DE510184C (en) * 1927-06-03 1930-10-16 Carl Mannich Dr Process for the preparation of 2,6-dimethyl-4-ketopiperidine-3,5-dicarboxylic acid esters
US5846980A (en) * 1994-03-25 1998-12-08 Cooperation Pharmaceutique Francaise N-(benzhydryloxyalkyl)-4-(carboxy/carbamoyl methyl)-piperidine derivatives as antidepressants
EP0982304A1 (en) * 1998-06-30 2000-03-01 Eli Lilly And Company Piperidine derivatives having effects on serotonin related systems

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MICOVIC ET AL.: "The Synthesis of Lactam Analogues of Fentanyl" J. CHEM. SOC. PERKIN TRANS. I, 1996, pages 2041-50, XP002910424 cited in the application *
NOLLER ET AL.: "The preparation of some piperidine derivatives by the mannich reaction" J. AM. CHEM. SOC, vol. 80, 1948, pages 3853-5, XP000971407 *

Also Published As

Publication number Publication date
EA200200101A1 (en) 2002-06-27
AU5453500A (en) 2001-01-31
US6538136B1 (en) 2003-03-25
SV2002000111A (en) 2002-01-23
NO20016151D0 (en) 2001-12-17
IL146339A0 (en) 2002-07-25
NO20016151L (en) 2001-12-17
ZA200109206B (en) 2003-05-28
HUP0201642A2 (en) 2002-09-28
CN1356982A (en) 2002-07-03
KR20020015068A (en) 2002-02-27
AU770759B2 (en) 2004-03-04
JP2003522122A (en) 2003-07-22
BR0011996A (en) 2002-03-05
MXPA01012727A (en) 2002-07-02
HUP0201642A3 (en) 2002-11-28
PE20010300A1 (en) 2001-03-07
PL364868A1 (en) 2004-12-27
EG22530A (en) 2003-03-31
SK19012001A3 (en) 2002-06-04
CO5200762A1 (en) 2002-09-27
HK1045309A1 (en) 2002-11-22
EP1196382A2 (en) 2002-04-17
WO2001000577A3 (en) 2002-01-24
CA2370491A1 (en) 2001-01-04
CZ20014548A3 (en) 2002-04-17

Similar Documents

Publication Publication Date Title
EP2240492B1 (en) Process for the preparation of asenapine and intermediate products used in said process
JP2024056754A (en) Pyrrolidinones and processes for preparing them
SK133198A3 (en) Piperazine and piperidine compounds, process for their preparation and pharmaceutical compositions containing them
US6538136B1 (en) Preparation of substituted piperidin-4-ones
US7598394B2 (en) Process for the synthesis of imidazoles
JP4538114B2 (en) Novel process for the preparation of derivatives of 4-phenyl-1,2,3,6-tetrahydropyridine and intermediates used
JP5008554B2 (en) Diastereoselective synthesis method for the preparation of imidazole compounds
JP6832918B2 (en) Stereoselective method
JPH0670064B2 (en) Bicyclic imidazole derivative
US20040152896A1 (en) Process for the preparation of pyrrolidinyl ethylamine compounds via a copper-mediated aryl amination
JP5635905B2 (en) Preparation method of mirtazapine
KR20150042736A (en) Method for preparation of 3-alkylthio-2-bromopyridine
JP3671252B2 (en) (S) -4-Amino-hepta-5,6-dienoic acid and its intermediates
US5580989A (en) Process for the preparation of N-4-[(substituted phenyl)alkylheterocyclic]-N
JP3149279B2 (en) Cyclopropenone derivative
JP2000007664A (en) Optically active piperazine compound, its intermediate and their production
JP4673313B2 (en) Process for producing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one or a salt thereof
US7880017B2 (en) Process for the synthesis of imidazoles
JP2004002206A (en) Method for producing optically active thiazolidinone derivative
JP3706154B2 (en) Novel halomethylene compounds or salts thereof
JP4236311B2 (en) Method for producing cycloheptimidazole derivative
JPH09227557A (en) Thienyloxazole derivative and thienylpyrazole derivative
KR20090082463A (en) Method for the synthesis of n-[3-[(2-methoxyphenyl)sulfanyl]-2-methylpropyl]-3,4-dihydro-2h-1,5-benzoxathiepin-3-amine
JPH0782208A (en) Optically active 2-(2-substituted acyl)menthopyrazole derivative, enantiomer, intermediate and their production and carboxylic acid derivative
JPH1077270A (en) 2-(1-chlorovinyl)pyridine derivative and its production

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 00809338.5

Country of ref document: CN

AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 515354

Country of ref document: NZ

ENP Entry into the national phase

Ref document number: 2370491

Country of ref document: CA

Ref document number: 2370491

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 54535/00

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: PA/a/2001/012727

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 10018036

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: PV2001-4548

Country of ref document: CZ

WWE Wipo information: entry into national phase

Ref document number: 2000939451

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 19012001

Country of ref document: SK

WWE Wipo information: entry into national phase

Ref document number: 1200101262

Country of ref document: VN

WWE Wipo information: entry into national phase

Ref document number: 1020017016848

Country of ref document: KR

AK Designated states

Kind code of ref document: A3

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

WWE Wipo information: entry into national phase

Ref document number: 200200101

Country of ref document: EA

WWP Wipo information: published in national office

Ref document number: 1020017016848

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: PV2001-4548

Country of ref document: CZ

Ref document number: 2000939451

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWW Wipo information: withdrawn in national office

Ref document number: 2000939451

Country of ref document: EP

WWR Wipo information: refused in national office

Ref document number: PV2001-4548

Country of ref document: CZ

WWG Wipo information: grant in national office

Ref document number: 54535/00

Country of ref document: AU

WWW Wipo information: withdrawn in national office

Ref document number: 1020017016848

Country of ref document: KR