Captopril

Captopril Basic information
Product Name:Captopril
Synonyms:(2S)-1-[(2S)-3-Mercapto-2-methylpropionyl]-2-pyrrolidinecarboxylic acid;1-[(S)-3-Mercapto-2-methylpropionyl]-L-proline;Captopril,N-[(S)-3-Mercapto-2-methylpropionyl]-L-proline;Captopril (200 mg);Captopril API;Captopril Cardiovascular;(S)-(-)-1-(3-Mercapto-2-methyl-1-oxopropyl)-L-proline (S)-(-)-1-(3-Mercapto-2-methylpropionyl)-L-proline;3-Mercapto-2-Methylpropanoic acid 1,2-diphenylethylaMine salt (MMPA)
CAS:62571-86-2
MF:C9H15NO3S
MW:217.29
EINECS:263-607-1
Product Categories:Active Pharmaceutical Ingredients;API's;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;FLUOROMAR;Angiotensin;APIS;Pharmaceutical intermediate;API;62571-86-2
Mol File:62571-86-2.mol
Captopril Structure
Captopril Chemical Properties
Melting point 104-108 °C (lit.)
alpha -129.5 º (c=1, EtOH)
Boiling point 427.0±40.0 °C(Predicted)
density 1.2447 (rough estimate)
refractive index -127.5 ° (C=1.7, EtOH)
storage temp. room temp
solubility H2O: 0.1 g/mL, very slightly hazy, colorless
pka3.7, 9.8(at 25℃)
form Crystalline Powder
color white to off-white
Water Solubility soluble
Merck 14,1774
BRN 477887
BCS Class3
Stability:Stable. Incompatible with strong oxidizing agents.
CAS DataBase Reference62571-86-2(CAS DataBase Reference)
NIST Chemistry ReferenceCaptopril(62571-86-2)
Safety Information
Hazard Codes Xn,Xi
Risk Statements 43-63-36/37/38-40
Safety Statements 36/37-37/39-26-36-22
WGK Germany 2
RTECS UY0550000
HS Code 29339900
Hazardous Substances Data62571-86-2(Hazardous Substances Data)
ToxicityLD50 in mice (mg/kg): 1040 i.v.; 6000 orally (Keim)
MSDS Information
ProviderLanguage
Captopril English
SigmaAldrich English
ACROS English
Captopril Usage And Synthesis
DescriptionCaptopril is the most studied of the angiotensin-converting enzyme inhibitors proposed as an antihypertensive drug. It blocks angiotensin-converting enzyme, which suppresses formation of angiotensin II and relieves its vasoconstricting effect on arterial and venous vessels. Overall vascular peripheral tension is reduced, which results in the lowering of arterial pressure.
Chemical PropertiesWhite or almost white, crystalline powder.
OriginatorLopirin,Von Heyden,W. Germany,1980
UsesOrally active angiotensin-converting enzyme (ACE) inhibitor
Usesanesthetic
Usesangiotensin-converting enzyme (ACE) inhibitor,anti-hypertensive
UsesCaptopril has also been shown to inhibit the formation of angiotensin II, a bioactive peptide that stimulates angiogenesis and increases microvessel density. Captopril demonstrates noncompetitive inhibition of tyrosinase monophenolase activity and competitive inhibition of diphenolase activity
DefinitionChEBI: A L-proline derivative in which L-proline is substituted on nitrogen with a (2S)-2-methyl-3-sulfanylpropanoyl group. It is used as an anti-hypertensive ACE inhibitor drug.
Manufacturing ProcessThe first step is the manufacture of L-proline tert-butyl ester. L-proline (230 g) is dissolved in a mixture of water (1 l) and 5 N sodium hydroxide (400 ml). The solution is chilled in an ice bath, and under vigorous stirring, 5 N sodium hydroxide (460 ml) and benzyloxycarbonyl chloride (340 ml) are added in five equal aliquots during a half-hour period. After one hour stirring at room temperature, the mixture is extracted twice with ether and acidified with concentrated hydrochloric acid. The precipitate is filtered and dried. Yield is 442 g; MP 78°C to 80°C.
The benzyloxycarbonyl-L-proline thus obtained (180 g) is dissolved in a mixture of dichloromethane (300 ml), liquid isobutylene (800 ml) and concentrated sulfuric acid (7.2 ml). The solution is shaken in a pressure bottle for 72 hours. The pressure is released, the isobutylene is allowed to evaporate and the solution is washed with 5% sodium carbonate, water, dried over magnesium sulfate and concentrated to dryness in vacuo, to obtain benzyloxycarbonyl-L-proline tert-butyl ester, yield 205 g.
Benzyloxycarbonyl-L-proline tert-butyl ester (205 g) is dissolved in absolute ethanol (1.2 l) and hydrogenated at normal pressure with 10% Pd on carbon (10 g) until only a trace of carbon dioxide is observed in the hydrogen exit gas (24 hours). The catalyst is filtered off and the filtrate is concentrated in vacuo at 30 mm Hg. The residue is distilled in vacuo, to obtain L-proline tert-butyl ester, BP1mm 50°C to 51°C.
The next step yields 1-(3-acetylthio-2-methylpropanoyl)-L-proline tert-butyl ester. L-proline tert-butyl ester (5.1 g) is dissolved in dichloromethane (40 ml) and the solution stirred and chilled in an ice bath. Dicyclohexylcarbodiimide (15 ml) is added followed immediately by a solution of 3-acetylthio-2- methylpropanoic acid (4.9 g) in dichloromethane (5 ml). After 15 minutes stirring in the ice bath and 16 hours at room temperature, the precipitate is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is dissolved in ethyl acetate and washed neutral. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo. The residue 1-(3- acetylthio-2-methylpropanoyl)-L-proline tert-butyl ester is purified by column chromatography (silica gel-chloroform), yield 7.9 g.
Then, 1-(3-acetylthio-2-methylpropanoyl)-L-proline is produced. The 1-(3- acetylthio-3-methylpropanoyl)-L-proline tert-butyl ester (7.8 g) is dissolved in a mixture of anisole (55 ml) and trifluoroacetic acid (110 ml). After one hour storage at room temperature the solvent is removed in vacuo and the residue is precipitated several times from ether-hexane. The residue (6.8 g) is dissolved in acetonitrile (40 ml) and dicyclohexylamine (4.5 ml) is added. The crystalline salt is boiled with fresh acetonitrile (100 ml), chilled to room temperature and filtered, yield 3.8 g, MP 187°C to 188°C. This material is recrystallized from isopropanol [α]D-67° (C 1.4, EtOH). The crystalline dicyclohexylamine salt is suspended in a mixture of 5% aqueous potassium bisulfate and ethyl acetate. The organic phase is washed with water and concentrated to dryness. The residue is crystallized from ethyl acetate-hexane to yield the 1-(3-acetylthio-2-D-methylpropanoyl)-L-proline, MP 83°C to 85°C.
Finally, Captopril is produced. The thioester (0.85 g) is dissolved in 5.5 N methanolic ammonia 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.




