DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR THE PREPARATION OF
(4S)-1-METHYL-2-OXOIMIDAZOLIDINE-4-CARBOXYLIC ACID t-BUTYL ESTER
KEY INTERMEDIATE OF IMIDAPRIL

We, SMS PHARMACEUTICALS LIMITED
a company incorporated under the companies act, 1956 having address at
Plot No.19-III, Road No.71; Opp. Bharatiya Vidya Bhavan Public School,
Jubilee Hills; Hyderabad; Telangana-500 096, India.

The following specification particularly describes and ascertains 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 improved process for the preparation of Imidapril of formula (I).

More particularly, the present invention relates to the process for the preparation of 1-methyl-2-oxoimidazolidine-4-carboxylate of general formula (II), which is a key starting material in the preparation of Imidapril and its pharmaceutically acceptable salts thereof.

wherein PG1 represents carboxylic acid protecting.

Background of the invention
Imidapril is an angiotensin-converting enzyme (ACE) inhibitor, used to treat hypertension and congestive heart failure. The compound is administered as its hydrochloride. The chemical designation is (4S)-3-[(2S)-2-[[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1-methyl-2-oxo-4-imidazolidinecarboxylic acid hydrochloride.
Considering the importance of Imidapril, several patents / patent documents namely., US 4,508,727, US 5,013,845, EP 0 373 881 B1, WO 2007/029267, US 5,977,380 etc., disclosed the preparation of Imidapril hydrochloride. The literature process widely use 2-oxoimidazolidine-4-carboxylic acid ester derivative of general formula (II) as a starting material. Thus, 1-methyl-2-oxoimidazolidine-4-carboxylate of general formula (II) is an important stating material in the preparation of Imidapril.
US 4,508,727 discloses the Imidapril and several processes for the preparation of Imidapril. According to this patent the 4(S)-1-methyl-2-oxoimidazolidine-4-carboxylate of formula (IIa) is prepared by debenzylation of compound of formula (IIIa) Debenzylation is carried out by catalytic hydrogenation at high pressure using Pd/C.

Scheme I

Similar process is also disclosed in Drugs of the Future 1992, 17(7), 551-558.
IN 764/KOL/2005 also discloses a similar process wherein debenzylation of compound of general formula (III) to produce 4(S)-1-methyl-2-oxoimidazolidine-4-carboxylate of general formula (II) is carried out catalytic hydrogenation using Pd/C in Ethanol.
WO 2007/029267 discloses the preparation of Imidapril hydrochloride by a) reacting esters of 4(S)-1-methyl-2-oxoimidazolidine-4-carboxylate (II) with (S)-ethyl-2-[(S)-4-methyl-2,5-dioxooxazolidin-3-yl]-4-phenylbutanoate (IV) followed by isolating the obtained product as salt of formula V, b) hydrolyzing with an alcoholic solvent by in-situ conversion of the product of formula V to the hydrochloride salt of formula I or de-benzylating using a catalyst and hydrogen and converting to the hydrochloride salt of formula-I.

Scheme II
The reported processes for the preparation of compound of general formula (II) by conventional catalytic hydrogenation require high pressures which is in general non-preferable for industrial scale due to safety concerns. Use of hydrogen under pressure may pose a serious risk of fire or explosion as well as the process is always accompanied with the formation of byproducts. Also, this process requires special high-pressure reactors and is quite uneconomical for manufacturing point of view.
Considering the importance of Imidapril, there is need for a simple, economical and industrially viable and odorless process for the synthesis of Imidapril. With a view to find a simple process the present applicant diligently worked and identified a robust and economical process for the preparation of 1-methyl-2-oxoimidazolidine-4-carboxylate.

Objectives of the invention
The main objective of the present invention is to provide an improved process for the preparation of Imidapril that avoids the use of high pressure hydrogenation and gaseous hydrogen under pressure.
Another objective of the present invention is to provide a robust and simple process for the preparation of 1-methyl-2-oxoimidazolidine-4-carboxylate with high purity and yield.
Summary of the invention
Accordingly, there is provided a process for the preparation of 1-methyl-2-oxoimidazolidine-4-carboxylate of formula (II),

the said process comprising the steps of deprotecting the amino protecting group in compound of formula (III),

using a metal catalyst, hydrogen donor and in the presence of solvent to provide compound of formula (II) wherein PG and PG1 represents protecting groups.
According to another embodiment of the present invention, there is provided an improved process for the preparation of 1-methyl-2-oxoimidazolidine-4-carboxylate of formula (II), the said process comprising the steps of:
i. deprotecting the amino protecting group in compound of formula (III), using a metal catalyst, hydrogen donor and in the presence of solvent to provide compound of formula (II); wherein the improvement consists of carrying out the reaction condition that avoids the gaseous hydrogen under pressure;
ii. optionally converting the compound formula (II) into Imidapril or its hydrochloride of formula (I).

