[ CAS No. 86541-74-4 ] {[proInfo.proName]}

Name: 86541-74-4|2-((S)-3-(((S)-1-Ethoxy-1-oxo-4-phenylbutan-2-yl)amino)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)acetic acid hydrochloride|98%
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SKU: A430288
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Quality Control of [ 86541-74-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 86541-74-4 ]

SDS Specification

Alternatived Products of [ 86541-74-4 ]

Product Details of [ 86541-74-4 ]

CAS No. :	86541-74-4	MDL No. :	MFCD00895734
Formula :	C₂₄H₂₉ClN₂O₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VPSRQEHTHIMDQM-FKLPMGAJSA-N
M.W :	460.95	Pubchem ID :	5362123
Synonyms :	CGS14824A;Benazepril (hydrochloride);CGS 14824A HCl;Benazepril hydrochloride	Chemical Name :	2-((S)-3-(((S)-1-Ethoxy-1-oxo-4-phenylbutan-2-yl)amino)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)acetic acid hydrochloride

Calculated chemistry of [ 86541-74-4 ]

Physicochemical Properties

Num. heavy atoms :	32
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.38
Num. rotatable bonds :	10
Num. H-bond acceptors :	6.0
Num. H-bond donors :	2.0
Molar Refractivity :	127.21
TPSA :	95.94 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.65 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	2.06
Log Po/w (WLOGP) :	2.99
Log Po/w (MLOGP) :	2.43
Log Po/w (SILICOS-IT) :	3.14
Consensus Log Po/w :	2.13

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.61
Solubility :	0.112 mg/ml ; 0.000244 mol/l
Class :	Soluble
Log S (Ali) :	-3.7
Solubility :	0.0912 mg/ml ; 0.000198 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-6.09
Solubility :	0.000377 mg/ml ; 0.000000818 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	4.08

Safety of [ 86541-74-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 86541-74-4 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 86541-74-4 ]
Downstream synthetic route of [ 86541-74-4 ]

[ 86541-74-4 ] Synthesis Path-Upstream 1~21

1
[ 109010-61-9 ]
[ 86541-74-4 ]

Yield	Reaction Conditions	Operation in experiment
91.6%	With hydrogenchloride In ethyl acetate	Part B: Preparation of Highly Pure Benazepril Hydrochloride Through a solution of t-butyl ester of Formula VI in ethyl acetate cooled to about 10 to 12°C was purged dry hydrogen chloride gas slowly without allowing the temperature to rise. The salt formation was monitored by TLC and after completion of the reaction, excess hydrogen chloride and solvent was completely removed under vacuum. To the residue was added, 45 ml acetone and the resultant mixture was stirred for 1 hour at 5-8°C. The product was filtered and dried to constant weight under vacuum at 45-50°C affording 8.27 gm of almost white product with a diastereoisomer ratio of SS: SR = 99. 36: 0. 18. Yield 91.6percent.
Ca. 114 g	With hydrogenchloride In ethyl acetate at 10℃; Reflux	The feed was heated to reflux and the ethyl acetate was distilled off at atmospheric pressure until the remaining feed solution had a volume of about 500 ml.Cooled to below 10° C , hydrogen chloride gas was bubbled until the absorption saturation, precipitation of solid.Filtered by suction, the filter cake was washed with an appropriate amount of recovered ethyl acetate.The resulting wet crude was added to 500 ml of ethyl acetate and heated to 75 ° C for 4 h.Slowly cool to about 10 ° C, filter, wash the filter cake with appropriate amount of ethyl acetate.After drying under vacuum at 60 ° C, the white benazepril hydrochloride product is about 114g, yield 72percent. The HPLC purity was 99.5percent.

