Claims:1. A process for production of (S)-1-(3-Ethoxy-4-methoxyphenyl)-2-Methanesulfonylethylamine (VIII) comprises:
a) chlorinating the 3-Ethoxy-4-methoxybenzoic acid (IV) by treatment with Thionyl chloride to obtain acid chloride followed by reacting with N,O-dimethyl hydroxylamine hydrochloride in presence of an organic base and a solvent to obtain 3-Ethoxy-N,4-dimethoxy-N-methylbenzamide (V);
b) reacting the 3-Ethoxy-N,4-dimethoxy-N-methylbenzamide (V) with Dimethyl sulfone in presence of n-BuLi in an ethereal solvent to obtain 1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (VI);
c) reacting the 1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (VI) with (R)-(-)-2-phenylglycinol in presence of an acid catalyst to obtain an intermediate imine followed by subjecting the imine to reduction with H2 / Pd/C at 15-20 psi or Sodium borohydride in an acidic medium followed by hydrolysis with mineral acid to obtain (R)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamino)-2-phenylethanol (VII); and
d) Hydrogenating the (R)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamino)-2-phenylethanol with 10% Pd/C in methanol to obtain (S)-1-(3-Ethoxy-4-methoxyphenyl)-2-Methanesulfonylethylamine (VIII).

2. The process according to claim 1, wherein, the organic base in step a) may be selected from pyridine, triethyl amine and N,N-diisopropylethyl amine.

3. The process according to claim 1, wherein, the solvent in step a) may be selected from inert solvents such as hydrocarbons selected from toluene, xylene and chlorinated hydrocarbons selected from methylene dichloride, ethylene dichloride.
4. The process according to claim 1, wherein, the reaction of step a) is carried out at 0-15°C.

5. The process according to claim 1, wherein, the ethereal solvent in step b) may be selected from the group consisting of diethyl ether, THF, Cyclopentyl methyl ether, Methyl THF and Dimethoxy ethane.

6. The process according to claim 1, wherein, the acid catalyst in step c) may be selected from p-toluene sulfonic acid or methane sulfonic acid.

7. The process according to claim 1, wherein, the acidic medium in step c) comprises acetic acid.

8. The process according to claim 1, wherein, the mineral acid may be selected from Hydrochloric acid or Sulfuric acid.

9. The process according to claim 1, wherein, the process further comprises a step of converting the (S)-1-(3-Ethoxy-4-methoxyphenyl)-2-Methanesulfonylethylamine (VIII) into Apremilast by treating with 3-acetamidophthalic anhydride in presence of glacial acetic acid under reflux conditions for a period of about 20 hrs.

10. The process according to claim 9, wherein, the apremilast is purified from ethanol and acetone in 2:1 ratio.

11. 3-Ethoxy-N,4-dimethoxy-N-methylbenzamide of formula (V).

12. (R)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamino)-2-phenylethanol (VII).

, Description:Field of invention:
The present invention relates to a process for preparation of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine (VIII), a key intermediate useful in the synthesis of Apremilast. More particularly, the invention relates to synthesis of (S)-1-(3-Ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine (VIII) using chiral auxiliary (R)-(-)-2-phenylglycinol, via novel intermediates viz., 3-Ethoxy-N,4-dimethoxy-N-methylbenzamide (V) and (R)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamino)-2-phenylethanol (VII) with good enantiomeric purity and its further conversion into (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, (Apremilast), with good purity.

Background and prior art:
Apremilast is a phosphodiesterase 4 (PDE4) inhibitor, chemically known as N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide having Formula (I).

Formula I
Apremilast is available under the trade name of OTEZLA® as an inhibitor of phosphodieasterase 4 (PDE4), indicated for the treatment of adult patients with active psoriatic arthritis.

Apremilast is first disclosed in US6020358 under substituted phenethylsulfones for reducing TNFa levels. US ‘358 discloses racemic 2-[1-(3-ethoxy-4-methoxy phenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide and process for its preparation, which comprises reacting 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl amine with 3-Acetamidophthalic anhydride in acetic acid at reflux for 15 hours.

