Abstract:
The present invention relates to an improved process for preparing 2-[(2E)-2-fluoro-2-(3-piperidinylidene)ethyl]-1H-isoindole-1,3(2H)-dione, or a salt thereof, which is an intermediate in the synthesis route of the antibacterial compound 7-[(3E)-3-(2-amino-1-fluoroethylidene)-1-piperidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo 3-quinolinecarboxylic acid.

Description:
FIELD OF THE INVENTION 
       [0001]    The present invention relates to an improved process for preparing 2-[(2E)-2-fluoro-2-(3-piperidinylidene)ethyl]-1H-isoindole-1,3(2H)-dione, or a salt thereof, which is an intermediate in the synthesis route of the antibacterial compound 7-[(3E)-3-(2-amino-1-fluoroethylidene)-1-piperidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo 3-quinolinecarboxylic acid. 
       BACKGROUND OF THE INVENTION 
       [0002]    WO-2006/101603 describes 7-amino alkylidenyl-heterocyclic quinolones as anti-microbial compounds and the synthesis of 7-[(3E)-3-(2-amino-1-fluoroethylidene)-1-piperidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo 3-quinoline-carboxylic acid is disclosed as compound (303) in Table 1 on page 20. This compound is conveniently referred to as compound ‘A’ hereafter. 
         [0000]    
       
                 
         
             
             
         
       
     
       7-[(3E)-3-(2-amino-1-fluoroethylidene)-1-piperidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo 3-quinolinecarboxylic acid 
       [0003]    The in vitro antibacterial properties of compound ‘A’ are described by Morrow B. J. et al. in Antimicrobial Agents and Chemotherapy, vol. 54, pp. 1995-1964 (2010). 
         [0004]    WO-2008/005670 discloses one-pot methods for the production of substituted allylic alcohols as well as extractive methods for the separation of certain isomeric alcohol products which are useful for preparing quinolones such as the antimicrobial compound 7-[(3E)-3-(2-amino-1-fluoroethylidene)-1-piperidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo 3-quinolinecarboxylic acid (i.e. compound ‘A’). 
         [0005]    An important intermediate in the overall synthesis route of said antimicrobial compound ‘A’ is 2-[(2E)-2-fluoro-2-(3-piperidinylidene)ethyl]-1H-isoindole-1,3(2H)-dione and its hydrochloric acid salt thereof: 
         [0000]    
       
                 
         
             
             
         
       
     
       2-[(2E)-2-fluoro-2-(3-piperidinylidene)ethyl]-1H-isoindole-1,3(2H)-dione 
       [0006]    
       
                 
         
             
             
         
       
     
         [0007]    Compound (1) introduces the desired E-stereochemistry into the overall synthesis route for the antimicrobial compound ‘A’. 
         [0008]    WO-2008/005670 discloses a synthesis route for compound (1) on page 38 as depicted below: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0009]    The detailed reaction procedure for compound (1) is disclosed in WO-2008/005670 in Example 1 on pages 37 to 44 affording compound (1) in Method A with a E:Z ratio of 97:3 in an approximate overall yield of 18% in Method A (step 1 for the first 3 heptane layers has a yield of 34% with a ratio E:Z of 71:29, step 2a has a yield of 53.4% with a ratio E:Z of 97:3, and step 3 has quantitave yield), or affording compound (1) in Method B with an approximate overall yield of 15% with a ratio E:Z of 94.4:5.6. 
         [0010]    WO-2008/005670 discloses a synthesis route for the hydrochloric acid addition salt of compound (1) on page 15 in Scheme 2 as depicted below: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0011]    The detailed reaction procedure to prepare the HCl salt of compound (1) is disclosed in WO-2008/005670 in Example 4 on pages 49 to 52 affording &gt;95% of desired E-isomer with an overall yield of 18-22% starting from N-boc-3-piperidone. 
         [0012]    The reaction procedures described in WO-2008/005670 for the preparation of compound (1) or its HCl salt are characterized by lack of selectivity of the Wadsworth-Emmons-Horner reaction which produces the undesired Z-isomer in large quantities. This undesired Z-isomer requires additional time consuming separation steps. 
         [0013]    Hence there is a need for a more efficient and less waste-producing procedure for the preparation of compound (1) or its HCl salt. 
         [0014]    WO-2010/056633 discloses a synthesis scheme XIV on page 87 to prepare tert-butyl 4-(2-ethoxy-2-oxoethylidene)piperidinyl-1-carboxylate and a synthesis scheme XXVI on page 111 to prepare (1-benzyl-piperidin-4-ylidene)bromoacetic acid ethyl ester. 
         [0015]    In a first embodiment the present invention relates to an improved process for preparing compounds of formula (III) having an improved ratio of the desired (E)-isomer over the undesired (Z)-isomer. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0016]    In a further embodiment the compound (E)-(III) is then converted in to compound (1) or its hydrochloric acid addition salt thereof. 
     
    
     DESCRIPTION OF THE INVENTION 
       [0017]    In one aspect, the present invention relates to a process for preparing a compound of formula (III), which is characterized by the steps of 
         [0000]    reacting a compound of formula (I) with a compound of formula (II) in a reaction-inert solvent 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein
 
R 1  is hydrogen, C 1-4 alkyl, aryl, arylmethyl, arylethyl, diphenylmethyl, allyl or 3-phenylallyl (cinnamyl);
 
R 2  is C 1-6 alkyl, phenyl or phenyl substituted with one substituent selected from halo, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, cyano or nitro;
 
A is C 1-4 alkyloxycarbonyl, hydroxycarbonyl, aminocarbonyl, or cyano; and
 
X is halo;
 
wherein aryl is phenyl, or phenyl substituted with one or two C 1-4 alkyloxy, halo, C 1-4 alkyl, nitro, or di(C 1-4 alkyl)amino.
 
         [0018]    The reaction-inert solvent can be any solvent such as dichloromethane, acetonitrile, ethyl acetate, heptanes, tetrahydrofuran (THF), cyclopentyl methyl ether (CPME), di-n-butyl ether (DBE), methylcyclohexane (MeCy), chlorobenzene, fluorobenzene, N,N-dimethylacetamide, N,N-dimethylformadide, toluene, or anisole or any mixture thereof. In practice the reaction-inert solvent is usually toluene. 
         [0019]    In a second aspect, the present invention relates to a process of reducing compound (III), which is a mixture of (E)-(III) and (Z)-(III), into compound (IV), which is a mixture of (E)-(IV) and (Z)-(IV), followed by isolating compound (E)-(IV) or a salt thereof as a precipitate. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0020]    The reduction can be performed with any art-known reducing agent such as LiBH 4 , LiAlH 4 , sodium bis(2-methoxyethoxy) aluminumhydride (Red-Al), and silane reducing agents such as trialkylsilanes (e.g. trimethylsilane, triethylsilane, tris(trimethylsilyl)-silane), triphenylsilane, trialkoxysilanes (e.g. triethoxysilane) and polymeric siloxanes like poly(methylhydrosiloxane) in the presence of a catalyst. 
         [0021]    The reduction reaction can be carried out in any suitable reaction-inert solvent such as e.g. toluene. 
         [0022]    The precipitation of compounds (E)-(IV) is obtained by mixing compounds (IV) with a suitable solvent such as e.g. diisopropyl ether or di-n-butyl ether (DBE) followed by isolation of the precipitated compounds (E)-(IV). Optionally the solvent is warmed after addition of compounds (IV) and upon cooling the compounds (E)-(IV) precipitate. 
         [0023]    In a third aspect, the present invention relates to a process for reacting a compound of formula (E)-(IV) with compound (V) under Mitsunobu reaction conditions thereby obtaining a compound of formula (VI) which can be converted into compound (1), optionally in the form of an addition salt, by removing substituent R 1  using art-known deprotection methods such as, e.g. hydrogenation or treatment with chloroformate. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0024]    In a fourth aspect, the primary hydroxyl group in compound (E)-(IV) is first converted into a leaving group Y such as halo or a sulfonyloxy group, e.g. methanesulfonyloxy, benzenesulfonyloxy, trifluoromethanesulfonyloxy, para-toluenesulfonyloxy before conducting the reaction with compound (V) or a salt thereof (e.g. potassium salt) and removing substituent R 1  using the procedures as described above. 
         [0025]    In a fifth aspect, the present invention also relates to novel compounds of formula (E)-(III) or (E)-(IV) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    or acid addition salts thereof, wherein
 
R 1a  is C 1-4 alkyl, aryl, arylmethyl, arylethyl, diphenylmethyl, allyl or 3-phenylallyl (cinnamyl);
 
A is C 1-4 alkyloxycarbonyl, hydroxycarbonyl, aminocarbonyl, or cyano;
 
wherein aryl is phenyl, or phenyl substituted with one or two C 1-4 alkyloxy, halo, C 1-4 alkyl, nitro, or di(C 1-4 alkyl)amino.
 
         [0026]    As used in the foregoing definitions:
       halo is generic to fluoro, chloro, bromo and iodo;   C 1-4 alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methyl-ethyl, 2-methylpropyl and the like;   C 1-6 alkyl is meant to include C 1-4 alkyl and the higher homologues thereof having 5 or 6 carbon atoms, such as, for example, 2-methylbutyl, pentyl, hexyl and the like.       
 
