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
"A NOVEL PROCESS FOR PREPARATION OF EPRAZINONE
DIHYDROCHLORIDE"
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.I.D.C., Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION
The present invention relates to an industrially viable, cost-effective and energy efficient process for the preparation of Eprazinone dihydrochloride (Ia), with purity conforming to regulatory specifications. More specifically, the invention relates to a convergent synthetic scheme, utilizing N-protected piperazine as starting material, which, upon in-situ alkylation and etherification, followed by Mannich reaction with propiophenone provides Eprazinone dihydrochloride of desired purity.
BACKGROUND OF THE INVENTION
Eprazinone of formula (I) is an anti-tussive drug which is employed in the treatment of respiratory tract ailments owing to its broncho-secretolytic and mucolytic activities. It is administered as a dihydrochloride salt in the formulations marketed under various brand names such as Debronc, Resplen, Molitoux, Muctux etc. The drug, which acts by dissolution of mucus in the respiratory tract, is an active ingredient in various expectorant formulations.
Eprazinone dihydrochloride (Ia), chemically known as 3-[4-(2-ethoxy-2-phenyl-ethyl) piperazin-1-yl]-2-methyl-1-phenyl-propan-1-one dihydrochloride was first disclosed in US 3,448,192.

Eprazinone dihydrochloride (Ia) US 3,448,192 discloses a process for preparation of Eprazinone dihydrochloride comprising reaction of 2-phenyl-2-ethoxy ethyl bromide with excess of anhydrous piperazine to give l-(2-ethoxy, 2-phenyI)ethyl piperazine, which on further reaction with propiophenone in presence of trioxymethylene and hydrochloric acid yields Eprazinone dihydrochloride. The starting material in this synthetic scheme, 2-phenyl-2-ethoxyethyl bromide, was obtained by the treatment of styrene with ethanol in presence of tertiary butyl hypobromite.

The reaction proceeds with a very modest overall yield of about 40%, which ultimately affects the overall yield and leads to increased batch sizes, requirement of higher quantities of reagents and associated energy demands. Further, the sequence also utilizes hazardous and a highly flammable reagent like tertiary butyl hypobromite. Factors such as these make the process industrially unviable.
ES 424173 discloses a process in which N-protected piperazine obtained by reaction of piperazine with benzyl chloroformate, is subjected to Mannich reaction with propiophenone. Deprotection of the resulting compound followed by N-alkylation employing 2-phenyl-2-ethoxyethyl bromide yields the desired product. The lengthy reaction time, especially for the N-alkylation type reaction, which takes about 27 hours, increases the probability of formation of impurities. This in turn leads to additional purification steps and lower yields. The synthetic scheme also involves an additional step for deprotection of piperazine derivative and steps such as neutralization of hydrobromide salts of intermediates to free bases prior to subsequent reactions, which ultimately results in a reaction sequence with low efficiency.
Further, the scope for commercial use of this sequence is further limited due to utilization of a hazardous reagent like benzyl chloroformate, which has a tendency to decompose into toxic and highly poisonous phosgene on heating.
JP 51088979 discloses a process which comprises reaction of a Grignard reagent like propyl-3-[4-(2-ethoxy-2-phenyl-ethyl)piperazin-1-yl]-2-magnesium bromide with benzonitrile using diethyl ether as a solvent. Hydrolysis of the resultant product with hydrochloric acid yields Eprazinone hydrochloride.
The preparation of Grignard reagent from the corresponding piperazine bromide and its subsequent reaction necessitates stringent anhydrous conditions due to the moisture sensitive nature of the reactions. Further, in addition to the expensive Grignard reaction conditions, the use of highly inflammable solvent such as diethyl ether renders the process unsuitable for commercial purpose.

It would be evident that the prior art processes utilize hazardous reagents such as tertiary butyl hypobromite, benzyl chloroformate, moisture sensitive Grignard reagents and highly flammable solvents like diethyl ether. Further, the obtained yields are comparatively quite low thereby generating a need for developing a process which not only avoids hazardous reagents and stringent reaction conditions, but is also convenient for implementation on a commercial scale. Also, the reactions need to be facile, high yielding and their sequence should be aptly designed so that the desired product is obtained with a minimum number of steps and with a stringent control on the level of impurities for circumventing additional purification steps.
The present inventors have developed a method which gives Eprazinone hydrochloride in high yield and results in a product conforming to regulatory specifications.
OBJECT OF THE INVENTION
An objective of the present invention is to provide Eprazinone dihydrochloride of formula (Ia) by a simple, convenient and cost-effective process which does not involve hazardous reagents.
Another object of the invention is to provide Eprazinone dihydrochloride (Ia) having purity conforming to regulatory guidelines.
Yet another object of the present invention is to provide a short, industrially feasible and convergent process for preparation of Eprazinone dihydrochloride (Ia) which involves readily available, cost-effective starting materials.
SUMMARY OF THE INVENTION
The present invention relates to an industrially viable process for the preparation of Eprazinone dihydrochloride (Ia), which avoids the shortcomings of the prior art processes.
An aspect of the present invention relates to an improved, cost-effective process for the preparation of Eprazinone dihydrochloride (Ia), comprising,