Reference： [1] Patent: WO2005/9972, 2005, A2, . Location in patent: Page/Page column 16-17
[2] Tetrahedron Asymmetry, 2003, vol. 14, # 15, p. 2239 - 2245
[3] Patent: WO2006/84761, 2006, A1, . Location in patent: Page/Page column 8; 21; 22
[4] Patent: CN105061312, 2017, B, . Location in patent: Paragraph 0031; 0034; 0038

2
[ 859635-53-3 ]
[ 86541-74-4 ]

Reference： [1] Patent: WO2005/66134, 2005, A1, . Location in patent: Page/Page column 7

3
[ 86541-75-5 ]
[ 86541-74-4 ]

Reference： [1] Patent: WO2006/84761, 2006, A1, . Location in patent: Page/Page column 22; 23

4
[ 64920-29-2 ]
[ 86499-53-8 ]
[ 86541-74-4 ]

Reference： [1] Patent: US4410520, 1983, A,
[2] Patent: US4575503, 1986, A,
[3] Patent: US4473575, 1984, A,

5
[ 4424-80-0 ]
[ 86541-74-4 ]

Reference： [1] Journal of Medicinal Chemistry, 1985, vol. 28, # 10, p. 1511 - 1516

6
[ 86499-22-1 ]
[ 86541-74-4 ]

Reference： [1] Journal of Medicinal Chemistry, 1985, vol. 28, # 10, p. 1511 - 1516

7
[ 86499-23-2 ]
[ 86541-74-4 ]

Reference： [1] Journal of Medicinal Chemistry, 1985, vol. 28, # 10, p. 1511 - 1516

8
[ 97278-68-7 ]
[ 86541-74-4 ]

Reference： [1] Journal of Medicinal Chemistry, 1985, vol. 28, # 10, p. 1511 - 1516

9
[ 92278-69-8 ]
[ 86541-74-4 ]

Reference： [1] Journal of Medicinal Chemistry, 1985, vol. 28, # 10, p. 1511 - 1516

10
[ 64920-29-2 ]
[ 86499-53-8 ]
[ 86541-74-4 ]
[ 86541-77-7 ]

Reference： [1] Journal of Medicinal Chemistry, 1985, vol. 28, # 10, p. 1511 - 1516

11
[ 577-59-3 ]
[ 86541-74-4 ]

Reference： [1] Tetrahedron Asymmetry, 2003, vol. 14, # 15, p. 2239 - 2245
[2] Tetrahedron Asymmetry, 2003, vol. 14, # 15, p. 2239 - 2245

12
[ 178114-28-8 ]
[ 86541-74-4 ]

Reference： [1] Tetrahedron Asymmetry, 2003, vol. 14, # 15, p. 2239 - 2245
[2] Tetrahedron Asymmetry, 2003, vol. 14, # 15, p. 2239 - 2245

13
[ 608148-58-9 ]
[ 86541-74-4 ]

Reference： [1] Tetrahedron Asymmetry, 2003, vol. 14, # 15, p. 2239 - 2245
[2] Tetrahedron Asymmetry, 2003, vol. 14, # 15, p. 2239 - 2245

14
[ 94793-89-2 ]
[ 86541-74-4 ]

Reference： [1] Journal of Medicinal Chemistry, 1985, vol. 28, # 10, p. 1511 - 1516

15
[ 86499-52-7 ]
[ 86541-74-4 ]

Reference： [1] Journal of Medicinal Chemistry, 1985, vol. 28, # 10, p. 1511 - 1516

16
[ 656830-87-4 ]
[ 86541-74-4 ]

Reference： [1] Tetrahedron Asymmetry, 2003, vol. 14, # 15, p. 2239 - 2245

17
[ 46460-23-5 ]
[ 86541-74-4 ]

Reference： [1] Tetrahedron Asymmetry, 2003, vol. 14, # 15, p. 2239 - 2245

18
[ 608148-60-3 ]
[ 86541-74-4 ]

Reference： [1] Tetrahedron Asymmetry, 2003, vol. 14, # 15, p. 2239 - 2245

19
[ 608148-63-6 ]
[ 86541-74-4 ]

Reference： [1] Tetrahedron Asymmetry, 2003, vol. 14, # 15, p. 2239 - 2245

20
[ 367909-45-3 ]
[ 86541-74-4 ]

