Abstract:
A biocatalytic process to obtain optically enriched derivatives of trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidines, based on the enzymatic resolution of racemic precursors of formula III (where R 3  is preferably phenyl or benzyl) by acylation of the hydroxyl group. Depending on the enzyme and the reaction conditions, either of the two enantiomers may be obtained with high enantiomeric purity. These compounds are important intermediates in the synthesis of the paroxetine anti-depressive agent.

Description:
FIELD OF THE INVENTION  
         [0001]    Paroxetine is an arylpiperidine acting as a selective inhibitor for serotonin (5-HT) re-uptake. Mainly, this compound has anti-depressive and anti-parkinsonian activity. Only the trans-(−) isomer, with absolute configuration (3S, 4R) may be used as a drug.  
           [0002]    The object of the present invention is a biocatalytic process to obtain optically enriched derivatives of trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidines with formulas II, III, IV and V, wherein Ar is a phenyl group, substituted by one or more halogen atoms, R 1  is hydrogen, alkyl or aralkyl, R 2  is hydrogen, R 3  is alkyl, alkenyl, aralkyl or aryl, R 4  is hydrogen, alkyl, alkenyl, aralkyl or aryl (FIG. 1). These are important intermediates in the synthesis of paroxetine.  
           [0003]    Another object of the invention are the new compounds obtained, III, IV and V both in the racemic and enatiomerically enriched forms, suitable for the synthesis of paroxetine, as well as their preparation processes.  
           [0004]    Prior State-of-the-Art  
         PRIOR ART  
         [0005]    The piperidinecarbinol compounds of formula II, were described for the first time, together with their preparation, in U.S. Pat. Nos. 3,912,743 and 4,007,196 (R 1 ═hydrogen or methyl and R 2 ═hydrogen). Paroxetine is prepared from said optically pure precursors (3S, 4R)-trans-II by means of the process described in U.S. Pat. No. 4,007,196. In patent application EP 812 827-A1 and in  Tetrahedron: Asymm.  1996, 7, 1591, the preparation of paroxetine from a piperidinecarbinol of formula II is described, with R 1 ═hydrogen (FIG. 2; P═R 1  or other protector group).  
           [0006]    In U.S. Pat. Nos. 4,007,196 and 4,902,801, said piperidinecarbinol II compound is firstly obtained as a racemic mixture and then resolved in its enantiomers by conventional methods, such as the crystallisation of its diastereoisomer salts with chiral acids, like (+)-tartaric, (+)-2′-nitrolartranylic or (−)-di-P-toluyltartaric. The drawback of this process is that crystallisation is cumbersome and relatively expensive.  
           [0007]    An alternative to said crystallisation of diastereoisomer salts are the biocatalytic enantiomer separation methods.  
           [0008]    In U.S. Pat. No. 5,258,517 and patent applications WO 93/22284-A1 and WO 98/02556-A3, resolution methods are described for enanantiomers of the intermediate I (R 1 ═Me) by means of enzymatic or microbial hydrolysis. After resolution, the imidoester (3S, 4R)-trans-1, enantiomerically enriched, is reduced by conventional methods to piperidinecarbinol (3S, 4R) -trans-II.  
           [0009]    In patent application WO 98/53824-A1, the preparation of optically enriched (3S, 4R)-trans-II (R 1 ═benzyl) is described, by means of synthesis from an enantiopure precursor, in turn, obtained by means of the enzymatic asymmetrisation of dimethyl 3-(4-fluorophenyl)-glutarate.  
           [0010]    On the other hand, derivatives of the piperidinecarbonil carbamate type (general formula III) are described in patent applications WO 97/24323-A1, EP 812 827-A1 and in WO 98/53824-A1. In all these cases, the optically enriched compounds (3S, 4R)-trans-III are obtained by means of conventional reactions from an optically pure (3S, 4R)-trans-II compound with R 2  equal to hydrogen. In said patents, paroxetine synthesis is described as from precursors of formula III with R 2  equal to hydrogen and different R 3  substituents.  
