WO2000026187A1 - Procede de production de 4-arylpiperidine-3-carbinols et composes correspondants - Google Patents

Procede de production de 4-arylpiperidine-3-carbinols et composes correspondants Download PDF

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WO2000026187A1
WO2000026187A1 PCT/IB1999/001762 IB9901762W WO0026187A1 WO 2000026187 A1 WO2000026187 A1 WO 2000026187A1 IB 9901762 W IB9901762 W IB 9901762W WO 0026187 A1 WO0026187 A1 WO 0026187A1
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group
compound
formula
process according
trans
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PCT/IB1999/001762
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Theodorus Hendricus Antonius Peters
Franciscus Bernardus Gemma Benneker
Hans Jan Hoorn
Frantisek Picha
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Synthon B.V.
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Priority to AU63609/99A priority Critical patent/AU6360999A/en
Priority to EP99951035A priority patent/EP1124802A1/fr
Publication of WO2000026187A1 publication Critical patent/WO2000026187A1/fr
Priority to NO20012099A priority patent/NO20012099L/no

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    • 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
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • 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

Definitions

  • the present invention relates to a novel process for producing 4-arylpiperidine-3-carbinols useful as intermediates for synthesizing certain pharmaceutically active compounds. More particularly, it relates to a process for producing trans-4-(p-fluorophenyl)-piperidine-3-carbinols. The present invention also relates to novel intermediates for producing the 4-arylpiperidine-3- carbinols and to a process for producing said intermediates.
  • X represents hydrogen, halogen, lower alkyl group, aralkyl group, alkoxy group, dialkylamino group or alkylthio group
  • R represents hydrogen, a lower alkyl group, an aryl group, an aralkyl group, an alkoxycarbonyl group, aralkoxycarbonyl group or an aryloxycarbonyl group
  • R" represents an alkyl group, alkynyl group, a substituted or unsubstituted phenyl group or a tetrahydronaphthyl group.
  • the compounds of formula 2 include paroxetine, a useful therapeutic agent for the treatment of depression or Parkinson's disease.
  • Ra is an alkyl or aryl group
  • Rai is a lower alkyl group
  • Y is hydrogen, a halogen atom, a methoxy group or a mercapto group.
  • the intermediates of the formula (3) are synthesized by a process which is characterized by the reaction of an aryl Grignard reagent with arecoline. The disadvantage of this process is in using expensive and irritaing arecoline and also in a row of side reactions leading to low yields and undesirably low purity of the product.
  • EP 223334 corresponding to US 4,902,801, describes the reduction of 4-aryl-2,6-dioxo- 3-piperidinecarboxylic acid esters of the general formula (4) with, preferably, lithium aluminium hydride,
  • Ra is hydrogen, a lower alkyl group or an aralkylgroup
  • Rai is a lower alkyl group
  • Y is a hydrogen, a halogen atom, a lower alkyl group, an aralkylgroup or a trifluoroalkyl group.
  • EP application 802185 describes the reduction of trans-4-aryl-6-oxopiperidine-3-carbinols of general formula (5), preferably by hydrides or metal hydrides,
  • Y is hydrogen, halogen, alkyl group, aryl group, an aralkyl group etc.
  • Ra is hydrogen, lower alkyl group or an aralkyl group
  • Rai is a hydrogen, a lower alkyl group, an aryl group or an aralkyl group.
  • the intermediate (5) is prepared by conjugate addition of a cyanoacetic acid ester to a cinnamic acid ester in the presence of base, followed by reduction and simultaneous cyclization of the thus produced 2-cyano-3-aryl glutaric acid derivative.
  • the reductive cyclization yields generally a cis/trans mixture of the intermediate product (5).
  • the present invention relates to the discovery that 4-arylpiperidine-3-carbinols as defined by the general formula (1) (frequently referred to hereinafter as "compounds (1)"). particularly the trans isomers thereof such as the (3S.4R) trans optical isomers thereof, can be prepared in high yields, good purity and under conditions which can be easily reproduced on an industrial scale, by the use of certain 4-aryl-2-oxo-3-piperidine carboxylates. Accordingly, a first aspect of the invention relates to a process that comprises reducing a compound of formula (7):
  • X represents a hydrogen atom, a halogen atom, a lower alkyl group, an aralkyl group, an alkoxy group, a dialkyla ⁇ -ino group or an alkylthio group
  • R represents a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group, an alkoxycarbonyl group, aralkoxycarbonyl group or an aryloxycarbonyl group
  • R 1 represents a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group.
