EP1124802A1

EP1124802A1 - Process for producing 4-arylpiperidine-3-carbinols and related compounds

Info

Publication number: EP1124802A1
Application number: EP99951035A
Authority: EP
Inventors: Theodorus Hendricus Antonius Peters; Franciscus Bernardus Gemma Benneker; Hans Jan Hoorn; Frantisek Picha
Original assignee: Synthon BV
Current assignee: Synthon BV
Priority date: 1998-11-02
Filing date: 1999-11-01
Publication date: 2001-08-22
Also published as: WO2000026187A1; NO20012099D0; AU6360999A; CZ20011465A3; NO20012099L

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 R1 represents a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group.

Description

PROCESS FOR PRODUCING 4-ARYLPIPERIDINE-3-CA- BINOLS AND RELATED COMPOUNDS

FIELD OF THE INVENTION

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. BACKGROUND OF THE INVENTION

4-aryl-piperidine 3-carbinols of the general formula (1)

(1) (2)

are key intermediates in the synthesis of certain pharmaceutically active compounds represented by general formula (2) (wherein 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; and 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.

Paroxetine

Several synthetic procedures leading to compounds of the general formula (1) and having certain industrial applicability have been described in the literature.

For example US 3912743 describes the reduction of 4-aryl-3-piperidinecarboxyIic acid esters of the general formula (3) with lithium aluminium hydride,

(3)

wherein 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,

(4)

wherein 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. These intermediates of formula (4) are synthesized either by addition of N-substituted amidomalonic acid ester to a cinnamic acid ester (EP 223334) or by conjugate addition of a malonic acid ester to cinnamamide (EP 374675). As the amidomalonic acid ester is produced only in very low yields (and it is thus very expensive) and as free amines are to be applied in the synthesis of cinnamamide (thus leading to a need of special equipment and handling), both variants of the above synthetic process are characterized with inevitably high manufacturing costs.

Moreover, if Y is fluorine (e.g. in the production of paroxetine), the required large excess of reducing agent causes easy dehalogenation even at mild reaction conditions; thus, a high amount of a des-fluoro impurity is formed and this impurity is difficult to remove. EP application 802185 describes the reduction of trans-4-aryl-6-oxopiperidine-3-carbinols of general formula (5), preferably by hydrides or metal hydrides,

(5)

wherein 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.

As taught in EP 802185, the reductive cyclization yields generally a cis/trans mixture of the intermediate product (5). To convert this mixture to substantially pure trans-product, it is necessary to separate the unwanted cis-product by fractional crystallization and/or to perform an additional step of isomerization.

US 4007196 or US 4593036 describe a process based on hydrogenation of 4-aryl-l-alkyl- l,2,3,6-tetrahydropyridine-3-carbinols of the formula (6). Dependent on the reduction agent, either the racemic (+/-) cis-isomers or the racemic (+/-) trans-isomers of (1) are obtained.

(6)

However, it has been reported elsewhere that the intermediates (6) in this synthesis are highly neurotoxic so that this process is quite unsafe as far as industrial applicability is concerned.

As there are two centers of optical chirality in the molecule of 4-arylpiperidine-3-carbinols of the formula (1) yielding, in theory, four optical isomers thereof, and as the final pharmaceutically active products are generally required to be in rigid configuration on piperidine ring (e.g. paroxetine is a single (3S,4R) trans isomer), it is highly desired that the produced piperidine-3-carbinols of the formula (1) consist from a single, preferably (3S,4R) trans, stereoisomer with high optical purity. Therefore, an additional step of optical resolution is to be included in all the above synthetic processes of the prior art, whenever necessary.

Already, a stereoselective synthetic process avoiding the step of optical resolution has been recently described in WO 97-24323, comprising stereoselective formation of N-acyl analogues of the compounds of the formula (1). But, by this process only the corresponding (3R,4S)-cis isomer is obtained.

