Olefination process to itaconate and succinate derivatives

Abstract: An efficient and selective process, capable of scale-up, to make itaconate derivatives of formula (IV), and/or succinate derivatives of formula (V) and/or (VI) by asymmetric hydrogenation of the itaconate derivatives. The process comprises formation of a compound of formula (IV) by reaction of an aldehyde of formula RCHO with a phosphorus compound of formula (IX): or a metal carboxylate optionally followed by, if a compound of formula (V) or (VI) is desired, asymmetric reduction of a compound of formula (IV) to provide a compound of formula (V) or (VI)

Description: The invention described herein relates to an olefination process which is useful for making certain itaconate and succinate derivatives. It is desirable in a number of instances to be able to have an efficient and selective process, capable of scale-up, to make itaconate derivatives of formula (I), and/or succinate derivatives of formula (II) and/or (III): wherein "R*" is a sterically bulky group. Of particular interest to us is the provision of compounds of the formula (IV), (V) and (VI), especially (IV) and (V): wherein R is aryl, C 3-8 cycloalkyl, C 1-10 alkyl, (aryl)C 1-10 alkylene, (C 3-8 cycloalkyl)C 1-10 alkylene, heterocyclyl, (heterocyclyl)C 1-10 alkylene, (aryl)C 3-8 cycloalkylene, (C 3-8 cycloalkyl)arylene or (C 1-10 alkylaryl)C 1-10 alkylene, wherein "aryl" is a mono- or bicyclic partially or fully unsaturated carbocyclic ring system containing from 4 to 10 atoms, such as phenyl or naphthyl, or a partially or fully unsaturated mono- or bicyclic heterocyclic moiety having up to 10 atoms in the ring system and with up to 4 hetero-atoms in the said ring system each independently selected from N, O and S, said carbocyclic ring system and heterocyclic moiety being optionally substituted by one or more substituents each independently selected from halogen, NO 2 , NH 2 , CO 2 R 9 , phenyl, C 1-6 alkyl(optionally substituted by one or more halogen), and C 1-6 alkoxy(optionally substituted by one or more halogen), and "heterocyclyl" is a 3- to 8-membered mono or bicyclic saturated heterocyclic group having from 1 to 4 ring hetero-atoms each independently selected from N, O and S, optionally substituted by one or more substituents each independently selected from halogen, NO 2 , NH 2 , CO 2 R 9 , phenyl, C 1-6 alkyl(optionally substituted by one or more halogen), and C 1-6 alkoxy(optionally substituted by one or more halogen); R 1 is C 1-6 alkoxy, R 2 is OH or O - M + ; R 9 is H or C 1-6 alkyl; and M + is the cation of a metal such as sodium, lithium or potassium, or is a protonated amine moiety such as (mono-, di- or tri-C 1-10 alkyl)ammonium, (mono-, di- or tri-C 3-10 cycloalkyl)ammonium, (C 1-10 alkyl) n1 (C 3-10 cycloalkyl) n2 ammonium, anilinium, benzylammonium, triethanolammonium, or ( S )-α-methylbenzylammonium, where n1 and n2 are each independently selected from 1 or 2 with the proviso that the sum of n1 and n2 is not greater than 3; Alkyl groups, and groups containing alkyl moieties such as alkoxy and alkylene groups, can be straight chain or branched if the number of carbon atoms allows, Halogen means fluorine, chlorine or bromine, Cycloalkyl groups attached to an ammonium moiety can contain 1, 2, or 3 rings, where the number of carbon atoms allows, for example adamantanammonium. Production of compounds related to (IV), (V) and (VI) has been disclosed previously, e.g. by Owton et al, in Synthetic Communications, 23(15), 2119-2125 (1993), MJ Burk et al, Angew. Chem. Int. Edn. (Eng.) (1998) 37, 13/14, 1931-1933, Monsanto, US Patent 4,939,288 or EP Patent 561758 by Chirotech Technology Ltd. in International Patent Application publication no. WO 99/31041. Known olefination reactions leading to systems related to (IV), generally result in poor E/Z selectivity, (for a review of the Stobbe condensation, see Org.React. 1951, 6, 1-73). Where selectivity has been controlled, however, for example by the use of phosphorus reagents, the substitution pattern is different from that required by us in formula (IV)(e.g. Monsanto, Owten, supra ). The products of the Owten chemistry are exemplified by compounds of the formula (VII): on which we attempted hydrolysis of the ethyl ester using conventional chemistry. In our hands this resulted in scrambling of the olefinic moiety resulting overall in a mixture of stereoisomers and regioisomers. Use of the Monsanto chemistry gives products of the formula (VIII): which has the wrong substitution pattern for our requirements. We have discovered an efficient olefination method which can be used to make compounds of formula (IV) in good yield and with good trans-selectivity, and which products can then be asymmetrically reduced to give compounds of formula (V) and (VI). The olefination is base-catalysed and can be used with enolisable aldehydes or aldehyde derivatives without significant amounts of self-condensation products. We also surprisingly observe no substantial double bond migration to give deconjugated isomers of (IV) under the basic conditions, which would afford other geometric and regio-isomers, which is another significant problem with similar prior art olefinations. Our olefination system is thus particularly useful when highly selective production of the compounds (IV), (V) and/or (VI) is required, or where separation of (IV), (V) and/or (VI) and/or the respective isomers thereof, may be difficult or undesirable, such as in processing to make pharmaceutical products and regulatory starting materials for such products. Thus, according to the present invention, there is provided a process for the preparation of compounds of formula (IV) as defined above, comprising reaction of an aldehyde of formula RCHO, or a protected derivative thereof such as a hemiacetal or adduct thereof such as a bisulphite, wherein R is as defined above, with a phosphorus compound of formula (IX): or a metal carboxylate salt thereof such as a sodium, lithium or potassium carboxylate salt thereof, wherein R 1 is as defined above, and "P" is a phosphonate moiety of