Title of Invention

"A PROCESS FOR PREPARING A SECOND COMPOUND STEREO-SELECTIVELY"

Abstract

A process for preparing a second compound stereo-selectively which process comprises reacting a substrate comprising at least one first compound with a reagent in the presence of a biological catalyst and a solvent comprising at least one (hydro) fluorocarbon which is conducted in the presence of water at a level which is less than that required for the water to form a separate aqueous phase in the reaction system.

Full Text

PROCESS FOR STEREO-SELECTIVE PREPARATION OF CHEMICAL COMPOUNDS EitJROFLTJOEOCX&BOH SOLVENTS The present invention relates to a process for preparing a second compound 'by catalytic'conversion1 'bf "a"first compound;'•'- More particularly, -the invention relates to a process for stereo-selectively preparing a second compound by reacting a substrate comprising a first compound with a reagent in the presence of a biological catalyst ' Catalysts are materials that act to increase the rates of reactions without themselves being consumed" by the reaction. Enzymes are natural catalysts that in many cases are sufficiently effective to .reduce reaction activation, energies to the point where the reaction becomes diffusion limited. An outstanding feature of enzyme catalysis is the observed substratespecificity, which determines biological function". Some enzymes ntijise onlyone-biological-substrate-and-are-said--to- -exhibit-ubstrate specificity. For example, glucolcinase will catalyse the transfer of phosphate from ATP to glucose but to no other sugar. • Other enzymes display much broader substrate specificity and are- able to utilise structurally related molecules which are often dissimilar to their natural substrates. These enzymes are said to exhibit relative group specificity. An example of this kind of enzyme is Candida cylindracea (C. cylindracea) lipase which will, catalyse a transesterification reaction between a variety of acyl donors and acjrl acceptors. In addition to chemical specificity, enzymes also exhibit stereo chemical specificity. • The International Union of Biochemistry has classified enzymes into six . categories according to the type of reaction .that they catalyse. Oxidoreductases catalyse oxidation and reduction reactions. More particularly, they catalyse the oxygenation of C-H, C-C and C=C bonds and th.e removal or addition of H atom equivalents.,Transferases catalyse the transfer; of various groups such as aldehyde, ketone, acyl, sugar, phosphoryl or methyl groups. Hydrolases catalyse the formation of, inter alia, esters, amides, lactones, Lyases catalyse the addition-elimination 'of small molecules onto C=C, C~N and C—0 .bonds. Isomarases catalyse isoiner'isation. reactionssuch .as- racemisations • and epirnerisations. Ligases catalyse the formation and cleavage of, C-O, C-S, C-N and- C-C bonds with concomitant triphosphate cleavage. In nature, some enzymes function within or at the lipid layer within a cell membrane. The lipases., for example., are active at the water-lipid interface. The lipid layer provides a non-aqueous and non-polar environment for the working enzyme. catalysts are also used commercially in a number of processes in order to' make use of their stereo-eelectively. For example, enzymes of the liydrolase class (proteases and lipases) are used commercially for the resolution of racemic mixtures of secondary alcohols and. carboxylic acids, in the conversion of prochrral and centrosynimetiic compounds into chiral compounds and in the desyinmetrisation of msso compounds. The enzymes operate most -effectively -in -non-polar-organic solvents, such as hexane. Increasing the polarity of the solvent tends to result in a rapid deactivation of the enzyme and/or a greatly reduced reaction rate. It would be desirable to improve upon the commercial enzyme catalysed processes by improving the reaction rate, selectivity and/or conversion to ™proaifc3rif wo13d dissolve a wide range of reaction substrates, which mitigates the . deactivation of the enzyme during the -reaction and which allows a given enzyme to be utilised effectively across a wide range of substrates. ha'particular, there'is: a heed for' an enzyme catalysed process that can- efficiently than the known processes that are in commercial use.toda.}'. According to the present invention, there is provided a. process for preparing a second compound stereo-selectively which process comprises reacting a starting material or substrate comprising at least one first compound with a reagent in the presence of a biological catalyst and a solvent comprising at least one (hydro)fliiorocarbon. The process of the present invention converts the at least one first compound, which xna}', for example, be ah achiral compound, a racemic mixture of compounds, an enaiitiomerically pure substance, a meso compound, a prochiral compound or a centros3^nnietric compound., into a particular chiral second compound or compounds stereo-selectively. By this we mean that the first compound), although capable, in principle, of reacting to form a mixture of stereoisomers, reacts preferentially or selectively under the influence .of , the. .biological -.catalyst toyield predominantly and preferably exclusively one euantionier. Li particular, we are referring to a process that yields one particular enantiomer predominantly and preferably exclusively. More particularly., the conversion of the starting material or substrate is such that the desired enantiornar is formed at an enantiomeric excess of greater than 50 %, more preferably of The process of the present invention can provide for good conversions, of. . the first compoxmd(s) to the second compound(s) at high stereo-selectivities,. "'Tli'e'corlversi'ons'aiiH' stereo-selectivities may be better than are obtainable in the known '..commercial processes.. . that use conventional hydro-carbon-' " "solventssuchas- hexane; F-uirheraibre, theprocess 'may_prqceed It rate than processes conducted in conventional hydrocarbon solvents. It is also believed that the (hydro)fluorocarb'on solvent that is used in the present process may result in less degradation of the biological catalyst thanwhen the . same reaction is conducted using conventional hydrocarbon, solvents such as hexane. This, in turn, could allow a continuous process to be run for a longer period of time before changing the catalyst or in a batch process could allow the catalyst to be re-used a greater number of times. The process of the present invention is conducted in the presence of a solvent mat comprises at least one (hydro)fluorocarbon. By the term "(hydro)fluorocarbon" we mean a compound selected from the. group consisting of the hydrofluorocarbons and the perfluorocaibons. By the term "hydrofluorocarbou" we mean a compound which contains only carbon, hydrogen and fluorine atoms. Hydrofiuorocarbon solvents are preferred. The solvent is usually in the liquid state, although we do not discount the use of supercritical fluids. Where the solvent comprises one or more low boiling compounds which are gases at room temperature, the desired liquid state may be attained by cooling the solvent to a suitably low temperature and/or by subjecting it to super-atmospheric pressures at some point in the the (hydro)fluorocarbon solvent is mixed with the substrate to be reacted and, if necessary, continuously during the pro cess. Suitable (hydro)fluorocarbons may be selected from the CW05 particularly tlie and especially theC Xhydrojfluorocsrbons. Preferred perfluorocarbons include hexafluoroethane (R-116) and octafluoropropane (R-218). Preferred hydrofluorocarbons are selected from the , particularly the and especially the "C hydrofluoroallcaii.es. Suitable Cw hydroiluoroalkanes include Irydrofluororaetbanes, such as trifhioromethane (R-23), fluoromethaue (R-41) and difluoromethaue (R-32); hydrofluoroetbanes, such as pentafluoroethane (R-125), 1,1,1- tiifluoroethane (R-143a), 1,1,2,2-tetofluoroethane (R-134), 1,1,1,2- tetrafluorpethane (R-134a) and 1,1-difluoro ethane (R-152a); hydrofluoropropanes, such as 1,1,1.,3,3-pentailuoropropane (R-245fa), 1.1.2,2,3-pentafluoropropane (R-245ca),pentafluoropropane (R245eb), 1,1,2,3,3-pentafluoropropane (R-245ea), 1,1,1,2,3,3- hexafiuoropropane (R-236ea), 1,1,1,2,2,3-hexafluoropropane (R-236"cb), 1, 1,1,3,3,3-hexaflucttopropaiie (R-236fa)3 I3l,l3233,3heptafluoropropaiie (R-22.7ea). and. ....... 