86541-74-4

Basic information

• Product Name: Benazepril hydrochloride
• Synonyms: 1h-1-benzazepine-1-aceticacid,2,3,4,5-tetrahydro-3-((1-(ethoxycarbonyl)-3-phe;cgs14824a;monohydrochloride,(s-(r*,r*))-nylpropyl)amino)-2-oxo;BenazeprilHclC24H28N205.HC1;1H-1-Benzazepine-1-acetic acid, 3-(1S)-1-(ethoxycarbonyl)-3-phenylpropylamino-2,3,4,5-tetrahydro-2-oxo-, monohydrochloride, (3S)-;1H-1-Benzazepine-1-acetic acid, 3-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-2-oxo-, monohydrochloride, [S-(R*,R*)]-;CGS 14824A HCl;Lotensin
• CAS NO: 86541-74-4
• Molecular Formula: C₂₄H₂₈N₂O₅*ClH
• Molecular Weight: 460.95
• EINECS: 1308068-626-2
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;Amines;Aromatics;Heterocycles;API;SONATA
• Mol File: 86541-74-4.mol
• Article Data: 13

Chemical Properties

• Melting Point: 188-190°C
• Boiling Point: 691.2 °C at 760 mmHg
• Flash Point: 371.8 °C
• Appearance: white/solid
• Storage Temp.: Desiccate at +4°C
• Solubility: DMSO: ~34 mg/mL, soluble
• Merck: 14,1031
• CAS DataBase Reference: Benazepril hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: Benazepril hydrochloride(86541-74-4)
• EPA Substance Registry System: Benazepril hydrochloride(86541-74-4)

Safety Data

• Safety Statements: 22-24/25
• RIDADR: 3077
• WGK Germany: 2
• RTECS: CX7065000
• Hazardous Substances Data: 86541-74-4(Hazardous Substances Data)

Usage

Description

Different sources of media describe the Description of 86541-74-4 differently. You can refer to the following data:
1. Benazepril hydrochloride, a prodrug of benazeprilat, is a long-acting angiotensionconverting enzyme (ACE) inhibitor useful in the treatment of essential hypertension. In healthy humans, it was well tolerated and showed no phmacokinetic interactions with furosemide, hydrochlorothiazide, chlorthalidone, digoxin, cimetidine, atenolol, or naproxen. Benazepril hydrochloride is under investigation as a cardiostirnulant.
2. Benazepril is a prodrug of the angiotensin converting enzyme (ACE) inhibitor benazeprilat . It is metabolized to benazeprilat by hepatic esterases. Benazepril inhibits the in vitro enzymatic activity of partially purified ACE isolated from rabbit lung (IC50 = 2 nM). It decreases the triglyceride and total cholesterol levels in normotensive rats when administered at a dose of 30 mg/kg and decreases aortic atherosclerosis in cholesterol-fed rabbits when administered at a dose of 3 mg/kg per day. Benazepril (0.1-10 mg/kg per day) reduces blood pressure in spontaneously hypertensive rats. It also decreases proteinuria in cats with chronic kidney disease when administered at doses ranging from 0.5 to 1 mg/kg per day. Formulations containing benazepril have been used to treat hypertension, congestive heart failure, and chronic kidney disease in both human and veterinary medicine.

Chemical Properties

Crystalline Solid

Uses

Used as an antihypertensive; angiotensin converting enzyme inhibitor.

Definition

ChEBI: A hydrochloride salt resulting from the reaction of benazepril with 1 mol eq. of hydrogen chloride. It is used as a prodrug for angiotensin-converting enzyme 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.

Brand name

Lotensin (Novartis);Cibacen.

Therapeutic Function

Antihypertensive

General Description

Pharmaceutical secondary standards for application in quality control provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards

Biological Activity

Non-peptide angiotensin-converting enzyme (ACE) inhibitor. Reduces blood pressure and myocardial hypertrophy in spontaneous hypertensive rats.