  • the compounds are preferably in the trans configuration.
  • the compound of formula (1) can then be converted into a compound of formula (2) by known and/or conventional techniques.
  • Another aspect of the present invention relates to certain compounds of the general formula (7) per se:
  • X represents a halogen atom, an aralkyl group, an alkoxy group, a dialkylamino group or an alkylthio group
  • R represents a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group, an alkoxycarbonyl group, aralkoxycarbonyl group or an aryloxycarbonyl group
  • R 1 represents a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group, and salts thereof (hereinafer frequently referred to as "compounds (7)"). It is understood that Formula (7) embraces the hydrate and solvate forms of the compounds.
  • the formula embraces cis and trans forms, both individually and in mixtures, as well as the individual or racemic mixtures of the optical isomers of each cis and trans form.
  • one aspect of the present invention relates to a compound of formula (1) or a pharmaceutically acceptable salt thereof that is substantially free of the corresponding des-fluoro impurity:
  • X represents fluoro and R represents a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group, an alkoxycarbonyl group, aralkoxycarbonyl group or an aryloxycarbonyl group.
  • a further aspect of the present invention relates to the production of the compounds (7), the general method for which comprises (a) reacting a compound of formula (8) with a malonic acid/ester of formula ( 13) to form a compound of formula (9):
  • lower alkyl means a straight or branched saturated alkyl group of 1 to 6 carbon atoms or a vinyl group; particularly preferred are methyl or ethyl groups.
  • An "aryl” group means phenyl group or a phenyl group substituted by one or more halogen, lower alkyl or alkyloxy groups or by a methylenedioxy group.
  • An “alkoxy” group preferably means lower alkoxy groups, i.e. having a straight or branched carbon chain of 1 to 6 carbon atoms, most preferably ethoxy or tert.butoxy group.
  • An "aryloxy” group means a phenyloxy group or phenyloxy group substituted by a halogen or lower alkyl group.
  • trans configuration and "cis configuration” mean that the phenyl substituent in the 4 position and the carbinol or carboxy substituent in the 3 position are in trans or cis orientation to one another, respectively.
  • the piperidine carbinols represented by the general formula (1) as well as the compounds (7) are preferably in the trans configuration, due to the presently preferred application of the intermediates in making paroxetine.
  • the scope of the invention is not, however, limited to the trans configuration compounds.
  • the trans- carbinol of the formula (1) can be resolved into two stereoisomers. It is preferred but not required, due to intended use, that the finally produced carbinol of the formula (1) is a single (3S,4R) trans stereoisomer.
  • the (3S,4R) trans optical isomer will be a (-) optical isomer.
  • paroxetine is known to be the single (-) trans optical isomer.
  • certain ccombinations of substituents could reverse the optical rotation and thus be more properly classified as (+) optical isomer.
  • the R,S nomenclature is frequently used throughout the specification, while the (+,-) nomenclature is used where appropriate and should not be taken as being contradictory thereto.
  • the first process of the present invention provides the compounds (1) by means of reduction of intermediating compounds (7).
  • a hydride reductant such as a metal hydride reductant, or a borane reductant are preferred. Suitable examples include lithium aluminium hydride, sodium borohydride, sodium bis(2-methoxyethoxy)aluminium hydride, aluminium hydride, diborane borane complexes such as borane/tetrahydrofuran and the like.
  • the reaction solvent any solvent that is not reducible itself may be used; preferred are hydrocarbon or ether-based solvents such " s toluene or tetrahydrofuran.
  • the reaction temperatures in the process are preferably from 0 to 100°C, most preferably from 0 to 50°C.