1,1,1,2,2,3,3-hepfeifluoropropane- ' • (R-227ca); 'aid' hydrofluorobutanes, such as 1,1,1,3,3-pentafluorobutaue (R-356mfc). The preferred hydrofluorocarbons are R-32, R-134a, R-134, R-152a, R-143a, R- 125, R-245fa, R-236ea and R-227ea, which are all low boiling making their removal from' the reaction mixture at the end of the process relatively facile. Of these, R-32 and R-134-a are particularly preferred, with R-134a being the mp.st.preferred.— Solvents containing mixtures of two or more {hydro)flu.orocarbons may.be.. used if desired. The solvent which, is' used in the process of the-present invention 'may also nse-an':brgaiiicxo-solve Suitable co-solvents include, inter alia, fluorine free and. more particularly halogen free compounds. Suitable halogen free co-solvents will typically have a 'boiling point of 200°C or below, for example in the range of from -85 Co 200°C. The. preferred co-solvents have a. boiling point of 120°C or below, for example iu the range of from -85 to 120°C, more preferably 100°C or below, for example in the range of from -70 to lOO'C, and particularly 10°C or below, for example in the range of from -60 to 10-°C. • Mixtures of two or more co-solvents may be used if desired. Suitable co-solvents may be selected from the C2.6, particularly the hydrocarbon compounds by which we mean compounds containing only carbon and hydrogen atoms. Suitable hydrocarbons include the alkanes and cycloallcanes, with alkanes such as ethane, n-propane, i-propane, n-butane, • butane and n-pentane being preferred. Other suitable co-solvents include the hydrocarbon ethers, by which we mean compounds having the formula R'-O-R2 in which R1 and R2 are independently hydrocarbyl groups containing only carbon and hydrogen atoms, such as C;,6 and particularly C).= alley! groups. Suitable dialkyl ethers include dimethyl ether, methyl ethyl ether and diethyl ether. Still further suitable co-solvents may be selected from the amides, sulphoxides, alcohols, ketones, carboxylic acids, cafboxylic acid derivatives, inorganic acids andnitro compounds. Suitable'amide'co-solvents include the N,N'-dialkylarnides 'and alkylarnidesdiinethjdfonnamide-and fonnauiide •Suitable sulphoxide co-solvents include the diaUcylsulphoxides, e.g. dimefhylsulphoxide. Suitable alcohol co-solvents include the aliphatic alcohols, particularly the allcanols. Suitable alkanols may be selected from the Q-g, particularly the Cj-,3 alkanols such as methanoL, etlianol, 1-propanol and 2-propanol. Suitable Icetone co-solvents include the aliphatic ketones, particularly the dialkyl Icetones such as acetone. Suitable carboxj'lic acid co-solvents include formic acid and acetic acid. Suitable caiboxylic acid derivatives for use as co-solvents include the anhydrides, e.g. acetic anhydride, and the C^g, particularly the Ci.3 alley! esters of particularly GU alkanoic acids, e.g. ethyl acetate. Suitable nitro compounds for use as co-solvents include the nitroalkanes and m'troaryl compounds, e.g. nitrometliane-and nitrobenzene. Although not preferred, when an organic co-solvent is used the solvent blend will typically comprise from 80.0 to 99.0 % by 'weight of the .{hyj3rpjfiuoiwarbonand Preferably, the solvent blend will comprise from 90.0 to 99.0 %'by weight of the (nydro)fluorocarbon and from 1 to 10.0 %'by weight of the cosolvent. As the polarity of the co-solvent is increased, it is generally desire of the co-solvent m order to avoid any problems with deac-ti vation, of the enzyme. As water is necessary for the proper functioning of most engines, the process of the present invention will typically be conducted in the presence of at least a small amount of water. However., the amount of water that is used will usually be such that the water does not form a separate phase in the reaction system. This is because an objective of the present process is to have the enzyme function in an environment that is predominantly composed of the (hydro)fiuorocarbon solvent. 'Preferably, the amount of water is kept below the saturation level of the solvent that is used. More preferably, the reaction is conducted in the presence of less than 1 % by weight of water based, on the total weight of the solvent The process of Hie present invention is conducted in the presence of a biologlcal catalyst. By a "biological catalyst15, we mean a catalyst that can be found in biological tissues or systems. Particular biological catalysts for use in the process of -the invention, are. the. enzymes .and .abzynies . The biological catalyst must, of course, be capable of catalysing a stereoselective conversion of the substrate into the second compound, Typically, the process of the present invention will be conducted in the presence of a single catalyst although we do not discount the possibility over Suitable enzymes for use in the present process.may be selected from any of Hie six classes of enzymes which have been identified supra: Ihe enzytiies tnay.be discrete in-the'sense-that they-have been isolated from . bgicaLtissu expression in a host organism. These discrete enzjTnes may be used aj; they are or they -may be lyophilised using standard literature processes, e,g. as described in Fitepatrick, P. A., KHbanov, A, M., J. Am, Cheni. Soc., 1991 113 3166. However, we have found that at least some enzymes are able to function as effectively in a (hydro)fraoro carbon solvent without prior lyqpbilisation, 'therefore offering the potential of avoiding a significant processing step. The enzymes, whether iyophilised or not are usually immobilised using standard literature processes. For example, the enzyme may be immobilised on a solid: insoluble matrix, for example by physical absorption ox bonding. Suitable matrices include, inter alia, glass, diatomaceous earth, silica. and organic polymers such as polystyrene and pofyacrylate homopolymers and copolymers. . Alternatively, the enzymes may be part of a .whole cell culture-suclras'a live cell culture, e.g. Lactobacillus. acidophilus, a resting cell culture, e.g. dried baker's yeast which can be activated by warm 'water or a non-viable cell culture which contains the enzyme and the required cofactor('s), e.g. dead yeast. The whole cell culture containing the .enzyme will usually be immobilised on a solid, insoluble matrix, for example .by physical •absoiption discussed above may be used for this purpose.Preferred enzymes for use in the process of the'present invention include -those in-the-hydro'se"categdir)r"Tafiiciiiar enzymes are the proteases, such as Subtilisin carlsberg and Sub tills in. JBPN, the lipases, such "as Porcine .pancreatic • lipase,. Candida Witarctlca lipase "Pseudpijionafcepacia ""lipase and the glycosidases such as a- and 3-galactosidase from Asperglllus orgzea. Abzynies catalytic antibodies., i.e. antibodies that are capable of catalysing specific.chemical reactions. A suitable abzyme may be aldolase antibody 3 8C2. . The abzym.es could be lyophilised and/or immobilised as discussed supra in. connection with enzymes. The process of the present invention is generally conducted at a temperature which provides for an acceptable rate of reaction and component solubility and. which avoids significant degradation of the biological catalyst, tlie first compouud(s) and the second compouiid(s)/ Typically, the process is conducted at a temperature in the range of from -60 to 120°C, preferably in 'the'range1 of'from-30 to SO°C"arid partieularly irrthe--range--of-from 0-tO" 60°C, for example at about 20°C. The process may "be conducted at atmospheric, sub-atmospliftric, ox superatroospheiic pressures. Hie precise operating pressure will depend, inter alia, on the solvent that is used, particularly its boiluig point Preferred "qppres in the range of from 0.5 to 30 bar and particularly in the range of from 1 to 15 bar. . The weight ratio of the (hydxo)fluorocarbon solvent to the substrate to be •ieacied.isprefexaHy.in the range of from 1:1 io'100'0:l5 more preferably in "lie"range" of ironrlrHo'500:1- and particularly in -the -range-of from---l-:-l---to • 10:1. The biological catalyst is typically used in very small amounts, for example of'the. order of 10~3 to 'KT* 'mole % of catalyst relative to the substrate. The precise amount will depend on the activity of the enzyme. Hie process of the present invention can be usefully applied to -various stereo-selective conversions. -It is particular^ useful for preparing compounds that can be used as intermediates in the manufacture of pharmaceutical compounds. hi one embodiment, the process of the present invention is used to resolve a racemic mixture.or racemic modification by reacting that mixture with, a reagent in the presence of the biological catatyst and (hydro)fluprocarbon • solvent so as to preferentially or selectively react one