The Production Of Optically Active Pharmaceutical Compounds Biology Essay

The molecules which are non ace imposable mirror images of one another are termed as chiral. These are a brace of enantiomorphs and are diasymmetric every bit good as optically active. Since they promote optical rotary motion, these enantiomorphs are besides known as optical isomers. These chiral molecules consist of a tetrahedral C atom which is attached to four different groups. The C atom is the stereogenic or the asymmetric Centre of the molecule. The enantiomorphs are similar in their physical and chemical belongingss in an achiral environment.

Enantiomorphs have different biological belongingss. This influences the efficaciousness and the toxicity of the compounds. Normally, one of the enantiomorphs is bioactive and the others may be inactive or toxic. Example, Verapamil is a Ca channel blocker used for the intervention for blood force per unit area, angina. The ( S ) isomer treats the addition in BP more efficaciously than the racemate signifier. The ( R ) isoform inhibits opposition of malignant neoplastic disease cells to anti malignant neoplastic disease drugs ( Crosby, 1991 ) .

The enantiomerically pure compounds are really utile and critical in the pharmaceutical and agrochemical industries. It has besides been shown that the optically pure and chiral compounds should be used instead than mixture of enantiomorphs. The optically active pure compounds are used to bring forth antibodies, endocrines, anti inflammatory, aminic acids, vitamins, anti malignant neoplastic disease drugs, cardiovascular drugs.

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Chiral chromatography or ligand exchange chromatography was an analytical technique used for dividing enantiomorphs. High public presentation liquid chromatography whereby chiral stationary stage is used was efficient in separation of enantiomorphs. The optically active ligands like amino acids are bound covalently to a solid support, thereby organizing a chiral stationary stage. Assorted aminic acid derived functions like N – ( 3,5-dinitrobenzoyl ) phenyl glycines are besides used. ( Pirkle and Pochapsky,1987 ) . The major advantage of chromatography is that it consequences in high enantiomeric surplus and is suited on the analytical graduated table. However, its drawback is that the graduated table up is hard.

The production of enantiomorphs for optically active drugs may be produced by different methods. Pure compounds are recovered by assorted extraction techniques from chiral compounds ( alkaloids, saccharides ) exist as pure enantiomorphs of course. Agitation of cheap substrates which are available in copiousness ( like molasses and saccharose ) was a widely used beginning of individual chiral molecules – lactic, tartaric and L- amino acids and besides for complex substances which include vitamins, antibiotics and endocrines. ( Buchta,1983 ) .

Optically pure compounds may be prepared from inactive get downing stuffs by asymmetric synthesis and declaration of racemates. In the procedure of asymmetric synthesis ( Stinson,1993 ) an enantiomeric reagent or accelerator is used for transporting out a specific reaction on an achiral substrate ( prochiral ) to bring forth a individual chiral merchandise. Overall, it is a selective technique as it leads to merchandise selectivity. Its disadvantages are that it may be expensive due to the legion stairss involved and besides because of the usage of dearly-won enantiomeric reagents. It is cheaper to bring forth a racemic mixture and so divide the enantiomorphs by physical methods like kinetic declaration or diastereomeric crystallisation. Covalent derived functions are formed utilizing optically pure deciding agents in the diastereomic crystallisation method. The drawback is that it is uneconomical since the unwanted isomer may be discarded. On the other manus, kinetic declaration is based on the rule that two enantiomorphs react at variable rates in the presence of a chiral accelerator like an enzyme. This method involves merchandise selectivity.

Biotransformation has besides become a cardinal engineering used to bring forth chiral substances. It was used by many companies Eg. Celgene Corporation developed processs to bring forth aminoalkanes by utilizing aminic transferase ( Celgene corporation,1990 ) .The chief advantage of this process is that it allows 100 % theoretical transition of the substrate into the concluding merchandise.

