62571-86-2

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);3-Mercapto-2-Methylpropanoic acid 1,2-diphenylethylaMine salt (MMPA);Captopril API;Captopril Cardiovascular;(S)-(-)-1-(3-Mercapto-2-methyl-1-oxopropyl)-L-proline (S)-(-)-1-(3-Mercapto-2-methylpropionyl)-L-proline
• CAS NO: 62571-86-2
• Molecular Formula: C₉H₁₅NO₃S
• Molecular Weight: 217.29
• EINECS: 263-607-1
• Product Categories: APIS;Pharmaceutical intermediate;API;FLUOROMAR;Active Pharmaceutical Ingredients;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;API's;Angiotensin
• Mol File: 62571-86-2.mol
• Article Data: 33

Chemical Properties

• Melting Point: 104-108 °C(lit.)
• Boiling Point: 427 °C at 760 mmHg
• Flash Point: 212.1 °C
• Appearance: white to off-white/Crystalline Powder
• Density: 1.2447 (rough estimate)
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: -127.5 ° (C=1.7, EtOH)
• Storage Temp.: -20°C Freezer
• Solubility: H2O: 0.1 g/mL, very slightly hazy, colorless
• PKA: 3.7, 9.8(at 25℃)
• Water Solubility: soluble
• Stability: Stable. Incompatible with strong oxidizing agents.
• Merck: 14,1774
• BRN: 477887
• CAS DataBase Reference: Captopril(CAS DataBase Reference)
• NIST Chemistry Reference: Captopril(62571-86-2)
• EPA Substance Registry System: Captopril(62571-86-2)

Safety Data

• Hazard Codes: Xn,Xi
• Statements: 43-63-36/37/38-40
• Safety Statements: 36/37-37/39-26-36-22
• WGK Germany: 2
• RTECS: UY0550000
• Hazardous Substances Data: 62571-86-2(Hazardous Substances Data)

Usage

Description

Captopril 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 Properties

White or almost white, crystalline powder.

Originator

Lopirin,Von Heyden,W. Germany,1980

Uses

Different sources of media describe the Uses of 62571-86-2 differently. You can refer to the following data:
1. Orally active angiotensin-converting enzyme (ACE) inhibitor
2. anesthetic
3. angiotensin-converting enzyme (ACE) inhibitor,anti-hypertensive
4. 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 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 name

Capoten (Par).

Therapeutic Function

Antihypertensive

Biological Functions

Captopril (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 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 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 Use

Captopril, 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 effects

Approximately 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.

Synthesis

Captopril, 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).

Veterinary Drugs and Treatments

The 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 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 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.

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].

References

1) 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

InChI:InChI=1/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)/p-1/t6-,7+/m1/s1

Synthetic route

+ L-proline (147-85-3) → captopril (62571-86-2)

β-hydroxy-α-methyl-N-acryloyl-(S)-proline (613256-52-3) → captopril (62571-86-2)

Conditions	Yield
Stage #1: β-hydroxy-α-methyl-N-acryloyl-(S)-proline With thionyl chloride In tetrahydrofuran at 20℃; for 5h; Stage #2: With ammonium sulfide In tetrahydrofuran at 0 - 20℃; for 3.5h;	87%

(S)-1-((S)-3-tert-Butylsulfanyl-2-methyl-propionyl)-pyrrolidine-2-carboxylic acid tert-butyl ester (114857-98-6) → captopril (62571-86-2)

Conditions	Yield
With mercury(II) diacetate; trifluoroacetic acid Yield given;

N-(6-Methyl-pyridin-2-yl)-3-propionylamino-benzamide; compound with (S)-1-((S)-3-mercapto-2-methyl-propionyl)-pyrrolidine-2-carboxylic acid → captopril (62571-86-2) + N-(6-Methyl-pyridin-2-yl)-3-propionylamino-benzamide (87055-70-7)

Conditions	Yield
In chloroform-d1 at 25℃; Equilibrium constant;

N-(6-Methyl-pyridin-2-yl)-3-((S)-2-phenyl-butyrylamino)-benzamide; compound with (S)-1-((S)-3-mercapto-2-methyl-propionyl)-pyrrolidine-2-carboxylic acid → captopril (62571-86-2) + N-(6-Methyl-pyridin-2-yl)-3-((S)-2-phenyl-butyrylamino)-benzamide (143956-57-4)