of the enaatiozners forming the mixture to form a new enantiomeric compound while leaving the other enantiomer largely or completely unreacted. Accordingly, in one embodiment of the present invention there is provided a process of resolving a racernic mixture which process comprises reacting that mixture with a reagent in the presence of a biological catalyst and a solvent comprising at least one (hydro)fluorooarbon so as to preferentially or selectively convert one of the enantiomers forming the racernic mixture into a new enant^nenci.cpjnpound.,_- The racernic mixture that is resolved in accordance with this'embodiment of the present invention may be a racemic mixture of R and S alcohols, R. and - "S-carboxylic-acids' or"esters',' R'lmcfS amino acid esters, R' and S amines, R: • and S thiols or Rand S amides,.Preferably, it is..a-mixture of Rand S amino-' . acid .esters.;..This- particular- res0hiti6n'"ir''er?ec ... selectively transforming a functional group attached to the chiral carbon(s) .of either the R or S- enantiomer. The biological catalyst' is preferably an. enzyrn.e. In a particular embodiment, the process is used to resolve the raoemic N-Pdl- phenylaianine alkyl ester, where P denotes a protecting group, by a transesterification reaction in which the alkoxy group of either the R or S •enantiomer is exchanged preferentially and preferably selectively by reaction with an allcanol that provides a different alkoxy group. Ordinarily, it is the S enantiomer that undergoes the transesterification reaction: The preferred protecting groups are acetyl and trifluoroacetyl and the preferred alkyl ester is propyl ester so that the preferred racemic mixtures are the N13 acetyl-dl-plienylalaiiine propyl esters and the N-trifluoroacctyl-dlphenylalamne propyl esters. The preferred allcanol is methauol. The biological catalyst is preferably an enzyme, more preferably a protease and preferay ' nwir'carerg: ' The molar ratio of the N-P-dl-phen3'lalanine alkyl ester to the allcanol is preferably m the range of from 1:0.1 to 1:100, more prefer ably, in the. range of from 1:1 to 1:50 and particularly in the range of from 1:1 to 1:10. ^J^ea^qu^^ preferably in the range of from- 1 to 36 hours and particularly in the range of torn 1 to 24 hours. • The • preferential/selective traasesterification of the R or S enantiomer (normaiiy &e S oW al®..ester "is'such'that the desiied -enantiomei-is- t3icalJy-iorrned--ai-an-eriariti6rn.eriG.- excess of greater than 50 %, preferably of greater than 70 % and particularly of greater than 90%, e.g. 100%. ' The resolution of the raceiuic N-acetyl-dl-phenylalaiiibe propyl ester using metlianol and assuming a 100 % enantiomeric excess of the S en.antiorrj.er is shown in Equation (1), The resolution of N-trifluoroacetyl-dl-phenylalanine propyl ester using methanol (assuming once again that the S enanu'omer is formed at a 100 %. e&antiomeric excess) would proceed analogously. In another embodiment;, the process--of'the present"iuven'tioa is used to -resolve racemic "1-phenylethaiibj;"fcjy. "a tfanisesfeiificaitioii reaction-in -which1 • the OH group of either the R or S enantiorner is exchanged preferentially and preferably selectively by reaction with a reagent. The reagent that is used is.preferably an acyl donor, e.g. an enol ester, such as a vinyl or • isopropenyl alkanoate, or an allcoxy enol ester. The preferred reagent is vinyl acetate. Ordinarily, it is 'the R enantiomer that undergoes the transesterification. The biological catalyst, is preferably a lipase, for. example Candida antarctica B Lipase. . The molar ratio of the 1-phenylethanol to the acyl donor is preferably in the range of from 1:0.2 to 1:100, more preferably in the range of from 1:1 to 1:50, for example 1:20. . . ' 15 Tlit reaction time is typically in ths range of from .0.1 to 48 hours, preferably in the range of from 1 to 36 hours and particularly in the range of from 1 to 24 hours. The preferential/selective transesterification of the R or S enantiomer (normally the R enantiomer) of the racernic 1-phenylethanol is such that the desired enautiomeris typically formed at an enantioroeric excess of greater than. 50 %, preferably of greater than 70 % and particularly of greater than 90 %, e.g. 100 %. ' The resolution of the racernic 1-phenylethanol using vinyl acetate and assuming a 100 % enantiomeric excess of the R enantiomer is shown in _ Equation ( 2 ) . _ ' _ _ _ (Figure Removed) Equation (2) In another embodiment, the process of the present invention is used to prepare a particular enantiomsr preferentially and preferably selectively from a meso compound by reacting me meso compound with a reagent in the presence of the biological catalyst and (hydi-o)fluorocarboix solvent The reaction of the'meso compound is also termed desymmetrisati.on, because the meso compound, which - is symmetrical by virtue of it being •superimposable.on its mirror image, is converted into an anantiomeric product. Ail enantiomer, of course, cannot be superimposed on its mirror image. is or .Accordingly, in a-further embodiment-of-the present: Mention'there' provided a process - of preparing a particular enantiomer preferentially selectively from a meso compound which process comprises reacting the meso compound with a reagent in the presence of a biological catalyst and a solvent comprising at least one (hydro)fluorocarbon. or transforming a functional group attached to one of the chiral carbons. The meso compound is preferably cis-4-cyclop_enten.e;l,3-diol_and.-the- ' reagent that is used is preferably an acyl donor, e.g. an enol ester, such as a- .vinyl or isopropcnyl--alkauoate, -or'am alko.xy'enoi ester.' The preferred. • reagent • - is -vinyl aceta'ter'.'"H6 wever, other, meso •• compounds' "and' "other' reagents may be used. The biological catalyst is preferably an. enzyme and when the meso compound is cis-4-cyclopentene-l,3-diol3 the enzyme is preferably a lipase and more preferably is Porcine pancreatic lipase, Candida antarctica B lipase or Pseudoinonos c&pacia lipase. The reaction may be conducted in the presence of a hindered amine, particularly a tertiary amine .such as triethylamine,. The presence of the aniine may contribute to faster reaction rates and greater conversions. However, omitting the enzyme can result in 'simpler downstream purification of the crude reaction mixture. The reaction of -meso cis-4-cyclopsntene-i.,3-diol with vinyl acetate proceeds as shown in Equation (3). (Figure Removed)Equation (3) The process is believed to take place in two stages. The first stage is the stereo-selective formation of the enantiomeiic mono-acetate product, i.e.. 3S)-(+)-4'Cyclopentene-ls3-dibl-l-acetatfe • (a)s (IS, 3R)-(-)-4- i-l,3-diol-l -acetate (b) or a mixture of enantiomsrs (a) and (b) •with one'of-the enanriomers being in excess. When Porcine-pancreatic 'Jipas'e, "Candida antarctica'Blipas'&'pf'PseuddmoTias cepacia Jipas~e".i.s'.used . as the enzyme the enantioiner (b) tends to be formed preferentially and often exclusively. hi the second stage, the mono-acetate {a) and/or (b) goes on to .form the diacetate cis-4-cyc].opentene-13-diacetate by reaction • with a. further ' molecule of the -vinyl acetate. The diacetate, of course, is another meso compound- Both of the monoacstate. products are key starting materials' in tlie synthesis of prostaglatidins, prostacydins and throinboxanes. The molar ratio of the cis-4-cyclopentene-l53-diol to the vinyl acetate is preferably in the range of from 1:0.1 to 1:100, more preferably in the range of from 1:1 to 1:50 and particularly in the range of from 1:1 to 1:20. • The reaction time is typically in the range of from 0.1 to 48 hours, preferably in the range of from 1 to 36 hours and particularly in the range of from 1 to 24 hours. • . The reaction of the cis-4-cyclopentene-l,3-diol with the vinyl acetate , noCTay.,., propeeds..