         GENERAL DESCRIPTION OF THE INVENTION  
         [0011]    For the first time, the present invention describes new compounds of formulas trans-IV and trans-V, both in the racemic and enantiomerically enriched forms (FIG. 3), where:  
           [0012]    R 1 : hydrogen, alkyl or aralkyl.  
           [0013]    R 3 : alkyl, haloalkyl, alkenyl, aralkyl or aryl.  
           [0014]    R 4 : hydrogen, alkyl, haloalkyl, alkenyl, aralkyl or aryl.  
           [0015]    Ar: Phenyl group substituted with one or more halogen atoms.  
           [0016]    Another object of the present invention is an enzymatic resolution process for piperidinecarbinol derivatives of formula (±)-trans III, in turn permitting to obtain compounds with enantiomerically enriched structures III and IV. Said process consists of the enantioselective acylation—catalysed by an enzyme—of the hydroxymethyl group of the (±)-trans-III compound to give a compound of trans-IV formula. This process has two variants, permitting the attainment, as required, of either of the two enantiomers of the trans-III compound of enantiomerically enriched forms, whether (3S, 4R)-III or (3R, 4S)-III. In the same process, the corresponding trans-IV isomer is also obtained with the opposite configuration (3R, 4S)-IV or (3S, 4R)-IV, respectively.  
           [0017]    Another object of the present invention is also a preparation process of compounds with formula (3S, 4R)-III, as from compounds of formula (3S, 4R)-IV.  
           [0018]    Another object of the present invention is a process to prepare trans-V formula compounds from trans-IV formula compounds, both in the racemic form and in the enantiomerically enriched form, where R 1  is hydrogen, alkyl or aralkyl.  
           [0019]    Another object of the present invention is also a process to prepare optically enriched trans-III formula compounds from (3S, 4R)-V formula compounds, consisting of the deacylation of the hydroxymethyl group to give a compound with formula (3S, 4R)-II and the further alcoxycarbonylation of the piperidine nitrogen.  
           [0020]    The piperidinecarbinol derivatives of formula III with configuration (3S, 4R) may be used to obtain paroxetine by known methods, already described in the literature.  
         DETAILED DESCRIPTION OF THE INVENTION  
         [0021]    The process object of the present invention, consists of making a racemic compound of formula trans-III react with an acylating agent in the presence of an enzyme, where R 3  and R 4  represent that mentioned previously and R 6  may be alkyl, haloalkyl, alkenyl, aralkyl, aryl, iminoalkyl or iminoaryl. By action of the enzyme, one of the enantiomers of the substrate is selectively acylated, obtaining the trans-IV ester, while the other enantiomer mainly remains without acylation.  
           [0022]    In the first variant of the process (FIG. 4), the enzyme preferably catalyses acylation of the enantiomer with configuration (3R, 4S)-III giving a compound (3R, 4S)-IV, while the isomer (3S, 4R)-III mainly remains without acylation.  
           [0023]    In a second variant of the process (FIG. 5), the enzyme preferably catalyses acylation of the enantiomer with configuration (3S, 4R)-III, giving a compound (3S, 4R)-IV, while the isomer (3R, 4S)-III, mainly remains without acylation.  
           [0024]    In either of the two variants of the enzymatic process, when the desired conversion is reached, normally about 50%, the reaction is stopped—for example, by filtering the enzyme—and the resulting compounds are separated. It should be considered that the choice of the enzyme and the specific reaction conditions determine which of the enantiomers is preferably acylated.  
           [0025]    When the reaction is sufficiently enantioselective, the reaction conversion should be about 50% to obtain the maximum yield of acylated product and remaining optically enriched substrate. However, when the enantioselectivity is moderate, other conversion values may be preferable to ensure an enantiomeric excess value, sufficiently high for any of the components of the reaction mixture. For example, it is known that as conversion increases under the given reaction conditions, the enantiomeric excess of the remaining substrate gradually increases and the enantiomeric excess of the product gradually decreases. The specific conversion value at which the reaction should be stopped will depend on the enantioselectivity of each specific case and the optical purity requirements of the products. Said value is determined by a known method by an expert in the matter, as described, for example in  J. Amer. Chem. Soc.  1982, 104, 7294.  