Biochem/physiol Actions

Benazepril is a long-acting angiotensin converting enzyme (ACE) inhibitor.

InChI:InChI=1/C24H28N2O5.ClH/c1-2-31-24(30)20(14-12-17-8-4-3-5-9-17)25-19-15-13-18-10-6-7-11-21(18)26(23(19)29)16-22(27)28;/h3-11,19-20,25H,2,12-16H2,1H3,(H,27,28);1H/t19-,20+;/m1./s1

Synthetic route

(2S,3'S)-2-(1-tert-butoxycarbonylmethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylamino)-4-phenylbutyric acid ethyl ester (109010-61-9) → benazepril hydrochloride (86541-74-4)

Conditions	Yield
With hydrogenchloride In ethyl acetate	91.6%
With hydrogenchloride In toluene at 0 - 20℃; for 1.5h;	90%
With hydrogenchloride In ethyl acetate at -10 - 25℃; for 16h; Industry scale;
With hydrogenchloride In ethyl acetate at 10℃; under 760.051 Torr; Solvent; Reflux;	Ca. 114 g
With hydrogenchloride In Isopropyl acetate at 10℃;	99.6 g

ethyl (S)-2-(((S)-1-(2-(benzyloxy)-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3- yl)amino)-4-phenylbutanoate → benazepril hydrochloride (86541-74-4)

Conditions	Yield
Stage #1: ethyl (S)-2-(((S)-1-(2-(benzyloxy)-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3- yl)amino)-4-phenylbutanoate With palladium 10% on activated carbon; hydrogen In ethanol at 20℃; for 3h; Stage #2: With hydrogenchloride In ethyl acetate; acetone Reflux;	91%

2-oxo-4-phenylbutanoic acid ethyl ester (64920-29-2) + (3S)-3-amino-1-(carboxymethyl)-2,3,4,5-tetrahydro-1H-<1>benzazepin-2-one sodium salt (86499-53-8) → benazepril hydrochloride (86541-74-4) + (3S)-1-(carboxymethyl)-<<(1S)-1-(ethoxycarbonyl)-3-phenylpropyl>amino>-2,3,4,5-tetrahydro-1H-<1>benzazepin-2-one hydrochloride (86541-77-7)

Conditions	Yield
With sodium cyanoborohydride In methanol; acetic acid Ambient temperature;	A 12% B 25%

2-acetylnitrobenzene (577-59-3) → benazepril hydrochloride (86541-74-4)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: 99 percent / sodium ethoxide / tetrahydrofuran / 2 h / 0 °C 2.1: phenacyl chloride; baker's yeast / diethyl ether; H2O / 24 h / 30 °C 3.1: H2; HCl / Pd/C / methanol / 20 °C 3.2: 42 percent / AcOH / toluene / 80 °C 4.1: Et3N / tetrahydrofuran / 16 h / 20 °C 5.1: 78 percent / 1,2-dimethoxy-ethane / 60 h / 50 °C 6.1: tetrabutylammonium bromide; KOH / tetrahydrofuran / 0.5 h / 0 °C 6.2: 98 percent / tetrahydrofuran / 5 h / 20 °C 7.1: 90 percent / HCl / toluene / 1.5 h / 0 - 20 °C View Scheme
Multi-step reaction with 8 steps 1.1: 99 percent / sodium ethoxide / tetrahydrofuran / 2 h / 0 °C 2.1: phenacyl chloride; baker's yeast / diethyl ether; H2O / 24 h / 30 °C 3.1: NaBH4; acetic acid / 2 h / 0 °C 4.1: H2 / Pd/C / methanol / 24 h / 20 °C 4.2: H2; hydrochloric acid / Pd/C / methanol / 36 h / 20 °C 4.3: 74 percent / AcOH / toluene / 16 h / 80 °C 5.1: Et3N / tetrahydrofuran / 16 h / 20 °C 6.1: 78 percent / 1,2-dimethoxy-ethane / 60 h / 50 °C 7.1: tetrabutylammonium bromide; KOH / tetrahydrofuran / 0.5 h / 0 °C 7.2: 98 percent / tetrahydrofuran / 5 h / 20 °C 8.1: 90 percent / HCl / toluene / 1.5 h / 0 - 20 °C View Scheme