(i) Reaction of tertiary butyl piperazine-1-carboxylate (II) with 2-bromo-1-phenylethanone (IV) to give tertiary butyl piperazine-4-(2-phenylethan-2-one)-1-carboxylate (V).
(ii) Reduction of (V) with sodium borohydride in methanol followed by reaction of the resulting alcohol of formula (VI) with an alkylating agent in presence of a base in an organic solvent to give compound of formula (VII),
(iii) Reaction of compound (VII) with propiophenone (VIII) and paraformaldehyde in presence of hydrochloric acid to give Eprazinone dihydrochloride (la) of desired purity.
Following detailed description will make the objectives of the present invention fully apparent.
DETAILED DESCRIPTION OF THE INVENTION
Meticulous and rigorous experimentation was carried out by the present inventors for developing a convergent synthetic approach for synthesis of Eprazinone. During the study, it was surprisingly observed that with the use of suitably protected piperazine intermediates, the reaction scheme could be maneuvered such that up to penultimate stage of synthesis, almost all the reactions could be carried out in-situ and the last stage of the sequence with simultaneous deprotection directly led to the desired product having the required purity. Further, by selecting a suitable acid-labile protecting group, deprotection could be achieved in the last stage itself, without any additional step.
The present inventors envisaged that the synthetic intermediate, tertiary butyl piperazine-(4-(2-phenyl-2-ethoxyethyl-l-yl))-l-carboxylate of formula (VII), could be prepared by a novel synthetic route starting with N-protected piperazine and without isolating the intervening intermediates.
Tertiary butyl piperazine-1-carboxylate of formula (II) was treated with 2-bromo-l-phenylethanone (IV), followed by reduction of the resulting compound (V) with an alkali borohydride and subsequent alkylation with and alkyl halide like ethyl bromide to give compound of formula (VII). The reaction of compound (VII) with propiophenone and

paraformaldehyde in presence of hydrochloric acid finally gave Eprazinone dihydrochloride (Ia) of desired purity and impurity level, conforming to regulatory guidelines.

Scheme I: Method embodied in the present invention for preparation of Eprazinone dihydrochloride
In an embodiment, tertiary butyl piperazine 1-carboxylate (II) was reacted with 2-bromo-l-phenylethanone of formula (IV) in presence of a base and in an organic solvent to give tertiary butyl piperazine 4-(2-phenylethan-2-one)-1-carboxylate (V).
The solvent was selected from the group comprising halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform or polar aprotic solvents such as dimethylformamide, dimethyl sulphoxide, N-rnethylpyrrolidone, dimethyl acetamide etc.
The base was selected from the group comprising of alkali metal carbonates such as sodium carbonate, potassium carbonate etc.

The compound of formula (V), tertiary butyl piperazine 4-(2-phenylethan-2-one)-l-carboxylate thus obtained, was reduced with sodium borohydride in methanol as solvent to give the corresponding alcohol, tertiary butyl piperazine 4-(2-phenyl-2-hydroxyethyl-l-yl)-1-carboxylate (VI). Optionally, the compound of formula (VI) was isolated from the reaction mass using hydrocarbon solvents such as petroleum ether, hexane, toluene, xylene etc.
Alkylation of the compound of formula (VI) with ethyl bromide in presence of a base in an
organic solvent followed by treatment with hydrochloric acid gave hydrochloride salt of
tertiary butyl piperazine (4-(2-phenyl-2-ethoxyethyl-l-yl))-l-carboxylate (VII).
The base was selected from the group comprising of carbonates and alkoxides of alkali
metals, preferably alkoxides of alkali metals.
The base was selected from the group comprising of lithium tertiary butoxide, sodium
tertiary butoxide and potassium tertiary butoxide.
The organic solvent was selected from the group comprising of tetrahydrofuran, N-methyl
pyrrolidone, acetonitrile etc.
The reaction of compound (VII) with propiophenone (VIII) and paraformaldehyde was carried out in presence of hydrochloric acid in refluxing isopropanol to yield Eprazinone dihydrochloride (Ia) having desired purity. The finished product so obtained had impurity levels conforming to regulatory specifications. It is pertinent to mention that deprotection of the piperazine nitrogen was carried out simultaneously during the Mannich reaction, without incurring any additional step for deprotection. Further, this also led directly to the isolation of finished product as the desired hydrochloride salt.
It should also be noted that all the aforementioned steps up to the penultimate stage, except for the last stage, were carried out in-situ, thus leading to considerable reduction in time for each batch run and saving on energy, cost and time incurred in isolating and purifying intermediates at the intermittent stages. Further, the desired purity of finished product could also be achieved by isolating the intermediate in the penultimate stage and subjecting purified material for the last reaction.