  • one advantage of the present invention is that overall milder reduction conditions can be effectively used in comparison to the process described in the 4,902,801 patent. This is because the compounds (7) have only one carbonyl group and one carboxy group to be reduced whereas the dioxo intermediates taught in the 4,902,801 patent have two carbonyl groups as well as the carboxy group to be reduced. Accordingly, less stringent conditions are needed in reducing the compounds (7), thereby reducing the chances of inadvertantly removing the fluorine atom.
  • the level of des-fluoro impurity (the compounds (1) wherein fluorine has been replaced with a hydrogen) can be advantageously minimized in the present invention.
  • the compounds (1) are formed substantially free of the des-fluoro impurity.
  • substantially free means less than about 2.5% des-fluoro impurity, preferably less than 1% des- fluoro impurity, based on the total amount of phenylpiperidene product. Because of the high purity level, such compounds of formula (I) that are substantially free of the corresponding des- fluoro impurity compound are a further aspect of the present invention.
  • the compounds (1) may, if desired, be converted into compounds wherein R is lower alkyl or arakyl, by reacting the same with an alkylation agent, preferably with an aldehyde or ketone or an equivalent thereof, under a reducing atmosphere and in suitable solvent.
  • an alkylation agent preferably with an aldehyde or ketone or an equivalent thereof
  • formaldehyde, acetaldehyde, benzaldehyde, acetone, paraformaldehyde are examples of preferred alkylation agents.
  • such compounds (1) may be converted into compounds wherein R is alkyloxycarbonyl, aralkoxycarbonyl group or aryloxycarbonyl group, by reaction with corresponding halofo ⁇ nate, e.g.
  • phenylchloroformate benzylchoroformate or ethylchloroformate, or with an analogue thereof, e.g. with di-tert.butyl dicarbonate, by general methods described in the prior art.
  • the compounds of formula ( 1 ) can be converted into compounds of formula (2) by known techniques such as described in US 4,007,196 and 4,721,723, which are generally characterized by, or involving, a substitution reaction:
  • R 2 represents an alkyl or alkynyl group having 1-4 carbon atoms; a substituted or unsubstituted phenyl group wherein the substituents are selected from the group consisting of - C alkyl, alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl, methylenedioxy, and combinations thereof, or a tetrahydronaphthyl group.
  • the compound of formula (2) is paroxetine.
  • paroxetine is to react the compound of formula (I) (X is para fiuoro) with either thionyl chloride or benzenesulphonyl chloride and then with an alkali salt of 3,4-methoxyphenoxide such as sodium 3,4-methoxyphenoxide.
  • the N-substituent if present as other than hydrogen, can then be removed by conventional reactions.
  • the process may further comprise reacting the compound of formula (2), especially paroxetine, with a pharmaceutically acceptable acid to form an acid addition salt.
  • Preferred acids include hydrochloric, acetic, sulfonic acids (methyl sulfonic acid, etc.), and maleic acid, although other acids which form pharmaceutically acceptable acid addition salts may be used.
  • the corresponding intermediating compound (7) should also be a trans isomer. It will be shown below that the process of the present invention for the production of compounds (7) provides the compounds (7) directly in the desired trans-configuration.
  • the trans-carboxylates (7) have two asymmetric centres in the molecule, so that they may exist as racemic-trans compounds or as single (-) trans or (+) trans stereoisomers.
  • the racemic trans-carboxylates (7) yield racemic trans-carbinols (1).
  • the single stereoisomer, preferably the (-) trans isomer, of the compound (1) from the racemic mixture conventional means of resolution of the racemic mixture can be applied to compounds (1), preferably converting the racemate into a salt with a suitable acid, such as dibenzoyltartaric acid, in a suitable solvent, crystallizing the sale of (-) trans isomer from the solution and liberating the free (-) trans isomer of the carbinol (1) from the salt.
  • a suitable acid such as dibenzoyltartaric acid
  • the single (-) or (+) trans-stereoisomer of the compound (1) can be obtained by reducing the corresponding single stereoisomer of the trans-carboxylate (7), under the general conditions of reductions as discussed above.
  • a preferred sub- genus involves X as a fluorine in the para-position, R is a hydrogen, methyl or benzyl group and R 1 is a methyl or ethyl group.
  • X as a fluorine in the para-position
  • R is a hydrogen, methyl or benzyl group
  • R 1 is a methyl or ethyl group.
