Captopril CAS 62571-86-2
Introduction：Basic information about Captopril CAS 62571-86-2, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Captopril Basic informationBackground
| 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;Pharmaceutical intermediate;API;APIS;Angiotensin;62571-86-2 |
| Mol File: | 62571-86-2.mol |
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 |
| form | Crystalline Powder |
| pka | 3.7, 9.8(at 25℃) |
| color | white to off-white |
| biological source | synthetic (organic) |
| Optical Rotation | -112.8°(C=0.01g/ml ETOH) |
| Water Solubility | soluble |
| Merck | 14,1774 |
| BRN | 477887 |
| BCS Class | 3 |
| Stability: | Stable. Incompatible with strong oxidizing agents. |
| InChI | 1S/C9H15NO3S/c1-6(5-14)8(11)10-4-2-3-7(10)9(12)13/h6-7,14H,2-5H2,1H3,(H,12,13)/t6-,7+/m1/s1 |
| InChIKey | FAKRSMQSSFJEIM-RQJHMYQMSA-N |
| SMILES | C[C@H](CS)C(=O)N1CCC[C@H]1C(O)=O |
| CAS DataBase Reference | 62571-86-2(CAS DataBase Reference) |
| NIST Chemistry Reference | Captopril(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 |
| Storage Class | 6.1C - Combustible acute toxic Cat.3 toxic compounds or compounds which causing chronic effects |
| Hazard Classifications | Muta. 2 Repr. 1B |
| Hazardous Substances Data | 62571-86-2(Hazardous Substances Data) |
| Toxicity | LD50 in mice (mg/kg): 1040 i.v.; 6000 orally (Keim) |
| Description | Captopril is the most studied of the angiotensin-converting enzyme inhibitors proposed as anantihypertensive drug. It blocks angiotensin-converting enzyme, which suppresses formationof angiotensin II and relieves its vasoconstricting effect on arterial and venous vessels. Overallvascular peripheral tension is reduced, which results in the lowering of arterial pressure. |
| Chemical Properties | White or almost white, crystalline powder. |
| Originator | Lopirin,Von Heyden,W. Germany,1980 |
| Uses | Orally active angiotensin-converting enzyme (ACE) inhibitor |
| Uses | anesthetic |
| Uses | angiotensin-converting enzyme (ACE) inhibitor,anti-hypertensive |
| Uses | Captopril 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 |
| Definition | ChEBI: 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 Process | The 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 sodiumhydroxide (460 ml) and benzyloxycarbonyl chloride (340 ml) are added in fiveequal aliquots during a half-hour period. After one hour stirring at roomtemperature, the mixture is extracted twice with ether and acidified withconcentrated hydrochloric acid. The precipitate is filtered and dried. Yield is442 g; MP 78°C to 80°C. The benzyloxycarbonyl-L-proline thus obtained (180 g) is dissolved in amixture of dichloromethane (300 ml), liquid isobutylene (800 ml) andconcentrated sulfuric acid (7.2 ml). The solution is shaken in a pressure bottlefor 72 hours. The pressure is released, the isobutylene is allowed to evaporateand the solution is washed with 5% sodium carbonate, water, dried overmagnesium sulfate and concentrated to dryness in vacuo, to obtainbenzyloxycarbonyl-L-proline tert-butyl ester, yield 205 g. Benzyloxycarbonyl-L-proline tert-butyl ester (205 g) is dissolved in absoluteethanol (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 exitgas (24 hours). The catalyst is filtered off and the filtrate is concentrated invacuo 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-butylester. 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 minutesstirring in the ice bath and 16 hours at room temperature, the precipitate isfiltered off and the filtrate is concentrated to dryness in vacuo. The residue isdissolved 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 columnchromatography (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 ina mixture of anisole (55 ml) and trifluoroacetic acid (110 ml). After one hourstorage at room temperature the solvent is removed in vacuo and the residueis precipitated several times from ether-hexane. The residue (6.8 g) isdissolved in acetonitrile (40 ml) and dicyclohexylamine (4.5 ml) is added. Thecrystalline salt is boiled with fresh acetonitrile (100 ml), chilled to roomtemperature and filtered, yield 3.8 g, MP 187°C to 188°C. This material isrecrystallized from isopropanol [α]D-67° (C 1.4, EtOH). The crystallinedicyclohexylamine salt is suspended in a mixture of 5% aqueous potassiumbisulfate and ethyl acetate. The organic phase is washed with water andconcentrated to dryness. The residue is crystallized from ethyl acetate-hexaneto 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 Nmethanolic ammonia and the solution is kept at room temperature for 2hours. 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, analyticalgrade) and eluted with water. The fractions that give positive thiol reaction arepooled 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 meltingpoint of 103°C to 104°C. |
| Brand name | Capoten (Par). |
| Therapeutic Function | Antihypertensive |
| Biological Functions | Captopril (Capoten) is an orally effective ACE inhibitorwith a sulfhydryl moiety that is used in binding to theactive site of the enzyme. Captopril blocks the bloodpressure responses caused by the administration of angiotensinI and decreases plasma and tissue levels of angiotensinII. |
| General Description | Captopril, 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 Actions | Angiotensin converting enzyme inhibitor. Inhibits the formation of angiotensin II, a bioactive peptide that stimulates angiogenesis and increases microvessel density. |