Tertiary butyl piperazine-1-carboxylate (II) was prepared by a conventional method, wherein piperazine was reacted with di-tertiary butyl dicarbonate in presence of acetic acid. 2-Bromo-l-phenylethanone (IV) was also prepared by well-known methods by halogenation of acetophenone (III) with bromine and dichloromethane as solvent.
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.
Example 1
Preparation of tertiary butyl piperazine-(4-(2-phenyl-2-ethoxyethyl-l-yl))-l-
carboxylate (VII)
A solution of bromine (266gms) in dichloromethane (200ml) was added to the mixture of acetophenone (200gms) in dichloromethane (400ml). The reaction mass was stirred at room temperature till completion of the reaction as monitored by HPLC to give 2-bromo-l-phenylethanone (IV)
Potassium carbonate (344 g) was added to the reaction mass and cooled to 20°C. A mixture of tertiary butyl piperazine-1-carboxylate (compound II, 372 g) in dichloromethane (800ml) was added to the reaction mixture and stirred at 20-30°C till completion of reaction as monitored by HPLC to give t-butyl piperazine-4-(2-phenylethan-2-one)- 1-carboxylate of formula (V).
The reaction mixture containing compound (V) was filtered and washed with water, followed by addition of sodium borohydride (31.5gms) to the separated organic layer. Methanol (200ml) was further added to the reaction mass and the mixture was stirred at 25-30 C till completion of reaction as monitored by HPLC.
Upon completion of the reaction, the reaction mass was quenched with water and the organic layer was separated and concentrated to give tertiary butyl piperazine- (4-(2-phenyl 2-hydroxyethyl-1-yl))-1-carboxylate of formula (VI). Optionally, toluene was added to the

concentrated mass and compound (VI), thus separating out as a solid was subjected to further reaction.
N-methyl pyrrolidone (800ml) was added to the concentrated mass containing the compound of formula (VI) and the mixture was cooled to 0-5°C. Potassium tert-butoxide (373gms) was added to the mixture with stirring, followed by addition of ethyl bromide (362gms).
The reaction mixture was warmed to 25-30°C and stirred at the same temperature. When the reaction was complete, as monitored by HPLC, water was added to the reaction mass followed by addition of dichloromethane (400ml). The organic layer was separated and concentrated to give crude t-butyl piperazine (4-(2-phenyl-2-ethoxyefhyl-l-yl))-l-carboxylate, which was converted to its hydrochloride salt (VIIa), by addition of hydrochloric acid in isopropyl alcohol (608g, 20%). Yield: 300 g. Purity: >99.5%.
Example 2
Preparation of Eprazinone dihydrochloride (la)
Paraformaldehyde (48.5g) and propiophenone (119g) were added with stirring to the mixture of hydrochloride salt of t-butyl piperazine (4-(2-phenyl-2-ethoxyethyl-l-yl))-l-carboxylate (300 g) of formula (VII) and isopropanol (900 ml). Hydrochloric acid (97 ml) was then added to the mixture and temperature of the reaction was raised to 75-80 °C. The reaction mass was stirred till completion of reaction as followed by HPLC. The reaction mass was cooled, filtered to give Eprazinone dihydrochloride (Ia), and optionally purified with methanol. Yield: 305 g. Purity: 99%

We Claim:
1. A process for the preparation of Eprazinone dihydrochloride (Ia), comprising,
(a) reaction of tertiary butyl piperazine-1-carboxylate (II) with 2-bromo-l-
phenylethanone (IV) in presence of a base and in an organic solvent to give tertiary
butyl piperazine-4-(2-phenylethan-2-one)-l-carboxylate (V)
(b) reduction of compound of formula (V) with sodium borohydride in alcohol as
solvent followed by reaction of the resulting alcohol of formula (VI) with an alkylating
agent in presence of a base and an organic solvent to give a compound of formula (VII),
which is optionally isolated as its hydrochloride salt (VIIa)
(c) reaction of compound (VII) or (VIIa) with propiophenone (VIII) and
paraformaldehyde in presence of hydrochloric acid and in an organic solvent gave
Eprazinone dihydrochloride of formula (Ia).
2. A process as claimed in claim 1(a), wherein the organic solvent is selected from
dichloromethane, ethylene dichloride, chloroform, dimethyl formamide, dimethyl
acetamide, dimethyl sulfoxide, N-methyl pyrrolidone and the base is selected from
sodium carbonate and potassium carbonate.
3. A process as claimed in claim 1(b) wherein the alcohol solvent is methanol.
4. A process as claimed in claim 1(b) wherein the compound of formula (VI) is optionally isolated by addition of a hydrocarbon.
5. A process as claimed in claim (lb) wherein the alkylating agent is ethyl bromide.
6. A process as claimed in claim (lb) wherein the base is selected from sodium tertiary butoxide and potassium tertiary butoxide.
7. A process as claimed in claim (lb) wherein the organic solvent is selected from tetrahydrofuran, N-methyl pyrrolidone and acetonitrile.

8. A process as claimed in claim 1(c) wherein the organic solvent is isopropanol.