Membrane chirotechnology is besides a widely used method for bring forthing optically pure isomers. In this process, the membrane itself possibly per se enantioselective. This means that the membrane represents a chiral system that separates the coveted isomers on the footing of spacial conformation. On the other manus, a membrane separation procedure may be combined with kinetic declaration by doing usage of an enantiospecific biocatalyst.That is, the membrane helps in the separation of the merchandise from the substrate on the footing of their chemical belongingss like solubility.

Enantiospecific catalytic membrane reactors may besides be used. These comprise of membrane procedures which are advantageous as they have the ability to work in a uninterrupted manner and tremendous sums of stuff could be procedures at one time. The competitory production of chiral substances requires a big graduated table, inexpensive procedure for the production and separation of the enantiomorphs. Eg. Pyridoxal – phosphate dependent lyase and transferase were used as accelerator in the synthesis of L- amino acid via the C – C bond formation. ( Sheldon,1993 )

The widely used enantiospecific membrane reactors are ultrafiltration hollow fiber membrane reactor ( Responsible for production of L – phenylalanine by utilizing dehydrogenase accelerator ( Schimdt et al, 1987 ) ) immobilized enzyme membrane reactor, packed bed uninterrupted bioreactor, biphasic membrane reactor etc.

Ultra filtration, electrodialysis and membrane extraction are common separation processes that are combined with biotransformation. Matson and Quinn ( 1979 ) showed the optimisation in production of aminic acids enantiomorphs and studied the separation of L amino acids from the racemate solution by doing usage of an impregnated liquid membrane entirely with an enzyme immobilised membrane. Production of L-phenylalanine from racemic mixture of D, L phenyl lactate was shown by 2 back-to-back biotransformation in an enzyme membrane reactor whereby the enzyme and cofactor ( NAD/H ) had been compartmentalised behind an extremist filtration membrane. ( Schmidt et al, 1987 ) .

Intrinsically enantioselective membranes are besides widely used. Substances which are optically active can be separated on the footing of at that place physical stereo selectivity. Polymeric membranes holding the enantioselective belongingss per se may be prepared doing usage of chiral polymers or by chiral alterations of the achiral porous membrane in the presence of chiral acknowledgment agent like cyclodextrins, cyclophane and oligopeptides. In order to fix the enantioselective membranes, optically active polyacryl amides and cellulose derived functions may be used. Yoshikawa et al,1996, showed separation of tryptophan, phenylalanine and alanine by extremist filtration utilizing the chiral picker which was molecularly imprinted polymeric membranes ( DIDE derived functions ) .

Enzymes have the ability to catalyze a wide spectrum of chemical reactions with great efficiency and selectivity under mild and environmentally friendly conditions. By working the selectivity of enzymes for one signifier of the enantiomorph of a racemic mixture, the enantiomerically enriched compound can be obtained by biocatalytic declaration. ( Thomas et al,2002 ) Most normally, the hydrolytic enzyme are used since they display a scope of advantages like stableness, specificity, no demand of cofactors. Among hydrolases, lipase is most normally used because of high enantioselectivity, commercial handiness and good stableness in assorted media. ( Seung Hwan et al,2004 )

Recently a new technique was introduced to expose the peptides and proteins on the surface of gram negative and gram positive bacteriums, barm or mammalian cells. This was done by blending the peptides to come up grounding motive ; and the technique is known as cell surface show. The cell surface show lipase proved to be an first-class biocatalytic system for the kinetic chiral declaration of the racemic compound.

Recent progresss have shown the usage of enzymes in the synthesis of optically pure drugs and biologically active compounds. Enzymes have the ability to separate between the enantiomorphs of racemic substrates. Assorted schemes have been developed to better the stereoselectivity of declarations catalysed by the enzyme. This includes alteration of the substrate, recycling of the merchandise and changing the reaction conditions. By doing usage of these schemes, enzymes with modest stereoselectivity can besides be used but merely one enantiomorph is produced with high output. Enzyme can catalyze transmutations with high part selectivity and chemo selectivity under mild reactions. This is of import in the alteration of chiral drugs. Eg. Penicillin acylase causes the hydrolysis of benzyl penicillin without impacting the beta lactam ring and allows the industrial readying of 6-aminopenicillanic acid which is a precursor for many semi man-made penicillins. Enzymes ( hydrolases ) have successfully been used in the synthesis of chiral pharmaceuticals, nevertheless modern methods of protein technology and industrial microbiology aid in the production of enzymes which are more cheap, stable with wide substrate specificity and high stereoselectivity. ( Alexey L.Margolin,1993 )

