76547-98-3

Basic information

• Product Name: Lisinopril
• Synonyms: mk522;PRINIL;PRINIVIL;n-{n-[(s)-1-carboxy-3-phenylpropyl]-l-lysyl}-l-proline;NOVATEC;MK-521;(S)-1-[(S)-6-AMINO-2-((S)-1-CARBOXY-3-PHENYL-PROPYLAMINO)-HEXANOYL]-PYRROLIDINE-2-CARBOXYLIC ACID;TENSOPRIL
• CAS NO: 76547-98-3
• Molecular Formula: C₂₁H₃₁N₃O₅
• Molecular Weight: 405.49
• EINECS: 278-488-1
• Mol File: 76547-98-3.mol
• Article Data: 12

Chemical Properties

• Melting Point: 162-165 °C
• Boiling Point: 666.4 °C at 760 mmHg
• Flash Point: 356.9 °C
• Appearance: white/solid
• Density: 1.251 g/cm³
• Vapor Pressure: 1.14E-18mmHg at 25°C
• Storage Temp.: 2-8°C
• Solubility: H2O: ≥10 mg/mL
• PKA: 2.18±0.10(Predicted)
• CAS DataBase Reference: Lisinopril(CAS DataBase Reference)
• NIST Chemistry Reference: Lisinopril(76547-98-3)
• EPA Substance Registry System: Lisinopril(76547-98-3)

Safety Data

• Safety Statements: 22-24/25
• WGK Germany: 3
• RTECS: TW3589990
• Hazardous Substances Data: 76547-98-3(Hazardous Substances Data)

Usage

Description

Lisinopril is an angiotensin-converting enzyme (ACE) inhibitor (IC50 = 1.2 nM). It reduces the formation of endothelin-1 and increases nitric oxide (NO) in human vascular endothelial cells when used at a concentration of 0.1 nM. Lisinopril inhibits the pressor response to angiotensin I in anesthetized rats and dogs (ID50s = 2.3 and 6.5 μg/kg, respectively).

Originator

Acebitor 5,Biddle Sawyer,India

Uses

Different sources of media describe the Uses of 76547-98-3 differently. You can refer to the following data:
1. Labeled Lisinopril, intended for use as an internal standard for the quantification fo Lisinopril by GC- or LC-mass spectrometry.
2. Lisinopril is an antihypertensive medication.

Manufacturing Process

2-Oxo-4-phenylbutyric acid and t-BOC-L-lysyl-L-proline are condensed in the presence of sodium cyanoborohydride. Essentially all of the t-BOC protecting group is cleaved when the product is absorbed on strong acid ion exchange resin. The crude N-(1-carboxy-3-phenylpropyl)-L-lysyl-L-proline is eluted from the resin with 10% ammonia, freeze dried, and purified by gel filtration chromatography (LH-20). A minute peak for t-BOC protons in the NMR spectrum disappears when the product is treated with ethyl acetate that is 4 N in hydrogen chloride gas. The NMR spectrum of the resulting HCl salt of the product is consistent with structure. The mass spectrum shows a molecular ion at 693 m/e for the tetrasilylated species. Chromatography on XAD-2 resin using 3.5% acetonitrile in 0.1 molar ammonium hydroxide affords N-α-((1S)- 1-carboxy-3-phenylpropyl)-L-lysyl-L-proline. The last peptide can be produced if 2-oxo-4-phenylbutyric acid and N-t-Boc-L-lysyl-L-proline are condensed in the presence of sodium cyanoborohydride. The product is absorbed on strong acid ion exchange resin, and eluted with 2% pyridine in water. Product-rich cuts are stripped to a glass and treated with 4 N HCl in ethylacetate to remove the t-Boc protecting group. The resulting hydrochloride salt is converted to the free base by absorbing on strong acid ion exchange resin and eluting with 2% pyridine in water. Freeze drying of product-rich cuts affords N-α-(1-carboxy-3-phenylpropyl)-L-lysyl-L-proline as a white fluffy solid. The NMR spectrum is consistent with structure. The mass spectrum shows a molecular ion at 549 for the disilylated species. Chromatography affords the desired isomer.

Brand name

Prinivil (Merck); Zestril (AstraZeneca).