           [0026]    The process is carried out by dissolving the substrate in a suitable solvent and adding the enzyme and acylating agent. As a reaction medium, a pure organic solvent or mixture of organic solvents may be used. Suitable solvents may be aliphatic or aromatic hydrocarbon esters, open or cyclic ethers, alcohols, etc. In another variant of the invention, the acylating agent itself may also act as a reaction solvent.  
           [0027]    For the acylating agent, activated of inactivated esters are used. This include alkyl, haloalkyl, alkenyl, aryl, aralkyl and oxime esters. The mole ratio of acylating agents and substrate may be equal, less or greater than 1:1.  
           [0028]    Enzymes suitable to catalyse this process are the hydrolases, both of animal and microbial origin, in pure or semipurified form, free or immobilised. A special object of the present invention is the use of lipases.  
           [0029]    The reaction should be performed between −20 and 100° C., preferably temperatures being between 0° C. and 60° C.  
           [0030]    It is a known fact, described for example in  Tetrahedrom  2000, 56, 2905, that certain additives like triethylamine or crown ethers, among others, may be beneficial for the course of the enzymatic reaction.  
           [0031]    According to the first variant of the process, once the (3S, 4R)-III isomer has been obtained with high enantiomieric richness, this may be transformed into paroxetine by following already known processes, like the mesylation of the hydroxymethyl group followed by the nucleophillic attack of the 3,4-(methylenedioxy)phenol and final deprotection of nitrogen.  
           [0032]    However, in the second variant of the enzymatic process, the enantiomer having the correct configuration to be converted into paroxetine, the (3S, 4R), is acylated by the enzyme to give optically enriched (3S, 4R)-IV. After separation of the compounds (3S, 4R)-IV and (3R, 4S)-III from the reaction mixture, in order to continue with the synthesis it is necessary to deacylate the hydroxymethyl group of (3S, 4R)-IV, hence transforming it into (3S, 4R)-III. This compound (3S, 4R)-III with high enantiomeric richness, may be converted into paroxetine by following already known processes, like mesylation of the hydroxymethyl group followed by the nucleophillic attack of the 3,4-(methylenedioxy)phenol and final deprotection of the nitrogen. (See FIG. 6, Ar═P-fluorophenyl).  
           [0033]    In general, formula III compounds, both in the racemic and enantiomerically enriched forms, may also be obtained from those of structure IV by means of known oxygen deprotection methods (for example, acid or alkaline hydrolysis, aminolysis or alcoholysis), choosing the most suitable method in each case according to R 3  and R 4  structures.  
           [0034]    The formula V compounds (R 2 ═H), both in the racemic and enantiomerically enriched forms, may be obtained from those of structure IV by means of known oxygen deprotection methods (for example, hydrolysis or hydrogenolysis), choosing the most suitable method in each case according to the R 3  and R 4  structures.  
           [0035]    It may occur that in the optically enriched compounds of formula III and IV, the most suitable nitrogen protector group for the enzymatic resolution is not convenient for continuation of the synthesis. In this case, after the enzymatic reaction, the first protector group may be eliminated—giving compounds of formula II and V, respectively—and introducing a new one, aspect which is included in the scope of this invention.  
           [0036]    Another object of the present invention are the new acylated compounds in the 3-hydroxymethyl group of the piperidine ring, with formulas IV and V, both in the racemic and enantiomerically enriched forms.  
           [0037]    Any new intermediate obtained following the process of this invention constitutes a further aspect of the invention. The processes and products of this invention may be applied to prepare active compounds described in the U.S. Pat. Nos. 3,912,743 and 4,007,196 and preferably to prepare paroxetine.  
           [0038]    For a better understanding of the process object of the present invention, the following examples are given, which should be taken as not limiting the scope of the invention. 
