WO2014202659A1

WO2014202659A1 - Process for the preparation of amides of n-[1-(s)-(ethoxycarbonyl)-3-phenylpropyl]-l-alanine

Info

Publication number: WO2014202659A1
Application number: PCT/EP2014/062814
Authority: WO
Inventors: Gerhard Kretzschmar; Kai Rossen
Original assignee: Sanofi-Aventis Deutschland Gmbh
Priority date: 2013-06-21
Filing date: 2014-06-18
Publication date: 2014-12-24
Also published as: TW201536720A

Abstract

A process for the production of amides of N-[1-(S)-(ethoxycarbonyl)-3-phenylpropyl]-L-alanine is described. The process can be used for the production of key intermediates and finally the ACE inhibitors such as Ramipril, Enalapril, Quinapril, Trandolapril, Delapril and Moexipril starting from N-[1-(S)-(ethoxycarbonyl)-3-phenylpropyl]-L-alanine by the reaction with the appropriate amines.

Description

Process for the preparation of amides of N-[1 -(S)-(ethoxycarbonyl)-3-phenylpropyl]-L- alanine

The present invention relates to a process of making amides of N-[1 -(S)- (ethoxycarbonyl)-3-phenylpropyl]-L-alanine and to their use as intermediates in the production of ACE inhibitors such as Ramipril, Enalapril, Quinapril, Trandolapril, Delapril and Moexipril.

N-[1 -(S)-(ethoxycarbonyl)-3-phenylpropyl]-L-alanine as shown in formula (I) is a common structural moiety incorporated in several commercially important drugs that belong to the family of ACE inhibitors (ACE = angiotensin converting enzyme).

(I)

These drugs are frequently employed to treat high blood pressure (hypertension), heart failure and related diseases. Examples for such known ACE inhibitors include Ramipril (INN), Enalapril (INN), Quinapril (INN), Trandolapril (INN), Delapril (INN) and Moexipril (INN), each of which is an amide composed of the amino acid of formula (I) and one distinct amino acid selected from the formulae (lla)-(llf) (Scheme 1 , R=H).

Ramipril ((2S,3aS,6aS)-1 -[(2S)-2-{[(2S)-1 -ethoxy-1 -oxo-4-phenylbutan-2-yl]amino} propanoyl]-octahydrocyclopenta[£>]pyrrole-2-carboxylic acid),

Enalapril ((2S)-1 -[(2S)-2-{[(2S)-1 -ethoxy-1 -oxo-4-phenylbutan-2-yl]amino} propanoyi] pyrrolidine-2-carboxylic acid),

Quinapril ((3S)-2-[(2S)-2-{[(2S)-1 -ethoxy-1 -oxo-4-phenylbutan-2-yl]amino}propanoyl]- 1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid),

Trandolapril ((2S,3a/=?,7aS)-1 -[(2S)-2-{[(2S)-1 -ethoxy-1 -oxo-4-phenylbutan-2- yl]amino}propanoyl]-octahydro-1 /-/-indole-2-carboxylic acid),

Delapril (2-[(2S)-/V-(2,3-dihydro-1 H-inden-2-yl)-2-{[(2S)-1 -ethoxy-1 -oxo-4-phenylbutan- 2-yl]amino}propanamido]acetic acid), and

Moexipril ((3S)-2-[(2S)-2-{[(2S)-1 -ethoxy-1 -oxo-4-phenylbutan-2-yl]amino}propanoyl]- 6,7-dimethoxy-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid)) are produced by forming an amide bond between the carboxylic acid group of the amino acid of formula (I) and the respective amine of one of the amino acids of the formulae (lla)-(llf) (Scheme 1 , R represents a carboxylic acid protecting group) for controlling the amide bond formation in an unambiguous fashion. This amide forming step is exemplified through the synthesis of Ramipril-benzylester of formula (Ilia) by condensation of the compounds of formula (I) and (I la) (Scheme 2, R=Bn).

Ramipril-benzylester (Ilia) cat. hydrogenation

Ramipril (IVa)

Scheme 2

Deprotection of the carboxyl terminus in the amide (Ilia) delivers Ramipril (IVa). In an analogous reaction sequence, compound (I) is reacted with compound (lib) (R=Bn) to deliver Enalapril (IVb), with compound (lie) (R=Bn) to give Quinapril (IVc), with compound (lid) (R=Bn) to give Trandolapril (IVd), with compound (lie) (R=Bn) to give Delapril (IVe) and with compound (llf) to give Moexipril. (Scheme 3)

Notably, the amino acid component of the formula (I) contains an unprotected secondary amino group which in principle should be protected to avoid self- condensation of the compound (I) under the conditions of amide formation with a compound of formulae (lla)-(llf). Numerous strategies exist to perform appropriate protection of amino groups, and typical examples for protecting group manipulations, coupling reagents and coupling procedures that are commonplace in peptide chemistry are described in textbooks and review articles like Protective Groups in Organic

Synthesis, T.W. Greene, P.G.M. Wuts, John Wiley & Sons, 3^rd. ed. 1999; The Practice of Peptide Synthesis, M. and A. Bodanszky, Springer Verlag, 1984. ; Amide bond formation and peptide coupling, C.A.G.N. Montalbetti, V. Falque, Tetrahedron 61 , 10827 (2005). However, prior art methods for the preparation of ACE inhibitors, which are derived from the amino acid of formula (I), have demonstrated that elaborate protection of the secondary amino group in compound (I) can sometimes be avoided by the preparation of certain reactive derivatives of compound (I). Such reactive derivatives are usually isolated and subsequently coupled with the respective amines (lla)-(llf) (Scheme 1 ). For example, in one method preparation of Ramipril and Enalapril is described in WO 2007/079871 A1 (Sanofi-Aventis) and in EP 0 215 335 A2 (Kanegafuchi), respectively, whereby the amino acid of formula (I) is transformed with phosgene into the N-carboxy anhydride (Leuch^'s anhydride) of the