Therapeutic Function

Antihypertensive

InChI:InChI:1S/C21H31N3O5/c22-13-5-4-9-16(19(25)24-14-6-10-18(24)21(28)29)23-17(20(26)27)12-11-15-7-2-1-3-8-15/h1-3,7-8,16-18,23H,4-6,9-14,22H2,(H,26,27)(H,28,29)

Synthetic route

Nε-(trifluoroacetyl)-Nα-<(S)-1-(ethoxycarbonyl)-3-phenylpropyl>-L-lysyl-L-proline (103300-91-0) → Lisinopril (76547-98-3)

Conditions	Yield
With water; sodium hydroxide at 40 - 45℃; pH=12 - 13;	92%

N2-<(S)-1-(ethoxycarbonyl)-3-phenylpropyl>-L-lysyl-L-proline (85955-58-4) → Lisinopril (76547-98-3)

Conditions	Yield
With sodium hydroxide for 24h; Ambient temperature;	75.8%

(S)-1-[N2-(1-carboxy-3-phenylpropyl]-L-lysyl]-L-proline (77726-95-5) → Lisinopril (76547-98-3) + lisinopril (85955-59-5)

Conditions	Yield
With hydrogenchloride In water Resolution of racemate;	A 75% B n/a

2-oxo-4-phenylbutyric acid (710-11-2) + H-Lys(Boc)-Pro-OH (4583-24-8) → Lisinopril (76547-98-3) + lisinopril (85955-59-5)

Conditions	Yield
With sodium hydroxide; Dowex 50 (H+, 50-100 mesh); sodium cyanoborohydride 1.) water, room temperature, pH 7.0; Yield given. Multistep reaction. Yields of byproduct given;

Nε-(trifluoroacetyl)-Nα-<(S)-1-(ethoxycarbonyl)-3-phenylpropyl>-L-lysyl-L-proline (103300-91-0) → Lisinopril (76547-98-3) + lisinopril (85955-59-5)

Conditions	Yield
With sodium hydroxide; sodium hydrogencarbonate at 40℃; for 4h;	A 75 % Chromat. B n/a
With sodium hydroxide; sodium hydrogencarbonate at 40℃; for 4h; Title compound not separated from byproducts;

N6-(tert-butoxycarbonyl)-N2-<(S)-1-(ethoxycarbonyl)-3-phenylpropyl>-L-lysyl-L-proline tert-butylester (120095-49-0) → Lisinopril (76547-98-3)

Conditions	Yield
With sodium hydroxide; trifluoroacetic acid Multistep reaction;
Multi-step reaction with 2 steps 1: 89 percent / TFA / 24 h / Ambient temperature 2: 75.8 percent / 1N NaOH / 24 h / Ambient temperature View Scheme

(S)-1-[(S)-6-tert-Butoxycarbonylamino-2-((R)-1-carboxy-3-oxo-3-phenyl-propylamino)-hexanoyl]-pyrrolidine-2-carboxylic acid tert-butyl ester; compound with (Z)-but-2-enedioic acid → Lisinopril (76547-98-3)

Conditions	Yield
With hydrogen; palladium on activated charcoal

L-proline benzyl ester hydrochloride (16652-71-4, 53843-90-6, 80089-24-3) → Lisinopril (76547-98-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 79 percent / Et3N, dicyclohexylcarbodiimide / CH2Cl2 / 0 deg C, 1 h -> room temperature, 15 h 2: 78 percent / H2 / Pd/C / ethanol; acetic acid / 15 h / 2068.6 Torr / Ambient temperature 3: 1.) aq. NaOH, aq. NaBH3CN, 2.) Dowex 50 (H+, 50-100 mesh) / 1.) water, room temperature, pH 7.0 View Scheme

N-(N2-benzyloxycarbonyl-N6-tert-butoxycarbonyl-L-lysyl)-L-proline benzyl ester (90826-23-6) → Lisinopril (76547-98-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 78 percent / H2 / Pd/C / ethanol; acetic acid / 15 h / 2068.6 Torr / Ambient temperature 2: 1.) aq. NaOH, aq. NaBH3CN, 2.) Dowex 50 (H+, 50-100 mesh) / 1.) water, room temperature, pH 7.0 View Scheme

N2-benzyloxycarbonyl-N6-tert-butoxycarbonyl-L-lysine → Lisinopril (76547-98-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 79 percent / Et3N, dicyclohexylcarbodiimide / CH2Cl2 / 0 deg C, 1 h -> room temperature, 15 h 2: 78 percent / H2 / Pd/C / ethanol; acetic acid / 15 h / 2068.6 Torr / Ambient temperature 3: 1.) aq. NaOH, aq. NaBH3CN, 2.) Dowex 50 (H+, 50-100 mesh) / 1.) water, room temperature, pH 7.0 View Scheme

3-benzoyl-2-propenoic acid (19522-26-0) → Lisinopril (76547-98-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) triethylamine / 1.) 5 h, RT, benzene; 2.) ethylacetate 2: H2 / Pd/C View Scheme