       
    
    
     EXAMPLES  
     Example 1  
     (±)-/trans-N-phenyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine (III, R 3 −Ph)  
       [0039]    1 g of (±)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine is dissolved in 15 ml dichloromethane. 15 ml of an aqueous solution of sodium carbonate (2-14 g) are added. At 0° C., 1.25 ml phenyl chloroformiate are added and stirred for one hour. Then, extracted with 15 ml dichloromethane, mixing the organic phases and washing with 5% sodium bicarbonate. The organic phase is concentrated to dryness and is purified by chromatography on silica gel. The product may be crystallised in an ether-hexane mixture. Yield: 68%. White solid, mp.: 129-131° C.  
         [0040]    IR (cm −1 ): 3435, 1705, 1509.  
         [0041]    [0041] 1 H-NMR (CDCL 3 ) δ (ppm): 1.71-1.94 (m,4H); 2.50-2.61 (m,1H); 2.65-3.05 (m,2H); 3.22-3.28 (dd, 1H); 3.41-3.48 (dd, 1H); 4.36-4.57 (m, 2H); 6.99 (dd, 2H); 7.01-7.20 (m, 2H), 7.36 (d, 2H).  
         [0042]    [0042] 13 C-NMR (CDCl 3 ) δ (ppm): 33.7 (CH 2 ); 43.4 (CH); 43.6 (CH); 44.5 (CH 2 ); 47.2 (CH 2 ); 62.6 (CH 2 ); 115.2-115.6 (CH); 121.6 (CH); 125.2 (CH); 128.4-128.5 (CH); 129.2 (CH); 138.8 (C), 151 (C); 153.5 (CO); 159.6-162.9 (C).  
         [0043]    EM-ESI+: 330 (M+H, 15%); 352 (M+Na, 19); 368 (M+K, 30).  
       Example 2  
     ±-trans-3-acetyloxymethyl-N-benzyloxycarbonyl-4-(4-fluorophenyl) piperidine. (IV, R 3 ═Bn, R 4 ═Me).  
       [0044]    1 g (±) -trans-N-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine is dissolved in 90 ml dichloromethane and 0.95 ml pyridine. At 0° C., 1.1 ml acetic anhydride are added and stirred for 8 hours. Then, it is washed with 1N hydrochloric acid and purified by chromatography on silica gel. Yield: 0.96 g (86%). White solid, mp: 114-115° C.  
         [0045]    IR (cm −1 ): 1735, 1691, 1510.  
         [0046]    [0046] 1 -NMR (CDCL 3 ) δ (ppm): 1.70-1.78 (m,2H); 1.99 (s,3H); 2.06 (m,1H); 2.44-2.51 (m,1H); 2.53-2.87 (m, 2H); 3.59-3.69 (dd, 1H); 3.81-3.88 (dd, 1H); 4.22-4.49 (m, 2H); 5.18 (s, 2H); 6.96 (dd, 2H); 7.11 (da, 2H); 7.33-7.41 (m, 5H).  
         [0047]    [0047] 13 C-NMR (CDCl 3 ) δ (ppm): 20.7 (CH 3 ); 34.2 (CH 2 ); 40.6 (CH); 44.4 (CH 2 ); 44.5 (CH); 47.2 (CH 2 ); 64.6 (CH 2 ); 67.2 (CH 2 ); 115.4-115.7 (CH); 127.9 (CH); 128.1 (CH); 128.5-128.6 (CH); 128.7 (CH); 136.6 (C); 138.4 (C); 155.1 (CO); 159.9-163.2 (C); 170.1 (CO).  
         [0048]    EM-1E+: 385 (M+, 1%); 342 (M−Ac, 3); 234 (95); 91 (100).  
       Example 3  
     (±)-trans-N-benzyloxycarbonyl-3-benzoyloxymethyl-4-(4-fluorophenyl)piperidine. (IV, R 3 —Bn, R 4 ═Ph).  
