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WO2001079176A1 - Procede de preparation de 3-[(1'-(alkoxycarbonyl)-3'-phenylpropyl)amino]-2-oxo-[1]-benzazepine et de ses derives - Google Patents

Procede de preparation de 3-[(1'-(alkoxycarbonyl)-3'-phenylpropyl)amino]-2-oxo-[1]-benzazepine et de ses derives Download PDF

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Publication number
WO2001079176A1
WO2001079176A1 PCT/IB2000/000478 IB0000478W WO0179176A1 WO 2001079176 A1 WO2001079176 A1 WO 2001079176A1 IB 0000478 W IB0000478 W IB 0000478W WO 0179176 A1 WO0179176 A1 WO 0179176A1
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Prior art keywords
compound
formula
halide
carbon atoms
alkyl group
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PCT/IB2000/000478
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English (en)
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Kauming Chen
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Scinopharm Singapore Pte Ltd
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Application filed by Scinopharm Singapore Pte Ltd filed Critical Scinopharm Singapore Pte Ltd
Priority to AU2000239828A priority Critical patent/AU2000239828A1/en
Priority to PCT/IB2000/000478 priority patent/WO2001079176A1/fr
Publication of WO2001079176A1 publication Critical patent/WO2001079176A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines

Definitions

  • the present invention relates to a process for the preparation of compounds which are useful in producing angiotensin-converting enzyme
  • ACE ACE inhibitors.
  • the process of the present invention is useful for preparing 3-[(r-(alkoxycarbonyl)-3'-phenylpropyl)ammo]-2-oxo-[ 1]- benzazepine and derivatives thereof.
  • the present invention relates to a process for the preparation of 3- [(l'-(alkoxycarbonyl)-3'-phenylpropyl)amino]-2-oxo-[l]-benzazepine and derivatives thereof, which are useful in producing angiotensin-converting enzyme (ACE) inhibitors.
  • ACE inhibitors are useful in the treatment of hypertension, chronic heart failure and progressive chronic renal insufficiency and which, by competing with angiotensin-converting enzyme for the substrate angiotensin I, block the conversion of angiotensin I to angiotensin II which is a potent vasoconstrictor and a negative-feedback mediator for renin activity.
  • angiotensin II plasma levels are lowered, blood pressure decreases and plasma renin activity increases.
  • baroreceptor reflex mechanisms are stimulated in response to the fall in blood pressure and the resistance against which the heart has to pump blood is lowered.
  • U.S. Patent Nos. 4,410,520 and 4,575,503 disclose processes for the preparation of 3-amino-[l]-benzazepine-2-one-l-alkanoic acids.
  • the processes are complex by either first bonding an amino group to the 1- position carbonyl group, or by attaching an amino group to the 3 '-position carbon with a good leaving group through a two-step reaction.
  • the processes require several complex reaction steps, which may be more costly.
  • a simpler and more efficient process for preparing 3-[(l'- (alkoxycarbonyl)-3 '-phenylpropyl)amiiio]-2-oxo-[ 1 ]-benzazepine- 1 -alkyl acids is required.
  • the present invention discloses a novel process of directly bonding an amino acid ester to the 3-position carbon of 2,3,4,5-tetrahydro- lH-l-benzazepine-2-one derivatives which simplifies the production process.
  • One object of the present invention is to provide processes for the preparation of 3-[(r-(alkoxycarbonyl)-3'-phenyl ⁇ ropyl)amino]-2-oxo ⁇ [l]- benzazepine and derivatives thereof.
  • the processes of the present invention can avoid racemization and require fewer steps in the operational procedures than conventional methods. Furthermore, the processes of the present invention are overall more practical and economical than those of conventional processes.
  • the present invention discloses a process for the preparation of a compound of the formula (I)
  • is hydrogen, or a lower alkyl group having 1 to 4 carbon atoms
  • R 2 is a lower alkyl group having 1 to 4 carbon atoms; and Xi is a hydrogen;
  • Z is a halogen, reactive esterified hydroxy, tosylate, rrifluoromethane sulfonate, halogenated phenyl sulfonate, or nitro phenyl sulfonate; and X ⁇ is as defined above;
  • Z 2 is a hydrogen; and Ri and R 2 are as defined above;
