EP1244622A1 - Procede de preparation de piperidines trans-2,4-disubstituees - Google Patents

Procede de preparation de piperidines trans-2,4-disubstituees

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Publication number
EP1244622A1
EP1244622A1 EP00980848A EP00980848A EP1244622A1 EP 1244622 A1 EP1244622 A1 EP 1244622A1 EP 00980848 A EP00980848 A EP 00980848A EP 00980848 A EP00980848 A EP 00980848A EP 1244622 A1 EP1244622 A1 EP 1244622A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
process according
alkyl
substituted
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Withdrawn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
EP00980848A
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German (de)
English (en)
Inventor
Sandra.S. Keast
Perry.C. Heath
Marvin.M. Hansen
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.)
Eli Lilly and Co
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Eli Lilly and Co
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Filing date
Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP1244622A1 publication Critical patent/EP1244622A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/12—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
    • 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
    • C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention allows for stereoselectively preparing trans-2, ⁇ - disubstituted piperidines in high yield.
  • the present invention provides an efficient synthesis of various trans-2,4-disubstituted piperidines which are useful intermediates in the preparation of pharmaceutical compounds.
  • the present invention provides a process for preparing a compound of formula I:
  • R represents C-i-C alkyl
  • X represents an alkyl, alkenyl, cycloalkyl, aryl, substituted aryl, heterocycle, or substituted heterocycle, comprising treating a compound of formula II:
  • the present invention further provides a process for preparing a compound of formula I:
  • R represents CrC 4 alkyl
  • X represents an alkyl, alkenyl, cycloalkyl, aryl, substituted aryl, heterocycle, or substituted heterocycle, comprising treating a compound of formula II:
  • the present invention comprises purifying the compound of formula I by treatment with a suitable reducing agent followed by addition of a suitable acylating agent and then acid-base extraction of the mixture.
  • R represents C1-C4 alkyl
  • X represents an alkyl, alkenyl, cycloalkyl, aryl, substituted aryl, heterocycle, or substituted heterocycle.
  • Me methyl, ethyl, propyl, isopropyl, butyl and tert-butyl, respectively.
  • alkyl refers to a straight or branched, monovalent, saturated aliphatic chain. It is understood that the term “alkyl” includes within its definition the terms “C C 2 o alkyl”, “C1-C10 alkyl”, “d-Ce alkyl”, and “C 1 -C 4 alkyl”.
  • C1-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.
  • C ⁇ -C 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.
  • C1-C 10 alkyl refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 10 carbon atoms and includes, but is not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2- methyl-2-hexyl, octyl, 4-methyl-3-heptyl and the like.
  • C1-C20 alkyl refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 20 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, 3-methylpentyl, 2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n- heptadecyl, n-nonadecyl, n-eicosyl and the like.
  • C C ⁇ alkoxy refers to a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom.
  • Typical Ci-C ⁇ alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like.
  • alkoxy includes within its definition the term “C 1 -C 4 alkoxy”.
  • 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(C- ⁇ -C 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(CrC 4 )alkyl".
  • cycloalkyl refers to a saturated hydrocarbon ring structure. It is understood that the term “cycloalkyl” includes within its definition the term “C 3 -C 8 cycloalkyl”. Typical C 3 -C 8 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • alkenyl refers to a straight or branched, monovalent, unsaturated aliphatic chain. It is understood that the term “alkenyl” includes within its definition the term “C 2 -C 6 alkenyl”. Typical C 2 -C 6 alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, 1 -methyl-1- propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1 -propenyl, 2-propenyl, 2- butenyl, 2-pentenyl, and the like.
  • aryl refers to a monovalent carbocyclic group containing one or more fused or non-fused phenyl rings and includes, for example, phenyl, 1- or 2-naphthyl, 1 ,2-dihydronaphthyl, 1 ,2,3,4- tetrahydronaphthyl, and the like.
  • heterocycle refers to a stable 5- to 7-membered monocyciic or 7- to 10-membered bicyclic heterocyclic ring which is saturated or unsaturated, and consists of carbon atoms and from one to three heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized and including a bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which affords a stable structure.
  • heterocycles include piperidinyl, piperazinyl, azepinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoazolyl, furyl, tetrahydrofuryl, tetrahydropyr
