FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION "NOVEL PROCESS FOR PREPARATION OF ACAMPROSATE
CALCIUM"
Emcure Pharmaceuticals Limited,
an Indian company, registered under the Indian Company's Act 1957
and having its registered office at
Emcure House, T-184, M.LD.C, Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION

FIELD OF THE INVENTION
The present invention relates to a novel, industrially feasible process for the preparation of calcium salt of 3-acetylaminopropane-l-sulfonic acid conforming to regulatory specifications. More specifically, the invention relates to the preparation of O-mesylated -3-amino propanol and its subsequent reaction with sodium sulfite to give 3-aminopropane-1-sulfonic acid, a key intermediate in the preparation of 3-acetylaminopropane-l-sulfonic acid.
BACKGROUND OF THE INVENTION
Acamprosate calcium of formula (I), chemically known as calcium salt of 3-acetylaminopropane-1-sulfonic acid, is used to treat alcohol dependence. The drug is known to act on brain pathways and stabilize the chemical balance in the brain which is disturbed by consumption of alcohol.

(I)
Aminoalkyl sulfonic acids, which are important synthetic precursors of 3-acetylaminopropane-1-sulfonic acid, are well known in the literature and different routes of synthesis have been reported for their preparation.
US 4,657,704 discloses a process for preparation of aminoalkyl sulfonic acid in which 3-chloropropylamine is reacted with aqueous sodium sulfite to furnish 3-aminopropyl sulfonic acid. The process has several disadvantages such as requiring a controlled rate of addition of the halogenated alkyl amine to the sulfite solution in an inert atmosphere with the quality of the product being found to depend on several factors such as temperature at the time of addition, molar ratio of the sulfite and the halogenated amine to be reacted. Also, the reaction requires not only high temperatures but also needs a typical sequence of

raising the reaction temperature for completion of reaction as well as for reduction in the level of impurities. All these stringent requirements for preparation of the aminoalkyl sulfonic acid are more suitable for academic purpose and are certainly not suitable for large scale industrial operations.
US 7,253,306 discloses another process for preparation of 3-amino-l-propanesulfonic acid wherein the sulfopropyl [-(CH2) 3SO3] group in the desired molecule is introduced using 1,3-propane sultone and the ring opening reaction of the sultone is carried out with gaseous ammonia or ammonium hydroxide. However, 1,3-propane sultone, which is a well known potential occupational carcinogen, has an associated side reaction wherein aqueous hydrolysis of 1,3-propane sultone leads to 3-hydroxy-l-propanesulfonic acid sodium salt. Therefore, the method requires stringent anhydrous conditions for minimizing the associated impurity and obtaining a product which conforms to the desired specifications.
Therefore, there still exists a need for a convenient, simple process for the preparation of 3-amino propane 1-sulfonic acid, which does not involve formation of associated impurities, requirement of hazardous reagents, inert reaction conditions and yields a product conforming to regulatory specifications with high yield.
The present inventors, during the course of their numerous experiments, had observed that Acamprosate calcium can be prepared by a simple, cost-effective method involving 3-amino-1-propanol. Sulfonation of the mesylate derivative of 3-amino 1-propanol proceeds under mild reaction conditions to give the desired sulfonic acid in excellent yields. Based on this finding, the inventors developed a novel, cost-effective synthetic route for synthesis of Acamprosate calcium of desired quality involving sulfonation of O-mesylate of 3-amino propanol. Further, it was also an unexpected finding that the level of the undesired sulfate impurity was well within permissible limits.
OBJECT OF THE INVENTION
An objective of the present invention is to provide Acamprosate calcium (I) by a novel synthetic route, which is economical and can be carried out under mild reaction conditions.