Conditions	Yield
In chloroform-d1 at 25℃; Equilibrium constant;

N-(6-Methyl-pyridin-2-yl)-3-((R)-2-phenyl-butyrylamino)-benzamide; compound with (S)-1-((S)-3-mercapto-2-methyl-propionyl)-pyrrolidine-2-carboxylic acid → captopril (62571-86-2) + N-(6-Methyl-pyridin-2-yl)-3-((R)-2-phenyl-butyrylamino)-benzamide (143956-58-5)

Conditions	Yield
In chloroform-d1 at 25℃; Equilibrium constant;

(S)-1-[(S)-3-chloro-2-methylpropanoyl]pyrrolidine-2-carboxylic acid → captopril (62571-86-2)

Conditions	Yield
With ammonium sulfide In methanol for 24h; Heating;	1.86 g
With sodium hydrogen sulfide In water; toluene at 125℃; under 10343.2 Torr; for 0.5h; Temperature; Time; Inert atmosphere; Flow reactor;

1-(3-bromo-2S-methylpropionyl)-pyrrolidine-2S-carboxylic acid (80629-35-2) → captopril (62571-86-2)

Conditions	Yield
With ammonium sulfide In methanol for 24h; Heating;	1.95 g

H-Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2 (17912-60-6) + Captopril disulfide (64806-05-9) → oxytocin (50-56-6) + captopril (62571-86-2)

Conditions	Yield
In water at 25℃; for 5h; Equilibrium constant; pH 7.0;

H-Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2 (17912-60-6) + Captopril disulfide (64806-05-9) → captopril (62571-86-2) + C52H81N13O15S3 + C52H81N13O15S3

Conditions	Yield
In water at 25℃; for 5h; Rate constant; Equilibrium constant; pH 7.0;

Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2 (34223-44-4) + Captopril disulfide (64806-05-9) → Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2 (113-79-1, 5591-81-1, 66513-06-2, 66513-07-3, 76023-59-1, 89576-32-9) + captopril (62571-86-2)

Conditions	Yield
In water at 25℃; for 5h; Equilibrium constant; pH 7.0;

Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2 (34223-44-4) + Captopril disulfide (64806-05-9) → captopril (62571-86-2) + C55H80N16O15S3 + C55H80N16O15S3

Conditions	Yield
In water at 25℃; for 5h; Rate constant; Equilibrium constant; pH 7.0;

C52H81N13O15S3 + C52H81N13O15S3 → oxytocin (50-56-6) + captopril (62571-86-2)

Conditions	Yield
In water at 25℃; for 5h; Rate constant; Equilibrium constant; pH 7.0;

C55H80N16O15S3 + C55H80N16O15S3 → Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2 (113-79-1, 5591-81-1, 66513-06-2, 66513-07-3, 76023-59-1, 89576-32-9) + captopril (62571-86-2)

Conditions	Yield
In water at 25℃; for 5h; Rate constant; Equilibrium constant; pH 7.0;

(2S,2'S)-1-<3-(Acetylthio)-2-methylpropionyl>prolin-methylester (97716-22-8) → captopril (62571-86-2)

Conditions	Yield
With sodium hydroxide In methanol at 20℃; for 5h; Hydrolysis;

S-Nitrosocaptopril (122130-63-6) → captopril (62571-86-2)

Conditions	Yield
With ethylenediaminetetraacetic acid; sodium hydrogensulfite In phosphate buffer at 25℃; pH=7.4; Kinetics; Substitution;

dehydrochlorinationby-product-N-acryloylproline (60460-30-2) → captopril (62571-86-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 47 percent / H2O; tetrahydrofuran / 48 h / 20 °C / ultrasound 2.1: 70 percent / H2 / 5 percent Pd/C / ethyl acetate / 4 h / 20 °C / 760 Torr 3.1: SOCl2 / tetrahydrofuran / 5 h / 20 °C 3.2: 87 percent / aq. NH4SH / tetrahydrofuran / 3.5 h / 0 - 20 °C View Scheme

