CZ20011465A3 - Process for preparing 4-arylpiperidine-3-methanols and related compounds - Google Patents

Abstract

Aryl-2-piperidones of formula (7) can be reduced to form aryl-piperidine carbinols of formula (1), which are useful in forming a variety of pharmaceutical compounds including paroxetine, in good yield and purity. Related compounds and synthesis schemes are also set forth. In said formulas, 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; R represents a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group, an alkoxycarbonyl group, aralkoxycarbonyl group or an aryloxycarbonyl group; and R<1> represents a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group.

Description

A process for the preparation of 4-arylpiperidine-3-methanol and related compounds

Technical field

The present invention relates to a novel process for the preparation of 4-arylpiperidine-3-methanol, useful as intermediates for the preparation of certain pharmaceutically active compounds. More specifically, the invention relates to a process for the preparation of trans -4- (p-fluorophenyl) piperidine-3-methanol. The present invention also relates to novel intermediates for the preparation of 4-arylpiperidine-3-methanol and to a process for the preparation of said intermediates.

BACKGROUND OF THE INVENTION

4-Arylpiperidine-3-methanols of formula 1

(2) are key intermediates for the preparation of certain pharmaceutically active compounds represented by the general formula 2 (wherein X is hydrogen, halogen, lower alkyl, aralkyl, alkoxy, dialkylamino or alkylthio; R is hydrogen, lower alkyl, aryl, aralkyl and R ² represents an alkyl group, an alkynyl group, a substituted or unsubstituted phenyl group, or a tetrahydronaphthyl group), or an alkoxycarbonyl group, an aralkoxycarbonyl group or an aryloxycarbonyl group;

The compounds of Formula 2 include paroxetine, a useful therapeutic agent for the treatment of Parkinson's disease.

Some synthetic processes leading to compounds of formula I and having some industrial utility are described in the literature.

For example, U.S. Pat. No. 3,912,743 describes the reduction of 4-aryl-3-piperidinecarboxylic acid esters of Formula 3 with lithium aluminum hydride.

(3) wherein R a is an alkyl or aryl group, R a is a lower alkyl group, Y is hydrogen, a halogen atom, a methoxy group, and a mercapto group. Intermediates of formula (3) are prepared by a process characterized by reacting a Grignard reagent with arecoline. The disadvantage of this process lies in the use of expensive and irritating arecoline and also in a number of side reactions resulting in low yields and undesirable low purity of the product.

EP 223 334, corresponding to U.S. Pat. No. 4,902,801, describes the reduction of 4-aryl-2,6-dioxo-3-piperidinecarboxylic acid esters of the general formula 4, preferably with lithium aluminum hydride

(4) wherein R 6 is hydrogen, lower alkyl or aralkyl, R 1a is lower alkyl, Y is hydrogen, halogen, lower alkyl, aralkyl or trifluoroalkyl. These intermediates of formula 4 are prepared either by addition of an N-substituted amidomalonic acid ester to cinnamic amide (EP 223 334) or by conjugate addition of a malonic acid ester to cinnamamide (EP 374 675). Since the amidomalonic acid ester is obtained only in low yields (and is therefore very expensive), and whereas free amines are to be used in the synthesis of cinnamamide (resulting in the need for special equipment), both variants of the above synthetic process characterized by high production costs.

In addition, when Y is fluorine (for example in the production of paroxetine) the desired large excess of reducing agent causes easy dehalogenation, even under mild conditions; therefore, large amounts of defluorinated impurities are formed which are difficult to remove.

EP-A-802 185 describes the reduction of trans-4-aryl-6-oxopiperin-3-methanol of the general formula 5, preferably hydrides or metal hydrides,

(5) where Y stands for hydrogen, halogen , an alkyl group, an aryl group, an aralkyl group, etc., R 6 is hydrogen, a lower alkyl group or an aralkyl group, R a is hydrogen, a lower alkyl group, an aryl group or an aralkyl group. Intermediate 5 is prepared by conjugate addition of a cyanoacetic acid ester to a cinnamic acid ester in the presence of a base and subsequent reduction and concomitant cyclization of the thus obtained 2-cyano-3-aryl glutaric acid derivative.

As disclosed in EP 802 185, reductive cyclization usually provides a cis / trans mixture of intermediate product 5. In order to convert this mixture to a substantially pure trans product, it is necessary to separate the undesired cis product by traction crystallization and / or perform a further step of isomerization.

U.S. Pat. Nos. 4,007,196 or 4,593,036 disclose a process based on the hydrogenation of 4-aryl-1-alkyl-1,2,3,6-tetrahydropyridine-3-methanol of formula 6. Depending on the reducing agent, either racemic (+ (-) cis-isomers or racemic (+/-) transisomers of formula (1).

(6)

However, it should be noted that the intermediates of formula (6) in this synthesis are highly neurotoxic, and therefore this process is dangerous when it comes to industrial use.

Since there are two chiral centers in the 4-arylpiperidine-3-methanol molecule of formula 1, theoretically there are four optical isomers and whereas the final pharmaceutically active products are usually required in a rigid configuration on the piperidine ring (e.g., paroxetine is individual (3S, 4R) trans isomer), it is highly desirable that the obtained pieridin-3-methanols of formula 1 consist of an individual, preferably (3S, 4R) trans stereoisomer of high optical purity. Therefore, in the above synthetic procedures, where necessary, a further stage of optical resolution is known in the art.

A stereoselective synthetic process that does not require an optical resolution step is described in WO 97-24323, involving the stereoselective formation of N-acyl analogs of compounds of formula 1. However, only the corresponding (3R, 4S) -cis isomer can be obtained by this process.

As is apparent from the above, it is highly desirable to find an alternative preparation process

4-Arylpiperidine-3-Methanol of Formula 1, particularly for trans-compounds of Formula 1, which would better meet the cost, safety and environmental requirements in the preparation of pharmaceutically active substances such as paroxetine.

