DESC:RELATED PATENT APPLICATION
This application claims the priority to and benefit of Indian Provisional Patent Application No. 202141016884 filed on April 10, 2021; the disclosure of which are incorporated herein by reference.

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of L-glutamine (1). It further discloses process for the purification of L-glutamine (1) having a purity greater than 99.0% (w/w) and more preferably greater than 99.5%(w/w) by High-performance liquid chromatography (HPLC).

BACKGROUND OF THE INVENTION
L-glutamine is an a-amino acid that is used in the biosynthesis of protein. It is classified as a charge-neutral, polar amino acid. In 2017, the U.S. Food and Drug Administration (FDA) approved L-glutamine oral powder, marketed as Endari, to reduce severe complications of sickle cell disease in people aged five years and older with the disorder.

The synthesis of L-glutamine (1) has been reported in few patents the contents of which are hereby incorporated as reference in their entirety.

US6984506 patent discloses processes for producing L-glutamine using the microorganisms Brevibacterium lactofermentum CJJA21.The main disadvantage of this process is long working hours

US8067211 patent provides process for producing L-glutamine using the microorganisms Corynebacterium glutamicum.

US8859241 patent discloses a process for producing an L-amino acid using a microorganism Escherichia coli.

The disclosed process involves use of different microorganism which is difficult to handle in large amounts during scale up in industry. Using of fermentation method in preparation of L-glutamine, results in formation of dimer and trimer impurities. Hence, the present invention involves synthetic procedure using acidic and basic resin for purification. basic resin is useful for removing impurities.

US2561323 patent discloses preparation of gamma-methyl glutamate an intermediate used for synthesizing L-glutamine using glutamic acid sulfuric acid methanol in presence of a methanolic base to form. The yield is very less, and the process does not disclose preparation of L-glutamine.

Tetrahedron Letters, 2014, Vol 55, page no. 4149-4151 discloses preparation of L-glutamine generically in scheme-1 using trifluoracetic acid but does not specifically disclose the L-glutamine preparation, its yield or purity.

Hence, there is a need for providing a synthetic process for the preparation of L-glutamine (1) which is commercially viable and economical. Therefore, the present inventors report an improved process for the preparation of L-glutamine (1) in good yields with high purity. Further, the present invention provides increased particle size of L-Glutamine which is advantageous in enhance the flow property of L-Glutamine as compared to the commercially available L-glutamine which is having particle size is less.

OBJECTIVE OF THE INVENTION
Accordingly, one objective of the present invention is to provide an improved process for the preparation of L-glutamine (1).

Another objective of the present invention is to provide a process for the purification of L-glutamine (1).

Further objective of the present invention is to provide L-glutamine (1) with purity greater than 99.0% (w/w), preferably greater than 99.5% (w/w) by High-performance liquid chromatography (HPLC).

SUMMARY OF THE INVENTION
Accordingly, in one embodiment the present invention provides an improved process for the preparation of L-glutamine (1).

In another embodiment, the steps involved in the preparation of L-glutamine (1) as shown in scheme 1 are as follows:
a) converting of (S)-2-aminopentanedioic acid or L-Glutamic acid (5) to (S)-2-amino-5-methoxy-5-oxopentanoic acid (4) in presence of a suitable methylating agent, acid and base;
b) protecting (S)-2-amino-5-methoxy-5-oxopentanoic acid (4) and converting to (S)-2-(tert-butoxycarbonylamino)-5-methoxy-5-oxopentanoic acid (3), optionally without isolation using a suitable protecting agent and base; and
c) converting (S)-2-(tert-butoxycarbonylamino)-5-methoxy-5-oxopentanoic acid (3) to (S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (2); and
d) deprotecting (S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (2) to ((S)-2,5-diamino-5-oxopentanoic acid or L-Glutamine (1).