According to yet another embodiment of the present invention, there is provided an improved process for the preparation of 1-methyl-2-oxoimidazolidine-4-carboxylate of formula (IIa),

the said process comprising the steps of:
i. deprotecting the amino protecting group in compound of formula (IIIa),

using a metal catalyst, hydrogen donor and in the presence of solvent to provide compound of formula (IIa); wherein the improvement consists of carrying out the reaction condition that avoids the gaseous hydrogen under pressure;
ii. optionally converting the compound formula (IIa) into Imidapril or its hydrochloride of formula (I).

Detailed description of the invention

In an embodiment of the present invention, the protecting group PG represents an amino protecting group capable of being removed by catalytic hydrogenation and is selected from carboxybenzyl (Cbz). Likewise the PG1 represents a carboxylic acid protecting group capable of being removed by acid treatment and is selected from t-butyl.
In another embodiment of the present invention the metal catalyst used in the present invention is selected from metal platinum, palladium, palladium on carbon (Pd/C), Raney nickel, magnesium tunings, etc.
In still another embodiment of the present invention the hydrogen donor compound used in step (i) is selected from the group consisting of aliphatic alcohol like methanol, ethanol and the like; alkali metal and amine esters of fatty acids such as sodium acetate, ammonium formate, sodium formate and potassium formate preferably ammonium formate.
In another embodiment of the present invention the preferred hydrogenation catalyst/hydrogen donor system is selected from Pd/C & ammonium formate and Magnesium turnings and methanol. The use of ammonium formate also has advantages of being readily available, inexpensive, stable and nontoxic compound. Thus the present invention offers a novel reduction method, which is more efficient because it is faster, easier and results in substantially improved yield of the desired product. It is also more convenient for scale up at plant, since no high-pressure autoclaves are required.
In yet another embodiment of the present invention, the solvent used in step (i) is selected from group comprising methanol, ethanol, isopropyl alcohol and the like.
Preparation of (4S)-1-Methyl-2-oxoimidazolidine-4-carboxylic acid t-butyl ester of formula (IIa):
To a stirred suspension of Compound of formula (III) (where PG represents Cbz and PG1 represents t-butyl), Pd/C in dry methanol, and anhydrous ammonium formate was added in a single portion under nitrogen. The resulting reaction mixture was stirred at reflux temperature and the reaction was monitored by TLC. After completion of reaction, the catalyst was removed by filtration through a celite pad. The combined organic filtrate, on evaporation under reduced pressure, afforded the compound of formula (IIa). The compound of formula (IIa) is converted to Imidapril of formula (I) by following the process described in literatures.
The staring material (III) is prepared by utilizing the process disclosed in the prior art.
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments.

EXAMPLES
Reference Example 1:
Preparation of Formula IIa using Pd/C and Hydrogen Pressure
Charge compound of formula IIIa (8.12 g), Methanol (110 ml) and Pd/C (1.8 g) into the hydrogenation kettle, apply the pressure to 3kg/cm2 and stir. After 15 min maintenance, stop stirring and allow releasing pressure repeat the process twice and stirring for 3 hrs at RT. Filter the catalyst and distilling completely. Add IPE (33 ml) and stir for ½ hour at 25-30ºC cool to 15º C and stir for ½ hour at 15ºC. filter the solid and wash with IPE to obtain t-butyl 4(S)-1-methyl-2-oxoimidazolidine-4-carboxylate of Formula IIa (4.6 g) HPLC 95%; melting range 133-135ºC.

Example 1
Preparation of Formula IIa using Magnesium turning and Methanol
To the mixture of compound of Formula IIIa (100 gm, 0.299 mole) and methanol (500 ml) was added activated magnesium turnings (36.3 gm, 1.49 mole) under nitrogen atmosphere at temperature of about 20-30ºC. Stirred the reaction mass for about 2-3 hrs and monitored by TLC (Thin layer Chromatography). Once TLC shows absence of starting material, RM was filtered through hyflo and washed with 100 ml of methanol. Distilled out methanol layer completely under vacuum below 45-50ºC. Dissolved the crude product in MDC (1000 ml), washed with 3N HCl (300ml X 2) followed by washing with water (300 ml). To the MDC layer was added activated charcoal, filtered through hyflo and treated with Sodium sulphate (15 gm). Distilled out MDC layer completely below 40ºC under vacuum followed by trituration with isopropyl ether (100 ml) and filtered under vacuum to get 45-50gm of dry Imidapril intermediate of formula IIa. HPLC 99.58% melting range 133-135ºC.