Catalytic asymmetric synthesis is the asymmetric synthesis that is catalysed by chiral ( passage ) metal composite. The reactions that are involved are Redox transmutations or C – C bond forming processes that complement enzymatic hydrolytic procedure. The three types of chemo accelerators that exist are heterogeneous metal accelerator, homogeneous composite and soluble chiral acid or bases. Emil Fisher ‘s work on asymmetric initiation which was based on cyanohydrin synthesis was the first reaction subjected to asymmetric contact action.

Enantiomerically pure amino acids, amino intoxicants, aminoalkanes, intoxicants and epoxides play an of import function as intermediates in the agrochemical and pharmaceutical industry whereby high degree of pureness and a big measure is required. The enantiomerically pure active compounds help in bettering the economic sciences of the procedure, thereby taking to cut down measures applied and less sum of an environmental impact.

Chemical procedure for the fabrication of aminic acids: Even though asymmetric syntheses of amino acids are known ( Michael Breuer et al,2004 ) , no economical procedure has been developed. Bucherer – Bergs bomber type which is Strecker synthesis was employed for the industrial fabrication of the racemic amino acids. The alpha amino cyanide is produced from hydrocyanic acid, ammonium hydroxide and an aldehyde and may be hydrolysed to the amino acid straight or in the presence of C dioxide it gets converted into hydantoin. The hydantoin is so subjected to hydrolysis in a basic media to give the racemic amino acid. Another path to the racemic amino acid is amido carbonylation in the presence of a passage metal. Although, there is no commercially feasible chemical procedure for the synthesis of enantiomerically pure amino acid, the production of racemic amino acid is still of great importance because the racemates may be converted to enantiomerically pure compounds by assorted biocatalytic methods. The accelerators used in the biotransformation are metabolically inactive cells or isolated enzymes. It is the method of pick for the production of enantiomerically pure D- amino acids and assorted other non natural amino acids. Lyases may be used as biocatalysts in the production of L- Aspartic acid from fumaric acid ( Beller et al,2000 ) . Amino acerb dehydrogenase ( deaminizing amino acid oxido reductase ) allows enantioselective biotransformation on an industrial graduated table. These enzymes have low substrate specificity due to which not natural compounds may besides be transformed. In add-on, they besides require carbon monoxide substrates which help in providing the hydride ions for the decrease of Schiff base. There is besides a chemo enzymatic method for amino acerb synthesis. In this, L- amino acid gets oxidised by L- amino acid oxidase. Imine ( intermediate ) gets reduced by Pd-C in ammonium formate buffer. In the ensuing racemic mixture, merely L – enantiomorph is utilised by oxidase where as the D- enantiomorph accumulates. Therefore, the enantiomeric signifier of the amino acid which is produced depends wholly on the specificity of the oxidase. The enantiomerically pure amino acid can besides be prepared by the racemate declaration. Eg: L and D amino acid can be prepared with the Hydantoinase-carbamoylase system.