  • Examples of particularly preferred species include: ethyl -rans-4(p-fluorophenyl)-2-oxopiperic ⁇ ne-3-c--rboxylate ethyl trans-4(p-f-uorophenyl)- 1 -methyl-2-oxopiperidine-3-carboxylate ethyl trans-4(p-fluorophenyl)- 1 -benzyl-2-oxopiperidine-3-carboxylate trans-4(p-fluorophenyl)-2-oxopiperidine-3-carboxylic acid trans-4(p-fluorophenyl)- 1 -methyl-2-oxopiperidine-3-carboxylic acid trans-4(p-fluorophenyl)-l-benzyl-2-oxopiperidine-3-carboxylic acid and (3S,4R) trans isomers of said compounds.
  • the compounds (7) can be formed by the following general method which comprises (a) reacting a compound of formula (8) with a malonic acid/ester of formula (13) to form a compound of formula (9):
  • X represents a hydrogen atom, a halogen atom, a lower alkyl group, an aralkyl group, an alkoxy group, a dialkylamino group or an alkylthio group and R ! and R 3 each independently represent a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group; and
  • the starting cinnamonitriles of the formula (8) are commercially available or they can be easily obtained from the corresponding benzaldehyde by reaction with acetonitrile in the presence of equimolar amount of a base.
  • the acetonitrile can preferably serve also as a solvent for the said reaction.
  • the cinnamonitrile (8) reacts in production step (a) with a malonic acid, half ester or ester ( 13), e.g. with diethyl malonate, in the presence of an equivalent amount of a base in suitable organic solvent.
  • a malonic acid, half ester or ester ( 13) e.g. with diethyl malonate
  • a base in suitable organic solvent.
  • Preferred are sodium alkoxide as a base and a lower alcohol as a solvent.
  • the resulting 4-cyanobutyrate (9) can be isolated from the reaction mixture after neutralizalion of the base by conventional means, e.g. by adding a water immiscible solvent such as ethyl acetate, extracting the water soluble salts with water and evaporation of the solvent.
  • Reductive cyclization means any step or combination of steps that converts a compound of formula (9) into a compound of formula (7).
  • reductive cyclization involves reducing and a ring forming or cyclizing step.
  • An alkylating or aralkylating step may also be performed in addition to the reducing and cyclizing steps.
  • the steps may be carried out sequentially or stepwise or two or more steps may be carried out simultaneously.
  • Three methods of reductive cyclization are described below, however, other methods and variations thereof are possibl as will become apparent to a worker skilled in this art.
  • reductive cyclization is carried out by reducing the cyanobutyrate (9) to form the intermediate 3-aminopropyl ⁇ -alonate (1 1).
  • This intermediate is - with or without isolation thereof - cyclized by dehydration.
  • the reduction can be preferably performed by means of catalytic hydrogenation, using conventional hydrogenation catalysts such as Raney nickel, Raney cobalt, palladium on carbon, Adams catalyst (platinum oxide) and the like.
  • a solvent organic solvents which cannot be hydrogenated itself are to be employed; suitable solvents comprise hydrocarbons such as toluene, ester solvents such as ethyl acetate, ether solvents such as tetrahydrofuran or alcohol solvents such as ethanol.
  • Acidic, neutral or alkaline environment may be employed, if appropriate for the reaction. Acidic conditions are the most preferred.
  • the intermediating amine (11) may be optionally isolated in the form of an acid addition salt with a suitable acid, e.g. hydrochloric acid.
  • the cyclization proceeds under mild conditions, optionally in the presence of a base.
  • the base may be an organic base such as an alkali metal alkoxide, hydride or amide in an inert solvent or an alkali metal in an inert solvent or in alcohol.
  • organic base such as an alkali metal hydroxide or carbonate in alcohol or in water may be employed.
  • the cyclization may run in the same solvent as the hydrogenation reaction. It is not required, though it is preferred, that the reduction and cyclization run stepwise and that the catalyst is filtered off before cyclization. Under these conditions, the original ester group of the starting malonate remains untouched or, in case of an alcoholic solvent, may be accordingly trans-esterified.
