Claims:1. A process for preparation of (S)-3-amino-2-(4-methylphenyl)propanoic acid the compound of formula - I or its salt,

Formula - I
which comprises the steps of:
a) reacting the compound, isopropyl 4-methylphenylacetate of formula - II

Formula - II
with paraformaldehyde in presence of polar aprotic solvent and an activator to get the compound, isopropyl 3-hydroxy-2-(4-methylphenyl)propanoate of formula - III;

Formula - III
b) reacting the compound of formula - III with a sulfonating agent to get the sulphonate ester compound of formula - IV in presence of base and solvent;

Formula - IV
wherein R is selected from methyl, trifluoromethyl, 4-methylphenyl, phenyl and
4-nitrophenyl;
c) reacting the compound of formula - IV with ammonia to get the compound, isopropyl 3-amino-2-(4-methylphenyl)propanoate or its salt of formula - V;

Formula - V
d) hydrolysing the compound of formula - V or its salt to get the racemic compound 3-amino-2-(4-methylphenyl)propanoic acid of formula - IA;

Formula - IA
e) resolving the compound of formula - IA with or without protection with suitable resolving reagent in presence of solvent yields the compound (S)-3-amino-2-(4-methylphenyl)propanoic acid of formula - I or its salt.

2. The process as claimed in claim 1, wherein the polar protic solvent used in step (a) of the process is selected from the group consisting of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide or a mixture thereof.

3. The process as claimed in claim 1, wherein activator used in step (a) of the process is a base selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate, sodium ethoxide, potassium tert-butoxide and sodium methoxide or a mixture thereof.
4. The process as claimed in claim 1, wherein the base used in step (b) is selected from the group consisting of triethylamine, trimethylamine, pyridine, N-methylmorpholine and N-methyl pyrrolidone.

5. The process as claimed in claim 1, wherein the solvent used in step (b) is selected from the group of chlorinated solvent consisting of dichloromethane, dichloroethane, carbon tetrachloride and tetrachloroethane.

6. The process as claimed in claim 1, wherein the sulfonating agent used in step b) is selected from the group consisting of methanesulphonyl chloride, trifluoromethanesulfonyl chloride, 4-methylphenylsulfonyl chloride and 4-nitrophenylsulfonyl chloride.

7. The process as claimed in claim 1, wherein the sulphonate ester compound of formula - IV in step (b) the R group is selected from methyl, trifluoromethyl, 4-methylphenyl and 4-nitrophenyl.

8. The process as claimed in claim 1, wherein the ammonia used for the reaction in step (c) is selected from methanolic ammonia, aqueous ammonia, and ammonia gas.

9. The process as claimed in claim 1, wherein the compound of formula - IA is protected using the compound selected from Boc-anhydride, acetyl chloride, acetic anhydride, benzyl chloroformate, benzoyl chloride, and benzoic anhydride.

10. The process as claimed in claim 1, wherein resolving reagent used for resolution of the compound of formula - IA is selected from the group consisting of (R)-1-phenylethan-1-amine, (R)-1-phenylpropan-1-amine, (R)-2-(3-chlorophenyl)propan-1-amine and (R)-(-)-4-phenyl-2-oxazolidinone.
11. The process as claimed in claim 1, wherein the solvent used for resolution process is selected from the group consisting of ethanol, isopropyl alcohol, ethyl acetate, acetone, isopropyl acetate, methyl ethyl ketone and methyl isobutyl ketone or mixture thereof.

12. Isopropyl 3-hydroxy-2-(4-methylphenyl)propanoate of formula - III.

Formula - III
13. A sulphonate ester compound of formula - IV;

Formula - IV
wherein R is selected from methyl, trifluoromethyl, 4-methylphenyl, phenyl and
4-nitrophenyl.
14. Isopropyl 3-(methanesulfonyloxy)-2-(4-methylphenyl)propanoate of formula - IVA.

Formula - IVA
15. Isopropyl 3-amino-2-(4-methylphenyl)propanoate of formula - V or its salt.