  • substituted as used in the term “substituted aryl” and “substituted heterocycle” signifies that one or more (for example one or two) substituents may be present on the aryl or heterocycle.
  • substituents which may be present are H, F, Cl, Br, I, C ⁇ -C 6 alkyl,
  • ⁇ refers to a bond that protrudes forward out of the plane of the page.
  • 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.
  • a convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or "ee”, which is found using the following equation:
  • 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 formulas I or la 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.
  • 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.
  • 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 structure (1) is treated with a suitable N-chlorinating reagent to provide the compound of formula II.
  • suitable N-chlorinating reagents are N-chlorosuccinimide, sodium hypochlorite, t-butylhypochlorite, N-chlorophthalimide, and the like.
  • N- chlorosuccinimide is the preferred N-chlorinating reagent.
  • compound (1) is dissolved in a suitable organic solvent, such as diethyl ether and tetrahydrofuran and treated with about 1 equivalent of N-chlorosuccinimide.
  • reaction mixture is stirred at room temperature for about 30 minutes to 16 hours and the product, compound of formula II, is then isolated by standard techniques well known in the art, such as extraction techniques.
  • the reaction is diluted with saturated aqueous sodium bicarbonate and water, and then extracted with diethyl ether or methyl tert-butyl ether.
  • the organic extracts are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the compound of formula II.
  • step B the compound of formula II is dehydrohalogenated with a suitable base in the presence of a suitable crown ether to provide the imine of formula III.
  • suitable bases are potassium hydroxide, potassium superoxide, and the like.
  • Potassium hydroxide is the preferred suitable base.
  • suitable crown ethers are 18-crown-6, dibenzo-18- crown-6, and the like. 18-crown-6 is the preferred crown ether.
  • the compound of formula II can be dehydrohalogenated with a suitable base which does not require addition of a suitable crown ether, to provide the imine of formula III.
  • the compound of formula II is dissolved in a suitable organic solvent, such as tetrahydrofuran and treated with about 0.05 equivalents to about 1.0 equivalents of a crown ether, such as 18-crown-6, with about 0.073 equivalents of crown ether being preferred.
  • a suitable organic solvent such as tetrahydrofuran
  • the solution is then treated with about 2 equivalents to about 3 equivalents of a suitable base in water, such as potassium hydroxide, with 3 equivalents of suitable base being preferred.
  • the reaction mixture is stirred at room temperature for about 8 to 24 hours and the resulting imine of formula III is isolated by techniques well known in the art, such as drying over anhydrous sodium sulfate and filtering to provide the imine of formula III in solution.
  • step B the compound of formula II is dissolved in a suitable organic solvent, such as tetrahydrofuran and treated with about 2 equivalents to about 3 equivalents of a suitable base, such as DBU, lithium tert- butoxide or lithium diisopropylamide.
  • a suitable organic solvent such as tetrahydrofuran
  • a suitable base such as DBU, lithium tert- butoxide or lithium diisopropylamide.
  • the reaction mixture is stirred for about 8 hours to about 24 hours at room temperature, and the resulting imine is isolated by techniques well known in the art, such as extraction, to provide the imine of formula III.
  • step C the imine of formula III is alkylated with a compound of structure (2) wherein M+ is a suitable cation, such as lithium.
  • compounds of structure (2) are methyllithium, butyllithium, and the like.
  • an excess of the compound of structure (2), such as methyl lithium in a suitable organic solvent, such as diethyl ether is cooled to about -25°C to about room temperature with about -10°C being preferred.
  • the imine of formula III in tetrahydrofuran is maintained at a temperature between about 5°C and about 25°C, and added to the above cooled solution of compound (2). After about 20 minutes, the reaction is allowed to warm to room temperature.
  • the crude compound of formula I is isolated by standard extractive techniques. For example, the reaction is diluted with water and the resulting layers are separated. The aqueous phase is extracted with diethyl ether or methyl tert-butyl ether, the organic layer and organic extracts are combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the crude compound of formula I.
  • step D the crude compound of formula I may be contaminated with unreacted imine of formula III and non-alkylated compound of formula I. These impurities may be removed by chromatography on silica gel. The impurities are also readily removed by dissolving the crude compound of formula I in a suitable solvent, such as methanol and tetrahydrofuran or methyl tert-butyl ether, and treating the solution with about 1 equivalents of a suitable reducing agent for every mole of imine impurity present.