As apparent from the discussion above, it is highly desired to find an alternative process for production of 4-arylpiperidine-3-carbinols of the general formula (1), especially for the trans- compounds of formula (1), which would better fulfill the demands of cost, safety and ecology in the production of pharmaceutically active substances such as paroxetine. SUMMARY OF THE INVENTION

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):

(7) to form a compound of formula (1):

(1) wherein X represents a hydrogen atom, a halogen atom, a lower alkyl group, an aralkyl group, an alkoxy group, a dialkylaπ-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; and R¹ 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:

(7)

wherein 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; and R¹ 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. Furthermore, 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. Similarly, 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:

(1 ) wherein 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):

(8) (13) (9) wherein 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 and R¹ and R³ each independently represent a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group; and

(b) performing reductive cyclization on the compound of formula (9) to form a compound of formula (7).

nF.TATT.Fn DESCRIPTION OF THE INVENTION

For purposes of this application, the term "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.

The terms "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.

Because there are two asymmetric centers in the molecule, 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. For most of the compounds of formula (1) and (7), the (3S,4R) trans optical isomer will be a (-) optical isomer. For example, paroxetine is known to be the single (-) trans optical isomer. However, it is possible that certain ccombinations of substituents could reverse the optical rotation and thus be more properly classified as (+) optical isomer. For clarity, 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). As the reductant, 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. As 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.

In case of compounds (7) where X is fluorine, lower, temperatures (e.g. 0 to 30°C) are preferred in order to avoid undesired replacement of fluorine for hydrogen. In this regard, 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. This means that 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. Preferably the compounds (1) are formed substantially free of the des-fluoro impurity. In this regard, "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. In the case where the compounds (1) have R as a hydrogen atom, they 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. For such purpose, formaldehyde, acetaldehyde, benzaldehyde, acetone, paraformaldehyde are examples of preferred alkylation agents. Alternatively, such compounds (1) may be converted into compounds wherein R is alkyloxycarbonyl, aralkoxycarbonyl group or aryloxycarbonyl group, by reaction with corresponding halofoπnate, 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:

(2)

wherein R² 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. Preferably the compound of formula (2) is paroxetine. One strategy for obtaining 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.

To prepare the compounds (1) as trans isomers, 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.

Similarly as discussed above, 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). To obtain 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.

Alternatively, 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.

Most of the carboxylates of the formula (7) are per se novel. A compound wherein X is hydrogen (see Koelsch, J.Adm.Chem.Soc.65,2459(1943)) and a compound wherein X is ethyl (see EP 0 007 067 and DE 28 01 195) have been mentioned in the prior literature. Thus, the compound (7) wherein X is not hydrogen or a lower alkyl is one of the preferred sub-genuses. More generally, among the compounds represented by the general formula (7), those are preferred in which X is fluorine, more preferably fluorine in the para-position. A preferred sub- genus involves X as a fluorine in the para-position, R is a hydrogen, methyl or benzyl group and R¹ is a methyl or ethyl group. Of course, these compounds are advantageously in the trans configuration and particularly in the (3S,4R) trans optical isomer configuration. Examples of particularly preferred species include: ethyl -rans-4(p-fluorophenyl)-2-oxopipericϋne-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):

(8) (13) 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 and R^! and R³ each independently represent a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group; and

(b) performing reductive cyclization on the compound of formula (9) to form a compound of formula (7). 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. 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). Generally 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.

In method (A), reductive cyclization is carried out by reducing the cyanobutyrate (9) to form the intermediate 3-aminopropylπ-alonate (1 1). This intermediate is - with or without isolation thereof - cyclized by dehydration.

( 1 1 ) 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. As 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. Similarly, inorganic 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.

Alternatively, 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). In the preferred embodiment, 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).

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

Dependent on the intended use, 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. In such a case 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. Similarly, 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.

If desired for the intended use, 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. Aqueous solutions of inorganic strong acids, such as hydrochloric acid, and/or aqueous alkali metal hydroxides, such as sodium hydroxide, are the most preferred for said purpose. As a result, carboxylic acids, i.e. compounds of the general formula (7), wherein R¹ is hydrogen, are formed. After work-up of the reaction mixture, 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. In the case where R¹ 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. Representative examples of the optically active amines include compounds disclosed, for example, in JP 06-116214. More particularly, the R(+)-N-(4-hydroxyphenylmethyl)-phenylmethyl-amine can be cited for said purpose. In the case where R¹ 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.