Formula - V
16. (R)-1-phenylethan-1-amine (S)-3-((tert-butoxycarbonyl)amino)-2-(4-methylphenyl)-propanoate, of formula - VI.

Formula - VI
17. (R)-1-phenylethan-1-amine (S)-3-amino-2-(4-methylphenyl)propanoate hydrochloride of formula - VII.

Formula – VII
, Description:Field of Invention:
The present invention relates to a novel process for the preparation of (S)-3-amino-2-(4-methylphenyl)propanoic acid and novel intermediates thereof. The present invention also relates to preparation of novel intermediates during the preparation of (S)-3-amino-2-(4-methylphenyl)propanoic acid.

Background and Prior art:
The compound (S)-3-amino-2-(4-methylphenyl)propanoic acid of formula - I is a ß-amino acid and they are main components of numerous natural products and precursors of active pharmaceutical ingredients, ß-lactams and ß-peptides.

Formula - I
Synthesis of (S)-3-amino-2-(4-methylphenyl)propanoic acid of formula - I is reported in European Journal of Organic Chemistry, (33), 6393-6403 (2010), where the compound is prepared by functionalization of (2S)-isopropyl-5-iodo-2,3-dihydro-4(H)-pyrimidin-4-ones by a Suzuki-Miyaura cross-coupling reaction using aryltrifluoroborate salts. The method is as follows. Cyclization of (S)-asparagine with isobutyraldehyde in presence of potassium hydroxide followed by reaction with benzoyl chloride in presence of sodium bicarbonate yields (2S,4S)-3-benzoyl-2-isopropyl-6-oxohexahydropyrimidine-4-carboxylic acid of formula - A. The compound of formula - A is reacted with diacetoxyiodobenzene and iodine followed by addition of boron trifluoride-etherate complex to form (S)-1-benzoyl-5-iodo-2-isopropyl-2,3-dihydropyrimidin-4(1H)-one of formula - B, which was purified by flash chromatography. The compound of formula - B is reacted with potassium 4-methylphenyltrifluoroborate in the presence of palladium diacetate and potassium carbonate in mixture of solvent dioxane-water to form (S)-1-benzoyl-2-isopropyl-5-(4-methylphenyl)-2,3-dihydropyrimidin-4(1H)-one of formula - C, which is purified by column chromatography using 1:1 ethyl acetate/hexane. The compound of formula - C is hydrogenated in presence of Raney nickel in solvent methanol to give (2S,5S)-1-benzoyl-2-isopropyl-5-(4-methylphenyl)tetrahydropyrimidin-4(1H)-one of formula - D, which is purified by flash chromatography followed by hydrolysis with 4N hydrochloric acid under microwave irradiation at 100°C yields (S)-3-amino-2-(4-methylphenyl)propanoic acid of formula - I, which is purified by flash silica gel chromatography using 5:2:1 isopropanol/methanol/ammonium hydroxide. The reaction sequence is represented as given in scheme - I.

Scheme - I
The drawback of above process involved the use of column chromatography/flash silica gel chromatography for purification of intermediate and the products, which renders the process uneconomical, time consuming and industrially unviable.
Another method for the preparation of (S)-3-amino-2-(4-methylphenyl)propanoic acid of formula - I is disclosed in Tetrahedron Letters, 55(1), 267-270 (2014) using asymmetric conjugate addition of arylboronic acids to 2-nitroacrylamide in the presence of cationic palladium-Chiraphos as catalyst. 2-Nitroacrylamide is reacted with 4-methylphenylboronic acid in the presence of catalyst [Pd(S,S)-Chiraphos)(PhCN)2](SbF6)2, AgBF4, HBF4 in solvent tetrahydrofuran-water to give (S)-3-nitro-2-(4-methylphenyl)propanamide of formula - E. The compound of formula - E is hydrogenated in the presence of Raney Nickel in solvent ethanol to give (S)-3-amino-2-(4-methylphenyl)propanamide of formula - F. Hydrolysis of the compound of formula - F with 6N hydrochloric acid to give (S)-3-amino-2-(4-methylphenyl)propanoic acid of formula - I. The reaction sequence is represented in scheme - II.