L-proline (147-85-3) + 3-CH3O-phenyl halide → captopril (62571-86-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 70 percent / aq. KOH / acetone / 3 h / 20 °C 2.1: 47 percent / H2O; tetrahydrofuran / 48 h / 20 °C / ultrasound 3.1: 70 percent / H2 / 5 percent Pd/C / ethyl acetate / 4 h / 20 °C / 760 Torr 4.1: SOCl2 / tetrahydrofuran / 5 h / 20 °C 4.2: 87 percent / aq. NH4SH / tetrahydrofuran / 3.5 h / 0 - 20 °C View Scheme

β-hydroxy-α-methylene-N-acryloyl-(S)-proline (613256-50-1) → captopril (62571-86-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 70 percent / H2 / 5 percent Pd/C / ethyl acetate / 4 h / 20 °C / 760 Torr 2.1: SOCl2 / tetrahydrofuran / 5 h / 20 °C 2.2: 87 percent / aq. NH4SH / tetrahydrofuran / 3.5 h / 0 - 20 °C View Scheme

proline tert-butyl ester (2812-46-6) → captopril (62571-86-2)

Conditions	Yield
Multi-step reaction with 2 steps 2: trifluoroacetic acid, mercuric acetate View Scheme

sodium ureido dithiocarbonate + sulfuric acid (7664-93-9) + 1-(3-bromo-2S-methylpropionyl)-pyrrolidine-2S-carboxylic acid (80629-35-2) + zinc (7440-66-6) → captopril (62571-86-2)

Conditions	Yield
With hydrogenchloride; sodium bicarbonate In hexane; ethyl acetate

S-allylthio-captopril + GLUTATHIONE (70-18-8) → prop-2-ene-1-thiol (870-23-5) + Oxidized glutathione (27025-41-8) + S-glutathionylthio-captopril (78636-30-3) + captopril (62571-86-2) + Allylglutathione sulphide

Conditions	Yield
at 20℃; for 20h; pH=6.5; aq. phosphate buffer;

S-allylthio-captopril + GLUTATHIONE (70-18-8) → prop-2-ene-1-thiol (870-23-5) + S-glutathionylthio-captopril (78636-30-3) + captopril (62571-86-2) + Allylglutathione sulphide

Conditions	Yield
at 20℃; for 3h; pH=6.5; aq. phosphate buffer;

S-allylthio-captopril + GLUTATHIONE (70-18-8) → captopril (62571-86-2) + Allylglutathione sulphide

Conditions	Yield
at 20℃; for 0.3h; pH=6.5; aq. phosphate buffer;

(2S)-1-[(2S)-3-acetylthio-2-methylpropanoyl]pyrrolidine-2-carboxylic acid (64838-55-7) → captopril (62571-86-2)

Conditions	Yield
With ammonia

L-proline (147-85-3) → captopril (62571-86-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide 2: ammonia View Scheme

Captopril disulfide (64806-05-9) → captopril (62571-86-2)

Conditions	Yield
With palladium on activated charcoal; hydrogen; zinc In dichloromethane; water at 80℃; under 4500.45 Torr; Acidic conditions;

(S)-3-mercapto-2-methyl propionyl chloride + L-proline (147-85-3) → captopril (62571-86-2)

Conditions	Yield
With sodium hydroxide at 0 - 20℃; for 3h; pH=7 - 9;
With sodium hydroxide at 0 - 20℃; for 3h; pH=7 - 9;
With sodium hydroxide at 0 - 20℃; for 3h; pH=7 - 9;

2-acetyl-1-((trifluoromethyl)thio)-1,2-dihydro-3H-1λ3-benzo[d][1,2]iodazol-3-one + captopril (62571-86-2) → ((S)-2-methyl-3-((trifluoromethyl)disulfanyl)propanoyl)-L-proline

Conditions	Yield
at 20℃; for 0.5h; Inert atmosphere;	99%

C21H28N7O6PolS3 + captopril (62571-86-2) → C21H34N4O5S3 (1354829-75-6)