SUMMARY OF THE INVENTION

The present invention relates to the finding that the 4-arylpiperidine-3-methanols defined by the general formula 1 (often referred to herein as "compounds 1"), especially their trans isomers such as their (3S, 4R) trans optical isomers, can be prepared in high yields, good purity and under conditions that can be easily reproduced on an industrial scale using certain 4-aryl-2-oxo-3-piperidinecarboxylates.

A first aspect of the present invention relates to a process comprising reducing a compound of formula 7:

(7) to form a compound of Formula 1:

O) ♦

wherein 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; R is hydrogen, lower alkyl, aryl, aralkyl, alkoxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl; and 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. A compound of formula 1 can be converted to a compound of formula 2 by known and / or conventional techniques.

Another aspect of the present invention relates to certain compounds of Formula 7 as such:

wherein X represents a halogen atom, an aralkyl group, an alkoxy group, a dialkylamino group or an alkylthio group; R is hydrogen, lower alkyl, aryl, aralkyl, alkoxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl; and R ¹ represents a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group; and salts thereof (often referred to herein as "compounds 7"). It will be appreciated that Formula 7 includes hydrate and solvate forms of the compounds. Further, the formula includes cis and trans forms, both individually and in mixtures, as well as individual or racemic mixtures of optical isomers, each in cis and trans form. Similarly, one aspect of the present invention pertains to a compound of Formula 1, or a pharmaceutically acceptable salt thereof, which is substantially free of the corresponding des-fluorine impurity:

R (1) wherein X is fluorine and R is hydrogen, lower alkyl, aryl, aralkyl, alkoxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl.

A further object of the present invention relates to the preparation of compounds of general formula 7. The general process comprises (a) reacting a compound of general formula 8 with malonic acid or a malonic ester of general formula 13 to form a compound of general formula 9:

CN

(9) (8) (13) wherein 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 ¹ and R ³ independently represent a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group ; and (b) reductively cyclizing the compound of Formula 9 to form a compound of Formula

7.

For the purposes of the present application, the term "lower alkyl" means a straight or branched saturated alkyl group having 1 to 6 carbon atoms or a vinyl group; methyl or ethyl are particularly preferred. The term "aryl" means a phenyl group or a phenyl group substituted by one or more halogen atoms, a lower alkyl or alkoxy group or a methylenedioxy group. The term "alkoxy" preferably means lower alkoxy groups, i.e. having a straight or branched carbon chain having 1 to 6 carbon atoms, most preferably ethoxy or tert-butoxy. The term "aryloxy" means a phenyloxy or phenyloxy group substituted with a halogen atom or a lower alkyl group.

The terms "trans configuration" and "cis configuration" mean that the phenyl substituent at the 4 position and the methanol or carboxy substituent at the 3 position are relative to each other in the trans or cis orientation.

The piperidine methanols represented by the general formula (1) as well as the compounds (7) are preferably in the trans configuration due to the preferred application of intermediates in the preparation of paroxetine. However, the scope of the invention is not limited to compounds with trans configuration.

Due to the existence of two asymmetric centers in the molecule, the trans methanol of Formula 1 can be separated into two stereoisomers. For the intended use, it is preferred, but not necessary, that the final methanol derivative of Formula 1 be the individual (3S, 4R) trans stereoisomer. For most compounds of Formulas 1 and 7, the (3S, 4R) optical isomer will be the (-) optical isomer. For example, paroxetine is known as the individual (-) trans optical isomer. However, it is possible that some combinations of substituents may change the optical rotation and thus be more appropriately classified as (+) optical isomers. For clarity, the R, S nomenclature is often used in the file, while the (+, -) nomenclature is used where appropriate and should not be construed as contradictory.

The first process of the present invention provides compounds of Formula 1 by means of reducing the intermediate compounds of Formula 7. Hydrides such as metal hydrides or borane reducing agents are suitable as reducing agents. Suitable examples include lithium aluminum hydride, sodium borohydride, sodium bis (2-methoxyethoxy) aluminum hydride, aluminum hydrides, diborane, borane complexes such as borane / tetrahydrofuran and the like. The reaction solvent may be a solvent which is not itself reducible; preferred solvents are hydrocarbon or ether based solvents such as toluene or tetrahydrofuran. The reaction temperature in the process is preferably from 0 to 100 ° C, most preferably from 0 to 50 ° C.

For compounds of formula 7 wherein X is fluorine, low temperatures (e.g. 0-30 ° C) are preferred to avoid undesirable replacement of fluorine with hydrogen. One of the advantages of the present invention resides in the fact that generally milder reducing conditions can be used effectively compared to the process described in US patent 4,902,801. This is because the compounds of formula 7 have only one carbonyl group and one carboxy group which The dioxo intermediates disclosed in U.S. Pat. No. 4,902,801 have two carbonyl groups and two carboxyl groups to be reduced. Therefore, reducing the compound of Formula 7 does not require stringent conditions, thereby reducing the possibility of inadvertent removal of the fluorine atom. That is, the level of des-fluorinated impurities (a compound of formula 1 wherein fluorine is replaced by hydrogen) can advantageously be minimized according to the present invention. Preferably, the compounds of formula 1 are prepared substantially free of des-fluorinated impurities. The term "substantially free" means less than about 2.5% of des-fluorinated impurities, preferably less than 1% of des-fluorinated impurities, based on the total amount of phenylpiperidine product. Due to the high level of purity, those compounds of formula I that are substantially free of the corresponding des-fluorinated impurities are another aspect of the present invention.

In the case where R in the compounds of the general formula represents a hydrogen atom, these compounds can, if desired, be converted to compounds in which R is lower alkyl or aralkyl by reacting them with an alkylating agent, preferably an aldehyde or ketone or equivalent in a reducing atmosphere and in a suitable solvent. Examples of alkylating agents for this purpose include formaldehyde, acetaldehyde, benzaldehyde, acetone, paraformaldehyde. Alternatively, such compounds 1 can be converted to compounds wherein R is an alkyloxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl group by reaction with a suitable haloformate, for example phenyl chloroformate, benzyl chloroformate or ethyl chloroformate, or analogs thereof, for example di-tert-butyl dicarbonate, by general techniques.