Scheme - II
The above process uses palladium catalyst containing chiral Chiraphos ligands that makes the process economically unviable on industrial scale.

Therefore, there remains a need in the art for a process for preparing the compound (S)-3-amino-2-(4-methylphenyl) propanoic acid of formula - I which employs safe and economical reagents for the reaction, makes the process industrially viable and hence, advantageous and reduces the time cycle of the reaction.

Accordingly, the present inventors have developed a novel process for the preparation of the compound, (S)-3-amino-2-(4-methylphenyl)propanoic acid of formula - I, which ameliorates the problems in the prior art by employing a commercially available compound isopropyl 4-methylphenylacetate, as starting material, yielding novel intermediates, thereby improving the economy of the process. The process provided in the present invention does not require costly reagents and column chromatography purification unlike the prior art processes.

OBJECTIVE OF THE INVENTION:
The main objective of the present invention is to prepare the compound, (S)-3-amino-2-(4-methylphenyl)propanoic acid of formula - I or its salt by robust, rigid and industrial friendly process.
Another objective of the present invention is to prepare the novel intermediate compound, viz., isopropyl 3-hydroxy-2-(4-methylphenyl)propanoate of formula - III.

Formula - III
Yet another objective of the present invention is to provide process for the preparation of the novel intermediate compound, isopropyl 3-hydroxy-2-(4-methylphenyl)propanoate of formula - III.
Yet another objective of the present invention is to prepare sulphonate ester compound of formula - IV;

Formula - IV
wherein, R is selected from methyl, trifluoromethyl, 4-methylphenyl, phenyl and 4- nitrophenyl.
Yet another objective of the present invention is to provide novel intermediate compound, isopropyl 3-(methanesulfonyloxy)-2-(4-methylphenyl)propanoate of formula - IVA and process for the preparation of the same.

Formula - IVA
Yet another objective of the present invention provides a novel intermediate compound, isopropyl 3-amino-2-(4-methylphenyl)propanoate or its salt of formula - V.

Formula - V
Yet another objective of the present invention is to provide process for the preparation of the novel intermediate compound, isopropyl 3-amino-2-(4-methylphenyl)propanoate or its salt of formula - V.
Yet another objective of the invention is to provide a novel intermediate, (R)-1-phenylethan-1-amine (S)-3-((tert-butoxycarbonyl)amino)-2-(4-methylphenyl)propanoate of formula - VI.

Formula - VI
Yet another objective of the present invention is to provide a process for preparation of (R)-1-phenylethan-1-amine (S)-3-((tert-butoxycarbonyl)amino)-2-(4-methylphenyl)propanoate of formula - VI.
An additional objective of the invention is to provide a novel intermediate, (R)-1-phenylethan-1-amine (S)-3-amino-2-(4-methylphenyl)propanoate hydrochloride of formula - VII.

Formula - VII
In a further object, the invention provides a process for preparation of (R)-1-phenylethan-1-amine (S)-3-amino-2-(4-methylphenyl)propanoate hydrochloride of formula - VII.

SUMMARY OF THE INVENTION:
The present invention provides a novel process for preparation of (S)-3-amino-2-(4-methylphenyl)propanoic acid of formula - I or its salt through various hither to unreported novel intermediates.

Formula - I
According to primary object of the present invention, there is provided a simple, cost effective and industrially safe process for the preparation of (S)-3-amino-2-(4-methylphenyl)propanoic acid, the compound of formula - I, which comprises the steps of:
a) reacting the compound isopropyl 4-methylphenylacetate of formula - II

Formula - II
with paraformaldehyde in presence of polar aprotic solvent and an activator to get the compound isopropyl 3-hydroxy-2-(4-methylphenyl)propanoate of formula - III;

Formula - III
b) reacting the compound of formula - III with suitable sulfonating agent in presence of a base and solvent to get the sulphonate ester compound of formula - IV;