  • phase transfer catalyst by catalysis of a phase transfer catalyst.
  • the present invention discloses a novel process of using a non-natural amino acid ester, L-homophenylalanine alkyl ester or derivatives thereof, as a key starting material which can be produced and obtained in large quantities in condensation with a 3-halo-2,3,4,5-tetrahydro-lH-l- benzazepine-2-one which can also be obtained easily in large quantities, using catalysis of a phase transfer catalyst to produce a 3-[(l'- (alkoxycarbonyl)-3'-phenylpropyl)amino]-2-oxo-[ l]-benzazepine which can be easily transformed to a carboxylic acid thereof.
  • L-homophenylalanine ethyl ester is ⁇ applied as the key starting material.
  • the L-homophenylalanine ethyl ester is an optical pure compound and the chiral center at 1 -position can avoid racemization, which is proved by product optical rotation.
  • the present invention further discloses a process for the preparation of a compound of the formula (IN)
  • Ri is hydrogen, or a lower alkyl group having 1 to 4 carbon atoms
  • R 2 is a lower alkyl group having 1 to 4 carbon atoms
  • R 3 is an alkyl group having 1 to 6 carbon atoms, benzyl, or allyl group;
  • R is a hydrogen, or a lower alkyl group having 1 to 4 carbon atoms
  • n is an integral number ranging from zero to three;
  • R 3 , R 4 and n are as defined above;
  • X 2 is a halogen, reactive este ⁇ fied hydroxy, reactive sulfonate, tosylate or trifluoromethanesulfonate.
  • the invention further discloses a process for the preparation of a compound of the formula (NI)
  • Ri is hydrogen, or a lower alkyl group having 1 to 4 carbon atoms
  • R 2 is a lower alkyl group having 1 to 4 carbon atoms
  • ⁇ is a hydrogen, or a lower alkyl group having 1 to 4 carbon atoms
  • n is an integral number ranging from zero to three;
  • the process of the present invention provides a simpler and more efficient way of preparing 3-[(l'-(alkoxycarbonyl)-3'-phenylpropyl)amino]- 2-oxo-[l]-benzazepine-l-alkyl acids, and more particularly, benazepril.
  • the process for the preparation of the compound of the formula (I) comprises reacting the compound of the formula (II) with the compound of the formula (III) by catalysis of a phase transfer catalyst.
  • the compound of the formula (II), a derivative of 3-substituted-iT-caprolactam, or 3- substimted-2-3,4,5-tetrahydro-lH-.l-benzazepme-2-one can be prepared by a method analogous to that given in Helvetica Chimica Acta (page 337, vol. 71, 1988).
  • the compound of formula (III) is a derivative of (+)-2-amino-4- phenylalkylic acid esters, or L-homophenylalanine alkyl esters.
  • the compound of formula (III) is ethyl (+)-2-amino-4-phenylbutyric ester, or L-homophenylalanine ethyl ester.
  • phase transfer catalysts can be used in the process according to the invention.
  • the phase transfer catalysts may be chiral or nonchiral, and includes a tetra-alkylammonium halide, such as tetra-n-butylammonium halide, N-dodecyl-N-methyl-ephediinium halide, such as (-)-N-dodecyl-N-methyl- ephedrinium bromide, phenyltrimethylammonium halide, phenyltrimethylammonium methosulfate, benzyltrimethylammonium halide, N-benzylcinchoninium halide, benzyldimethyldodecylammonium halide or benzethonium halide.
  • a tetra-alkylammonium halide such as tetra-n-butylammonium halide
  • the reaction can be further catalyzed by using earth metal salts such as sodium iodide, lithium iodide and potassium iodide.
  • the phase transfer catalyst is preferably tetra-n-butylammonium bromide.
  • the reaction temperature is from 60 J to 1500 J, preferably from 90 J to HO J.
  • the reaction can be carried out in a basic condition which is generally provided by a known base, such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, lithium carbonate, barium carbonate.
  • a known base such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, lithium carbonate, barium carbonate.
  • the solvents suitable for the process according to the invention can be N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylacetamide, acetonitrile, hexamethy .phosphoric rriamide, or any polar aprotic solvents.
  • (rS,3S)-3-[(l'-(ethoxycarbonyl)-3'- phenylpropyl)amino]-2,3,4,5-tetrahydro-2-oxo-lH-benzazepine is prepared by reacting 3-bromo-2,3.4,5-tetrahydro-lH-l-benzazepine-2-one with (+)- L-homophenylalanine ethyl ester in the presence of a phase transfer catalyst.