In some embodiment, the present invention provides a process for the purification of L-Glutamine (1), comprising:
1. providing a solution of L-Glutamine (1), in a suitable solvent or mixture of solvents;
2. heating the reaction mixture to a suitable temperature.
3. adding a suitable basic resin and filtering.
4. adjusting the pH of the filtrate with a suitable acidic resin; and
5. isolating pure L-Glutamine (1).

In another embodiment the present invention provides process for the purification of L-glutamine (1) with purity greater than 99.0% (w/w), preferably greater than 99.5% (w/w) by High-performance liquid chromatography (HPLC).

BRIEF DESCRIPTION OF DRAWINGS
Figure 1: illustrates X-Ray powder diffraction pattern (XRPD) of L-Glutamine (1).
Figure 2: illustrates X-Ray powder diffraction pattern (XRPD) of L-Glutamine (1).
Figure 3: illustrates X-Ray powder diffraction pattern (XRPD) of L-Glutamine (1).
Figure 4: illustrates differential scanning calorimetry (DSC) of L-Glutamine (1).
Figure 5: illustrates infrared (IR) spectra of L-Glutamine (1).

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, in one embodiment, the present invention provides an improved process for the preparation of L-glutamine (1) with purity greater than 99.0% (w/w), preferably greater than 99.5% (w/w) by High-performance liquid chromatography (HPLC) as illustrated in scheme 1 below:

Scheme-1
In another embodiment, the steps involved in the preparation of L-glutamine (1) as shown in scheme 1 are as follows:
a) converting of (S)-2-aminopentanedioic acid or L-Glutamic acid (5) to (S)-2-amino-5-methoxy-5-oxopentanoic acid (4) in presence of a suitable methylating agent, acid and base;
b) protecting (S)-2-amino-5-methoxy-5-oxopentanoic acid (4) and converting to (S)-2-(tert-butoxycarbonylamino)-5-methoxy-5-oxopentanoic acid (3), optionally without isolation using a suitable protecting agent and base;
c) converting (S)-2-(tert-butoxycarbonylamino)-5-methoxy-5-oxopentanoic acid (3) to (S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (2); and
d) deprotecting (S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (2) to ((S)-2,5-diamino-5-oxopentanoic acid or L-Glutamine (1).

In some embodiment, step a) of the present invention provides converting of (S)-2-aminopentanedioic acid or L-Glutamic acid (5) to (S)-2-amino-5-methoxy-5-oxopentanoic acid (4). L-Glutamic acid (5) in presence of a suitable methylating agent, preferably methanol was used in the present invention and acid and cooled to a suitable temperature of 0-30 oC, preferably 10-15 oC. A suitable base was then added and (S)-2-amino-5-methoxy-5-oxopentanoic acid (4) was isolated.

In another embodiment, step b) proceeds with protecting the -NH2 group of (S)-2-amino-5-methoxy-5-oxopentanoic acid (4) and converting to (S)-2-(tert-butoxycarbonylamino)-5-methoxy-5-oxopentanoic acid (3), optionally without isolation using a suitable protecting agent and base. (S)-2-amino-5-methoxy-5-oxopentanoic acid (4) was added to a suitable solvent and treated with a suitable protecting agent and base at a suitable temperature of 0-30oC, preferably 0-5oC. The pH of the reaction mass was adjusted using a suitable acid and (S)-2-(tert-butoxycarbonylamino)-5-methoxy-5-oxopentanoic acid (3) was isolated from suitable solvent.

In another embodiment, step c) involves converting (S)-2-(tert-butoxy carbonyl amino)-5-methoxy-5-oxopentanoic acid (3) to (S)-5-amino-2-(tert-butoxycarbonyl amino)-5-oxopentanoic acid (2). (S)-2-(tert-butoxy carbonylamino)-5-methoxy-5-oxopentanoic acid (3) may be added to a suitable solvent, under suitable temperature of 0-30oC, preferably 0-5oC and a suitable aqueous base may be added. The aqueous layer was separated, concentrated and pH of the aqueous layer was adjusted using a suitable acid. The aqueous layer was then extracted with a suitable aprotic solvent and the layers separated. The organic layer was separated and distilled off to yield intermediate (S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (2). The use of aqueous base along with a suitable solvent preferably dichloromethane is advantageous as it prevents formation of mixture of Boc protected acid and ester impurities. Further, the use of ethyl acetate, or 1,4-dioxane in-place of dichloromethane enhances the formation of pyroglutamic acid and glutamic acid impurities. Hence, aqueous base preferably aqueous ammonia along with dichloromethane serves as best choice for better yield and purity of intermediate (S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (2).