Another object of the invention is to provide Acamprosate calcium (I) with good yield and having purity complying with regulatory specifications.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of Acamprosate calcium (I) which overcomes the limitations faced in the prior art.
An aspect of the present invention relates to a cost-effective process for the preparation of Acamprosate calcium (I), comprising
i) reaction of 3-amino-l-propanol (II) with di-tertiarybutyl dicarbonate in presence
of an inorganic base and a solvent to give compound of formula (III), treating with methane sulfonyl chloride in presence of an organic base to give compound of formula (IV)
ii) deprotection of the compound (IV) with a mineral acid to give 3-amino-l-propanol mesylate of formula (V) followed by reaction with sodium sulfite to give compound of formula (VI)
iii) acetylating the compound of formula (VI) to give acamprosate free base of formula (VII), isolating the calcium salt of formula (I) by treating the compound of formula (VII) with calcium hydroxide.
The following detailed description will make the objectives of the present invention fully apparent.
DETAILED DESCRIPTION OF THE INVENTION
The present inventors, while carrying out extensive experimentation for developing a cost-effective, convenient, industrially viable route of synthesis for Acamprosate calcium have evolved a novel synthetic route in which it was found that the intermediate, 3-aminopropane-1-sulfonic acid (VI) can be easily obtained by the reaction of 3-amino propanol mesylate (V) with sodium sulfite. The intermediate, 3-amino propanol mesylate (V) is in turn prepared 3-amino-l-propanol through a novel route, which is convenient, safe and easy to handle on a commercial scale.


Scheme 1: Method embodied in the present invention for preparation of Acamprosate calcium (I)
In an embodiment, 3-amino 1- propanol (II) was reacted with di-tertiary butyl dicarbonate (BOC anhydride) in an organic solvent and in presence of an inorganic base to give N-Boc 3-amino 1- propanol (III). The reaction was carried out at ambient temperature.
The solvent was selected from the group of halogenated alkanes such as chloroform, dichloromethane, ethylene dichloride etc. but preferably dichloromethane while the base was selected from the group of alkali metal hydroxides such as sodium hydroxide, potassium hydroxide etc.
After completion of the reaction, the reaction mixture was concentrated to give the compound of formula (III).

A solvent selected from the group comprising halogenated alkanes such as chloroform, dichloromethane, ethylene dichloride etc. but preferably dichloromethane was added to the residue followed by the addition of an organic base.
The organic base was selected from the group of alkyl amines such as triethyl amine, trimethyl amine, diisopropyl ethyl amine, pyridine etc. but preferably triethyl amine.
Methane sulfonyl chloride was added to the mixture at a temperature between 0°C and 5°C and stirred till completion of the reaction as monitored by HPLC. The organic layer was then concentrated and the compound of formula (IV) was isolated by addition of ethyl acetate to the residue. The compound (IV) was filtered and dried.
N-Boc-3-amino-l- propanol mesylate of formula (IV) was dissolved in dioxane. One mole equivalent of hydrochloric acid was added to the reaction mixture and stirred at ambient temperature till completion of reaction, as monitored by TLC. The reaction mixture was concentrated to yield a residue containing 3-amino-1- propanol mesylate of formula (V).
Compound (V) was dissolved in water and an aqueous solution of sodium sulfite was added to the mixture at a temperature between 25°C to 30°C and stirred till completion of reaction. Aqueous hydrochloric acid was added to the mixture and the hydrochloride salt of 3-aminopropane 1-sulfonic acid was isolated by adding methanol to the mixture.
The free base of 3-aminopropane 1-sulfonic acid (VI) was obtained by treating the hydrochloride salt with sodium hydroxide and isolated by addition of an alcohol like methanol.
3 -aminopropane-1 -sulfonic acid of formula (VI) was then treated with an acetylating agent such as acetic anhydride or acetyl chloride in presence of calcium hydroxide.
Calcium hydroxide was added to water and the mixture was warmed to 55°C. The compound of formula (VI) was added to the mixture at the same temperature and maintained for 1-2 hours. The mixture was cooled to ambient temperature and an