Reference： [1] Tetrahedron Asymmetry, 2003, vol. 14, # 15, p. 2239 - 2245

21
[ 90315-82-5 ]
[ 86541-74-4 ]

Reference： [1] Patent: CN105061312, 2017, B,

[ 86541-74-4 ] Synthesis Path-Downstream 1~13

1
[ 109010-61-9 ]
[ 86541-74-4 ]

Yield	Reaction Conditions	Operation in experiment
91.6%	With hydrogenchloride In ethyl acetate	5.B Part B: Preparation of Highly Pure Benazepril Hydrochloride Through a solution of t-butyl ester of Formula VI in ethyl acetate cooled to about 10 to 12°C was purged dry hydrogen chloride gas slowly without allowing the temperature to rise. The salt formation was monitored by TLC and after completion of the reaction, excess hydrogen chloride and solvent was completely removed under vacuum. To the residue was added, 45 ml acetone and the resultant mixture was stirred for 1 hour at 5-8°C. The product was filtered and dried to constant weight under vacuum at 45-50°C affording 8.27 gm of almost white product with a diastereoisomer ratio of SS: SR = 99. 36: 0. 18. Yield 91.6%.
90%	With hydrogenchloride In toluene at 0 - 20℃; for 1.5h;
	With hydrogenchloride In ethyl acetate at -10 - 25℃; for 16h; Industry scale;	1 Example 1; Preparation and Washing of Crude Benazepril Hydrochloride; The following reactions were performed in a 2000 gallon reactor. Approximately 1200 pounds of the tartrate salt of compound A of Scheme I were coupled to the triflate of compound B (X = OSO2CF3) prepared from approximately 600 pounds of the corresponding alcohol (compound B where X = OH). This provided crude benazepril t-butyl ester.The crude benazepril t-butyl ester (compound C, Scheme I) was dissolved in ethyl acetate (6000 Ib) and cooled to a temperature between -100C and EPO +100C. Dry hydrochloric acid gas (706 Ib) was added, and the mixture was allowed to warm to room temperature. It was held at 20-250C for 16 hours, by which time it had formed a slurry. The mixture was leaf filtered to remove ethyl acetate and excess hydrochloric acid. It was then washed twice with isopropyl acetate (2 x 2370 Ib) to ensure removal of excess hydrochloric acid, providing crude benazepril hydrochloride as a wet cake.

Ca. 114 g	With hydrogenchloride In ethyl acetate at 10℃; Reflux;	1 Example 1 Preparation of benazepril hydrochloride The feed was heated to reflux and the ethyl acetate was distilled off at atmospheric pressure until the remaining feed solution had a volume of about 500 ml.Cooled to below 10° C , hydrogen chloride gas was bubbled until the absorption saturation, precipitation of solid.Filtered by suction, the filter cake was washed with an appropriate amount of recovered ethyl acetate.The resulting wet crude was added to 500 ml of ethyl acetate and heated to 75 ° C for 4 h.Slowly cool to about 10 ° C, filter, wash the filter cake with appropriate amount of ethyl acetate.After drying under vacuum at 60 ° C, the white benazepril hydrochloride product is about 114g, yield 72%. The HPLC purity was 99.5%.
99.6 g	With hydrogenchloride In Isopropyl acetate at 10℃;	6-7 The filter cake of the previous step was dried and suspended in 250 mL of isopropyl acetate, and carbonyldiimidazole was added, the mixture was stirred at room temperature for 4 hours, and then 100 mL of ethanol was added.After 4 hours of reaction, the solvent was distilled off, 300 ml of isopropyl acetate and 100 mL of water were added to the mixture, and then phase separation was performed. The organic phase was washed twice with water, the solvent was distilled off, 100 ml of isopropyl acetate was added to the mixture, and cooled Below 10 ° C, hydrogen chloride gas is introduced until absorption is saturated, and solids are precipitated.Filter with suction and wash the filter cake with an appropriate amount of recovered isopropyl acetate.The obtained wet crude product was added to 500ml of isopropyl acetate, heated to 75 ° C and stirred for 4h.Slowly cool to about 10 ° C, filter, and wash the filter cake with an appropriate amount of isopropyl acetate.After vacuum drying at 60 ° C, about 99.6 g of white benazepril hydrochloride boutique was obtained, with a total yield of 63%. The purity by HPLC was 99.3%.