In method B of the reductive cyclization, 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. In this method, corresponding nitrilium salts of the formula (10), wherein R¹ is lower alkyl or aralkyl, are first produced. For said purpose, trialkyloxonium tetrafluoroborates or dialkoxycarbonium tetrafluoroborates cited by Borch are the preferred agents.

(10)

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 The intermediating secondary amine of the formula (12), preferably without isolation thereof, is subsequently subjected to cyclization- under elevated temperature and, advantageously, under presence of a base, preferably in the same solvent. In the preferred aspect, the hydride reductant serves itself as the base.

Alternatively, 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. Instead, 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

(12) compound (7) even during the reaction, as the amine serves itself also as the base. The most preferred reductant is hydrogen in the presence of a suitable catalyst, e.g. Adams catalyst (Pt0₂). 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 R¹ 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.

In relation with the intended use, 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. Specifically, 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 Ν-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):

(11) (14) (12)

wherein R⁴ is hydrogen atom, Cι.₅ alkyl group, an aryl group, or an aralkyl group having 1 to 5 carbons in the alkyl moiety. The Ν-acyl group is then reduced by a reductant such as by catalytic hydrogenation as discussed above to the corresponding Ν-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. Preferably 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.

The following 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.

(7) where R=H (7) where R not H 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

The following examples illustrate the invention but it should be understood that the present invention is by no means restricted to these specific examples:

Example 1) Synthesis of p-fluorocinnamonitrile.

12.4 g of p-fluorobenzaldehyde was 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 in 150 g of crushed ice. The mixture was extracted with 2x100 ml of dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness leaving a dark green oil which crystallized upon standing.

13 g (88%) of a green solid was obtained.

The compound is a mixture of cis- and trans isomer. NMR (delta scale): 5.43+ 5.43 + 5.80 (d, 1H, cis-H_c_ _N+trans-Hc-CN)< ⁷-⁰⁹ + ⁷-⁴⁵ (m, 4H, Aro H), 7.35 (d, 1H, H_c._Ph)

Example 2) Synthesis of diethyl 2-(l'-(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, 5 g of p-fluorocinnamonitrile from Example 1 in 10 ml of ethanol was added and the mixture heated to 50°C for 3 hours. Then 3 ml of acetic acid and 10 ml of water were added and the resulting mixture was evaporated to near dryness. The residue was suspended in 100 ml of ethyl acetate and extracted with 50 ml of IM HC1 and 50 ml of 5% sodium sulfate and evaporated to dryness leaving 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,2'-H), 3.73 (m,lH,l'-H), 3.91 (d,lH,2-H), 4.23 (m,4H,CH₂), 7.04+7.28 (m,4H,Arom.H)

Example 3) Synthesis of diethyl 2-( -phenyl-2'-cyanoethyl)malonate. In an analogous way as in example 2, the title compound was prepared as a white solid when using cirmamonitrile instead of p-fluorocinnamonitrile.

NMR: (delta scale): 0.99(t,3H, CH₃), 1.28(t,3H,CH₃), 2.88 (m, 2H, 2'-H), 3.73 (m, 1H,1'-H), 3.85 (d, 1H, 2-H), 3.95+4.25 (m, 4H, CH₂), 7.31(m,5H,Arom.H)

Example 4) Synthesis of diethyl 2-( -(p-fluorophenyl)-3'-aminopropyl)-malonate hydrochloride.

10 g of the product from the example 2) was dissolved under nitrogen in 20 ml of ethanol, and 0.8 g of Adams catalyst was added together with 35 ml of ethanolic HC1. The mixture was hydrogenated for 6 hours under 5 MPa pressure. 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 2x100 ml of water. Combined water layers were evaporated and 9.2 g of a yellow oil was obtained 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.1'-H), 3.60 (d, 1H.2-H), 3.91+4.22(m, 4H, CH₂), 6.98+7.28 (m, 4H, arom.H), 8.27(bs, 3H, N-H)

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.

