IN THE PREPARATION OF SACUBITRIL

Field

The invention generally relates to methods of preparing a compound, in particular a pharmaceutical compound. The invention more specifically relates to preparing a NEP inhibitor. The invention also relates to pharmaceutical compositions comprising such compounds, processes and intermediates for preparing such compounds.

Introduction

Neprilysin (neutral endopeptidase, EC 3.4.24.11) (NEP), is an endothelial membrane bound Zn ²⁺ metallopeptidase found in many organs and tissues, including the brain, kidneys, lungs, gastrointestinal tract, heart, and the peripheral vasculature. NEP degrades and inactivates a number of endogenous peptides, such as enkephalins, circulating bradykinin, angiotensin peptides, and natriuretic peptides, the latter of which have several effects including, for example, vasodilation and natriure sis/diuresis, as well as inhibition of cardiac hypertrophy and ventricular fibrosis. Thus, NEP plays an important role in blood pressure homeostasis and cardiovascular health.

The present invention is related to the preparation of the NEP inhibitor sacubitril (Formula I). Sacubitril is (2R,4S)- 5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentan oic acid ethyl ester, also named N-(3-carboxy-l- oxopropyl)-(4S)-(p-phenylphenylmethyl)-4- amino-2R-methylbutanoic acid ethyl ester.

The use of sacubitril for treating cardiovascular disorders is described in U.S. Patent No. 5,217,996. Sacubitril is useful as a neutral endopeptidase (NEP) inhibitor, e.g. as inhibitors of the ANF-degrading enzyme in mammals, which prolong and potentiate the diuretic, natriuretic and vasodilator properties of ANF in mammals by inhibiting the degradation thereof to less active metabolites. In particular, sacubitril is useful for the treatment of conditions and disorders responsive to the inhibition of neutral endopeptidase EC 3.4.24.11, particularly cardiovascular disorders, such as hypertension, renal insufficiency including edema and salt retention, pulmonary edema and congestive heart failure.

Processes for preparing NEP-inhibitors have been described in U.S. Patent No. 5,217,996, which discloses N-(3- carboxyl-l-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2 R)-methyl butanoic acid ethyl ester prepared by hydrogenating N-t-butoxycarbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-met hyl-2-butenoic acid ethyl ester in the presence of palladium on charcoal. However, a major drawback of the process is that he hydrogenation step is not very selective and yields N-t-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-2-met hylbutanoic acid ethyl ester as an 80:20 mixture of diastereomers. Moreover, the process for preparing N-t-butoxycarbonyl-(4R)- (p-phenylphenylmethyl)-4-amino-(2)-methyl(2)-butenoic acid ethyl ester requires D-tyrosine as starting material, which is an unnatural amino acid and is not readily available.

U.S. Patent No. 8,877,938 discloses trisodium sacubtril-valsartan hemipentahydrate in crystalline form, a dual- acting compound where the angiotensin receptor blocker and neutral endopeptidase inhibitor are linked via non- covalent bonding.

U.S. Patent No. 7,468,390 discloses pharmaceutical composition of valsartan or a pharmaceutically acceptable salt thereof with sacubitril or a pharmaceutically acceptable salt thereof.

Summary

The present invention provides (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester as well as method of preparing said compound:

(II)

The present invention is based on the compound of formula II and its use as intermediate in a process of obtaining sacubitril. In particular, the invention provides a substantially optically pure (4S)-(p- phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester.

As understood herein, substantially optically pure means that the desired enantiomer is synthesized or isolated at an stereoisomeric purity of at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% purity relative to other enantiomer(s). In a preferred embodiment, substantially optically pure means that the desired enantiomer is synthesized or isolated at an stereoisomeric purity of at least 95%. In another preferred embodiment, substantially optically pure means that the desired enantiomer is synthesized or isolated at an stereoisomeric purity of at least 98%. In another preferred embodiment, substantially optically pure means that the desired enantiomer is synthesized or isolated at an stereoisomeric purity of at least 99%.

The invention provides a process of preparing compound of formula (II) from the compound of formula (III), namely, preparing (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester from (4S)-(p- phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester illustrated by the following scheme:

(III) (IV) wherein XA is a chiral acid, preferably a chiral organic acid.