  • suitable reducing agents are sodium borohydride, lithium aluminum hydride, and the like. Sodium borohydride is the preferred suitable reducing agent.
  • a suitable acylating agent such as a suitable anhydride or a suitable dicarbonate
  • a suitable anhydride or a suitable dicarbonate with about 0.25 equivalents being preferred depending upon the amount of non-alkylated piperidine impurity present.
  • suitable anhydrides are pivalic anhydride, acetic anhydride, propionic anhydride, and the like.
  • Pivalic anhydride is the preferred suitable anhydride.
  • suitable dicarbonates include di-tert-butyl dicarbonate, dimethyl dicarbonate, and the like.
  • the reaction is then stirred for about 0.4 hours to about 2 hours, with about 1 hour being preferred.
  • the purified compound of formula I is then isolated by acid-base extraction.
  • the mixture is partitioned between a suitable aqueous acid, such as 1 N aqueous HCI, and a suitable organic solvent, such as diethyl ether or methyl tert-butyl ether.
  • a suitable organic solvent such as diethyl ether or methyl tert-butyl ether
  • the aqueous layer is washed with a suitable organic solvent, such as diethyl ether or methyl tert-butyl ether, and the aqueous is then made basic with a suitable base, such as 5 N sodium hydroxide.
  • the aqueous is then extracted with a suitable organic solvent, such as diethyl ether or methyl tert-butyl ether.
  • the combined organic extracts are washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the purified compound of formula I.
  • the compound of formula II can be dissolved in a suitable organic solvent, such as tetrahydrofuran and treated with a catalytic amount of a suitable base, such as potassium tert-butoxide or lithium diisopropylamide (LDA), and a compound of structure (2) as defined hereinabove.
  • a suitable organic solvent such as tetrahydrofuran
  • a catalytic amount of a suitable base such as potassium tert-butoxide or lithium diisopropylamide (LDA)
  • LDA lithium diisopropylamide
  • an excess of the compound of structure (2) is added at a temperature between about 5°C and 20°C. After about 20 minutes, the reaction is allowed to warm to room temperature. After stirring for about 18 hours at room temperature the crude compound of formula I is isolated by standard extractive techniques. For example, the reaction is diluted with water and the resulting layers are separated.
  • aqueous phase is extracted with diethyl ether or methyl tert-butyl ether, the organic layer and organic extracts are combined, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the crude compound of formula I.
  • steps B and C as described directly above, the compound of formula I can be prepared in one pot.
  • Boc-piperidone (155.1 g, 778 mmol) in THF (816 mL) was added. After 2 h, the mixture was poured into H 2 O and methyl tert-butyl ether (2 L each). The layers were separated and the organic layer was washed with 1 N HCI (2.1 L), then H 2 0
  • the title compound is prepared from ⁇ /-f-butoxycarbonyl-4-hydroxy-4-(6- methylbenzo[_b]thiophen-2-yl)piperidine (prepared in preparation 3) in a manner analogous to the procedure described in preparation 5.
  • the title compound is prepared from ⁇ /-f-butoxycarbonyl-4-(8- methoxynaphth-2-yl)-4-piperidinol (prepared in preparation 4) in a manner analogous to the procedure described in Preparation 5.
  • step A To 10 g (37 mmol) of 4-(3-methylbenzo[b]thiophen-5-yl)- piperidine hydrochloride was added 160 mL of ether, 34 mL of H 2 O and 41 mL (41 mmol, 1.1 equiv, prepared in preparation 5) of 1 M NaOH. The mixture was stirred until the solid dissolved and the layers were separated using a separatory funnel.
  • step B To 13.9 g (51 .9 mmol) of N-chloro-4-(3- methylbenzo[b]thiophen-5-yl)-piperidine was added 207 mL of THF, 1.0 g (3.8 mmol, 0.073 equiv) of 18-crown-6 and a slurry of 10.16 g (assume 85% KOH and 15% H 2 0, 156 mmol, 3 equiv) of potassium hydroxide in 4 mL of H 2 O. After stirring for 16 h, the resulting solution of imine was dried over Na ⁇ O,,, filtered and the cake rinsed with 20 mL of THF.
  • step C A solution of methyllithium in ether (185 mL, 1.5 M, 260 mmol, 5 equiv) was cooled to -10 °C and the precooled (5 °C) imine solution from above was added over 1 min. After 20 min, the cooling bath was removed and the mixture was allowed to stir at ambient temperature. After 2 h, 200 mL of H 2 0 was added, the layers were separated and the aqueous layer was extracted with ether (200 mL). The combined organic layers were washed with water (300 mL) and dried (Na,SO 4 ). The solvent was evaporated to afford the crude final title compound, fra ⁇ s-2-methyl-4-(3-methylbenzo[b]-thiophen-5-yl)piperidine, (13.6 g) of a viscous oil.
  • step D The crude final title compound was dissolved in 80 mL of methanol and 25 mL of THF and 0.55 g (12 mmol) of NaBH 4 was added. After 2 h, pivalic anhydride (2.8 g, 12 mmol), was added. After 2 h, the methanol was removed by evaporation and the mixture was partitioned between 200 mL of 1 N HCI and 100 mL of ether. The layers were separated and the aqueous layer was washed with ether. The aqueous layer was made basic with 5 N NaOH and extracted with ether (2 x 150 mL).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