Reference： [1]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2005/9972, 2005, A2 Location in patent: Page/Page column 16-17
[2]Chang, Ching-Yao; Yang, Teng-Kuei [Tetrahedron Asymmetry, 2003, vol. 14, # 15, p. 2239 - 2245]
[3]Current Patent Assignee: DSM-FIRMENICH AG - WO2006/84761, 2006, A1 Location in patent: Page/Page column 8; 21; 22
[4]Current Patent Assignee: SHENZHEN SALUBRIS PHARMACEUTICALS CO., LTD.; SHANDONG SALUBRIS PHARMACEUTICALS CO., LTD.; HUIZHOU XINLITAI PHARMACEUTICAL - CN105061312, 2017, B Location in patent: Paragraph 0031; 0034; 0038
[5]Current Patent Assignee: HUNAN XUKANG MEDICINE TECH - CN110835319, 2020, A Location in patent: Paragraph 0076; 0078-0079; 0081

2
[ 4424-80-0 ]
[ 86541-74-4 ]

Yield	Reaction Conditions	Operation in experiment
	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

Reference： [1]Watthey; Stanton; Desai; Babiarz; Finn [Journal of Medicinal Chemistry, 1985, vol. 28, # 10, p. 1511 - 1516]

3
[ 86499-22-1 ]
[ 86541-74-4 ]

Yield	Reaction Conditions	Operation in experiment
	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

Reference： [1]Watthey; Stanton; Desai; Babiarz; Finn [Journal of Medicinal Chemistry, 1985, vol. 28, # 10, p. 1511 - 1516]

4
[ 86499-23-2 ]
[ 86541-74-4 ]

Reference： [1]Journal of Medicinal Chemistry,1985,vol. 28,p. 1511 - 1516

5
[ 859635-53-3 ]
[ 86541-74-4 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In ethyl acetate at 0℃; for 2 - 3h;	4 Example 4; Benazepril hydrochloride; 15.6 g (20 mmol) of the bis-D-tartrate salt of Example 1 is suspended in 200 mL of EtOAc. To the suspension of the salt is added a 10% aqueous solution of potassium carbonate (ca. 120 mL) at room temperature under vigorous stirring. The phases are separated and the organic phase is washed twice with water, dried and evaporated to dryness. The residue is dissolved in dry EtOAc and the solution is again evaporated to dryness. The resulting diester free base which is obtained as an oil is again dissolved in 100 mL of dry ethyl acetate. To this solution is added a stream of dry HCI gas (ca. 6-8 mole equivalents) at 0°C under stirring in order to cleave the t-butyl ester. After stirring at 0°C for 2-3 hours, benazepril hydrochloride begins to crystallize. Stirring at room temperature is continued for an additional 4-5 hours. The suspension is cooled to 0°C and then filtered. The collected solid product is washed with ethyl acetate and finally dried in vacuum at 40°C to obtain benazepril hydrochloride of high purity.

Reference： [1]Current Patent Assignee: VIATRIS INC - WO2005/66134, 2005, A1 Location in patent: Page/Page column 7