Subsequently, US7427638 discloses stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, substantially free of its (-) isomer, or a pharmaceutically acceptable metabolite, salt, solvate or hydrate thereof and its pharmaceutical composition.

Ample literature is available on the synthetic methods of Apremilast, various solid forms, and pharmaceutical compositions comprising the same.

US7893101 discloses various solid forms including crystal forms of Apremilast including A, B, C, D, E, F, G and amorphous forms and pharmaceutical compositions comprising these solid forms.

WO2012083153 discloses the preparation of Apremilast by acetylating (S)-4-amino-2-(1-(3- ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)isoindoline-1,3-dione with Acetic anhydride and Acetic acid at 125°C for 30 minutes.

WO2016146990 discloses process for preparing Apremilast of formula I, or a pharmaceutically acceptable salt thereof which comprises acetylating (S)-4-amino-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl) isoindoline-1,3-dione with an acetylating agent selected from Acetyl chloride, Acetic acid or mixtures thereof in the presence of a base selected from an inorganic or organic base to obtain Apremilast of formula I.

US2013/0217918 discloses processes for the preparation of Aminosulfone intermediates for the synthesis of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione and further discloses processes for the commercial production of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine using chiral auxiliaries.
CN103864670 discloses the preparation of Apremilast by a process which comprises condensing 1-[(R)-amino(phenyl)methyl]-2-naphthol with 3-ethoxy-4-methoxybenzaldehyde in the presence of triethyl amine to yield the naphtho[1,2-e][1,3] oxazine derivative, which upon addition of Dimethylsulfone lithium salt in tetrahydrofuran gives N-[(2S)-(1-(3-ethyoxyl-4-methoxyphenyl)-2-methylsulfonylethyl)]-(1R)-(a-amino-benzyl)-2-isonaphthol which undergoes hydrogenation over Pd/C in methanol to yield 1 (S)-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamine, which is finally condensed with 3- Acetamidophthalic anhydride in refluxing glacial Acetic acid for 24 hours.

As is evident from the above, (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine (VIII) is a key intermediate in the synthesis of (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, (Apremilast), which needs to be synthesized by robust process with great enantiomeric purity.

Therefore, it is an objective of the present invention to provide (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine (VIII), using chiral auxiliary (R)-(-)-2-phenylglycinol with good enantiomeric purity and its further conversion into (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, (Apremilast) with good purity.

Summary of the invention:
In line with the above objective, the invention provides process for preparation of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine (VIII), with good enantiomeric purity and its further conversion into Apremilast by treatment with 3- Acetamidophthalic anhydride.
Accordingly, the process for preparation of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine (VIII) comprises:
a) methylating 3-ethoxy-4-hydroxybenzaldehyde with Dimethyl sulphate to obtain 3-ethoxy-4-methoxybenzaldehyde (III);
b) Oxidizing the 3-ethoxy-4-methoxybenzaldehyde (III) using Jones reagent to obtain 3-Ethoxy-4-methoxybenzoic acid (IV);
c) chlorinating the 3-ethoxy-4-methoxybenzoic acid (IV) by treatment with Thionyl chloride to obtain acid chloride followed by reacting with N,O-dimethyl hydroxylamine hydrochloride in presence of an organic base and a solvent to obtain 3-ethoxy-N,4-dimethoxy-N-methylbenzamide (V);
d) reacting the 3-ethoxy-N,4-dimethoxy-N-methylbenzamide (V) with dimethyl sulfone in presence of n-BuLi in an ethereal solvent to obtain 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (VI);
e) reacting the 1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (VI) with (R)-(-)-2-phenylglycinol in presence of an acid catalyst to obtain an intermediate imine followed by subjecting the imine to reduction with H2/Pd/C at 15-20 psi or Sodium borohydride in an acidic medium followed by hydrolysis with mineral acid to obtain (R)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamino)-2-phenylethanol (VII); and
f) Hydrogenating the (R)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamino)-2-phenylethanol with 10% Pd/C in methanol to obtain (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine (VIII).

The process of the present invention proceeds through hitherto unexplored intermediates viz., 3-Ethoxy-N,4-dimethoxy-N-methylbenzamide (V) and (R)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamino)-2-phenylethanol (VII).