(V)

The preparation and isolation of the N-carboxy anhydride of the formula (V) involves heating of compound (I) with phosgene in dichloromethane for about 8 hours, removal of dichloromethane, hydrochloric acid and an excess of phosgene by distillation, and subsequent crystallization of the product from a hydrocarbon solvent at a temperature below 0°C, as described for example in EP 1 283 204 A1 (Kaneka Corp.).

EP 0 967 221 A1 (Kaneka Corp.) illustrates the broader applicability of intermediate (V) for the preparation of other ACE inhibitors. A typical example is the synthesis of

Trandolapril using the anhydride (V) as described in WO 2007/003947 A2 (Cipla Ltd). In the following, this method using compound (V) for the purpose of an ACE inhibitor synthesis is designated as the anhydride method.

Another method to synthesize Ramipril is described by G.C. Malakondaiah et al., Synthetic Communications 38, 1737-1744 (2008) that comprises the reaction of the amino acid of formula (I) with phosphorous pentachloride (PCI₅) to provide the acid he formula (VI).

(VI)

The procedure involves heating compound (I) and PCI₅ for several hours in

dichloromethane and then precipitation of the product (VI) with a hydrocarbon solvent to remove the phosphorous oxychloride (POCI₃) by-product, filtration, washing and drying. Application of this method for the purpose of an ACE inhibitor synthesis is designated as the acid chloride method. Thus, ACE inhibitors based on the amino acid of formula (I) are prepared in general by using either the isolated anhydride of the formula (V) (anhydride method) or the isolated acid chloride of the formula (VI) (acid chloride method), which are coupled with the respective amine of the formulae (lla)-(llf). One disadvantage of using the anhydride method consists in the requirement for an extra synthesis and isolation step to provide the activated intermediate of the formula (V). On an industrial scale, additional manipulations are causing additional overall cost and negative environmental impact. Since the N-carboxy anhydride (V) per se is moisture sensitive, careful handling and storage are required.

Another disadvantage consists in handling the phosgene gas (COCI₂). Phosgene is a highly toxic gas and the presence of large quantities on a site represents a major hazard. Regulatory requirements in transportation and know-how in handling and safety have restricted its uses to specialized companies, (see: The Recent Advance in

Phosgene Chemistry, Author Jean-Pierre G. Senet; Societe Nationale de Poudres et Explosifs SA, 2004, 375 pages). Likewise, a significant disadvantage of using the acid chloride method consists in the requirement for an extra synthesis and isolation step to provide the activated

intermediate of the formula (VI), which is precipitated as a solid using a large volume of organic solvents, as described e.g. in US 2006/0079698 A1 (Glenmark

Pharmaceuticals). The precipitate is contaminated with the toxic POCI₃ by-product and the bulk of this toxic by-product remains in the mother liquor which must be removed and disposed of. Likewise, the intermediate (VI) per se is moisture sensitive and careful handling and storage are required.

In addition to the anhydride and acid chloride methods, two other procedures for amide coupling have been described for the production of Ramipril. One of these is the conventional peptide coupling using 1 -hydroxybenzotriazole (HOBT) and

dicyclohexylcarbodiimide (DCC) in the presence of a base, as described for example in WO 2009/122433 A2 (IPCA Laboratories Ltd.), to deliver the coupling product of the formula (Ilia) in 50-75% yield. Apart from the low yield and allergenic properties of the DCC reagent, these reagents are expensive and quantitative removal the N,N- dicyclohexyl-urea by-product is a pertinent problem. The preparation of Quinapril and Moexipril using such methods is described in EP 0049605 A1 (Warner-Lambert Comp.). Delapril and its preparation is described in EP 0051391 A1 (Takeda Chem. Ind. Ltd.). Preparation of Trandolapril via coupling the amine in the presence of n-ethylmorpholine and DCC is described is WO 2007/026371 A2 (Wockardt Ltd).

Another method described in EP 0135181 A2 (Hoechst AG) uses alkane phosphonic acid anhydrides as coupling reagents for the production of Ramipril. However, this method is suffering from limited commercial availability and high cost of such

phosphonic acid anhydrides, and from problems in the disposal of the alkane

phosphorous acid waste that is produced as a by-product.

Finally, another method for coupling amino acids different from a compound of formula (I) by way of using an acid chloride has been described in the literature. In this case Ν,Ν-dimethyl-chloromethyl-iminium chloride (Vilsmeier reagent) (VII) ^Cl ^ci

VII

has been used in a peptide coupling reaction to prepare amino acid chlorides from the respective acid (Jass et al., Tetrahedron 2003, 59(45), 9019-9029 (2003). In this case N-protected amino acids were used, which were protected especially with the N- trifluoroacetyl group. The N-protecting group is a necessary feature and a lot of efforts have been spent to identify a suitable one. Again the acid chloride was made which also took some hours of reaction time to prepare. Nothing more seems to have been published since then on this reagent for the purpose of forming an amide. For the production of ACE inhibitors, a preferred process should involve a minimum number of reaction steps which proceed in a time-efficient manner in high yield and high selectivity to provide the desired compound with high purity. Safety, environmental compatibility and cost of starting materials and reagents are further major requirements, especially for large scale production.

