WO2001079176A1

WO2001079176A1 - Process for preparation of 3-[(1'-(alkoxycarbonyl)-3'-phenylpropyl)amino]-2-oxo-[1]-benzazepine and its derivatives

Info

Publication number: WO2001079176A1
Application number: PCT/IB2000/000478
Authority: WO
Inventors: Kauming Chen
Original assignee: Scinopharm Singapore Pte Ltd
Current assignee: Scinopharm Singapore Pte Ltd
Priority date: 2000-04-18
Filing date: 2000-04-18
Publication date: 2001-10-25
Anticipated expiration: 2002-10-18
Also published as: AU2000239828A1

Abstract

The present invention relates to a process for the preparation of 3-[(1'-(alkoxycarbonyl)-3'-phenylpropyl)amino]-2-oxo-[1]-benzazepine, whose derivatives are angiotensin-converting enzyme (ACE) inhibitors useful in the treatment of hypertension, chronic heart failure and progressive chronic renal insufficiency. By using a non-natural amino acid ester, L-homophenylalanine alkyl ester, as a key starting material in the condensation with a 3-halo-2,3,4, 5-tetrahydro-1H-1-benzazepine-2-one which can be obtained easily in large quantities, the processes of the present invention can avoid racemization and require fewer steps in the operational procedures and are more practical and economical than conventional processes.

Description

PROCESS FOR PREPARATION OF 3-[(l -fALKOXYCARBONYLV 3'-PHENYLPROPYL MINO]-2-OXO-[l]-BENZAZEPINE AND ITS

DERIVATIVES

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to a process for the preparation of compounds which are useful in producing angiotensin-converting enzyme

(ACE) inhibitors. In particular, the process of the present invention is useful for preparing 3-[(r-(alkoxycarbonyl)-3'-phenylpropyl)ammo]-2-oxo-[ 1]- benzazepine and derivatives thereof.

Description of the Prior Art

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. Thus, when angiotensin II plasma levels are lowered, blood pressure decreases and plasma renin activity increases. In addition, 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.

One of the most popular ACE inhibitors is benazepril hydrochloride,

3-[(l-(ethoxycarbonyl)-3-phenyl-(lS)-propyl) amino]-2,3,4,5-tetrahydro-2- oxo- 1H-[1]-10(3 S)-benzazepine- 1 -acetic acid monohydrochloride salt, which has a general formula of

and is generally in monohydrochloride form (benazepril HCl) and administered orally in therapeutic use.

Previous publications and patents have disclosed processes for the preparation of benazepril, including Helvetica Chimica Acta (page 337, vol. 71, 1988), Journal of the Chemical Society: Perkin Transaction I (page 1011, 1986), U. S. Patent Nos. 4,410,520 (1983), 4,473,575 (1984), 4,575,503 (1986), 4,600,534 (1986), 4,785,089 (1988), 5,066,801 (1991), and 5,098,841 (1992).

Conventional methods use sulfuric acid esters or 2-oxo ester of 4- phenyl butyl alkyl molecular in condensing with 3-(S)-amino-£ - caprolactam for the synthesis of benazepril. However, the use of sulfuric acid esters requires a chiral ethyl 2-(R)-hydroxy-4-ρhenyl butanoic carboxylate and the expensive leaving group, substituted phenyl sulfonic chloride which sometimes lead to racemization.

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.

SUMMARY OF THE INVENTION

One object of the present invention is to provide processes for the preparation of 3-[(r-(alkoxycarbonyl)-3'-phenylρropyl)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.

To achieve the object and avoid the disadvantages of the prior art, the present invention discloses a process for the preparation of a compound of the formula (I)

wherein R| is hydrogen, or a lower alkyl group having 1 to 4 carbon atoms;

R₂ is a lower alkyl group having 1 to 4 carbon atoms; and Xi is a hydrogen;

comprising the step of reacting a compound of the formula (II)

wherein Z is a halogen, reactive esterified hydroxy, tosylate, rrifluoromethane sulfonate, halogenated phenyl sulfonate, or nitro phenyl sulfonate; and X^ is as defined above;

with a compound of the formula (III)

CO₂R₂

(III)

wherein Z₂ is a hydrogen; and Ri and R₂ are as defined above;

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.

In a preferred embodiment, 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.

To achieve the object of readily obtaining 3-[(l'-(alkoxycarbonyl)-3'- ρhenylpropyl)amino]-2-oxo-[l]-benzazepine-l-alkyl acids, the present invention further discloses a process for the preparation of a compound of the formula (IN)

wherein Ri is hydrogen, or a lower alkyl group having 1 to 4 carbon atoms;

R₂ is a lower alkyl group having 1 to 4 carbon atoms;

R₃ 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; and

n is an integral number ranging from zero to three;

comprising the steps of:

(a) producing a compound of the formula (I) according to the process of claim 1; and (b) condensing the compound of the formula (I) with a compound of the formula (N)

R — CH — (CH₂)n — COOR3

^χ2 (V

wherein

R₃, R₄ and n are as defined above;

X₂ is a halogen, reactive esteπfied hydroxy, reactive sulfonate, tosylate or trifluoromethanesulfonate.