Formula - IV
wherein R is selected from methyl, trifluoromethyl, 4-methylphenyl, phenyl and
4-nitrophenyl;
c) reacting the compound of formula - IV with ammonia to get the compound isopropyl 3-amino-2-(4-methylphenyl)propanoate or its salt of formula - V;

Formula - V
d) hydrolysing the compound of formula - VI or its salt to get the racemic compound. 3-amino-2-(4-methylphenyl)propanoic acid of formula - IA;

Formula - IA
e) resolving the compound of formula - IA with or without protection using suitable reagent and in presence of solvent to get the compound (S)-3-amino-2-(4-methylphenyl)propanoic acid of formula - I or its salt.
In another aspect, the present invention provides a novel compound, isopropyl 3-hydroxy-2-(4-methylphenyl) propanoate of formula - III.

Formula - III
In another aspect, the present invention provides a novel compound, sulphonate ester of formula - IV;

Formula - IV
wherein R is selected from methyl, trifluoromethyl, 4-methylphenyl, phenyl and
4-nitrophenyl.
In yet another aspect, the present invention provides a novel compound, isopropyl 3-(methanesulfonyloxy)-2-(4-methylphenyl)propanoate of formula - IVA.

Formula - IVA
In another aspect, the present invention provides a novel compound, isopropyl 3-amino-2-(4-methylphenyl)propanoate or its salt of formula - V or its salt.

Formula - V
In yet another aspect, the invention provides (R)-1-phenylethan-1-amine (S)-3-((tert-butoxycarbonyl)amino)-2-(4-methylphenyl)propanoate of formula - VI.

Formula - VI
In a further aspect, the present invention provides process for preparation of (R)-1-phenylethan-1-amine (S)-3-((tert-butoxycarbonyl)amino)-2-(4-methylphenyl)propanoate of formula - VI.
In an additional aspect, the invention provides (R)-1-phenylethan-1-amine (S)-3-amino-2-(4-methylphenyl)propanoate hydrochloride of formula - VII.

Formula - VII
In a further aspect, the invention provides a process for preparation of (R)-1-phenylethan-1-amine (S)-3-amino-2-(4-methylphenyl)propanoate hydrochloride of formula - VII.

DETAILED DESCRITION OF THE INVENTION:
The present invention describes a novel process for preparing the compound, (S)-3-amino-2-(4-methylphenyl)propanoic acid of formula - I or its salt.

Formula - I
The present invention discloses novel synthetic route for the preparation of (S)-3-amino-2-(4-methylphenyl)propanoic acid. Within the context of the present disclosure, various novel intermediates are formed during the synthesis of (S)-3-amino-2-(4-methylphenyl)propanoic acid which provides an improved and efficient method for the synthesis of the compound, (S)-3-amino-2-(4-methylphenyl)propanoic acid of formula - I or its salt.
In an aspect, the present invention provides a process for the preparation of (S)-3-amino-2-(4-methylphenyl) propanoic acid of formula - I or its salt, which comprises the steps of;
a) reacting the compound isopropyl 4-methylphenylacetate of formula - II

Formula - II
with paraformaldehyde in presence of polar aprotic solvent and an activator to get isopropyl 3-hydroxy-2-(4-methylphenyl)propanoate of formula - III;

Formula - III
b) reacting the compound of formula - III with suitable sulfonating agent in presence of a base and solvent to get the sulphonate ester compound of formula - IV;

Formula - IV
wherein R is selected from methyl, trifluoromethyl, 4-methylphenyl, phenyl and
4-nitrophenyl;
c) reacting the compound of formula - IV with ammonia to get the compound isopropyl 3-amino-2-(4-methylphenyl)propanoate or its salt of formula - V;

Formula - V
d) hydrolysing the compound of formula - V or its salt to get the racemic compound, 3-amino-2-(4-methylphenyl)propanoic acid of formula - IA;