In another aspect, the invention provides a process for preparation of Apremilast by condensing the (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine (VIII) with 3-Acetamidophthalic anhydride in presence of glacial Acetic acid under reflux for about 20 hrs to obtain Apremilast.

Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

The present invention provides a process for preparation of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine, with good enantiomeric purity and its further conversion into Apremilast by treatment with 3- Acetamidophthalic anhydride.

Accordingly, the process for production of (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine (VIII) comprises:
a) chlorinating the 3-ethoxy-4-methoxybenzoic acid (IV) by treatment with Thionyl chloride to obtain acid chloride followed by reacting with N,O-dimethyl hydroxylamine hydrochloride in presence of an organic base and a solvent to obtain 3-ethoxy-N,4-dimethoxy-N-methylbenzamide (V);
b) reacting the 3-ethoxy-N,4-dimethoxy-N-methylbenzamide (V) with Dimethyl sulfone in presence of n-BuLi in an ethereal solvent to obtain 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (VI);
c) reacting the 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (VI) with (R)-(-)-2-phenylglycinol in presence of an acid catalyst to obtain an intermediate imine followed by subjecting the imine to reduction with H2/Pd/C at 15-20 psi or Sodium borohydride in an acidic medium followed by hydrolysis with a mineral acid to obtain (R)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamino)-2-phenylethanol (VII); and
d) Hydrogenating the (R)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamino)-2-phenylethanol with 10% Pd/C in methanol to obtain (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine (VIII).
In another aspect, the invention provides a process for preparation of Apremilast by condensing the (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine (VIII) with 3-Acetamidophthalic anhydride in presence of glacial Acetic acid at reflux for about 20 hrs to obtain Apremilast, which is further purified by crystallization from Ethanol and Acetone in 2:1 ratio.
The reaction scheme in accordance with the present invention is shown below in scheme 1.

Scheme 1:

3-Ethoxy-4-methoxybenzoic acid (IV) is prepared by subjecting 3-ethoxy-4-methoxybenzaldehyde to oxidation by Jones reagent in suitable solvent and can be isolated by extraction using an organic solvent such as Dichloromethane. 3-ethoxy-4-methoxybenzaldehyde (III) is prepared by the reaction of 3-ethoxy-4-hydroxybenzaldehyde with Dimethyl sulphate in a solvent such as Acetone and in presence of a base such as Potassium carbonate under stirring for 6hrs. The reaction mass is filtered and concentrated followed by dilution with DCM and washed with water. The organic layer is separated and concentrated to obtain the compound. The preparation of 3-ethoxy-4-methoxybenzaldehyde (III), may be carried out at a temperature of 50 to 70°C.

Accordingly, in an aspect, the 3-Ethoxy-4-methoxybenzoic acid (IV) is reacted with a chlorinating agent in presence of catalytic amounts of DMF under stirring at 45-50°C for 3hrs, to obtain the corresponding acid chloride, which is further treated with N,O-dimethyl hydroxylamine hydrochloride in presence of an organic base and solvent under stirring at a temperature range of 0-15°C to obtain a novel intermediate, 3-ethoxy-N,4-dimethoxy-N-methylbenzamide (V). The organic base may be selected from Pyridine, Triethyl amine and N,N-diisopropylethyl amine etc. The solvent may be an inert solvent selected from hydrocarbons such as Toluene, Xylene; chlorinated hydrocarbons such as Methylene dichloride, Ethylene dichloride etc.

In a further aspect, the 3-ethoxy-N,4-dimethoxy-N-methylbenzamide (V) thus obtained is further subjected to sulfonation by reacting with Dimethyl sulfone in presence of n-BuLi in an ethereal solvent at -70-75°C for a period of 1 to 3hrs under stirring. After completion of the reaction, the reaction mass is quenched with 6N HCl, extracted with DCM and concentrated to obtain 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (VI). The ethereal solvent may be selected from Diethylether, THF, Cyclopentyl methyl ether, Methyl THF and Dimethoxyethane.