The invention further discloses a process for the preparation of a compound of the formula (NI)

C0₂R₂

wherein Ri is hydrogen, or a lower alkyl group having 1 to 4 carbon atoms;

R₂ 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; and

n is an integral number ranging from zero to three;

comprising the steps of:

(a) producing a compound of the formula (IN) according to the process of claim 8; and (b) reducing the compound of the formula (IN) under an acidic condition.

3 -[( 1 '-(alkoxyc arb ony l)-3 '-pheny lpropyl)amino]-2-oxo-[ 1 ]-benzazepine- 1 - alkyl acids can be derived by further reducing the compound of the formula (IN) under acidic conditions.

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.

DETAILED DESCRIPTION OF THE INVENTION

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. Preferably, the compound of formula (III) is ethyl (+)-2-amino-4-phenylbutyric ester, or L-homophenylalanine ethyl ester.

Any known 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. 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. 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.

In one embodiment, (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 direct bonding of an amino acid ester to the 3-position carbon of 2,3,4,5-tetrahydro-lH-l-benzazepine-2-one, in which the 3-position carbon is bonded with a reactive leaving group such as a halide or a hydroxy sulfonate group, according to the above process provides a simple and low cost way in comparison with conventional methods. However, there are also applications demanding a further reaction of the compound of the formula (1). Therefore, the present invention further discloses a process for the preparation of the compound of the formula (IV).

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. In one embodiment, 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.

To produce effective ACE inhibitors, such as benazepril, 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). Generally, 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.

In a preferred embodiment of the present invention, 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

C^Q ₂Et

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 mixture was further extracted and analyzed by high pressure liquid chromatography (HPLC) and the results showed that 39.5% of (l'S,3S)-3-[(r-(ethoxycarbonyl)-3'-phenylpropyl)amino]-2,3,4,5- tetrahydro-2-oxo- lH-benzazepine and 40.31% of (l'S,3R)-3-[(r- (ethoxycarbonyl)-3'-phenylpropyl)amino]-2,3,4,5-tetrahydiO-2-oxo-lH- benzazepine and 19 H of side products were produced. The SS form of the product has physical and chemical data of m.p. 119-12O0J, j££\|^α ₂o- - 204el(cja0.99, EtOH); IR(KBr):3250, 1726, 1671 cm^"1 'HNMR (CDC1₃, 400MHz) £_1.14(t, Jja7.2Hz, 3H), 1.91-2.07(m, 3H), 2.43-2.53(br m, 2H), 2.59-2.64(m, 1H), 2.68-2.75(m, 211), 2.82-2.92(m_: 1H), 3.25-3.35(m, 2H), 4.01-4. l l(m, 2H), 6.95-7.04(m, 1H), 7.10-7.29(m, 8H), 8.64-8.80(br s, 1H), ¹³ CNMR(CDC1₃, 50MHz) £_14.1, 28.8, 32.0, 35.0, 37.8, 56.6, 60.0, 60.5, 122.0, 125.8, 125.9, 127.5(3C), 127.6, 128.2, 129.5, 134.3, 136.5, 141.3, 174.2, 175.2, HRMS, Cal. - for C₂₂H₂₆0₃N₂:366.1945(Mjϊ), Found:366.1950(Mjϊ)

€0₂Et

C0 Et

(rS,3S)-3-[( (Ethoxycarbonyl)-3'-phenyIpropyl)amino]-2,3,4,5- tetrahydro-2-oxo-lH-benzazepine (1.83g), t-butyl-bro mo-acetate (1.07g), and N,N-dimethylacetamide (DMA, 20 ml) were added to a flask and mixed completely. The mixture was ice bathed for 10 min at a temperature between 10 and 150J. Sodium hydride (0.26 g) was added in portions, 5 times, to the flask within 5 minutes. A large quantity of hydrogen was produced and the^' solution became muddy white. The solution turned from pale yellow to brown yellow, and the muddy white disappeared gradually. The temperature was raised to about 20 or 23 j in 50 minutes. By checking with HPLC, the reaction was completed.

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 Η NMR (AC 200, CDC1₃).

C0₂Et

C0₂Et

The step of the reaction could be demonstrated by a method analogous to that given in Helvetica Chimica Acta (page 337, vol. 71, 1988). Hydrogen chloride in dioxane (4M, 7.5 ml) were added simultaneously to (l'S-3S)-3- [(r(ethoxycarbonyl)-3'-phenylpropyl)amino]-2,3,4,5-tetrahydro-2-oxo-lH- benzazepine (2.41 g) in a flask (50 ml) under nitrogen. The mixture was stirred for 6 hours at room temperature.