Conditions	Yield
In water; N,N-dimethyl-formamide for 0.5h;	96%

1-(hexadecynyl)-1,2-benziodoxol-3(1H)-one + captopril (62571-86-2) → (S)-1-((S)-3-(hexadec-1-yn-1-ylthio)-2-methylpropanoyl)pyrrolidine-2-carboxylic acid

Conditions	Yield
Stage #1: captopril With 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine In tetrahydrofuran; water Stage #2: 1-(hexadecynyl)-1,2-benziodoxol-3(1H)-one In tetrahydrofuran; water at 23℃; for 0.0833333h;	94%

3-(1H-benzotriazol-1-ylcarbonyl)-2H-chromene-2-one (312929-01-4) + captopril (62571-86-2) → 1-{(S)-3-[(2-oxo-2H-chromene-3-carbonyl)thio]-2-methylpropanoyl}pyrrolidine-2-carboxylic acid (1327278-84-1)

Conditions	Yield
With triethylamine In water; acetonitrile at 25℃; for 1h;	92%

captopril (62571-86-2) + zinc(II) oxide → Zn(2+)*C9H13NO3S(2-) = [Zn(C9H13NO3S)]

Conditions	Yield
In methanol at 20℃;	91.4%

captopril (62571-86-2) → ((R)-2-methylpropanoyl-3-d)-L-proline

Conditions	Yield
With di-tert-butyl peroxide; water-d2; ethydiphenylphosphine oxide In dichloromethane at 20℃; for 10h; Solvent; Irradiation; Green chemistry;	91%

captopril (62571-86-2) + zinc(II) chloride (7646-85-7) → Zn(2+)*C9H13NO3S(2-) = [Zn(C9H13NO3S)]

Conditions	Yield
With sodium hydroxide In water	90.3%

7-methoxy-3-(1H-benzotriazol-1-ylcarbonyl)-2H-chromene-2-one (1286276-26-3) + captopril (62571-86-2) → 1-{(S)-3-[(7-methoxy-2-oxo-2H-chromene-3-carbonyl)thio]-2-methylpropanoyl}pyrrolidine-2-carboxylic acid (1327278-90-9)

Conditions	Yield
With triethylamine In water; acetonitrile at 25℃; for 1h;	90%

3-(1H-benzotriazol-1-ylcarbonyl)-7-(diethylamino)-2H-chromen-2-one (1286276-78-5) + captopril (62571-86-2) → 1-((S)-3-{[7-(diethylamino)-2-oxo-2H-chromene-3-carbonyl]thio}-2-methylpropanoyl)pyrrolidine-2-carboxylic acid (1327278-88-5)

Conditions	Yield
With triethylamine In water; acetonitrile at 25℃; for 1h;	90%

captopril (62571-86-2) + 1-[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one → (S)-1-((S)-2-methyl-3-(((triisopropylsilyl)ethynyl)thio)propanoyl)pyrrolidine-2-carboxylic acid (1443746-71-1)

Conditions	Yield
Stage #1: captopril With N,N,N',N'-tetramethylguanidine In tetrahydrofuran; water at 20℃; for 0.0833333h; Stage #2: 1-[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one In tetrahydrofuran; water at 20℃; for 0.0833333h; chemoselective reaction;	90%

aquocobalamin chloride + captopril (62571-86-2) → CapSCbl

Conditions	Yield
In water Kinetics; soln. captopril in water (pH adjusted to 4.3) was added dropwise to soln. HOCbl*HCl in water (pH adjusted to 6.6), final react. mixt. pH 4.2, 3 h at 0°C in the dark; soln. was poured into chilled acetone (-20°C), ppt. was filtered,washed with chilled acetone (-20°C), Et2O (-20°C) and dri ed in vacuo (50°C, 5E-2 mbar) overnight;	88%

trityl chloride (76-83-5) + captopril (62571-86-2) → (2-methyl-3-(tritylthio)propanoyl)proline

Conditions	Yield
In dichloromethane at 20℃; for 12h; Inert atmosphere;	86%
In N,N-dimethyl-formamide at 20℃; for 5h;

captopril (62571-86-2) + [14C]-Irofulven (158440-71-2) → C24H31NO5S

Conditions	Yield
With sulfuric acid In acetone at 20℃; for 12h; Condensation;	84%

captopril (62571-86-2) → 1-(1-oxo-2-methylpropyl)-L-proline (23500-15-4)