formula -P(O)(OR 3 )(OR 4 ), wherein R 3 and R 4 are either each independently selected from H, C 1-6 alkyl, benzyl and phenyl (optionally substituted by one or more C 1-6 alkyl), or R 3 and R 4 taken together are C 2-5 alkylene, or "P" is a phosphorane moiety of formula -(PR 5 R 6 R 7 ) + X - wherein R 5 , R 6 and R 7 are each independently selected from C 1-6 alkyl and phenyl, and X is bromine, chlorine or iodine, in the presence of a sodium, lithium or potassium C 1 -C 6 alkoxide base, in an inert solvent, and at a temperature of from -80°C to 20°C. Preferably the reaction time is less than 24 hours. Preferably R is (aryl)C 1-10 alkylene or (C 3-8 cycloalkyl)C 1-10 alkylene. More preferably R is phenylethyl, cyclohexylethyl or (2-methyl-1,1'-biphenyl-4-yl)ethyl. Preferably R 1 is t-butoxy. Preferably R 2 is OH, O - Li + , O - Na + , O - K + , O - cyclohexylammonium + , O - adamantanammonium + , O - triethanolammonium + or O - ( S )-α-methylbenzylammonium + . Preferably the olefination reaction is carried out using the aldehyde RCHO or the sodium bisulphite adduct thereof RCH(OH)SO 3 - Na + . Preferably "P" is P(O)(OC 2 H 5 ) 2 , P(O)(OCH 2 CH 2 O) or a triphenylphosphinium halide moiety. More preferably P is P(O)(OC 2 H 5 ) 2 . Preferably the base is potassium t-butoxide, sodium t-butoxide or sodium methoxide. When the the base alkoxide and R 1 are different there is a possibility of transesterification taking place during the olefination reaction. We have found that this apparently has no detrimental effect on the course of the reaction at the olefination centre, in terms of stereochemistry, and may not be important with respect to the use made of the product, e.g. if it is used as an intermediate and the R 1 moiety is later removed, e.g. by displacement, hydrolysis or deprotection. Preferably the olefination reaction solvent is anhydrous tetrahydrofuran, anhydrous toluene or R 1 H, where R 1 takes the meaning as specified above with respect to the compounds of formulae (IV), (V) and (VI), or a mixture thereof. More preferably the reaction solvent is selected from tetrahydrofuran and toluene when the aldehyde RCHO is used as a substrate, and selected from tetrahydrofuran/t-butanol and toluene when the bisulphite adduct is used as substrate. Preferably the reaction is carried out at a temperature from -20°C to 10°C. More preferably the reaction is carried out at a temperature from -10°C to 10°C. Most preferably the reaction is carried out at a temperature from 0°C to 5°C. When the aldehyde RCHO is used as substrate, it is preferable to add the phosphorus compound to the base/solvent mixture, followed by addition of the aldehyde. Alternatively, the phosphorus compound and aldehyde are combined, then the base is added. A further alternative is to add the base to the phosphorus compound followed by addition of the aldehyde. When the bisulphite is used as the substrate, it is preferable to add the base to a mixture of the bisulphite adduct and the phosphorus compound, or, alternatively, the bisulphite is added to a mixture of the phosphorus compound and the base. 'Bisulphite' or 'bisulphite adduct' is taken to mean an α-hydroxysulphonate, which is the product of the reaction of an aldehyde with sodium, potassium or lithium bisulphite. Other suitable bisulphites are known in the art. The skilled person will appreciate that the substrates, and starting material of formula (IX), can be obtained from commercial sources, or made by methods known in the art, e.g. by adaptation of the methods herein described in the sections below, and/or adaptation thereof, for example by methods known in the art. Suitable guides to synthesis, functional group transformations, use of protecting groups, etc. are found in standard organic chemistry textbooks, for example, "Comprehensive Organic Transformations" by RC Larock, VCH Publishers Inc. (1989), "Advanced Organic Chemistry" by J March, Wiley Interscience (1985), "Designing Organic Synthesis" by S Warren, Wiley Interscience (1978), "Organic Synthesis - The Disconnection Approach" by S Warren, Wiley Interscience (1982), "Guidebook to Organic Synthesis" by RK Mackie and DM Smith, Longman (1982), "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley and Sons Inc. (1999), and PJ Kocienski, in "Protecting Groups", Georg Thieme Verlag (1994), and any updated versions of said standard works. The above olefination process is optionally followed by conversion of the product of formula (IV) where R 2 is O - M + wherein M + is a metal such as Na, Li or K, to a compound of formula (IV) where R 2 is OH by treatment with a proton source, which may optionally be converted to a compound of formula (IV) wherein R 2 is O - M + (where M + is a protonated amine moiety as previously defined), by treatment with a corresponding amine. A further aspect of the invention is the asymmetric hydrogenation of itaconate compounds of the formula (IV) to give succinate compounds of the formula (V) or (VI). Asymmetric hydrogenation of compounds of formula (IV) may be achieved in a multitude of ways, including methods known in the art. For example use may be made of catalytic hydrogenation using chiral rhodium or ruthenium complex of an optically active biphosphine or biphosphinite compound such as (4R,5R)-(-)-O-Isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane [(R,R)-DIOP], (R,R)-(-)-1,2-Bis[(O-methoxyphenyl)(phenyl)phosphino]ethane [(R,R)-DIPAMP], (-)-(R)-N,N-Dimethyl-1-((S)-1',2-Bis(Diphenylphosphino)ferrocenyl)ethylamine [(R)-(S)-BPPFA], (-)-(2S,4S)-2-Diphenylphosphinomethyl-4-diphenylphosphino-1-t-butoxycarbonylpyrrolidine [(S,S)-BPPM], (2S,3S)-(-)-Bis(diphenylphosphino)butane [(S,S)-CHIRAPHOS], R-(+)-1,2-Bis(diphenylphosphino)propane [(R)-PROPHOS], (2R,3R)-(-)-2,3-Bis(diphenylphosphino)bicyclo[2.2.1]hept-5-ene [(R,R)-NORPHOS], (R)-(+)-2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl [(R)-BINAP], (R)-1,2-bis(diphenylphosphino)-1-cyclohexylethane [(R)-CYCPHOS], (2R,4R)-(+)-2,4-Bis(diphenylphosphino)pentane [(R,R)-BDPP], N-benzyl-(3R,4R)-3,4-bis(diphenylphosphino)pyrrolidine [(R,R)-DEGPHOS], (-)-1,2-Bis((2R,5R)-2,5-dimethylphospholano)benzene [(R,R)-Me-DUPHOS], (-)-1,2-Bis((2R,5R)-2,5-diethylphospholano)benzene [(R,R)-Et-DUPHOS], N,N'-bis[(R)-(+)-α-methylbenzyl]-N,N'-bis(diphenylphosphino)ethylenediamine [(R)-PNNP], (R)-(-)-2,2'-bis(dicyclohexylphosphino)-6,6'-dimethyl-1,1'-biphenyl [(R)-BICHEP], (1R,2S,4R,5S)-2,5-dimethyl-7-phosphadicyclo[2.2.1]heptane [(R,S,R,S)-Me-PENNPHOS], (2S,2'S)-Bis(diphenylphosphino)-(1S,1'S)-bicyclopentane [(S,S)-BICP], 1,1'-bis[(2 S ,4 S )-2,4-diethylphosphetano]ferrocene [(S,S)-Et-FerroTANE], (R,R)-1,2-bis(di-t-butylmethylphosphino)methane [(R,R)-t-butylminiPHOS], (R)-(+)-2,2'-Bis(di-p-tolylphosphino)-1,1'-binaphthyl [(R)-tol-BINAP], (R)-(+)-2-(Diphenylphosphino)-2'-methoxy-1,1'-binaphthyl [(R)-MOP], (R)-(+)-1-(2-Diphenylphosphino-1-naphthyl)isoquinoline [(R)-QUINAP], Methyl α-D-glucopyranoside-2,6-dibenzoate-3,4-di(bis(3,5-dimethylphenyl)phosphinite) (CARBOPHOS), (R)-(-)-1-[(S)-2-(Diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine [(R)-(S)-JOSIPHOS], (R)-(-)-4,12-Bis(diphenylphosphino)-[2.2]-paracyclophane [(R)-PHANEPHOS], (R)-(6,6'-Dimethoxybiphenyl-2,2-diyl)-bis(diphenylphosphine) [(R)-MeO-BIPHEP],], (R)-(6-Chloro-6'-methoxybiphenyl-2,2-diyl)-bis(diphenylphosphine) [(R)-Cl-MeO-BIPHEP] or 2,2'-bis(diphenylphosphino)-4,4',6,6'-tetrakis(trifluoromethyl)-1,1'-biphenyl (BIFUP) which are well-known to the skilled chemist working in the asymmetric hydrogenation art. It is to be appreciated that other examples include related structures, such as those with alternative alkyl substituents, and stereoisomers of the above-mentioned examples. Some catalysts are mentioned in the Examples, and other suitable catalysts which may be useful are mentioned in the following publications and references therein, all of which are herein incorporated by reference in their entirety: US Patent 4,939,288 (Monsanto); International Patent Application publication no. WO 98/02445 (Chiroscience Ltd); International Patent Application publication no. WO 99/31041 (Chirotech Technology Ltd); European Patent Application 0 673 911 A1 (Takasago International Corporation); International Patent Application publication no. WO 00/27855 (Chiroscience Technology Ltd); X. Zhang, Enantiomer (1999), 4(6), 541; H.Tye, JCS Perkin I, (2000) (3) 275-298; J.M. Brown, Compr. Asymmetric Catal. I-III (1999), 1, 121-182; M.J. Burk, Spec.Chem. (1998) 18(2) 58-59, 62; T. Yamagishi, Organomet. News (1995) (4), 113-118; J.P. Genet, ACS Symp. Ser. (1996) 641 (Reductions in Organic Synthesis), 31-51; H. Kumobayashi, Recl.Trav.Chim.Pays-Bas (1996) 115(4) 201-210; M.J. Burk et al, Pure Appl. Chem. (1996) 68(1) 37-44; H. Takaya et al, Catal. Asymm.Synth. (1993) 1-39; S.Akutagawa, Chirality Ind. (1992) 325-339; A.Borner et al, Transition Met.Org.Synth. (1998) 2 3-13; D.G.Blackmond, CATTECH (1998) 2(1), 17-32; R.Noyori, Acc.Chem.Res. (1997) 30(2) 97-102; W.S.Knowles, Chem.lnd.(Dekker) (1996) 68(Catalysis of Organic Reactions) 141-152; U.Behrens, Spec.Chem.(1996) 16(5) 174, 176-177; R.Noyori, Acta Chem.Scand. (1996) 50(4), 380-390; H.B.Kagan, Mec., Phys., Chim., Astron., (1996) 322(2) 131-143; A.S.C.Chan et al, Chem.lnd.(Dekker) (1994) 53(Catalysis of Organic Reactions) 49-68; K.Inoguchi et al, Synlett (1992) (3) 169-78; G.Webb et al, Catal.Today (1992) 12(2-3) 319-337; D.Arntz et al; Catal.Met.Complexes (1991) 12(Met.Promoted Sel.Org.Synth.) 161-189; K.Harada, Asymmetric Synth. (1985) 5 345-383; and W.S.Knowles, Acc. Chem.Res.(1983) 16(3) 106-112. The person skilled in the art will appreciate that the use of one enantiomer of such chiral catalysts will give one enantiomer (V) or (VI), and use of the other enantiomer will give the other enantiomer. Some of the suitable catalysts may be generically defined by the formula P*-cat-P** wherein "cat" is a metal such as rhodium or ruthenium, and P* and P** each independently represents a chiral phosphine moiety, optionally conjoined. Preferably the catalyst used for reduction of compounds of formula (IV) where R 2 is O - M + , is ruthenium based, such as ruthenium complexes of BINAP and derivatives thereof, such as [( S )-2,2'-bis(diphenylphosphino-1,1'-binaphthyl]chloro( p -cymene)ruthenium chloride. Preferably the catalyst used for reduction of compounds of formula (IV) where R 2 is OH, is rhodium-based, such as Rh-DUPHOS (1,2-bis[(2S,5S)-2,5-diethylphospholano]benzene-(1,5-cyclooctadien)-rhodium (I) tetrafluoroborate) or Rh-Ferrotane (1,1'-bis[(2S,4S)-2,4-diethylphosphetano]ferrocene-(1,5-cyclooctadiene)-rhodium (I) tetrafluoroborate). Suitably the hydrogenation of the acid (IV, R 2 is OH), can be carried out in the presence of a base such as sodium bicarbonate, cyclohexylamine, isopropylamine, t-butylamine, adamantanamine, or (S)-α-methylbenzylamine. The hydrogenation can be carried out on a preformed salt (IV, R 2 is O - M + ). The reaction is suitably carried out in an inert solvent such as an aqueous C 1-3 alcohol e.g. aqueous methanol, or C 1-3 alcohol e.g. methanol. Other suitable inert solvents include, but is not limited to, tetrahydrofuran, ethyl acetate, tert -butyl methyl ether, α, α, α- trifluorotoluene, methylene chloride or toluene. The reaction is carried out optionally at an elevated temperature, under a positive pressure of hydrogen. Suitable temperatures for good yield and selectivity for the ruthenium-catalysed hydrogenation has been found to be approximately 60°C, and for the rhodium-catalysed reactions at approximately 20°C. The skilled chemist will realise that suitable conditions for particular hydrogenations of compounds of formula (IV) can be found by routine modification of those mentioned herein. The invention is illustrated in the following Examples and Preparations section, but is not limited to these illustrations. Preparation 1: 3-(diethoxyphosphoryl)succinic acid 1- tert -butyl ester Triethylphosphonoacetate (12.0Kg, 53.5 mol) was added over 30 minutes to a stirred solution of potassium tert -butoxide (7.20Kg, 64.2 mol) in THF (118 litres), between 0 and 5°C, under nitrogen. The mixture was warmed to 25-30°C where it was stirred for 1 hour and then added over 