6
[ 86541-74-4 ]
[ 86541-75-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In Isopropyl acetate; water; at 20℃;pH 4 - 5;Industry scale;	Example 2; Preparation of Benazepril To the crude benazepril hydrochloride, water (about 300 gal) and isopropyl acetate (4600 Ib) were added, forming a biphasic solution. The temperature was kept below 2O0C during these additions. Aqueous potassium carbonate (47% K2CO3, approximately 500 Ib) was then added until the pH was between 4.2 and 4.8, measured internally, producing a solution of benazepril in isopropyl acetate and an aqueous layer. The aqueous layer was then removed, and was back-extracted with a portion of isopropyl acetate, which was added to the benazepril solution. This solution was washed once with water, and then the solvent was removed by distillation. The distillation was started at atmospheric pressure, and as soon as the temperature of the distillation pot reached 88C, heating was stopped. The pot was then placed under partial vacuum, and distillation was continued under 23 in. Hg of relative vacuum until substantially all of the isopropyl acetate had been removed, without permitting the distillation pot temperature to exceed 600C. Example 5; Crude benazepril hydrochloride was prepared by the method described in Example 1 , except that the crude product was not washed with isopropyl acetate before proceeding with the process described in Example 2.To the crude benazepril hydrochloride, water and isopropyl acetate were added, forming a biphasic solution. The temperature was kept below 200C during these additions. Aqueous potassium carbonate (47% K2CO3, approximately 500 Ib) was then added until the pH was between about 4 and 5, producing a solution of benazepril in isopropyl acetate. The aqueous layer was then removed, and was back- extracted with a portion of isopropyl acetate, which was added to the benazepril solution. This solution was washed once with water, and then the solvent was removed by distillation. After the isopropyl acetate-water azeotrope had been distilled off, removal of isopropyl acetate was continued at 88-900C for 2-4 hours. The pot was then placed under about 20 in. Hg of relative vacuum and distillation was continued until substantially all of the isopropyl acetate had been removed. Using the procedure described in Example 3, benazepril hydrochloride of Form B was isolated.

Reference： [1]Patent: WO2006/84761,2006,A1 .Location in patent: Page/Page column 22; 23

7
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[ 86541-74-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 3; Preparation of <strong>[86541-75-5]Benazepril</strong> Hydrochloride Comprising Form B; The pot from the above distillation was cooled, and acetone (792 gal) was added to the <strong>[86541-75-5]benazepril</strong> residue. Activated carbon (Darco KB, 17 Ib) and Celite (17 Ib) were then added, and the mixture was heated to reflux for one hour and filtered to provide an acetone solution of the free base of <strong>[86541-75-5]benazepril</strong>. This solution was cooled to 10-200C, and gaseous hydrochloric acid was added in an amount calculated to neutralize the theoretical yield of <strong>[86541-75-5]benazepril</strong> present. The batch was then warmed to 40-500C for three hours, cooled to 20-250C, and centrifuged to provide <strong>[86541-75-5]benazepril</strong> hydrochloride as a wet cake. The wet cake was washed with 300 gallons of acetone and then dried at 50-600C to provide approximately 1150 pounds of <strong>[86541-75-5]benazepril</strong> EPO <DP n="24"/>hydrochloride containing less than 0.15% <strong>[86541-75-5]benazepril</strong> (BPat), and substantially in Form B.The batches of <strong>[86541-75-5]benazepril</strong> hydrochloride BP4-09 to BP4-28 in Figure 4 illustrate the consistently low quantity of BPat in <strong>[86541-75-5]benazepril</strong> hydrochloride produced by this method.Samples from three randomly chosen batches exhibited melting points of 184.8-185.4C; 185.0-187.60C; and 185.0-187.90C. These melting points, which were obtained without recrystallization of the samples, are in good agreement with the melting point reported in J. Med. Chem., 28, 1511-1516 (1985), which was 188-19O0C (recrystallized from 3-pentanone plus methanol). However, since no IR or XRD data was provided in that reference, it is not possible to compare the crystal form obtained in this Example to that obtained in the cited reference

Reference： [1]Patent: WO2006/84761,2006,A1 .Location in patent: Page/Page column 22; 23

