L-Proline Captopril

Estaban,J. M.T. Vidal, C. M. Marine, J. R. Diaz,J. M., Process for the preparation of 3-mercapto-2-(S)-methylpropionyl-L-proline [captopril]. Spanish patent ES 556,990 (1987) (assigned to Sueros, Antibioticos y Laboratorio de Vacunoterapia, Sociedad Ltds.) see Chem. Abstr. 1988, 109, 23391m. 

Several peptides isolated from the venom of the South American snake Bothrops jararaca are potent ACE inhibitors and were briefly used for the treatment of hypertension, but were soon superseded by surprisingly simple molecules with high inhibitory effect. At the Squibb Institute for Medical Research in Princeton, New Jersey, Miguel A. Ondetti (Plate 32) recognized that ACE is similar in its substrate specificity to the well studied protease car-boxypeptidase A. He designed, therefore, molecules that should fit into the active site of ACE (presumably similar to the active site of carboxypeptidase A) and form complexes with the enzyme. The dipeptide , 2-D-methyl-3-mercapto-propionyl-L-proline, captopril [7] strongly associated with the enzyme and... 

One of the homochiral starting materials (45) for the acetylcholinesterase (ACE) inhibitor captopril [62571 -86-2] (47) is produced by a Hpase enzyme-catalyzed resolution of racemic 3-methyl-4-acetylthiobutyric acid (44) and L-proline (46) (65). 

Finally,Captopril is produced. Thethioester (0.85g) isdissolved in5.5N methanolicammonia and the solution is kept at room temperature for 2 hours. The solvent is removed in vacuo and the residue Is dissolved in water, applied to an ion exchange column on the H cycle (Dowex 50, analytical grade) and eluted with water. The fractions that give positive thiol reaction are pooled and freeze dried. The residue Is crystallized from ethyl acetate-hexane, yield 0.3 g. The 1 -(3-mercapto-2-D-methylpropanoyl)-L-proline has a melting point of 103°C to 104°C. 

C 3H,5N04 1148-11-4) see Angiotensinamide Captopril 7V-benzyloxycarbonyl-L-proline tert-butyl ester (C17H23NO4 16881-39-3) see Captopril 7V-benzyloxycarbonyl-L-serine (CiiHijNOj 7745-80-8) see Nelfinavir mesylate iV-benzyloxycarbonyl-L-serine-P-lactone (C Hi,N04 26054-60-4) see Nelfinavir mesylate 7V-benzyloxycarbonylsuccinimide... 

Captopril Captopril, l-[(2S)-3-mercapto-2-methylpropionyl]-L-proline (22.7.4), is synthesized by direct acylation of L-prohne with 3-acetylthio-2-methylpropionic acid chloride (22.7.2), which is synthesized from 3-acetylthio-2-methylpropionic acid (22.7.1), which is in turn synthesized by reacting methacrylic and thioacetic acid. l-(3-Acetylthio-2-D-methylpropanoyl)-L-proline (22.7.3) is formed by reacting L-proline with 3-acetylthio-2-methylpropionic acid chloride, and it undergoes further ammonolysis with ammonia, to give the desired captopril (22.7.4). 

In one synthesis of this drug, L-proline (11-2) is acylated with the acid chloride (11-1) obtained from the addition of hydrogen chloride to the double bond in methacrylic acid followed by reaction with thionyl chloride to give amide (11-3) as a mixture of diastereomers. The pure 2S isomer is then isolated from the mixture by fractionation as the dicyclohexylamine salt. Treatment of that compound with ammonium hydrosulfide leads to the displacement of chlorine by a thiol group and the formation of captopril (11-4) [13]. 

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. 

Captopril is designated chemically as l-[(2S)-3-mercapto-2-methylpropionyl]-L-proline (14) (Fig. 8). It is used as an antihypertensive agent through suppression of the renin-angiotensin-aldosterone system [36,37], Captopril and other compounds such as enalapril and lisinopril prevent the conversion of angiotensin I to angiotensin II by inhibition of ACE. 

Converting enzyme (ACE) inhibitors 176) likewise prevent the formation of angiotensin II and are used in the treatment of renal and essential hypertension. Examples of orally active ACE-inhibitors are (2)-l-[(2S)-3-[N-(S)-mercapto-2-methylpro-panoyl]proline170) (captopril 77), l-[N-(S)-l-carboxy-3-phenylpropyl]-L-alanyl-L-proline-1 -ethyl ester177 (enalapril 78), and 2-[N-[(S)-l-ethoxycarbonyl-3-phenyl-propyl]-L-alanyl]-(lS,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid178) (Hoe 498 79). 

S)-3-acetylthio-2-methylpropanoyl]-L-proline (CnH,7N04S 64838-55-7) see Alaccpril Captopril... 

Teprotide was used as an active antihypertensive drug in patients with essential hypertension, but due to a lack of oral activity it was administered parenterally. Teprotide has been the first lead for novel orally active AC E-inhibitors, with three important lead-molecules having been discovered as follows succinyl-L-proline, (2S)-methylsuccinyl-L-proline and 3-mercaptopropanoyl-L-proline affording at the end the first successful drug in this class captopril, as discovered by Ondetti, Rubin and Cushman [1] (Fig. 6.3). 

The discovery of teprotide led to a search for new, specific, orally active ACE inhibitors. Ondetti et al. (172) proposed a hypothetical model of the active site of ACE, based on analogy with pancreatic carboxypeptidase A, and used it to predict and design compounds that would occupy the carboxy-terminal binding site of the enzyme. Carboxyalkanoyland mer-captoalkanoyl derivatives of proline were found to act as potent, specific inhibitors of ACE and 2-D-methyl-3-mercaptopropanoyl-L-proline (131) (captopril) was developed and launched in 1981 as an orally active treatment for patients with severe or advanced hypertension. Captopril, modeled on the biologically active peptides found in the venom of the pit viper, made an important contribution to the understanding of hypertension and paved the... 

Captopril, l-[(2S)-3-mercapto-2-methyl-propionyl]-L-proline, the first orally active inhibitor of the angiotensin-converting enzyme (ACE) on the market. The positive effects of captopril and other ACE inhibitors like enalapril in hypertension and heart failure result primarily from suppression of the renin-angiotensin-aldosterone system. Captopril causes a fall in blood pressure in hypertensive patients [M. A. Ondetti et al.. Science 1977,196,441 ... 

S -Captopril (>S-l-[3-mercapto-2-methyl-l-oxopropyl]-L-proline) [62571-86-2] M 217.3, m 103-104°(polymorphic unstable form m 86 , melts at 87-88 solidifies and then melts again at 104-105 ), [a] ... 

The angiotensin-converting enzyme (ACE) inhibitor, captopril (D-2-methyI-3-mercaptopropanoyl-L-proline, Figure 6.49), was derivatised with A-(4-dimethyla-minophenyl)maleimide to give a stable product. Detection was at a GCE (+0.9 V vs Ag/AgCl). The LoD was 10pgL whole blood (0.5 mL sample). The HPLC-ED of captopril is also discussed in Chapter 5, Section 5. 

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