Accordingly, it is an object of the present invention to provide an improved process for the preparation of key intermediates useful in the preparation of ACE inhibitors derived from the amino acid of formula (I), which avoids the disadvantages of using either the anhydride or acid chloride methods or the use of additional N-protecting groups, and which proceeds with high efficiency, high yield and selectivity to provide the desired products.

It has been found that the above object is achieved by reaction of N-[1 -(S)- (ethoxycarbonyl)-3-phenylpropyl]-L-alanine (I) with N,N-dimethyl-chloromethyl-iminium chloride (Vilsmeier reagent) of the formula (VII) and direct treatment of the reaction mixture with an amine selected from one of the formulae (lla)-(llf) in the presence of a base to give the respective amide in almost quantitative yield and high purity. There is no need for any N-protecting group and the reaction proceeds under mild reaction conditions in a very short time. Moreover, there is also no need to isolate any

intermediate such as the acid chloride. Accordingly, in one embodiment the invention relates to a process for the preparation of a compound of formula (Ilia), (lllb), (lllc), (llld, (llle) or (lllf)

(llle) (lllf) wherein R is a protecting group,

characterized by

carbonyl)-3-phenylpropyl]-L-alanine of the formula (I)

(I)

in the presence of an acid

with Ν,Ν-dimethyl-chloromethyl-iminium chloride

in a suitable organic solvent; b) reacting the product obtained in step a) with an amine selected from a compound of formula (lla), (lib), (lie), (lid), (lie) or (Ilf)

wherein R is a protecting group,

in the presence of a base

in a mixed solvent system of water and a water immiscible solvent,

to obtain a compound of formulae (Ilia) - (lllf).

Regarding the various features of the reaction steps performed in the process of the present invention the following embodiments apply, which alone or in combination are also part of the present invention.

Step a)

For step a), which is designated the activation step, the N,N-dimethyl-chloromethyl- iminium chloride (VII) is available from chlorination of cheap N,N-dimethyl-formamide (DMF) with phosgene, phosphorous pentachloride or thionyl chloride (H. Eilingsfeld et al., Angew. Chem., 72(22), 836 (1960)) or it can be purchased commercially (e.g.

Aldrich). A process for the safe production of reagent (VII) on a large scale from DMF and thionyl chloride (SOCI₂) as a chlorination reagent in the industrial production of the artificial nutrient sweetener Sucralose is described in WO 2007/099557 A2 (Pharmed Medicare PVT. Ltd.). In the present invention reagent (VII) can be utilized as prepared by either of the published methods listed above. In one embodiment, the reagent (VII) is prepared from DMF and thionylchloride and used as such in the same vessel for the conversion of compound (I). In another embodiment, the commercially available reagent (VII) is used for the same purpose and with equal result. The reagent is also cheap compared to the other reagents described in the art and/or it causes no problems in terms of critical by products compared with the other coupling methods described in the art above for a compound of formula (I) or a derivative thereof. In the reaction compound (I) is used as a salt. In one embodiment the salt can be made and isolated in advance and then dissolved in a suitable solvent or compound (I) is added to a solvent and a suitable acid is added to form the salt in solution. Various salts may be used which can be prepared from the corresponding acid. A strong acid should be used to allow formation of the salt. Suitable acids are HCI or HBr. In one

embodiment the acid is hydrochloric acid (HCI).

Thus, in one embodiment of the coupling step the hydrochloride salt of N-[1 -(S)- (ethoxycarbonyl)-3-phenylpropyl]-L-alanine (I) is prepared by the addition of a minimum of at least one molar equivalent of hydrochloric acid (HCI) to a compound (I) in an appropriate organic solvent. In one embodiment organic solvents that can be used in activation step a) are, but not limited to, dichloromethane, chloroform, 1 ,2- dichloroethane, n-butyl-acetate or methyl-isobutyl-ketone.

More than a molar equivalent, e.g. more than 1 .2 mol equivalent, may be added.

However, this is not necessary for performing the process but would require the addition of more base in the next reaction step.

Then reagent (VII) is added at a temperature of -40 °C to +30 °C, preferably at a temperature of minus 15°C to minus 5°C. The amount of the reagent is not critical. In one embodiment of the process a molar equivalent up to a slight excess (1 ,0-1 ,3 equivalents) of reagent (VII) is used. More reagent can also be used but this does not improve the overall performance of the process but the reagent needs to be disposed later after work up as waste. Compared to other reactions described in the art for coupling a compound of formula (I), the time for preparing the reaction mixture is very short and the reaction does not require heating as shown in the Examples. Step b)

For reaction step b), which is designated transfer step, the following embodiments apply. The reaction mixture resulting from step a) is transferred to a mixed solvent system of water and a water immiscible solvent containing the protected amino acid selected from a compound of formula (lla)-(llf) and the base. Mixing may be performed for example by stirring, agitation or ultrasonic irradiation. In one embodiment the mixture is stirred.

In one embodiment suitable water immiscible organic solvents that can be used in the transfer step b) are selected from dichloromethane, chloroform, 1 ,2-dichloroethane, methyl-tert.-butylether, n-butyl-acetate, ethyl acetate, methyl-isobutyl-ketone, 2-methyl- tetrahydrofuran or toluene. The amount/ratio of water and organic solvent is not critical and - for practical reasons - is adjusted as low as possible but sufficient to dissolve the reactants.