         [0030]    The addition salts as mentioned hereinabove are meant to comprise the acid addition salt forms that the compounds of formula (I) are able to form. These acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. 
         [0031]    Conversely said salt forms can be converted by treatment with an appropriate base into the free base form. 
         [0032]    Interesting processes of the present invention are those wherein one or more of the following restrictions apply:
   a) R 1  is C 1-4 alkyl, aryl, arylmethyl, arylethyl, diphenylmethyl, allyl or 3-phenylallyl; or   b) R 1  is methyl, ethyl, allyl, phenylethyl, diphenylmethyl, or arylmethyl wherein aryl is phenyl, or a methoxy substituted phenyl; in particular R 1  is arylmethyl wherein aryl is phenyl; or   c) R 2  is methyl, ethyl, butyl, isobutyl or phenyl; in particular R 2  is methyl; or   d) X is bromo; and   e) A is hydroxycarbonyl, aminocarbonyl, cyano or C 1-4 alkyloxycarbonyl wherein   
 
         [0038]    C 1-4 alkyl is methyl, ethyl, or tert-butyl; in particular A is C 1-4 alkyloxycarbonyl wherein C 1-4 alkyl is ethyl. 
       CHEMICAL DEFINITIONS 
       [0039]    The term “isomer” means compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. Such substances have the same number and kind of atoms but differ in structure. The structural difference may be in constitution (geometric isomers) or may result from different spatial arrangements of the groups in the molecule (stereoisomers). 
         [0040]    The term “stereoisomer” means isomers of identical constitution that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are stereoisomers wherein an asymmetrically substituted carbon atom acts as a chiral center. The term “chiral” refers to a molecule that is not superposable on its mirror image, implying the absence of an axis and a plane or center of symmetry. 
         [0041]    An isomer is designated as being in the “Z” (zusammen=“together”) configuration if the groups of highest priority lie on the same side of a reference plane passing through the double bond and perpendicular to the plane containing the bonds linking the groups to the double-bonded atoms; the other isomer is designated as “E” (entgegen=“opposite”). The term “priority” used to determine E and Z isomers herein refers to the rules established for the purpose of unambiguous designation of isomers described in R. S. Cahn, C. K. Ingold and V. Prelog. 
       EXPERIMENTAL PART 
       [0042]    The following abbreviations will be used in the following part: 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 AcOEt 
                 ethyl acetate 
               
               
                   
                 MeTHF 
                 2-methyltetrahydrofuran 
               
               
                   
                 CPME 
                 cyclopentyl methyl ether 
               
               
                   
                 DBE 
                 di-n-butyl ether 
               
               
                   
                 DBU 
                 1,8-diazabicyclo [5.4.0]undec-7-ene 
               
               
                   
                 DCM 
                 dichloromethane 
               
               
                   
                 DIAD 
                 diisopropylazodicarboxylate 
               
               
                   
                 DIPE 
                 diisopropyl ether 
               
               
                   
                 DMA 
                 N,N-dimethylacetamide 
               
               
                   
                 DMF 
                 N,N-dimethylformamide 
               
               
                   
                 MeCN 
                 acetonitrile 
               
               
                   
                 MeCy 
                 methylcyclohexane 
               
               
                   
                 MIBK 
                 5-methyl-2-pentanone 
               
               
                   
                 TBAI 
                 tetrabutylammonium iodide 
               
               
                   
                 THF 
                 tetrahydrofuran 
               
               
                   
                 Red-Al 
                 sodium bis(2-methoxy-ethoxy)aluminumhydride 
               
               
                   
                   
               
             
          
         
       
     
       Example 1 
     Preparation of Compounds of Formula (I) 
       [0043]    Compounds of formula (I) when isolated as a hydrochloric acid addition salt can be present either in the ketone form (I) or as in the gem-diol form (VII) (“hydrate”) or as a mixture of both in a variable ratio. However, during the neutralization of the salt (formation of the free amine), the gem-diol spontaneously looses a molecule of water to form the ketone. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0044]    In the following text, the term “HCl salt of compound (I)” will always refer to either strictly speaking “HCl salt of compound (I)”, to “HCl salt of compound (VII)” or to a mixture of both. 
       Step 1: Synthesis of 3,3-dimethoxypiperidine 
       [0045]    25 g (125.5 mmol) of N-boc-3-piperidone was dissolved in 125 ml of methanol. 9.1 ml (138 mmol) of methanesulfonic acid was added and the reaction mixture was stirred a few hours at room temperature then at 50° C. until completion. The reaction mixture was neutralized with 15.96 g (150.6 mmol) of sodium carbonate, diluted with 125 ml of toluene, and the methanol was removed under vacuum. The resulting suspension was further diluted with 125 ml of toluene. The solid materials were filtered off and rinsed with 63 ml of toluene and the combined filtrates were concentrated under vacuum. The residue was distilled under reduced pressure (100-105° C., 25 mbar) to afford 7.61 g of 3,3-dimethoxypiperidine as a colorless liquid (yield: 42%) (bp: 100-105° C., 25 mbar). 
         [0046]      1 H NMR (360 MHz, chloroform-d) δ ppm 3.12 (s, 6H), 2.71 (s, 2H), 2.58-2.68 (m, 2H), 1.63-1.70 (m, 2H), 1.57 (br. s., 1H), 1.43-1.51 (m, 2H). 
         [0047]      13 C NMR (91 MHz, chloroform-d) δ ppm 96.69, 51.01, 47.31, 45.90, 31.05, 24.27. GC-MS (EI): 145 (M + ), 130 (M-Me), 114 (M-MeO). 
       Step 2: Synthesis of Compound (Ia) to (Ij) 
       [0048]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                 Compound 
                 R 1   
               
               
                   
                   
               
             
             
               
                   
                 (Ia) •HCl 
                 Bn 
               
               
                   
                 (Ib) •HCl 
                 Me 
               
               
                   
                 (Ic) •HCl 
                 Et 
               
               
                   
                 (Id) •HCl 
                 Allyl 
               
               
                   
                   
               
               
                   
                 (Ie) •HCl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 (If) •HCl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 (Ig) •HCl 
                 H 
               
               
                   
                   
               
               
                   
                 (Ih) •HCl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 (Ii) •HCl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 (Ij) •HCl 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
             
          
         
       
       
         
           
             Bn: benzyl 
             Me: methyl 
             Et: ethyl 
             Ph: phenyl 
             Allyl: H 2 C═CH—CH 2 — 
           
         
       