Compounds of formula 1 can be converted to compounds of formula 2 by known methods, as described in US Patent Nos. 4,007,196 and 4,721,723, which are generally characterized by a substitution reaction:

(2)

wherein R ² represents an alkyl or alkynyl group having 1-4 carbon atoms; substituted or unsubstituted phenyl, wherein the substituents are selected from the group consisting of C 1 -C 4 alkyl, alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl, methylenedioxy, and combinations thereof, or tetrahydronaphthyl. Preferably, the compound of formula II is paroxetine. One method for obtaining paroxetine involves reacting a compound of formula I (X is para-fluoro) with either thionyl chloride or benzenesulfonyl chloride and then an alkali salt of 3,4-methoxyphenoxide, such as 3,4methoxyphenoxide. The N-substituent, if other than hydrogen, can be removed by conventional reactions. The process may further comprise reacting a compound of Formula 2, especially paroxetine, with a pharmaceutically acceptable acid to form an acid addition salt. Preferred acids include hydrochloric acid, acetic acid, sulfonic acids (methylsulfonic acid, etc.), and maleic acid, although other acids that form pharmaceutically acceptable acid addition salts may be used.

To prepare compounds of Formula 1 as trans isomers, the corresponding intermediate compound 7 will also be a trans isomer. It will be further noted that the process of the present invention for preparing compounds of Formula 7 provides compounds of Formula 7 directly in the desired trans configuration.

Similarly, as mentioned above, trans-carboxylates 7 have two asymmetric centers in the molecule, so that they can exist as racemic trans-compounds or as individual (-) trans or (+) trans stereoisomers. Racemic trans-carboxylates 7 provide racemic transmethanols 1. To obtain the individual stereoisomer, preferably the (-) trans isomer of compound 1 from a racemic mixture, conventional methods of separating the racemic mixture into compounds 1 may be applied, preferably converting the racemate into a salt with a suitable acid, dibenzoyltartaric, in a suitable solvent, crystallizing the salt of the (-) trans isomer from solution and releasing the free (-) trans isomer of methanol 1 from the salt.

Alternatively, the individual (-) or (+) trans-stereoisomer of Compound 1 can be obtained by reducing the corresponding individual stereoisomer of trans-carboxylate 7 under conventional reduction conditions as described above.

Most of the carboxylates of formula 7 are novel as such. A compound wherein X is hydrogen (see Koelsch. J. Adm. Chem. Soc. 65, 2459 (1943)) and a compound wherein X is ethyl (see EP

007 067 and DE 28 01 195) are disclosed in the literature. Thus, compound 7 wherein X is not hydrogen or lower alkyl is one of the preferred subgroups. More generally, of the compounds represented by the general formula 7, those wherein X is fluorine, more preferably fluorine at the para position are preferred. Preferably, the subset includes X as fluorine in the para-position, R is hydrogen, methyl or benzyl

And R ¹ is methyl or ethyl. However, these compounds are preferably in the trans configuration, and in particular the (3S, 4R) trans optical isomer configuration. Examples of particularly preferred compounds include:

ethyl trans-4- (p-fluorophenyl) -2-oxopiperidine-3-carboxylate ethyl trans-4- (p-fluorophenyl) -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- trans-4- (p-fluorophenyl) -1-benzyl-2-oxopiperidine-3-carboxylic acid carboxylic acid and (3S, 4R) trans isomers of said compounds.

Compounds 7 can be formed by the following general method, which comprises (a) reacting a compound of Formula 8 with malonic acid or an ester thereof of Formula 13 to form a compound of Formula 9:

(8)

(9) wherein 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 ¹ and R ³ independently represent a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group; and (b) reductively cyclizing the compound of Formula 9 to form a compound of Formula 7.

The starting cinnamonitriles of formula 8 are commercially available or can be readily obtained from the corresponding benzaldehyde by reaction with acetonitrile in the presence of an equimolar amount of base. Acetonitrile can predominantly serve as a solvent for the reaction.

Cinnamonitrile 8 is reacted in production step (a) with a malonic acid, a semi-ester or an ester 13, for example diethyl malonate, in the presence of an equimolar amount of a base in a suitable organic solvent. Sodium alkoxide as base and lower alcohol as solvent are preferred. The resulting 4-cyanobutyrate 9 can be isolated from the reaction mixture after neutralizing the base by conventional means, for example by adding a water-immiscible solvent such as ethyl acetate, extracting the water-soluble salt with water and evaporating the solvent.

"Reduction cyclization" means any step or combination of steps that converts a compound of Formula 9 to a compound of Formula 7. In general, reduction cyclization involves reduction and ring formation or a cyclization step. The alkylation or aralkylation step can also be performed by adding to the reduction and cyclization steps. These steps may be performed sequentially or in steps, or two or more steps may be performed simultaneously. Reduction cyclization methods are described below, although it will be apparent to one skilled in the art that other methods may be used.

In process A, reductive cyclization is performed by reduction of cyanobutyrate 9 to give intermediate 3-aminopropylmalonate 11. This intermediate is - with or without isolation - cyclized by dehydration.

Italy (11)

The reduction can advantageously be carried out by catalytic hydrogenation using conventional hydrogenation catalysts such as Raney nickel, Raney cobalt, palladium or coal, Adams catalyst (platinum oxide) and the like. As the solvent, organic solvents can be used which alone cannot be hydrogenated; suitable solvents are hydrocarbons such as toluene, ester solvents such as ethyl acetate, ether solvents such as tetrahydrofuran or alcohol solvents such as ethanol. If appropriate for the reaction, an acidic, neutral or alkaline reaction medium may be used. Most preferred is an acidic medium.

The intermediate amine 11 may optionally be isolated in the form of an acid addition salt with a suitable acid, for example hydrochloric acid.