In another embodiment, step d) involves deprotecting (S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (2) to ((S)-2,5-diamino-5-oxopentanoic acid or L-Glutamine (1). (S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (2) was added to a suitable solvent at a temperature of 0-15oC, preferably at 5-10oC and a suitable acid reagent, preferably ethyl acetate hydrochloride was added. The reaction temperature was raised to 20-40oC, preferably at 25-30oC. The solid formed was filtered to yield(S)-2,5-diamino-5-oxopentanoic acid or L-Glutamine (1). The use of a suitable acid reagent solvent is advantageous as it reduces the formation of pyroglutamic acid and glutamic acid impurities. So, the present invention uses acids like hydrochloric acid, sulphuric acid or the like, preferably hydrochloric acid added to ethyl acetate was used in the present invention. If we use methyl tert-butyl ether, (MTBE) hydrochloride or 1,4, dioxane hydrochloride the reaction is slow and there is loss of yield.

The suitable protecting agent is selected from but not limited to alkoxycarbonyl such methoxycarbonyl (Moc), ethoxycarbonyl, tert- butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ), 9-fluorenylmethyloxy carbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate group, p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl (DMPM), tosyl (Ts), trifluoroacetyl (TFA), trichloroethyl chloroformate (Troc), pivaloyl (Piv) group and the like; Preferably tert- butyloxycarbonyl (Boc) was used in the present invention.

In some embodiment, the suitable acids used may be selected from a group comprising of organic and inorganic acids, which was selected from a group comprising of sulphuric acid, hydrochloric acid, nitric acid, phosphoric acid, ethyl acetate hydrochloric acid, MTBE hydrochloric acid, 1,4,-dioxane hydrochloric acid, lactic acid, acetic acid, formic acid, citric acid, oxalic acid, uric acid, malic acid, tartaric acid or the like, preferably citric acid, sulphuric acid, hydrochloric acid, and ethyl acetate hydrochloride was used in the present invention.

In some embodiment, the bases used may be selected from a group comprising of organic or inorganic bases which may be selected from the group comprising of sodium hydroxide, potassium hydroxide, calcium hydroxide, caesium hydroxide, sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium tertiary butoxide, potassium ethoxide, sodium methoxide, lithium tertiary butoxide, diethylamine, triethylamine trimethyl amine, diisopropylethylamine, diethyl amine, isopropyl amine, N-butyl lithium, imidazole, morpholine, N-methyl morpholine, pyridine, ammonia, or the like. Preferably, diethylamine, triethylamine and aqueous ammonia were used in the present invention.

The suitable resin used in the present invention may be selected from a group comprising basic resins and acidic resins. Basic resins may be selected from a group comprising of strong basic resins comprising of Indion 810, Indion 820, Indion 830, Indion FFIP, Indion NIP, weak basic resins comprising of Indion 850, Indion 860, Indion 860 S and acidic resins may be selected strong acidic resins comprising of Indion 220Na, Indion 225Na, Indion 225H+, Indion 303H+, Indion 720H+ and weak acidic resin comprising of Indion 236H+. Preferably, Indion 810 and Indion 225H+ were used in the present invention.

In another preferred embodiment, the present invention provides a process for the preparation of (S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (2), which involves reacting (S)-2-(tert-butoxycarbonylamino)-5-methoxy-5-oxopentanoic acid (3) in presence of suitable base and suitable solvent.
In some embodiment, the present invention provides a process for the purification of L-Glutamine (1), comprising:
1. providing a solution of L-Glutamine (1), in a suitable solvent or mixture of solvents;
2. heating the reaction mixture to a suitable temperature;
3. adding a suitable basic resin and filtering;
4. adjusting the pH of the filtrate with a suitable acidic resin; and
5. isolating pure L-Glutamine (1).