       [0049]    1 g of (±)-trans-N-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine is dissolved in 90 ml dichloromethane and 0.95 ml pyridine. At 0° C., 1.35 ml benzoyl chloride is added and stirred for 14 hours. Then, it is washed with 1N HCl and purified by chromatography on silica gel.  
         [0050]    Yield: 0.91 g (70%), oil.  
         [0051]    IR (cm −1 ): 1692; 1510.  
         [0052]    [0052] 1 H-NMR (CDCl 3 ) δ (ppm): 1.64-1.84 (m,2H)r 2.18 (m, 1H); 2.56-2.63 (m, 1H); 2.76-2.92 (m, 2H); 3.86-3.95 (dd, 1H); 4.08-4.15 (dd, 1H); 4.29-4.38 (m, 1H); 4.41-4.55 (m, 1H); 5.22 (s, 2H); 6.96 (dd, 2H); 7.13 (dd, 2H); 7.27-7.47 (m, 6H); 7,57 (d, 2H); 7.96 (d, 2H).  13 C-NMR (CDCl 3 ) δ (ppm): 34.1 (CH 2 ); 41.2 (CH); 44.5 (CH 2 ); 44.7 (CH); 47.3 (CH 2 ); 65.0 (CH 2 ); 67.2 (CH 2 ); 115.5-115.8 (CH); 127.8 (CH); 128.0 (CH); 128.3-128.5 (CH); 128.6-128.7 (CH); 128.8 (CH); 129.4 (C); 129.8 (CH); 130.5 (CH); 133.0 (CH); 136.6 (C); 138.4 (C); 155.1 (CO); 160-163.3 (C); 166.1 (CO). EM-IE+: 447 (M+, 3%); 312 (M−Cbz, 10); 234 (97); 91 (100).  
       Example 4  
     Enzymatic Resolution of the Intermediate III. (R 3 ═Bn, R 4 ═Me).  
       [0053]    0.1 g of (±)-trans-N-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxyomethylpiperidine is dissolved in a suspension of 17 ml toluene and 0.125 g lipase CAL-B. 0.32 ml isopropylene acetate is added and stirred at 30° C. When a conversion close to 50% is reached, the enzyme is filtered and concentrated to dryness. The resulting oil is purified by chromatography on silica gel obtaining (3S, 4R)-trans-N-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine (99% ee) and (3R, 4S)-trans-3-acetyloxymethyl-N-benzyloxycarbonyl-4-(4-fluorophenyl) piperidine (79% ee).  
         [0054]    Conversion: 56%.  
       Example 5  
     Enzymatic Resolution of the Intermediate III (R 3 ═Bn, R 4 ═Me).  
       [0055]    0.1 g of (±)-trans-N-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine is dissolved in a suspension of 14.5 ml tort-butylmethylether and 0.6 g lipase of Mucor miehel. 0.27 ml vinyl acetate is added and stirred at 30° C. When the desired conversion is reached, the enzyme is filtered and concentrated to dryness. The resulting oil is purified by chromatography on silica gel obtaining (3S, 4R)-trans-N-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine (13% ee) and (3R, 4S)-trans-3-acetyloxymethyl-N-benzyloxycarbonyl-4-(4-fluorophenyl) piperadine (66% ee)  
         [0056]    Conversion: 16%.  
       Example 6  
     Enzymatic Resolution of the Intermediate III. (R 3 ═Bn, R 4 ═Me).  
       [0057]    0.1 g (±) -trans-N-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine is dissolved in a suspension or 17 ml toluene and 0.125 g lipase CAL-A. 0.27 ml vinyl acetate is added and stirred at 15° C. When a conversion close to 50% is reached, the enzyme is filtered and concentrated to dryness. The resulting oil is purified by chromatography on silica gel, obtaining (3R, 4S)-trans-N-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine (88% ee) and (3S, 4R)-trans-3-acetyloxymethyl-N-benzyloxycarbonyl-4-(4-fluorophenyl) piperidine (96% ee) [α] p   18 =5.1, c 0.8, MeOH). Conversion: 48%.  