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, IH, l -H), 3.63 (d, 1H,2-H), 3.87+4.21(m, 4H, CH₂), 7.22 (m, 5H, arom.H), 8.23(bs, 3H, N-H)

Example 6) One-pot synthesis of ethyl (+/-)trans- 4-phenyl-2-oxo-3-piperidinecarboxylate (Compound 7,X=hydrogen, R = H, R¹ = ethyl).

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 layers were separated, the water layer was extracted with ethyl acetate and the combined organic layers were dried by sodium sulfate and evaporated, 5.6 g of white powder was obtained which was 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,lH,3-H), 4.06(q,2H,CH₂), 7.26(m,5H, arom.H), 6.62 (S.1H.N-H)

Example 7) Synthesis of ethyl (+/-)trans- 4-(p-fluorophenyl)-2-oxo-3- piperidinecarboxylate (Compound 7, X=p-fluoro, R = H, R¹ = ethyl).

Under conditions described in example 6), but using the compound from example 2) as the starting material, the title product was prepared as a white precipitate after recrystallization from ethyl acetate/heptane. NMR: (delta scale): 1.08 (t,3H,CH₃), 1.90-2.10 (m,2H, 5-H, 3.35-3.55(m, 4H, 3-H+4- H+CH₂₎ 4.00-4.15(m,2H,6-H, 7.01+7.19 (m,4H,arom.H), 7.43 (bs,lH,NH)

Example 8) Synthesis of ethyl trans(+/-)-l -methyl-2-oxo-4-phenyl-3-piperidine- carboxylate (Compound 1, X=H, R=CH₃, R^ethyl).

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 yield was 0.7 g of colourless oil which was purified by chromatography on silica gel (eluent chloroform-methanol 19:1). The compound is a racemic mixture of (+) and (-) enantiomers.

NMR: (delta scale): 1.05(t,3H,CH₃), 2.07(m,2H,5-H), 2.98(s,3H, N-CH₃), 3.40 (m,3H, 4-H+6-H), 3.52(d,lH, 3-H), 4.03 (q,2H,CH₂), 7.20+7.30(m,5H.aromH)

Example 9): Synthesis of ethyl trans(+/-)-l-methyl-2-oxo-4-(p-fluorophenyl)-3- piperidine-carboxylate (Compound 7, X=p-fluoro, R=CH₃, R'=ethyl).

In an analogous way as in example 8 but using the product from example 2 as starting material, the title compound (a mixture of (+) and (-) enantiomers) was obtained as a white solid.

NMR: (delta scale): 1.08 (t,3H, CH₃), 2.00-2.10(m,2H,5-H), 3.00(s,3H, N-CH₃), 3.30- 3.60 (m,4H,3-H+4-H+CH₂), 4.00-4.12 (m,2H,6-H), 7.00+7.17(m,4H,arom.H)

Example 10): Synthesis of trans(+/-)-l-methyl-4-(p-fluorophenyl)piperidine-3-carbinol (Compound 1, X=p-fluoro, R=CH ). 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. Then, the mixture was cooled to 0°C and 0.5 ml of water and 1 ml of IM solution of sodium hydroxide in water were added. The resulted solid was separated by filtration over a thin layer of Hyflo and washed with 2x5ml of toluene. The filtrate was evaporated to volume of about 1.5 ml and 1 ml of n-heptane was added. After several minute a solid was formed which was filtered off. After drying in vacuum oven, 0.15 g of the product was obtained. The content of des-fluoro impurity was less that 1% (HPLC).

Example 11): Synthesis of ethyl trans(+/-)-l-methyl-2-oxo-4-(p-fluorophenyl)-3- piperidine-carboxylate (Compound 7, X=p-fluoro, R=CH₃, R'=ethyl).