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;

'HNMR(DMSO-d6, 400MHz) £_l . l l(t, Jja7.2Hz, 3H), 2.13-2.19(m, 2H),

2.37-2.50(m, 1H), 2.55-2.67(m, 2H), 2.72-2.83(m, 2H), 3.21-3.29(m, 1H), 3.85-3.97(m, 2H), 4.01-4.16(m, 2H), 4.50, 4,65 (AB, Jjal7.5Hz, 2H), 7.19- 7.40(m, 9H); ¹³CNMR(DMSO-d6, 50MHz) £_13.7, 26.5, 30.4, 31.2, 32.8, 50.1, 56.1, 57.4, 61.9, 123.2, 126.2, 127.2, 128.2, 128.3(2C), 128.4(2C), 129.4, 134.5, 139.7, 140.2, 167.0, 168.1, 169.7; HRMS, Cal. for

C₂₄H₂₈O₅N₂:424.1999(Mjϊ), Found:424.1991(Mjϊ)

Example 2

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

The procedures of Example 1 were repeated, except that the phase transfer catalyst was replaced by (-)-N-dodecyl-N-methyl-ephedrinium bromide.

By the disclosure of the present invention, the process for the preparation of 3-[(r-(alkoxycarbonyl)-3'-phenylpropyl)amino]-2-oxo-[l]- benzazepine and derivatives thereof, and particularly benazepril, becomes more practical and more economical than conventional methods.

With the disclosed invention, apparently numerous modifications and variations can be made without departing from the scope and spirit of the present invention and are intended to be limited as indicated in the following claims.

Claims

WHAT IS CLAIMED IS:

1. A process for the preparation of a compound of the formula (I)

wherein R_t is hydrogen, or a lower alkyl group having 1 to 4 carbon atoms;

R₂ is a lower alkyl group having 1 to 4 carbon atoms; and

Xι is a hydrogen;

comprising the step of reacting a compound of the formula (II)

wherein Z| is a halogen, reactive esterified hydroxy, tosylate, trifluoromethane sulfonate, halogenated phenyl sulfonate, or nitro phenyl sulfonate; and

Xi is as defined above; with a compound of the formula (III)

CO2R2

(111)

wherein Z₂ is a hydrogen; and

Ri and R₂ are as defined above;

by catalysis of a phase transfer catalyst.

2. The process of claim 1, wherein the phase transfer catalyst is tetra-n- alkylammonium halide, N-dodecyl-N-methyl-ephedrinium halide, phenyltrimethylammonium halide, phenylπϊmethylammonium methosulfate, benzyltrimethylammonium halide, N-benzylcinchoninium halide, benzyldimethyldodecylammonium halide, or benzethonium halide.

3. The process of claim 1, wherein the phase transfer catalyst is tetra-n- butylammonium halide.

4. The process of claim 1, wherein reaction is further catalyzed by an earth metal halide salt.

5. The process of claim 1, wherein the reaction takes place in a solvent selected from the group consisting of N,N-dimethylacetamide, N,N- dimethylformamide, dimethylsulfoxide, N-methylacetamide, acetonitrile, hexamethylphosphoric triamide, or any polar aprotic solvents.

6. The process of claim 1, wherein the reaction is carried out in a basic condition which is provided by a base selected from the group consisting of Na₂C0₃, NaHCO₃, K₂CO₃, Li₂C0₃, (CH₃COO)₃N, and (i- CH₃CH₂COO)₃N.

7. The process of claim 1, wherein the reaction temperature is between 600 J and 14O0J.

8. A process for the preparation of a compound of the formula (IV)

wherein Rj is hydrogen, or a lower alkyl group having 1 to 4 carbon atoms;

R₃ is an alkyl group having 1 to 6 carbon atoms, benzyl, or allyl group;

R-_t is a hydrogen, or a lower alkyl group having 1 to 4 carbon atoms; and

n is an integral number ranging from zero to three;

comprising the steps of:

(a) producing a compound of the formula (1) according to the process of claim 1 ; and

(b) condensing the compound of the formula (I) with a compound of the formula (V) R₄ — CH — (CH₂)n — COOR3 X2 (V)

wherein

R₃, ; and n are as defined above;

X₂ is a halogen, reactive esterified hydroxy, reactive sulfonate, tosylate or trifluoromethanesulfonate.

9. A process for the preparation of a compound of the formula (VI)

CO2R2

wherein Ri is hydrogen, or a lower alkyl group having 1 to 4 carbon atoms;

R₂ is a lower alkyl group having 1 to 4 carbon atoms;

i is a hydrogen, or a lower alkyl group having 1 to 4 carbon atoms; and

n is an integral number ranging from zero to three;

comprising the steps of:

(a) producing a compound of the formula (IV) according to the process of claim 8; and

(b) reducing the compound of the formula (IV) under an acidic condition.