45 minutes to a solution of tert -butyl bromoacetate (11.5Kg, 59.0 mol) in THF (28 litres), between 0 and 5°C, under nitrogen. The mixture was stirred at 0-5°C for 1 hour and then demineralised water (6.1 litres) and ethanol (30 litres) were added. A solution of potassium hydroxide (4.2Kg, 75.0 mol) in demineralised water (84 litres) was then added over 2 hours, between -5 and 0°C. The mixture was stirred at -10°C for 16 hours and then a solution of citric acid (16.5Kg, 85.8 mol) in demineralised water (32 litres) was added. The mixture was concentrated in vacuo to a volume of 180 litres and then ethyl acetate (90 litres) was added. The organic phase was separated and the aqueous phase was re-extracted with ethyl acetate (30 litres). The combined organic phases were washed with water (30 litres) and then stripped and replaced with cyclohexane by distillation at atmospheric pressure, at a constant volume of 72 litres. tert -Butylmethyl ether (18 litres) was added and the mixture was stirred at 20-25°C for 12 hours and then filtered. The residue was washed with a mixture of cyclohexane (16 litres) and tert -butylmethyl ether (3.6 litres) then dried in vacuo for 16 hours to give the title compound as a colourless solid (10.0Kg, 60% yield, 98% pure by HPLC). 1 H-NMR (CDCl 3 ) δ : 4.20-4.10 (4H, m), 3.49-3.36 (1H, m), 3.00-2.85 (1 H, m), 2.72-2.60 (1H, m), 1.20 (9H, s), 1.37-1.27 (6H, m) Example 1: ( E )-2-[2-( tert -butoxy)-2-oxoethyl]-5-phenyl-2-pentenoic acid A solution of 3-(diethoxyphosphoryl)succinic acid 1- tert- butyl ester (100g, 0.32mol) in THF (300ml) was added dropwise over 15 min to a stirred solution of potassium tert -butoxide (110g, 0.98mol) in THF (300ml), between -10 and -5°C, under nitrogen. The mixture was stirred at -10°C for 15 min and then a solution of hydrocinnamaldehyde (46.8g, 0.35mmol) in THF (100ml) was added dropwise over 15 min, between -13 and -8°C. The mixture was stirred at -10°C for 30 min and then a solution of citric acid (111 g, 0.58mol) in demineralised water (500ml), and ethyl acetate (500ml), were added. The pH was adjusted to pH 4 with aqueous sodium hydroxide solution (50%) and the phases were separated. The aqueous fraction was washed with ethyl acetate (500ml) and the combined organic fractions were washed with saturated sodium bicarbonate solution (500ml), citric acid solution (10%, 500ml) and demineralised water (500ml) and then concentrated in vacuo. The resulting solid was slurried in cyclohexane (470ml) for 1 hour and then the mixture was filtered. The residue was washed with cyclohexane (2x50ml) and dried in vacuo to leave the title compound as a colourless solid (76g, 81 % yield, 99% pure by HPLC). MS : 289 [(M-H)] - 1 H-NMR (CDCl 3 ) δ : 7.33-7.16 (5H, m), 7.05 (1H, br t), 3.20 (2H, s), 2.89 (2H, br t), 2.50 (2H, br dd), 1.41 (9H, s) Example 2: ( R )-2-[2-( tert -butoxy)-2-oxoethyl]-5-phenylpentanoic acid A solution of ( E )-2-[2-( tert -butoxy)-2-oxoethyl]-5-phenyl-2-pentenoic acid (5.8g, 20 mmol) and 1,1'-bis[(2 S ,4 S )-2,4-diethylphosphetano]ferrocene-(1,5-cyclooctadiene)-rhodium (I) tetrafluoroborate (7.4mg, 10µmol) in methanol (10ml) was stirred at 20-25°C for 24 hours, under hydrogen (4 atmospheres, 60p.s.i.). The mixture was then concentrated in vacuo to leave the title compound as a yellow oil (5.8g, 98% conversion, enantiomeric excess=97%, 95% pure by NMR). 1 H-NMR (CDCl 3 ) δ : 7.30-7.17 (5H, m), 2.85-2.78 (1H, m), 2.66-2.58 (3H, m), 2.37 (1 H, br dd), 1.75-1.51 (4H, m), 1.40 (9H, s) Example 3: ( R )-2-[2-( tert -butoxy)-2-oxoethyl]-5-phenylpentanoic acid cyclohexylamine salt A stirred solution of cyclohexylamine (266ml, 2.32 mol), ( E )-2-[2-( tert -butoxy)-2-oxoethyl]-5-phenyl-2-pentenoic acid (688g, 2.37 mol) and [( S )-2,2'-bis(diphenylphosphino-1,1'-binaphthyl]chloro( p -cymene)ruthenium chloride (4.4g, 4.7 mmol) in methanol (6.9 litres) was heated to 60°C, under hydrogen (60p.s.i.), for 47 hours and then allowed to cool to 20-25°C (enantiomeric excess= 88%). The mixture was filtered through a filter aid Celite® and then the solvent was stripped and replaced with acetone by distillation at atmospheric pressure, at a constant volume of 4.2 litres. The resulting suspension was cooled to 20-25°C, stirred for 4 hours and then filtered. The residue was washed with acetone (2x 1 litre) and then dried in vacuo at 45°C for 16 hours to leave the title compound as a colourless solid (590g, 64% yield, enantiomeric excess=98.9%, 97% pure by HPLC). 1 H-NMR (CD 3 OD) δ: 7.23-7.09 (5H, m), 3.05-2.98 (1H, m), 2.64-2.56 (3H, m), 2.53 (1H, dd, J 15.2, 7.2Hz), 2.23 (1H, dd, J 15.2, 7.2Hz), 2.00-1.97, (2H, m), 1.85-1.81 (2H, m), 1.72-1.20 (10H, m), 1.40 (9H, s) Example 4: ( R )-2-[2-( tert -butoxy)-2-oxoethyl]-5-phenylpentanoic acid sodium salt A stirred solution of sodium bicarbonate (28.6g, 0.34 mol), ( E )-2-[2-( tert -butoxy)-2-oxoethyl]-5-phenyl-2-pentenoic acid (100g, 0.34 mol) and [( S )-2,2'-bis(diphenylphosphino-1,1'-binaphthyl]chloro( p -cymene)ruthenium chloride (0.63g, 0.68 mmol) in methanol (750ml) and water (250ml) was heated to 60°C, under hydrogen (60p.s.i.), for 24 hours and then allowed to cool to 20-25°C (enantiomeric excess 87%). The mixture was filtered through a filter aid Celite® and the solvent was stripped and replaced with acetonitrile by distillation at atmospheric pressure, at a constant volume of 500ml. The resulting suspension was cooled to 20-25°C and was stirred for 24 hours, then filtered. The residue was washed with acetonitrile (3x 25ml) and then dried in vacuo at 45°C for 3 hours to leave the title compound as a colourless solid (65g, 61% yield, enantiomeric excess=94.3%, 95% pure by NMR). 