There is no need to use the same solvent in both steps a) and b). Thus in one

embodiment the solvent used in step a) and b) is, independently of each step, selected from the group of dichloromethane, chloroform, 1 ,2-dichloroethane, n-butyl-acetate or methyl-isobutyl-ketone.

For practical reasons the same solvent is used in both steps. Thus, in a further embodiment the same organic solvent is used in step a) and in step b) which is selected from dichloromethane, chloroform, 1 ,2-dichloroethane, n-butyl-acetate or methyl- isobutyl-ketone. In another embodiment the solvent used in steps a) and b) is

dichloromethane, chloroform or 1 ,2-dichloroethane. In a further embodiment the organic solvent used in reaction steps a) and b) is dichloromethane. In one embodiment the pH-value of the mixture in step b) is kept in the range of 7.0 to 9.0. In a further embodiment the pH has a value of 7.5 to 8.0. The pH value adjustment can be performed either by the presence of an excess of a mild base, for example a buffered aqueous solution, or by successive addition of a base during the transfer step. Appropriate mild bases which can be used in excess, for example, are sodium hydrogencarbonate (NaHC0₃) and potassium hydrogencarbonate (KHC0₃). Other bases which can be added for continuous pH adjustment of the reaction mixture during the transfer step include aqueous sodium hydroxide (NaOH) or potassium hydroxide (KOH). Thus in one embodiment of the present invention the base in step b) is a water soluble inorganic base selected from sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide. In another embodiment the base is sodium bicarbonate.

The temperature of the biphasic reaction mixture during the transfer step is adjusted in a range of 0°C to 40 °C, preferably in a range of 0°C and 10°C. The speed of the transfer step is controlled by the rate of the pH adjustment in the reaction mixture.

Under these conditions, the amide coupling process occurs instantaneously with quantitative conversion of the reaction components. After completion of the transfer step, the organic phase containing one of the products of formulae (llla)-(lllf) is separated and washed about one to three times with water.

The amide coupling step according to the present invention matches the stoichiometry, that is to say there is no requirement for an excess of either the acid component (I) or the amine component (II) in order to achieve an almost quantitative conversion and yield of the coupling product. In one embodiment of step b) the components (I) and (II) are used in equimolar amounts. In another embodiment, a slight excess (up to 5 mol%) of the acid component of formula (I) may be applied for operational reasons on scale. After evaporation of the organic solvent, the crude amide coupling product is obtained in 95-99% purity. The compounds (llla)-(lllf) are valuable intermediates in the preparation of the final ACE inhibitors. DMF is the major by-product of the reaction in the aqueous phase which is not critical from an environmental and safety point of view and can be easily disposed.

Basically any carboxylic acid protecting group known in the art may be used in a compound of formula (II). However, more suitable carboxyl protecting groups for use in the process of the present invention are those which can be removed later after the coupling reaction in step b) for obtaining the final ACE inhibitor without cleaving the ethyl ester in the part originating from the molecule of formula (I). Accordingly, in one embodiment a protecting group suitable for use in one of the compounds of formulae (lla)-(llf) may be the benzyl group or the tertiary butyl group. In a further embodiment the protecting group R in the compounds of the formulae (llla)-(lllf) is a benzyl group (R = Bn).

In a further reaction step the product of step b) can be directly converted by known standard procedures into the respective ACE inhibitor. In the embodiment wherein the protecting group R in any of the products of the formulae (llla)-(lllf) is a benzyl group (R = Bn), this group can be removed selectively by catalytic hydrogenation in an organic solvent like methanol, ethanol, isopropanol or ethyl acetate in the presence of a palladium catalyst. Such catalyst is usually on active charcoal. The tert.-butyl group may be removed by conditions described in the art. With adding an acid (e.g. HCI) during the hydrogenation reaction the salt of a compound of formula (IVa)-(IVf) may be directly obtained.

Accordingly, in a further embodiment of the process of the present invention a compound of formulae (llla)-(lllf) is prepared wherein R is H, i.e. a compound of formulae (IVa)-(IVf) is prepared. For achieving this, the product obtained in step b) is converted into the ACE inhibitors (IVa)-(IVf). Each of these compounds may optionally be further converted into a pharmaceutically acceptable salt thereof. Thus in this embodiment of the process of the present invention in a further step c) the protecting group R in one of the compounds of formula (llla)-(lllf) obtained in step b) is removed (R becomes H) to obtain a compound of formula (IVa), (IVb), (IVc), (IVd), (IVd) or (IVf)

(IVe) (IVf) and optionally converting the compound into a pharmaceutically acceptable salt thereof. The compounds obtained correspond to Ramipril (IVa), Enalapril (IVb), Quinapril (IVc), Trandolapril (IVd), Delapril (IVe) and Moexipril (IVf), respectively.

As mentioned, the resulting ACE inhibitors of formulae (IVa)-(IVf) can be converted as described in the art into the pharmaceutically form commercially used, which is often a pharmaceutically acceptable salt thereof. For instance, Ramipril is conveniently crystallized from an organic solvent, Enalapril is crystallized as its maleate salt,

Quinalapril and Delapril are crystallized as hydrochloride salts.

In a further embodiment of the process of the present invention a compound of formula (IVa) (Ramipril)

(IVa)

or a pharmaceutically acceptable salt thereof, is prepared.