4-(2-nitrophenyl)-2,4-dioxobutanoic acid ethyl ester (178114-28-8) → benazepril hydrochloride (86541-74-4)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: phenacyl chloride; baker's yeast / diethyl ether; H2O / 24 h / 30 °C 2.1: H2; HCl / Pd/C / methanol / 20 °C 2.2: 42 percent / AcOH / toluene / 80 °C 3.1: Et3N / tetrahydrofuran / 16 h / 20 °C 4.1: 78 percent / 1,2-dimethoxy-ethane / 60 h / 50 °C 5.1: tetrabutylammonium bromide; KOH / tetrahydrofuran / 0.5 h / 0 °C 5.2: 98 percent / tetrahydrofuran / 5 h / 20 °C 6.1: 90 percent / HCl / toluene / 1.5 h / 0 - 20 °C View Scheme
Multi-step reaction with 7 steps 1.1: phenacyl chloride; baker's yeast / diethyl ether; H2O / 24 h / 30 °C 2.1: NaBH4; acetic acid / 2 h / 0 °C 3.1: H2 / Pd/C / methanol / 24 h / 20 °C 3.2: H2; hydrochloric acid / Pd/C / methanol / 36 h / 20 °C 3.3: 74 percent / AcOH / toluene / 16 h / 80 °C 4.1: Et3N / tetrahydrofuran / 16 h / 20 °C 5.1: 78 percent / 1,2-dimethoxy-ethane / 60 h / 50 °C 6.1: tetrabutylammonium bromide; KOH / tetrahydrofuran / 0.5 h / 0 °C 6.2: 98 percent / tetrahydrofuran / 5 h / 20 °C 7.1: 90 percent / HCl / toluene / 1.5 h / 0 - 20 °C View Scheme

ethyl 2-amino-4-phenyl-(2S)-butyrate (46460-23-5) → benazepril hydrochloride (86541-74-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 78 percent / 1,2-dimethoxy-ethane / 60 h / 50 °C 2.1: tetrabutylammonium bromide; KOH / tetrahydrofuran / 0.5 h / 0 °C 2.2: 98 percent / tetrahydrofuran / 5 h / 20 °C 3.1: 90 percent / HCl / toluene / 1.5 h / 0 - 20 °C View Scheme

(3R)-3-hydroxy-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (608148-60-3) → benazepril hydrochloride (86541-74-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: Et3N / tetrahydrofuran / 16 h / 20 °C 2.1: 78 percent / 1,2-dimethoxy-ethane / 60 h / 50 °C 3.1: tetrabutylammonium bromide; KOH / tetrahydrofuran / 0.5 h / 0 °C 3.2: 98 percent / tetrahydrofuran / 5 h / 20 °C 4.1: 90 percent / HCl / toluene / 1.5 h / 0 - 20 °C View Scheme