^ formed preferentially/selectively (normally (IB, 3R)-(-)-4-cyclopentene-l53-diol-lacetate) is formed at an enantiomeric excess of greater than 50 %} more preferably of greater-than 70 % and-'partioularly of greater than 9_0 %3 e.g..... In yet another embodiment, the process'pf'the present invention is-used to prepare a particular enantiomer preferentially and preferably selectively from a prochiral compound by reacting the prochiral compound with a reagent in the presence of the biological catalyst and (hydro)fluoiocarbon solvent. The reaction of the prochiral compound is also termed desymmetrisation, because an optically-inactive precursor is converted into a less-symmetrical, optically-active product. Accordingly,, in a further embodiment of the present invention there is provided a -process of preparing a .particular enantiomer preferentially or selectively from a prochiral compound which process' comprises reacting the prochiral compound with a reagent in the presence of a biological catalyst and a solvent comprising at least one (hydro)fluorbcarbon. The process is effected by preferentially or selectively converting at least one achiial carbon atom into a chiral carbon atom with four different • functional groups-around the. cbiral centre.,-..... . . . . . . . ...... .,...._.. . . . . . . . The procbiral compound is preferably 2-etlrylprapane-l,3-diol and the reagent that is used is preferably an acyl donor, e.g. an enol ester, such as a •vinyl or isopropenyl alkanoate, or an alkoxy enol ester. The preferred reagent is vinyl acetate. However, other prochiral compounds and other ~ re'ag'&nfs 'may be' iins'e'd:" The biological catalyst is preferably an. enzyme and when the prochiral compound is 2-ethylpropan£-l,3-diol3 the enzyme is preferably a lipase and,' more preferably is Pseudomonas cepacia lipase, The..reaction .of i-efliylpropane-'l^-diol"wtE "vinyl'.TacetaTeVprQcaeds'.""as shown hi Equation (4). . (Figure Removed)Equation (4) . As shown in equation. (4), the pro-chixal 2-ethylpi'opaH.e-l,3-.didl is converted .'firstly to the monoacetate compound l-lrydrox3'-3-acetoxy-2- ethylpropane. This conversion may result in the fonnation of the R 01; S 20 enantiomer exclusively or may result in the formation of a mixture of the two enantiomers with one of the two predominating. When Pseudomonas cepacia lipase is used as the enzyme, the R enantiomer tends to be formed preferentially a n d often exclusively. • • • • • • • • • • • • Thereafter, the monoacetate can. go on to form tie diacetate, 2- ethylpropane-l,3-diacetate, by reaction with a further-molecule of-the vinyl acetate. The triacetate, of course, is also prochiraL -•Both»of--the-mono-aD"etate'prd'du"ctg'"Sre Key"Building blocks in the synthesis of platelet activating factor (as described in Faber, K., Biotransformations in Organic Chemistry, Springer-Verlag, 1997). The molar ratio of the 2-&thylpropaae-i,3-diol to the vinyl acetate is preferably in the range of from 1:0,1 to 1:100, more preferably in the range - of fro'ml:! to" l:50'arid particularly in the range of from 1:1 to 1:10. - - - - - • The reaction time is typically in the range of from 0.1 to 48 hours, preferably in the range of from 1 to 36 hours and particularly in the range of from 1 to 24 hours. • . . The reaction of the 2-erh.ylpropane-l,3-dioI with the vinyl acetate normally proceeds so that the enantiomer that is formed preferentially/selectively . (normally the R enantiomer) is formed at an enantiomeric excess of greater than 50 %, more preferably of greater than 70 % and particularly of greater . than 90 % e.g. 100%. The process of tlie present invention may be operated in baton mode or continuously. Where a (hydro)fhiorocarboii solvent that has a "boiling point below ambient is used, the reaction vessel will typical!}' be a pressure vessel 'that is capable of withstanding elevated pressures. In the batch process, the (hydro)fluorocarbon solvent is removed at the end of the process, e.g. by flash evaporation if the (hydro)fiuorocarbon is a gas at ambient temperatures or by distillation, to yield a crude reaction mixture . •which can then be purified, if required, to isolate the desired second compo'ond(s). In a continuous process, a reactant stream comprising the .. (hydro)fluorocarbon .solvent and the. reactants is conveyed continuously. through a reaction vessel containing the catalyst. Typically, the xeaciant . stream is passed over a bed of immobilised catalyst. The crude reaction '"mixture that exits the reaction vessel is then treated,, e.g.-in a solventevaporator, to remove the (hydro)fiuorocarbon solvent and recover the one or more desired second compounds that -have been formed in the process. The (hydro)fhiorocarbon solvent that has been removed can be condensed and. recycled if desired to minimise solvent infantries. Unreacted starting , material may also be recycled if desired. Where solvent is to be recycled, a suitable recovery system for low boiling point solvents., by which v/e mean solvents having-a boiling point of 25°C or below, e.g. 0°C'or below, comprises an evaporator into which the crude reaction mixture emerging from the process is passed, a compressor fox compressing the vapour generated in the evaporator and a condenser for coolmg-ttie compressed vapour emerging from the compressor. The solvent is removed from the crude reaction mixture in the evaporator by flash evaporation induced by suction from the compressor and the solvent vapour so generated then passes to the compressor, which may be a diaphragm compressor, where it is compressed. ' Froih the compressor, the solvent vapour passes to the condenser where it is cooled and returned to liquid form for recharging to the process or possibly to a solvent reservoir supplying solvent to the process. The condenser, which may take the form of a coiled tube, can be arranged inside the evaporator so that the latent heat of condensation provides at least some of the energy required to evaporate -thesolvent/--" •-'- r"-""" ""' '"""'""" --•""—' A further suitable recovery system for low boiling point solvents comprises • . ' a solvent recycling circuit comprising an evaporator into which, the reaction •• • mixture emerging'from the process is passed and in which the solvent is evaporated and a condenser in ' which the vapour emerging from the. "evaporator is cooled and returned to liquid form -for recharging to the ' process or.possibly to a solvent reservoir supplying solvent to the process. Heating of the evaporator and cooling of the condenser may be carried out independently, but in a preferred embodiment an external heat pump system is used to both heat the evaporator and to cool the condenser. The external heat puinp system comprises an evaporator, a compressor, a condenser and an' expansion valve which are sequentially arranged in a circuit through which a heat transfer fluid is caused to flow. The evaporator of the external • heat pump system, which may take the form of a coiled tube, is arranged inside or around the outside of the condenser of the solvent recycling circuit so that evaporation of the heat transfer fluid in the' evaporator cools the condenser and provides for the condensation of the solvent vapour passing through the solvent recycling circuit. The vapour generated in the evaporator of the external heat pump system is then compressed and passes to the condenser where it condenses and gives off heat The condenser of the external -heat pump system., winch may also take the form of a coiled 'tube./is arranged inside or around the-outside of the evaporator -of the solvent recycling circuit so that the latent heat of condensation associated with the condensation, of the heat transfer fluid provides the heat required to evaporate the solvent passing through the solvent recycling circuit. The condensed heat transfer fluid is then returned through ail expansion valve to tlie evaporator so completing the cycle-in the external heat pump.system. As .an alternative to an external heat pump system, an external circulating heat-transfer fluid may he used to transfer the heat of solvent condensation to the'evaporator vessel to provide heat for solvent evaporation. When the process of the present invention is complete, the oi-ude'"reaction mixture may be subjected t o - a purification step in order-to • isolate-.foe desired product. The pure product may then, be subjected to. one or more further synthetic steps; e.g. ' to yield a pharmaceutical compound. Alternatively, the crude reaction mixture may .be used directly in a furrhei synthesis. Suitable purification techniques include those that are routinely \ised in chemical synthesis such as chromatography, crystallisation and distillation. In the Figures: • . . Figure 1 is a time-course plot for the reactions studied in Example 6. Figure 2 is. a time-course-plot for the Ps&udomonas cepacia catalysed desymmetrisation of cis-4-oyclopeixtene-l.13-diol in R-134a as studied in Example 7. Figure 3 is a time-course-plot for Pseudomonas cepacia catalysed desymmetrisation of cis-4-cyclopentene-1,3-diol in J2.-32 as studied in Example?. ' . Figure 4 is a time-course-plot for Pseudomonas cepacia catalysed iesymmetrisation.