8
[ 64920-29-2 ]
[ CAS Unavailable ]
[ 86541-74-4 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium cyanoborohydride In methanol; dichloromethane; acetic acid; butanone	12 1-Carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino)2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one A solution of the above sodium salt (12.9 g) and ethyl benzylpyruvate (31 g) in acetic acid (100 ml) and methanol (75 ml) was stirrred at room temperature under a dry nitrogen atmosphere for one hour. A solution of sodium cyanoborohydride (3.8 g) in methanol (30 ml) was then added dropwise over a 4 hour period. The combined solutions were stirred overnight at room temperature. Concentrated hydrochloric acid (10 ml) was added dropwise and the mixture stirred at room temperature for 1 hour followed by the evaporation of solvents. The residue was partitioned between water (400 ml) and ether (100 ml) and the pH adjusted to 9.3 with 40% sodium hydroxide. The layers were separated and the ether layer discarded. The aqueous layer was adjusted to pH 4.3 with concentrated hydrochloric acid and extracted with ethyl acetate (3*100 ml). The organic phases were combined, dried (magnesium sulfate), and evaporated. Hydrogen chloride gas was bubbled through a solution of the crude product in methylene chloride (150 ml) for 5 minutes. The solvent was evaporated and the resulting foam was dissolved in hot methyl ethyl ketone (100 ml). The solid which precipitated was collected by filtration to give a 95:5 diastereomeric mixture as determined by high pressure liquid chromatography. The product was recrystallized from 3-pentanone/methanol (10:1) to give 1-carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one hydrochloride, m.p. 188°-190°, [α]D =-141.0° (c=0.9 in ethanol), of formula Ic wherein Cn H2n is ethylene, R6 is ethoxy, R7 is hydroxy and R8 is phenyl.
	With hydrogenchloride; sodium cyanoborohydride In methanol; dichloromethane; acetic acid; butanone	12 1-Carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino)2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one A solution of the above sodium salt (12.9 g) and ethyl benzylpyruvate (31 g) in acetic acid (100 ml) and methanol (75 ml) was stirred at room temperature under a dry nitrogen atmosphere for one hour. A solution of sodium cyanoborohydride (3.8 g) in methanol (30 ml) was then added dropwise over a 4 hour period. The combined solutions were stirred overnight at room temperature. Concentrated hydrochloric acid (10 ml) was added dropwise and the mixture stirred at room temperature for 1 hour followed by the evaporation of solvents. The residue was partitioned between water (400 ml) and ether (100 ml) and the pH adjusted to 9.3 with 40% sodium hydroxide. The layers were separated and the ether layer discarded. The aqueous layer was adjusted to pH 4.3 with concentrated hydrochloric acid and extracted with ethyl acetate (3*100 ml). The organic phases were combined, dried (magnesium sulfate), and evaporated. Hydrogen chloride gas was bubbled through a solution of the crude product in methylene chloride (150 ml) for 5 minutes. The solvent was evaporated and the resulting foam was dissolved in hot methyl ethyl ketone (100 ml). The solid which precipitated was collected by filtration to give a 95:5 diastereomeric mixture as determined by high pressure liquid chromatography. The product was recrystallized from 3-pentanone/methanol (10:1) to give 1-carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one hydrochloride, m.p. 188°-190°, [α]D =141.0° (c=0.9 in ethanol), of formula Ic wherein Cn H2n is ethylene, R6 is ethoxy, R7 is hydroxy and R8 is phenyl.

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US4410520, 1983, A
[2]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US4575503, 1986, A Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US4473575, 1984, A

9
[ 86541-74-4 ]
[ 86541-78-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydroxide In methanol; water	19 1-Carboxymethyl-3S-(1S-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one EXAMPLE 19 1-Carboxymethyl-3S-(1S-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one A solution of sodium hydroxide (0.27 g) in water (2 ml) was added to a solution of 1-carboxymethyl-3S-(1S-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one hydrochloride (1 g) in methanol (10 ml). The reaction mixture was stirred for 18 hours at room temperature and the solvents removed under reduced pressure. The residue was dissolved in water (25 ml), and the pH adjusted to 3 by the addition of 4N hydrochloric acid. The resulting solid was filtered off, washed with water, and dried to give 1-carboxymethyl-3S-(1S-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 270°-272°, [α]D =-200.5° (c=1, 3% aqueous ammonia).
	With sodium hydroxide for 0.5h; Reflux;	2.3.2. Preparation of the alkaline degradation product of BENZ (BENZT) BENZwas subjected to basic degradation. 100 mgof the powderwasweighed, transferred to a conical flask. Then, 0.1N NaOHwas added andthe flask was refluxed for 0.5 h for basic degradation. After the reflux,the solution was neutralized against 0.1 N HCl, and then completed to100 mL by distilled water.