The product from example 2 (2.5 g) was dissolved in 4 ml of dichloromethane, 2.5 g of the trimethyloxonium tetrafluoroborate was added and the mixture was stirred for 18 hours under reflux. Then the mixture was quenched with 1 ml of ethanol and evaporated to dryness. The resulted 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 under cooling.. The mixture was stirred for two hours, made acidic with concentrated hydrochloric acid and evaporated to dryness. The solid residue was dissolved in 10 ml of water and made alkaline with potassium carbonate. The solution was extracted with 2x 25 ml of ethyl acetate, the organic phase was dried over magnesium sulphate, the solvent was evaporated and the rest was crystallized from ethyl acetate. White solid was obtained.

NMR spectrum of the product was identical with that of example 9.

Example 12): Synthesis of ethyl trans(+/-)-l -methyl-2-oxo-4-(p-fluorophenyl)-3- piperidine-carboxylate (Compound 7, X=p-fluoro, R=CH₅, R'=ethyl). 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.

The NMR spectrum of the product was identical with that of Example 9.

Example 13): Synthesis of trans(+/-)-l-methyl-2-oxo-4-(p-fluorophenyl)-3-piperidine- carbinol (Compound 1, X=p-fluoro, R=CH₃)

0.45 grams of the compound from example 11 was dissolved in 5 ml of dry tetrahydrofuran. To this solution, 3.4 ml of a IM solution of BH₃ in tetrahydrofuran was added at room temperature in 15 minutes under stirring. The mixture was stirred at room temperature for 2 hours, then 1.6 ml of the same solution of BH₃ 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 for 1 hour in 10 ml of a 6M HC1 solution. After cooling to room temperature the mixture was neutralized with potassium carbonate, extracted 3x15 ml of toluene and evaporated to dryness leaving 0.25 g of product as a blanc oil The NMR confirmed the identity of the above-named product and the content of des- fluoro -----purity was 0.5% (HPL .

The invention having been described, it will be readily apparent to those skilled in the art at further changes and modifications in actual implementation of the concepts described herein can easily be made or may be learned by practice of the invention, without departing from the spirit and scope of the invention as defined by the following claims.

Claims

1. A compound of formula (7) :

(7) wherein 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; and R¹ represents 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. The compound according to claim 1, wherein the substituents in the 3 and 4 position on the piperidine ring are in the trans orientation to one another.

3. The compound according to claim 2, wherein said compound is the (3S,4R) trans optical isomer.

4. The compound according to claim 1, wherein X represents fluorine, R represents a hydrogen, methyl, ethyl, or benzyl group, and R¹ represents a hydrogen, methyL or ethyl group.

5. The compound according to claim 4, wherein said compound is the (3S,4R) trans optical isomer.

6. The compound according to the claim 1, wherein the compound is selected from the group consisting of: trans-4-(p-fluorophenyl)-2-oxopiperidine-3-carboxylic acid, ethyl trans-4-(p- fluorophenyl)-2-oxopiperidine-3-carboxylate, trans-4-(p-fluorophenyl)- 1 -methyl-2-oxopiperidine- 3-carboxylic acid, ethyl trans-4-(p-fluorophenyl)-l-methyl-2-oxopiperidine-3-carboxylate, trans- 4-(p-fluorophenyl)-l-benzyl-2-oxopiperidine-3-carboxy-ic acid and ethyl tr--ns-4-(p-fluorophenyl)- l-benzyl-2-oxopiperidine-3-carboxylate.

7. The compound according to claim 6, wherein said compound is the (3S.4R) trans optical isomer.

8. A process, which comprises reducing a compound of formula (7):

(7) to form a compound of formula (1):

(1) 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 represents a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group, an alkoxycarbonyl group, aralkoxycarbonyl group or an aryloxycarbonyl group; and R¹ represents a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group.

9. The process according to claim 8, wherein said reducing step is performed with a hydride or borane reducing agent.

10. The process according to claim 9, wherein said hydride reducing agent is a metal hydride.

11. The process according to claim 10, wherein said metal hydride is lithium aluminum hydride.

12. The process according to claim 8, wherein said compound of formula (7) and said compound of formula (1) are each in the trans configuration.

13. The process according to claim 12, wherein said compound of formula (7) and said compound of formula (1) are each in the (3S,4R) trans optical isomer configuration.