The cyclization takes place 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 an alcohol. Similarly, an inorganic base such as an alkali metal hydroxide or carbonate in alcohol or water may be used. The cyclization can be carried out in the same solvent as the hydrogenation reaction. It is preferred, although not required, that the reduction and cyclization be performed in steps and the catalyst is filtered off prior to cyclization. Under these conditions, the original ester group of the starting malonate remains intact or, in the case of an alcoholic solvent, may be transesterified.

Alternatively, an aqueous base such as sodium hydroxide solution may be added to the reaction mixture after reduction or cyclization, and the mixture is allowed to react at elevated temperature. In this way, cyclization is followed by alkaline hydrolysis of the ester group (see step d) below). In a preferred embodiment, the production steps a) and b) are carried out in the same solvent, preferably in a lower alcohol such as ethanol. In this case, both steps can be carried out in a single run, without isolation of the intermediate cyanobutyrate 9.

Under the cyclization conditions described above, compounds 7 wherein R is hydrogen are predominantly formed in the trans configuration. Most preferably, the undesired cis isomer content is less than 5%. Under other conditions, a mixture or a higher cis isomer content may be formed.

Depending on the intended use, the thus obtained intermediate compounds 7, where R is hydrogen, can either be directly used in the reduction step described above to give compounds 1, where R is also hydrogen, or, if desired, subjected to the (c) N-substitution to give compounds of Formula 7 wherein R is alkyl, aryl or aralkyl. In such a case, they may be alkylated in a suitable inert solvent, preferably in the presence of a base, using a conventional alkylating or aralkylating agent such as an alkyl halide, aralkyl halide or dialkyl sulfate, wherein benzyl bromide or dimethyl sulfate are examples of preferred reagents. Similarly, compounds 7 wherein R is hydrogen can be converted to their N-alkyloxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl analogs by reaction with the corresponding haloformates or corresponding reagents under the conditions described above.

If desired for the intended use, the products of reaction step b) or c) may be subjected to reaction step d), acid or alkaline hydrolysis of the ester group by conventional methods. Aqueous solutions of inorganic or organic strong acids, such as hydrochloric acid, and / or aqueous alkali metal hydroxides, such as sodium hydroxide, are most suitable for this purpose. This gives carboxylic acids, i.e. compounds of formula 7, wherein R ¹ is hydrogen. After working up the reaction mixture, the resulting acids can be isolated as such or in the form of their salts.

• · · · · · · · · · · · · · ·

Compounds 7 resulting from any of previous steps b), c) and / or d) can be used for subsequent reduction either as such to provide racemic trans compounds 1 or, if desired, subjected to reaction step e) for resolution to its optical isomers. When R ¹ is hydrogen, compounds 7 can be resolved into the optical isomers by conventional fractional crystallization of their salts with suitable optically active amines in a suitable solvent such as methanol, ethanol, ethyl acetate, water, and mixtures thereof. Representative examples of optically active amines include compounds described, for example, in JP 06-116214. More preferably, R (+) - N- (4-hydroxyphenylmethyl) phenylmethylamine may be mentioned for this purpose. In the case where R ¹ is lower alkyl or aryl, such compounds 7 can be resolved into their optical isomers, preferably by stereo selective hydrolysis of the ester moiety using an enzyme, for example by the methods described in WO 94-03428 or WO 93-22284.

The compounds 7 of any of the preceding steps b) to e) are generally in solid form and can be isolated preferably in a crystalline state, either as such or as acid addition salts thereof with suitable organic or inorganic acids. Preferred acids are hydrochloric acid, maleic acid or tartaric acid. Depending on the method of isolation, they may form hydrates or solvates. A preferred method of isolation is the crystallization of a salt, hydrate or solvate from a suitable solvent and separation of the resulting solid by filtration or centrifugation.

In process B of reductive cyclization, the butanoic acid derivative 9 is subjected in step b) to alkylation or aralkylation of the cyano group under reductive conditions. The general method described by Borch in J. Org. Chem. 84, 627 (1969). In this process, the corresponding nitrile salts of the general formula 10, where R ¹ is lower alkyl or aralkyl, are first obtained. For these purposes, Borchem is cited as preferred reagents as trialkyloxonium tetrafluoroborates or dialkoxycarbonium tetrafluoroborates.

(10)

The reaction is generally carried out at ambient temperature, preferably at 0 to 50 ° C, in an inert solvent such as methylene chloride. The reaction product may be isolated, although it is preferred that it is subjected to further in situ processing. This conversion involves the reduction of the nitrile salt to the secondary amine, preferably using a hydride such as borohydride in a suitable solvent such as ethanol. The intermediate secondary amine 12 is preferably, without isolation, subsequently subjected to cyclization at elevated temperature and preferably in the presence of a base, preferably in the same solvent. In a preferred aspect, the hydride itself serves as the base.

Alternatively, the conversion of compound 9 to the desired compound 7 can also be carried out in a simpler manner, where it is not necessary to first convert the nitrile 9 to the nitrile salt. Instead, the starting nitrile may be subjected to reductive alkylation in the presence of an alkylating agent or an aralkylating agent. A preferred reagent is an amine, especially an alkylamine. The intermediate secondary amine 12 cycles spontaneously to the desired

(12) compound 7, even during the reaction, since the amine itself serves as a base. The most preferred reducing agent is hydrogen in the presence of a suitable catalyst, for example an Adams catalyst (PtO ₂ ). A preferred solvent for the reaction is an inert organic solvent such as ethanol or methanol. The reaction proceeds at ambient temperature or at a slightly elevated temperature, typically at a temperature of 0 to 50 ° C.

The resulting compounds of 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 separation methods such as extraction, evaporation, chromatography, precipitation or crystallization.