Brand nameCapoten (Par).
Therapeutic FunctionAntihypertensive
Biological FunctionsCaptopril (Capoten) is an orally effective ACE inhibitor with a sulfhydryl moiety that is used in binding to the active site of the enzyme. Captopril blocks the blood pressure responses caused by the administration of angiotensin I and decreases plasma and tissue levels of angiotensin II.
General DescriptionCaptopril, 1-[(2S)-3-mercapto-2-methyl-1-oxopropionyl]proline (Capoten), blocks the conversion of angiotensinI to angiotensin II by inhibiting the convertingenzyme. The rational development of captopril as an inhibitorof ACE was based on the hypothesis that ACE and carboxypeptidaseA functioned by similar mechanisms. It wasnoted that d-2-benzylsuccinic acid was a potent inhibitor ofcarboxypeptidase A, but not ACE. By use of this small molecule as a prototype, captopril was designed with a carboxylgroup on a proline and a thiol group was introduced toenhance the binding to the zinc ion of ACE. The importantbinding points at the active site of ACE are thought to be anarginine residue, which provides a cationic site that attracts acarboxylate ion, and a zinc ion, which can polarize a carbonylgroup of an amide function to make it more susceptible to hydrolysis.Hydrophobic pockets lie between these groups in theactive site, as does a functional group that forms a hydrogenbond with an amide carbonyl.
Biochem/physiol ActionsAngiotensin converting enzyme inhibitor. Inhibits the formation of angiotensin II, a bioactive peptide that stimulates angiogenesis and increases microvessel density.
PharmacologyTreatment with captopril reduces blood pressure in patients with renovascular disease and in patients with essential hypertension.The decrease in arterial pressure is related to a reduction in total peripheral resistance. Most studies demonstrate a good correlation between the hypotensive effect of inhibitors and the degree of blockade of the renin–angiotensin system.Many of the pharmacological effects of captopril are attributable to the inhibition of angiotensin II synthesis. However, ACE is a relatively nonselective enzyme that also catabolizes a family of kinins to inactive products. Bradykinin, one of the major kinins, acts as a vasodilator through mechanisms related to the production of nitric oxide and prostacyclin by the vascular endothelium. Thus, administration of the ACE inhibitor captopril not only inhibits angiotensin II production but also prevents the breakdown of bradykinin. Increases in bradykinin concentrations after administration of ACE inhibitors contribute to the therapeutic efficacy of these compounds in the treatment of hypertension and congestive heart failure. However, alterations in bradykinin concentrations are also thought to contribute to cough and angioedema sometimes seen after ACE inhibition. The hypotensive response to captopril is accompanied by a fall in plasma aldosterone and angiotensin II levels and an increase in plasma renin activity. Serum potassium levels are not affected unless potassium supplements or potassium-sparing diuretics are used concomitantly; this can result in severe hyperkalemia.
There is no baroreflex-associated increase in heart rate, cardiac output, or myocardial contractility in response to the decrease in pressure, presumably because captopril decreases the sensitivity of the baroreceptor reflex.
Captopril enhances cardiac output in patients with congestive heart failure by inducing a reduction in ventricular afterload and preload. Converting enzyme inhibitors have been shown to decrease the mass and wall thickness of the left ventricle in both normal and hypertrophied myocardium. ACE inhibitors lack metabolic side effects and do not alter serum lipids.