acetylating agent like acetic anhydride or acetyl chloride was added to the mixture gradually and the reaction mixture heated at 55°C till completion of the reaction. The reaction mixture was concentrated under reduced pressure and aqueous acetic acid was added to the mixture. The mixture after being heated at 50°C for 30-60 minutes was cooled and filtered. An alcohol like methanol was added to the reaction mass and filtered. Acamprosate calcium (I), thus obtained, was found to conform to regulatory specifications with associated impurities normally encountered with prior art methods, well below the permissible limits.
The following examples are meant to be illustrative of the present invention. These examples exemplify the invention and are not to be construed as limiting the scope of the invention.
EXAMPLES
Example 1
Preparation of N-Boc- 3-amino 1-propano! (III)
Aqueous sodium hydroxide (210 ml, 30%) was added to a stirred mixture of 3-amino 1-propanol (100g) and dichloromethane (500 ml) at 25°C to 30°C. Boc anhydride (435 g) was gradually added to the reaction mass and stirred at 25°C to 30°C till completion of the reaction as monitored by HPLC. After completion of the reaction, the organic layer was concentrated to give N-Boc- 3-amino 1-propanol (III). Yield: 209.0 g
Example 2
Preparation of 3-amino 1-propanol mesylate (V)
N-Boc-3-amino-l-propanoI (140 g) of formula (III) was dissolved in dichloromethane (500 ml). Triethyl amine (147 g) was gradually added to the mixture at 0 to 5°C, followed by addition of methane sulfonyl chloride (153 g) in 30 minutes. The reaction mass was stirred at same temperature till completion of the reaction, as monitored by TLC. The organic layer was concentrated and ethyl acetate was added to the residue to give N-Boc-3-amino-1-propanol mesylate (IV) mass which was filtered.

Treatment of (IV) with hydrogen chloride in 1,4 dioxane (400 ml), at 25 to 30°C yielded 3-amino-l-propanol mesylate (V). Yield: 110.0 g
Example 3
Preparation of 3-aminopropane l-sulfonic acid (VI)
3-Amino 1-propanol mesylate (V), (110 g) was added to water (400 ml). Sodium sulfite (198 g) in water (230 ml) was added to the mixture and stirred at 25 to 30 °C. Upon completion of the reaction, as monitored by HPLC, the reaction mixture was concentrated and residue was treated with concentrated HC1 (205 ml) at 40 to 45 °C. The mixture was filtered and concentrated. Methanol (500 ml) was added to the residue and solid separating out was filtered. The wet hydrochloride salt was neutralized with aqueous sodium hydroxide solution (10%) at ambient temperature and the product was precipitated by adding methanol (500 ml) to give 3-aminopropane l-sulfonic acid (VI). Yield: 85.0 g. Purity: 99.5 %
Example 4
Preparation of Acamprosate Calcium (I)
3-Aminopropane-l-sulfonic acid (100 g), calcium hydroxide (58.5 g) and water (300 ml) were heated to 55 to 60°C, followed by addition of acetic anhydride (146.8gms) and continued stirring. After the reaction was complete, the product was isolated by distillation, addition of acetic acid and precipitation with methanol gave Acamprosate calcium (I), Yield: 100.0 g. Purity: 99.5 %

Claims
1. A process for the preparation of Acamprosate calcium (I), comprising
a) reaction of 3-amino-l-propanol (II) with di-tertiarybutyl dicarbonate in presence of an inorganic base and a solvent to give compound of formula (III), treating with methanesulfonyl chloride acid in presence of an organic base to give compound of formula (IV)
b) deprotection of compound (IV) with a mineral acid-in a solvent to give 3-amino 1-propanol mesylate of formula (V) followed by reaction with sodium sulfite to give compound of formula (VI)
c) acetylating the compound of formula (VI) to give acamprosate free base of formula (VII), isolating the calcium salt of formula (I) by treating the compound of formula (VII) with calcium hydroxide.

2. A process as claimed in claim 1(a), wherein the solvent is dichloromethane.
3. A process as claimed in claim 1(a), wherein the inorganic base is sodium hydroxide while the organic base is triethyl amine.
4. A process as claimed in claim 1(b), wherein the mineral acid is hydrochloric acid.
5. A process as claimed in claim 1(b), wherein the acid for deprotection of compound of formula (IV) is hydrochloric acid and the solvent is dioxane.
6. A process as claimed in claim 1(c), wherein the acetylating agent is acetic anhydride or acetyl chloride.