In some embodiment, the purification of L-Glutamine (1) proceeds with dissolving L-Glutamine (1), in a suitable solvent or mixture of solvents and heating the reaction mass to a suitable temperature of 30-60oC, preferably at 35-40oC.A suitable basic resin was then added. The pH of the filtrate was adjusted using a suitable acidic resin, activated charcoal was added to the reaction mass and filtered. The filtrate was heated at 40-80oC, preferably at 45-50oC and cooled to isolate L-Glutamine (1).

In another embodiment, the L-glutamine (1) so obtained is having purity greater than 99.0% (w/w) and preferably greater than 99.5% (w/w) by High-performance liquid chromatography (HPLC).

The suitable solvent used herein can be selected from the group comprising water, methanol, ethanol, propanol, isopropanol, and the like and aprotic solvents selected from a group comprising of acetone, dichloromethane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexane, heptane, toluene, tetrahydrofuran, methyl tertiary-butyl ether, 1,4-dioxane, ethyl acetate, isopropyl acetate, acetonitrile, chloroform, and mixtures thereof. Preferably, water, methanol, 1,4-dioxane, methanol, ethyl acetate, methyl tertiary butyl ether and dichloromethane were used.
In some embodiment, L-glutamine (1) so obtained is having the below impurities less than 1.0% (w/w), preferably less than 0.5% (w/w), more preferably less than 0.05% (w/w).

In another embodiment, the present invention provides the pyroglutamic acid impurity is less than 0.15 % (w/w), preferably less than 0.05% and glutamic acid is less than 0.15 % (w/w), preferably less than 0.05%; and any unknown impurities less than 0.15%; preferably less than 0.05%.

Pyroglutamic acid impurity
Glutamic acid impurity

In another embodiment, the present invention provides chloride content less than 0.15%, preferably less than 0.05%, sulfate content of less than 0.15%, preferably less than 0.03% and iron content less than 200ppm, preferably less than 50ppm.

In another embodiment, L-glutamine obtained in the present invention is having residual solvents such as methanol, ethanol, acetone, isopropyl alcohol, methyl tert-butyl ether, ethyl acetate, cyclohexane and 1,4-dioxane. wherein each solvent is controlled less than 5000 ppm, preferably less than 2000ppm and more preferably less than 1000ppm.

In another embodiment, the present invention provides the L-glutamine (1) obtained is having particle size of: D (10) 38.7 µm; D (50):114.4 µm and D (90):264.38µm.
In another embodiment, the crystalline form of L-Glutamine obtained according to the present invention is characterised by X-ray powder diffractions (XRD) pattern with characteristic peaks at (2?) values as illustrated in figure 1 and the 2 theta values as provided in Table 1.

Table 1:
Two theta (2T) values Relative Intensity (%)
11.18 10.6
11.26 16.4
12.83 8.2
20.26 7.2
20.58 4.7
21.41 7.6
22.02 10
22.39 12.7
23.54 32.9
23.7 100
23.76 81.4
24.75 12.6
25.05 19.8
25.5 21
25.7 32.4
26.8 11.6
28.2 5.9
28.4 11.4
29.5 5.3
30.0 11.4
34.8 8.4
36.1 11
36.3 50.8
36.4 24.9
41.0 17.8
41.1 14.7
41.3 10.3
41.5 7.6
44.8 4.8
46.9 5.6
47.2 17.9
47.3 10.3
55.1 5.4