1 H-NMR (CD 3 OD) δ : 7.23-7.10 (5H, m), 2.62-2.58 (3H, m), 2.53 (1 H, dd, J 15.2, 7.6Hz), 2.22 (1H, dd, J 15.2, 7.6Hz), 1.74-1.42 (4H, m), 1.40 (9H, s) Example 5: ( E )-2-[2-( tert -butoxy)-2-oxoethyl]-5-cyclohexyl-2-pentenoic acid cyclohexylamine salt Potassium tert -butoxide (20.2g, 0.18mol) was added portionwise over 10 minutes to a solution of 3-(diethoxyphosphoryl)succinic acid 1- tert -butyl ester (25.4g, 82 mmol) in THF (115ml), at 0°C, under nitrogen. The mixture was stirred at 0°C for 40 minutes and then cooled to -20°C. A solution of 3-cyclohexylpropan-1-al (11.5g, 82 mmol in THF (60ml) was added dropwise over 10 minutes between -20 and -10°C, under nitrogen. The mixture was stirred between -20 and -5°C for 3 hours and then aqueous citric acid (10%, 250ml) and ethyl acetate (200ml) was added. The organic phase was separated and the aqueous fraction was washed with ethyl acetate (200ml). The combined organic fractions were washed with saturated sodium bicarbonate solution (2x 100ml), aqueous citric acid solution (10%, 100ml) and demineralised water (100ml) and then concentrated in vacuo. The resulting solid was taken up in ethyl acetate (150ml) and cyclohexylamine (9.4ml, 82 mmol) was added dropwise over 5 minutes at 20-25°C. The mixture was stirred at 20-25°C for 16 hours and then filtered. The residue was dried in vacuo at 40°C for 4 hours to leave the title compound as a colourless solid (21.7g, 67% yield, 95% pure by NMR). 1 H-NMR (CD 3 OD) δ : 6.70 (1H, t, J 7.2Hz), 3.26 (2H, s), 3.10-3.00 (1H, m), 2.76-2.63 (2H, m), 2.19-0.90 (23H, m), 1.41 (9H, s) Example 6: ( R )-2-[2-( tert -butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid A solution of ( E )-2-[2-( tert -butoxy)-2-oxoethyl]-5-cyclohexyl-2-pentenoic acid (0.74g, 2.5 mmol) and 1,1'-bis[(2 S ,4 S )-2,4-diethylphosphetano]ferrocene-(1,5-cyclooctadiene)-rhodium (I) tetrafluoroborate (18mg, 25µmol) in methanol (2.5ml) was stirred at 20-25°C for 24 hours, under hydrogen (4 atmospheres, 60p.s.i.). The mixture was then concentrated in vacuo to leave the title compound as a yellow oil (0.74g, 98% conversion, enantiomeric excess=95%, 95% pure by NMR). 1 H-NMR (CDCl 3 )δ : : 2.82-2.76(1H, m), 2.60(1H, br dd), 2.37(1H, br dd), 1.70-1.60 (6H, m), 1.51-1.30(3H, m), 1.42 (9H, s), 1.23-1.11 (6H, m), 0.96-0.80 (2H, m) Reference Example 7: ( R )-2-[2-( tert -butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid A solution of ( R )-2-[2-( tert -butoxy)-2-oxoethyl]-5-phenylpentanoic acid (2.2g, 7.5mmol) and 5% rhodium on carbon (0.22g) in methanol (220ml) was stirred at 20-25°C, under hydrogen (10 atmospheres, 150p.s.i.) for 24 hours and then filtered through celite. The filtrate was concentrated in vacuo to leave the title compound as an oil (2.0g, 89% yield, 95% pure by NMR). 1 H-NMR (CDCl 3 ) δ : 2.82-2.76 (1H, m), 2.60 (1 H. br dd), 2.37 (1H, br dd), 1.70-1.60 (6H, m), 1.51-1.30 (3H, m), 1.42 (9H, s), 1.23-1.11 (6H, m), 0.96-0.80 (2H, m) Reference Example 8: ( R )-2-[2-( tert -butoxy)-2-oxoethyl]-6-cyclohexylpentanoic acid cyclohexylamine salt ( R )-2-[2-( tert -Butoxy)-2-oxoethyl]-5-phenylpentanoic acid cyclohexylamine salt (691g, 1.77 mol) and ethyl acetate (7.0 litres) were added to an aqueous solution of citric acid (10%, 6.3 litres) and the organic phase was separated, washed with water (7.0 litres) and concentrated in vacuo to a yellow oil. A solution of the oil and 5% rhodium on carbon (51.6g) in methanol (7.0 litres) was stirred at 20-25°C, under hydrogen (10 atmospheres, 150p.s.i.) for 48 hours and then filtered through celite. To the filtrate was added cyclohexylamine (202ml, 1.77 mol) and the methanol solution was stripped and replaced with methylethyl ketone by distillation at atmospheric pressure, to a volume of 5.5 litres. The mixture was allowed to cool to 20-25°C where it was stirred for 48 hours and then filtered. The residue was washed with methylethyl ketone (2x 500ml) and then dried in vacuo at 45°C for 4 hours to leave the title compound as a colourless solid (495g, 71 %yield, 99% pure by HPLC). 1 H-NMR (CD 3 OD) δ: 3.06-2.99 (1H, m), 2.63-2.56 (1H, m), 2.53 (1H, dd, J 15.2, 7.2Hz), 2.23 (1H, dd, J 15.2, 7.2Hz), 2.02-1.97 (2H, m), 1.77-1.15 (21H, m), 1.43 (9H, s), 0.93-0.82 (2H, m) Reference Example 9: ( R )-2-[2-( tert -butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid sodium salt ( R )-2-[2-( tert -Butoxy)-2-oxoethyl]-5-phenylpentanoic acid cyclohexylamine salt (6.8g,17 mmol) and ethyl acetate (100ml) were added to en aqueous solution of citric acid (10%, 100ml) and the organic phase was separated and washed with water (100ml). Iso -propyl alcohol (20ml) and 5% rhodium on alumina (51.6g) were added and the mixture was stirred at 20-25°C, under hydrogen (10 atmospheres,150p.s.i.) for 48 hours and then filtered through celite. To the filtrate was added a solution of sodium hydroxide (0.67g, 17 mmol) in water and the mixture was stripped and replaced with acetonitrile by distillation at atmospheric pressure to a volume of 30ml. The mixture was allowed to cool to 20-25°C and was stirred for 24 hours. The mixture was cooled to 0°C and then filtered. The residue was washed with acetonitrile (2x 10ml) and then dried in vacuo at 45°C for 2 hours to leave the title compound as a colourless solid (3.6g 69% yield, 95% pure by NMR). 1 H-NMR (CD 3 OD) δ: 2.62-2.57 (1H, m), 2.53 (1H, dd, J 14.8, 7.2Hz), 2.23 (1H, dd, J 14.8, 7.2Hz), 1.76-1.18 (15H, m), 1.44 (9H, s), 0.93-0.82 (2H, m) Preparation 2: Sodium 1-hydroxy-3-(2-methyl-1,1'-biphenyl-4-yl)-1-propanesulfonate A stirred solution of 4-bromo-2-methyl-1,1'-biphenyl (20g, 81mmol), allyl alcohol (14ml, 0.20mol), tetrabutylammonium chloride (22g, 81mmol), sodium bicarbonate (17g, 0.20mol), palladium(II)acetate (0.91g, 4.0mmol) and tri- o -tolylphosphine (2.5g, 8.1mmol) in acetonitrile (200ml) was heated to reflux for 1 hour, under nitrogen, and then cooled. Ethyl acetate (200ml) was added and the mixture was washed with water (2x200ml), aqueous citric acid solution (10%, 100ml) and brine (100ml). Magnesium sulphate (20g) and charcoal (2g) were added and the mixture was filtered and concentrated in vacuo to an oil. The oil was taken up in methanol (100ml) and a solution of sodium metabisulfite (11.2g) in water (20ml) was added dropwise, over 10 min. The resulting mixture was stirred at 20-25°C for 16 hours and then filtered. The residue was washed with ethyl acetate (3x20ml) and dried in vacuo to leave the title compound as a solid (15.9g, 42% yield, 95% pure by NMR). 