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

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

Uses

Used in Pharmaceutical Industry:
Benazepril hydrochloride is used as an antihypertensive and angiotensin-converting enzyme (ACE) inhibitor for the treatment of essential hypertension. It helps lower blood pressure and is also used to treat congestive heart failure and chronic kidney disease in both human and veterinary medicine.
Used in Cardiovascular Applications:
Benazepril hydrochloride is used as a cardiostimulant under investigation, potentially offering benefits in cardiovascular health by improving heart function and overall cardiovascular system performance.
Used in Veterinary Medicine:
In veterinary medicine, benazepril hydrochloride is used as an antihypertensive and ACE inhibitor to treat hypertension, congestive heart failure, and chronic kidney disease in animals, helping to manage and improve their health conditions.

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

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

• 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 
• 109010-61-9 (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 
• 577-59-3 2-acetylnitrobenzene 
• 178114-28-8 4-(2-nitrophenyl)-2,4-dioxobutanoic acid ethyl ester 
• 46460-23-5 ethyl 2-amino-4-phenyl-(2S)-butyrate 
• 4424-80-0 2,3,4,5-tetrahydro-1H-1-benzo[b]azepin-2-one 
• 86499-22-1 3,3-dichloro-2,3,4,5-tetrahydro-1H-<1>benzazepin-2-one 
• 86499-23-2 3-chloro-2,3,4,5-tetrahydro-1H-<1>benzazepin-2-one 
• 97278-68-7 3-azido-2,3,4,5-tetrahydro-2-oxo-1 H-1-benzazepine 
• 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 
• 86541-75-5 benazepril 
• 90315-82-5 ethyl (R)-2-hydroxy-4-phenylbutyrate 

Downstream Products

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

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.

Synthesis method of benazepril intermediate and benazepril hydrochloride

The invention relates to a synthesis method of a benazepril intermediate and a benazepril hydrochloride. The synthesis method comprises: carrying out a reaction on 3-bromo-2,3,4,5-tetrahydro-1H-[1]-benzoazepine-2-keto-1-tert-butyl acetate and (S)-homophenylalanine, and carrying out dynamic kinetic resolution to obtain a benazepril intermediate; and carrying out an esterification reaction, and introducing hydrogen chloride gas to obtain a benazepril hydrochloride refined product. According to the invention, the benazepril hydrochloride is efficiently prepared by utilizing a dynamic kinetic resolution technology, so the steps are short, the operation is simple, the total yield is high, the atom economy is high, the environmental pollution is small, and the method is suitable for industrial production.

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.

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.

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.

CRYSTALLINE POLYMORPHS OF BENAZEPRIL HYDROCHLORIDE

The present invention relates to a specific polymorph form of crystalline benazepril hydrochloride referred to as Form B, methods for producing this form of benazepril hydrochloride, compositions containing it, and methods for using it.

BIS-DICARBOXYLIC ACID SALTS OF BENAZEPRIL AND PREPARATION OF BENAZEPRIL VIA THESE SALTS

Dicarboxylic acid salts of compounds of the formula (II) wherein R represents a selectively removable protecting group; and (S) denotes the (S)-configuration of the asymmetric carbon atoms, which are useful as intermediates for the preparation of benazepril or pharmaceutically acceptable salts thereof.

PROCESS FOR PREPARATION OF BENAZEPRIL

The present invention relates to an improved process for preparation of highly pure benazepril of Formula I, wherein R is hydrogen or pharmacologically acceptable salt thereof by completely eliminating the impurity of 7-bromo analogue of benazepril of Formula Ia, wherein R is bromo group.

Asymmetric synthesis of ACE inhibitor-Benazepril HCl via a bioreductive reaction

An enantioselective synthesis of the potent angiotensin converting enzyme (ACE) inhibitor (2S, 3′S)-2-(1-carboxymethyl-2-oxo-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3-ylamino)-4-phenylbutyric acid ethyl ester hydrochloride, Benazepril HCl 4, has been achieved through an asymmetric reduction of 4-(2-nitrophenyl)-2,4-dioxobutyric acid ethyl ester 6b employing baker's yeast as the reductive catalyst.

3-Amino-[1]-benzazepin-2-one-1-alkanoic acids

Variously substituted 1-carboxymethyl-3-(carboxymethylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-ones and functional derivatives are angiotensin converting enzyme inhibitors and are useful as antihypertensive agents. Synthesis of, compositions and methods of treatment utilizing such compounds are included.