In another embodiment, the crystalline form of L-Glutamine obtained according to the present invention is characterised by X-ray powder diffractions (XRD) pattern with characteristic peaks at (2?) values as illustrated in figure 2 and the 2 theta values as provided in Table 2.
Table 2:
Two theta (2T) values Relative Intensity (%)
11.0 8.1
12.6 10
12.7 12.1
15.8 4.5
19.9 7.8
20.2 11.3
21.2 7.1
21.9 6.3
22.1 12.3
22.2 9
23.0 6.2
23.5 100
23.6 84.6
24.8 22.8
25.02 30.1
25.4 50
25.5 59
28.2 11.1
28.4 10
30.1 6.9
30.9 6.8
36.2 20.1
36.4 24.3
38.3 7.5
38.4 12.7
38.6 10.2
40.7 34.4
40.8 27.3
41.0 17.3
41.2 10.1
45.9 6
49.6 5.3
50.0 5.2
52.1 4.9
53.0 4.7
55.0 6.9
55.1 5.5

In another embodiment, the crystalline form of L-Glutamine obtained according to the present invention is characterised by X-ray powder diffractions (XRD) pattern with characteristic peaks at (2?) values as illustrated in figure 3 and the 2 theta values as provided in Table 3.
Table 3:
Two theta (2T) values Relative Intensity (%)
2.0 0.0
5.4 0.08
11.0 29.7
12.6 15.6
15.8 3.2
18.1 0.5
20.1 39.8
20.4 1.2
20.8 0.7
21.4 0.6
22.1 13.9
22.8 0.3
23.3 16.2
23.5 100
23.9 0.8
24.8 14.6
24.9 85.4
25.2 8.0
25.3 19.7
25.4 33.2
26.6 2.4
28.3 32.3
28.7 3.4
29.3 2.0
29.9 5.3
30.1 27.0
30.4 2.6
30.8 3.4
32.0 3.1
33.2 0.7
33.4 0.7
34.9 3.2
35.4 1.2
36.1 9.8
36.2 11.6
36.3 8.3
36.6 2.5
38.3 1.5
38.4 4.6
38.6 1.9
39.2 4.5
40.4 2.1
40.8 13.4
40.9 59.4
41.4 6.9
42.5 0.3
43.1 0.8
43.6 0.2
44.6 1.8
45.0 0.7
45.9 1.4
46.6 0.5
47.0 4.3
49.9 0.0

In another embodiment, the crystalline form of L-Glutamine obtained according to the present invention is characterised by a differential scanning calorimetry (DSC) curve as illustrated in figure 4 and infrared (IR) spectra as illustrated in figure 5.

The following examples further illustrate the present invention, but should not be construed in anyway, as to limit its scope.

EXAMPLES

Example 1: Preparation of (S)-2-amino-5-methoxy-5-oxopentanoic acid (4)
250g of L-glutamic acid (5) was added to 3000mL of methanol and cooled to 10-15oC, 125 mL of sulphuric acid was then added and stirred. The temperature of the reaction mass was raised to 25-30oC for 4-5hrs. On completion of reaction, the reaction mass was cooled to 10-15oC and pH adjusted to 6-7 using diethylamine. The reaction mass was further cooled to 0-5oC and the solid so formed was washed with methanol and dried under vacuum to yield (S)-2-amino-5-methoxy-5-oxopentanoic acid (4). Yield: 80% (w/w); Purity: 65%(w/w).

Example 2: Preparation of (S)-2-(tert-butoxycarbonylamino)-5-methoxy-5-oxopentanoic acid (3)
100g of S)-2-amino-5-methoxy-5-oxopentanoic acid (4) was added to 500 mL of water and stirred at 25-30 oC.500 mL of 1,4-dioxane was then added to the reaction mixture and cooled to 0-5oC.160g of Di-tert-butyl decarbonate (Boc-anhydride) and 250 mL of triethylamine were added to the reaction mass at 0-5oC, and temperature of the reaction mass raised to 25-30oC. On completion of reaction, 5 volumes of methyl tertiary butyl ether were added and stirred. The aqueous layer was collected and cooled to 0-5oC and the pH maintained at 3-4 using citric acid. The temperature of the reaction mass raised to 25-30oC and the aqueous layer extracted with 200 mL of ethyl acetate. The organic layers were washed with aqueous sodium chloride solution and filtered. The solvent of the filtrate was distilled of under vacuum to yield (S)-2-(tert-butoxycarbonylamino)-5-methoxy-5-oxopentanoic acid (3). Yield: 98% (w/w); Purity: 65%(w/w).