Clinical UseCaptopril, as well as other ACE inhibitors, is indicated in the treatment of hypertension, congestive heart failure, left ventricular dysfunction after a myocardial infarction, and diabetic nephropathy. In the treatment of essential hypertension, captopril is considered firstchoice therapy, either alone or in combination with a thiazide diuretic. Decreases in blood pressure are primarily attributed to decreased total peripheral resistance or afterload. An advantage of combining captopril therapy with a conventional thiazide diuretic is that the thiazide-induced hypokalemia is minimized in the presence of ACE inhibition, since there is a marked decrease in angiotensin II–induced aldosterone release.
If the patient is asymptomatic, captopril can be used as monotherapy in the treatment of congestive heart failure. The use of ACE inhibitors in the treatment of congestive heart failure is supported by results from large-scale clinical trials demonstrating a general reduction in the relative risk of death. In symptomatic patients captopril should be used in conjunction with a diuretic because of the weak natriuretic properties of ACE inhibitors. In combination, captopril will reduce afterload and preload and prevent diuretic-induced activation of the renin–angiotensin system. Finally, ACE inhibitors may slow the progression of congestive heart failure by limiting left ventricular hypertrophy.
In the treatment of diabetic nephropathy associated with type I insulin-dependent diabetes mellitus, captopril decreases the rate of progression of renal insufficiency and retards the worsening of renal function.

Side effectsApproximately 10% of the patients treated with captopril report a dose-related maculopapular rash that often disappears when the dosage of captopril is reduced. Other common adverse effects are fever, a persistent dry cough (incidence as high as 39%), initial dose hypotension, and a loss of taste that may result in anorexia. These effects are reversed when drug therapy is discontinued. More serious toxicities include a 1% incidence of proteinuria and glomerulonephritis; less common are leukopenia and agranulocytosis. Since food reduces the bioavailability of captopril by 30 to 40%, administration of the drug an hour before meals is recommended. All converting enzyme inhibitors are contraindicated in patients with bilateral renal artery disease or with unilateral renal artery disease and one kidney. Use under these circumstances may result in renal failure or paradoxical malignant hypertension.
SynthesisCaptopril, 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline (22.7.4), is synthesized by direct acylation of L-proline 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. 1-(3-Acetylthio-2-Dmethylpropanoyl)- 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).