Chiral acids can be used for enantioresolution which facilitates the synthesis of desired enantiomers with absolute configurational assignment. As used herein, "resolution" or "enantioresolution" refers to a process for the separation of racemic compounds into their enantiomers.

The chiral acid can typically be selected from the group consisting of mandelic acid (2-Hydroxy-2-phenylacetic acid), tartaric acid (2,3-dihydroxybutanedioic acid), di-p-toluyl tartaric acid (2,3-bis (4- methylbenzoyijoxyjbutanedioic acid), dibenzoyl tartaric acid (2,3-dibenzoyloxybu†anedioic acid), camphor sulfonic acid ((7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-l-yl)methanesulfoni c acid ) and the like.

Other suitable chiral acids may be determined by testing and the use thereof in a process as described above falls within the scope of the present invention. Preferably the chiral acid employed in a process according to the present invention is, but not limited to, a chiral organic acid, such as mandelic acid, tartaric acid, di-p-toluyl tartaric acid, dibenzoyl tartaric acid, camphor sulfonic acid and the like. Additional chiral acids are known to a skilled person in the art.

The process according to the present invention which uses a chiral acid has a number of advantages. The process in particular allows to efficiently provide the compound of formula II in an optical purity of at least 98.5% without the need for additional purification steps such as liquid chromatography, which inevitably result in decreased yield.

Additionally, the present invention provides different synthesis schemes for synthesizing the compound of formula II.

In scheme I, the process comprises steps of

a) treating (4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester of formula III in a solvent, with chiral organic acid to obtain compound of formula (IV);

b) reacting the compound of formula (IV) with base to obtain compound of formula (II).

(III) (IV) (ii) wherein XA is any chiral acid, preferably a chiral organic acid.

The compound of formula II can also be produced by the synthetic routes illustrated in the following scheme. Scheme II:

(ill-A) (IV) (II) wherein X ^" is the anion of the organic or inorganic acid which forms salt with compound of formula III, and XA is any chiral acid, preferably any chiral organic acid.

The salt of (4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester of formula (III-A) may be first treated with base depending on the conjugated acid of the acid addition salt. If the compound III-A is acid addition salt of strong conjugate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, oxalic acid, maleic acid, malonic acid and the like, the acid addition salt is treated with base before treatment with the chiral organic acid.

If the compound III-A is acid addition salt of weak conjugate acid, such as mandelic acid, acetic acid, succinic acid, propionic acid, crotonic acid, lactic acid, formic acid, glutaric acid, adipic acid, benzoic acid and the like, the acid addition salt does not need to be treated with base before treatment with the chiral organic acid.

The present invention also provides a method of preparing an acid salt of formula IV

(III) (IV) comprising reacting the amine compound of formula III with a chiral acid (XA), preferably a chiral organic acid. The amine compound can be either in the form of the free base or acid addition salt. If the amine compound is in the form of acid addition salt conjugated to an acid which is stronger than the chiral acid used, the method further comprises treating the the acid addition salt with base before the step of reacting with the chiral acid (XA).

If the amine compound is in the form of acid addition salt conjugated to an acid which is weaker than the chiral acid used, the acid addition salt is not pretreated with base before the step of reacting with the chiral acid (XA).

In more detail, the invention provides a process of preparing an amine salt of a chiral acid, preferably chiral organic acid, of formula IV,

W-Ai CSV}

(Scheme Ila)

comprising

a) treating salt of (4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester of formula (III- A) with chiral acid to obtain compound of formula (IV);

b) reacting the compound of formula (IV) with base to obtain compound of formula (II);

when X ^" is the anion of an acid which is weaker than the chiral acid.

For example, the conjugated acid may be selected from the group consisting of mandelic acid, acetic acid, succinic acid, Propionic acid, crotonic acid, lactic acid, formic acid, glutaric acid, adipic acid, benzoic acid and the like. The invention also provides a process of preparing an amine salt of a chiral acid of formula IV,

P-A) O ) )

(Scheme lib)

comprising

a) treating salt of (4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester of formula (III- A) with base followed by treatment with chiral acid to obtain compound of formula (IV); b) reacting the compound of formula (IV) with base to obtain compound of formula (II);

when X ^" is the anion of an acid which is stronger than the chiral acid. For example, the conjugated acid may be selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, oxalic acid, maleic acid, malonic acid.