Benzoylacrylic acid (17812-07-6) → Lisinopril (76547-98-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) triethylamine / 1.) 5 h, RT, benzene; 2.) ethylacetate 2: H2 / Pd/C View Scheme

L-Lys(Boc)-L-Pro-OBut (32489-85-3) → Lisinopril (76547-98-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) triethylamine / 1.) 5 h, RT, benzene; 2.) ethylacetate 2: H2 / Pd/C View Scheme
Multi-step reaction with 2 steps 1: 1.) triethylamine / 1.) 5 h, RT, benzene; 2.) ethylacetate 2: H2 / Pd/C View Scheme

3-phenyl-propionaldehyde (104-53-0) + sodium- → Lisinopril (76547-98-3)

Conditions

Yield

Multi-step reaction with 7 steps 1: 45 percent / methanol; H2O / 8 h / 70 °C 2: 99.3 percent / NH4Cl / aq. NH3 / 50 h / 37 °C / enzymatic hydrolysis with Pseudomonas putida at pH 9 3: 1.) NaNO2, 2N H2SO4; 2.) KBr, NaNO2, 3N H2SO4 / 1.) 50percent CH3COOH, r.t., 24 h; 2.) 50percent CH3COOH, 0-5 deg C, 1 h 4: 95 percent / SOCl2 / 24 h / Ambient temperature 5: 70 percent / (NH4)2CO3 / H2O; nitromethane / 96 h / 50 °C 6: 89 percent / TFA / 24 h / Ambient temperature 7: 75.8 percent / 1N NaOH / 24 h / Ambient temperature View Scheme

5-phenylethyl-imidazolidine-2,4-dione (120379-81-9) → Lisinopril (76547-98-3)

Conditions

Yield

Multi-step reaction with 6 steps 1: 99.3 percent / NH4Cl / aq. NH3 / 50 h / 37 °C / enzymatic hydrolysis with Pseudomonas putida at pH 9 2: 1.) NaNO2, 2N H2SO4; 2.) KBr, NaNO2, 3N H2SO4 / 1.) 50percent CH3COOH, r.t., 24 h; 2.) 50percent CH3COOH, 0-5 deg C, 1 h 3: 95 percent / SOCl2 / 24 h / Ambient temperature 4: 70 percent / (NH4)2CO3 / H2O; nitromethane / 96 h / 50 °C 5: 89 percent / TFA / 24 h / Ambient temperature 6: 75.8 percent / 1N NaOH / 24 h / Ambient temperature View Scheme

(R)-2-bromo-4-phenylbutyric acid (121842-76-0) → Lisinopril (76547-98-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: 95 percent / SOCl2 / 24 h / Ambient temperature 2: 70 percent / (NH4)2CO3 / H2O; nitromethane / 96 h / 50 °C 3: 89 percent / TFA / 24 h / Ambient temperature 4: 75.8 percent / 1N NaOH / 24 h / Ambient temperature View Scheme

(R)-ethyl 2-bromo-4-phenylbutyrate (121842-77-1) → Lisinopril (76547-98-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 70 percent / (NH4)2CO3 / H2O; nitromethane / 96 h / 50 °C 2: 89 percent / TFA / 24 h / Ambient temperature 3: 75.8 percent / 1N NaOH / 24 h / Ambient temperature View Scheme

N-carbamyl (R)-2-amino-4-phenylbutyric acid (121842-75-9) → Lisinopril (76547-98-3)

Conditions	Yield
Multi-step reaction with 5 steps 1: 1.) NaNO2, 2N H2SO4; 2.) KBr, NaNO2, 3N H2SO4 / 1.) 50percent CH3COOH, r.t., 24 h; 2.) 50percent CH3COOH, 0-5 deg C, 1 h 2: 95 percent / SOCl2 / 24 h / Ambient temperature 3: 70 percent / (NH4)2CO3 / H2O; nitromethane / 96 h / 50 °C 4: 89 percent / TFA / 24 h / Ambient temperature 5: 75.8 percent / 1N NaOH / 24 h / Ambient temperature View Scheme

2-oxo-4-phenylbutyric acid (710-11-2) → Lisinopril (76547-98-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) molecular sieves, sodium acetate, catecholborane / 1.) CH2Cl2, -15 - 0 deg C, 1 h.; 2.) CH2Cl2 2: 1.) TFA; 2.) 1M NaOH View Scheme

ethanol (64-17-5) + Lisinopril (76547-98-3) → lisinopril diethyl ester (877865-60-6)

