Benazepril hydrochloride, TWT-8154, CGS-14824A, Cibacene, Briem, Cibacen, Lotensin, -Drug Synthesis Database

【结构式】

【药物名称】Benazepril hydrochloride, TWT-8154, CGS-14824A, Cibacene, Briem, Cibacen, Lotensin

【化学名称】1-Carboxymethyl-3(S)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one monohydrochloride
　　　　　　3(S)-[1(S)-Ethoxycarbonyl-3-phenylpropylamino]-2-oxo-2,3,4,5-tetrahydro-1-benzazepine-1-acetic acid monohydrochloride

【CA登记号】86541-74-4, 86541-75-5 (free base)

【分子式】C₂₄H₂₉ClN₂O₅

【分子量】460.96213

【开发单位】Novartis (Originator), Pierre Fabre (Licensee), Andrx (Generic), Eon Labs (Generic), KV Pharmaceutical (Generic), Mylan (Generic)

【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Angiotensin-I Converting Enzyme (ACE) Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

A new synthesis of CGS-14824A is given: The reaction of 3-bromo-1-phenylpropane (I) with KCN gives 4-phenylbutyronitrile (II), which is hydrolyzed to the corresponding butyric acid (III). The cyclization of (III) with polyphosphoric acid affords 1-tetralone (IV), which is brominated to 2-bromo-1-tetralone (V) and treated with hydroxylamine to give the oxime (VI). The Beckman rearrangement of (VI) yields 3-bromo-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is treated with sodium azide to afford the azide derivative (VIII). The N-alkylation of (VIII) with ethyl bromoacetate (IX) by means of KOH and tetrabutylammonium bromide in THF gives the N-alkylated azide (X), which is reduced by catalytic hydrogenation to the corresponding amine (XI). The hydrolysis of the ester group of (XI) with NaOH yields the free acetic acid derivative (XII), which is finally reductocondensed with ethyl 2-oxo-4-phenylbutyrate (XIII) by means of sodium cyanoborohydride.

参考文献中间体

【1】 Chaudhuri, N.K.; Patera, R.; Markus, B.; Sung, M.-S.; Synthesis of 14C-labeled 3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid hydrochloride ([14C]CGS 14824A). J Label Compd Radiopharm 1987, 24, 10, 1177-84.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	20884	1-(3-bromopropyl)benzene	637-59-2	C₉H₁₁Br	详情	详情
(II)	20885	4-phenylbutanenitrile	2046-18-6	C₁₀H₁₁N	详情	详情
(III)	20886	Benzenebutyric acid; 4-Phenylbutyric acid	1821-12-1	C₁₀H₁₂O₂	详情	详情
(IV)	20720	3,4-dihydro-1(2H)-naphthalenone	529-34-0	C₁₀H₁₀O	详情	详情
(V)	20721	2-bromo-3,4-dihydro-1(2H)-naphthalenone		C₁₀H₉BrO	详情	详情
(VI)	20722	2-bromo-3,4-dihydro-1(2H)-naphthalenone oxime		C₁₀H₁₀BrNO	详情	详情
(VII)	20723	3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one		C₁₀H₁₀BrNO	详情	详情
(VIII)	20891	3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one		C₁₀H₁₀N₄O	详情	详情
(IX)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(X)	20893	ethyl 2-(3-azido-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate		C₁₄H₁₆N₄O₃	详情	详情
(XI)	20894	ethyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate	109010-60-8	C₁₄H₁₈N₂O₃	详情	详情
(XII)	20895	2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid		C₁₂H₁₄N₂O₃	详情	详情
(XIII)	20896	Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester	64920-29-2	C₁₂H₁₄O₃	详情	详情

合成路线2

The reaction of 2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (I) with PCl5 in hot xylene gives 3,3-dichloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (II), which is treated with sodium acetate and reduced with H2 over Pd/C in acetic acid yielding 3-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (III). The reaction of (III) with sodium azide in DMSO affords 3-azido-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (IV), which is condensed with benzyl bromoacetate (V) by means of NaH in DMF giving 3-azido-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VI). The treatment of (VI) with Raney-Ni in ethanol-water yields 3-amino-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol affording 3-amino-1-(carboxymethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VIII). Finally, this compound is condensed with ethyl 3-benzylpyruvate (IX) by means of sodium cyanoborohydride in methanol acetic acid.

参考文献中间体

【1】 Watthey, J.W.H. (Novartis AG); Benzazepin-2-ones, process for their preparation, pharmaceutical preparations containing these compounds and the compounds for therapeutical use. EP 0072352; GB 2103614; JP 8338260 .
【2】 Castaner, J.; Serradell, M.N.; CGS-14824 A. Drugs Fut 1984, 9, 5, 317.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	30511	1,3,4,5-tetrahydro-2H-1-benzazepin-2-one		C₁₀H₁₁NO	详情	详情
(II)	30512	3,3-dichloro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one		C₁₀H₉Cl₂NO	详情	详情
(III)	30513	3-chloro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one		C₁₀H₁₀ClNO	详情	详情
(IV)	20891	3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one		C₁₀H₁₀N₄O	详情	详情
(V)	12869	benzyl 2-bromoacetate	5437-45-6	C₉H₉BrO₂	详情	详情
(VI)	30514	benzyl 2-(3-azido-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate		C₁₉H₁₈N₄O₃	详情	详情
(VII)	30515	benzyl 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate		C₁₉H₂₀N₂O₃	详情	详情
(VIII)	30516	2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetic acid		C₁₂H₁₄N₂O₃	详情	详情
(IX)	20896	Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester	64920-29-2	C₁₂H₁₄O₃	详情	详情

合成路线3

The reaction of 2(R)-hydroxy-4-phenyl butyric acid ethyl ester (I) with trifluoromethanesulfonic anhydride in dichloromethane gives the corresponding triflate (II), which is then condensed with the amino benzazepinone (III) by means of NMM in the same solvent to provide the target benazepril.

参考文献中间体

【1】 Kumar, Y.; De, S.; Thaper, R.K.; Kumar, D.S.M. (Ranbaxy Laboratories Ltd.); Process for the preparation of benazepril. WO 0276375 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	58105	(R)-2-Hydroxy-4-phenylbutyric acid ethyl ester; Ethyl (R)-2-hydroxy-4-phenylbutyrate	90315-82-5	C₁₂H₁₆O₃	详情	详情
(II)	20818	ethyl (2R)-4-phenyl-2-[[(trifluoromethyl)sulfonyl]oxy]butanoate		C₁₃H₁₅F₃O₅S	详情	详情
(III)	20895	2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid		C₁₂H₁₄N₂O₃	详情	详情

Extended Information