In a further specific embodiment of the process of the present invention a compound of

(IVb)

or a pharmaceutically acceptable salt thereof, is prepared.

In a further embodiment of the process of the present invention a compound of formula (IVc (Quinapril)

(IVc)

or a pharmaceutically acceptable salt thereof, is prepared.

In a further embodiment of the process of the present invention a compound of formula (IVd) (Trandolapril)

(IVd)

or a pharmaceutically acceptable salt thereof, is prepared.

In a further embodiment of the process of the present invention a compound of formula (IVe (Delapril)

(IVe)

or a pharmaceutically acceptable salt thereof, is prepared.

In a further embodiment of the process of the present invention a compound of formula (IVf (Moexipril)

(ivf)

or a pharmaceutically acceptable salt thereof, is prepared.

Each step of the process described in the process of the present invention may be operated either batch by batch or as a continuous process or in a semicontinuous mode. The process can be used to prepare larger amounts than described in the examples. In a further embodiment the present invention relates to the use of the compounds of formulae (llla)-(lllf), wherein R is a protecting group, prepared according to any one of the process embodiments described above for the preparation of the ACE inhibitors Ramipril, Enalapril, Quinapril, Trandolapril, Delapril and Moexipril.

The process of the invention for the amide coupling of N-[1 -(S)-(ethoxycarbonyl)-3- phenylpropyl]-L-alanine of the formula (I) is not restricted to using the amines of formulae (lla)-(llf) but it is also applicable to coupling with other amines. Abbreviations:

ca. circa

h hour(s)

i. vac. in vacuum

LC-MS liquid chromatography-mass spectrometry

MTBE methyl-tert.-butylether

NMR nuclear magnetic resonance

DCM dichloromethane

Bn benzyl The invention is described in more detail by the following examples. These examples are designated to illustrate the invention, but do not limit its scope.

The NMR assignments are for illustration only based on analysis of the one-dimensional ¹H NMR spectra. A more detailed analysis of the spectra may lead to minor

reassignments of some NMR peaks, which obviously does not change the overall assignment. All ¹ H NMR spectra are recorded on a 500 MHz instrument, shifts are relative to TMS in [ppm]; the solvent is always DMSO-d₆.

Example 1 : Preparation of the Vilsmeier reagent (VII) and conversion of N-[1 -(S)- (ethoxycarbonyl)-3-phenylpropyl]-L-alanine (I) into Ramipril-benzylester (Ilia).

0.70 ml (9.62 mmol) thionylchloride were added dropwise under Argon and cooling to 0.67 g (9.17 mmol) dry Ν,Ν-dimethylformamide. The mixture was stirred for one hour at 40 °C and then another 2 hours at 40 °C i.vac. (up to 1 mbar, complete removal of S02 and of excess thionylchloride). A viscous semi-crystalline mass (1 .17 g, 100%) was formed upon cooling in an ice-bath. Under an argon atmosphere at a temperature of - 10°C, this material was combined with a suspension of 2.39 g (8.56 mmol) of N-[1 -(S)- (ethoxycarbonyl)-3-phenylpropyl]-L-alanine (I) in 25 ml of dry DCM containing 10 mmol of dry HCI. The mixture gave a clear solution within ca. 10 minutes which was stirred further 15 minutes in a temperature range from -10°C to

-5°C. The cold solution was then transferred within ca. 3 minutes into a vigorously stirred mixture of water (5ml), sodium bicarbonate (3.4 g), DCM (5 ml) and 2.00 g (8.15 mmol) of (2S,3aS,6aS)-cyclopenta[b]pyrrole-2-carboxylic acid-benzylester (I la, R=Bn). The organic phase was separated, washed 3 times with 5 ml of water, dried over sodium sulfate and carefully concentrated at up to 20 °C i.vac. to yield 4.1 1 g (99.5%) of crude Ramipril-benzylester (Ilia) as a clear oil.

LC-MS purity was 96.6% (peak area) (MH⁺ 507).

¹H NMR (2 rotamers) 1 .03 (d, 3H, Me), 1 .18 (t, 3H, OCH₂CH₃), 1 .25-2.45 (m, 10H), 2.57 (m, 2H, PhCH₂), 2.73 (m, 1 H), 3.13 (m, 1 H), 3.62 (m, 1 H), 4.08 (q, 2H, OCH₂CH₃), 4.33 (m, 1 H), 4.47, 4.73 (m, 1 H), 5.10 (m, 2H, OBn), 7.10-7.40 (m, 10H, Ar-H).

Example 2: Preparation of Ramipril-benzylester (Ilia) from N-[1 -(S)-(ethoxycarbonyl)-3- phenylpropyl]-L-alanine (I) using commercial Vilsmeier reagent (VII)

2.70 g (8.56 mmol) of the hydrochloride of N-[1 -(S)-(ethoxycarbonyl)-3-phenylpropyl]-L- alanine (I), obtained from 2.39 g (8.56 mmol) of compound I and ca. 12 mmol of dry HCI in 25 ml of dry dichloromethane, were cooled under argon and stirred at -10°C. Then 1 .15 g (8.56 mmol) of Vilsmeier reagent (95%, from Aldrich Chemicals) was added in one portion. No significant evolution of heat was observed and a clear solution was obtained within 10 minutes. After stirring for a total of 30 minutes in a temperature range of -10°C to -5°C, the solution became slightly turbid and was transferred in the same manner as described in example 1 into the aqueous DCM/water mixture containing the same amounts of compound lla and sodium bicarbonate. Further work-up was done as described in example 1 to give crude Ramipril-benzylester (Ilia) in practically the same yield and purity as described in example 1 . Example 3: Preparation of Ramipril (IVa) from Ramipril-benzylester (Ilia)

4.1 g (8.09 mmol) of Ramipril-benzylester (Ilia), as obtained from example 2, were hydrogenated at 20 °C in 30 ml of methanol with a 10% Pd on charcoal catalyst (ca. 100 mg at atmospheric pressure (balloon). After complete consumption of the starting material, as detected by LC-MS, the catalyst was filtered off and the solvent was evaporated i.vac. at 20°C. Crude Ramipril was obtained as a viscous oil in almost quantitative yield (3.35 g).