     
       Compounds (Ia) .HCl Salt and (Ic) .HCl Salt are Commercially Available 
     Compound (Ib) .HCl Salt was Prepared from 3-hydroxypyridine Following a Procedure of the Literature (Lyle, R. E.; Adel, R. E., Lyle, G. G.  J. Org. Chem.  1959, 24, 343) 
     Synthesis of Compound (Id) .HCl Salt 
       [0054]    19.8 g (136 mmol) 3,3-dimethoxypiperidine and 19 ml (136 mmol) of triethylamine were dissolved in 136 ml of THF. 15.6 ml (150 mmol) of allyl chloride was added and the reaction mixture was stirred at room temperature then at 50° C. until complete conversion of the starting materials (2 days). After cooling to room temperature, the insoluble materials were filtered off and washed with a few ml of toluene. The combined filtrate and washing layer were concentrated under vacuum to dryness. The oily residue was redissolved in 20 ml of ethyl acetate and filtered through a pad of silica gel. The pad was rinsed with 100 ml of ethyl acetate and the combined filtrates were concentrate under vacuum to deliver 20.5 g of N-allyl-3,3-dimethoxypiperidine whose structure was confirmed by NMR and LC-MS (yield: 81%). 19 g of N-allyl-3,3-dimethoxypiperidine was dissolved in 100 ml of aqueous 3M HCl solution and 30 ml THF and stirred 4 hours at 60° C. Toluene was added to the reaction mixture and the layers were separated. The water layer was concentrated under vacuum to dryness and co-evaporated twice with dichloromethane. The resulting solid was stirred in a few ml of acetone then filtered and dried, yielding 8.5 g of compound (Id) .HCl salt (yield: 47%). 
       Compound (Id) .HCl Salt (Ratio Ketone/Hydrate: About 1/1) 
       [0055]    Appearance: white solid. 
         [0056]      1 H NMR (360 MHz, DMSO-d 6 , mixture of ketone and hydrate) δ=12.19 (br. s., 0.55H), 9.51 (br. s., 0.45H), 6.10-5.85 (m, 1H), 5.62-5.42 (m, 2H), 3.92 (m, 0.55H), 3.82 (d, J=7.0 Hz, 1.1H), 3.78-3.43 (m, 2.3H), 3.39-3.04 (m, 1.4H), 2.94-2.73 (m, 0.9H), 2.67-2.38 (m, 0.5H), 2.26 (br. s., 0.55H), 2.12 (br. s., 0.55H), 1.95-1.67 (m, 1.5H), 1.62-1.44 (m, 0.55H). 
         [0057]      13 C NMR (91 MHz, DMSO-d 6 , signal for the ketone form) δ ppm 200.80, 126.93, 125.20, 58.49, 57.35, 48.69, 36.89, 19.17 
         [0058]      13 C NMR (91 MHz, DMSO-d 6 , signal for the hydrate form) δ ppm 127.69, 124.78, 90.20, 58.41, 58.02, 51.35, 34.25, 19.72 High resolution MS: calculated for C 8 H 14 NO (ketone form, M+H): 140.1070. found: 140.1064. calculated for C 8 H 16 NO 2  (hydrate form, M+H): 158.1176. found: 158.1190. 
       Synthesis of Compound (Ie) .HCl Salt 
       [0059]    8.0 g (55.1 mmol) of 3,3-dimethoxypiperidine and 7.1 ml (60.6 mmol) of phenylacetaldehyde are dissolved in 83 ml of MeTHF and the solution is inerted. 2.37 g of wet 5% Pd/C are added and the reaction mixture is stirred for 5 hours at room temperature under 6 bar of hydrogen. After completion, the pressure is released, the catalyst is filtered off and the filtrate is concentrate under vacuum to dryness to afford 13.7 g of crude 3,3-dimethoxy-N-phenethylpiperidine (quantitative crude yield). The crude acetal is dissolved in 66 ml of aqueous 1M HCl. The aqueous solution is washed with 55 ml of isopropyl acetate then slowly concentrated under vacuum (temperature: 60° C.) to dryness. 110 ml of MIBK were added and the resulting mixture was slowly evaporated under vacuum. 110 ml of MIBK were added again and the mixture was refluxed for 2 hours before being stirred overnight at room temperature. The suspension was concentrated to dryness and the residue was recrystallized from 30 ml of acetonitrile to yield 5.51 g of compound (Ie) .HCl salt (yield: 42%) as a pale yellow solid. 
       Compound (Ie): 3,3-dimethoxy-N-phenylethylpiperidine 
       [0060]      1 H NMR (360 MHz, chloroform-d) δ=7.30-7.23 (m, 2H), 7.22-7.14 (m, 3H), 3.22 (s, 6H), 2.88-2.78 (m, 2H), 2.67-2.56 (m, 2H), 2.49 (d, J=15.4 Hz, 4H), 1.67 (br. s., 4H). 
         [0061]      13 C NMR (91 MHz, chloroform-d) δ ppm 140.2, 128.5, 128.2, 125.8, 98.0, 60.5, 57.4, 53.7, 47.6, 33.2, 31.1, 22.2. 
         [0062]    LC-MS: 21.38 (M-OMe), 250.34 (M+H). 
       Compound (Ie) .HCl Salt (Mixture of Ketone and Hydrate) 
       [0063]      1 H NMR (360 MHz, DMSO-d 6 , signal for the ketone form) δ ppm 12.14 (br. s., 1H), 7.33-7.39 (m, 2H), 7.24-7.33 (m, 3H), 3.99 (dd, J=15.4, 8.4 Hz, 1H), 3.87 (d, J=15.4 Hz, 1H), 3.73 (d, J=12.1 Hz, 1H), 3.27-3.48 (m, 3H), 3.07-3.18 (m, 2H), 2.44-2.67 (m, 2H), 2.24-2.42 (m, 1H), 2.07-2.20 (m, 1H) 
         [0064]      13 C NMR (151 MHz, DMSO-d 6 , signals for the ketone form) δ ppm 200.90, 137.10, 128.76, 128.67, 126.84, 58.90, 56.66, 51.80, 34.42, 29.43, 19.86 
         [0065]      13 C NMR (151 MHz, DMSO-d 6 , signals for the hydrate form) δ ppm 136.98, 128.73, 128.67, 126.84, 90.21, 59.14, 56.39, 49.50, 36.88, 29.19, 19.27 
         [0066]    High resolution MS: calculated for C 13 H 18 NO (ketone form, M+H): 204.1388. found: 204.1395. calculated for C 13 H 20 NO 2  (hydrate form, M+H): 222.1489. found: 222.1551. 
       Compound (If) .HCl Salt 
       [0067]    5.00 g (34 mmol) of 3,3-dimethoxypiperidine was dissolved in 69 ml of MeTHF. 5.71 g (41 mmol) of potassium carbonate and 8.51 g (34 mmol) of bromodiphenylmethane were added and the reaction mixture was refluxed overnight. After cooling to room temperature, the inorganic materials were washed out with 34 ml of water. 39 ml of aqueous 1 M HCl solution were added to the organic layer and the resulting biphasic mixture was refluxed then concentrated under vacuum to dryness. The semi-solid residue was refluxed in 39 ml of MIBK. After cooling to room temperature, the solid was filtered, washed with a few of MIBK and dried, yielding 7.48 g of compound (If) .HCl salt as a tanned solid (yield: 72%). 
         [0068]      1 H NMR (360 MHz, DMSO-d 6 ) δ ppm 13.12 (br. s., 1H), 7.78-8.16 (m, 4H), 7.20-7.56 (m, 6H), 5.81 (d, J=7.7 Hz, 1H), 3.85 (dd, J=13.2, 7.0 Hz, 1H), 3.22-3.54 (m, 3H), 2.55 (br. s., 2H), 2.50-2.53 (m, 1H), 2.12 (br. s., 1H) 
         [0069]      13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 199.93, 135.81, 134.96, 129.35, 129.22, 128.86, 128.56, 127.94, 73.96, 58.62, 49.56, 36.86, 18.54 
         [0070]    High resolution MS: calculated for C 18 H 20 NO (ketone form, M+H): 266.1545. found: 266.1549. calculated for C 18 H 22 NO 2  (hydrate form, M+H): 284.1651. found: 284.1654. 
       Compound (Ig) .HCl Salt 
       [0071]    37.6 ml (37.6 mmol) of 1M aqueous HCl solution were added to 5 g (25.1 mmol) of N-boc-3-piperidone and the reaction mixture was stirred at room temperature for a few hours before concentration under vacuum. The residue was recrystallized from isopropanol to afford 3.40 g of compound (Ig) .HCl salt as a solid (yield: 63%). 
         [0072]      1 H NMR (360 MHz, DMSO-d6) δ ppm 9.74 (br. s., 2H), 3.66 (br. s., 2H), 3.15-3.36 (m, 2H), 2.50 (m, 2H), 1.95-2.22 (m, 2H) 
       Compound (Ih) .HCl Salt 
       [0073]    A mixture of 800 mg (5.51 mmol) of 3,3-dimethoxypiperidine and 750 mg (5.51 mmol) of 2-methoxybenzaldehyde in 8.3 ml of methanol was stirred under 1 bar of hydrogen in the presence of 59 mg (0.055 mmol) of 10 w/w % Pd/C. After completion of the reaction (a few hours), the reaction mixture was purged with nitrogen, filtered and 6.6 ml of aqueous 1M HCl was added to the filtrate. The mixture was concentrated under vacuum to dryness. The residue was redissolved in 4.4 ml of hot acetone. 4.4 ml of MIBK was added to the hot solution, the mixture was refluxed for a few hours then cooled to room temperature. The suspension was filtered and the collected solid was washed with a few ml of MIBK then dried under vacuum to afford 950 mg of compound (Ih) .HCl salt as a off-white solid (yield: 68%). 
         [0074]    Ratio ketone/hydrate about 95/5. 
         [0075]      1 H NMR (360 MHz, DMSO-d 6 , signals for the ketone) δ ppm 11.88 (br. s., 1H), 7.63 (dd, J=7.5, 1.6 Hz, 1H), 7.35-7.55 (m, 1H), 7.14 (d, J=7.7 Hz, 1H), 7.03 (td, J=7.3, 0.7 Hz, 1H), 4.35 (br. s., 2H), 3.90 (dd, J=15.5, 9.5 Hz, 1H), 3.86 (s, 3H), 3.59 (d, J=15.0 Hz, 1H), 3.50 (d, J=11.7 Hz, 1H), 3.26 (q, J=9.9 Hz, 1H), 2.25-2.62 (m, 3H), 2.00-2.16 (m, 1H). 
         [0076]      13 C NMR (91 MHz, DMSO-d 6 , signals for the ketone form) δ ppm 200.64, 148.10, 133.37, 131.56, 120.47, 116.91, 111.47, 58.91, 55.69, 53.05, 48.90, 36.71, 19.25. 
         [0077]      13 C NMR (91 MHz, DMSO-d 6 , signals for the hydrate form) δ ppm 148.10, 133.37, 131.56, 120.47, 116.91, 111.47, 90.18, 58.91, 55.69, 51.28, 41.06, 37.48, 19.93. 
         [0078]    High resolution MS: calculated for C 13 H 18 NO 2  (ketone form, M+H): 220.1332. found: 220.1326. calculated for C 13 H 20 NO 3  (hydrate form, M+H): 238.1438. found: 238.1463. 
       Compound (Ii) .HCl Salt 
       [0079]    A mixture of 800 mg (5.51 mmol) of 3,3-dimethoxypiperidine and 750 mg (5.51 mmol) of 3-methoxybenzaldehyde in 8.3 ml of methanol was stirred under 1 bar of hydrogen in the presence of 59 mg (0.055 mmol) of 10 w/w % Pd/C. After completion of the reaction (a few hours), the reaction mixture was purged with nitrogen, filtered and 6.6 ml of aqueous 1M HCl was added to the filtrate. The mixture was concentrated under vacuum to dryness. The residue was suspended in 4.4 ml of hot acetone. 4.4 ml of MIBK was added and acetone was distilled off. The suspension then cooled to room temperature and filtered. The collected solid was washed with a few ml of MIBK then dried under vacuum to afford 1.09 g of compound (Ii) .HCl salt as a off-white solid (yield: 77%). 
         [0080]    High resolution MS: calculated for C 13 H 18 NO2 (ketone form, M+H): 220.1332. found: 220.1312. calculated for C 13 H 20 NO 3  (hydrate form, M+H): 238.1438. found: 238.1444. 
         [0081]    Ratio ketone/hydrate: about 95/5. 
         [0082]      1 H NMR (360 MHz, DMSO-d 6 , signals for the ketone) δ ppm 12.20 (br. s., 1H), 7.30-7.42 (m, 2H), 7.17 (d, J=7.7 Hz, 1H), 7.02 (dd, J=8.2, 2.4 Hz, 1H), 4.38 (br. s., 2H), 3.86 (dd, J=15.0, 8.8 Hz, 1H), 3.79 (s, 3H), 3.57 (d, J=15.0 Hz, 1H), 3.50 (d, J=12.1 Hz, 1H), 3.11-3.33 (m, 1H), 2.41-2.63 (m, 2H), 2.21-2.41 (m, 1H), 2.10 (br. s., 1H) 
         [0083]      13 C NMR (91 MHz, DMSO-d 6 ) δ ppm 200.55, 159.32, 130.70, 129.83, 123.30, 116.63, 115.26, 58.70, 58.39, 55.20, 48.88, 36.88, 19.09 
       Example 2 
       [0084]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 Compound 
                 R 2   
                 A 
                 X 
                 Yield 
               
               
                   
                   
               
             
             
               
                   
                 (IIa) 
                 Me 
                 CO 2 Et 
                 Br 
                 87% 
               
               
                   
                 (IIb) 
                 Et 
                 CO 2 Et 
                 Br 
                 84% 
               
               
                   
                 (IIc) 
                 Bu 
                 CO 2 Et 
                 Br 
                 100% (crude) 
               
               
                   
                 (IId) 
                 iBu 
                 CO 2 Et 
                 Br 
                 11% 
               
               
                   
                 (IIe) 
                 Ph 
                 CO 2 Et 
                 Br 
                 53% 
               
               
                   
                 (IIf) 
                 Me 
                 CO 2 Me 
                 Br 
                 95% 
               
               
                   
                 (IIg) 
                 Me 
                 CO 2 tBu 
                 Br 
                 73% 
               
               
                   
                 (IIh) 
                 Me 
                 CONH 2   
                 Br 
                 33% 
               
               
                   
                 (IIi) 
                 Me 
                 CO 2 H 
                 Br 
               
               
                   
                 (IIj) 
                 Me 
                 CN 
                 Br 
               
               
                   
                   
               
             
          
         
       