An acid which is stronger than the chiral organic acid would have a lower pKa value than the chiral acid. For example, if the chiral acid has a pKa of 3.0, a stronger acid is an acid that has a pKa that is less than 3.0. If the chiral acid has multiple acidic groups, the term can refer to the weaker of the groups. The term can also refer to acids that are stronger than all of the multiple acidic groups. For example, Tartaric acid has two acidic groups, with pKa values of about 2.89 and about 3.22, respectively. An acid that is stronger than tartaric acid can therefore be an acid with a pKa less than 3.22.

In some embodiments, the chiral acid is tartaric acid, and the acid that is stronger than tartaric acid has a pKa that is less than about 3.22, less than about 3.2, less than about 3.0, less than about 2.9, or less than about 2.8.

An acid that is weaker than the chiral acid, by contrast, is an acid with a pKa that is greater than the chiral acid. For example, if the chiral acid is tartaric acid, the acid that is weaker than tartaric acid can be an acid with a pKa that is greater than 3.22, greater than 3.3 or greater than 3.3.

For example, if tartaric acid is used as chiral organic acid, an acid which is stronger than tartaric acid could example be hydrochloric acid, phosphoric acid, sulfuric acid and other inorganic acid, toluene sulfonic acid, benzene sulfonic acid, or camphor sulfonic acid and the like.

The present invention is based on the discovery of a novel intermediate useful for synthesizing sacubitril. The invention provides (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester or salt thereof preferably in substantially optically pure form. The compound can be obtained by reacting (4S)-(p- phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester with a suitable chiral acid. The invention further provides an acid salt of compound of formula IV, wherein XA is a chiral acid, preferably a chiral organic acid:

(IV)

It has been discovered that preparation of sacubitril or salt thereof through compound IV results in compounds of high purity and yield. Moreover, the processes as disclosed are cost effective and feasible on large scale synthesis.

Further, the invention provides an acid salt compound of formula IV:

(IV) wherein XA is tartaric acid, dibenzoyl tartaric acid, or di-para-toluoyl tartaric acid.

Preferably, the compound is (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester D-(-)- tartrate.

The present invention additionally provides crystalline (4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester D-(-)-tartrate. Preferably, the compound is characterized by at least one of

a) powder X-ray diffraction peaks with 2-theta 5.59, 8.63, 11.13, 14.82, 16.22, 16.82, 18.45, 19.86, 20.73 & 21.29, or

b) a differential scanning calorimetric thermogram with a endothermic peak at about 177°C.

The (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester D-(-)-tartrate can be characterized by at least one of: X-ray diffraction peaks with 2-theta values 5.59, 8.63, 11.13, 14.82, 16.22, 16.82, 18.45, 19.86, 20.73 & 21.29 as shown in Fig. 1 and a differential scanning calorimetric thermogram with an endothermic peak at about 177°C as shown in Fig. 2. The invention can also be extended to provide further conversion of the compound of formula (II) to obtain sacubitril. Process for the conversion is known to a skilled artisan and described in U.S. Patent No. 5,217,996, the entire contents of which are hereby incorporated by reference.

The above features along with additional details of the invention, are described further in the examples below, which are intended to further illustrate the invention but are not intended to limit its scope in any way.

Brief description of the drawings

The skilled person will understand that the drawings, described below, are for illustration purposes only. The drawings are not intended to limit the scope of the present teachings in any way.

Figure 1 shows structural analysis of (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester D-(-)-tartrate by X-ray diffraction (XRD), as obtained by the process of the invention.

Figure 2 shows an Infrared Spectrum (IR) of (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester D-(-)-tartrate, as obtained by the process of the invention.

Figure 3 shows results of Differential Scanning Calorimetry (DSC) of (4S)-(p-phenylphenylmethyl)-4-amino- (2R)-methylbutanoic acid ethyl ester D-(-)-tartrate, as obtained by the process of the invention.

Figure 4 shows results of HPLC analysis of compound IV-A obtained by the process according to the invention.