Conditions	Yield
With triethyl borane; tributylphosphine; triethyl phosphite In acetonitrile for 36h; Irradiation;	83%

methanol (67-56-1) + captopril (62571-86-2) → methyl 1-(3-mercapto-2-methylpropanoyl)pyrrolidine-2-carboxylate

Conditions	Yield
With thionyl chloride at 0 - 60℃;	82%
With thionyl chloride at 0 - 60℃; for 7h;	50%

4-Nitrophthalonitrile (31643-49-9) + captopril (62571-86-2) → 4-captopril phthalonitrile (1446888-23-8)

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide at 20℃; for 48h; Inert atmosphere;	76.3%

dimethyl-4-nitrophenylsulfonium trifluoromethanesulfonate + captopril (62571-86-2) → ((S)-2-methyl-3-((4-nitrophenyl)thio)propanoyl)-L-proline

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere; Schlenk technique;	75%

captopril (62571-86-2) + ethyl iodide (75-03-6) → ethyl 1-(3-(ethylthio)-2-methylpropanoyl)pyrrolidine-2-carboxylate

Conditions	Yield
Stage #1: captopril With potassium carbonate In acetone at 20℃; for 1h; Stage #2: ethyl iodide In acetone at 50℃; for 24h;	72%

(S)-N-(1-(1H-benzo[d][1,2,3]triazol-1-yl)-1-oxo-3-phenylpropan-2-yl)-2-propylpentanamide + captopril (62571-86-2) → ((S)-2-methyl-3-(((2-propylpentanoyl)phenylalanyl)thio)propanoyl)proline

Conditions	Yield
Stage #1: (S)-N-(1-(1H-benzo[d][1,2,3]triazol-1-yl)-1-oxo-3-phenylpropan-2-yl)-2-propylpentanamide; captopril In methanol; water at 20℃; for 0.0833333h; Stage #2: With potassium hydrogencarbonate In methanol; water	71%

1-(1H-benzo[d][1,2,3]triazol-1-yl)-2-propylpentan-1-one + captopril (62571-86-2) → ((S)-2-methyl-3-((2-propylpentanoyl)thio)propanoyl)proline

Conditions	Yield
Stage #1: 1-(1H-benzo[d][1,2,3]triazol-1-yl)-2-propylpentan-1-one; captopril In methanol; water at 20℃; for 0.0833333h; Stage #2: With potassium hydrogencarbonate In methanol; water	70%

7-(2-(3,3-dimethyl-1λ3-benzo[d][1,2]iodaoxol-1(3H)-yl)-1,1,2,2-tetrafluoroethoxy)-4-methyl-2H-chromen-2-one + captopril (62571-86-2) → C21H21F4NO6S

Conditions	Yield
In dichloromethane at -78℃; for 1h;	68%

(S)-N-(1-(1H-benzo[d][1,2,3]triazol-1-yl)-3-methyl-1-oxobutan-2-yl)-2-propylpentanamide + captopril (62571-86-2) → ((S)-2-methyl-3-(((2-propylpentanoyl)valyl)thio)propanoyl)proline

Conditions	Yield
Stage #1: (S)-N-(1-(1H-benzo[d][1,2,3]triazol-1-yl)-3-methyl-1-oxobutan-2-yl)-2-propylpentanamide; captopril In methanol; water at 20℃; for 0.0833333h; Stage #2: With potassium hydrogencarbonate In methanol; water	68%

benzoyl chloride (98-88-4) + captopril (62571-86-2) → S-benzoylcaptopril

Conditions	Yield
With sodium hydroxide In water; toluene at 5 - 20℃; for 1h;	65%

captopril (62571-86-2) + hexachloro[60]fullerene (151013-83-1) → C105H71N5O15S5

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In toluene for 0.0833333h;	63%

+ captopril (62571-86-2) → ((S)-3-(((4-methoxyphenyl)ethynyl)thio)-2-methylpropanoyl)-L-proline