In view of their intended use, the above products of step b) may either be used directly for the preparation of the corresponding compounds 1 or may be subjected to one or more stages of derivatization at the nitrogen atom, hydrolysis of the ester group,

resolution of optical isomers or conversion to salts or the like. Specifically, one of the following additional steps may be performed:

c) reacting the product of step b) with an aqueous acid or base solution to hydrolyze the ester group;

d) reacting any product of step b) or c) with an agent to effect substitution of the N-alkyl or aralkyl group with an alkyloxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl group;

e) replacing the N-substituent in the product of step b), c) or d) with hydrogen;

f) resolving any of the compounds of steps b), c), d) or e) into the optical isomers; or

g) converting any of the compounds of steps b), c), d), e) or f) to an acid addition salt, hydrate or solvate. The conditions of such processes are described above with respect to process A, steps c) to e).

Method C for reductive cyclization reduces the nitrile 9 to give the amine 11. The amine 11 is then reacted with an acylating agent such as formic acid under conventional conditions to provide a compound of formula 14:

Italy (11)

t (14)

(12) wherein R ⁴ represents a hydrogen atom, a C 1 -C 5 alkyl group, an aryl group, a C 1 -C 5 aralkyl group in the alkyl moiety. The N-acyl group is then reduced with a reducing agent such as catalytic hydrogenation as described above for the corresponding N-alkyl group above to give a secondary amine of formula 12. The secondary amine is then cyclized to give compound 7. Similar to the above reaction The reduction of the N-acyl group and the cyclization can be carried out simultaneously without isolation of the secondary amine. Preferably, the cyclization is carried out under acidic conditions. This method, although requiring an extra degree, provides high purity and is only used when the reactants are readily available and cheap, making such a method advantageous from a commercial point of view. The following steps c) to g) may also be used as described for method B.

The following reaction scheme illustrates certain embodiments of the above three A-C methods. It should be noted that although alkylation is reported, it can be used for aralkylation as mentioned above.

··

9,999 ♦ 9 9

9 9 9 9

Possible degree depending on the value of R (7) where R = H

R (7) wherein R is not H

9 9 9 9 9 9 9 ·· · 9 9 9 ·· · «« ······ 9 · * V ··· ·· 9 · 99999

One of the main objects of the present invention is to provide a process for the preparation of (-) trans -4- (p-fluorophenyl) -1-methyl-3-piperidinemethanol, preferably for use as a key intermediate for the preparation of paroxetine. The preferred ethyl trans (+/-) 4- (p-fluorophenyl) -1-methyl-2-oxopiperidine-3-carboxylate according to the invention can be prepared from p-fluorocinnamonitrile by combining the above processes, preferably by method B or C. sequential degrees of reduction and resolution of the (-) trans isomer. Details of each step are given above.

The following examples illustrate the present invention. It is to be understood that these examples are illustrative only and in no way limit the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of p-fluorocinonitrile.

12.4 g of p-fluorobenzaldehyde are dissolved in 20 ml of acetonitrile. This solution was added to a boiling suspension of 6.6 g of powdered potassium hydroxide in 80 ml of acetonitrile, the mixture was stirred at reflux for 10 minutes and then poured into 150 g of crushed ice. The mixture was extracted with 2x100 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and evaporated to dryness to give a dark green oil which crystallized on standing. 13 g (80%) of a green solid are obtained. The compound is a mixture of the cis and trans isomers. NMR (.delta. Spectrum): 5.43 + 5.43 + 5.80 (d, 1H, cis-Hc-cN + trans-Hc-cN), 7.09 + 7.45 (m, 4H, Arom. H). 7.35 (d, 1H, H-ph).

Example 2

Preparation of diethyl 2- (1 '- (p-fluorophenyl) -2'-cyanoethyl) malonate.

Sodium (0.86 g) was dissolved in 25 ml of ethanol and the solution was cooled to room temperature. A solution of 5.8 g of diethyl malonate in 10 ml of ethanol was added and the mixture was stirred for 15 minutes. To this solution was added 5 g of p-fluorocinonitrile from Example 1 in 10 ml of ethanol, and the mixture was heated at 50 ° C for 3 hours. 3 ml of acetic acid and 10 ml of water are then added and the resulting mixture is evaporated to near dryness. The residue was suspended in 100 mL of ethyl acetate and extracted with 50 mL of 1M HCl and 50 mL of 5% sodium sulfate and evaporated to dryness to give 10 g of the title product as an orange oil. NMR: delta scale): 1.03 (t, 3H, CH3), 1.28 (t, 3H, _CH3), 2.86 (m, 2H, 2H);

3.73 (m, 1H, Γ-Η), 3.91 (d, 1H, 2-H), 4.23 (m, 4H, CH _2), 7.04 + 7.28 (m, 4H, Arom.

Example 3

Preparation of diethyl 2- (r-phenyl-2'-cyanoethyl) malonate.

In an analogous manner to that described in Example 2, the title compound is prepared as a white solid when cinamonitrile is used in place of p-fluorocinonitrile. NMR (delta scale): 0.99 (t, 3H, _CH3), 1.28 (t, 3H, CH _3), 2.88 (m, 2H, 2 H), 3.73 (m, 1H , Γ-Η), 3.85 (d, 1H, 2-H), 3.95 + 4.25 (m, 4H, _CH2), 7.31 (m, 5H, arom. H).

Example 4

Preparation of diethyl 2- (1 '- (p-fluorophenyl) -3'-aminopropyl) malonate hydrochloride.

g of the product of Example 2 was dissolved in 20 ml of ethanol under a nitrogen atmosphere, and 0.8 g of Adams catalyst was added together with 35 ml of ethanolic HCl. The mixture was hydrogenated at 50 psi for 6 hours. The catalyst was filtered off and the solution was evaporated to dryness. The remaining oil was dissolved in 50 mL of ethyl acetate and extracted with 2 x 100 mL of water. The combined aqueous layers were evaporated to give 9.2 g of a yellow oil which solidified on standing. NMR (delta scale): 1.00 (t, 3H, _CH3), 1.26 (t, 3H, _CH3), 2.13 + 2.27 (d, 2H, 2'-H) 2, 73 (bs, 2H, 3 ' -H), 3.52 (bt, 1H, [delta]), 3.60 (d, 1H, 2-H), 3.91 + 4.22 (m, 4H, CH ₂ ), 6.98-7.28 (m, 4H, arom. H), 8.27 (bs, 3H, NH).