(2R)-2-hydroxy-4-(2-nitrophenyl)-4-oxobutyric acid ethyl ester (608148-58-9) → benazepril hydrochloride (86541-74-4)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: H2; HCl / Pd/C / methanol / 20 °C 1.2: 42 percent / AcOH / toluene / 80 °C 2.1: Et3N / tetrahydrofuran / 16 h / 20 °C 3.1: 78 percent / 1,2-dimethoxy-ethane / 60 h / 50 °C 4.1: tetrabutylammonium bromide; KOH / tetrahydrofuran / 0.5 h / 0 °C 4.2: 98 percent / tetrahydrofuran / 5 h / 20 °C 5.1: 90 percent / HCl / toluene / 1.5 h / 0 - 20 °C View Scheme
Multi-step reaction with 6 steps 1.1: NaBH4; acetic acid / 2 h / 0 °C 2.1: H2 / Pd/C / methanol / 24 h / 20 °C 2.2: H2; hydrochloric acid / Pd/C / methanol / 36 h / 20 °C 2.3: 74 percent / AcOH / toluene / 16 h / 80 °C 3.1: Et3N / tetrahydrofuran / 16 h / 20 °C 4.1: 78 percent / 1,2-dimethoxy-ethane / 60 h / 50 °C 5.1: tetrabutylammonium bromide; KOH / tetrahydrofuran / 0.5 h / 0 °C 5.2: 98 percent / tetrahydrofuran / 5 h / 20 °C 6.1: 90 percent / HCl / toluene / 1.5 h / 0 - 20 °C View Scheme

(R)-2,4-Dihydroxy-4-(2-nitro-phenyl)-butyric acid ethyl ester (656830-87-4) → benazepril hydrochloride (86541-74-4)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: H2 / Pd/C / methanol / 24 h / 20 °C 1.2: H2; hydrochloric acid / Pd/C / methanol / 36 h / 20 °C 1.3: 74 percent / AcOH / toluene / 16 h / 80 °C 2.1: Et3N / tetrahydrofuran / 16 h / 20 °C 3.1: 78 percent / 1,2-dimethoxy-ethane / 60 h / 50 °C 4.1: tetrabutylammonium bromide; KOH / tetrahydrofuran / 0.5 h / 0 °C 4.2: 98 percent / tetrahydrofuran / 5 h / 20 °C 5.1: 90 percent / HCl / toluene / 1.5 h / 0 - 20 °C View Scheme

4-(2-nitro-phenyl)-2,4-dioxo-butyric acid butyl ester → benazepril hydrochloride (86541-74-4)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: phenacyl chloride; baker's yeast / diethyl ether; H2O / 24 h / 30 °C 1.2: H2; hydrochloric acid / Pd/C / methanol / 20 °C 1.3: AcOH / toluene / 80 °C 2.1: Et3N / tetrahydrofuran / 16 h / 20 °C 3.1: 78 percent / 1,2-dimethoxy-ethane / 60 h / 50 °C 4.1: tetrabutylammonium bromide; KOH / tetrahydrofuran / 0.5 h / 0 °C 4.2: 98 percent / tetrahydrofuran / 5 h / 20 °C 5.1: 90 percent / HCl / toluene / 1.5 h / 0 - 20 °C View Scheme

4-nitrobenzenesulfonic acid (3R)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl ester (608148-63-6) → benazepril hydrochloride (86541-74-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 78 percent / 1,2-dimethoxy-ethane / 60 h / 50 °C 2.1: tetrabutylammonium bromide; KOH / tetrahydrofuran / 0.5 h / 0 °C 2.2: 98 percent / tetrahydrofuran / 5 h / 20 °C 3.1: 90 percent / HCl / toluene / 1.5 h / 0 - 20 °C View Scheme

(2S,3'S)-2-(2'-oxo-2',3',4',5'-tetrahydro-1H-benzo[b]azepin-3'-ylamino)-4-phenylbutyric acid ethyl ester (367909-45-3) → benazepril hydrochloride (86541-74-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: tetrabutylammonium bromide; KOH / tetrahydrofuran / 0.5 h / 0 °C 1.2: 98 percent / tetrahydrofuran / 5 h / 20 °C 2.1: 90 percent / HCl / toluene / 1.5 h / 0 - 20 °C View Scheme

2,3,4,5-tetrahydro-1H-1-benzo[b]azepin-2-one (4424-80-0) → benazepril hydrochloride (86541-74-4)