LC-MS: MH 17,

1H NMR (2 rotamers) 1 .06 (d, 3H, Me), 1 .19 (t, 3H, Me), 1 .30-2.05 (m, 8H), 2.27-2.47 (m, 1 H), 2.57 (m, 2H, PhCH₂), 2.72 (m, 1 H), 3.13, 3.19 (m, 1 H), 3.30 (m, 1 H), 3.63 (m, 1 H), 4.08 (q, 2H, OCH₂CH₃), 4.30, 4.50 (m, 2H), 7.1 2-7.30 (m, 5H, ArH).

A sample was crystallized from acetone to give the compound in >99.9 purity (LC-MS peak area).

Example 4: Preparation of Enalapril-benzylester (1Mb, R=Bn) from N-[1 -(S)- (ethoxycarbonyl)-3-phenylpropyl]-L-alanine (I)

1 .15 g (8.56 mmol) of Vilsmeier reagent (estimated purity of 95%, prepared as described in example 1 from DMF and thionylchloride) and 2.69 g (8.55 mol) of the hydrochloride of N-[1 -(S)-(ethoxycarbonyl)-3-phenylpropyl]-L-alanine (I), obtained in the same manner as described in example 1 , were dissolved in 20 ml of dry DCM under Argon at -10°C within 10 minutes. After stirring for overall ca. 30 minutes at a temperature range of -10°C to -5°C, the slightly cloudy solution was transferred within ca. 5 minutes under vigorous stirring at ca. 5°C into the aqueous DCM (5ml)/water (5 ml) mixture containing 3.06 g of potassium bicarbonate and 1 .76 g of (7.28 mmol) S- proline-benzylester hydrochloride. The organic phase was separated, washed 3 times with 5 ml of water, dried over sodium sulfate and carefully concentrated at up to 20 °C to give 3.40 g (quantitative yield) of crude Enalapril-benzylester (I I lb, R=Bn) as a clear oil. LC-MS: MH⁺ 467.

¹H NMR (2 rotamers) 1 .05 (d, 3H, Me), 1 .19 (t, 3H, OCH₂CH₃), 1 .65-1 .95 (m, 5H), 2.17 (m, 2H, PhCH₂CH₂), 2.58 (m, 2H, PhCH₂), 3.16 (m, 1 H), 3.55 (m, 3H), 4.08 (q, 2H, OCH₂CH₃), 4.38, 4.68 (2m, 1 H), 5.10 (m, 2H, OBn), 7.12-7.42 (m, 10H, Ar-H). Example 5: Preparation of Enalapril (IVb)-maleate from Enalapril-benzylester (1Mb, R=Bn)

The crude Enalapril-benzylester (1Mb, R=Bn) obtained from example 4 was

hydrogenated at 15-20°C in 30 ml of methanol with a 5% Pd on charcoal catalyst (ca. 100 mg) at atmospheric pressure (balloon). After complete consumption of the starting material, as detected by LC-MS, the catalyst was filtered off and the solvent was evaporated. The resulting colorless solid foam was combined with one equivalent of maleic acid (0.817 g, 7.039 mmol) and dissolved in 7 ml of acetonitrile. This solution was treated with MTBE until it became slightly turbid and then was allowed to stand at room temperature. After a while the product crystallized as fine needles. The yield of pure Enalapril (IVb)-maleate was 3.25 g (91 %). LC-MS purity 99.5% peak area, MH+ 377. ¹ H NMR data as measured in the same solvent (DMSO-d₆) were in accord with the reported data by Hitoshi Kubota et al., Chem.Pharm. Bull., 39(6), 1374-1377 (1991 ), except for the singulett signal of two protons at 6.10 ppm (maleic acid) which were omitted in this publication.

¹H NMR (2 rotamers): 1 .24 (t, 3H, OCH₂CH₃), 1 .32,1 .37 (2d, 3H, Me), 1 .80-2.30 (m, 6H), 2.50-2.80 (m, 2H), 3.28-4.25 (m, 7H), 4.30, 4.60 (2m, 1 H), 6.10 (s, 2H, maleate), 7.1 1 (m, 3H, Ar-H), 3.30 (m, 2H, Ar-H).