Conditions	Yield
With pyridine; (1,2-dimethoxyethane)dichloronickel(II); (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile In N,N-dimethyl-formamide; acetonitrile at 20℃; for 0.5h; Inert atmosphere; Sealed tube; Irradiation;	61%

captopril (62571-86-2) + acetyl chloride (75-36-5) → (2S)-1-[(2S)-3-acetylthio-2-methylpropanoyl]pyrrolidine-2-carboxylic acid (64838-55-7)

Conditions	Yield
With triethylamine In dichloromethane at -5 - 20℃; for 4.5h; pH=8 - 9;	59.8%
With triethylamine In dichloromethane at -5 - 20℃; for 4.5h; pH=8-9;	503.9 mg
for 0.0833333h;

zinc(II) nitrate (10196-18-6) + captopril (62571-86-2) → Zn(2+)*C9H13NO3S(2-) = [Zn(C9H13NO3S)]

Conditions	Yield
With NH3 In water (inert atmosphere); pH 8.5, stirring 1 h; concn. (vac.), cooling to 4°C for 1 d, filtration, washing (H2O),drying (vac.); elem. anal.;	51%

Upstream product

• 34223-44-4 Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH₂ 
• 64806-05-9 Captopril disulfide 
• 7664-93-9 sulfuric acid 
• 80629-35-2 1-(3-bromo-2S-methylpropionyl)-pyrrolidine-2S-carboxylic acid 
• 7440-66-6 zinc 
• 78825-16-8 1-(3-mercapto-2-D-methyl-1-oxopropyl)-L-proline 
• 147-85-3 L-proline 
• 64838-55-7 (2S)-1-[(2S)-3-acetylthio-2-methylpropanoyl]pyrrolidine-2-carboxylic acid 
• 70-18-8 GLUTATHIONE 
• 2812-46-6 proline tert-butyl ester 
• 613256-50-1 β-hydroxy-α-methylene-N-acryloyl-(S)-proline 
• 60460-30-2 dehydrochlorinationby-product-N-acryloylproline 
• 613256-52-3 β-hydroxy-α-methyl-N-acryloyl-(S)-proline 
• 122130-63-6 S-Nitrosocaptopril 

Downstream Products

• 17912-60-6 H-Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH₂ 
• 64806-05-9 Captopril disulfide 
• 34223-44-4 Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH₂ 
• 64838-57-9 captopril disulfide 
• 870-23-5 prop-2-ene-1-thiol 
• 70-18-8 GLUTATHIONE 
• 78636-30-3 S-glutathionylthio-captopril 
• 27025-41-8 Oxidized glutathione 

Relevant articles and documents

Spectroscopic investigation on kinetics and mechanistic aspects to electron-transfer process into quinolinium dichromate oxidation of a high blood pressure drug captopril in acidic medium

This study investigated on kinetics of oxidation of captopril by QDC was studied spectrophotometrically in acidic medium along with its mechanistic pathway. Such studies are greatly helpful in gaining an insight into the interaction of metal ions through the study of the mechanistic pathway of CPL in redox reactions. The oxidative product of captopril was found to be captopril disulfide was separated, and identified by FT-IR. A suitable free radical mechanism was proposed. The reaction exhibited first-order kinetics with respect to [oxidant] and fractional order in CPL. Consequently, the interaction between the complex species and CPL is supported kinetic orders of reaction by spectrophotometric verification, positive entropy of activation and the first-order rate constant increased with the increase in the dielectric constant and increase ionic strength of the medium. The reaction constants involved in the mechanism were computed and the overall activation parameters were evaluated which lend support to the proposed mechanism.

THE ASYMMETRIC SYNTHESIS OF (-)-CAPTOPRIL UTILISING THE IRON CHIRAL AUXILIARY 5-C5H5)Fe(CO)(PPh3)>

Stereoselective alkylation of (R)-5-C5H5)Fe(CO)(PPh3)COCH2CH3> with bromomethyl-t-butyl sulphide, followed by oxidative decomplexation in the presence of L-proline t-butyl ester gave, after deprotection, (-)-Captopril enantiomerically and diastereomerically pure in an overall yield of 59percent.

Chemoenzymatic Synthesis in Flow Reactors: A Rapid and Convenient Preparation of Captopril

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For renin-angiotensin-aldosterone system dual inhibitor compounds

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