Conditions	Yield
With thionyl chloride for 3h; Reflux;	100%
Stage #1: ethanol; Lisinopril With thionyl chloride for 5.5h; Heating / reflux; Stage #2: With sodium hydrogencarbonate In water

Lisinopril (76547-98-3) → N-{N-[(S)-1-cyclohexylcarboxy-3-propyl]-L-lysyl}-L-proline

Conditions	Yield
With platinum(IV) oxide; hydrogen; acetic acid In methanol at 30℃; under 1292.9 - 1551.49 Torr; for 48h; Solvent; Temperature;	75%

zinc perchlorate + water (7732-18-5) + Lisinopril (76547-98-3) → 4C21H29N3O5(2-)*4Zn(2+)*16H2O

Conditions	Yield
With triethylamine In methanol at 79.84℃; for 38h; High pressure;	60%

diazomethane (186581-53-3, 908094-01-9) + Lisinopril (76547-98-3) → (S)-1-[(S)-6-Amino-2-((S)-1-methoxycarbonyl-3-phenyl-propylamino)-hexanoyl]-pyrrolidine-2-carboxylic acid methyl ester

Conditions	Yield
In methanol; diethyl ether at 5 - 10℃; for 0.5h;

4-azido-2,3,5,6-tetrafluorobenzonitrile (31469-89-3) + Lisinopril (76547-98-3) → (S)-1-{(S)-6-Amino-2-[N-((S)-1-carboxy-3-phenyl-propyl)-N'-(4-cyano-2,3,5,6-tetrafluoro-phenyl)-hydrazino]-hexanoyl}-pyrrolidine-2-carboxylic acid

Conditions	Yield
In d(4)-methanol Irradiation;

succinimidyl 4-azido-2,3,5,6-tetrafluorobenzoate (126695-58-7) + Lisinopril (76547-98-3) → (S)-1-[(S)-6-(4-Azido-2,3,5,6-tetrafluoro-benzoylamino)-2-((S)-1-carboxy-3-phenyl-propylamino)-hexanoyl]-pyrrolidine-2-carboxylic acid

Conditions	Yield
In N,N-dimethyl-formamide

Lisinopril (76547-98-3) + C11H14F4N7O4P (197070-57-8) → C32H45F4N8O9P

Conditions	Yield
In d(4)-methanol Irradiation;

Lisinopril (76547-98-3) + N-succinimidyl 4-[18F]fluorobenzoate (141762-27-8) → 4-[18F]fluorobenzoyllisinopril

Conditions	Yield
With triethylamine In water; acetonitrile at 20℃; for 0.25h;

Lisinopril (76547-98-3) → C21H29(3)H2N3O5

Conditions	Yield
Stage #1: Lisinopril With N-Bromosuccinimide; sulfuric acid at 65℃; for 2h; Stage #2: With hydrogen; triethylamine; palladium/alumina In methanol at 20℃;

di-tert-butyl dicarbonate (24424-99-5) + Lisinopril (76547-98-3) + triethylamine (121-44-8) → (S)-1-[N2-(1-carboxy-3-phenylpropyl)-L-lysyl(boc)]-L-proline (811788-06-4)

Conditions	Yield
In 1,4-dioxane; water at 0 - 20℃;

Upstream product

• 710-11-2 2-oxo-4-phenylbutyric acid 
• 4583-24-8 H-Lys(Boc)-Pro-OH 
• 103300-91-0 N^ε-(trifluoroacetyl)-N^α-<(S)-1-(ethoxycarbonyl)-3-phenylpropyl>-L-lysyl-L-proline 
• 120095-49-0 N⁶-(tert-butoxycarbonyl)-N²-<(S)-1-(ethoxycarbonyl)-3-phenylpropyl>-L-lysyl-L-proline tert-butylester 
• 85955-58-4 N²-<(S)-1-(ethoxycarbonyl)-3-phenylpropyl>-L-lysyl-L-proline 
• 16652-71-4 L-proline benzyl ester hydrochloride 
• 90826-23-6 N-(N²-benzyloxycarbonyl-N⁶-tert-butoxycarbonyl-L-lysyl)-L-proline benzyl ester 
• 77726-95-5 (S)-1-[N₂-(1-carboxy-3-phenylpropyl]-L-lysyl]-L-proline 
• 121842-75-9 N-carbamyl (R)-2-amino-4-phenylbutyric acid 
• 121842-77-1 (R)-ethyl 2-bromo-4-phenylbutyrate 
• 121842-76-0 (R)-2-bromo-4-phenylbutyric acid 
• 120379-81-9 5-phenylethyl-imidazolidine-2,4-dione 
• 104-53-0 3-phenyl-propionaldehyde 
• 32489-85-3 L-Lys(Boc)-L-Pro-OBu^t 