1 H-NMR (DMSO) δ : 7.49-7.30 (5H, m), 7.11-7.04 (3H, m), 5.26 (1H, br d), 3.84-3.78 (1H, m), 2.81-2.70 (1H, m), 2.20 (3H, s), 2.12-1.99 (1H, m), 1.85-1.74 (1H, m) Example 10: ( E )-2-[2-( tert -butoxy)-2-oxoethyl]-5-(2-methyl-1.1'-biphenyl-4-yl)-2-pentenoic acid cyclohexylamine salt A solution of potassium tert -butoxide (6.6Kg, 59 mol) in THF (22 litres) was added over 1 hour to a stirred solution of sodium 1-hydroxy-3-(2-methyl-1,1'-biphenyl-4-yl)-1-propanesulfonate (4.55Kg, 13.8 mol) and 3-(diethoxyphosphoryl)succinic acid 1- tert -butyl ester (4.94Kg, 15.9 mol) in THF (5.2 litres) and tert -butanol (18.3 litres), from -5 to 0°C, under nitrogen. The mixture was stirred from -5 to 0°C for 4 hours and then a solution of citric acid (12.0Kg, 62 mol) in demineralised water (28 litres) was added in one portion. The pH was adjusted to pH4-5 by the addition of aqueous sodium hydroxide solution (40%) and the organic phase was separated. The organic phase was concentrated in vacuo to a volume of approximately 25 litres and then recombined with the aqueous phase. Ethyl acetate (28 litres) was added and the organic phase was separated and then washed with a solution of sodium bicarbonate (3.18Kg) in demineralised water (45 litres). Demineralised water (15 litres) was added and the pH was adjusted to pH 4-5 by the addition of a solution of citric acid (2.27Kg) in demineralised water (23 litres). The organic phase was separated, washed with demineralised water (14 litres) and then azeotropically dried by distillation at atmospheric pressure at a constant volume of 56 litres. The reaction was cooled to 35 to 40°C and cyclohexylamine (1.10Kg, 11.1 mol) was added in one portion. The mixture was cooled to 20-25°C and was stirred for 18 hours. The mixture was then cooled to 0°C, and was stirred for 2 hours and then filtered. The residue was washed with ethyl acetate (5 litres), then dried in vacuo at 40-45°C to leave the title compound as a colourless solid (4.1 Kg, 61% yield, 89% pure by HPLC). 1 H-NMR (CDCl 3 ) δ: 7.42-7.30 (5H, m), 7.16 (1H, d, J 7.6Hz), 7.15-7.05 (2H, m), 6.83 (1H, t, J 7.2Hz), 3.29 (2H, s), 2.50-2.43 (2H, m), 2.26 3H, s), 2.03-1.98 (2H, m), 1.78-1.71 (2H, m), 1.61-1.57 (1H, m), 1.44 (9H, s), 1.30-1.10 (5H, m) Example 11: ( E )-2-[2-( tert -butoxy)-2-oxoethyl]-5-(2-methyl-1,1'-biphenyl-4-yl)-2-pentenoic acid adamantanamine salt A solution of potassium phosphate tribasic (160g, 0.762 moles) in demineralised water (500ml) was added over 15 minutes to a stirred slurry of sodium 1-hydroxy-3-(2-methyl-1,1'-biphenyl-4-yl)-1-propanesulfonate (125g, 0.381 moles) in toluene (1500ml) and demineralised water (1000ml). The mixture was stirred at 20-25°C for 16 hours. The organic phase was separated and the aqueous phase was extracted with toluene (100ml). The combined organic extracts were washed with demineralised water (1000ml), and the solution was azeotropically dried by distillation of toluene at 40°C under reduced pressure. The volume of solution was reduced to 250ml, and allowed to cool to 20-25°C. Meanwhile, 3-(diethoxyphosphoryl)succinic acid 1- tert -butyl ester (112g, 0.360moles) was added portionwise over 10 minutes to a solution of sodium tert -butoxide (114g, 1.175moles) in toluene (1120ml) at -10°C under nitrogen. The mixture was stirred for 30 minutes at -10°C. The toluene solution prepared previously was added over 45 minutes between -10°C and 0°C. The mixture was stirred at -10°C for 1 hour and aqueous citric acid solution (10%w/v, 1000ml) was added. The biphasic mixture was stirred at 20-25°C for 16 hours. The organic phase was separated and washed with demineralised water (1000ml). The organic phase was azeotropically dried by distillation at 40°C under reduced pressure at a constant volume of 1330ml. The solution was maintained at 40-45°C, and a solution of adamantanamine (53g, 0.350moles) in toluene (665ml) was added in one portion. The mixture was cooled to 20-25°C, and was stirred for 16 hours. The precipitate was collected by filtration, washed with toluene (150ml) and dried in vacuo at 50°C to leave the title compound as a colourless solid (153g, 76% yield). 1 H-NMR (CDCl 3 ) δ: 7.42-7.05 (8H, m), 6.91 (1H, t, J 7.2Hz), 3.29 (2H, s), 2.79-2.71 (2H, m), 2.52-2.43 (2H, m), 2.25 (3H, s),2.08 (3H, s), 1.81 (6H s), 1.65 (6H s), 1.42 (9H, s), Example 12: ( E )-2-[2-( tert -butoxy)-2-oxoethyl]-5-(2-methyl-1,1'-biphenyl-4-yl)-2-pentenoic acid sodium salt A solution of potassium tert- butoxide (7.25g, 64.6mmol) in THF (24ml) was added over 1 hour to a stirred solution of sodium 1-hydroxy-3-(2-methyl-1,1'-biphenyl-4-yl)-1-propanesulfonate (5.0g, 15.2mmol) and 3-(diethoxyphosphoryl)succinic acid 1- tert- butyl ester (5.5g, 17.7mmol) in THF (6ml) and tert -butanol (30ml), between -5 and 0°C, under nitrogen. The mixture was stirred between -5 and 0°C for 4 hours and then a solution of citric acid (13.2g) in demineralised water (132ml) was added in one portion. The pH was adjusted to pH4-5 by the addition of aqueous sodium hydroxide solution (40%) and the organic phase was separated. The organic phase was concentrated in vacuo and then recombined with the aqueous phase. Ethyl acetate (55ml) was added and the organic phase was separated and then washed with a solution of sodium bicarbonate (3.5g) in demineralised water (50ml). The organic phase was separated and washed with citric acid (5.0g) in demineralised water (50ml), demineralised water (50ml) and then concentrated in vacuo to an orange oil. The oil was taken up in acetonitrile (30ml) and a solution of sodium bicarbonate (0.65g, 4.1mmol) in demineralised water (5ml) was added. The solution was azeotropically dried by distillation at a constant volume of acetonitrile and the mixture was granulated at 20-25°C overnight. The mixture was filtered and the residue dried in vacuo at 45°C to give the title compound as a white solid (2.6g, 43% yield, 95% pure by NMR). 