Formula - IA
e) resolving the compound of formula - IA with or without protection using suitable reagent and solvent to get the compound 7(S)-3-amino-2-(4-methylphenyl)propanoic acid of formula - I or its salt.
In an embodiment of the present invention, the polar protic solvent used in step (a) of the process is selected from the group consisting of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide and dimethylsulfoxide or a mixture thereof.
In an embodiment of the present invention, the preferred solvent used in step (a) of the process is selected from N,N-dimethylformamide, N,N-dimethylacetamide and dimethylsulfoxide, wherein the most preferred solvent used is dimethylsulfoxide.
In an embodiment of the present invention, the activator used in step (a) of the process is a base selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate, sodium ethoxide, potassium tert-butoxide and sodium methoxide or a mixture thereof.
In an embodiment of the present invention, the preferred activator used in step (a) of the process is sodium bicarbonate.
The compound of formula - II used in the present invention is commercially available or it can be freshly prepared as per the prior art process.
In an embodiment of the present invention, the base used in step (b) is selected from the group consisting of triethylamine, trimethylamine, pyridine, N-methylmorpholine and N-methyl pyrrolidone.

In an embodiment of the present invention, the solvent used in step (b) is selected from the group consisting of chlorinated solvent consisting of dichloromethane, dichloroethane, carbon tetrachloride and tetrachloroethane.
In an embodiment of the present invention, the sulfonating agent used in step b) is selected from the group consisting of methanesulphonyl chloride, trifluoromethanesulfonyl chloride, 4-methylphenylsulfonyl chloride and 4-nitrophenylsulfonyl chloride.

Accordingly, in an embodiment of the present invention, the sulphonate ester the compound of formula - IV in step (b), wherein, the R group is selected from methyl, trifluoromethyl, 4-methylphenyl and 4-nitrophenyl.
In an embodiment of the present invention, the ammonia used for the reaction in step (c) is selected from the group consisting of methanolic ammonia, aqueous ammonia and ammonia gas.
In an embodiment of the present invention, the compound of formula - V is isolated as free base or its salt.

In an embodiment of the present invention, the hydrolysis in step (d) is carried out by using a base selected from sodium hydroxide or potassium hydroxide.
In an embodiment of the present invention, the compound of formula - IA obtained in step (d) is taken for resolution either with protection or without protection of the compound to get the final compound, (S)-3-amino-2-(4-methylphenyl)propanoic acid of formula - I or its salt.

In an embodiment of the present invention, the compound of formula - IA is protected using the compound selected from Boc-anhydride, acetyl chloride, acetic anhydride, benzyl chloroformate, benzoyl chloride, and benzoic anhydride. One preferred compound used for the protection is Boc-anhydride.
Accordingly, in an embodiment of the present invention, the compound of formula - IA after protection is reacted with the resolving reagent in presence of solvent to obtain the final compound, (S)-3-amino-2-(4-methylphenyl)propanoic acid of formula - I or its salt.

In an embodiment of the present invention, the resolving reagent used for resolution of the compound of formula - IA is selected from the group consisting of (R)-1-phenylethan-1-amine, (R)-1-phenylpropan-1-amine, (R)-2-(3-chlorophenyl)propan-1-amine and (R)-(-)-4-phenyl-2-oxazolidinone, wherein the preferred reagent used for the resolution is (R)-1-phenylethan-1-amine.
In an embodiment of the present invention, the solvent used for resolution process is selected from the group consisting of ethanol, isopropyl alcohol, ethyl acetate, acetone, isopropyl acetate, methyl ethyl ketone and methyl isobutyl ketone or mixture thereof.

The advantage of using the protected compound of formula - IA for resolution stage is that the isolated compound can be used for further reaction without deprotection to prepare the compound Netarsudil.
In another embodiment of the present invention, the compound of formula - IA without protection is reacted with the resolving reagent in presence of solvent to obtain the final compound, (S)-3-amino-2-(4-methylphenyl)propanoic acid of formula - I or its salt.