Figure 5 shows results of HPLC analysis of the chiral purity of compound II obtained by the process according to the invention.

Figure 6 shows results of HPLC analysis of the chiral purity of compound III obtained by the process according to the invention.

Figure 7 shows results of HPLC analysis of the chiral purity of compound IV-A obtained by the process according to the invention.

Description of various embodiments

In the following, exemplary embodiments of the invention will be described, referring to the figures. These examples are provided to provide further understanding of the invention, without limiting its scope.

In the following description, a series of steps are described. The skilled person will appreciate that unless required by the context, the order of steps is not critical for the resulting configuration and its effect. Further, it will be apparent to the skilled person that irrespective of the order of steps, the presence or absence of time delay between steps, can be present between some or all of the described steps.

As used herein, including in the claims, singular forms of terms are to be construed as also including the plural form and vice versa, unless the context indicates otherwise. Thus, it should be noted that as used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. The invention is based on the discovery of (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester (compound of formula II) and its novel use for preparing sacubitril. In particular, substantially optically pure (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester can be converted in to Sacubitril by the similar process disclosed in U.S. Patent No. 5,217,996, in particular as described in Example 1.

(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester can be prepared by the methods as described in the present invention.

The present invention provides a method of preparing an acid salt of formula IV

(III) (IV) comprising reacting the amine compound of formula III with a chiral acid (XA), preferably a chiral organic acid, to obtain the compound of formula IV:

Then, the compound of formula IV can be treated with base to obtain the compound of formula II.

CtV

The resolution step using chiral acid is achieved with a suitable chiral acid in a suitable polar solvent. Suitable solvents comprise water, methanol, ethanol, propanol, isopropanol, butanol, dimethylformamide, dimethylsulfoxide and the like. Preferably, the polar solvent is a lower alcohol such as methanol or ethanol, although again other suitable solvents can be determined by testing and the use thereof in a process as described above falls within the scope of the present invention. Most preferably, the solvent is methanol or ethanol.

Basic solutions useful in the present invention can be organic or inorganic base. Organic base can be triethylamine, dimethylamine, pyridine, piperidine, diisopropylethylamine, ammonia or the like. Inorganic base can be sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like. Preferably, the base used in the method provided in the present invention is ammonia. Prefeably, the base is provided in in a suitable solvent, which can be an apolar solvent or mixture of an apolar solvent and polar solvent. Apolar solvent can be dichloromethane, chloroform or the like, and polar solvent can be selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, butanol, dimethylformaide, dimethylsulfoxide or the like. Preferably, the apolar solvent is dichloromethane.

In addition, the invention provides a process of preparing (4S)-(p-phenylphenylmethyl)-4-amino-(2R)- methylbutanoic acid ethyl ester of formula (II) by the following scheme:

Scheme III:

A distinct advantage of the process of the invention is that compound with formula (II) is obtained in high yield and very pure form. Preferably, the compound is the D-(-)-tartrate salt of a compound with formula (IV- A). The D-(-)-tartrate salt of the compound with formula (IV- A) is obtained with purity in excess of 99% by HPLC. The compound further has a characteristic endothermic differential scanning calorimetric (DSC) peak in the range of 169 to 185°C, preferably in range of 175-179°C, more preferably 176-178.4°C, and even more preferably at about 177°C. Compound with formula (IV-A) obtained by the synthetic route is further characterized by a powder x-ray diffraction pattern that comprises peaks with 2-theta values of 5.59, 8.63, 11.13, 14.82, 16.22, 16.82, 18.45, 19.86, 20.73 & 21.29. Preferably, the compound is characterized by an x-ray diffraction pattern as shown in Figure 1.

The novel D-(-)-tartrate salt of compound IV-A that is obtained by the methods of the invention results in the formation of compound II in high yield and remarkable purity, without the requirement of further purification by liquid chromatography, which inevitably results in decreased yield. The process is further easily scalable, and thus useful on an industrial level.

Various non-limiting embodiments include the following:

I . (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester or salt thereof.