     
       Compound (IIa) 
       [0085]    74 g (400 mmol) of ethyl bromofluoroacetate are added slowly to 400 ml (400 mmol) of 1M trimethylphosphine solution in toluene and the reaction mixture is stirred overnight at room temperature. The compound (IIa) is filtered, washed with 80 ml of toluene and dried under vacuum at 40° C. Yield: 90.97 g (87% yield). 
         [0086]    Appearance: white solid. 
         [0087]      1 H-NMR (360 MHz, CDCl 3 ) δ=7.34 (dd, J=7.0, 43.5 Hz, 1H), 4.52-4.33 (m, 2H), 2.49 (d, J=15.0 Hz, 6H), 1.39 (t, J=7.1 Hz, 3H). 
         [0088]      13 C-NMR (90.6 MHz, CDCl 3 ) δ=163.51 (dd, J=1.8, 20.7 Hz), 83.80 (dd, J=63.0, 206.3 Hz), 64.05, 14.11, 6.81 (d, J=52.6 Hz). 
         [0089]      31 P-NMR (162 MHz, CDCl 3 ) δ=35.05 (d,  2 J P-F =64.6 Hz). 
         [0090]      19 F NMR (376 MHz, chloroform-d) δ ppm −212.30 (dd, J=65.2, 43.9 Hz, 1F). 
       Compound (IIb) 
       [0091]    74 g (400 mmol) of ethyl bromofluoroacetate are added slowly to 58.8 ml (400 mmol) of triethylphosphine dissolved in 400 ml of toluene. The reaction mixture is stirred overnight at room temperature then a few hours at 0° C. before the compound (IIb) is filtered, washed with 80 ml of toluene and dried. Yield: 102 g (84%). 
         [0092]    Appearance: white solid (mp: 135-210° C.). 
         [0093]      1 H NMR (400 MHz, CDCl 3 ) δ=7.47 (dd, J=6.8, 43.3 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 2.65 (qddd, J=7.7, 13.6, 15.6, 51.8 Hz, 6H), 1.21 (t, J=7.0 Hz, 3H), 1.22 (td, J=7.8, 19.1 Hz, 9H). 
         [0094]      13 C-NMR (101 MHz, CDCl 3 ) δ=163.3 (dd, J=1.5, 20.5 Hz), 83.60 (dd, J=52.8, 206.9 Hz), 63.53, 13.55, 11.3 (d, J=44.8 Hz), 5.6 (d, J=5.9 Hz). 
         [0095]      19 F-NMR (377 MHz, CDCl 3 ) δ=−209.53 (d,  2 J P-F =55.6 Hz). 
         [0096]      31 P-NMR (162 MHz, CDCl 3 ) δ=44.07 (d,  2 J P-F =56.7 Hz). 
         [0097]    Compound (IIc) (Compound Described in the Literature: Thenappan, A.; Burton, D. J.  J. Org. Chem.  1990, 55, 2311-2317): 
         [0098]    3.71 g (20 mmol) of ethyl bromofluoroacetate were added to a solution of 5 ml (20 mmol) of tributylphosphine in 50 ml of ethyl acetate. The solution was stirred overnight at room temperature before concentration under vacuum to afford the crude compound (IIc) as a semi-solid compound (crude yield: quantitative). 
         [0099]      1 H NMR (400 MHz, chloroform-d) δ ppm 7.55 (dd, J=43.3, 6.5 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 2.53-2.89 (m, 6H), 1.62-1.74 (m, 6H), 1.49-1.59 (m, 6H), 1.39 (t, J=7.2 Hz, 3H), 0.98 (t, J=7.3 Hz, 9H) 
         [0100]      13 C NMR (101 MHz, chloroform-d) δ ppm 163.77 (dd, J=20.9, 1.8 Hz), 83.17 (dd, J=208.3, 53.5 Hz), 63.74, 23.74 (d, J=16.1 Hz), 23.43 (d, J=5.1 Hz), 17.94 (d, J=43.3 Hz), 13.85, 13.11 
         [0101]      31 P NMR (162 MHz, chloroform-d) δ ppm 38.94 (d,  2 J P-F =55.3 Hz). 
         [0102]      19 F NMR (376 MHz, chloroform-d) δ ppm −208.67 (dd, J=56.1, 43.4 Hz, 1F). 
       Compound (IId) 
       [0103]    4.57 g (24.7 mmol) of ethyl bromofluoroacetate were added to a solution of 5 g (24.7 mmol) of triisobutylphosphine in 25 ml of THF. The solution was stirred 4 days at room temperature before concentration under vacuum. The residue was dried under high vacuum to form a solid. The solid was resuspended in a few ml of toluene, filtered, washed and dried under vacuum to afford 1.07 g of compound (IId) (yield: 11%). 
         [0104]    Appearance: white solid (mp: 101° C.). 
         [0105]      1 H NMR (400 MHz, chloroform-d) δ=7.64 (dd, J=6.5, 42.6 Hz, 1H), 4.39-4.07 (m, 2H), 2.71 (ddd, J=6.0, 13.4, 15.5 Hz, 3H), 2.50 (ddd, J=6.5, 14.2, 15.5 Hz, 3H), 2.24-2.04 (m, 3H), 1.24 (t, J=7.2 Hz, 3H), 1.03 (d, J=6.8 Hz, 9H), 1.00 (d, J=6.5 Hz, 9H) 
         [0106]      13 C NMR (101 MHz, chloroform-d) δ=163.8 (dd, J=2.5, 20.5 Hz), 83.2 (dd, J=53.6, 210.5 Hz), 63.4, 27.8 (d, J=38.9 Hz), 24.5, 24.4, 24.3, 24.2, 23.2 (d, J=4.4 Hz), 13.6 
         [0107]      19 F-NMR (377 MHz, CDCl 3 ) δ=−123.75 (d,  2 J P-F =56.4 Hz). 
         [0108]      31 P-NMR (162 MHz, CDCl 3 ) δ=37.82 (d,  2 J P-F =56.7 Hz). 
         [0109]    High-resolution MS (phosphonium cation): calculated for C 16 H 33 FO 2 P (phosphonium cation): 307.2202. found: 307.2225. 
         [0110]    Compound (IIe) (Compound Described in the Literature: Thenappan, A.; Burton, D. J.  J. Org. Chem.  1990, 55, 2311-2317) 
         [0111]    3.52 g (19 mmol) of ethyl bromofluoroacetate were added to a solution of 5 g (19 mmol) of triphenylphosphine in 15 ml of dichloromethane. The reaction mixture is stirred at room temperature before concentration under vacuum. The residue is resuspended in hot ethyl acetate-isopropanol (80/20) then filtered after cooling to room temperature and dried under vacuum to afford 4.54 g of compound (IIe) (yield: 54%). 
         [0112]    Appearance: white solid. 
         [0113]      1 H NMR (360 MHz, chloroform-d) δ ppm 9.71 (dd, J=41.7, 5.9 Hz, 1H), 8.01 (dd, J=13.2, 8.1 Hz, 6H), 7.79-7.89 (m, 3H), 7.71 (td, J=7.9, 3.7 Hz, 6H), 4.11 (q, J=7.2 Hz, 2H), 1.00 (t, J=7.1 Hz, 3H) 
         [0114]      13 C NMR (91 MHz, chloroform-d) δ ppm 163.34 (dd, J=21.5, 2.8 Hz, 1C), 135.70 (d, J=3.5 Hz, 3C), 134.75 (d, J=10.4 Hz, 6C), 130.34 (d, J=13.1 Hz, 6C), 114.53-115.85 (m, 3C), 83.61-86.96 (m, 1C), 63.60 (s, 1C), 13.56 (s, 1C) 
       Compound (IIf) 
       [0115]    4.27 g (25 mmol) of methyl bromofluoroacetate were added to 25 ml (25 mmol) of a 1M solution of trimethylphosphine in toluene. The reaction mixture was stirred overnight at room temperature, filtered and the collected solid was washed with a few ml of toluene then dried under vacuum to afford 5.88 g of compound (IIf) as a white solid (yield: 95%). 
         [0116]    Appearance: white solid (mp: 110° C.). 
         [0117]      1 H NMR (400 MHz, DMSO-d 6 ) δ=6.88 (dd, J=7.4, 43.4 Hz, 1H), 3.87 (s, 3H), 2.18 (d, J=15.6 Hz, 9H) 
         [0118]      13 C NMR (101 MHz, DMSO-d 6 ) δ ppm 163.51 (d, J=22.7 Hz), 83.82 (dd, J=199.5, 58.7 Hz), 54.01, 5.47 (d, J=51.4 Hz) 
         [0119]      19 F NMR (376 MHz, DMSO-d 6 ) δ=−212.44 (dd, J=64.9, 43.6 Hz, 1F) 
         [0120]      31 P NMR (162 MHz, DMSO-d 6 ) δ=35.75 (d, J=65.2 Hz, 1P) 
         [0121]    High-resolution MS (phosphonium cation): calculated for C 6 H 13 FO 2 P (phosphonium cation): 167.0637. found: 167.0645. 
       Compound (IIg) 
       [0122]    10.65 g of t-butyl bromofluoroacetate were added to 50 ml (50 mmol) of a 1M solution of trimethylphosphine in toluene and the reaction mixture was stirred overnight at room temperature then a few hours at 0° C. The formed solid was filtered, washed with a few ml of toluene and dried under vacuum. 10.55 g of compound (IIg) were obtained (yield: 73%). 
         [0123]    Appearance: white solid (mp: 97.8° C.). 
         [0124]      1 H NMR (400 MHz, DMSO-d 6 ) δ=6.69 (dd, J=7.3, 43.6 Hz, 1H), 2.14 (d, J=15.4 Hz, 9H), 1.51 (s, 9H) 
         [0125]      13 C NMR (101 MHz, DMSO-d 6 ) δ=161.9 (d, J=21.3 Hz), 86.4, 83.4 (dd, J=200.3, 58.7 Hz), 27.5, 5.7 (d, J=51.4 Hz) 
         [0126]      19 F NMR (376 MHz, DMSO-d 6 ) δ=−209.98 (dd, J=65.6, 43.7 Hz, 1F) 
         [0127]      31 P NMR (162 MHz, DMSO-d 6 ) δ=35.17 (d, J=65.2 Hz, 1P) 
         [0128]    High-resolution MS (phosphonium cation): calculated for C 9 H 19 FO 2 P (phosphonium cation): 209.1107. found: 209.1111. 
       Compound (IIh) 
       [0129]    100 ml (100 mmol) of a 1M solution of trimethylphosphine in toluene were added to a solution of 15.60 g (100 mmol) of bromofluoroacetamide in 150 ml of MeTHF. The reaction mixture was stirred overnight at room temperature then the compound (IIh) was filtered, washed with a few ml of toluene and dried under vacuum. Yield: 7.60 g (33%). 
         [0130]    Appearance: white solid (mp: 166.5° C.). 
         [0131]      1 H NMR (400 MHz, DMSO-d 6 ) δ=8.33 (br. s., 1H), 8.28 (br. s., 1H), 6.49 (dd, J=6.0, 44.8 Hz, 1H), 2.08 (dd, J=0.5, 15.4 Hz, 9H) 
         [0132]      13 C NMR (101 MHz, DMSO-d 6 ) δ=165.1 (d, J=52.1 Hz), 84.9 (dd, J=63.8, 209.1 Hz), 5.7 (d, J=18.3 Hz) 
         [0133]      19 F NMR (376 MHz, DMSO-d 6 ) δ=−205.4 (dd, J=44.9, 64.8 Hz, 1F) 
         [0134]      31 P NMR (162 MHz, DMSO-d 6 ) δ=65.2 (d, J=65.2 Hz, 1P) 
         [0135]    High-resolution MS (phosphonium cation): measured: 152.069, theor.: 152.0641 
         [0136]    Elemental analysis: calculated: C (25.88%), H (5.21%), N (6.04%) found: C (25.78%), H (5.24%), N (5.90%). 
       Example 3 
       [0137]    
       