--of;--cis-4^bycl'6peiitBiie-l;3-dibT m Il-227ea~"as" studied in 3xample 7. Figure 5 is a time-course-plot for Pseudomonas cepacia catalysed desymmetrisation of cis-4-cyclopentene-i,3-dioI in THF~Bt3N as studied in .Example 1. ••• •••. " " ' Figure 6 is a. time-course-plot for Novozyrn 435 catalysed desyrarnetrisation of ciis-4-cyclopentene-l;3-diol.' in R-134a as studied in Example 7. Figure 7 is a time-course-plot for Novozyrn 435 catalysed desynunetrisation of cis-4-cyclop8ntene-l,3-diol in R-32 as studied in Example 7. Figure 8 is a time-course-plot for Novozym 435 catalysed desyranietrisation of cis-4-cyclopeatene-l,3-diol in R-227ea as studied in Example 7. i Figure 9 is a time-course-plot for Novozym 435 catalysed desymmetrisatiorl of cis-4-cyclopentene-l,3-diol in THF-Et3N as studied in Example 7. Figure 10 is a iime-course-plot for Pseudomonas cepacia catalysed dBsyinnietrisaiiou of cis-4-cyclopenten&-1,3-diol in all four solvents used in Example 7, showing consumption of the diol. Figure 11 is a rime-course-plot for Novozym 435 catalysed desyrometrisatioA of cis-4-cyclopeutene-l:,3-diol in all four solvents 'osed in Example 7, showing consumption of the diol. The present invention is now illustrated but not limited by the following '''"'"^^^^ •'•'-••"•'•••--•••• General Procedures Preparation ofN-trifluoroacefyl-dl-phenylalaninepropyl ester The.racernic N-rrirluoroacetyl-dl-phenylalanine prop}'! ester was prepared 'using the method disclosed by Curphey, T. I, J. Org. Cheazu3 19795 44. 2805-2807 as follows: To an oven dried flask was added phenyl alanrne. The flask was then purged with N2 gas and DMF (solvent)^ diisopropjd ethylamine (1 equivalent) and ethyl tiifluoroacetate (1.25 eq;uivalentB)) were added. The solution was left to stir at 50°C for seventeen hours, then, propyl iodide was added (1.25 equivalents). The solution was left to stir for.a. further 72 hours. The crude product was re-extracted and isolated by column chromatography using gradient erotica. Stalling with 400 nil hexaiie the polarity was gradually increased by adding 300 ml 9:1 liexane-ethyl acetate, then 300 ml 4:1 hexane:ethyl acetate, then 200 ml 3.5:1 hexane:ethyl acetate and finally 200 ml 2:1 hexane:ethyl acetate. The isolated yield was 4.17 g, 28%. The isolated product was then fiuther purified by Kugelrohr distillation followed by recrystallisation from a mixture of peri-oleum spirit and ethyl acetate (9:1 respectively). The purified N-trifluoroacetylTdl-phenylalaiiine propyl ester was a white crystalline solid. Product identity was confirmed by NMR and GC-mass spectroscopy. Preparation of2-ethylpropane-l,3-diol The2-ethylpr.ppane7l,3.-diol. wasprepared =as-follows:'•'•;'•'• To a solution of diethyl ethyl malonate (2.0g, 10.7rnmol) \v&s added a suspension of LiAlH^ (2.5 equivalents) in dry ethanol at 0°C. The reaction mixture was allowed to warm to room temperature with stirring and after 1 hour was refluxed for a further 1 hour. After cooling in an ice bath; 1 ml of .distilled water was added to-the reaction mixture with stilting followed by 1 ml of 2M NaOH solution. The mixture was then filtered, and the filtrate washed with ethyl acetate. The combined washings were evaporated under reduced pressure to leave a yellow oil which, was purified by flash chromatography on silica using 5:1 ethyl acetate:hexane as the solvent. The product was obtained as an oil in 75% yield. Product identity -was confirmed by NMR and GC-mass spectroscopy. R-134a and R-32 were supplied by Ineos Fluor Ltd. and used without further purification. Both solvents were maintained in the liquid state under autogenous pressure by conducting the reaction in standard plastic-coated 10 ml glass aerosol bottles. The enzymes were obtained from Aldrich Chemical Company., Sigma Chemical Company or Pluka Chemical Company and used, without further treatment or after lyophilisation using the procedure described in •fttzpatrick, P:A.;KlibanovyA; M:; J: Am. Chem-Soc- 199VH3-3166.- •- The hydrofluoiocarbons (R-134a, R-32 and R-227ea) were supplied by Ineos Fluor Limited. All other chemicals and solvents were purchased from Aldrich Chemical Company or Sigma Chemical Company and used without further purification. Aerosols were supplied, by Ineos Fluor Limited. Gas chromatograms were recorded using a SMmadzu GC-17a instrument, equipped with an HP SE-54 capillary column (25m x 0.21mm i.d). Crural gas chromatogra'rns' were obtained on a Chronrpaak CP9001 instnrme'iit' fitted with a Chiraldex GTA capillary cohrrnoi (30m x 0.25mm i.d..). Flame ionisation detectors were used in both cases and response factors calibrated for individual substances using standard solutions. The samples that were removed from the reacting mixture were taken up in dichloromethaue solvent and where necessary naphthalene was used as an internal standard Example 1 Subtilisin carlsberg catalysed resolution of racemic Nacerjl- dl-phenylalanme propyl ester In this Example, the resolution of the racemic N-acetyl-dl-phenylalanine propyl ester by converting the S enanriomer of the racemic mixture to the corresponding methyl ester using Subtilisin carlsberg was investigated. The reaction has been explained in greater detail supra. A solution of lOniM N-acetyl-dl-phenylalanine propyl ester and 200mM inethanoLwas prep are d-in-each of t^e! solvents'ibifexaneytetriiHydfbiuraii, and acetonitrile. To 4 ml of each solution was added 4.0mg of lyophilised Subtilisin carlsberg. The resulting suspensions were stirred at room temperature and samples taken periodically for analysis by gas 'chrornatography for both yield and enantiomeric excess. •The .same reaction-was also investigated using R-134a"and R-32 as the solvents. Two mixtures of 10 mM N-acetyl-dl-phenylalanine propyl ester, 200 mM methanol and 4.0 ing of lyophilised Subtilisin carlsberg were prepared in glass aerosol bottles. The aerosol bottles were then capped, the caps crimped in place and a weighed quantity of the liquid iydrofluorocarbon solvent introduced through the aerosol valve from a larger pressure vessel. The resulting suspensions were then stirred magnetically at room temperature and samples of the reaction mixture were taken periodically for analysis by gas chromatography for both yield and enantiomeric excess. The samples were removed by venting a proportion of the reaction mixture through the valve . into a sample vial. The hydrofmorocarbon solvent evaporated in the process to leave the low volatility residue of the reaction mixture in the sample vial. This residue was then taken up into a known quantity of solvent containing an internal standard, if required, for the GC analysis. The reactams and products showed good, solubility in each of the solvents examined. The results are presented in Table I. • (Table Removed) It is clear from Table 1 that R-134a provides a more rapid reaction and greater ultimate conversion than the conventional solvents, such as hexane. Hexane is regarded generally as the best conventional solvent for the process of Example 1. R-32 shows good performance compared to each of acetonitrile and tetrahydrofuran and approaches hexane in the earlier parts of the reaction up to around 1 hour. Both R.-134a and R-32 show excellent enanrioselectivity. ..Example..2,.: Subtilisin^ catlslerg* -catalysed resdltitiotf ' of racemic" Ktrifluoroacetyl- dl-phenylalanme propyl ester Example 1 was repeated using lOinM N-trifluoroacetyl-dl-phenylalanine 'propyl ester instead of N-acetyl-dl-phenylaJaniue propyl ester. This Example was conducted in order to test the sensitivity of the enzyme- . solvent pair towards substrate specificity. The results are presented in Table (Table Removed) It is clear that with the use of the fluoiinated N-protectuig group, R-134a provides a distinct improvement in conversion compared to that obtained in tone. In addition, when the solvent is R-134a, the process appears to continue at an appreciable rate beyond the 72 hours, whilst the rate observed for hexane is considerably lower. This may suggest that R-134a degrades the enzyme to a lesser degree than hexane. This property could allow the enzyme to be re-nsed to a greater degree in hydrofluorocarbon solvents than in the conventional organic solvents with consequent economic benefits. The rate of reaction in tetrahydrofuran in this process is significantly reduced compared to Example 1. This shows that the hydrofluorocarbon solvents, in contrast to conventional solvents of similar polarity such as tetrahydrofuran, may allow the enzymes to function with greater efficacy across a wider range of substrates. Examples Up** catalysed reaction of raeso cis-4~cyclopeitene-i33- diol In this Example, the enzyme catalysed reactions of cis-4-cyclopentene-l 3, diol with vinyl acetate in R-!34a and tetrajiydrofuran using Porcine pancreatic lipate were compared. This reaction has been explained in greater detail supra and results in the preferential formation of one ' particular eaantiomer. The method followed was thai described in Thai! et al., Tetrahedron, 1991, 47, 7569. The diol (L0012g, l.O^nol) and triothylarome (0.070g, O.Trmnol) were added to 0.5g Porcine Pancreatic lipase (PPL) and vinyl acetete (0.600g, 7mmol). 