Example 6: Preparation of Quinapril-benzylester (I lie, R=Bn) from N-[1 -(S)- (ethoxycarbonyl)-3-phenylpropyl]-L-alanine (I)

1 .09 g (3.46 mmol) of the hydrochloride of N-[1 -(S)-(ethoxycarbonyl)-3-phenylpropyl]-L- alanine (I), obtained from 0.96 g (3.46 mmol) of compound (I) and ca. 4 mmol of dry HCI in 10 ml of dry DCM, were cooled under argon and stirred at -10°C. Then 0.46 g (3.46 mmol) of Vilsmeier reagent (96%, from Acros Chemicals) was added in one portion. After stirring for a total of ca. 20 minutes in a temperature range of -10°C to -5°C, the clear solution was transferred within about one minute into a cooled (ca. 5°C) and vigorously stirred mixture of water (5 ml), potassium bicarbonate (1 .65 g), DCM (5 ml) and 1 .00 g (3.29 mmol) of (S)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

benzylester hydrochloride (lie, R=Bn). The organic phase was separated, washed 3 times with 5 ml of water, dried over sodium sulfate and carefully concentrated i. vac. at up to 20 °C to yield 1 .74 g (100%) of the crude title compound as colourless oil.

LC-MS purity was 98.2% (peak area) (MH⁺ 529).

Example 7: Preparation of Quinapril (IVc)-hydrochloride from Quinapril-benzylester (I lie, R=Bn)

1 .73 g (3.29 mmol) of Quinapril-benzylester (lllc, R=Bn), as obtained from example 6, were hydrogenated at 15-20°C in 40 ml of ethyl acetate containing ca. 5 mmol of dry HCI with a 5% Pd on charcoal catalyst (ca. 100 mg) at atmospheric pressure (balloon). After complete consumption of the starting material, as detected by LC-MS, the catalyst was filtered off and the filtrate was concentrated and triturated with MTBE to give the title compound as a colorless powder, yield 1 .40 g (90%) with LC-MS purity >98% (MH⁺ 439).

¹H NMR (two rotamers): 1 .18, 1 .25 (2t, 3H, OCH₂CH₃), 1 .52 (2d, 3H, CH₃), 2.08-2.30 (m, 2H, PhCH₂CH₂), 2.62, 2.78 (2m, 2H, PhCH₂), 3.10-3.35 (m, 2H, H-4), 3.80, 3.93 (2m, 1 H, NCHC=0), 4.14, 4.21 (2m, 2H, OCH₂), 4.45-4.90 (3m, 3H, H-1 , H-1 ^', H-3), 5.15 (m, 1 H, NH₂ ⁺CHCH₃), 7.15-7.35 (m, 9H, Ar), 9.80 (broad m, 2H, NH₂ ⁺), 12.80 (broad m, 1 H, COH). Quinapril hydrochloride can be further purified by crystallization from ethyl acetate/toluene as described by S. Klutchko et al. in J.Med.Chem. 1986, 29, 1953-1961 .

Example 8: Preparation of Trandolapril-benzylester (I I Id, R=Bn) from N-[1 -(S)- (ethoxycarbonyl)-3-phenylpropyl]-L-alanine (I)

1 .12 g (3.55 mmol) of the hydrochloride of N-[1 -(S)-(ethoxycarbonyl)-3-phenylpropyl]-L- alanine (I) in 12 ml of dry dichloromethane were cooled under argon and stirred at - 10°C. Then 0.47 g (3.55 mmol) of Vilsmeier reagent (96%, from Acros Chemicals) was added in one portion. A clear solution was obtained within 10 minutes. After stirring for a total of 30 minutes in a temperature range of minus 10°C to minus 5°C, the solution was transferred in the same manner as described in example 1 into the vigorously stirred DCM/water mixture containing 1 .00 g (3.38 mmol) of the hydrochloride of (2S,3aR,7aS- octahydroindole-2-carboxylic acid-benzylester (lid, R=Bn) and 1 .42 g (16.9 mmol) of sodium bicarbonate. Further work-up as described in example 1 afforded 1 .70 g (97%) of the title compound.

LC-MS: MH+521 ¹H NMR (2 rotamers) 1 .03 (d, 3H, Me), 1 .20 (t, 3H, Me), 1 .30-1 .95 (m), 2,13 (m,1 H), 2.27 (m, 1 H), 2.57 (m, 2H), 3.12, 3.55, 3.86 (3m), 4.08 (q, 2H, OCH₂CH₃), 4.30, 4.48 (2m), 5.10 (q, 2H, OBn), 7.10-7.40 (m, 10H Ar-H). Example 9: Preparation of Trandolapril (IVd) from Trandolapril-benzylester (llld, R=Bn)

1 .60 g (3.07 mmol) of Trandolapril-benzylester (llld, R=Bn), as obtained from example 8, were hydrogenated at 20 °C in 20 ml of ethanol with 100 mg of a 5% Pd on charcoal catalyst (balloon). After complete consumption of the starting material, as detected by LC-MS, the catalyst was filtered off and the solvent was evaporated i.vac. at 20 °C. In this manner 1 .3 g (98%) of crude Trandolapril were obtained as viscous oil which was purified by crystallization from diisopropylether.

LC-MS: MH 31

¹H NMR (two rotamers) 1 .00-1 .92 (m, 17H), 1 .05 (d, Me), 1 .20 (t, Me), 2.10 (m, 1 H), 2.25 (m, 1 H), 2.57 (m, 2H, PhCH₂), 3.1 2 (m, 2H), 3.55 (m, 1 H), 3.90-4.20 (m, 3H), 4.08 (q, OCH₂), 7.12-7.30 (m, 5H ArH).

