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Benazepril

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Benazepril Basic information

Product Name:
Benazepril
Synonyms:
  • 2-[(4s)-4-[[(1s)-1-ethoxycarbonyl-3-phenyl-propyl]amino]-5-oxo-6-azabicyclo[5.4.0]undeca-7,9,11-trien-6-yl]acetic acid
  • genazepril
  • BENAZEPRIL HCL, RELATED COMPOUND B(3S)-3-[[(1R)-1-(ETHOXYCARBONYL)-3-PHENYLPROPYL]AMINO]-2,3,4,5-TETRAHYDRO-2-OXO-1H-1-BENAZAPINE-1-ACETIC ACID, MONOHYDROCHLORIDE USP STANDARD
  • BENAZEPRIL HCL, MM(CRM STANDARD)
  • BENAZEPRIL HCL, USP STANDARD
  • BENAZEPRIL HCL USP(CRM STANDARD)
  • BENAZEPRIL MM
  • BENAZEPRIL MM(CRM STANDARD)
CAS:
86541-75-5
MF:
C24H28N2O5
MW:
424.49
Product Categories:
  • API
  • Antihypertensive
  • Active Pharmaceutical Ingredients
Mol File:
86541-75-5.mol
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Benazepril Chemical Properties

Melting point:
148-149°
alpha 
D -159° (c = 1.2 in ethanol)
Boiling point:
691.2±55.0 °C(Predicted)
Density 
1.26±0.1 g/cm3(Predicted)
storage temp. 
2-8°C
solubility 
Soluble in DMSO
pka
3.73±0.10(Predicted)
BCS Class
1
CAS DataBase Reference
86541-75-5(CAS DataBase Reference)
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Safety Information

Safety Statements 
22-24/25
Hazardous Substances Data
86541-75-5(Hazardous Substances Data)
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Benazepril Usage And Synthesis

Originator

Lotensin,Novartis

Uses

Benazepril Free base is a non-sulfhydryl ACE inhibitor.

Definition

ChEBI: A benzazepine that is benazeprilat in which the carboxy group of the 2-amino-4-phenylbutanoic acid moiety has been converted to the corresponding ethyl ester. It is used (generally as its hydrochloride salt) as a prodrug for the angiotensin-converting enzy e inhibitor benazeprilat in the treatment of hypertension and heart failure.

Manufacturing Process

The synthesis of benzazepril based on a benzazepinone. It started by chlorination of lactam - 1,2,4,5-tetrahydrobenzo[b]azepin-2-one to the dichloro derivative 3,3-dichloro-1,2,4,5-tetrahydrobenzo[b]azepin-2-one. Catalytic reduction removed one of the gem chloro substituents to give 3- chloro-1,2,4,5-tetrahydrobenzo[b]azepin-2-one; the halogen was then displaced with sodium azide to give 3-azido-1,3,4,5- tetrahydrobenzo[b]azepin-2-one. Alkylation of the amide with ethyl bromoacetate in the presence of base yielded the ester (3-azido-2-oxo- 2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)acetic acid ethyl ester. Hydrogenation then converted the azide to an amino group to give 3-amino-2-oxo-2,3,4,5- tetrahydrobenzo[b]azepin-1-yl)acetic acid ethyl ester. It was then resolved by classical salt formation and crystallization. Saponification of the S enantiomer - S-(3-amino-2-oxo-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)acetic acid ethyl ester with sodium hydroxide afforded (3-amino-2-oxo-2,3,4,5- tetrahydrobenzo[b]azepin-1-yl)acetic acid. Reductive alkylation of it with 2- oxo-4-phenylbutyric acid ethyl ester and sodium cyanoborohydride gave the desired product as 70:30 mixture of diastereoisomers. The isolation of the predominant isomer gave benazepril. The epimerization occurred thermally and therefore required a sufficiently high temperature. The high temperature condition can be achieved by either using a high boiling-point solvent such as xylene or by heating the reaction mixture under pressure to increase its boiling-point temperature. Good results can be achieved in both polar and non-polar solvent systems. For example, both p-xylene and ethylene glycolwater systems are found suitable to conduct this process. The crude product acid 3-[(1-ethoxycarbonyl)-3-phenyl-(1S)-propylamino]-2,3,4,5-tetrahydro-2- oxo-1H-1-benzazepine-1-acetic acid was heated to reflux temperature for 30 hours in p-xylene. The mixture was cooled down to room temperature. Solvent removal resulted in a solid, which was then dried at reduced pressure to give a 98:2 diasteriomeric mixture as determined by HPLC, MP: 287°- 290°C. IR and 1H-NMR spectrum analysis. was confirmed the structure of product.

Therapeutic Function

Antihypertensive

Enzyme inhibitor

This ACE-directed pro-drug (FWfree-acid = 424.50 g/mol; CAS 86541-75-5), also known as 3-((1-(ethoxycarbonyl)-3-phenylpropyl)amino)-2,3,4,5- tetrahydro-2-oxo-(S-(R*,R*))-1H-1-benzazepine-1-acetic acid, Lotensin and CGS 14824A, is rapidly metabolized to its diacid benazeprilat (CGS 14831; FWfree-diacid = 396.44 g/mol), the latter a potent, long-acting inhibitor of peptidyl-dipeptidase A, or angiotensin I-converting enzyme, IC50 = 1.7 nM. Lotensin is used to treat hypertension, congestive heart failure, and chronic renal failure. The antihypertensive effects of benazepril begin as early as 30 min after a single dose, and those effects during consecutive dosing are also sustained for 24 h with a lesser diurnal variation in blood pressure

Benazepril Preparation Products And Raw materials

Raw materials

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