Synthesis_62571-86-2

Veterinary Drugs and TreatmentsThe principle uses of captopril in veterinary medicine, at present, are as a vasodilator in the treatment of CHF and in the treatment of hypertension. Because of fewer adverse effects, enalapril and benazepril have largely supplanted the use of this drug in veterinary medicine.
Drug interactionsPotentially hazardous interactions with other drugs
Anaesthetics: enhanced hypotensive effect.
Analgesics: antagonism of hypotensive effect and increased risk of renal impairment with NSAIDs; hyperkalaemia with ketorolac and other NSAIDs.
Antihypertensives: increased risk of hyperkalaemia, hypotension and renal failure with ARBs and aliskiren.
Bee venom extract: possible severe anaphylactoid reactions when used together.
Ciclosporin: increased risk of hyperkalaemia and nephrotoxicity.
Cytotoxics: increased risk of angioedema with everolimus.
Diuretics: enhanced hypotensive effect; hyperkalaemia with potassium-sparing diuretics.
ESAs: increased risk of hyperkalaemia; antagonism of hypotensive effect.
Gold: flushing and hypotension with sodium aurothiomalate.
Lithium: reduced excretion, possibility of enhanced lithium toxicity.
Potassium salts: increased risk of hyperkalaemia.
Tacrolimus: increased risk of hyperkalaemia and nephrotoxicity
MetabolismThe onset of action following oral administration of captopril is about 15 minutes, with peak blood levels achieved in 30 to 60 minutes. Its apparent biological half-life is approximately 2 hours, with its antihypertensive effects observed for 6 to 10 hours. The kidneys appear to play a major role in the inactivation of captopril.
storage+4°C
Purification MethodsPurify it by recrystallisation from EtOAc/hexane. It is also purified by dissolving in EtOAc and chromatographed on a column of Wakogel C200 using a linear gradient of MeOH in EtOAc (0-100o) and fractions which give a positive nitroprusside test (for SH), are combined, evaporated and recrystallised from EtOAc/hexane (1:1), to give white crystals with [] D -128.2o (c 2.0, EtOH). [Nam J Pharm Sci 73 1843 1984]. Alternatively, dissolve it in H2O, apply to a column of AG-50Wx2 (BioRad) and elute with H2O. The free acid is converted to the dicyclohexylamine salt in MeCN by addition of the amine until the pH is 8-9. The salt is converted to the free acid by shaking with EtOAc and 10% aqueous KHSO4 or passage through an AG50Wx2 column. The EtOAc solution is dried (MgSO4), evaporated to dryness and the residue is recrystallised as above from EtOAc/hexane [Cushman et al. Biochemistry 16 5484 1977, NMR and IR: Horii & Watanabe Yakugaku Zasshi (J Pharm Soc Japan) 81 1786 1961]. It is an antihypertensive because it is a potent competitive inhibitor of the angiotensive convertive enzyme (ACE-inhibitor) with a Ki value of 0.0017\M [Shimazaki et al. Chem Pharm Bull Jpn 30 3139 1982].
References1) Cushman?et al. (1999),?Design of angiotensin converting enzyme inhibitors; Nat.Med.,?5?1110 2) Orning?et al. (1991),?Inhibition of leukotriene A4 hydrolase/aminopeptidase by captopril; J.Biol.Chem.,?266?16507
CAPTOPRIL DISULPHIDE CAPTOPRIL ETHYL ESTER MM,CAPTOPRIL ETHYL ESTER MM(CRM STANDARD) Captopril-D7 capozide CAPTOPRIL IMP. D (PHARMEUROPA):(2RS)-3-BROMO-2-METHYLPROPANOIC ACID Zofenopril Moveltipril Moveltipril calcium captopril-cysteine captopril N-ethylmaleimide sulfone Zofenoprilat Captopril CAPTOPRIL HCL S-nitrosocaptopril S-benzoyl captopril CAPTOPRIL DISULFIDE Zofenopril calcium 1-(3-ACETHYLTHIO-2-D-METHYLPROPANONYL)-L-PROLINE (ATMP)/CAPTOPRIL

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