Example 10: Preparation of Delapril-benzylester (I lie, R=Bn) from N-[1 -(S)- (ethoxycarbonyl)-3-phenylpropyl]-L-alanine (I)

1 .56 g (4.96 mmol) of the hydrochloride of N-[1 -(S)-(ethoxycarbonyl)-3-phenylpropyl]-L- alanine (I), obtained from 1 .39 g (4.96 mmol) of compound I and ca. 6 mmol of dry HCI in 1 5 ml of dry DCM, were cooled under argon and stirred at -10°C. Then 0.68 g (5.05 mmol) of Vilsmeier reagent (96%, from Acros Chemicals) were added in one portion. After stirring for a total of 30 minutes at a temperature ranging from -10°C to -5°C, the clear solution was transferred within about 3 minutes into a cooled (ca. 0°-5°C) and vigorously stirred mixture of water (5 ml), sodium bicarbonate (2.00 g), DCM (5 ml) and 1 .67 g (4.72 mmol) of the hydrochloride of N-(2,3-dihydro-1 H-inden-2-yl)-glycine benzylester (lie, R=Bn) (purity ca. 90%, prepared as described by J. W. Skiles in

J.Med.Chem. 1992, 35, 641 -662.). The organic phase was separated, washed 3 times with 5 ml of water, dried over sodium sulfate and carefully concentrated at up to 20 °C i. vac. to yield 2.5 g (97%) of the crude title compound as colorless oil. LC-MS: (MH⁺ 543). ¹H NMR: 1 .12 (d, 3H, CH₃), 1 .19 (t, 3H, OCH₂CH₃), 1 .80 (m, 2H, PhCH₂CH₂), 2.58 (m, 2H, PhCH₂), 2.80-3.12 (m, 4H, indanyl-CH₂), 3.20 (m, 1 H, CHC=0), 3.85-4.30 (m, 5H, OCH₂CH₃, CH₂N, indanyl-CHN), 5.00-5.17 (m, 3H, OBn, CHC=0), 7.05-7.40 (m, 14H, Ar).

Example 1 1 : Preparation of Delapril (IVe)-hydrochloride from Delapril-benzylester (I lie, R=Bn)

1 .90 g (3.50 mmol) of Delapril-benzylester (We, R=Bn), as obtained from example 10, were hydrogenated at 15-20°C in 30 ml of ethyl acetate/ethanol (9/1 ) containing ca. 5 mmol of dry HCI with a 5% Pd on charcoal catalyst (ca. 100 mg) at atmospheric pressure (balloon). After complete consumption of the starting material, as detected by LC-MS, the catalyst was filtered off and the solvents were evaporated to afford a colourless foam. This material was dissolved in minimum amount of methanol, diluted with ca. 100 ml of ethyl acetate and upon evaporation of the solvents the title compound appeared as a colorless powder, yield 1 .55 g (91 %);

LC-MS: MH⁺ 453.

¹H NMR: 1 .22, 1 .25 (2t, 3H, OCH₂CH₃), 1 .44 (d, 3H, CH₃), 2.05-2.30 (m, 2H,

PhCH₂CH₂), 2.62, 2.75 (2m, 2H, PhCH₂), 2.75-3.30 (m, 4H, indanyl-CH₂), 3.75-4.13 (2m, 3H, NCHC=0, CH₂N), 4.14-4.33, 4.73 (2m, 3H, OCH₂, indanyl-CHN), 4.95, 5.03 (2m, 1 H, NH₂ ⁺CHCH3), 7.10-7.47 (m, 9H, Ar), 9.80 (broad m, 2H, NH₂ ⁺), 12.80 (broad m, 1 H, COH).

Claims

1 . A process for the preparation of a compound of formula (Ilia), (lllb), (lllc), (llld), (llle) or (lllf)

(llle) (lllf)

wherein R is a protecting group;

characterized by

carbonyl)-3-phenylpropyl]-L-alanine of the formula (I)

(I)

in the presence of an acid with Ν,Ν-dimethyl-chloromethyl-iminium chloride,

in a suitable organic solvent; b) reacting the product obtained in step a) with an amine selected from a compound of formula lla), (lib), (lie), (lid), (lie) or (Ilf)

Me

wherein R is a protecting group, in the presence of a base

in a mixed solvent system of water and a water immiscible solvent,

to obtain a compound of formulae (Ilia) - (lllf).

2. The process according to anyone of claim 1 , wherein the acid is hydrochloric acid.

3. The process according to claim 1 or 2, wherein the solvent used in step a) is selected from dichloromethane, chloroform, 1 ,2-dichloroethane, n-butyl-acetate or methyl-isobutyl-ketone.

4. The process according to claim 1 or 2, wherein the solvent used in step b) is selected from dichloromethane, chloroform, 1 ,2-dichloroethane, methyl-tert.-butylether, n-butyl-acetate, ethyl acetate, methyl-isobutyl-ketone, 2-methyl-tetrahydrofuran, or toluene.

5. The process according to any of claims 1 to 4, wherein the solvent used in step a) and b) is dichloromethane.

6. The process according to any one of claims 1 to 5, wherein the pH-value in step b) is in the range of 7.0 to 9.0.

7. The process according to any one of claims 1 to 6, wherein the base in step b) is a water soluble inorganic base selected from sodium bicarbonate, potassium

bicarbonate, sodium hydroxide or potassium hydroxide.

8. The process according to anyone of claims 1 to 7, wherein the carboxyl protecting group is a benzyl group.

9. The process according to any one of claims 1 to 8, wherein in a further step c) the protecting group R is removed to obtain a compound of formula (IVa), (IVb), (IVc), (IVd), (IVd) or (IVf)

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