14. The process according to claim 12, wherein X is a fluorine atom in the para-position, R is hydrogen atom, a methyl group, a benzyl group, a tert.butyloxycarbonyl group a benzyloxy group or a phenyloxycarbonyl group, and R¹ is a hydrogen, methyl, or ethyl group.

15. The process according to claim 14, wherein X is a fluorine atom in para-position and R is a methyl group.

16. The process according to claim 15, wherein said compound of formula (7) and said compound of formula (1) are each in the (3S,4R) trans configuration.

17. The process according to claim 8, wherein R is hydrogen and which further comprises subsequently reacting the compound of formula (1) with an alkylating or aralkylating agent or with an alkyl. aralkyl or aryl halo formate to convert R in the compound of formula (1) from hydrogen to a lower alkyl, aralkyl, alkoxycaronyl, aryloxycarbonyl or aralkyloxycarbonyl group.

18. The process according to claim 17, which further comprises isolating the (3S,4R) trans optical isomer of the converted compound of formula (1).

19. The process according to claim 8, which further comprises reacting said compound of formula (1) to obtain a compound of formula (2):

(2)

wherein R^: 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 - C₄ alkyl, alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl, methylenedioxy, and combinations thereof, or a tetrahydronaphthyl group.

20. The process according to claim 19, wherein said compound of formula (1) and (2) are each in the trans configuration.

21. The process according to claim 20, wherein said compound of formula (2) is paroxetine.

22. The process according to claim 21 , which further comprises reacting said paroxetine with an acid to form a pharmaceutically acceptable paroxetine addition salt.

23. The process according to claim 8, which further comprises forming said compound of formula (7) by the steps oft

(a) reacting a compound of formula (8) with a malonic acid/ester of formula (13) to form a compound of formula (9):

(8) (13) (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, R³ independently represent a hydrogen atom a lower alkyl group, an aryl group or an aralkyl group, and R¹ is as defined in formula (7); and

24. The process according to claim 23, wherein said reductive cyclization comprises sequentially reducing the compound of formula (9) in an acidic, neutral or alkaline environment and subsequently cyclizing in a neutral or alkaline environment, and wherein R in the compound of formula (7) represents hydrogen.

25. The process according to claim 24, which further comprises at least one of the following additional steps: c) reacting the product from the step b) with an agent to carry out substitution of the N- hydrogen with an alkyl, aralkyl, alkyloxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl group;

d) reacting any of the products from the steps b) or c) with a water solution of an acid or base to hydrolyze the ester group into a carboxylic acid;

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

f) converting any of the compounds from the steps b), c), d) or e) into an acid addition salt, hydrate or solvate.

26. The process according to claim 23, wherein said reductive cyclization comprises alkylating or aralkylating said compound of formula (9), reducing, and cyclizing; wherein R in the compound of formula (7) is a lower alkyl or aralkyl group.

27. The process according to claim 26, wherein said reductive cyclization comprises performing alkylation with an alkylamine under reducing conditions and allowing spontaneous cyclization.

28. The process according to claim 26, which further comprises at least one of the following additional steps:

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 N-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.

29. The process according to claim 23, wherein said reductive cyclization comprises reducing said compound of formula (9), acylating the reduced compound, reducing the acylated compound and cyclizing to form a compound of formula (7).

30. The process according to claim 29, which further comprises at least one of the following additional steps:

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 jV-alkyl or aralkyl group with an alkyloxycarbonyl, aralkoxycarbonyl or aryloxycarbonyl group;

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.

31. The process according to claim 8, wherein X is fluoro and said reduction step forms the compound of formula (1) substantially free of the des-fluoro product.

32. The process according to claim 31, wherein said reduction step produces less than 1% des-fluoro impurity based on the total amount of phenylpiperidine product.

33. A compound of formula ( 1) or a pharmaceutically acceptable salt thereof that is substantially free of the corresponding des-fluoro impurity:

(1) wherein X represents fluoro and R represents a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group, an alkoxycarbonyl group or an aryloxycarbonyl group.

34. The compound according to claim 33, wherein the amount of des-fluoro impurity is 1% or less, based on the total amount of said compound and impurity.