2ml of a solvent was immediately added and the reaction mixture' stirred magnetically at room temperature for a defined time. The reaction using R-I34a was conducted in a glass aerosol bottle using exactly the same ' technique as described in Example 1. Material was removed from the reaction mixture for GC analysis for both yield and enantiomeric excess and the results are presented in Table 3. (Table Removed) Table 3 shows that in the presence of taethylanoine, R~134a is as efficient and selective a solvent as tetraiiydrofaran in the desyminetrisatioii reaction, using Porcine Pancreatic lipase. Tefrahydrofuran. was found by Tlaeil et al, to be the most effective of the conventional non-aqueous solvents. ' • - Example 4 Lipase catalysed reaction of meso cis-4-cyclopentene-l,3-... diol Example 3 was repeated using Pseudomonas cepacia lipase. R-32 was also investigated and this reaction, like the R-1.34a reaction, was conducted in a glass aerosol bottle. For the hydrofhiorocarbon solvents, no tiletliylamrne •was added. The results obtarned are show in. Table 4. (Table Removed) From the results in Table 4, both R-134a and R-32 appear to show a higher degree of selectivity towards the generation of the chiral mono-ester (b) in. the early stages of the reaction than tetrahydro&ran. This is shown by the. considerably higher enantiomeric excess in the products by the 2 hour stage. In addition to this improved selectivity, R-134a and R-32 showed a high degree and rate of conversion in the absence of any added friethylamine,, possibly providing a simpler downstream product isolation and pmification procedure. Example 5 Lipase catalysed reaction of 2-ethylpropane-l,3-dioJ In this Example, the enzyme catalysed reactions of 2-ethylpropane-l,3-diol with vinyl acetate in R-I34a, R-32 and chloroform using Pseudomonas cepacia lipase were investigated. This reaction has been explained in greater detail supra and results in the preferential formation of one particular enantiomei'. : The results that were obtained were compared to literature data obtained in chloroform (as disclosed in Gill ei al., Tetrahedron, 1991, 47, 7569). 1.0 moiol of diol, 3.9roi»ol of vinyl acetate and. 0.01112g of Pseudomonas cepacia lip as e were mb;sd with 2rnl of a solvent and stirred magnetically at room temperature for 19 hours. The reactions using R-134a and R-32 -were conducted IrT'gtass "aerosol 'Bottles" Win»"uexactly'tlie-'saine '•iechrdque'as: desoribed in Example 1. The mixture was sampled and analysed by GC for both yield and enantiomaic excess and the results presented in Table 5. (Table Removed) As with the reactions of Examples 3 and 4, the transformations in R-134a and R-32 clearly show a significantly higher degree of enantioselectMty than that observed in the conventional solvent, chloroform. . .Example 6 Lipase catalysed resolution of racemic I-phenylefclianol In this Example, the resolution of racemic 1-phenylethanol by converting the R enantiomer of the racemic to the corresponding acetate using Candida antarctica B Lipase was investigated. The process was carried out using various hydrofluorocarbon. solvents and using hexane. The reactions using a hydrofluorcarbon as the solvent were conducted as follows: .. Nc.yozym,43-5• (0,-Q095g;-95l units• ^ 10,1V 000' umts/g'(lmi]iobilised Candida antarctica B Lipase)) was added to the l-phertylethanol (0.0620g; 0.5rnmol) and vinyl acetate (O.S609g; lOrnmol) in an aerosol. The aerosol was sealed, and charged with R-134a (6.0500g; 5.00ml), 01R-32 (4.8000g; 5.00ml), or R-227ea (6.93OOOg; 5.00ral). The reaction was stirred magnetically at room temperature (about -20'C). Samples were abstracted periodically by . inversion of the aerosol and depression of the valve causing expulsion of a small volume (about 50ul) of the reaction solution into a glass vial. The sample, was then dissolved in dichloromethane (O.lml) and analysed by gas chromatography. The reaction using hexane as the solvent were conducted as follows: ^ovozyin 435 (0.0095g; 95 units - 10, OOOunits/g (Immobilised Candida '.ntarctica B lipase)) was added to the 1-pheiiylethauol (O.Q(S20g; O.Smmol) nd vinyl acetate (0.8609g; lOmmol) in a Suppelco™ vial. The hexane 5.00ml) was then added. The reaction was stirred magnetically at room wperature.(about 20°C). Samples, luj, were taken periodically using a amilton syringe (1 ul) and analysed by gas clirornatography. 17 The results are presented m Table 6. The reaction time-courses in each / solvent are presented graphically in Figure L (Table Removed) catatysed "by lipases are most efficient in apolar-hydrophobic solvents such as hexane., (more polar solvents can strip the enzyme of its essential water) (G. Kirchner, M. P. Scollar, A. M. Klibanov J. Am. Chem. Soc. 19853 207, ' 7072-7076 and A. Zaks, A. M, Klibanov Proc. Natl. Acad. Sci. USA 1985, 52, 3132-3196). The resolution of ' 1-pheuylethan.ol in various hydrofluorocarbons was comparad to the resolution of l-pheaiylethanol •under identical conditions in hexane. It is evident from the results in Table 6 that reaction is superior in all of the hydrofluorocarbons investigated, both in terms of yield and enantiomeric excess (e.e). Figure 1 is a time-course plot for the solvents studied in this Example. Figure 1 clearly skov's the superior activity of Novozyni 435 ia the hydrofluorocarbon solvents tested; the rates of reaction in the hydrofhiorocarbon solvents are greater than in Hexane. Using !R-32, a resolution yield of 50% of each enantiomer with enantiomeric excess of >99% for each (S-l and J?-3) was obtained. Similar results were obtained . when, the reaction was carried out in R-134a or R-227ea However, when the reaction was carried out in hexane the yields and optical purities obtained were lower. Example 7 Lipase catalysed reaction of meso cis-4-cyciopentene-l33- diol using Candida antarctica B Hpase or-lipwe from Pseudomontzs cepacia In this Example, the enzyme catalysed reactions of cis-4-cydopeirtene-l,3- diol with vinyl acetate using Candida antarctica B lipase or lipase from Pseudomonas cepacia was investigated. The reactions were conducted in each ofR-134a, R-32, R-227ea and THF-Bt3N. , ....... ....,.,..,, The reactions using a hydrofluorcarbon as the solvent were conducted as follows: Novozym 435 (O.OOlOg; 10 units - 10, OOOunits/g (Immobilised Candida antarctica B lipase)) or lipase from Pseudotnonas cepacia (0.0050g; 0.463 units - 92.6units/g (powdered iyophilised enzyme)) was added to the cis~4- cyclopentene-l,3-diol (0.0050g; O.OSmmol)) and vinyl acetate (0.0869g; Immol)) in an aerosol. The aerosol was sealed and charged with R-134a (6.0500g; 5.00ml), or R-32 (4,8000g; 5.00ml), or'R-227Ea (6.93000g; 5.00ml). The reaction was stirred magnetically at room temperature (about 20°C). Samples were abstracted periodically by inversion of the aerosol and depression of the valve causing expulsion of a small volume (about 50ul) of rhe reaction solution into a glass vial. The sample was then dissolved in dichloromethane (0.1ml) and analysed by gas chromatograpiiy. The reactions in anhydrous THF-Et3N were conducted as follows: Novozyra'435 (O.OOlOg; 10 units - 10, OOOunits/g (Immobilised Candida antarctica B)) or lipase from Pseudomonas cepacia (O.OOSOg; 0.453 units - 92.6miits/g (powdered lyophilised enzyme)) was added to a solution (5.00ml) If. the ds-4-cyclopentene-U-diol (O.OOSOg; O.OSmmol)), vinyl acetate (0.0869g; Immol)) and triethylaroine (0.0101E O.lxnmol (Et3N)) in anhydrous THF (5.00ml) in a. Suppelco™ vial, The reaction was stirred magnetically at room temperature (about 20'C). Samples, l^ ware taken periodically using a Hamilton syringe (l.ul) and analysed by gas cbiornatography. The results are presented in Table 7. The reaction time-courses in each -W&t;?6fefc]r^^ Figures 2 to 95 MAc stands for mono acetate, DAc stands for diacetate, diol states for ci5-4-cyclopenteae-l53-diol and e.e. stands for eaantiomeric excess, (Table Removed) Until now, it has been widely accepted that the best solvent system for the reaction of ois-4-cyclopentene-l,3-diol and vinyl acetate catalysed by lipases is the THF-Et3N system (F. Theil, H. Schiclc, G. Winter, -0. Reck Tetrahedron 1991, 47, 7569-7582, S. R. Ghorpade, R. K. Kharul, R. R. Joshi, U. R. Kalkote, T. Ravindranathan, Tetrahedron Asymmetry 1999,10, 891-899 and C. R. Johnson, S. J. Bis Tetrahedron Lett 1992, 3.?, 7287- 7290). The desymrnetrisation of cis-4-cyclopentene-l,3-diol in various hydrofiuorocafbons was, therefore, compared •with the same reaction carried out under identical conditions in THF-Et3N....It is .evident.,£rom,,the.results-- provided in Table 7 that the reaction using Pseudomonas cepacia lipase when carried out in R-32 or R-134a is superior to the reaction carried out in THF-Et3N- (as evidenced by the greater yields of the monoacetate product). When the reaction is carried out in R-227ea the yield of the monoacetate product is roughly equivalent to that obtained when the reaction is earned out in THF-EfrjN, however, the yield is achieved in a much shorter time. When Novozym 435 lipase was used, superior yields of the monoacetate product were obtained in all of the hydro fluorocarbon solvents used, and shorter reaction times gave a greater enantiomeric excess compared with conducting the reaction in THF-Bt3N. • This is also illustrated by Figures 2 to I I . For example, Figure 10 shows the superior rates of reaction in the hydrofluorocarbon solvents, as illustrated by the the steepness' of the curves depicting the consumption of cis-4-cyclopentene-l,3-diol. Similar conclusions can be made from inspection of Figure 11. It is clear that the rates of reaction in the hydrofluorcarbon solvents were found to be much greater than in THPBtgN. For the Pseudomonas cepacia lipase catalysed desymmetrisation of ds-4-cvdopentene~l,3-diol, the reaction in R-32 is the most efficient, delivering * 60% yield of the monoacetate product with 99% eaantiomeric excess. For Novozym 435 lipase catalysed desymmetnsation of cis-4-cyclopentenel: 3-diol3 reaction ID 227Ea was found to be. the most efficient, giving a 61% yield of the monoacetate product with 99% enaiitiameric excess. WE CLAIM: 1. A process for stereo-selectively preparing a second compound of the kind such as herein described which process comprises reacting a substrate comprising at least one first compound which may be an achiral compound, a racemic mixture, an enantiomerically pure substance, a meso compound, a prochiral compound or a centrosymmetric compound of the kind such as herein described with a reagent in the presence of a biological catalyst of the kind such as herein described, characterized in that it is conducted in the presence of a solvent comprising at least one (hydro) fluorocarbon and water at a level which is less than that required for the water to form a separate aqueous phase in the reaction system. 2. A process as claimed in claim 1, wherein the biological catalyst is an enzyme. 3. A process as claimed in claim 2, wherein the enzyme is a hydrolase. 4. A process as claimed in claim 3, wherein the enzyme is selected from the proteases and lipases. 5. A process as claimed in any one of claims 2 to 4, wherein the enzyme is part of a whole cell culture. 6. A process as claimed in claim 1, wherein the biological catalyst is an abzyme. 7. A process as claimed in any one of the preceding claims, wherein the substrate is reacted to form an enantiomer at an enantiomeric excess of greater than 50 %. 8. A process as claimed in claim 1, wherein said first compound is a racemic mixture. 9. A process as claimed in claim 8, wherein the racemic mixture is a mixture of R and S alcohols, R and S carboxylic acids, R and S carboxylic acid esters, R and S amino acid esters, R and S amines, R and S thiols or R and S amides. 10. A process as claimed in claim 9, wherein the racemic mixture is a mixture of R and S amino acid esters or a mixture of R and S alcohols. 11. A process as claimed in claim 10, wherein the racemic mixture is a mixture of N-P-dl-phenylalanine alkyl esters, where P denotes a protecting group, and the reagent is an alkanol. 12. A process as claimed in claim 11, wherein the racemic is a mixture of N-acetyl-dl-phenylalanine propyl esters or a mixture of N- trifluoroacetyl-dl-phenylalanine propyl esters and the alkanol is methanol. 13. A process as claimed in claim 10, wherein the racemic mixture is a mixture of 1-phenylethanols and the reagent is vinyl acetate. 14. A process as claimed in any one of claims 8 to 13, wherein the new enantiomeric compound is formed at an enantiomeric excess of greater than 50%. 15. A process as claimed in any one of claims 8 to 14, wherein the biological catalyst is an enzyme. 16. A process as claimed in claim 14, wherein the enzyme is a hydrolase. 17. A process as claimed in claim 16, wherein the enzyme is a protease. 18. A process as claimed in claim 17, wherein the enzyme is Subtilisin carlsberg. 19. A process as claimed in claim 1, wherein said first compound is a meso compound which process comprises reacting the meso compound with a reagent in the presence of a biological catalyst and a solvent comprising at least one (hydro) fluorocarbon to stereo selectively obtain a particular enantiomer. 20. A process as claimed in claim 19, wherein the meso compound is cis-4-cyclopentene-1, 3-diol and the reagent is an acyl donor. 21. A process as claimed in claim 20, wherein the acyl donor is an enol ester. 22. A process as claimed in claim 20, wherein the acyl donor is vinyl acetate. 23. A process as claimed in any one of claims 20 to 22, wherein the reaction is conducted in the presence of a hindered amine. 24. A process as claimed in claim 23, wherein the hindered amine is a tertiary amine. 25. A process as claimed in any one of claims 19 to 24, wherein the particular enantiomer is formed at an enantiomeric excess of greater than 50 %. 26. A process as claimed in any one of claims 19 to 25, wherein the biological catalyst is an enzyme. 27. A process as claimed in claim 26, wherein the enzyme is a hydrolase. 28. A process as claimed in claim 27, wherein the enzyme is a lipase. 29. A process as claimed in claim 28, wherein the enzyme is Porcine pancreatic lipase, Candida antarctica B lipase or Pseudomonas cepacia lipase. 30. A process as claimed in claim 1, wherein said first compound is a prochiral compound which process comprises reacting the prochiral compound with a reagent in the presence of a biological catalyst and a solvent comprising at least one (hydro) fluorocarbon to stereo selectively obtain a particular enantiomer in the presence of water at a level which is less than that required for the water to form a separate aqueous phase in the reaction system. 31. A process as claimed in claim 30, wherein the prochiral compound is 2-ethylpropane-1, 3-diol and the reagent is an acyl donor. 32. A process as claimed in claim 31, wherein the acyl donor is an enol ester. 33. A process as claimed in claim 31, wherein the acyl donor is vinyl acetate. 34. A process as claimed in any one of claims 30 to 33, wherein the particular enantiomer is formed at an enantiomeric excess of greater than 50 %. 35. A process as claimed in any one of claims 30 to 34, wherein the biological catalyst is an enzyme. 36. A process as claimed in claim 35, wherein the enzyme is a hydrolase. 37. A process as claimed in claim 36, wherein the enzyme is a lipase. 38. A process as claimed in claim 37, wherein the enzyme is Pseudomonas cepacia lipase. 39. A process as claimed in any one of the preceding claims, wherein the solvent comprises at least one Ci-io hydrofluoroalkane. 40. A process as claimed in claim 39, wherein the at least one Ci-io hydrofluoroalkane is selected from the group consisting of difluoromethane (R-32), pentafluoroethane (R-125), 1,1,1-trifluoroethane (R-143a), 1,1, 2,2-tetrafluoroethane (R-134), 1,1, 1,2-tetrafluoroethane (R-134a), 1,1-difluoroethane (R-152a), 1,1, 1,3, 3-pentafluoropropane (R-245fa), 1,1, 1,2, 3,3-hexafluoropropane (R-236ea) and 1, 1, 1, 2, 3, 3, 3- heptafluoropropane (R-227ea). 41. A process as claimed in claim 40, wherein the solvent comprises at least one of difluoromethane (R-32) and 1,1, 1, 2-tetrafluoroethane (R-134a). 42. A process as claimed in any one of the preceding claims, wherein the at least one (hydro) fluorocarbon is used in combination with a co-solvent. 43. A process as claimed in claim 42, wherein the co-solvent is halogen free. 44. A process as claimed in any one of the preceding claims, wherein the solvent is in the liquid state. 45. A process as claimed in any one of the preceding claims wherein the amount of water that is used is less thanl% by weight of water based on the total weight o the solvent.