Example 5

Preparation of diethyl 2- (r-phenyl-3'-aminopropyl) malonate hydrochloride.

Under the conditions described in Example 4 but using the compound of Example 3 as the starting material, the title product was prepared as a white precipitate by recrystallization from ethyl acetate. NMR: (delta scale): 0.95 (t, 3H, _CH3), 1.25 (t, 3H, _CH3), 2.13 + 2.29 (d, 2H, 2'H) 2, 77 (bs, 2H, 3 ' -H), 3.53 (dt, 1H, [delta]), 3.63 (d, 1H, 2-H), 3.87-4.21 (m, 4H, CH ₂ ), 7.22 (m, 5H, arom. H), 8.23 (bs, 3H, NH).

Example 6

Preparation of ethyl (+/-) trans-4-phenyl-2-oxo-3-piperidinecarboxylate (compound 7, X = hydrogen, R = H, R ¹ = ethyl) in one pot.

The product of Example 3 (7.2 g) was dissolved in absolute ethanol saturated with HCl and 0.59 g of Adams catalyst was added. The reaction mixture was hydrogenated at room temperature under 60 psi 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 1M hydrochloric acid. 50 ml of ethyl acetate were added to the combined aqueous layers, and the mixture was basified with potassium carbonate to pH 9. The layers were evaporated, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate and evaporated to give 5.6 g of white powder. recrystallized from ethyl acetate for analytical purposes. NMR (delta scale): 1.07 (t, 3H, _CH3), 2.04 (m, 2H, 5-H)

3.43 (m, 3H, 4-H + 6-H), 3.53 (d, 1H, 3H), 4.06 (q, 2H, _CH2), 7.26 (m, 5H, arom. H, 6.62 (s, 1H, NH).

Example 7

Preparation of ethyl (+/-) trans -4- (p-fluorophenyl) -2-oxo-3-piperidinecarboxylate (compound 7, X = fluorine, R = H, R ¹ = ethyl).

Under the conditions described in Example 6 but using the compound of Example 2 as the starting material, the title product was prepared as a white precipitate after recrystallization from a mixture of ethyl acetate and heptane. NMR: (delta scale): 1.08 (t, 3H, CH _3), 1.90 to 2.10 (m, 2H, 5-H) 3.35 - 3.55 (m, 4H, 3H + 4-H + CH ₂ ), 4.00-4.15 (m, 2H, 6-H), 7.01-7.19 (m, 4H, aromatic H),

7.43 (bs, 1H, NH).

Example 8

Preparation of ethyl trans (+/-) - 1-methyl-2-oxo-4-phenyl-3-piperidinecarboxylate (Compound 7, X = H, R = CH ₃ , R ¹ = ethyl).

The product of Example 3 (1.06 g) was dissolved in 20 ml of absolute ethanol and 0.4 g of Adams catalyst and 15 ml of a 2M solution of methylamine in methanol were added. The reaction mixture was hydrogenated at 50 psi hydrogen for 24 hours at room temperature. The catalyst was removed by filtration and the clear filtrate was evaporated to dryness. The residue was dissolved in 20 ml of ethyl acetate, washed with 1 x 10 ml of 1M hydrochloric acid, dried over sodium sulfate and evaporated to dryness. The yield was 0.7 g of a colorless oil which was purified by silica gel chromatography (eluent chloroform-methanol 19: 1). The compound is a racemic mixture of the (+) and (-) enantiomers. NMR (delta scale): 1.05 (t, 3H, _CH3), 2.07 (m, 2H, 5-H), 2.98 (s, 3H, N-CH _3), 3.40 (m , 3H, 4-H + 6-H), 3.52 (d, 1H, 3H), 4.03 (q, 2H, CH _2), 7.20 + 7.30 (m, 5H, arom H).

Example 9

Preparation of ethyl trans (+/-) - 1-methyl-2-oxo-4- (p-fluorophenyl) -3-piperidinecarboxylate (compound 7, X = p-fluoro, R = CH ₃ ), R ¹ = ethyl).

By analogy to Example 8, but using the product of Example 2 as the starting product, the title compound (mixture of (+) and (-) enantiomers) was obtained as a white solid. NMR (delta scale): 1.08 (t, 3H, CH _3), 2.00 to 2.10 (m, 2H, 5-H), 3.00 (s, 3H, N-CH ₃₎ 3 30 - 3.60 (m, 4H, H-3 + 4H + _CH2), 4.00 - 4.12 (m, 2H, 6-H), 7.00 + 7.17 (m, 4H, arom.

Example 10

Preparation of trans (+/-) - 1-methyl-4- (p-fluorophenyl) piperidine-3-methanol (Compound 1, X = fluoro, R = CH ₃ ).

The product of 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 aluminum hydride in a mixture of 2 ml of tetrahydrofuran and 8 ml of toluene at such a rate that the temperature was kept below 5 ° C. After the addition is complete, the mixture is stirred at 0-5 ° C for 3 hours and at room temperature for 16 hours. The mixture was then cooled to 0 ° C and 0.5 ml of water and 1 ml of 1M sodium hydroxide solution were added. The resulting solid was collected by filtration over a thin Hyflo layer and washed with 2 x 5 mL toluene. The filtrate was evaporated to a volume of about 1.5 ml and 1 ml of n-heptane was added. After a few minutes a solid formed and was filtered off. After drying under vacuum, 0.15 g of product is obtained. The des-fluorinated impurity content was less than 1% (HPLC).

• 999 · 999

9

9

Example 11

Preparation of ethyl trans (+/-) - 1-methyl-2-oxo-4- (p-fluorophenyl) -3-piperidinecarboxylate (compound 7, X =) -fluorine, R = CH ₃ , R ¹ = ethyl).