                 
         
             
             
         
       
     
         [0138]    The results of the formation of the compounds (III) are reported in the table below. 
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                   
               
               
                   
                 From 
                   
                   
                   
                   
               
               
                 Compound (III) 
                 compounds 
                   
                 T° 
                 % 
                 E/Z 
               
             
          
           
               
                   
                 R 1   
                 A 
                 (I) 
                 (II) 
                 Solvent 
                 (° C.) 
                 yield 
                 ratio 
               
               
                   
               
             
          
           
               
                 (IIIa) 
                 Bn 
                 CO 2 Et 
                 (Ia) 
                 (IIa) 
                 Toluene 
                 0 
                 96 
                 80/20 
               
               
                   
                   
                   
                   
                   
                 Toluene 
                 60 
                 71 
                 70/30 
               
               
                   
                   
                   
                   
                   
                 Toluene 
                 40 
                 77 
                 75/25 
               
               
                   
                   
                   
                   
                   
                 Toluene 
                 22 
                 87 
                 76/24 
               
               
                   
                   
                   
                   
                   
                 Toluene 
                 −20 
                 56 
                 83/17 
               
               
                   
                   
                   
                   
                   
                 Toluene 
                 −33 
                 49 
                 84/16 
               
               
                   
                   
                   
                   
                   
                 DCM 
                 0 
                 86 
                 60/40 
               
               
                   
                   
                   
                   
                   
                 DMA 
                 0 
                 55 
                 67/33 
               
               
                   
                   
                   
                   
                   
                 MeCN 
                 0 
                 80 
                 56/44 
               
               
                   
                   
                   
                   
                   
                 AcOEt 
                 0 
                 60 
                 76/24 
               
               
                   
                   
                   
                   
                   
                 Heptanes 
                 0 
                 32 
                 74/26 
               
               
                   
                   
                   
                   
                   
                 CPME 
                 0 
                 46 
                 77/23 
               
               
                   
                   
                   
                   
                   
                 MeCy 
                 0 
                 36 
                 74/26 
               
               
                   
                   
                   
                   
                   
                 THF 
                 0 
                 34 
                 78/22 
               
               
                   
                   
                   
                   
                   
                 DIPE 
                 0 
                 40 
                 74/26 
               
               
                   
                   
                   
                   
                   
                 Anisole 
                 0 
                 68 
                 72/28 
               
               
                   
                   
                   
                   
                   
                 PhF 
                 0 
                 44 
                 72/28 
               
               
                   
                   
                   
                   
                   
                 DBE 
                 0 
                 52 
                 76/24 
               
               
                   
                   
                   
                   
                   
                 PhCl 
                 0 
                 45 
                 73/27 
               
               
                   
                   
                   
                 (Ia) 
                 (IIb) 
                 Toluene 
                 0 
                 72 
                 76/24 
               
               
                   
                   
                   
                 (Ia) 
                 (IIc) 
                 Toluene 
                 0 
                 52 
                 73/27 
               
               
                   
                   
                   
                 (Ia) 
                 (IId) 
                 Toluene 
                 0 
                 49 
                 71/29 
               
               
                   
                   
                   
                 (Ia) 
                 (IIe) 
                 Toluene 
                 0 
                 3 
                 67/33 
               
               
                 (IIIb) 
                 Me 
                 CO 2 Et 
                 (Ib) 
                 (IIa) 
                 Toluene 
                 0 
                 35 
                 96/4 
               
               
                 (IIIc) 
                 Et 
                 CO 2 Et 
                 (Ic) 
                 (IIa) 
                 Toluene 
                 0 
                 65 
                 84/16 
               
               
                 (IIId) 
                 Allyl 
                 CO 2 Et 
                 (Id) 
                 (IIa) 
                 Toluene 
                 0 
                 40 
                 90/10 
               
               
                   
               
               
                 (IIIe) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CO 2 Et 
                 (Ie) 
                 (IIa) 
                 Toluene 
                 0 
                 86 
                 93/7 
               
               
                   
               
               
                 (IIIf) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CO 2 Et 
                 (If) 
                 (IIa) 
                 Toluene 
                 0 
                 85 
                 67/33 
               
               
                   
               
               
                 (IIIg) 
                 H 
                 CO 2 Et 
                 (Ig) 
                 (IIa) 
                 Toluene 
                 0 
                   
                   
               
               
                   
               
               
                 (IIIh) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CO 2 Et 
                 (Ih) 
                 (IIa) 
                 Toluene 
                 0 
                 58 
                 81/19 
               
               
                   
               
               
                 (IIIi) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CO 2 Et 
                 (Ii) 
                 (IIa) 
                   
                   
                   
                   
               
               
                   
               
               
                 (IIIj) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 CO 2 Et 
                 (Ij) 
                 (IIa) 
                   
                   
                   
                   
               
               
                   
               
               
                 (IIIk) 
                 Bn 
                 CO 2 Me 
                 (Ia) 
                 (IIf) 
                 Toluene 
                 0 
                 76 
                 83/17 
               
               
                 (IIIl) 
                 Bn 
                 CO 2 tBu 
                 (Ia) 
                 (IIg) 
                 Toluene 
                 0 
                 32 
                 58/42 
               
               
                 (IIIm) 
                 Bn 
                 CONH 2   
                 (Ia) 
                 (IIh) 
                 Toluene 
                 0 
                   
                   
               
               
                 (IIIn) 
                 Bn 
                 CO 2 H 
                 (Ia) 
                 (IIi) 
                   
                   
                   
                   
               
               
                 (IIIo) 
                 Bn 
                 CN 
                 (Ia) 
                 (IIj) 
               
               
                   
               
             
          
         
       
     