In an embodiment of the present invention, the resolving reagent used for resolution the compound of formula - IA is selected from the group consisting of (R)-1-phenylethan-1-amine, (R)-1-phenylpropan-1-amine, (R)-2-(3-chlorophenyl)propan-1-amine and (R)-(-)-4-phenyl-2-oxazolidinone,. wherein the preferred reagent used for the resolution is (R)-1-phenylethan-1-amine.
In an embodiment of the present invention, the solvent used for resolution process is selected from the group consisting of ethanol, isopropyl alcohol, ethyl acetate, acetone, isopropyl acetate, methyl ethyl ketone and methyl isobutyl ketone or mixture thereof.

In an aspect, the present invention provides a novel compound, isopropyl 3-hydroxy-2-(4-methylphenyl)propanoate of formula - III.

Formula - III
In another aspect of the present invention provides a novel compound sulphonate ester of formula - IV

Formula - IV
wherein R is selected from methyl, trifluoromethyl, 4-methylphenyl, phenyl and
4-nitrophenyl.
In another aspect of the present invention provides a novel compound, isopropyl 3-(methanesulfonyloxy)-2-(4-methylphenyl)propanoate of formula - IVA.

Formula - IVA
In yet another aspect, the present invention provides a novel compound, isopropyl 3-amino-2-(4-methylphenyl)propanoate or its salt of formula - V or its salt.
*
Formula - V
In yet another aspect, the present invention provides (R)-1-phenylethan-1-amine (S)-3-((tert-butoxycarbonyl)amino)-2-(4-methylphenyl)propanoate, of formula - VI.

Formula - VI
In a further aspect, the present invention provides process for preparation of (R)-1-phenylethan-1-amine (S)-3-((tert-butoxycarbonyl)amino)-2-(4-methylphenyl)propanoate, of formula - VI.
In an additional aspect, the invention provides (R)-1-phenylethan-1-amine (S)-3-amino-2-(4-methylphenyl)- propanoate hydrochloride of formula - VII.

Formula - VII
In a further aspect, the invention provides proves for preparation of (R)-1-phenylethan-1-amine (S)-3-amino-2-(4-methylphenyl)- propanoate hydrochloride of formula - VII.

The following examples, which fully illustrate the practice of the preferred embodiments of the present invention, are intended to be for illustrative purpose only, and should not be considered to be limiting to the scope of the present invention.

EXAMPLES:

Example 1: Preparation of isopropyl 4-methylphenylacetate:
A dry round bottom flask was charged 4-methylphenylacetic acid (50 g, 0.33 mole), isopropyl alcohol (350 ml) and sulphuric acid (2.4 g, 0.235 mole). The reaction mass was refluxed under stirring for 6 to 7 hours. The reaction mass was concentrated under vacuum maintaining the temperature at 50°C to 55°C to get residual mass. Purified water (300 ml) was charged and adjusted the pH of the reaction mass between 9 to 10 using 10% sodium hydroxide solution. Dichloromethane (250 ml) was charged, stirred and the organic layer was separated. The organic layer was washed with purified water and concentrated under vacuum to get the oily mass of isopropyl 4-methylphenylacetate.
Yield: 62.1 g (97.03%);
HPLC purity: 99.0%.

Example 2: Preparation of isopropyl 3-hydroxy-2-(4-methylphenyl)propanoate:

In a dry round bottom flask, charged isopropyl 4-methylphenylacetate (6.0 g, 0.031 mole), dimethylsulfoxide (48 ml), sodium bicarbonate (0.52 g, 0.0062 mole) and paraformaldehyde (1.12 g, 0.037 mole) and stirred for 36 to 47 hours maintaining temperature at 25°C to 30°C. Charged purified water (150 ml) and ethyl acetate (50 ml), stirred and separated the organic layer. The aqueous layer was extracted one more time with ethyl acetate (25 ml). The organic layers were combined, washed with water and dried the organic layer over sodium sulphate. Distilled out the solvent under vacuum at 50°C to obtain isopropyl 3-hydroxy-2-(4-methylphenyl) propanoate.
Yield: 6.10 g (88.02%);
HPLC Purity: 85.0%.
1H-NMR - d 1.21 - 1.30 (m, 6H), d 2.50 (s, 3H), d 2.60 (t, 1H), d 3.88 (m, 2H), d 4.2 (m, 1H), d 5.2 (t, 1H), and d 7.28 (s, 4H).