Conditions

Yield

Multi-step reaction with 8 steps 1: 90 percent / PCl5 / xylene / 0.5 h / 90 °C 2: 95 percent / H2, sodium acetate / 5percent Pd/C / acetic acid / 0.5 h / 760 Torr / Ambient temperature 3: 90 percent / sodium azide / dimethylsulfoxide / 3 h / 80 °C 4: 96 percent / Bu4NBr, KOH / tetrahydrofuran / 1.5 h / Ambient temperature 5: 93 percent / H2 / 10percent Pd/C / ethanol / 1.5 h / 2280 Torr / Ambient temperature 7: 89 percent / aq. NaOH / methanol / 2 h / Ambient temperature 8: 12 percent / sodium cyanoborohydride / acetic acid; methanol / Ambient temperature View Scheme

3,3-dichloro-2,3,4,5-tetrahydro-1H-<1>benzazepin-2-one (86499-22-1) → benazepril hydrochloride (86541-74-4)

Conditions

Yield

Multi-step reaction with 7 steps 1: 95 percent / H2, sodium acetate / 5percent Pd/C / acetic acid / 0.5 h / 760 Torr / Ambient temperature 2: 90 percent / sodium azide / dimethylsulfoxide / 3 h / 80 °C 3: 96 percent / Bu4NBr, KOH / tetrahydrofuran / 1.5 h / Ambient temperature 4: 93 percent / H2 / 10percent Pd/C / ethanol / 1.5 h / 2280 Torr / Ambient temperature 6: 89 percent / aq. NaOH / methanol / 2 h / Ambient temperature 7: 12 percent / sodium cyanoborohydride / acetic acid; methanol / Ambient temperature View Scheme

3-chloro-2,3,4,5-tetrahydro-1H-<1>benzazepin-2-one (86499-23-2) → benazepril hydrochloride (86541-74-4)

Conditions

Yield

Multi-step reaction with 6 steps 1: 90 percent / sodium azide / dimethylsulfoxide / 3 h / 80 °C 2: 96 percent / Bu4NBr, KOH / tetrahydrofuran / 1.5 h / Ambient temperature 3: 93 percent / H2 / 10percent Pd/C / ethanol / 1.5 h / 2280 Torr / Ambient temperature 5: 89 percent / aq. NaOH / methanol / 2 h / Ambient temperature 6: 12 percent / sodium cyanoborohydride / acetic acid; methanol / Ambient temperature View Scheme

3-azido-2,3,4,5-tetrahydro-2-oxo-1 H-1-benzazepine (97278-68-7) → benazepril hydrochloride (86541-74-4)

Conditions	Yield
Multi-step reaction with 5 steps 1: 96 percent / Bu4NBr, KOH / tetrahydrofuran / 1.5 h / Ambient temperature 2: 93 percent / H2 / 10percent Pd/C / ethanol / 1.5 h / 2280 Torr / Ambient temperature 4: 89 percent / aq. NaOH / methanol / 2 h / Ambient temperature 5: 12 percent / sodium cyanoborohydride / acetic acid; methanol / Ambient temperature View Scheme

ethyl 3-azido-2,3,4,5-tetrahydro-1H-<1>benzazepin-2-one-1-acetate (92278-69-8) → benazepril hydrochloride (86541-74-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 93 percent / H2 / 10percent Pd/C / ethanol / 1.5 h / 2280 Torr / Ambient temperature 3: 89 percent / aq. NaOH / methanol / 2 h / Ambient temperature 4: 12 percent / sodium cyanoborohydride / acetic acid; methanol / Ambient temperature View Scheme

3-(S)-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepine-2-one (94793-89-2) → benazepril hydrochloride (86541-74-4)

Conditions	Yield
Multi-step reaction with 3 steps 2: 89 percent / aq. NaOH / methanol / 2 h / Ambient temperature 3: 12 percent / sodium cyanoborohydride / acetic acid; methanol / Ambient temperature View Scheme