In yet another aspect, 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (VI) is further reacted with (R)-(-)-2-phenylglycinol in presence of an acid catalyst in an organic solvent under stirring at 110-1150C for about 20 hrs to obtain an intermediate imine. The imine is further reduced using H2/Pd/C at 15-20 psi or Sodium borohydride in acidic medium followed by hydrolysis using a mineral acid to obtain a novel intermediate, (R)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamino)-2-phenylethanol (VII).
The acidic medium comprises Acetic acid and the mineral acid may be Hydrochloric acid, Sulfuric acid etc. The acid catalyst may be selected from p-toluene sulfonic acid and hydrochloric acid.

In a further aspect, the (R)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamino)-2-phenylethanol (VII) is subjected to hydrogenation by treating with 10% Pd/C in Methanol at 75-80 psi for about 8hrs. The reaction mixture is filtered through celite and concentrated to obtain the key intermediate, (S)-1-(3-Ethoxy-4-methoxyphenyl)-2-Methanesulfonylethylamine (VIII), with HPLC purity of 99.5% and with 99% chiral purity.

In another embodiment, the key intermediate, (S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine, obtained as per the process of the present invention is reacted with 3-Acetamidophthalic anhydride in presence of glacial Acetic acid under reflux for a period of about 20hrs. After completion of the reaction, the RM is cooled to RT, the solvent is concentrated and the residue is dissolved in Ethyl acetate, washed with water followed by saturated aqueous Sodium bicarbonate solution. The solvent is concentrated to get crude product which is recrystallized from mixture of Ethanol and Acetone (2:1) to give pure Apremilast with 99% ee.
In yet another aspect, the present invention provides novel intermediates useful in the preparation of Apremilast, as below.
a) 3-ethoxy-N,4-dimethoxy-N-methylbenzamide of formula (V)

b) (R)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamino)-2-phenylethanol (VII)

The above intermediates are further characterized by 1H NMR and Mass spectroscopy.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples
Example 1
Preparation of 3-Ethoxy-4-methoxybenzaldehyde (III):
To a solution of 3-ethoxy-4-hydroxybenzaldehyde (100g, 0.60 mol) in Acetone (1000 mL), Potassium carbonate (166g, 1.20 mol) was added and stirred for 30 min. Dimethyl sulphate (79.78g, 0.63 mol) was added to the reaction mixture and stirred at 55-60°C for 6hrs. Reaction mass was filtered and concentrated. The residue was diluted with DCM (1000 mL) and washed with water (500 mL). The organic layer was concentrated to get 92g of compound with 85.41% yield.

Preparation of 3-ethoxy-4-methoxybenzoic acid (IV):
3-Ethoxy-4-methoxybenzaldehyde (92g, 0.51 mol) was dissolved in Acetone (644 mL) and cooled 5-8°C. Jones reagent (60g, 0.51mol) was added dropwise at 5-8°C for 45 min, and then stirred for 4hrs at RT. The reaction mass was quenched with Isopropyl alcohol (180 mL) and stirred for 30 min. The reaction mass was concentrated and taken in DCM (800 mL). Organic layer was washed with water (1000 mL) and concentrated. 70g of pure product was isolated with 70% yield.

Preparation of 3-Ethoxy-N,4-dimethoxy-N-methylbenzamide (V):
3-Ethoxy-4-methoxybenzoic acid (68g, 0.35mol) was dissolved in dichloromethane (408 mL) and cooled 5-10°C; Thionyl chloride (61.9g, 0.52 mol) was added dropwise for a period of 20 mins and catalytic amount of DMF was added. The reaction was stirred at 45-50°C for 3hrs, and then concentrated to get acid chloride which was dissolved in DCM (200 mL).
A suspension of N,O-dimethyl hydroxylamine hydrochloride (50.62g, 0.52 mol) and dichloromethane (480 mL) was cooled to 0-5°C. Triethylamine (69.96g, 0.70 mol) was added dropwise followed by above acid chloride and stirred for 5hrs. The reaction mass was diluted with dichloromethane (500mL), washed with water (1000mL) and concentrated to get 77g of compound with 93% yield. 1H NMR in (CDCl3, 300 MHZ), d 1.49-1.44 (t, 3H), 3.35(s, 3H), 3.57 (s, 3H), 3.90 (s, 3H), 4.09-4.16 (q, 2H), 6.88-6.85 (d,1H), 7.331(s, 1H), 7.39-7.36 (d, 1H), m/z M+1 240.