1 H-NMR (CDCl 3 ) δ: 7.38-7.21 (5H, m), 7.10 (1H, d, J 7.6Hz), 7.05 (1H, s), 7.02(1H, d J 7.2Hz), 6.89 (1H, t, J 7.2Hz), 3.30 (2H, s), 2.70-2.65 (2H, m), 2.47-2.41 (2H, m), 2.19 (3H, s), 1.40 (9H, s). Example 13: ( R )-2-[2-( tert -butoxy)-2-oxoethyl]-5-(2-methyl-1,1'-biphenyl-4-yl)-pentanoic acid A solution of ( E )-2-[2-( tert -butoxy)-2-oxoethyl]-5-(2-methyl-1,1'-biphenyl-4-yl)-2-pentenoic acid (3.8g, 10 mmol) and 1,1'-bis[(2 S ,4 S )-2,4-diethylphosphetano]ferrocene-(1,5-cyclooctadiene)-rhodium (I) tetrafluoroborate (7.8mg, 10µmol) in methanol (10ml) was stirred at 20-25°C for 24 hours, under hydrogen (60p.s.i.). The mixture was then concentrated in vacuo to leave the title compound as a yellow oil (3.8g, 98% conversion, enantiomeric excess=95%, 95% pure by NMR). 1 H-NMR (CDCl 3 ) δ : 7.42-7.30 (5H, m), 7.18-7.03 (3H, m), 2.94-2.82 (1H, m), 2.70-2.62 (3H, m), 2.41 (1H, br dd), 2.23 (3H, s), 1.80-1.59 (4H, m), 1.43 (9H, s) Example 14: ( R )-2-[2-( tert -butoxy)-2-oxoethyl]-5-(2-methyl-1,1'-biphenyl-4-yl)-pentanoic acid cyclohexylamine salt A stirred solution of ( E )-2-[2-( tert -butoxy)-2-oxoethyl]-5-(2-methyl-1,1'-biphenyl-4-yl)-2-pentenoic acid cyclohexylamine salt (1.1Kg, 2.3 mol) and [( S )-2,2'-bis(diphenylphosphino-1,1'-binaphthyl]chloro( p -cymene)ruthenium chloride (2.2g, 2.4 mmol) in methanol (8.2 litres) and water (2.8 litres) was heated to 60°C, under hydrogen (60p.s.i.), for 40 hours and then allowed to cool to 20-25°C (enantiomeric excess= 88%). The mixture was concentrated in vacuo to a volume of 3 litres and then ethyl acetate (5 litres) was added. The mixture was distilled at constant volume of ethyl acetate until water droplets appeared in the distillate. The mixture was then cooled to 20-25°C and then demineralised water (2.9 litres) and citric acid (485g, 2.5 mol) were added. The organic phase was separated and washed with demineralised water (1.1 litre) and then dried azeotropically by distillation at a constant volume of 8.25 litres. Methylethyl ketone (8.25 litres) was added and the mixture was warmed to 40°C. Cyclohexylamine (228g, 2.28mol) was added in one portion and the mixture was allowed to cool to 20-25°C, then was stirred for 16 hours. The mixture was filtered and the residue was washed with a mixture of ethyl acetate (55ml) and methylethyl ketone (55ml) and then dried in vacuo at 45°C to leave the title compound as a colourless solid (0.71 Kg, 65% yield, enantiomeric excess=98.6%, 99% pure by HPLC). 1 H-NMR (CDCl 3 ) δ : 7.42-7.25 (5H, m), 7.11 (1H, d, J 7.6Hz), 7.08-7.00 (2H, m), 2.90-2.82 (1H, m), 2.67-2.58 (4H, m), 2.30 (1H, br dd), 2.23 (3H, s), 2.00-1.86 (2H, m), 1.80-1.50 (7H, m), 1.41 (9H, s), 1.38-1.09 (5H, m) Example 15: ( R )-2-[2-( tert -butoxy)-2-oxoethyl]-5-(2-methyl-1,1'-biphenyl-4-yl)-pentanoic acid ( S )- alpha -methylbenzylamine salt ( R )-2-[2-( tert -butoxy)-2-oxoethyl]-5-(2-methyl-1,1'-biphenyl-4-yl)-pentanoic acid can be enantiomerically upgraded as the ( S )- alpha -methylbenzylamine salt. Thus, ( R )-2-[2-( tert -butoxy)-2-oxoethyl]-5-(2-methyl-1,1'-biphenyl-4-yl)-pentanoic acid cyclohexylamine salt (50g, 0.10 mol, enantiomeric excess= 72%) was partitioned between ethyl acetate (750ml) and aqueous citric acid solution (10%, 750ml). The organic phase was separated, washed with water (500ml), then azeotropically dried by distillation at constant volume. ( S )- alpha -methylbenzylamine (13.2ml, 0.10 mol) was added dropwise over 5 min at 40°C, the mixture was allowed to cool to 20-25°C, and was then stirred for 24 hours. The mixture was filtered and the residue was washed with ethyl acetate (100ml) and then dried in vacuo ) at 45°C for 2 hours to leave the title compound as a colourless solid (41.0g, 91% yield, enantiomeric excess= 96.4%, 95% pure by NMR). 1 H-NMR (CDCl 3 ) δ : 7.40-7.22 (10H, m), 7.12 (1H, d, J 7.6Hz), 7.06-7.02 (2H, m), 4.22-4.18 (1H, m), 2.80-2.76 (1H, m), 2.63-2.59 (3H, m), 2.34 (1H, dd, J 16.4, 5.6Hz), 2.24 (3H, s), 1.77-1.70 (3H, m), 1.61-1.56 (1H, m), 1.47 (3H, d, J 6.8Hz), 1.40 (9H, s)

Claims: A process for the preparation of a compound of the formula (IV), (V) or (VI): wherein R is aryl, C 3-8 cycloalkyl, C 1-10 alkyl, (aryl)C 1-10 alkylene, (C 3-8 cycloalkyl)C 1-10 alkylene, heterocyclyl, (heterocyclyl)C 1-10 alkylene, (aryl)C 3-8 cycloalkylene, (C 3-8 cycloalkyl)arylene or (C 1-10 alkylaryl)C 1-10 alkylene, wherein "aryl" is a mono- or bicyclic partially or fully unsaturated carbocyclic ring system containing from 4 to 10 atoms, or a partially or fully unsaturated mono- or bicyclic heterocyclic moiety having up to 10 atoms in the ring system and with up to 4 hetero-atoms in the said ring system each independently selected from N, O and S, said carbocyclic ring system and heterocyclic moiety being optionally substituted by one or more substituents each independently selected from halogen, NO 2 , NH 2 , CO 2 R 9 , phenyl, C 1-6 alkyl(optionally substituted by one or more halogen), and C 1-6 alkoxy(optionally substituted by one or more halogen), and "heterocyclyl" is a 3- to 8-membered mono or bicyclic saturated heterocyclic group having from 1 to 4 ring hetero-atoms each independently selected from N, O and S, optionally substituted by one or more substituents each independently selected from halogen, NO 2 , NH 2 , CO 2 R 9 , phenyl, C 1-6 alkyl(optionally substituted by one or more halogen), and C 1-6 alkoxy(optionally substituted by one or more halogen); R 1 is C 1-6 alkoxy; R 2 is OH or O - M + ; R 9 is H or C 1-6 alkyl; and M + is the cation of a metal or is a protonated amine moiety; which comprises: formation of a compound of formula (IV) as defined above, by reaction of an aldehyde of formula RCHO, or a protected derivative thereof or adduct thereof, wherein R is as defined above, with a phosphorus compound of formula (IX): or a metal carboxylate salt thereof, wherein R 1 is as defined above, and "P" is a phosphonate moiety of formula -P(O)(OR 3 )(OR 4 ), wherein R 3 and R 4 are either each independently selected from H, C 1-6 alkyl, benzyl and phenyl (optionally substituted by one or more C 1-6 alkyl), or R 3 and R 4 taken together are C 2-5 alkylene, or "P" is a phosphorane moiety of formula -(PR 5 R 6 R 7 ) + X - wherein R 5 , R 6 and R 7 are each independently selected from C 1-6 alkyl and phenyl, and X is bromine, chlorine or iodine, in the presence of a sodium, lithium or potassium