(S)-3-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (86499-52-7) → benazepril hydrochloride (86541-74-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 89 percent / aq. NaOH / methanol / 2 h / Ambient temperature 2: 12 percent / sodium cyanoborohydride / acetic acid; methanol / Ambient temperature View Scheme

3-[[1-(t-butoxy-carbonyl)-3-phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid ethyl ester (859635-53-3) → benazepril hydrochloride (86541-74-4)

Conditions	Yield
With hydrogenchloride In ethyl acetate at 0℃; for 2 - 3h;

benazepril (86541-75-5) → benazepril hydrochloride (86541-74-4)

Conditions	Yield
Stage #1: benazepril With Celite; pyrographite In acetone for 1h; Heating / reflux; Industry scale; Stage #2: With hydrogenchloride In water; acetone at 10 - 50℃; for 3h;

2-oxo-4-phenylbutanoic acid ethyl ester (64920-29-2) + (3S)-3-amino-1-(carboxymethyl)-2,3,4,5-tetrahydro-1H-<1>benzazepin-2-one sodium salt (86499-53-8) → benazepril hydrochloride (86541-74-4)

Conditions	Yield
With hydrogenchloride; sodium cyanoborohydride In methanol; dichloromethane; acetic acid; butanone
With hydrogenchloride; sodium cyanoborohydride In methanol; dichloromethane; acetic acid; butanone

ethyl (R)-2-hydroxy-4-phenylbutyrate (90315-82-5) → benazepril hydrochloride (86541-74-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / ethyl acetate / 3 h / 0 - 25 °C 2: sodium carbonate / ethyl acetate / 20 h / 80 °C / 760.05 Torr 3: hydrogenchloride / ethyl acetate / 10 °C / 760.05 Torr / Reflux View Scheme

3-bromo-2,3,4,5-tetrahydro-1H-[1]-benzoazepine-2-one-1-acetic acid tert-butyl ester → benazepril hydrochloride (86541-74-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triethylamine / methanol / 24 h / 60 °C 2.1: 1,1'-carbonyldiimidazole / Isopropyl acetate / 4 h / 20 °C 2.2: 4 h 3.1: hydrogenchloride / Isopropyl acetate / 10 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / isopropyl alcohol / 24 h / 60 °C 2.1: 1,1'-carbonyldiimidazole / Isopropyl acetate / 4 h / 20 °C 2.2: 4 h 3.1: hydrogenchloride / Isopropyl acetate / 10 °C View Scheme

D-homophenylalanine (943-73-7) → benazepril hydrochloride (86541-74-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: triethylamine / methanol / 24 h / 60 °C 2.1: 1,1'-carbonyldiimidazole / Isopropyl acetate / 4 h / 20 °C 2.2: 4 h 3.1: hydrogenchloride / Isopropyl acetate / 10 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / isopropyl alcohol / 24 h / 60 °C 2.1: 1,1'-carbonyldiimidazole / Isopropyl acetate / 4 h / 20 °C 2.2: 4 h 3.1: hydrogenchloride / Isopropyl acetate / 10 °C View Scheme

benzyl 2-((S)-3-(((S)-1-((2-nitrobenzyl) amino)-1-oxo-4-phenylbutan-2-yl) amino)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)acetate → benazepril hydrochloride (86541-74-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: trifluoroacetic acid / 5 h / Reflux 2.1: palladium 10% on activated carbon; hydrogen / ethanol / 3 h / 20 °C 2.2: Reflux View Scheme