  • the preparation of the compound of the formula (IV) comprises a step of producing the compound of the formula (I) according to the above process and a step of condensing the compound of the formula (I) with a compound of the formula (V).
  • the reaction is preferably carried out in the presence of a strong base such as sodium hydride, potassium hydride and lithium hydride.
  • tert-butyl-(l'S,3S)-3-[( -(ethoxycarbonyl)-3'- phenylpropyl)amino]-2,3,4,5-tetrahydro-2-oxo-lH-benzazepine-l-acetate is produced by reacting (l'S,3S)-3-[(l'-(ethoxycarbonyl)-3'- phenylpropyl)amino]-2,3,4,5-tetrahydro-2-oxo-lH-benzazepme with t-butyl bromo acetate or t-butyl cbloro acetate in the presence of sodium hydride.
  • the compound of the formula (IN) can be further reduced under an acidic condition to obtain a compound of formula (VI):
  • the reaction is generally a hydrogenation or hydrolysis of the compound of the formula (IV).
  • the acidic condition is provided by a known acid, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, sulfurous acid and other inorganic or organic acids.
  • benazepril i.e. 3 - [( 1 -(ethoxycarbonyl)-3 -phenyl-( 1 S)-propyl) amino] -2, 3 ,4, 5 -tetrahydro-2- oxo- lH-l-(3S)-benzazepine- l-acetic acid, is prepared by reducing the above tert-butyl-( S,3S)-3-[( -(ethoxycarbonyl)-3'-phenylpropyl)amino]-2,3,4,5- tetrahydro-2-oxo-lH-benzazepine-l -acetate in the presence of hydrochloric acid.
  • Example 1
  • 3-Bromo-2,3,4,5-tetrahydro-lH-l-benzazepine-2-one was prepared by a method analogous to that given in Helvetica Chimica Acta (page 337, vol. 71, 1988).
  • Sodium bicarbonate (6.84 g), tetra-n-butyl ammonium bromide (TBAB, 1.191 g), 3-bromo-2,3,4,5-tetrahydro-lH-l-benzazepine- 2-one (17.68 g), and N, N-dimethylacetamide (40 ml) were subsequently added to a flask under nitrogen.
  • L-homophenylalanine ethyl ester (L- HPAEE, 19.91 g) was mixed with N, N-dimethylacetamide (70 ml) and the mixture was then added to the flask. The mixture was stirred and heated to 1 1O J for 6 hours.
  • the reaction mixmre was slowly added to 50 ml of water and extracted with 40 ml and 30 ml of ethylacetate respectively. The combined extracts were washed by water (35 ml) and brine (25 ml) and dried by magnesium sulfate for 30 minutes. The mixmre was filtered and dried under reduced pressure and brown oil (2.4 lg, crude) was obtained and the product yield was near 1OO H. The product was analyzed by ⁇ NMR (AC 200, CDC1 3 ).
  • the product of the step holds physical and chemical data of m.p. -138 X(cjal, EtOH); IR(KBr):3600-3350, 2990, 1735, 1670, 1515, 1220, 1005cm "1 ;
  • Example 3 The procedures of Example 1 were repeated, except that sodium iodide (0.96 g) was added to enhance reaction rates in exchanging halogens and to reduce the amount of by products and except that the first step of reaction lasted for 8.5 hours. The results showed that 40.7% of (l 'S,3S)-3- [(r-(ethoxycarbonyl)-3'-phenylpropyl)amino]-2,3,4,5-tetrahydro-2-oxo- lH-benzazepine and 41.4% of (l'S,3R)-3-[(l'-(ethoxycarbonyl)-3'- phenylpropyl)amino]-2,3,4,5-tetrahydiO-2-oxo- lH-benzazepine and 1O.2 H of side products were produced.
  • Example 3 Example 3
  • Example 1 The procedures of Example 1 were repeated, except that the phase transfer catalyst was replaced by (-)-N-dodecyl-N-methyl-ephedrinium bromide.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de fabrication de 3-[(1'-(alkoxycarbonyl)-3'-phénylpropyl)amino]-2-oxo-[1]-benzazépine dont les dérivés sont des inhibiteurs de l'enzyme de conversion de l'angiotensine (ACE), utiles dans les traitements d'hypertension, de crise cardiaque chronique, et d'insuffisance rénale chronique progressive. Par l'utilisation d'un ester d'acide aminé non naturel, un ester d'alkyle de L-homophénylalanine, comme matériau clé de départ dans la condensation avec une 3-halo-2,3,4,5-tétrahydro-1H-1-benzazépine-2-one, qui peut être obtenue en quantités importantes, les procédés de la présente invention permettent d'éviter une racémisation, demandent moins d'étapes de procédures opérationnelles et sont plus pratiques et plus économiques que les procédés classiques.
PCT/IB2000/000478 2000-04-18 2000-04-18 Procede de preparation de 3-[(1'-(alkoxycarbonyl)-3'-phenylpropyl)amino]-2-oxo-[1]-benzazepine et de ses derives WO2001079176A1 (fr)