The product of Example 2 (2.5 g) was dissolved in 4 ml of dichloromethane, 2.5 g of trimethyloxonium tetrafluoroborate was added and the mixture was stirred under reflux for 18 hours. The mixture was then quenched with 1 mL of ethanol and evaporated to dryness. The resulting solid was dissolved in 10 mL of methanol and a suspension of 1.5 g of sodium borohydride in 10 mL of methanol was added during cooling. The mixture was stirred for 2 hours, acidified with concentrated hydrochloric acid and evaporated to dryness. The solid residue was dissolved in 10 ml of water and basified with potassium carbonate. The solution is extracted with 2 x 25 ml of ethyl acetate, the organic phase is dried over magnesium sulphate, the solvent is evaporated and the residue is crystallized from ethyl acetate. A white solid is obtained. The NMR spectrum of this product was consistent with the NMR spectrum of the product of Example 9.

Example 12

Preparation of ethyl trans (+/-) - 1-methyl-2-oxo-4- (p-fluorophenyl) -3-piperidinecarboxylate (compound 7, X = p-fluoro, R = CH ₃ , R ¹ = ethyl).

The amine from Example 4 (0.97 g) was dissolved in 20 ml formic acid and heated with 2 ml acetic anhydride 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 aqueous sodium bicarbonate solution and water, the organic phase was dried over sodium sulfate and evaporated to give 0.71 g of a yellowish oil. NMR confirms the identity of N-formylamine.

The oil was dissolved in 10 mL of tetrahydrofuran, cooled to -5 ° C, and 0.8 mL of dimethylsulfide borane complex was added dropwise at the same temperature. Then the mixture was stirred at 0 ° C for 30 minutes and then stirred at 45 ° C for 1 hour. After cooling to 0 ° C, the reducing agent was quenched by the addition of 10 mL of absolute ethanol and 1 mL of 12M ethanolic HCl. The reaction mixture is evaporated to dryness, the residue is dissolved in 20 ml of ethyl acetate and washed with 4 x 10 ml of 1M hydrochloric acid. The combined organic layers were basified with potassium carbonate and extracted with 2 x 20 mL ethyl acetate. The organic layer is dried over sodium sulphate. 9 99

9 9 9 9 9 9 9 9 99

9 9 9 9 9 99

9 99 99 · 9 9 9 999 9 and evaporated to dryness to give 0.44 g of a yellowish oil. The NMR spectrum of this product was identical to that of Example 9.

Example 13

Preparation of trans (+/-) - 1-methyl-2-oxo-4- (p-fluorophenyl) -3-piperidinemethanol (compound 1, X = p-fluoro, R = CH ₃ ).

0.45 g of the compound of Example 11 is dissolved in 5 ml of dry tetrahydrofuran. To this solution was added 3.4 ml of a 1M solution of BH ₃ in tetrahydrofuran with stirring at room temperature. The mixture was stirred at room temperature for 2 hours, then 1.6 mL of the same BH ₃ solution was added and the mixture was stirred at 40 ° C for 18 hours. The mixture was then cooled to 0 ° C and 5 mL of ethanol was added. The mixture was evaporated to dryness and the remaining solid was boiled in 10 ml of 6M HCl solution for 1 hour. After cooling to room temperature, the mixture was neutralized with potassium carbonate, extracted with 3 x 15 mL toluene and evaporated to dryness to give 0.25 g of the product as a white oil. NMR confirmed the identity of the above product and the desfluorinated impurity content was 0.5%. (HPLC).

It will be apparent to those skilled in the art that other changes and modifications to the terms described herein may be made without departing from the spirit and scope of the invention as defined in the following claims.

Claims (34)