Example 3: Preparation of (S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (2)
45g of (S)-2-(tert-butoxycarbonylamino)-5-methoxy-5-oxopentanoic acid (3) was added to 100mL of dichloromethane at 25-30oC. The reaction mass was then cooled to 0-5o C and 250 mL of aqueous ammonia solution was added to the reaction mass. The temperature of the reaction mass was raised to 25-30oC. On completion of reaction, the layers were separated, and the aqueous layer washed with dichloromethane. The aqueous layer was concentrated and cooled to 0-5oC. The pH of the concentrate was adjusted to 2- 3 using hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was separated and distilled off to yield (S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (2). Yield: 92.3% (w/w); Purity: 60% (w/w).

Example 4: Preparation of ((S)-2,5-diamino-5-oxopentanoic acid or L-Glutamine (1)
95g of (S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (2) was added to 400 mL of ethyl acetate at 25-30oC and stirred. The reaction mass was then cooled to 5-10oC, 145 mL of ethyl acetate hydrochloride was added and stirred for 15-20 mins. The temperature of the reaction mass was raised to 25-30oC. On completion of reaction, the solid formed was filtered and washed with ethyl acetate to yield ((S)-2,5-diamino-5-oxopentanoic acid or L-Glutamine (1). Yield: 84%(w/w); Purity: 99.5% (w/w).

Example 5: Purification of ((S)-2,5-diamino-5-oxopentanoic acid or L-Glutamine (1)
100g of L-Glutamine (1) was added to 1500 mL of water and heated to 35-40oC. The reaction mass was cooled to 25-30 °C. 200 mL of basic resin was added to the reaction mass and stirred for 1-2hrs at 25-30oC. The reaction mass was filtered, and the pH of the filtrate was adjusted to 5.5. to 6.0 using a suitable acidic resin. The reaction mass was filtered and 3gm of activated charcoal was added to the reaction mass, stirred, and filtered through Hyflo. The filtrate was heated to 20-30°C and 1500 mL of methanol was added to the filtrate. The reaction mass was filtered and dried under vacuum to yield ((S)-2,5-diamino-5-oxopentanoic acid or L-Glutamine (1). Yield: 82% (w/w); Purity: 99.8% (w/w). XRD: Figure 1.

Example 6: Purification of ((S)-2,5-diamino-5-oxopentanoic acid or L-Glutamine (1)
100g of L-Glutamine (1) was added to 1500 mL of water and heated to 35-40oC. 200 mL of basic resin was added to the reaction mass and stirred for 45-60 mins at 35-40oC. The reaction mass was filtered, and the filtrate cooled to 25-30oC.The pH of the filtrate was adjusted to 5.5. to 6.0 using a suitable acidic resin and 3gm of activated charcoal was added to the reaction mass, stirred, and filtered through Hyflo. The filtrate was heated to 40-45oC and 1500 mL of methanol was added to the filtrate. The reaction mass was then cooled to 25-30oC and the solid formed was filtered, washed with methanol, and dried under vacuum to yield ((S)-2,5-diamino-5-oxopentanoic acid or L-Glutamine (1). Yield: 85% (w/w); Purity: 99.8% (w/w). XRD: Figure 2.
,CLAIMS:1. An improved process for the preparation of L-Glutamine (1),

comprising the steps of:
a) methylating L-Glutamic acid (5)

with methanol in the presence of a suitable acid to obtain (S)-2-amino-5-methoxy-5-oxopentanoic acid (4);

b) protecting (S)-2-amino-5-methoxy-5-oxopentanoic acid (4) with suitable protecting agent in the presence of a suitable base to obtain (S)-2-(tert-butoxycarbonylamino)-5-methoxy-5-oxopentanoic acid (3), optionally without isolation.

c) aminating (S)-2-(tert-butoxycarbonylamino)-5-methoxy-5-oxopentanoic acid (3) with aqueous ammonia to obtain (S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (2).

d) deprotecting (S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (2) with a suitable acid to obtain L-Glutamine (1); and
e) purifying L-Glutamine (1).