       Example 7  
     Enzymatic Resolution of the Intermediate III (R 3 ═Bn, R 4 ═Me)  
       [0058]    0.1 g of (±)-trans-N-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine is dissolved in a suspension of 9 ml vinyl acetate and 0.110 g lipase PS-C. Stirred at 30° C. When a suitable conversion is reached, the enzyme is filtered and concentrated to dryness. The resulting oil is purified by chromatography on silica gel, obtaining (3S, 4R)-trans-N-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine (23% ee) and (3R, 4S)-trans-3-acetyloxymethyl-N-benzyloxycarbonyl-4-(4-fluorophenyl) piperidine (82% ee). Conversion: 22%.  
       Example 8  
     Enzymatic Resolution of the Intermediate III. (R 3 —Bn, R 4 —Ph).  
       [0059]    0.1 g or (±)-trans-N-benzyloxycarbonyl-4-(4-fluorophenyl)3 hydroxymethylpiperidine is dissolved in a suspension of 17 ml toluene, 0.4 ml vinyl benzoate and 0.125 g lipase CAL-B. Stirred at 30° C. until a suitable conversion is obtained, the enzyme is filtered and concentrated to dryness. The resulting oil is purified by chromatography on silica gel obtaining (3S, 4R)-trans-N-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine (98% ee) and (3R, 4S)-trans-N-benzyloxycarbonyl-3-benzoyloxymethyl-4-(4-fluorophenyl) piperidine (93% ee). [α] d   18 =−5.24, c 1.03, MeOH). Conversion: 51%.  
       Example 9  
     Enzymatic Resolution of the Intermediate III. (R 3 ═Ph, R 4 ═Me).  
       [0060]    0.1 g of (±)-trans-N-phenyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine is dissolved in a suspension of 18 ml toluene, 0.28 vinyl acetate and 0.130 g lipase CAL-A. Stirred at 30° C. until a suitable conversion is obtained, the enzyme is filtered and concentrated to dryness. The resulting oil is purified by chromatography on silica gel, obtaining (3R, 4S)-trans-N-phenyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine (97% ee); [α] d   10 =+3.89, c 136, MeOH) and (3S, 4R)-trans-N-phenyloxycarbonyl-3-acetyloxymethyl-4-(4-fluorophenyl) piperidine (92% ee); [α]hd d 10 =−5.03, c 0./4, MeOH). Conversion: 51%.  
         [0061]    (3S, 4R)-trans-N-phenyloxycarbonyl-3-acetyloxymethyl-4-(4-fluorophenyl) piperidine:  
         [0062]    IR (cm −1 ): 1714 (broad, 2 signals), 1510.  
         [0063]    [0063] 1 H-NMR (CDCl 3 ) δ (ppm): 1.76-1.90 (m,2H); 2.00 (s,3H); 2.07-2.14 (m,1H); 2.52-2.61 (m, 1H); 2.63-2.92 (m, 2H); 3.74 (dd, 1H); 3.88 (dd, 1H); 4.42-4.56 (m, 2H); 7.02 (dd 2H); 7.14-7.36 (m, 5H); 7.47 (t, 2H).  
         [0064]    [0064] 13 C-NMR (CDCl 3 ) δ (ppm): 20.6 (CH 3 ); 33.9 (CH 2 ) 40.7 (CH); 44.3 (CH); 44.6 (CH 2 ); 47.1 (CH 2 ); 64.3 (CH 2 ); 115.4-115.8 (CH); 121.6 (CH); 125.2 (CH); 128.4-128.5 (CH); 129.1 (CH); 138.2 (C); 151.2 (C); 153.5 (CO); 160.0-163.2 (C); 170.7 (CO).  
         [0065]    EM-ESI+: 372 (M+H, 6%); 394.1 (M+Na, 100); 410 (M+K, 30).  
       Example 10  
     Enzymatic Resolution of the Intermediate III. (R 3 ═Bn, R 4 ═Me).  