  • an aqueous base such as sodium hydroxide solution can be added to the reaction mixture after reduction or cyclization and the mixture allowed to react under elevated temperature. This way, the cyclization is followed by alkaline hydrolysis of the ester group (see step d) below).
  • the production steps a) and b) are performed in the same solvent, preferably in a lower alcohol such as ethanol. In such a case, both steps can be advantageously performed in one run, without isolation of the intermediating cyanobutyrate (9).
  • the compounds (7), wherein R is hydrogen are preferentially formed in the trans-configuration.
  • the content of the undesired cis -isomer is less than 5%.
  • a mixture or a higher cis-content may be formed.
  • the intermediated compounds (7) thus produced wherein R is hydrogen can be either directly used in the reduction step described above to yield the final compounds (1), also having R as hydrogen or, if desired, they can be subjected, in step (c), to N- substitution yielding compounds of the general formula (7) wherein R is alkyl, aryl or aralkyl.
  • R is alkyl, aryl or aralkyl.
  • they may be alkylated in suitable inert solvent, preferably in the presence of a base, by using conventional alkylating or aralkylation agent such as alkylhalide, aralkylhalide or dialkylsulfate, wherein benzylbromide or dimethyl sulfate are examples of the preferred agents.
  • these compounds (7) wherein R is hydrogen can be converted into their N- alkyloxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl analogues by reaction with corresponding haloformates or similar agents, under conditions already described hereinabove.
  • the products from the reaction step b) or c) may be subjected, in reaction step d), to acidic or alkaline hydrolysis of the ester group by conventional methods.
  • carboxylic acids i.e. compounds of the general formula (7), wherein R 1 is hydrogen, are formed.
  • the resulting acids can be isolated as such or in the form of their salts.
  • the compounds (7) resulting from any of the preceded steps b), c) and/or d) may be utilized for subsequent reduction either as such to provide racemic trans compounds (1), or, if desired, they may be subjected in reaction step e) to resolution into their optical isomers.
  • R 1 is hydrogen
  • the compounds (7) can be resolved into optical isomers by conventional fractional crystallization of salts thereof with suitable optically active amines in an appropriate solvent such as methanol, ethanol, ethyl acetate, water and mixtures thereof.
  • suitable optically active amines include compounds disclosed, for example, in JP 06-116214.
  • R(+)-N-(4-hydroxyphenylmethyl)-phenylmethyl-amine can be cited for said purpose.
  • R 1 is lower alkyl or aryl
  • such compounds (7) can be resolved into their optical isomers preferably by a stereoselective hydrolysis of the ester portion using an enzyme, for example by methods disclosed in WO 94-03428 or in WO 93-22284.
  • the compounds (7) from any of the preceding steps b) to e) are generally solids and they may be isolated, preferably in crystalline state, either as such or as their acid addition salts with suitable organic or inorganic acids.
  • Preferred acids are hydrochloric, maleic or tartaric acid. Accordingly and dependent on the method of isolation, they may form hydrates or solvates.
  • the preferred process of the isolation is the crystallization of the salt, hydrate or solvate from an appropriate solvent and separation of the resulting solid by filtration or centrifugation.
  • butyric acid derivative (9) is subjected, in the step b), to alkylation or aralkylation of the cyano group under reductive conditions.
  • a general method as described by Borch in J.Org.Chem 84, 627 ff (1969) may be employed.
  • corresponding nitrilium salts of the formula (10), wherein R 1 is lower alkyl or aralkyl are first produced.
  • trialkyloxonium tetrafluoroborates or dialkoxycarbonium tetrafluoroborates cited by Borch are the preferred agents.
  • the reaction proceeds generally at temperatures close to ambient, preferably at 0 to 50°C, in an inert solvent such as methylene chloride.
  • the reaction product may be isolated, however, it is preferred that it is subjected to the next conversion in situ.
  • This conversion represents reduction of the nitrilium salt to a secondary amine, preferably by means of a hydride reductant such as sodium borohydride in a suitable solvent such as ethanoL
  • a hydride reductant such as sodium borohydride
  • a suitable solvent such as ethanoL
  • the intermediating secondary amine of the formula (12) is subsequently subjected to cyclization- under elevated temperature and, advantageously, under presence of a base, preferably in the same solvent.