2. Substantially optically pure (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester or salt thereof.

3. An acid salt of compound of formula IV, wherein XA is a chiral acid, preferably a chiral organic acid.

4. The acid salt of clause 3, wherein XA is tartaric acid, dibenzoyl tartaric acid, mandelic acid, camphor sulfonic acid or di-para-toluoyl tartaric acid.

5. A tartrate salt of compound with the formula IV.

6. (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester D(-)-tartrate of compound of formula IV-A.

7. Crystalline (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester D-(-)-tartrate.

8. A crystalline (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester D-(-)-tartrate of clause 7 characterized by at least one of of the following:

a) Powder X-ray diffraction peaks with 2-theta values of 5.59, 8.63, 11.13, 14.82, 16.22, 16.82, 18.45, 19.86, 20.73 & 21.29.

b) A differential scanning calorimetric thermogram with a endothermic peak at about 177°C

10. Use of (4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester or salt thereof in clause 1 or 2 to prepare sacubitril or salt thereof.

I I . Use of the acid salt of compound of formula IV in clause 3 or 4 to prepare sacubitril or salt thereof.

12. Use of the tartrate salt in any one of clause 5-8 to prepare sacubitril or salt thereof.

13. A method of preparing an acid salt of formula IV, comprising reacting the amine compound of formula III with a chiral acid (XA), preferably a chiral organic acid.

14. The method of clause 13, comprising adding a chiral organic acid to the amine compound of formula III in a solvent.

15. The method of clause 13 or 14, wherein the amine compound is in the form of the free base or acid addition salt. 16. The method of clause 15, wherein the amine compound is in the form of acid addition salt conjugated to an acid which is stronger than the chiral acid, and wherein the method further comprises treating the the acid addition salt with base before the step of reacting with a chiral acid (XA).

17. A method of preparing an acid salt of formula IV, by reacting the compound with formula III with a chiral acid with formula XA, and wherein the amine compound of formula III is in the form of acid addition salt conjugated to an acid which is stronger than the chiral acid, comprising the steps of

- treating the acid addition salt of the compound with formula III with base in a solvent or mixture of solvents and then

- treating the solution with chiral organic acid in a solvent or mixture of solvents to obtain compound of formula IV.

(Ill) (IV) wherein XA is a chiral acid, and wherein the amine compound of formula III is in the form of acid addition salt conjugated to an acid which is weaker than the chiral acid, comprising the steps of treating the acid addition salt with chiral organic acid in a solvent or mixture of solvent to obtain compound of formula IV.

19. The method according any one of the preceding clauses, wherein the chiral acid is chiral organic acid.

20. The method of clause 19, wherein chiral organic acid is selected from the group consisting tartaric acid, dibenzoyl tartaric acid, or di-para-toluoyl tartaric acid.

21. The method of clause 20, wherein tartaric acid is D-(-)- tartaric acid.

22. The method of clause 13, 16 or 17, wherein the amine compound of formula III is in the form of acid addition salt conjugated to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, oxalic acid, maleic acid, or malonic acid.

23. The method of clause 13 or 18, wherein the amine compound of formula III is in the form of acid addition salt conjugated to mandelic acid, acetic acid, succinic acid, proponic acid, crotonic acid, lactic acid, formic acid, glutaric acid, adipic acid, benzoic acid and the like.

24. Use of a chiral organic acid to prepare sacubitril.

25. Use of a chiral organic acid to prepare the compound of formula II. 26. The use of clause 24 or clause 25, wherein the chiral organic acid is selected from tartaric acid, dibenzoyl tartaric acid, mandelic acid, camphor sulfonic acid or di-para-toluoyl tartaric acid.

27. The use according clause 26, wherein tartaric acid is D-(-)- tartaric acid.

Examples

Example 1: Preparation of (4S)-(p-phenylphenylmethyl)-4-amino-(27?)-methylbutanoic acid ethyl ester D- (-)-tartrate salt

In a round bottom flask was added (45)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester hydrochloride (20g) followed by addition of dichloromethane (200ml) and water (20ml) and reaction was stirred for five to ten minutes. To this mixture liquor ammonia solution (about 200ml) was added till clear solution was obtained. Reaction mass was allowed to settle for about 30 minutes. Organic layer was separated and aqueous layer was extracted by dichloromethane (3 χ 50ml). Combined organic layers were dried over sodium sulfate. Solvent was removed by distillation to obtain 14.5g (81%) product as oil.