Example 2
Preparation of Formula IIa using Pd/C with ammonium formate
To a mixture of compound of Formula IIIa (100 gm, 0.299 mole) and dry methanol (1000 ml) was added 10 % Pd/C (10 gm) and ammonium formate (66 gm, 3.5mole) under nitrogen atmosphere at temperature of about 20-30ºC. Heated the reaction mass to reflux temperature of about 66-68ºC and maintained the reaction mass at the same temperature for about 3-4 hr under stirring and TLC (Thin layer Chromatography) monitoring. Once TLC shows absence of starting material, RM was filtered through hyflo and washed with 100 ml of methanol. Distilled out methanol layer completely under vacuum below 45-50ºC. The obtained crude product was dissolved in MDC (1000 ml) and washed with 3N HCl (300 ml X 2) followed by washing with water (300 ml). To the MDC layer was added activated charcoal, filtered through hyflo and treated with Sodium sulphate (15 gm). Distilled out MDC layer completely under vacuum below 40ºC followed by trituration with isopropyl ether (100 ml) and filtered under vacuum to get 45-50 gm of dry Imidapril intermediate of formula IIa.

Example 3
Preparation of formula IIa using Magnesium turning and Ethanol
To a mixture of compound of Formula IIIa (100 gm, 0.299 mole) and ethanol (500 ml) was added Magnesium turnings (36.3 gm, 1.49 mole) under nitrogen atmosphere at temperature in between 20-30oC. The reaction mass was stirred for about 2-3 hrs and monitored by TLC (Thin layer Chromatography). Once TLC shows absence of starting material, RM was filtered through hyflo and washed with 100 ml of ethanol. Total ethanol layer was distilled out completely under vacuum below 45-50ºC. Dissolved the crude product in MDC (1000 ml), sodium bicarbonate (300 ml X 2) followed by NaCl wash (300 ml). To the MDC layer added Activated charcoal and filtered through hyflo and treated with Sodium sulphate (15 gm). Total MDC layer distil out completely below 40oC under vacuum followed by trituration with Isopropyl ether (100 ml) and filtered under vacuum to get 45-50 gm of dry Imidapril intermediate of formula IIa. HPLC 99.01% Melting range 133-135ºC.

Example 4
Preparation of formula IIa using Magnesium turning and isopropanol

To a mixture of compound of Formula IIIa (10 gm, 0.0299 mole) and isopropanol (100 ml) was added Magnesium turnings (3.63 gm, 0.1493 mole) under nitrogen atmosphere at temperature in between 20-30oC. The reaction mass was stirred for about 2-3 hrs and monitored by TLC (Thin layer Chromatography). Once TLC shows absence of starting material, RM was filtered through hyflo and washed with 100 ml of isopropanol. Total isopropanol layer was distilled out completely under vacuum below 45-50ºC. Dissolved the crude product in MDC (1000 ml), and washed with sodium bicarbonate (300 ml X 2) followed by NaCl wash (300 ml). Total MDC layer distil out completely followed by trituration with Isopropyl ether (30 ml) and filtered to get 4.5 gm of dry Imidapril intermediate of formula IIa. HPLC 99.66% melting range 133-135ºC.

Example 5
Preparation of maleate salt of t-butyl-(4S)-3-[(2S)-2-[[(1S)-1 (Ethoxycarbonyl-3-phenylpropynamino]-1-oxopropyl]-1-methyl-oxo-imidazolidine carboxylate

Charge THF (190 ml) and t-butyl 4(S)-1-methyl-2-oxoimidazolidine-4-carboxylate (IIa) (20.9 g) at RT and cool to -50ºC, charge potssium t-butoxide at -50º and maintain for 30min, raise the temperature to -45ºC and charge (S)-ethyl-2-[ (S)-4-methyl-2,5-dioxooxazolidin-3-yl]-4-phenylbutanoate (IV)(30.5 g) at -45ºC, take another flask and with ethyl acetate (370 ml) and aectic acid (7 g) and NaCl (140 ml). added the above reaction mixture to ethyl acetate containing flask, stir for 15 min, separate the organic layer and wash with sodium bicarbonate, water and NaCl, dry the organic layer with Na2SO4, add to Maleic acid (10.8 g) and distilled, IPE (110 ml) is added to the crude and stir fot 30 min at RT, cool to 15-20ºC and maintain for 30 mins. Filter the solid and wash with ethylacetate and IPE to obtain title compound (Va) (36 g) optical Rotation -52º (c= 1 in EtOH) HPLC 98.43% Melting range 117-121ºC.