2. A process for the preparation of (S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (2),

comprising of:
a) aminating (S)-2-(tert-butoxycarbonylamino)-5-methoxy-5-oxopentanoic acid (3)

with aqueous ammonia to obtain (S)-5-amino-2-(tert-butoxycarbonyl amino)-5-oxopentanoic acid (2)

3. One pot process for the preparation of (S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (2),

comprising the steps of:
a) protecting (S)-2-amino-5-methoxy-5-oxopentanoic acid (4)

with suitable protecting agent in the presence of a suitable base in a suitable solvent to form (S)-2-(tert-butoxycarbonylamino)-5-methoxy-5-oxopentanoic acid (3).

b) aminating (S)-2-(tert-butoxycarbonylamino)-5-methoxy-5-oxopentanoic acid (3) with aqueous ammonia in a suitable solvent to obtain (S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (2);

4. A process for the purification of L-Glutamine (1), comprising the steps of:
1. dissolving L-Glutamine (1) in a water;
2. adding a suitable basic resin and stirring;
3. adjusting the pH of the filtrate with a suitable acidic resin;
4. treating with activated charcoal and filtering;
5. heating the filtrate to a suitable temperature;
6. adding suitable solvent to the filtrate;
7. seeding with L-glutamine;
8. optionally cooling the reaction mixture to 25-30 °C; and
9. isolating pure L-Glutamine

5. The process as claimed in claim 1 and claim 3, wherein the protecting agent is selected from the group consisting of alkoxycarbonyl such methoxycarbonyl (Moc), ethoxycarbonyl, tert- butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ), 9-fluorenylmethyloxy carbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate group, p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl (DMPM), tosyl (Ts), trifluoroacetyl (TFA), trichloroethyl chloroformate (Troc), pivaloyl (Piv) group and the like;

6. The process as claimed in claim 1, wherein the suitable acids refer to an organic and or inorganic acid, wherein the inorganic acid is selected from sulphuric acid, hydrochloric acid, nitric acid, phosphoric acid, ethyl acetate hydrochloric acid, MTBE hydrochloric acid, 1,4, -dioxane hydrochloric acid and the organic acid is selected from lactic acid, acetic acid, formic acid, citric acid, oxalic acid, uric acid, malic acid, tartaric acid, or the like.

7. The process as claimed in claim 1 and claim 3, wherein the suitable bases refers to an organic or inorganic bases, wherein the inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, caesium hydroxide, sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium tertiary butoxide, potassium ethoxide, sodium methoxide, lithium tertiary butoxide, and the organic base is selected from the group consisting of diethylamine, triethylamine trimethyl amine, diisopropylethylamine, diethyl amine, isopropyl amine, N-butyl lithium, imidazole, morpholine, N-methyl morpholine, pyridine, ammonia, or the like.

8. The process as claimed in claim 1, 2, 3 and claim 4, wherein the suitable solvent is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, and the like and aprotic solvents selected from a group comprising of acetone, dichloromethane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexane, heptane, toluene, tetrahydrofuran, methyl tertiary-butyl ether, 1,4-dioxane, ethyl acetate, isopropyl acetate, acetonitrile, chloroform, and mixtures thereof.

9. The process as claimed in claim 4, wherein suitable resin refers to basic and acidic resins, wherein the basic resins are selected from the group consisting of Indion 810, Indion 820, Indion 830, Indion FFIP, Indion NIP Indion 850, Indion 860, Indion 860 S and the acidic resins are selected from the group consisting of Indion 220Na, Indion 225Na, Indion 225H+, Indion 303H+, Indion 720H+ and Indion 236H+.