  • the hydride reductant serves itself as the base.
  • the conversion of the compound (9) to the desired compound (7) can also be realized by a more simple way wherein it is not strictly necessary to first convert the nitrile (9) into a nitrilium salt.
  • the starting nitrile can be subjected to reductive alkylation in the presence of an alkylation agent or aralkylation agent.
  • a preferred agent is an amine, especially an alkylamine. The intermediating secondary amine (12) spontaneously cyclizes to the desired
  • the most preferred reductant is hydrogen in the presence of a suitable catalyst, e.g. Adams catalyst (Pt0 2 ).
  • the preferred solvent for the reaction is an inert organic solvent such as ethanol or methanol. The reaction proceeds under ambient or slightly elevated temperatures and typically is carried out within the range 0 to 50°C.
  • the resulting compounds of the formula (7), wherein R is lower alkyl or aralkyl and R 1 is lower alkyl, aryl or aralkyl, may be isolated from the reaction mixture by conventional methods of separation such as extraction, evaporation, chromatography, precipitation and/or crystallization.
  • the above products of the step b) can be either used directly for production of corresponding compounds (1) or they may be subjected to one or more steps of derivatization on the nitrogen atom, hydrolysis of the ester group, resolution of optical isomers or conversion to salts, etc.
  • one or more of the following additional steps can be carried out: c) reacting the product from the step b) with a water solution of an acid or base to hydrolyze the ester group; d) reacting any of the products from the steps b) or c) with an agent to carry out substitution of the N-alkyl or aralkyl group with an alkyloxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl group; e) replacing the ⁇ -substituent in the product from the steps b), c) or d) with hydrogen; f) resolving any of the compounds form the steps b), c), d), or e) into optical isomers; or g) converting any of the compounds from the steps b), c), d), e), or f) into an acid addition salt, hydrate or solvate.
  • the conditions for such procedures are as described above with respect to method A steps c) through e).
  • the method C for reductive cyclization reduces the nitrile (9) to form the amine (11).
  • the amine (11) is then reacted with an acylating agent such as formic acid under conventional conditions to form a compound of formula (14):
  • R 4 is hydrogen atom, C ⁇ . 5 alkyl group, an aryl group, or an aralkyl group having 1 to 5 carbons in the alkyl moiety.
  • the ⁇ -acyl group is then reduced by a reductant such as by catalytic hydrogenation as discussed above to the corresponding ⁇ -alkyl group thereby forming a secondary amine of formula (12).
  • the secondary amine is allowed to cyclize to form the compounds (7). Similar to the above reaction, the reduction of the N-acyl group and the cyclization can proceed simultaneously, without isolation of the secondary amine.
  • the cyclization is carried out under acidic conditions. This method, although requiring an extra step, provides high purity levels and uses only readily available and inexpensive reactants, making such a method advantageous from a commercial point of view.
  • the subsequent steps c) through g) as described for method B may also be empolyed.
  • reaction scheme illustrates certain embodiments of the above three methods A-C, It should be noted that while, aklyation is indicated, such could also be aralkylation, etc., as described above.
  • One of the main objects of the present invention is to provide a process for producing (-) trans-4-(p-fluorophenyl)-l-methyl-3-piperidinecarbinol, preferably for use as the key intermediate in the synthesis of paroxetine.
  • the starting ethyl trans (+/-) 4-(p-fluorophenyl)-l-methyl-2- oxopiperidine-3-carboxylate of the present invention can be prepared from p-fluorocinnamonitrile by combining the above-mentioned processes, preferably by the method B or C. In further steps, the sequence of steps of reduction and resolution of the (-)trans isomer is preferred. Details of each step are described above. EXAMPLES
  • Example 3 Synthesis of diethyl 2-( -phenyl-2'-cyanoethyl)malonate.
  • the title compound was prepared as a white solid when using cirmamonitrile instead of p-fluorocinnamonitrile.
  • Example 5 Synthesis of diethyl 2-(r-phenyl-3'-aminopropyl)malonate hydrochloride. Under conditions described in example 4), but using the compound from example 3) as the starting material, the title product was prepared as a white precipitate after recrystallization from ethyl acetate.