       Compound (IIIa) 
       [0139]    30 g (124 mmol) of 94 w/w % compound (Ia) .HCl salt are suspended in 124 ml of toluene. 124 ml of water and 13.14 g of sodium carbonate are added and the resulting mixture is stirred a few minutes at room temperature before decantation. The two layers are separated and the organic one is dried over sodium sulfate then filtered to give 142 g of solution of 16.6 w/w % of compound (Ia) in toluene. The so-obtained solution of compound (Ia) is added to a suspension of 38.8 g (148 mmol) of compound (IIa) at 0° C. 22.5 g (148 mmol) of DBU are added and the reaction mixture is stirred overnight at 0° C. before being quenched with 62 ml of water. The two layers are separated and the organic one is washed with 62 ml of water, dried over sodium sulfate and filtered to give 251.7 g of 12.9 w/w % of compound (IIIa) solution in toluene that is used as such in the next step. (yield: 96%, E/Z ratio: 80/20). 
         [0140]    The same procedure was used in different solvents and at different temperatures. 
         [0141]    A solution of 50.5 mmol of compound (IIIa) in toluene is concentrated under vacuum and the residue is purified by chromatography to give 11.36 g of compound (IIIa) (mixture of (E)- and (Z)-isomer) as an oil with a limited stability. Yield: 81%. 
         [0142]    5.56 g of p-toluenesulfonic acid monohydrate are added to a solution of 8.12 g of compound (IIIa) in MIBK and the reaction mixture is warmed up to complete dissolution then cooled to room temperature. 12 g of tosylate salt of compound (IIIa) is obtained as a stable solid after filtration, washing and drying under vacuum (E/Z ratio: 85/15). 
         [0143]    12 g of compound (IIIa) are purified by preparative HPLC on ChiralPak AD column to deliver 4.16 g of compound (E)-(IIIa) and 820 mg of compound (Z)-(IIIa). 
         [0144]    2.85 g (15.0 mmol) of p-toluenesulfonic acid monohydrate are added to 4.16 g (15 mmol) of compound (E)-(IIIa) dissolved in 34 ml of MIBK. The mixture is warmed up until the salt is dissolved, filtered hot then let cooled down to room temperature. The so-obtained solid is filtered, washed with a few ml of MIBK and dried. 5.23 g of compound (E)-(IIIa) .TsOH salt are obtained as a white solid (Yield: 78%). 0.57 g (3 mmol) of p-toluenesulfonic acid monohydrate are added to 820 mg (2.96 mmol) of compound (Z)-(IIIa) dissolved in 10 ml of MIBK and 3 ml of ethanol. The mixture is warmed up until the salt is dissolved, filtered hot then let cooled down to room temperature. The so-obtained solid is filtered, washed with a few ml of MIBK and dried. 790 mg of compound (Z)-(IIIa) .TsOH salt are obtained as a white solid (Yield: 59%). 
       Compound (E)-(IIIa) 
       [0145]    Appearance: pale yellow liquid, darkens rapidly. 
         [0146]      1 H NMR (361 MHz, chloroform-d) δ ppm 7.17-7.46 (m, 5H), 4.19 (q, J=7.0 Hz, 2H), 3.56-3.66 (m, 4H), 2.52-2.55 (m, 2H), 2.37-2.40 (m, 2H), 1.69-1.75 (m, 2H), 1.22 (t, J=7.1 Hz, 3H) 
         [0147]      19 F NMR (377 MHz, chloroform-d) δ=−128.28 (s, 1F). 
       Compound (E)-(IIIa) .TsOH Salt 
       [0148]    Appearance: white solid (mp: 103.5° C.). 
         [0149]      1 H NMR (400 MHz, chloroform-d) δ=10.66 (br. s., 1H), 7.74 (d, J=8.1 Hz, 2H), 7.52 (d, J=7.1 Hz, 2H), 7.44-7.36 (m, 1H), 7.36-7.30 (m, 2H), 7.16 (d, J=8.1 Hz, 2H), 4.85 (d, J=13.6 Hz, 1H), 4.31 (d, J=5.3 Hz, 2H), 4.20-4.04 (m, 2H), 3.89 (ddd, J=4.2, 8.1, 13.7 Hz, 1H), 3.58-3.44 (m, 1H), 3.22-3.04 (m, 1H), 2.72 (td, J=4.2, 14.5 Hz, 1H), 2.35 (s, 3H), 2.25 (tdd, J=4.3, 10.3, 14.5 Hz, 1H), 2.14-1.98 (m, 1H), 1.95-1.82 (m, 1H), 1.18 (t, J=7.2 Hz, 3H) 
         [0150]      13 C NMR (101 MHz, chloroform-d) δ ppm 159.68 (d, J=35.2 Hz), 145.06 (d, J=259.7 Hz), 142.57, 139.91, 131.17, 129.90, 129.15, 128.72, 128.41, 125.79, 121.84 (d, J=19.8 Hz), 61.96, 59.27, 50.85, 49.40 (d, J=5.1 Hz), 22.74 (d, J=8.1 Hz), 21.21, 20.85, 13.79. 
         [0151]      19 F NMR (376 MHz, chloroform-d) δ ppm −118.96 (br. s., 1F) 
         [0152]    LC-high resolution MS: calculated for C 16 H 21 FNO 2  (compound E-(IIIa)+H): 287.1551. found: 278.1563 
         [0153]    Elemental analysis: calculated for C 23 H 28 FNO 5 S: C (61.45%), H (6.28%), N (3.12%). found: C (60.67%), H (6.24%), N (3.14%) 
       Compound (Z)-(IIIa) 
       [0154]    Appearance: pale yellow liquid, darkens rapidly. 
         [0155]      1 H NMR (400 MHz, chloroform-d) δ ppm 7.22-7.34 (m, 5H), 4.28 (q, J=7.2 Hz, 2H), 3.62 (s, 2H), 3.25 (d, J=3.0 Hz, 2H), 2.73-2.80 (m, 2H), 2.51-2.58 (m, 2H), 1.72 (dt, J=11.5, 5.5 Hz, 2H), 1.33 (t, J=7.0 Hz, 3H) 
         [0156]      13 C NMR (101 MHz, chloroform-d) δ ppm 161.40 (d, J=35.2 Hz,), 141.78 (d, J=250.9 Hz), 137.38 (d, J=2.9 Hz), 129.14, 128.30, 127.26, 62.45, 61.18, 52.84, 51.88 (d, J=11.7 Hz), 25.46 (d, J=1.5 Hz), 24.95, 14.14 
         [0157]      19 F NMR (377 MHz, chloroform-d,) δ=−128.47 (s, 1F) 
       Compound (Z)-(IIIa) .TsOH 
       [0158]    Appearance: white solid (mp: 167.1° C.) 
         [0159]      1 H NMR (400 MHz, chloroform-d) δ ppm 10.63 (br. s., 1H), 7.74 (d, J=8.3 Hz, 2H), 7.52 (d, J=6.8 Hz, 2H), 7.34-7.42 (m, 1H), 7.26-7.34 (m, 2H), 7.15 (d, J=7.8 Hz, 2H), 4.33 (d, J=5.3 Hz, 2H), 4.20-4.28 (m, 3H), 4.17 (d, J=13.6 Hz, 1H), 3.70 (ddd, J=13.6, 7.7, 2.6 Hz, 1H), 3.39-3.53 (m, 1H), 3.08-3.30 (m, 2H), 2.43-2.59 (m, 1H), 2.35 (s, 3H), 1.94-2.09 (m, 1H), 1.87 (s, 1H), 1.30 (t, J=7.2 Hz, 3H). 
         [0160]      13 C NMR (101 MHz, chloroform-d) δ ppm 159.83 (d, J=35.2 Hz), 144.46 (d, J=263.4 Hz), 142.50, 139.92, 131.16, 129.91, 129.15, 128.72, 128.32, 125.79, 121.54 (d, J=10.3 Hz), 61.80, 59.19, 50.84, 48.35 (d, J=11.7 Hz), 23.07, 21.20, 21.16, 13.89. 
         [0161]      19 F NMR (376 MHz, chloroform-d) δ ppm −120.65 (br. s., 1F) 
         [0162]    LC-high resolution MS: calculated for C 16 H 21 FNO 2  (compound (Z)-(IIIa)+H): 287.1551. found: 278.1559 
         [0163]    Elemental analysis: calculated for C 23 H 28 FNO 5 S: C (61.45%), H (6.28%), N (3.12%). found: C (60.91%), H (6.34%), N (3.15%) 
       Compound (IIIb) 
       [0164]    1.0 g (6.68 mmol) of compound (Ib) .HCl salt, 2.09 g (8.02 mmol) of compound (IIa) and 924 mg (6.68 mmol) of potassium carbonate were suspended in 13 ml of toluene. After cooling to 0° C., 1.21 ml (8.02 mmol) of DBU were added and the reaction mixture was stirred overnight at 0° C. 13 ml of water were added to the reaction mixture and the two layers were separated after a few minutes of stirring. The water layer was extracted with 13 ml of toluene and the combined organic ones were dried over sodium sulfate and filtered to afford 50.6 g of a 0.94 w/w % solution of compound (IIIb) in toluene (in situ yield: 35%). The solution was concentrated under vacuum and the residue was purified by filtration through a pad of silica gel (eluent: acetone) to afford 404 mg of purified product (yield: 30%). E/Z ratio: 96/4. 
         [0165]    Appearance: pale orange oil. 
       Compound (E)-(IIIb) 
       [0166]      1 H NMR (400 MHz, chloroform-d) δ ppm 4.27 (q, J=7.2 Hz, 2H), 3.52 (d, J=2.0 Hz, 2H), 2.47-2.51 (m, 2H), 2.34-2.39 (m, 1H), 2.34 (s, 3H), 1.71-1.79 (m, 2H), 1.34 (t, J=7.1 Hz, 3H) 