| Pharmacology | Treatment with captopril reduces blood pressure inpatients with renovascular disease and in patients withessential hypertension.The decrease in arterial pressureis related to a reduction in total peripheral resistance.Most studies demonstrate a good correlation betweenthe hypotensive effect of inhibitors and the degree ofblockade of the renin–angiotensin system.Many of thepharmacological effects of captopril are attributable tothe inhibition of angiotensin II synthesis. However,ACE is a relatively nonselective enzyme that also catabolizesa family of kinins to inactive products. Bradykinin, one of the major kinins, acts as a vasodilatorthrough mechanisms related to the productionof nitric oxide and prostacyclin by the vascular endothelium.Thus, administration of the ACE inhibitorcaptopril not only inhibits angiotensin II production butalso prevents the breakdown of bradykinin. Increases inbradykinin concentrations after administration of ACEinhibitors contribute to the therapeutic efficacy of thesecompounds in the treatment of hypertension and congestiveheart failure. However, alterations in bradykinin concentrations are also thought to contribute to coughand angioedema sometimes seen after ACE inhibition.The hypotensive response to captopril is accompaniedby a fall in plasma aldosterone and angiotensin IIlevels and an increase in plasma renin activity. Serumpotassium levels are not affected unless potassium supplementsor 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 responseto the decrease in pressure, presumably because captoprildecreases the sensitivity of the baroreceptor reflex. Captopril enhances cardiac output in patients withcongestive heart failure by inducing a reduction in ventricularafterload and preload. Converting enzyme inhibitorshave been shown to decrease the mass and wall thickness of the left ventricle in both normal and hypertrophiedmyocardium. ACE inhibitors lack metabolicside effects and do not alter serum lipids. |
| Clinical Use | Captopril, as well as other ACE inhibitors, is indicatedin the treatment of hypertension, congestive heartfailure, left ventricular dysfunction after a myocardialinfarction, and diabetic nephropathy. In the treatmentof essential hypertension, captopril is considered firstchoicetherapy, either alone or in combination with athiazide diuretic. Decreases in blood pressure are primarilyattributed to decreased total peripheral resistanceor afterload. An advantage of combining captopriltherapy with a conventional thiazide diuretic is that thethiazide-induced hypokalemia is minimized in the presenceof ACE inhibition, since there is a marked decreasein angiotensin II–induced aldosterone release. If the patient is asymptomatic, captopril can be usedas monotherapy in the treatment of congestive heartfailure. The use of ACE inhibitors in the treatment ofcongestive heart failure is supported by results fromlarge-scale clinical trials demonstrating a general reductionin the relative risk of death. In symptomatic patientscaptopril should be used in conjunction with a diureticbecause of the weak natriuretic properties ofACE inhibitors. In combination, captopril will reduceafterload and preload and prevent diuretic-induced activationof the renin–angiotensin system. Finally, ACEinhibitors may slow the progression of congestive heartfailure by limiting left ventricular hypertrophy. In the treatment of diabetic nephropathy associatedwith type I insulin-dependent diabetes mellitus, captoprildecreases the rate of progression of renal insufficiencyand retards the worsening of renal function. |
| Side effects | Approximately 10% of the patients treated withcaptopril report a dose-related maculopapular rashthat often disappears when the dosage of captopril isreduced. Other common adverse effects are fever, apersistent dry cough (incidence as high as 39%), initialdose hypotension, and a loss of taste that may result inanorexia. These effects are reversed when drug therapyis discontinued. More serious toxicities include a1% incidence of proteinuria and glomerulonephritis;less common are leukopenia and agranulocytosis.Since food reduces the bioavailability of captopril by30 to 40%, administration of the drug an hour beforemeals is recommended. All converting enzyme inhibitorsare contraindicated in patients with bilateralrenal artery disease or with unilateral renal artery diseaseand one kidney. Use under these circumstancesmay result in renal failure or paradoxical malignanthypertension. |
| Synthesis | Captopril, 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline (22.7.4), is synthesizedby 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 isin 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, togive the desired captopril (22.7.4). |
| Veterinary Drugs and Treatments | The principle uses of captopril in veterinary medicine, at present,are as a vasodilatorin the treatment of CHF and in the treatmentof hypertension. Because of fewer adverse effects,enalapril andbenazepril have largely supplanted the use of this drug in veterinarymedicine. |
| Drug interactions | Potentially 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 |
| Metabolism | The onset of action following oral administration ofcaptopril is about 15 minutes, with peak blood levelsachieved in 30 to 60 minutes. Its apparent biologicalhalf-life is approximately 2 hours, with its antihypertensiveeffects observed for 6 to 10 hours. The kidneys appearto play a major role in the inactivation of captopril. |
| storage | +4°C |
| Purification Methods | Purify 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]. |
| Background | Captopril is a selective and reversible angiotensin-converting enzyme inhibitor with an IC50 value of 0.022 μM. This small molecule selectively lowers angiotensin II, a hormone that when upregulated has been linked to increased hypertension, atherosclerosis, myocardial hypertrophy, and obesity. Captopril has also been shown to regulate inflammatory pathways as a reversible inhibitor of leukotriene A4 hydrolase, reducing leukotriene B4 synthesis. |
| References | [1] DAVID W. CUSHMAN Miguel A O. Design of angiotensin converting enzyme inhibitors[J]. Nature Medicine, 1999, 5 10: 1110-1112. DOI:10.1038/13423 [2] L ORNING. Inhibition of leukotriene A4 hydrolase/aminopeptidase by captopril.[J]. The Journal of Biological Chemistry, 1991, 266 25: 16507-16511. |
Captopril Preparation Products And Raw materials
| Raw materials | Ethyl acetate-->Magnesium sulfate-->Carbon dioxide-->Isobutylene-->Isobutyric acid-->Dicyclohexylcarbodiimide-->Benzyl chloroformate-->Cyclohexylamine-->L-Proline-->Thioacetic acid-->Pressure vessels-->Ammonia-->Hydrogen-->Trifluoroacetic acid |