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4142-DELNP-2005-Abstract-(17-11-2008).pdf

4142-DELNP-2005-Abstract-(28-01-2008).pdf

4142-delnp-2005-abstract.pdf

4142-DELNP-2005-Claims-(06-01-2009).pdf

4142-DELNP-2005-Claims-(17-11-2008).pdf

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4142-DELNP-2005-Correspondence-Others-(08-09-2010).pdf

4142-DELNP-2005-Correspondence-Others-(17-11-2008).pdf

4142-DELNP-2005-Correspondence-Others-(28-01-2008).pdf

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4142-delnp-2005-description (complete).pdf

4142-DELNP-2005-Drawings-(28-01-2008).pdf

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4142-DELNP-2005-Form-1-(28-01-2008).pdf

4142-delnp-2005-form-1.pdf

4142-delnp-2005-form-18.pdf

4142-DELNP-2005-Form-2-(28-01-2008).pdf

4142-delnp-2005-form-2.pdf

4142-DELNP-2005-Form-3-(28-01-2008).pdf

4142-delnp-2005-form-3.pdf

4142-delnp-2005-form-5.pdf

4142-DELNP-2005-GPA-(08-09-2010).pdf

4142-DELNP-2005-GPA-(17-11-2008).pdf

4142-DELNP-2005-GPA-(28-01-2008).pdf

4142-delnp-2005-gpa.pdf

4142-delnp-2005-pct-101.pdf

4142-delnp-2005-pct-210.pdf

4142-delnp-2005-pct-237.pdf

4142-delnp-2005-pct-304.pdf

4142-delnp-2005-pct-308.pdf

4142-delnp-2005-pct-409.pdf

4142-delnp-2005-pct-416.pdf

4142-DELNP-2005-Petition-137-(28-01-2008).pdf

4142-DELNP-2005-Petition-138-(28-01-2008).pdf