Solution of D-(-)-tartaric acid (6.98g) in ethanol (70ml) was added to a solution of (45)-(p-phenylphenylmethyl)- 4-amino-2-methylbutanoic acid ethyl ester (14.5g) in ethanol (70ml) under stirring. Solid product formation was observed. Reaction mixture was stirred for two to three hours. Product was filtered and washed with ethanol (29ml). After drying 11.25g (75%) product was obtained with 99% purity.

The final producted is characterized a powder X-ray diffraction (XRD) pattern as shown in Figure 1. The XRD pattern shows the following main peaks as 2-theta values as indicated in the following table:

Table 1

Example 2: Preparation of (4S)-(p-phenylphenylmethyl)-4-amino-(27?)-methylbutanoic acid ethyl ester D- (-)-tartrate salt

In a round bottom flask was added (45)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester hydrochloride (20g) followed by addition of dichloromethane (200ml) and water (20ml) and reaction was stirred for five to ten minutes. To this mixture liquor ammonia solution (about 200ml) was added till clear solution was obtained. Reaction mass was allowed to settle for about 30 minutes. Organic layer was separated and aqueous layer was extracted by dichloromethane (3 χ 50ml). Combined organic layers were dried over sodium sulfate. Solvent was removed by distillation to obtain 14.5g (81%) product as oil.

Solution of D-(-)-tartaric acid (6.98g) in ethanol (70ml) was added to a solution of (45)-(p-phenylphenylmethyl)- 4-amino-2-methylbutanoic acid ethyl ester (14.5g) in ethanol (70ml) under stirring. Solid product formation was observed. Reaction mixture was heated to reflux and water (40 ml) was added in to the reaction mixture. Reflux was continued for about five to ten minutes, during this time clear solution was observed. Reaction mixture was cooled to room temperature and stirred for two to three hours. Product was filtered and washed with ethanol (29ml). After drying 8.4g (56%) product was obtained with more than 99% purity.

Example 3: Preparation of (4S)-(p-phenylphenylmethyl)-4-amino-(27?)-methylbutanoic acid ethyl ester succinate salt

(45)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester was prepared by process similar to that of disclosed in example 1 by treating (45)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester hydrochloride with liquor ammonia.

To a solution of (45)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester (3g) and acetone (24ml) was added succinic acid (1.13g) under stirring. Solid product formation was observed. Reaction mixture was stirred for two to three hours. Product was filtered and washed with acetone (6ml). After drying 2.6g (62.8%) product was obtained with 99% purity.

Example 4: Preparation of (4S)-(p-phenylphenylmethyl)-4-amino-(27?)-methylbutanoic acid ethyl ester D- (-)-tartrate salt

In a round bottom flask added (45)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester succinate (500mg) and ethanol (10ml), and the mixture was stirred for 10-15 minutes. To this suspension was added D-(-)- tartaric acid (200mg) under stirring. Reaction mixture was heated to reflux and water (3 ml) was added during reflux to obtain clear solution. Reaction mixture was cooled to room temperature and was stirred for two to three hours at this temperature. Product was filtered and washed with ethanol (2ml). After drying 300mg (55.8%) product was obtained with 99% purity.

Example 5: Preparation of (4S)-(p-phenylphenylmethyl)-4-amino-(27?)-methylbutanoic acid ethyl ester

In a round bottom flask (45)-(p-phenylphenylmethyl)-4-amino-(2i?)-methylbutanoic acid ethyl ester tartrate salt (8g) and dichloromethane (25ml) was added and mixture was stirred for ten minutes. Water (50ml) was added in to the reaction mixture and reaction mixture was stirred for another ten minutes. Reaction mixture was cooled to 10-15°C and slowly added liquor ammonia solution (about 25ml) till reaction mass becomes clear. Reaction mixture was stirred for 10-15 minutes at 10-15°C and then allowed to settle for 20 minutes. Organic layer was separated and aqueous layer was extrated with dichloromethane (3 ^χ 25ml). Combined organic layers was dried over sodium sulfate. Solvent was removed by distillation to obtain 5g (92.5%) of product.