3-phenyl-propionaldehyde (104-53-0) → benazepril hydrochloride (86541-74-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: titanium tetrachloride / 2,2,2-trifluoroethanol / 7 h / 25 °C 2.1: trifluoroacetic acid / 5 h / Reflux 3.1: palladium 10% on activated carbon; hydrogen / ethanol / 3 h / 20 °C 3.2: Reflux View Scheme

benzyl (3S)-3-amino-2,3,4,5-tetrahydro-2-oxo-1H-benzazepine-1-acetate (183508-58-9) → benazepril hydrochloride (86541-74-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: titanium tetrachloride / 2,2,2-trifluoroethanol / 7 h / 25 °C 2.1: trifluoroacetic acid / 5 h / Reflux 3.1: palladium 10% on activated carbon; hydrogen / ethanol / 3 h / 20 °C 3.2: Reflux View Scheme

benazepril hydrochloride (86541-74-4) → benazepril (86541-75-5)

Conditions	Yield
With potassium carbonate In Isopropyl acetate; water at 20℃; pH=4 - 5; Industry scale;

benazepril hydrochloride (86541-74-4) → benazeprilate (86541-78-8)

Conditions	Yield
With hydrogenchloride; sodium hydroxide In methanol; water
With sodium hydroxide for 0.5h; Reflux;

Upstream product

• 46460-23-5 ethyl 2-amino-4-phenyl-(2S)-butyrate 
• 94793-89-2 3-(S)-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepine-2-one 
• 86499-52-7 (S)-3-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one 
• 943-73-7 D-homophenylalanine 
• 183508-58-9 benzyl (3S)-3-amino-2,3,4,5-tetrahydro-2-oxo-1H-benzazepine-1-acetate 
• 104-53-0 3-phenyl-propionaldehyde 
• 90315-82-5 ethyl (R)-2-hydroxy-4-phenylbutyrate 
• 64920-29-2 2-oxo-4-phenylbutanoic acid ethyl ester 
• 86499-53-8 (3S)-3-amino-1-(carboxymethyl)-2,3,4,5-tetrahydro-1H-<1>benzazepin-2-one sodium salt 
• 86541-75-5 benazepril 
• 859635-53-3 3-[[1-(t-butoxy-carbonyl)-3-phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid ethyl ester 
• 92278-69-8 ethyl 3-azido-2,3,4,5-tetrahydro-1H-<1>benzazepin-2-one-1-acetate 
• 97278-68-7 3-azido-2,3,4,5-tetrahydro-2-oxo-1 H-1-benzazepine 
• 86499-23-2 3-chloro-2,3,4,5-tetrahydro-1H-<1>benzazepin-2-one 

Downstream Products

• 86541-78-8 benazeprilate 
• 86541-75-5 benazepril 

Relevant articles and documents

Use of convertible isocyanides for the synthesis of benazepril hydrochloride

Herein, we have described a novel and concise synthesis of the potent angiotensin-converting enzyme (ACE) inhibitor, benazepril hydrochloride (7) in trifluoroethanol via an Ugi three-component reaction in shorter reaction times. The key step is the trifluoroacetic acid-mediated hydrolysis of secondary amides (4a and 4b) followed by esterification as a domino process to form corresponding ethyl ester (6). Mainly two universal convertible isocyanides (1a and 1b) were used for the synthesis of benazepril hydrochloride. Graphic abstract: [Figure not available: see fulltext.] Synopsis: An efficient synthesis of benazepril hydrochloride using Ugi three-component reaction.

An improved method for preparing of the benazepril hydrochloride and containing the pharmaceutical composition of the benazepril hydrochloride

The invention discloses an improved preparation method of benazepril hydrochloride and pharmaceutical composition containing the benazepril hydrochloride. With the adoption of the preparation method, the safety is high, the cost is low, the clean production value is high, industrial production is easy to realize, and meanwhile, the pharmaceutical composition is easy to prepare and use.

IMPROVED PROCESS FOR CRYSTALLIZATION OF BENAZEPRIL HYDROCHLORIDE

An improved process for the crystallization of benazepril hydrochloride to obtain in at least 99.8% diastereomeric purity. The process comprises making a concentrated solution of benazepril hydrochloride in ethanol and adding the resulting solution to a non-solvent diisopropyl ether.