  • Example 3 The product from the Example 3 (7.2 g) was dissolved in absolute ethanol saturated with HC1 and 0.59 g of Adams catalyst was added. The reaction mixture was hydrogenated at room temperature under 6.0 MPa of hydrogen for 5 hours. The catalyst was filtered off and the clear solution was evaporated to dryness. The residue was dissolved in 50 ml of ethyl acetate and extracted with 3x50 ml of IM hydrochloric acid. To the combined water layers, 50 ml of ethylacetate was added and the mixture was basified with potassium carbonate until pH 9.
  • the product from the example 3 (1.06 g) was dissolved in 20 ml of absolute ethanol and 0.4 g of Adams catalyst and 15 ml of 2M solution of methylamine in methanol were added.
  • the reaction mixture was hydrogenated under 5.8 MPa of hydrogen at ambient temperature for 24 hours.
  • the catalyst was separated by filtration and the clear filtrate was evaporated to dryness.
  • the residue was dissolved in 20 ml of ethylacetate, washed with 1x10 ml of IM hydrochloric acid, dried over sodium sulfate and evaporated to dryness.
  • the product from example 9 (0.45 g) was dissolved in 7 ml of anhydrous toluene. This solution was added to a stirred suspension of 0.12 g of lithium aluminiumhydride in a mixture of 2 ml of tetrahydrofuran and 8 ml of toluene in such rate that the temperature was maintained below 5°C. After completion of the addition, this mixture was stirred for 3 hours at 0-5°C and 16 hours at room temperature.
  • the amine from example 4 (0.97 g) was dissolved in 20 ml of formic acid and heated with 2 ml of acetanhydride at 100°C for 5 hours. The reaction mixture was evaporated to dryness and the residue was dissolved in ethyl acetate. The solution was washed with saturated solution of sodium hydrogencarbonate and with water, the organic phase was dried over sodium sulfate and evaporated yielding 0.71 g of pale yellow oil.
  • the NMR confirmed the identity of the N-formyl amine.
  • the oil was dissolved in 10 ml of tetrahydrofurane, cooled to -5°C and 0.8 ml of borane dimethyl sulfide complex was dropwise added at the same temperature. Then the mixture was stirred for 30 minutes at 0°C and then heated 1 hour at 45°C. After cooling to 0°C, the reductant was decomposed by adding of 10 ml of absolute ethanol and 1 ml of 12M ethanolic HC1. The reaction mixture was evaporated to dryness, the residue was dissolved in 20 ml of ethyl acetate and washed with 4 xlO ml of IM hydrochloric acid. The combined water layers were basified by potassium carbonate and extracted with 2 x20 ml of ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness yielding 0.44 g of a pale yellow oil.

Abstract

L'invention porte sur des aryl-2-pipéridones de la formule (7) qui peuvent être réduites de façon à produire des aryl-pipéridine carbinols de la formule (1) qui sont utiles dans la fabrication d'une variété de composés pharmaceutiques tels que la paroxétine, et présentent un bon rendement et une grande pureté. Des composés correspondants et des schémas de synthèse sont également décrits. Dans ces formules, X représente un atome d'hydrogène, un atome d'halogène, un groupe alkyle inférieur, un groupe aralkyle, un groupe alcoxy, un groupe dialkylamino ou un groupe alkylthio; R représente un atome d'hydrogène, un groupe alkyle inférieur, un groupe aryle, un groupe aralkyle, un groupe alcoxycarbonyle, un groupe aralcoxycarbonyle ou un groupe aryloxycarbonyle; et R1 représente un atome d'hydrogène, un groupe alkyle, un groupe aryle ou un groupe aralkyle.