C 1 -C 6 alkoxide base, in an inert solvent, and at a temperature of from -80°C to 20°C, said process being optionally followed by conversion of the product of formula (IV) where R 2 is O - M + wherein M + is a metal to a compound of formula (IV) where R 2 is OH by treatment with a proton source, which may optionally be converted to a compound of formula (IV) wherein R 2 is O - M + (where M + is a protonated amine moiety as previously defined), by treatment with a corresponding amine, optionally followed by, if a compound of formula (V) or (VI) is desired, asymmetric reduction of a compound of formula (IV) to provide a compound of formula (V) or (VI) with the proviso that R 3 and R 4 are not simultaneously ethyl when R is -(CH 2 ) 2 -C 6 H 5 and R 1 is t-butoxy. A process according to claim 1 wherein the olefination is carried out in a reaction time of less than 24 hours. A process according to claim 1 or 2, where R is (aryl)C 1-10 alkylene or (C 3-8 cycloalkyl)C 1-10 alkylene. A process according to claim 3, where R is phenylethyl, cyclohexylethyl or (2-methyl-1,1'-biphenyl-4-yl)ethyl. A process according to any preceding claim, where R 1 is t-butoxy. A process according to any preceding claim, where R 2 is OH, O - Li + , O - Na + , O - K + , O - cyclohexylammonium + , O - adamantanammonium + , O - triethanolammonium + or O - ( S )-α-methylbenzylammonium + . A process according to any preceding claim, where the olefination reaction is carried out using the aldehyde RCHO or the sodium bisulphite adduct thereof RCH(OH)SO 3 - Na + . A process according to any preceding claim, where "P" is P(O)(OC 2 H 5 ) 2 , P(O)(OCH 2 CH 2 O) or a triphenylphosphinium halide moiety. A process according to claim 8, where "P" is P(O)(OC 2 H 5 ) 2 . A process according to claim 1, where the base is potassium t-butoxide, sodium t-butoxide or sodium methoxide. A process according to any preceding claim, where the olefination reaction solvent is anhydrous tetrahydrofuran, anhydrous toluene or anhydrous R 1 H, or a mixture thereof. A process according to claim 11, where the reaction solvent is selected from tetrahydrofuran and toluene when the aldehyde RCHO is used as a substrate, and selected from tetrahydrofuran, t-butanol and toluene when the bisulphite adduct is used as substrate. A process according to any preceding claim, where the olefination reaction is carried out at a temperature of from -20°C to 10°C. A process according to claim 13, where the reaction is carried out at a temperature of from -10°C to 10°C. A process according to claim 14, where the reaction is carried out at a temperature of from 0°C to 5°C. A process according to claim 1, where in the olefination reaction, the aldehyde RCHO is used as substrate, and the reaction is carried out by adding the phosphorus compound to the base and solvent mixture, followed by addition of the aldehyde. A process according to claim 1, where in the olefination reaction, the aldehyde RCHO is used as substrate, and the reaction is carried out by combining the phosphorus compound and the aldehyde, followed by addition of the base. A process according to claim 1, where in the olefination reaction, the aldehyde RCHO is used as substrate, and the reaction is carried out by adding the base to the phosphorus compound followed by addition of the aldehyde. A process according to claim 1, where in the olefination reaction, the bisulphite is used as the substrate, and the reaction is carried out by adding the base to a mixture of the bisulphite adduct and the phosphorus compound. A process according to claim 1, where in the olefination reaction, the bisulphite is used as the substrate, and the reaction is carried out by adding the bisulphite to a mixture of the phosphorus compound and the base. A process according to claim 1 for the preparation of a compound of formula (V) or (VI) which comprises the asymmetric hydrogenation of compounds of the formula (IV) as defined in claim 1. A process according to claim 1 or claim 21, where the catalyst used for reduction of compounds of formula (IV) where R 2 is O - M + , is ruthenium based. A process according to claim 1 or claim 22, where the catalyst used is a ruthenium complex of BINAP or a derivative thereof. A process according to claim 1 or claim 23, where the catalyst used is [( S )-2,2'-bis(diphenylphosphino-1,1'-binaphthyl]chloro( p -cymene)ruthenium chloride. A process according to claim 1 or claim 21, where the catalyst used for reduction of compounds of formula (IV) where R 2 is OH, is rhodium-based. A process according to claim 1 or claim 25, where the catalyst used is Rh-DUPHOS (1,2-bis[(2S,5S)-2,5-diethylphospholano]benzene-(1,5-cyclooctadien)-rhodium (I) tetrafluoroborate), or Rh-Ferrotane (1,1'-bis[(2S,4S)-2,4-diethylphosphetano]ferrocene-(1,5-cyclooctadiene)-rhodium (I) tetrafluoroborate). A process according to claim 1 or claim 21, where the hydrogenation of the acid (IV, R 2 is OH) is carried out in the presence of a base. A process according to claim 27, where the base is sodium bicarbonate, cyclohexylamine, isopropylamine, t-butylamine, adamantanamine or (S)-α-methylbenzylamine. A process according to claim 1 or claim 21, where the hydrogenation can be carried out on a preformed salt (IV, R 2 is O - M + ). A process according to claim 1 or claim 21, where the hydrogenation is carried out in an inert solvent, under a positive pressure of hydrogen. A process according to claim 30, wherein the solvent is an aqueous C 1-3 alcohol or a C 1-3 alcohol. A process according to claim 1 or claim 21, where the reaction is carried out with a ruthenium-based catalyst and the reaction temperature is approximately 60°C. A process according to claim 1 or claim 21, where the reaction is carried out with a rhodium-based catalyst and the reaction temperature is approximately 20°C.

Inventors: DERRICK ANDREW MICHAEL, THOMSON NICHOLAS MURRAY, DERRICK, ANDREW MICHAEL, THOMSON, NICHOLAS MURRAY
Applicants: PFIZER, PFIZER LTD, PFIZER INC., PFIZER LIMITED
Application year: 2001
Main classification: C07C67
IPC codes: C07B61, C07C67, C07C69, C07B53, C07C51, C07F1