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US4575503, 1986, A Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US4410520, 1983, A Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US4473575, 1984, A
[2]Hemdan [Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 2016, vol. 164, p. 52 - 60]

10
[ 90315-82-5 ]
[ 86541-74-4 ]

Reference： [1]Patent: CN105061312,2017,B

11
[ 943-73-7 ]
[ 86541-74-4 ]

Reference： [1]Patent: CN110835319,2020,A
[2]Patent: CN110835319,2020,A

12
[ 86499-28-7 ]
[ 86541-74-4 ]

Yield	Reaction Conditions	Operation in experiment
91%	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 10% Pd/C; hydrogen In ethanol at 20℃; for 3h; Stage #2: With hydrogenchloride In ethyl acetate; acetone Reflux;	2.9 2-((S)-3-(((S)-1-ethoxy-1-oxo-4-phenylbutan2-yl) amino)-2-oxo-2,3,4,5-tetrahydro-1Hbenzo[b]azepin-1-yl)acetic acid (7): (benazepril HCl) A solution of compound (6) (11 gm, 21.4 mmol, 1 eq.) was subjected for hydrogenation in ethanol using 10% Pd/C (2 gm) under 60 psi for 3 h at room temperature. The reaction was monitored by TLC (ethyl acetate/hexane, 7:3). After completion of the reaction, the reaction mixture was filtered over a celite bed and the bed was washed with ethanol (5 mL). The filtrate was concentrated under reduced pressure. A residue was dissolved in ethyl acetate and treated with HCl gas for 1 h to form a white slurry. It was filtered, solid refluxed in ethyl acetate and ace≠ tone (95: 5 ratio) (50 mL) for 20 min, then filtered, and dried under vacuum at 40-45 °C to get benazepril HCl (7).

Reference： [1]Borase, Bhushan B; Godbole, Himanshu M; Singh, Girij P; Upadhyay, Pritesh R; Trivedi, Anurag; Bhat, Varadaraj; Shenoy, Gautham G [Journal of Chemical Sciences, 2021, vol. 133, # 2]

13
[ 64-17-5 ]
[ 86541-74-4 ]
[ 86499-45-8 ]

Yield	Reaction Conditions	Operation in experiment
	With dichlorosulfoxide In acetonitrile at 4℃; for 0.5h;	Derivatization of Carboxyl Groups. General procedure: To derivatize carboxyl groups, theisolated glucuronide metabolite from liver microsomal incubation, or 10 nmol ofsubstrate if the authentic standard is available, was first dried down using Speed-Vac (SPD1010; Thermo Fisher Scientific Inc.) and reconstituted in 40 mL ofEtOH. A reaction was initiated by adding 10 mL of ACN that contains 2%SOCl2 (v/v). After incubating at 4C in Thermomixer (900 rpm) for 30 minutes,reactions were stopped by adding 100 mL of water. 10 mL of the reaction mixturewas then injected into liquid chromatography-high-resolution mass spectrometer.

Reference： [1]Guo, Yukuang; Shah, Abhi; Oh, Eugene; Chowdhury, Swapan K.; Zhu, Xiaochun [Drug Metabolism and Disposition, 2022, vol. 50, # 5, p. 716 - 724]

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A651804[ 86541-75-5 ]

2-((S)-3-(((S)-1-Ethoxy-1-oxo-4-phenylbutan-2-yl)amino)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)acetic acid

Reason: Free-salt

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H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

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