Captopril, manufacture

Esterases, lipases, and proteases are widely used in enzymatic resolution processes of racemic carboxy acid ester substrates. Industrially relevant examples are the manufacture of D-)ff-acetylmercaptoisobutyric acid, the optically active side-chain of the ACE inhibitor captopril (43) [104] (Scheme 26), and synthesis... 

Neal G. Anderson, Ph.D., has worked for over 20 years in chemical process R D in the pharmaceutical industry. He earned a B.S. from the University of Illinois and a Ph.D. in medicinal chemistry from the University of Michigan and completed postdoctoral studies at McNeil Laboratories. With almost 18 years in process R D at Bristol-Myers Squibb Co. in New Brunswick, New Jersey, Dr. Anderson has extensive hands-on experience in laboratory, pilot plant, and manufacturing facilities. He has made key contributions to processes for the manufacture of four major drug substances, including captopril, has participated in 12 manufacturing start-ups, and has successfully introduced many processes to pilot plants. He received the Bristol-Myers Squibb Presidents Award and spot awards, and his final position was Principal Scientist. 

They later discovered it was possible to forego the second thio function (the thiophenol) by careful selection of the thioester, the enzyme, and reaction conditions [27]. This considerably broadened the scope of the new reaction, but their first communication suggested a new path for our process. The use of thioesters as substrates in enzymatic resolution is not frequent but it is still well prece-dented [26-28]. In particular, an example of its use in large-scale pharmaceutical manufacture is our company s preparation of the antihypertensive Captopril [29]. 

The UK manufacturer of captopril also warns that neutropenia and agranulocytosis, resulting in serious infection, have occurred in patients taking captopril and other ACE inhibitors, and that concurrent treatment with allopurinol may be a complicating factor, especially in those with renal impairment. However, the US manufacturer notes that, while renal impairment and a relatively high dose of captopril markedly increases the risk of neutropenia, no association between allopurinol and captopril and neutropenia has appeared in US reports. ... 

These interaetions are not elearly established, and the reaction appears to he rare and unpredictable. All that can he constructively said is that patients taking both drugs should he very closely monitored for any signs of hypersensitivity (e.g. skin reactions) or low white cell count (sore throat, fever), especially if they have renal impairment. The UK manufacturer of captopril recommends that diffeiential white hlood cell counts should be performed before adding allopurinol, then every 2 weeks during the first 3 months of treatment, and periodically thereafter. Similar caution and advice is given by the UK manufacturers of several other ACE inhibitors. For other possible interactions with ACE inhihitors that might result in an increased risk of leucopenia see also ACE inhihitors + Azathioprine , p.l8 and ACE inhibitors + Procainamide , p.33. 

The evidence that the concurrent use of ACE inhibitors and azathioprine increases the risk of leucopenia is also limited. However, the UK manufacturer of captopril recommends that captopril should be used with extreme caution in patients receiving immunosuppressants, especially if there is renal impairment. They advise that in such patients differential white blood cell counts should be performed before starting captopril, then every 2 weeks in the first 3 months of treatment, and periodically thereafter. The UK manufacturers of a number of other ACE inhibitors also state in their prescribing information that the use of ACE inhibitors with cytostatic or immunosuppressive drugs may lead to an increased risk of leucopenia. For other potential interactions with ACE inhibitors that might lead to an increased risk of leucopenia, see also ACE inhibitors + Allop-urinoE, p.l3, and ACE inhibitors + Proeainamide , p.33. 

Although food did not significantly affect the pharmacokinetics of a single 4-mg dose of perindopril, the AUC of its active metabolite perindoprilat was reduced by 44%. The blood pressure-lowering effects were not assessed, but it seems possible that they would not be affected (see captopril, above). Nevertheless, the UK manufacturer recommends that perindopril should be taken in the morning before a meal. ... 

Cimetidine did not appear to alter the pharmacokinetics or pharmacological effects of captopril or enalapril, or the pharmacokinetics of fosinopril or quinapril in studies in healthy subjects. The manufacturers of cilazapril say that no clinically significant interaction occurred with H2-receptor antagonists (not specifically named) and the manufacturers of moexipril, " ramipril, and trandolapril say that no important pharmacokinetic interaction occurred with cimetidine. The manufacturers of spirapril briefly note in a review that cimetidine did not alter the plasma concentrations of spirapril or its active metabolite spiraprilat. None of these pairs of drugs appears to interact to a clinically relevant extent, and no special precautions appear to be necessary. 

Two kidney transplant patients on ciclosporin developed acute renal failure 10 to 42 days after starting to take enalapril 5 to 10 mg twice daily. Recovery was complete when the enalapril was stopped in one of the patients, and when both enalapril and ciclosporin were stopped in the other. The latter patient had no problems when the ciclosporin was restarted. Both recovered renal function after 10 to 30 days. Neither had any previous evidence of renal artery stenosis or chronic rejection, which are conditions known to predispose to renal failure during ACE inhibitor treatment. Two other patients appeared to tolerate concurrent use well. Two further kidney transplant patients developed acute renal failure when given enalapril. Neither had renal arterial stenosis or acute rejection. The manufacturer briefly mentions that transient oliguria was seen in a kidney transplant patient given ciclosporin and 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.)... 

Section 6.4.4), both in the nature of the reaction [which requires a lyase to add water (rather than ammonia) across a carbon-carbon double bond] and in the use of growing cells. Purified fumarate hydrolyase is used to manufacture some 500 tonnes of L-(S)-malate (43) each year, while maleic hydrolyases will catalyse the synthesis of D-(/ )-malate (44), a product for which there is as yet no substantial market. Such reactions are also important in the synthesis of both L-camitine (45) and captopril (46) (Scheme 6.21). 

Captopril is an ACE inhihitor used to treat high hlood pressure. It is manufactured from two chemicals, D-(3-hydroxy-isohutyric acid and L-proline. These building blocks are both manufactured by fermentation, with the yeast Candida rugosa and the bacterium Corynebacterium sp., respectively. Then both raw materials are joined by conventional chemistry in a reactor directly producing captopril. The fermentation process requires milder conditions and less toxic chemicals (see Fig. 9.10). 

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

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