PATENT REQUIREMENTS w - 4 í /! S> A 4-arylpiperidine-3-methanol of the general formula 7 (7) wherein X represents a halogen atom, an aralkyl group, an alkoxy group, a dialkylamino group or an alkylthio group; R is hydrogen, lower alkyl, aryl, aralkyl, alkoxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl; and R ¹ represents a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group, and a salt thereof, a hydrate thereof and a solvate thereof. (2) wherein R ² represents an alkyl or alkynyl group having 1-4 carbon atoms; substituted or unsubstituted phenyl, wherein the substituents are selected from the group consisting of C 1 -C 4 alkyl, alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl, methylenedioxy, and combinations thereof, or tetrahydronaphthyl. The 4-arylpiperidine-3-methanol of claim 1, wherein the substituents at the 3 and 4 positions on the piperidine ring are in trans orientation with each other. The 4-arylpiperidine-3-methanol of claim 2, wherein said compound is the (3S, 4R) trans optical isomer. 4-Arylpiperidine-3-methanol according to claim 1, wherein X is fluoro, R is hydrogen, methyl, ethyl or benzyl and R ¹ is hydrogen, methyl or ethyl. The 4-arylpiperidine-3-methanol of claim 4, wherein said compound is the (3S, 4R) trans optical isomer. The 4-arylpiperidine-3-methanol of claim 1, wherein the compound is selected from the group consisting of trans-4- (p-fluorophenyl) -2-oxopiperidine-3-carboxylic acid, ethyl trans-4- (p26-). · · ♦ · · · · φ φ φ φ φ φ φ · · · · φ φ φ φ φ φ φ φ φ φ φ φ (Φ · ···· fluorophenyl) -2-oxopiperidine-3-carboxylate, trans-4- (p-fluorophenyl) -1-methyl-2-oxopiperidine-3 carboxylic acid, ethyl trans-4 (p-fluorophenyl) -1-methyl-2-oxopiperidine-3-carboxylate, trans -4- (p-fluorophenyl) -1-benzyl-2-oxopiperidine-3-carboxylic acid and ethyl trans-4- (fluorophenyl) -1-benzyl-2- oxopiperidine-3-carboxylate. 7. The 4-arylpiperidine-3-methanol of claim 6, wherein said compound is the (3S, 4R) trans optical isomer. A process for the preparation of a compound of formula (7): (7) to produce a compound of formula (1): (D wherein X is hydrogen, halogen, lower alkyl, aralkyl, alkoxy, dialkylamino or alkylthio; R is hydrogen, lower alkyl, aryl, aralkyl, alkoxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl; and R ¹ represents a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group. • · ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** Φ · Φ · · · · · · · · · · · · · · · 9. The method of claim 8 wherein said reduction step is performed with a hydride or borane reducing agent. 10. The process of claim 9 wherein said hydride reducing agent is a metal hydride. The method of claim 10, wherein said metal hydride is lithium aluminum hydride. 12. The method of claim 8 wherein said compound of formula (7) and said compound of formula (1) are each trans is optically isomers. The method of claim 12, wherein said compound of formula 7 and said compound of formula 1 are each optical isomers in the (3S, 4R) trans configuration. 14. The method of claim 12 wherein X is a fluorine atom in the para position, R is hydrogen, methyl, benzyl, tert-butyloxycarbonyl, benzyloxy or phenyloxycarbonyl, and R &lt; ¹ &gt; is hydrogen, methyl or ethyl . 15. The method of claim 14 wherein X is a fluorine atom in the para-position and R is a methyl group. 16. The method of claim 15 wherein said compound of formula (7) and said compound of formula (1) are each in the (3S, 4R) trans configuration. 17. The method of claim 8 wherein R is hydrogen and the method further comprises the subsequent reaction of a compound of Formula 1 with an alkylating agent or aralkylating agent or an alkyl, aralkyl or haloformate to convert R in the compound of general formula I. of formula 1 from hydrogen to an alkyl, aralkyl, alkoxycarbonyl, aryloxycarbonyl or aralkyloxycarbonyl group. The method of claim 17, further comprising isolating the optical isomer (3S, 4R) of the trans converted compound of Formula 1. 19. The method of claim 8 comprising reacting said compound of Formula 1 to obtain a compound of Formula 2: 20. The method of claim 19 wherein said compound of formula (1) and (2) is in the trans configuration. 21. The method of claim 20 wherein said compound of formula (2) is paroxetine. 22. The method of claim 21, further comprising reacting paroxetine with an acid to form a pharmaceutically acceptable paroxetine addition salt. 23. The method of claim 8, further comprising forming said compound of formula (7) by the following steps: (a) reacting a compound of Formula 8 with a malonic acid or a malonic ester of Formula 13 to form a compound of Formula 9: • ♦ • 0 0 0 ··· ·· * 00 00 wherein X is hydrogen, halogen, lower alkyl, aralkyl, alkoxy, dialkylamino or alkylthio, R ³ is independently hydrogen, lower alkyl, aryl or an aralkyl group; and R ¹ is as defined for formula 7 and (b) reductively cyclizing a compound of formula 9 to form a compound of formula 24. The method of claim 23 wherein said reductive cyclization comprises sequential reduction of a compound of Formula 9 in an acid, neutral, or alkaline medium, followed by cyclization in a neutral or alkaline medium, and wherein R in the compound of Formula 7 is hydrogen. 25. The method of claim 24, comprising at least one of the following steps: c) reacting the product of step b) with an agent for substituting N-hydrogen with an alkyl, aralkyl, alkyloxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl group; d) reacting any of the products of step b) or c) with an aqueous solution of an acid or base to hydrolyse the ester group to the carboxylic acid; e) resolving any of the compounds of steps b), c) or d) into the optical isomers; or f) converting any of the compounds of steps b), c), d) or e) to an acid addition salt, hydrate or solvate. 26. The method of claim 23 wherein said reductive cyclization comprises alkylating or arylating said compound of Formula 9, reducing and cyclizing; wherein R in the compound of Formula 7 is a lower alkyl or aralkyl group. The method of claim 26, wherein said reductive cyclization comprises performing alkylation with an alkylamine under reducing conditions and allowing spontaneous cyclization. 28. The method of claim 26, further comprising at least one of the following steps: c) reacting the product of step b) with an aqueous acid or base solution to hydrolyze the ester group; d) reacting any of the products of step b) or c) with an agent to effect substitution of the N-alkyl or aralkyl group with an alkyloxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl group; e) replacing the N-substituent in the product of step b), c) or d) with hydrogen; f) separating any of the compounds of steps b), c) d) or e into optical isomers; or g) converting any of the compounds of step b), c), d), e) or f) to an acid addition salt, hydrate or solvate. 29. The method of claim 23, wherein said reductive cyclization comprises reducing said compound of formula 9, acylating the reduced compound, reducing acylated compound, and cyclizing to form a compound of formula 7. The method of claim 29, comprising at least one of the following additional steps: c) reacting the product of step b) with an aqueous acid or base solution to hydrolyze the ester group; d) reacting any product of step b) or c) with an agent to effect substitution of the N-alkyl or aralkyl group with an alkyloxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl group; e) replacing the N-substituent in the product of step b), c) or d) with hydrogen; * T t t t t t t t t * * * * * * · · · · · · · · · ························ f) resolving any of the compounds of steps b), c), d) or e) into the optical isomers; or g) converting any of the compounds of step b), c), d), e) or f) to an acid addition salt, hydrate or solvate. 31. The process of claim 8 wherein X is fluoro and said reduction step yields a compound of formula (1) substantially free of desfluorinated product. 32. The process of claim 31 wherein less than 1% of des-fluorinated impurities are formed in said reduction step relative to the total amount of the phenylpiperidine product. 33. 4-Alylpiperidine-3-methanol of formula (I), or a pharmaceutically acceptable salt thereof, substantially free of the corresponding des-fluorinated impurities: d) wherein X is fluorine and R is hydrogen, lower alkyl, aryl, aralkyl, alkoxycarbonyl or aryloxycarbonyl. 34. The 4-arylpiperidine-3-methanol of claim 33, wherein the amount of des-fluorinated impurities is 1% or less based on the total amount of said compound and impurities.