Example 3: Preparation of isopropyl 3-(methanesulfonyloxy)-2-(4-methylphenyl)- propanoate:

Charged isopropyl 3-hydroxy-2-(4-methylphenyl)propanoate (20.0 g, 0.090 mole), triethylamine (22.74 g, 0.22 mole) in solvent dichloromethane (200 ml) and stirred. Charged methanesulphonyl chloride (12.36 g, 1.20 mole) at 25°C to 35°C and continued stirring the reaction mass for six hours maintaining temperature between 35°C to 40°C. Purified water (200 ml) was charged to the reaction mass, stirred and separated the organic layer. The organic layer was washed with water (50 ml) and dried over anhydrous sodium sulphate. Concentrated the solvent under vacuum at 50°C to obtain the compound, isopropyl 3-(methanesulfonyloxy)-2-(4-methylphenyl)propanoate.
Yield: 6.1 g (81.42%);
HPLC purity: 85.0%.

Example 4: Preparation of isopropyl 3-amino-2-(4-methylphenyl)propanoate hydrochloride:

In a round bottom flask, charged isopropyl 3-(methanesulfonyloxy)-2-(4-methylphenyl)propanoate (5.0 g, 0.016 mole), and drop wise added methanolic ammonia solution (10 ml), stirred the reaction mass for 15 to 20 hours maintaining temperature at 25°C to 30°C. Concentrated the solvent under vacuum at 50°C to 55°C and to the residual mass charged purified water (25 ml), acidified the reaction solution using concentrated hydrochloric acid. Charged diisopropyl ether (50 ml) and stirred to precipitate out solid. Filtered the solid mass and washed with diisopropyl ether and dried the wet mass at 55°C to 60°C to get isopropyl 3-amino-2-(4-methylphenyl)propanoate hydrochloride.
Yield: 2.6 g (60.46%).
1H-NMR - d 3.13 - 3.17 (m, 6H), d 2.26 (s, 3H), d 3.51 (dd, 1H), d 3.53 (dd, 1H), d 4.15 (dd, 1H), d 4.90 (m, 1H), d 7.12 - 7.17 (s, 4H), and d 9.09 - 9.12 (s, 2H).

Example 5: Preparation of 3-amino-2-(4-methylphenyl) propanoic acid hydrochloride:

In round bottom flask, charged isopropyl 3-amino-2-(4-methylphenyl)propanoate hydrochloride (2.0 g, 0.0077 mole), methanol (20 ml), purified water (20 ml) and sodium hydroxide (0.68 g, 0.17 mole). The reaction mass was stirred and maintained at 45°C to 50°C for 6 to 8 hours. Concentrated the reaction mass under vacuum at 55°C to 60°C to get residual mass. Charged purified water (16 ml) and ethyl acetate (16 ml), stirred and separated the lower aqueous layer. Charged ethyl acetate (20 ml) to the aqueous layer and adjusted pH of the solution to 1.0 to 2.0 using concentrated hydrochloric acid. The separated solid mass was filtered, washed with ethyl acetate and dried the product at 55°C to 60°C to get 3-amino-2-(4-methylphenyl)propanoic acid hydrochloride.
Yield: 1.2 g (74.07%).
1H-NMR - d 2.20 - 2.30 (s, 3H), d 2.88-2.92 (m, 1H), d 3.28 (t, 1H), d 3.75 (m, 1H), d 9.07 (s, 2H) and d 7.12 (s, 4H).