Preparation of 1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (VI):
Dimethyl sulfone (23.38g, 0.25 mol) was dissolved in THF (330 mL) and cooled to -75°C. n-BuLi (14.13g, 0.22 mol) was added dropwise for a period of 30 min at -70 -75°C, and stirred for 1h.
3-Ethoxy-N,4-dimethoxy-N-methylbenzamide (22g, 0.092 mol) was dissolved in THF and added dropwise to the reaction mass over a period of 20 min and stirred for 2hrs at -70-75°C. The reaction mass was quenched with 6N HCl solution, extracted with DCM and concentrated. The product was recrystallized with Toluene to get 17.5g of compound with 70% yield.

Preparation of (R)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamino)-2-phenylethanol (VII):
Method: A
To a suspension of 1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (6g, 0.022 mol) in toluene, 30ml (R)-(-)-2-phenylglycinol (3.02g, 0.022 mol), PTSA (0.0044 mol), was added and stirred at 110-115°C for 20hrs using Dean Stark apparatus. Filtered the reaction mixture and reduced using H2/ Pd/C at 15-20 psi for 3h. The reaction mass was filtered and concentrated to yield 6.5g of compound with 75% yield.
Method: B

To a suspension of 1-(3-Ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone (6g, 0.022 mol) in toluene, 30ml (R)-(-)-2-phenylglycinol (3.02g, 0.022 mol), PTSA (0.0044 mol) was added and stirred at 110-115°C for 20hrs using Dean Stark apparatus. Acetic acid (3 ml) was added to the reaction mixture, followed by Sodium borohydride (1.25g, 0.032 mol) and stirred for 2hrs. The reaction mixture was basified with Sodium hydroxide solution and layers were separated and aqueous layer was extracted with Ethyl acetate. The combined organic layer was concentrated to obtain 7g of compound with 80.83% yield.

1H NMR in (CDCl3, 300 MHZ), d 1.44-1.39 (t, 3H), 2.87 (s, 3H), 3.31-3.25 (dd, 1H), 3.45-3.38 (dd, 1H), 3.68-3.62(dd, 1H), 3.82-3.72(m, 1H), 3.85 (s, 3H), 4.01-3.94 (q, 2H), 4.04-3.98 (m, (1H), 4.42-4.38 (m, 1H), 6.71- (s, 1H), 6.79-6.78(d, 1H), 7.20-7.17 (d, 2H), 7.26-7.23 (m, 3H). 13C NMR in (CDCl3, 300 MHZ) d 14.79, 42.85, 56.05, 56.42, 61.68, 61.89, 64.49, 65.96, 111.64, 111.87, 119.21, 127.32, 127.54, 128.55, 133.31, 141.32, 148.77, 149.25.
Mass: (M+1) 394.

Preparation of (S)-1-(3-Ethoxy-4-methoxyphenyl)-2-Methanesulfonylethylamine (VIII):
(R)-2-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethylamino)-2-phenylethanol (5g, 0.012 mol ), 10% Pd/C (1g) and Methanol (100 mL) was hydrogenated at 75-80 psi for 8hr. The reaction mixture was filtered through celite and the filtrate was concentrated to get 2.6g with 75% yield, 99.5% HPLC, 99.5% chiral purity.

Preparation of Apremilast (I)
To a solution of (S)-1-(3-Ethoxy-4-methoxyphenyl)-2-Methanesulfonylethylamine (2g, 7.316 mmol,), 3-acetamidophthalic anhydride (1.57g 7.652 mmol), glacial Acetic acid (20ml) was added. The mixture was refluxed for 16hrs and cooled to RT. The solvent was concentrated to get residue which was dissolved in Ethyl acetate and washed with water (25 mlx2) followed by saturated aqueous Sodium bicarbonate solution (20mlx2). The solvent was concentrated to obtain crude compound and the crude compound was recrystallized with a mixture of Ethanol and Acetone (2:1) 10ml to obtain 2.69g of pure compound with Specific rotation (+) 27.780 and with 99% enantiomeric excess.