PCT/IB1999/001762 1998-11-02 1999-11-01 Procede de production de 4-arylpiperidine-3-carbinols et composes correspondants WO2000026187A1 (fr)

Priority Applications (3)

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AU63609/99A AU6360999A (en) 1998-11-02 1999-11-01 Process for producing 4-arylpiperidine-3-carbinols and related compounds
EP99951035A EP1124802A1 (fr) 1998-11-02 1999-11-01 Procede de production de 4-arylpiperidine-3-carbinols et composes correspondants
NO20012099A NO20012099L (no) 1998-11-02 2001-04-27 Fremgangsmåte for fremstilling av 4-arylpiperidin-3- karbinoler og beslektede forbindelser

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US60/106,673 1998-11-02

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EP1140832A1 (fr) * 1998-12-22 2001-10-10 Pentech Pharmaceuticals, Inc. Procede de preparation d'intermediaires et de derives de arylpiperidine carbinol
WO2001085688A1 (fr) * 2000-05-12 2001-11-15 Synthon B.V. Tosylates de 4-(p-fluorophenyl)-piperidine-3-carbinols
WO2002053537A1 (fr) * 2001-01-04 2002-07-11 Ferrer Internacional, S.A. Procede de preparation de (?)-trans-4-p-fluorophenyl-3-hydroxymethyl-1-methylpiperidine
WO2002076940A2 (fr) * 2001-03-22 2002-10-03 Pentech Pharmaceuticals, Inc. Procede relatif a l'elaboration d'intermediaires et de derives d'arylpiperidine carbinols
US6489347B1 (en) 1997-05-29 2002-12-03 Smithkline Beecham Plc Process
US6703408B2 (en) 2001-10-22 2004-03-09 Synthon Bct Technologies, Llc N-formyl derivatives of paroxetine
WO2007089193A1 (fr) * 2006-02-02 2007-08-09 Astrazeneca Ab Procédé de synthèse du 2-hydroxy-3-[5-(morpholin-4-ylméthyl)pyridin-2-yl]1h-indole-5-carbonitrile sous forme de base libre ou de ses sels

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EP0802185A1 (fr) * 1996-04-15 1997-10-22 Asahi Glass Company Ltd. Procédé pour la préparation de 4-aryl-3-hydroxyméthylpiperidines
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6489347B1 (en) 1997-05-29 2002-12-03 Smithkline Beecham Plc Process
US6716985B2 (en) * 1997-05-29 2004-04-06 Smithkline Beecham P.L.C. Process for making paroxetine
EP1140832A1 (fr) * 1998-12-22 2001-10-10 Pentech Pharmaceuticals, Inc. Procede de preparation d'intermediaires et de derives de arylpiperidine carbinol
EP1140832A4 (fr) * 1998-12-22 2004-11-03 Pentech Pharmaceuticals Inc Procede de preparation d'intermediaires et de derives de arylpiperidine carbinol
WO2001085688A1 (fr) * 2000-05-12 2001-11-15 Synthon B.V. Tosylates de 4-(p-fluorophenyl)-piperidine-3-carbinols
WO2002053537A1 (fr) * 2001-01-04 2002-07-11 Ferrer Internacional, S.A. Procede de preparation de (?)-trans-4-p-fluorophenyl-3-hydroxymethyl-1-methylpiperidine
US6881845B2 (en) 2001-01-04 2005-04-19 Ferrer Internacional, S.A. Process for preparing (±)trans-4-p-fluorophenyl-3-hydroxymethyl-1-methylpiperidine
WO2002076940A2 (fr) * 2001-03-22 2002-10-03 Pentech Pharmaceuticals, Inc. Procede relatif a l'elaboration d'intermediaires et de derives d'arylpiperidine carbinols
WO2002076940A3 (fr) * 2001-03-22 2003-05-22 Pentech Pharmaceuticals Inc Procede relatif a l'elaboration d'intermediaires et de derives d'arylpiperidine carbinols
US6703408B2 (en) 2001-10-22 2004-03-09 Synthon Bct Technologies, Llc N-formyl derivatives of paroxetine
WO2007089193A1 (fr) * 2006-02-02 2007-08-09 Astrazeneca Ab Procédé de synthèse du 2-hydroxy-3-[5-(morpholin-4-ylméthyl)pyridin-2-yl]1h-indole-5-carbonitrile sous forme de base libre ou de ses sels

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NO20012099L (no) 2001-07-02
NO20012099D0 (no) 2001-04-27
EP1124802A1 (fr) 2001-08-22
CZ20011465A3 (cs) 2001-08-15
AU6360999A (en) 2000-05-22

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