Example 6: Preparation of 3-(tert-butoxycarbonylamino)-2-(4-methylphenyl)propanoic acid:

In a round bottom flask, charged 3-amino-2-(4-methylphenyl)propanoic acid hydrochloride (7.0 g, 0.032 mole), acetone (105 ml) and potassium carbonate (9.86 g, 0.071 mole), stirred and maintained the reaction mass at 10°C to 15°C. Charged BOC-anhydride maintaining temperature at 10°C to 15°C and maintained the reaction mass under stirring for 18 hours. Charged purified water (300 ml) and adjusted pH of the reaction mass to 3.0 to 3.5 using dilute hydrochloric acid. Charged ethyl acetate (70 ml), stirred and separated the organic layer. Washed the organic layer with purified water (10 ml) and concentrated the solution under vacuum at 45°C to 50°C to get the product 3-((tert-butoxycarbonyl)amino)-2-(4-methylphenyl)propanoic acid.
Yield: 9.4 g (91.70%);
HPLC purity: 95.0%.

Example 7: Preparation of (R)-1-phenylethan-1-amine (S)-3-((tert-butoxycarbonyl)amino)-2-(4-methylphenyl)propanoate:

In round bottom flask charged 3-(tert-butoxycarbonylamino)-2-(4-methylphenyl)propanoic acid (2.0 g, 0.0092 mole), isopropyl alcohol (20 ml) and (R)-1-phenylethan-1-amine (0.56 g, 0.0046 mole), stirred and maintained the reaction mass at 65°C to 70°C for two hours. Gradually cooled the reaction mass to 25°C to 30°C and maintained for four hours. Filtered the solid mass, washed with isopropyl alcohol and dried to get (S)-1-phenylethan-1-amine 3-((tert-butoxycarbonyl)amino)-2-(4-methylphenyl)propanoate.
Yield: 0.95 g (33.21%).

Example 8: Preparation of (S)-3-((tert-butoxycarbonyl)amino)-2-(4-methylphenyl)- propanoic acid:

In round bottom flask, charged (S)-1-phenylethan-1-amine 3-((tert-butoxycarbonyl)amino)-2-(4-methylphenyl)propanoate (2.0 g, 0.0066 mole) and purified water (20 ml), stirred and adjusted pH of reaction solution between 12.0 to 14.0 using 50% sodium hydroxide solution. Stirred and charged dichloromethane (10 ml). The organic layers were separated and extracted the aqueous layer once with dichloromethane (10 ml). The combined organic layer was washed with purified water (10 ml) and concentrated under vacuum maintaining temperature at 40°C to isolate the compound (S)-3-((tert-butoxycarbonyl)amino)-2-(4-methylphenyl)propanoic acid.
Yield: 0.46 g (32.66%).

Example 9: Preparation of (R)-1-phenylethan-1-amine (S)-3-amino-2-(4-methylphenyl)- propanoate hydrochloride:

In round bottom flask charged 3-amino-2-(4-methylphenyl)propanoic acid hydrochloride (2.0 g, 0.0092 mole), isopropyl alcohol (20 ml) and (R)-1-phenylethan-1-amine (0.56 g, 0.0046 mole), stirred and maintained the reaction mass at 65°C to 70°C for two hours. The reaction mass was gradually cooled to 25°C to 30°C and maintained for four hours. The solid mass was filtered, washed with isopropyl alcohol and dried to get (R)-1-phenylethan-1-amine (S)-3-amino-2-(4-methylphenyl)propanoate hydrochloride.
Yield: 0.721 g (36.07%).

Example 10: Preparation of (S)-3-amino-2-(4-methylphenyl)propanoic acid hydrochloride:

In round bottom flask, charged (R)-1-phenylethan-1-amine (S)-3-amino-2-(4-methylphenyl)propanoate hydrochloride (2.0 g 0.0066 mole) and purified water (20 ml). Stirred and adjusted pH of the reaction solution to 12.0 to 14.0 using 50% sodium hydroxide solution. Stirred and charged dichloromethane (10 ml). The organic layer was separated and extracted the aqueous layer once more with dichloromethane (10 ml). The combined organic layer was washed with purified water (10 ml) and concentrated under vacuum maintaining temperature at 40°C to isolate (S)-3-amino-2-(4-methylphenyl)propanoic acid hydrochloride.
Yield: 0.52 g (36.5%).