         [0167]      13 C NMR (101 MHz, chloroform-d) δ ppm 161.04 (d, J=35.9 Hz, 1C), 142.15 (d, J=250.9 Hz, 1C), 130.39 (d, J=13.9 Hz, 1C), 61.21, 55.40, 54.36 (d, J=5.1 Hz, 1C), 46.13 (s, 1C), 24.90 (d, J=2.2 Hz, 1C), 24.53 (d, J=8.8 Hz, 1C), 14.08 
         [0168]      19 F NMR (376 MHz, chloroform-d) δ ppm −129.72 (br. s., 1F) 
         [0169]    High resolution MS: calculated for C 10 H 17 FNO 2  (Compound (IIIb)+H): 202.1238. found: 202.1225 
       Compound (Z)-(IIIb) 
       [0170]      1 H NMR (400 MHz, chloroform-d) δ ppm 3.12 (d, J=3.0 Hz, 2H) 
         [0171]      13 C NMR (101 MHz, chloroform-d) δ ppm 61.13, 55.49, 53.78 (d, J=11.7 Hz, 1C), 25.29 (d, J=2.2 Hz, 1C) 
         [0172]      19 F NMR (376 MHz, chloroform-d) δ ppm −129.12 (br. s., 1F) 
       Compound (IIIc) 
       [0173]    The compound (IIIc) was obtained from the compounds (Ic) .HCl salt and (IIa) using the same procedure as for the compound (IIIa). Yield: 65%. E/Z ratio: 85/15. 
         [0174]    Appearance: pale yellow liquid, darkens rapidly. 
       Compound (E)-(IIIc) 
       [0175]      1 H NMR (360 MHz, chloroform-d) δ ppm 1.13 (t, J=7.32 Hz, 3H) 1.34 (t, J=7.14 Hz, 3H) 1.77 (dd, J=6.59, 5.12 Hz, 2H) 2.40 (td, J=6.40, 2.56 Hz, 2H) 2.48-2.56 (m, 2H) 2.60 (d, J=5.49 Hz, 2H) 3.62 (d, J=1.46 Hz, 2H) 4.28 (q, J=7.32 Hz, 3H) 
       Compound (Z)-(IIIc) 
       [0176]      1 H NMR (360 MHz, chloroform-d) δ ppm 1.13 (t, J=7.32 Hz, 3H) 1.34 (t, J=7.14 Hz, 3H) 1.77 (dd, J=6.59, 5.12 Hz, 2H) 2.52 (q, J=7.32 Hz, 2H) 2.56-2.62 (m, 2H) 2.73-2.81 (m, 2H) 3.21 (d, J=2.93 Hz, 2H) 4.28 (q, J=7.32 Hz, 2H) 
       Compound (IIId) 
       [0177]    The compound (IIId) was obtained from the compound (Id) .HCl salt and (IIa) using the same procedure than for the compound (IIIa). Yield: 40%, E/Z ratio: 90/10 
         [0178]    Appearance: pale yellow liquid, darkens rapidly. 
       Compound (E)-(IIId) 
       [0179]      1 H NMR (400 MHz, chloroform-d) δ ppm 1.33 (t, J=7.05 Hz, 3H) 1.68-1.81 (m, 2H) 2.33-2.46 (m, 2H) 2.50-2.61 (m, 2H) 3.02-3.14 (m, 2H) 3.57 (d, J=2.01 Hz, 2H) 4.27 (d, J=7.05 Hz, 2H) 5.12-5.29 (m, 2H) 5.77-5.99 (m, 1H) 
         [0180]      13 C NMR (91 MHz, chloroform-d) δ ppm 14.42 (s, 1C) 20.91 (s, 1C) 23.50 (d, J=7.61 Hz, 1C) 49.69 (d, J=4.84 Hz, 1C) 50.99 (s, 1C) 58.28 (s, 1C) 62.67 (s, 1C) 125.91 (s, 1C) 127.17 (s, 1C) 145.65 (d, J=260.90 Hz, 1C) 160.47 (d, J=31.80 Hz, 1C) 
         [0181]      19 F NMR (377 MHz, chloroform-d,) δ=−128.85 (s, 1F) 
       Compound (IIIe) 
       [0182]    The compound (IIIe) was obtained from the compound (Ie) .HCl salt and (IIa) using the same procedure than for the compound (IIIa). Yield: 86%. E/Z ratio: 93/7. 
         [0183]    Appearance: pale yellow liquid, darkens rapidly. 
       Compound (E)-(IIIe) 
       [0184]      1 H NMR (400 MHz, chloroform-d) δ=7.28-7.24 (m, 2H), 7.19-7.15 (m, 3H), 4.26 (q, J=7.2 Hz, 2H), 3.69 (d, J=2.0 Hz, 2H), 2.85-2.81 (m, 2H), 2.68-2.63 (m, 2H), 2.63-2.60 (m, 2H), 2.38 (dt, J=2.6, 6.5 Hz, 2H), 1.77-1.73 (m, 2H), 1.31 (t, J=7.1 Hz, 3H). 
         [0185]      13 C NMR (101 MHz, chloroform-d) δ=160.9 (d, J=35.4 Hz), 142.0 (d, J=251.3 Hz), 139.9, 130.3 (d, J=13.4 Hz), 128.5, 128.1, 125.8, 61.0, 59.8, 53.3, 52.1 (d, J=4.6 Hz), 33.6, 25.0 (d, J=8.1 Hz), 24.6 (d, J=1.7 Hz), 13.9. 
         [0186]      19 F NMR (377 MHz, chloroform-d,) δ=−128.85 (s, 1F). 
       Compound (Z)-(IIIe) 
       [0187]      1 H NMR (400 MHz, chloroform-d, signals for Z-isomer) δ=7.28-7.24 (m, 2H), 7.19-7.15 (m, 3H), 4.25 (q, J=7.1 Hz, 2H), 3.26 (d, J=3.0 Hz, 2H), 2.85-2.81 (m, 2H), 2.80-2.73 (m, 4H), 2.68-2.63 (m, 2H), 1.77-1.71 (m, 2H), 1.31 (t, J=7.1 Hz, 3H). 
         [0188]      13 C NMR (101 MHz, chloroform-d, signals for Z-isomer) δ=161.1 (d, J=35.8 Hz), 141.5 (d, J=250.9 Hz), 139.9, 130.1 (d, J=11.7 Hz), 128.5, 128.1, 125.8, 60.9, 59.8, 53.2, 51.7 (d, J=11.6 Hz), 33.5, 25.4 (d, J=1.5 Hz), 24.6 (d, J=1.7 Hz), 13.9.  19 F NMR (377 MHz, chloroform-d, signals for Z-isomer) δ=−128.48 (s, 1F). 
       Compound (IIIf) 
       [0189]    The compound (IIIf) was obtained from the compound (If) .HCl salt and (IIa) using the same procedure than the one used for the compound (IIIa). 
         [0190]    Appearance: pale yellow liquid, darkens rapidly. 
       Compound (IIIg) 
       [0191]    The compound (IIIg) was obtained from the compounds (Ig) .HCl salt and (IIa) using the same procedure than the one used for the compound (IIIa). 
         [0192]    Appearance: pale yellow liquid, darkens rapidly. 
       Compound (IIIh) 
       [0193]    The compound (IIIh) was obtained from the compound (Ih) .HCl salt and (IIa) using the same procedure than the one used for the compound (IIIa). 
         [0194]    Appearance: pale yellow liquid, darkens rapidly. 
       Compound (E)-(IIIh) 
       [0195]      1 H NMR (360 MHz, chloroform-d) δ ppm 7.32 (dd, J=7.5, 1.6 Hz, 2H), 7.23 (td, J=7.9, 1.8 Hz, 2H), 6.92 (td, J=7.5, 1.1 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 4.20 (q, J=7.3 Hz, 2H), 3.81 (s, 3H), 3.62-3.68 (m, 4H), 2.54-2.63 (m, 2H), 2.37 (td, J=6.5, 2.7 Hz, 2H), 1.68-1.79 (m, 2H), 1.24 (t, J=7.1 Hz, 3H) 
         [0196]      13 C NMR (91 MHz, chloroform-d) δ ppm 160.97 (d, J=36.7 Hz, 1C), 157.73 (s, 1C), 142.06 (d, J=247.7 Hz, 1C), 130.62 (s, 1C), 128.07 (s, 1C), 125.67 (s, 1C), 120.16 (s, 1C), 110.29 (s, 1C), 61.04 (s, 1C), 55.51 (s, 1C), 55.28 (s, 1C), 52.76 (s, 1C), 52.47 (d, J=4.8 Hz, 1C), 25.00 (d, J=8.3 Hz, 1C), 24.59 (d, J=2.1 Hz, 1C), 13.95 (s, 1C) 
       Compound (IIIk) 
       [0197]    The compound (IIIk) was obtained from the compound (Ia) .HCl salt and (IIf) using the same procedure than for the compound (IIIa). 
         [0198]    Appearance: pale yellow liquid, darkens rapidly. 
       Compound (E)-(IIIk) 
       [0199]      1 H NMR (600 MHz, chloroform-d) δ ppm 7.28-7.34 (m, 4H), 7.23-7.28 (m, 1H), 3.70 (s, 3H), 3.59 (br. s, 4H), 2.48-2.56 (m, 2H), 2.39 (td, J=6.4, 2.6 Hz, 2H), 1.67-1.76 (m, 2H) 
         [0200]      13 C NMR (151 MHz, chloroform-d) δ ppm 161.50 (d, J=36.2 Hz), 142.05 (d, J=248.1 Hz), 137.69, 130.82 (d, J=13.2 Hz), 129.25, 128.21, 127.16, 62.61, 52.78, 52.63 (d, J=5.5 Hz), 51.93, 25.14 (d, J=8.8 Hz), 24.65. 
         [0201]    High resolution MS: calculated for C 15 H 18 FNO 2) (M+°): 263.1322. found: 263.1325. 
       Compound (Z)-(IIIk) 
       [0202]      1 H NMR (600 MHz, chloroform-d) δ ppm 7.28-7.34 (m, 5H), 3.81 (s, 3H), 3.59 (s, 2H), 3.22 (d, J=3.0 Hz, 2H), 2.76 (td, J=6.4, 1.9 Hz, 2H), 2.48-2.56 (m, 2H), 1.67-1.76 (m, 2H). 
         [0203]      13 C NMR (151 MHz, chloroform-d) δ ppm 161.85 (d, J=35.1 Hz), 141.50 (d, J=250.3 Hz), 137.64, 130.97 (d, J=12.1 Hz), 129.06, 128.27, 127.18, 62.58, 52.89, 52.63 (d, J=5.5 Hz), 52.00, 25.52 (d, J=2.2 Hz), 25.09. 
         [0204]    High resolution MS: calculated for C 15 H 18 FNO 2) (M+°): 263.1322. found: 263.1328. 
       Experiment 4 
       [0205]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                 Compound 
                 R 1   
               