Downstream Products

• 1132650-67-9 N-{N-[(S)-1-cyclohexylcarboxy-3-propyl]-L-lysyl}-L-proline 
• 877865-60-6 lisinopril diethyl ester 
• 811788-06-4 (S)-1-[N₂-(1-carboxy-3-phenylpropyl)-L-lysyl(boc)]-L-proline 

Related news

The incidence of all-cause, cardiovascular and respiratory disease admission among 20,252 users of Lisinopril (cas 76547-98-3) vs. perindopril: A cohort study07/19/2019

BackgroundMajor international guidelines do not offer explicit recommendations on any specific angiotensin-converting enzyme inhibitor (ACEI) agent over another within the same drug group. This study compared the effectiveness of lisinopril vs. perindopril in reducing the incidence of hospital a...detailed

Fast and sensitive LC–MS/MS method for the simultaneous determination of Lisinopril (cas 76547-98-3) and hydrochlorothiazide in human plasma07/18/2019

A sensitive and rapid liquid chromatography-tandem mass spectrometry (LC–MS/MS) method has been developed for the simultaneous determination of lisinopril (LIS) and hydrochlorothiazide (HCTZ) in human plasma using their labeled internal standards (ISs). Sample pre-treatment involved solid phase...detailed

Daily Lisinopril (cas 76547-98-3) vs Placebo for Prevention of Chemoradiation-Induced Pulmonary Distress in Patients With Lung Cancer (Alliance MC1221): A Pilot Double-Blind Randomized Trial07/16/2019

PurposeChemoradiation (CRT) is an integral treatment modality for patients with locally advanced lung cancer. It has been hypothesized that current use of an angiotensin-converting enzyme inhibitor during CRT may be protective for treatment-related lung damage and pneumonitis.detailed

The cough reflex is upregulated by Lisinopril (cas 76547-98-3) microinjected into the caudal nucleus tractus solitarii of the rabbit07/15/2019

We have previously shown that cough potentiation induced by intravenous administration of the AT1 receptor antagonist losartan is lower than that induced by the ACE inhibitor lisinopril in anesthetized and awake rabbits. Since losartan and lisinopril cross the blood–brain barrier, their central...detailed

An innovative validated spectrofluorimetric method for determination of Lisinopril (cas 76547-98-3) in presence of hydrochlorothiazide; application to content uniformity testing07/14/2019

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Relevant articles and documents

On the Michael Type Addition of Dipeptides to 4-Oxo-4-phenyl-2-butenoic Acid Derivatives

The title reaction afforded the adducts 3 in variable selectivity, but the isomers of (S,S,S)-configuration were easily isolated; the reversibility of the reaction permits the recovery of the starting materials from the mother liquor.High selectivity has been observed in one case only. - Keywords: Michael type addition; 4-Oxo-4-phenyl-2-butenoic acids; (S)-Alanyl-(S)-proline; (S)-Lysyl-(S)-proline

COMPOSITIONS AND METHODS FOR DIAGNOSING AND TREATING SALT SENSITIVITY OF BLOOD PRESSURE

To characterize the urinary exosome miRNome, microarrays were used to identify the miRNA spectrum present within urinary exosomes from ten individuals that were previously classified for their salt sensitivity status. The present application discloses distinct patterns of selected exosomal miRNA expression that were different between salt-sensitive (SS), salt-resistant (SR), and inverse salt-sensitive (ISS) individuals. These miRNAs can be useful as biomarkers either individually or as panels comprising multiple miRNAs. The present invention provides compositions and methods for identifying, diagnosing, monitoring, and treating subjects with salt sensitivity of blood pressure. The applications discloses panels of miRNAs useful for comparing profiles, and in some cases one or more of the miRNAs in a panel can be used. The miRNAs useful for distinguishing SS and SR or ISS and SR subjects. One or more of the 45 miRNAs can be used. Some of the miRNAs have not been previously reported to be circulating. See those miRNAs with asterisks in FIG. 1 and below. The present invention encompasses the use of one or more of these markers for identifying and diagnosing SR, SS, and ISS subjects.

USE OF SUBSTITUTED 2 PHENYLBENZIMIDAZOLES AS MEDICAMENTS

The present invention relates to the use of a substituted 2-phenylbenzimidazole of formula I wherein R1, R2, R3, R 4, R5 and m have the meanings given in the claims, for the preparation of a medicament for the treatment or prevention of diseases involving glucagon receptors, as well as new compounds of formula I wherein R1 is a group of formula