Priority Applications (2)

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AU2000239828A AU2000239828A1 (en) 2000-04-18 2000-04-18 Process for preparation of 3-((1'-(alkoxycarbonyl)-3'-phenylpropyl)amino)-2-oxo-(1)- benzazepine and its derivatives
PCT/IB2000/000478 WO2001079176A1 (fr) 2000-04-18 2000-04-18 Procede de preparation de 3-[(1'-(alkoxycarbonyl)-3'-phenylpropyl)amino]-2-oxo-[1]-benzazepine et de ses derives

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PCT/IB2000/000478 WO2001079176A1 (fr) 2000-04-18 2000-04-18 Procede de preparation de 3-[(1'-(alkoxycarbonyl)-3'-phenylpropyl)amino]-2-oxo-[1]-benzazepine et de ses derives

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104788376A (zh) * 2014-01-17 2015-07-22 海门慧聚药业有限公司 一种盐酸贝那普利的新晶型及其制备方法
CN110835319A (zh) * 2018-08-16 2020-02-25 湖南旭康医药科技有限公司 一种贝那普利中间体和贝那普利盐酸盐的合成方法

Citations (4)

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Publication number Priority date Publication date Assignee Title
US4575503A (en) * 1983-02-10 1986-03-11 Ciba-Geigy Corporation 3-Amino-[1]-benzazepin-2-one-1-alkanoic acids
US4600534A (en) * 1984-02-06 1986-07-15 Ciba-Geigy Corporation Process and intermediates for manufacture of 3-(5-amino-1-carboxypentylamino)-tetrahydro-1-benzazepin-2-one-1-acetic acid
US4785089A (en) * 1985-06-13 1988-11-15 Ciba-Geigy Corporation Novel sulfonic acid esters and their preparation
EP0903337A1 (fr) * 1996-05-10 1999-03-24 Kaneka Corporation Procede de preparation de derives de 1-alcoxycarbonyl-3-phenylpropyle

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4575503A (en) * 1983-02-10 1986-03-11 Ciba-Geigy Corporation 3-Amino-[1]-benzazepin-2-one-1-alkanoic acids
US4600534A (en) * 1984-02-06 1986-07-15 Ciba-Geigy Corporation Process and intermediates for manufacture of 3-(5-amino-1-carboxypentylamino)-tetrahydro-1-benzazepin-2-one-1-acetic acid
US4785089A (en) * 1985-06-13 1988-11-15 Ciba-Geigy Corporation Novel sulfonic acid esters and their preparation
EP0903337A1 (fr) * 1996-05-10 1999-03-24 Kaneka Corporation Procede de preparation de derives de 1-alcoxycarbonyl-3-phenylpropyle

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ATTWOOD M R ET AL: "THE DESIGN AND SYNTHESIS OF THE ANGIOTENSIN CONVERTING ENZYME INHIBITOR CILAZAPRIL AND RELATED BICYCLIC COMPOUNDS", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1,GB,CHEMICAL SOCIETY. LETCHWORTH, 1986, pages 1011 - 1019, XP000196065, ISSN: 1470-4358 *
BEYER S K ET AL: "NOTIZ ZUR SYNTHESE EINES OPTISCH AKTIVES ACE-HEMMERS MIT AMINO-OXO-BENZAZEPIN-1-ALKANSAEURE-STRUKTUR MITTELS ENANTIOKONVERGIERENDER, KRISTALLISATIONSINDUZIERTER RACEMAT-TREMUNG", HELV CHIM ACTA, vol. 71, 1988, pages 337 - 343, XP000916421, ISSN: 0743-7463 *
J W WATTHEY ET AL: "Synthesis and biological properties of (carboxyalkyl)amino-substituted bicyclic lactam inhibitors of angiotensin converting enzyme", JOURNAL OF MEDICINAL CHEMISTRY, vol. 28, no. 10, 1985, pages 1511 - 1516, XP000942750 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104788376A (zh) * 2014-01-17 2015-07-22 海门慧聚药业有限公司 一种盐酸贝那普利的新晶型及其制备方法
CN110835319A (zh) * 2018-08-16 2020-02-25 湖南旭康医药科技有限公司 一种贝那普利中间体和贝那普利盐酸盐的合成方法
CN110835319B (zh) * 2018-08-16 2023-06-20 杭州馨佳源环保科技有限公司 一种贝那普利中间体和贝那普利盐酸盐的合成方法

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