Example 6
Preparation of t-butyl-(4S)-3-[(2S)-2-[[(1S)-1 (Ethoxycarbonyl-3-phenyl propylamino]-1-oxopropyl]-1-methyl-oxo-imidazolidine carboxylate hydrochloride

Charge compound of Example 5 (36 g) and methylene dichloride (219 ml) at RT and stir for 15 mins. Adjust the pH with K2CO3 upto 9. Stir for 15 mins and separate the organic layer and wash with water followed by brine solution for twice. Dry the organic layer and distill the organic solvent completely, to the obatined crude add IPE and stir for 15 min. add slowly IPA.HCl to the reaction mixtire around ½ hour at RT. Stir for ½ hour at RT. Cool to 15-20ºC. maintain for ½ hour. Filter the solid and wash with IPE. Dry the material at 60-65ºC to obatin title compound (31 g) having a specific rotation of -57.4º and melting range of 117-122.6ºC.

Example 7
Preparation of Imidarpril Hydrochloride
Charge compound obatined in example 6 (31 g) into a flask which contains 150 ml of dichloromethane and 200 ml of demineralised water. The pH of the reaction mixture was adjusted to 10 using aqueous potassium carbonate soluntion. The organic layer was seperated and washed with brine solution (2X 50 ml) and dreid over sodium sulphate. After complete removal of the solvent under reduced pressure, Isopropanolic HCl (75 ml) was added and stirred for 6 hours at 25-30ºC. 90 ml of diisopropyl ether was added after cooling the reaction mass to 10-15ºC. the precipitated crystals were filtered and dried to obtain 24.4 g of title compound having a specific rotation of -64.2ºC, melting point 215-217ºC and purity by HPLC 99.82%.

Dated this Fifth (05th) day of October 2015.

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883 ,CLAIMS:We Claim:
1. A process for the preparation of 1-methyl-2-oxoimidazolidine-4-carboxylate of formula (II),

the said process comprising the step of deprotecting the amino protecting group in compound of formula (III),

using a metal catalyst, hydrogen donor and in the presence of solvent to provide compound of formula (II) wherein PG and PG1 represents protecting groups.

2. An improved process for the preparation of 1-methyl-2-oxoimidazolidine-4-carboxylate of formula (II), the said process comprising the steps of:
i. deprotecting the amino protecting group in compound of formula (III), using a metal catalyst, hydrogen donor and in the presence of solvent to provide compound of formula (II); wherein the improvement consists of carrying out the reaction condition that avoids the gaseous hydrogen under pressure;
ii. optionally converting the compound formula (II) into Imidapril or its hydrochloride of formula (I).

3. The process as claimed in claims 1 and 2 wherein the protecting group PG represents an amino protecting group capable of being removed by catalytic hydrogenation which is selected from carboxybenzyl (Cbz).

4. The process as claimed in claims 1 and 2 wherein the protecting group PG1 represents a carboxylic acid protecting group capable of being removed by acid treatment and is selected from t-butyl.

5. The process as claimed in claims 1 and 2 the metal catalyst used is selected from metal platinum, palladium, palladium on carbon (Pd/C), Raney nickel, magnesium tunings.

6. The process as claimed in claim 5, preferred hydrogenation catalyst/hydrogen donor system is selected from Pd/C & ammonium formate and Magnesium turnings and methanol.

7. The process as claimed in claims 1 and 2 the hydrogen donor compound used in step (i) is selected from the group consisting of aliphatic alcohol like methanol, ethanol and the like; alkali metal and amine esters of fatty acids such as sodium acetate, ammonium formate, sodium formate and potassium formate preferably ammonium formate.

8. An improved process for the preparation of 1-methyl-2-oxoimidazolidine-4-carboxylate of formula (IIa),

the said process comprising the steps of:
i. deprotecting the amino protecting group in compound of formula (IIIa),

using a metal catalyst, hydrogen donor and in the presence of solvent to provide compound of formula (IIa) ; wherein the improvement consists of carrying out the reaction condition that avoids the gaseous hydrogen under pressure;
ii. optionally converting the compound formula (IIa) into Imidapril or its hydrochloride of formula (I).