               
                   
                   
               
             
             
               
                   
                 (IVa) 
                 Bn 
               
               
                   
                 (IVb) 
                 Me 
               
               
                   
                 (IVc) 
                 Et 
               
               
                   
                 (IVd) 
                 Allyl 
               
               
                   
                   
               
               
                   
                 (IVe) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 (IVf) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 (IVg) 
                 H 
               
               
                   
                   
               
               
                   
                 (IVh) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 (IVi) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 (IVj) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
             
          
         
       
     
       Compound (E)-(IVa) 
       [0206]    437 mmol of compound (IIIa) in solution in toluene is cooled to 0° C. 212 g (682 mmol) of 65 w/w % sodium bis(2-methoxyethoxy)aluminumhydride (Red-Al) solution in toluene are added and the reaction mixture is stirred 1 hour at 0° C. the excess of Red-Al is quenched with 77 ml of acetone and the reaction mixture is allowed to warm to room temperature. 568 ml of water and 235 ml of 50 w/w % sodium hydroxide aqueous solution are added and the resulting mixture is warmed to 50° C. before decantation. The two layers are separated and the organic one is washed with 437 ml of water, dried over sodium sulfate, filtered and concentrated under vacuum. 1170 ml of heptanes are added to the oily residue and the resulting solid is filtered and recrystallized from 188 ml of diisopropyl ether to give 53.5 g of compound (E)-(IVa). Yield: 52%, E/Z ratio &gt;99/1. 
         [0207]    Appearance: solid (mp: 92.0° C.). 
         [0208]      1 H NMR (360 MHz, chloroform-d) δ ppm 1.51-1.71 (m, 2H) 2.20-2.30 (m, 2H) 2.51 (t, J=5.90 Hz, 2H) 2.96 (d, J=1.46 Hz, 2H) 3.54 (s, 2H) 4.15 (d, J=23.05 Hz, 2H) 7.13-7.36 (m, 5H) 
         [0209]      13 C NMR (91 MHz, chloroform-d) δ ppm 24.18 (d, J=7.61 Hz, 1C) 25.39 (s, 1C) 53.97 (d, J=7.61 Hz, 1C) 54.15 (s, 1C) 57.87 (d, J=31.83 Hz, 1C) 63.21 (s, 1C) 116.05 (d, J=16.61 Hz, 1C) 127.73 (s, 1C) 128.75 (s, 2C) 129.69 (s, 2C) 137.85 (s, 1C) 152.75 (dd, J=248.43, 1.00 Hz, 1C) 
         [0210]      19 F NMR (377 MHz, chloroform-d) δ ppm −120.14 (s, 1F) 
         [0211]    Elemental analysis: calculated: C (71.46%), H (7.71%), F (8.07%), N (5.95%), O (%). found: C (71.38%), H (7.91%), N (5.99%) 
       Compound (E)-(IVe) 
       [0212]    5.6 ml (19.5 mmol) of a 70 w/w % solution of sodium bis(2-methoxyethoxy)aluminum-hydride (Red-Al) in toluene were added to 38 g (10.2 mmol) of a 7.8 w/w % solution of compound (Me) in toluene kept at 0° C. After an hour at 0° C., the excess of Red-Al was quenched with 1.2 ml (16.4 mmol) of acetone and the reaction mixture was stirred overnight at room temperature. The reaction mixture was warmed to 50° C. and 14 ml of water and 5.5 ml (105 mmol) of a 50 w/w % aqueous solution of sodium hydroxide were added. The layers were separated and the organic one was washed with 14 ml of water, dried over sodium sulfate and filtered. The filtrate was evaporated under vacuum to dryness to give 2.40 g of crude compound (IVe) (LC-assay: 94.1 w/w %, E/Z ratio: 92/8, yield: 89%). The crude product was recrystallized from 6 ml of DBE to afford 1.87 g of compound (E)-(IVe) as a solid product (yield: 73%, E/Z ratio: 98/2). LC analysis of the mother-liquor revealed a E/Z ratio of 40/60, as a proof of the selective precipitation of the compound (E)-(IVe). 
         [0213]    Appearance: tanned solid (mp: 110.5° C.). 
         [0214]      1 H NMR (400 MHz, chloroform-d) δ ppm 7.25-7.32 (m, 2H), 7.15-7.23 (m, 3H), 4.20 (d, J=23.2 Hz, 2H), 3.89 (br. s., 1H), 3.04 (d, J=1.3 Hz, 2H), 2.76-2.86 (m, 2H), 2.55-2.68 (m, 4H), 2.27 (td, J=6.2, 1.8 Hz, 2H), 1.62-1.75 (m, 2H) 
         [0215]      13 C NMR (101 MHz, chloroform-d) δ ppm 152.80 (d, J=247.9 Hz), 139.94, 128.61, 128.42, 126.11, 115.20 (d, J=16.1 Hz), 60.27, 57.04 (d, J=31.5 Hz), 53.88 (d, J=8.1 Hz), 53.81, 33.39, 25.06 (d, J=1.5 Hz), 23.76 (d, J=8.1 Hz) 
         [0216]      19 F NMR (376 MHz, chloroform-d) δ ppm −119.40 (t, J=23.0 Hz, 1F) 
         [0217]    High resolution MS: calculated for C 15 H 21 NOF (M+H): 250.1607. found: 250.1604. 
         [0218]    Elemental analysis: calculated: C (72.26%), H (8.09%), F (7.62%), N (5.62%), 0 (6.42%). found: C (71.29%), H (8.20%), N (5.51%) 
       Experiment 5 
       [0219]    
       
                 
         
             
             
         
       
     
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                 Compound 
                 R 1   
               
               
                   
                   
               
             
             
               
                   
                 (VIa) 
                 Bn 
               
               
                   
                 (VIb) 
                 Me 
               
               
                   
                 (VIc) 
                 Et 
               
               
                   
                 (VId) 
                 Allyl 
               
               
                   
                   
               
               
                   
                 (VIe) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 (VIf) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 (VIg) 
                 H 
               
               
                   
                   
               
               
                   
                 (VIh) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 (VIi) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 (VIj) 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
             
          
         
       
     
       Compound (VIa) Via the Mesylate of the Compound (IIIa) 
       [0220]    28.2 g (120 mmol) of compound (E)-(IVa) and 18.4 ml (132 mmol) of triethylamine are dissolved in 180 ml of toluene at 0° C. 14.4 g (125.8 mmol) of methanesulfonyl chloride are added slowly and the reaction mixture is stirred 1 hour at 0° C. The formed triethylamine hydrochloride is washed out with 120 ml of cold water and the organic layer is dried over sodium sulphate, filtered and added to a suspension of 22.2 g (120 mmol) of potassium phtalimide (compound (V), M=K) and 2.43 g (6.6 mmol) of TBAI in 60 ml of toluene. The reaction mixture is stirred overnight at room temperature than washed with 120 ml of water, filtered and concentrated under vacuum. The residue is crystallized from 30 ml of isopropanol to give 33 g of a white solid. Yield: 76%. 
         [0221]    Appearance: white solid (mp: 125.1° C.). 
         [0222]      1 H NMR (360 MHz, chloroform-d) δ ppm 1.47-1.76 (m, 4H) 2.20-2.28 (m, 2H) 2.47-2.56 (m, 2H) 3.22 (d, J=1.46 Hz, 2H) 3.63 (s, 2H) 4.40 (d, J=20.90 Hz, 2H) 7.12-7.42 (m, 5H) 7.72 (dd, J=5.49, 3.29 Hz, 2H) 7.85 (dd, J=5.49, 2.93 Hz, 2H) 
         [0223]      13 C NMR (91 MHz, chloroform-d) δ ppm 24.14 (s, 1C) 25.24 (d, J=1.38 Hz, 1C) 35.39 (d, J=32.52 Hz, 1C) 53.94 (s, 1C) 54.35 (d, J=7.61 Hz, 1C) 63.31 (s, 1C) 117.42 (d, J=12.46 Hz, 1C) 123.83 (s, 1C) 125.73 (s, 1C) 127.53 (s, 1C) 128.68 (d, J=4.15 Hz, 2C) 129.46 (s, 1C) 129.67 (s, 1C) 132.47 (s, 1C) 134.45 (s, 254C) 134.26-134.58 (m, 2C) 138.46 (s, 1C) 147.70 (d, J=248.43 Hz, 1C) 168.04 (s, 1C) 
         [0224]      19 F NMR (377 MHz, chloroform-d) δ ppm −118.91 (s, 1F) 
         [0225]    Elemental analysis: calculated: C (72.51%), H (5.81%), F (5.21%), N (7.69%), 0 (8.78%). found: C (72.68%), H (5.84%), N (7.66%) 
       Compound (VIa) Via a Mitsunobu Reaction 
       [0226]    8.43 ml (42.5 mmol) of DIAD were added dropwise to a cold (−10° C.) solution of 10 g (42.5 mmol) of compound (E)-(IVa), 6.25 g (42.5 mmol) of phtalimide and 11.15 g (42.5 mmol) of triphenylphosphine in 85 ml of toluene. After 24 hours at −10° C., water was added. The insoluble materials were filtered off and the filtrate was allowed to decante. The two layers were separated and the organic one was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was recrystallized from isopropanol to afford 10.2 g of compound (VIa) (yield: 66%). NMR and MS spectra identical to those of the compound (VIa) obtained via the mesylate of the compound (IIIa). 
       Compound (VIe) Via the Mesylate of the Compound (IIIe) 
       [0227]    0.49 ml (6.32 mmol) of methanesulfonyl chloride are added over 10 minutes to a solution of 1.50 g (6.02 mmol) of compound (IVe) and 0.92 ml (6.62 mmol) of triethylamine in 9 ml of toluene kept at 0° C. After 1 hour at 0° C., 6 ml of water were added. The layers were separated and the organic one was dried over sodium sulfate and filtered. The so-obtained solution of mesylate was added over 5 minutes to a suspension of 1.17 g (6.32 mmol) of potassium phtalimide (compound (V), M=K) and 133 mg (0.36 mmol) of TBAI in 3 ml of toluene. The reaction mixture was stirred at 10° C. for 2 hours then overnight at room temperature. 6 ml of water were added, the insoluble materials were filtered off, the filtrate was allowed to decant, the water layer was discarded and the organic one was dried over sodium sulfate and filtered to afford 25.12 g of a 4.6 w/w % solution of compound (VIe) in toluene (in situ yield: 51%). The solution was concentrated under vacuum and the residue was recrystallized from n-butanol to afford 1.02 g of compound (VIe). The mother-liquor was concentrated under vacuum and filtered through a pad of silica gel (eluent: heptanes-ethyl acetate 1/1 to 1/3) to yield 0.11 g more of compound (VIe). Combined yield: 47%. 
         [0228]    Appearance: white solid (mp: 97.0° C.). 
         [0229]      1 H NMR (600 MHz, chloroform-d) δ ppm 7.85 (dd, J=5.3, 3.0 Hz, 2H), 7.72 (dd, J=5.7, 3.0 Hz, 2H), 7.28-7.32 (m, 2H), 7.24-7.27 (m, 2H), 7.21 (t, J=7.2 Hz, 1H), 4.50 (d, J=21.9 Hz, 2H), 3.29 (s, 2H), 2.89-2.94 (m, 2H), 2.69-2.74 (m, 2H), 2.59-2.63 (m, 2H), 2.26 (t, J=5.5 Hz, 2H), 1.63-1.73 (m, 2H) 
         [0230]      13 C NMR (151 MHz, chloroform-d) δ ppm 167.60, 147.56 (d, J=247.0 Hz), 140.27, 134.04, 131.98, 128.71, 128.39, 126.03, 123.41, 117.02 (d, J=15.4 Hz), 60.50, 53.95, 53.84 (d, J=7.7 Hz), 34.99 (d, J=32.9 Hz), 33.73, 24.92, 23.71 (d, J=7.7 Hz) 
         [0231]      19 F NMR (377 MHz, chloroform-d,) δ=−117.73 (s, 1F). 
         [0232]    High resolution MS: calculated for C 23 H 24 N 2 O 2 F (M+H): 379.1822. found: 379.1820. 
         [0233]    Elemental analysis: calculated: C (73.00%), H (6.13%), F (5.02%), N (7.40%), 0 (8.46%). found: C (72.53%), H (6.42%), N (7.32%) 
       Experiment 6 
       [0234]    
       
                 
         
             
             
         
       
     
       Compound (I) .HCl Salt from Compound (VIa) 
       [0235]    9.8 ml (90.6 mmol) of 1-chloroethyl chloroformate are added slowly to a solution of 30 g (82.3 mmol) of compound (E)-(Va) in 165 ml of toluene kept at 0° C. The reaction mixture is stirred 1 hour at room temperature than 1 hour at 80° C. and filtered. 24 ml of ethanol and 15.35 ml (90.6 mmol) of 6M HCl solution in isopropanol are added to the filtrate and the resulting mixture is refluxed for 4 hours then cooled to 0° C. The precipitate is filtered, washed with 16 ml of acetone and 16 ml of toluene and dried under vacuum to give 21.94 g of compound (1) .HCl salt. Yield: 86%. NMR and MS data are identical to those of the literature.