La présente invention concerne un procédé de préparation d'un composé de formule (I), dans laquelle R représente alkyle C1-C4, et X représente alkyle, alcényle, cycloalkyle, aryle, aryle substitué, un hétérocycle ou un hétérocycle substitué. Ce procédé consiste à traiter un composé de formule (II) avec un éther couronne approprié et une base appropriée, puis à ajouter un composé de formule R-M+, dans laquelle M+ est un cation approprié.
EP00980848A 1999-12-20 2000-12-06 Procede de preparation de piperidines trans-2,4-disubstituees Withdrawn EP1244622A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US172416P 1999-12-17
US17272499P 1999-12-20 1999-12-20
PCT/US2000/032428 WO2001046143A1 (fr) 1999-12-20 2000-12-06 Procede de preparation de piperidines trans-2,4-disubstituees

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EP1244622A1 true EP1244622A1 (fr) 2002-10-02

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EP00980848A Withdrawn EP1244622A1 (fr) 1999-12-20 2000-12-06 Procede de preparation de piperidines trans-2,4-disubstituees
EP00982251A Withdrawn EP1244623A1 (fr) 1999-12-20 2000-12-06 Procede de preparation de piperidines 4 substituees

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EP1673725A4 (fr) 2003-10-14 2008-02-06 Amfit Inc Procede de saisie et de reproduction d'un contour 3d
UA98698C2 (en) 2008-03-03 2012-06-11 Х. Луннбек А/С Phenylsulfanylphenyl-piperidines and process for the preparation thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001009126A1 (fr) * 1999-07-29 2001-02-08 Eli Lilly And Company Benzothiophenes serotoninergiques

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Publication number Priority date Publication date Assignee Title
US5846982A (en) * 1996-06-14 1998-12-08 Eli Lilly And Company Inhibition of serotonin reuptake
US6303627B1 (en) * 1998-06-19 2001-10-16 Eli Lilly And Company Inhibitors of serotonin reuptake

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001009126A1 (fr) * 1999-07-29 2001-02-08 Eli Lilly And Company Benzothiophenes serotoninergiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO0146143A1 *

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EP1244623A1 (fr) 2002-10-02
AU1805701A (en) 2001-07-03
WO2001046147A8 (fr) 2002-06-06
WO2001046147A1 (fr) 2001-06-28
WO2001046143A1 (fr) 2001-06-28

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