Captopril chirality

Where more than one chiral centre is present in a molecule there is the possibility of diastereoisomers, e.g. captopril. Another example of a synthetic drug with two chiral centres is labetalol. The number of diastereoisomers arising from n chiral centres is 2"i.e. 2 in the case of labetalol. In the structure shown in Figure 2.5 chiral centres 1 and 2 in structure A have the configurations R and S respectively the enantiomer of this structure (B) has the S and R configurations in centres 1 and 2. In addition there is a pair of enantiomers C and D that are diastereoisomers of the structures A and B, which have the configurations R2R and 16 25 . 

Maltodextrins (dextrose equivalent (DE) 4.0-7.0, 13.0-17.0 and 16.5-19.5) are proposed as novel chiral selectors for the construction of EPMEs for S-captopril assay [36]. The EPMEs can be used reliably for the assay of S-captopril as raw material and from pharmaceutical formulations as Novocaptopril tablets, using direct potentiometry. The best response was obtained when maltodextrin with higher DE was used for the electrode s construction. The best enantioselectivity and stability in time was achieved for the lower DE maltodextrin. L-Proline was found to be the main interferent for all proposed electrodes. The surface of the electrodes can be regenerated by simply polishing, obtaining a fresh surface ready to be used in a new assay. 

The potency of captopril (14) as an inhibitor of ACE depends critically on the configuration of the mercaptoalkanoyl moiety the compound with the S-configuration is about 100 times more active than its corresponding R-enantiomer [37], The required 3-mercapto-(25)-methylpropionic acid moiety has been prepared from microbially derived chiral 3-hydroxy-(2R)-methylpropionic acid, which is obtained by the hydroxylation of isobutyric acid [38-40],... 

The use of extracellular lipases of microbial origin to catalyze the stereoselective hydrolysis of esters of 3-acylthio-2-methylpropionic acid in an aqueous system has been demonstrated to produce optically active 3-acylthio-2-methyl-propionic acid [41-43], The synthesis of the chiral side chain of captopril by the lipase-catalyzed enantioselective hydrolysis of the thioester bond of racemic 3-acetylthio-2-methylpropionic acid (15) to yield 5 -(-)-(15) has been demonstrated [44], Among various lipases evaluated, lipase from Rhizopus oryzae ATCC 24563 (heat-dried cells), BMS lipase (extracellular lipase derived from the fermentation of Pseudomonas sp. SC 13856), and lipase PS-30 from Pseudomonas cepacia in an organic solvent system (l,l,2-trichloro-l,2,2-tri-fluoroethane or toluene) catalyzed the hydrolysis of thioester bond of undesired enantiomer of racemic (15) to yield desired S-(-) (15), R-(+)-3-mercapto-2-methylpropionic acid (16) and acetic acid (17) (Fig. 8A). The reaction yield of... 

In an alternative approach to prepare the chiral side chain of captopril (14) and zofenopril (18), the lipase-catalyzed stereoselective esterification of racemic 3-benzoylthio-2-methylpropionic acid (19) (Fig. 8B) in an organic solvent system was demonstrated to yield i -(+)-methyl ester (20) and unreacted acid enriched in the desired S-( )-enantiomer (19) [45], Using lipase PS-30 with toluene as solvent and methanol as nucleophile, the desired S-(-)-(19) was obtained in 37% reaction yield (theoretical max. 50%) and 97% e.e. Substrate was used at 22-g/ liter concentration. The amount of water and the concentration of methanol supplied in the reaction mixture was very critical. Water was used at 0.1 % concentration in the reaction mixture. More than 1% water led to the aggregation of enzyme in the organic solvent, with a decrease in the rate of reaction which was due to... 

Utilising Candida cylindracea lipase (CCL) a chiral propionic acid was resolved by DSM [34, 46]. Only the undesired enantiomer of the ester was hydrolysed and at a conversion of 64% the remaining desired ester had an ee of 98% (Scheme 6.12). Although this means that the yield of the enantiopure ester is below 40% it did enable a new access to enantiopure captopril. 

R)-a-hydroxyphenylbutyric acid chiral pool for ACE inhibitors Captopril... 

The manufacture of fine chemicals, particularly drugs, fragrances, and flavors, is undergoing a major revolution now as a result of the capability of chemists to prepare these chemicals, mainly drugs, in their purest isomeric forms (as stereoisomers). This shift to pure forms has been described by Brown in the following words (1990) (see also Deutsch, 1991) A mixture of stereoisomers in a medicine will (now) need to be justified just the same way as any other mixture of compounds. Indeed, in the United States today (as in many other advanced countries), the use of pure enantiomeric forms is practically a requirement since extensive justification is needed to continue with racemates (FDA, 1992). As a consequence, the combined sales of the chiral top ten drugs (ammoxydllin, enalapril, ampicillin, captopril, pravastatine, diltiazem, ibuprofen, lovastatin, naproxen, and fluoxetine) in 1994 amounted to more than 16 billion dollars (Sheldon, 1996). (Of these, ibuprofen and fluoxetine are still sold as racemates.)... 

Types of chiral processes amenable to scale-up Specific examples of the manufacture of chiral drugs Diltiazem Captopril Enalapril Naproxen... 

Some of the common drugs used in human medicine (e.g., aspirin) (Section 18.5B) are achiral. Others are chiral and sold as single enantiomers. The penicillin and erythromycin classes of antibiotics and the drug capto-pril are aU chiral drugs. Captopril, which is very effective for the treatment of high blood pressure and conges-... 

The rate of esterification also decreased as the methanol to substrate ratio was increased from 1 1 to 4 1. Higher methanol concentrations inhibited the esterification reaction by stripping the essential water from the enzyme. Cmde lipase PS-30 was immobilized on Accurel polypropylene (PP) with absorption efficiencies of 98.5%. The immobilized lipase efficiently catalyzed the esterification reaction at substrate input of 224 g/L with 0.4 M methanol, 0.1% water, and 120 g/L immobilized enzyme giving a 45% reaction yield of (S)-37a with 97.7% ee. The immobilized enzyme under identical conditions gave a similar ee and yield of produrt in twenty three additional reaction cycles without any loss of activity and productivity [91]. (S)-3-benzylthio-2-methylpropanoic acid, (S)-37 is a key chiral intermediate in the synthesis of Zofenopril [92] and Captopril [93]. 

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