       [0066]    0.1 g of (±)-trans-N-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine is dissolved in a suspension of 17 ml toluene and 0.125 g lipase CAL-A. 0.29 ml ethyl acetate is added. Stirred at 50° C. until a suitable conversion is obtained, tho enzyme is filtered and concentrated to dryness. The resulting oil is purified by chromatography on silica gel obtaining (3R, 4S)-trans-N-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine (28% ee) and (3S, 4R)-trans-N-benzyloxycarbonyl-3-acetyloxymethyl-4-(4-fluorophenyl) piperidine (95% ee).  
         [0067]    Conversion: 21%.  
       Example 11  
     Enzymatic Resolution of the Intermediate III. (R 3 ═Bn, R 4 ═Me).  
       [0068]    0.1 g of (±)-trans-N-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine is dissolved in a suspension of 17 ml toluene and 0.125 g lipase CAL-A. 1.7 g acetonoxime acetate is added and stirred at 30° C. When a conversion of about 50% is obtained, the enzyme is filtered and concentrated to dryness. The resulting oil is purified by chromatography on silica gel obtaining (3R, 4S)-trans-N-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine (92% ee) and (3S, 4R)-trans-3-acetyloxymethyl-N-benzyloxycarbonyl-4-(4-fluorophenyl) piperidine (83% ee).  
         [0069]    Conversion: 53%.  
       Example 12  
     (±)-trans-N-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine  
       [0070]    100 mg of (±)-trans-3-acetyloxymethyl-N-benzyloxycarbonyl-4-(4-fluorophenyl) piperidine are dissolved in 6 ml dry MeOH. 10 ml sodium methoxide solution are slowly added in 0.2 ml methanol at 0° C. After 1 hour stirring at 0° C., it is allowed to heal to room temperature and Dowex 50×4-400 is added until neutral or slightly acid pH. The resin is filtered, washing with MeOH and evaporated to dryness obtaining 78.4 mg of (±)-trans-N-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine. Yield: 88%.  
       Example 13  
     (3S, 4R)-trans-4-(4-fluorophenyl)-3-hydroxymethylpiperidine  
       [0071]    1 g of (3S, 4R)-trans-N-benzyloxycarbonyl-4-(4-fluorophenyl)-3-hydroxymethylpiperidine, is dissolved in 50 ml ethanol and 300 mg palladium catalyst over carbon in a hydrogen atmosphere is added. On completion of the reaction, it is filtered over Celite and concentrated to dryness. Yield: 87%; [α] d   10 =−24.3 (c 0.46, MeOH).  
       Example 14  
     (3S, 4R)-trans-4-(4-fluorophenyl)-3-acetoxymethylpiperidine  
       [0072]    1 g of (3S, 4R)-trans-N-benzyloxycarbonyl-4-(4-fluorophenyl)-3-acetoxymethylpiperidine is dissolved in 50 ml ethanol and 300 mg palladium catalyst over carbon in a hydrogen atmosphere is added. On completion of the reaction, it is filtered over Celite and concentrated to dryness. Yield: 60.1%; [α] d   18 =−30.9 (c 1.12, MeOH, 92% ee).  
         [0073]    IR (cm −1 ) 3347, 1510  
         [0074]    [0074] 1 H-NMR (CDCl 3 ) δ (ppm): 2.10-2.25 (m,5H); 2.63 (m, 1H); 2.93-3.00 (m,1H); 3.13-3.32 (m, 2H); 3.66-3.89 (m, 3H); 4.03-4.07(d, 1H, J=11.4 Hz); 7.22-7.28 (d, 2H, J=8.4 Hz); 7.46-7.51 (t, 2H, J=8.4 Hz).  
         [0075]    [0075] 13 C-NMR (CDCl 3 ) δ (ppm): 20.8 (CH 3 ); 32.4 (CH 2 ); 40.2 (CH); 43.5 (CH); 45.8 (CH 2 ); 48.0 (CH 2 ); 62.9 (CH 2 ); 116.9-117.2 (CH); 130.6-130.7 (CH); 139.7 (C); 162.1-163.4 (C); 172.8 (CO).