Production of carboxylic acids: Carboxyl acid can be isolated from natural beginnings ( chiral pool ) .Naturally happening chiral compounds obtained from the chiral pool are an alternate to the synthesis of enantiomerically pure merchandises. An illustrations of a chiral carboxylic acid that is isolated from the natural beginnings is L – ( + ) tartaric acid ( Mitsugi et al,1978 ) . During the agitation of grape, the isomeric signifier of tartaric acid separates out as tartarate ( potassium H tartarate ) .On responding with Ca chloride or Ca hydrated oxide and sulfuric acid, isomeric tartaric acid is released ; gypsum and barm residues occur as the by merchandises. Natural saccharide edifice blocks were used for several decennaries for the readying of sugar acids which were enantiomerically pure. Another method is the classical chemical synthesis which involves crystallisation with enantiomerically pure aminoalkanes. The enantiomorphs of the racemic carboxylic acids are known to divide by fractional crystallisation of the diastereomeric salts which are formed with the enantiomerically pure aminoalkanes. Eg: Thiazolidine carboxylic acid ( enantiomerically pure ) , an intermediate in the synthesis of CP-060- S is isolated by the declaration of racemate with N- benzyl-1-phenylethylamine. ( Pompejus et al, 2001 )

Production of aminoalkanes: The chemical procedure involved is the crystallisation with chiral carboxylic acids. Isolation of enantiomerically pure aminoalkanes can be carried out by the crystallisation of diastereomeric salts of chiral carboxylic acids with chiral aminoalkanes ( Jacques et al,1980 ) . Thus ( R ) or ( S ) – 1- phenylethlyamine may be produced on an industrial graduated table by the crystallisation with either ( R ) – mandelic acid or ( S ) – malic acid. Mandelic acid was shown to be an of import resolution agent for legion Numberss of aminoalkanes. Dutch declaration is a discrepancy of the classical racemate declaration. In order to cut down the hunt for an appropriate resolution agent for an aminoalkane through combinative attack, a mixture of many optically active acids were used. The salt that was precipitated contained several acerb anions.

Production of optically active amino intoxicants: ( S ) -2-Aminobutanol is an of import amino intoxicant intermediate which is used for the synthesis of ethambutol ( tuberculostatic ) and it must be administered in its enantiomerically pure signifier as it may take to blindness. The enantiomerically pure signifier can be obtained from the racemate by transporting out the crystallisation with L-Tartaric acid. ( Sheldon et al,1993 )

Production of intoxicants: The chief procedure involved was the asymmetric hydrogenation of ketones. Noyori et Al showed the development of asymmetric hydrogenation of keto esters and ketones. The accelerators used were ruthenium composites of binap and derived functions like tol-binap ( Akutagawa,1995 ) and segphos. The biotechnological procedure is chiefly the enzyme catalysed declaration. For the declaration of racemate intoxicants, enzymatic acylations were developed in early 1980’s.The racemic intoxicants are made to respond with an acylating agent under enzyme contact action whereby one enantiomorph is unpersuaded whereas the other enantiomorph is esterified. The biocatalysts used are bacterial and fungous lipases.

Production of epoxides: This includes sharpless asymmetric dihydroxylation. The path to the formation of chiral epoxides is based on the optically active glycols which may be converted to their several oxiranes. Another method is the Jacobsen asymmetric epoxidation which is based on ( salen ) manganese III precatalyst and the hypochlorite is used as the stoichiometric oxidizing agent.

The chemical procedures may be compared with the biotransformation with regard to the environmental impact and economic efficiency. The drawbacks of the chemical paths are solvent emanation or toxicity of certain compounds. On the other manus, chiral engineerings are developing quickly. Highly various engineerings and processs are introduced. Most chiral intermediates are produced in minute measures. Therefore, the standards that should be considered for the methods introduced are that they should hold a wide substrate spectrum, non necessitate specialized equipment and have a cost effectual entree to a scope of merchandises.

It is non possible to do general decisions about the high quality of one type of engineering in comparing with the others. The most economic technique will depend on their constituent which is why each instance should be investigated separately. However, in the overall procedure, the chiral measure should be introduced every bit early as possible but this may be hindered by other factors like racemisation of the unwanted isomer.

Membrane chirotechnology is besides an emerging technique holding several advantages with regard to the pureness of simple isomers, productiveness and easiness of graduated table up. These techniques have chiefly been used at the research lab graduated table. Application on a big graduated table needs more investing particularly in developing the experimental set up instead than probes which have been carried out on chirality that have been developed in the chromatographic field.