Title of Invention

A PROCESS FOR THE PREPARATION OF N-{2-[4-(AMINOSULFONYL) PHENYL] ETHYL}-3-ETHYL-4-METHYL-2-OXO-2,5-DIHYDRO-1H-PYRROLE-1-CARBOXAMIDE

Abstract The present invention relates to an improved process for the preparation of N- {2-[4-(aminosulfonyl) phenyl] ethyl} –3ethyl-4-methyl-2oxo-2, 5-dihydro-1H-pyrrole-1-carboxamide. This compound is useful as a key intermediate in the synthetic preparation of trans-3-Ethyl-2, 5-dihydro-4-methyl-N- [2- [4- [[[[(4-methyl cyclohexyl) amino] carbonyl] amino] sulfonyl] phenyl] ethyl]-2-oxo-1H-pyrrole-1-carboxamide of high purity, commonly known as glimepiride.
Full Text FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"A process for the preparation of N- {2-[4-(aminosulfonyl) phenyl] ethyl}-3-
ethyl-4-methyl-2-oxo-2,5-dihydro-lH-pyrrole-l-carboxamide"
2. APPLICANT
(a) NAME: M/S. INDOCO REMEDIES LIMITED.
(b) NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: Indoco House, 166 C. S. T. Road, Santacruz (East), Mumbai -
400 098. Maharashtra, India
3.PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention:

Field of the invention:
The present invention relates to an improved process for the preparation of N- {2-[4-(aminosulfonyl) phenyl] ethyl}-3-ethyl-4-methyl-2-oxo-2, 5-dihydro-lH-pyrrole-l-carboxamide. This compound is useful as a penultimate intermediate in the synthetic preparation of trans-3-Ethyl-2, 5-dihydro-4-methyl-N- [2- [4- [[[[(4-methyl cyclohexyl) amino] carbonyl] amino] sulfonyl] phenyl] ethyl]-2-oxo-lH-pyrrole-l-carboxamide, commonly known as glimepiride. The present invention, thus, also relates to a method for preparation of glimepiride of high purity.
Background of the invention:
Glimepiride of formula (1) is described in US patent 4,379, 785. Glimepiride is known for its anti diabetic properties and finds medicinal applications and is commercially available since many years.





Formula (1)
Many process for the manufacture of Glimepiride are disclosed in the literature, from which it is apparent that the N- {2-[4-(aminosulfonyl) phenyl] ethyl}-3-ethyl-4-methyl-2-oxo-2, 5 -dihydro-1 //-pyrrole- 1-carboxamide is the key intermediate for the manufacture of glimepiride.






Formula (2)

2

United States Patent 4,379, 785 discloses a three-step process for the preparation of trans-3-Ethyl-2,. 5-dihydro-4-methyl-N- [2- [4- [[[[(4-methyl cyclohexyl) amino] carbonyl] amino] sulfonyl] phenyl] ethyl]-2-oxo-lH-pyrrole-l-carboxamide starting with reaction of 3-Ethyl- 4-methyl-3-pyrrolidin-2-one and 2-phenyl ethyl isocyanate followed by reaction with chlorosulfonic acid and amidation by liquor ammonia.
PCT publication WO 2005/049532 describes a process for obtaining pure Glimepiride. Glimepiride was purified using an alkanol (C1-C4) and ammonia.
Another PCT publication no WO03057131 discloses a process for the preparation of N-{2-[4-(amino sulfonyl)phenyl]ethyl} -3-ethyl-4-methyl-2-oxo-2,5-dihydro-1 //-pyrrole-1 -carboxamide, via a novel intermediate, 4-nitrophenyl 3-ethyl-4-methyl-2-oxo-2, 5-dihydro-1 H-pyrrole-1 -carboxylate.
The major drawbacks of the prior art processes include:
- A key intermediate sulphonamide, N- {2-[4-(amino sulfonyl)phenyl]ethyl}-3-ethyl-4-methyl-2-oxo-2,5-dihydro-l//-pyrrole-l-carboxamide obtained does not exceed HPLC purity of more than 80-85%.
- It requires repeated purifications of sulphonamide, which can improve purity up to 90-95% by HPLC.
- Large volume of solvents is required for purification to obtain pharmacopoeial acceptable quality of Glimepiride.
- The existing art processes are less economical commercially.
- Use of large quantities of organic solvents and water becomes less eco friendly.
Objectives of the invention:
The present invention tackles the problem of providing an alternate process for the synthesis of N- {2-[4-(aminosulfonyl)phenyl]ethyl} -3-ethyl-4-methyl-2-oxo-2,5-dihydro-
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l//-pyrrole-l-carboxamide,which overcomes all or some of the aforementioned
problems.
The objective of the present invention is to prepare the intermediate compound of
formula (2), viz., N- {2-[4-(aminosulfonyl) phenyl] ethyl}-3-ethyl-4-methyl-2-oxo-2, 5-
dihydro-1 //-pyrrole-1 -carboxamide, of higher purity.
A further objective of the present invention is to prepare the intermediate compound of formula (2), viz., N- {2-[4-(aminosulfonyl) phenyl] ethyl}-3-ethyl-4-methyl-2-oxo-2, 5-dihydro-1//-pyrrole-1 -carboxamide, to obtain the desired quality product by a cost effective process.
Yet another objective of the present invention is to prepare trans-3-ethyl 2,5-dihydro-4-methyl-N- [2- [4- [[[[(4-methyl cyclohexyl) amino] carbonyl] amino] sulfonyl] phenyl] ethyl]- 2-oxo-1 H-pyrrole-1-carboxamide, i.e. glimepiride of pharmaceutically acceptable quality, by employing the intermediate compound of formula (2), viz., N- {2-[4-(aminosulfonyl) phenyl] ethyl}-3-ethyl-4-methyl-2-oxo-2, 5-dihydro-l//-pyrrole-1-carboxamide, which is prepared by the process of the present invention.
Detailed description of the invention:
We have found that the sulphonamide of Formula (2) can be prepared directly with high purity from the reaction mixture by employing a suitable solvent. The solvent is selected from a group of aromatic and aliphatic acetates preferably aliphatic acetates such as isoamyl acetate, isopropyl acetate, butyl acetate, methyl acetate, ethyl acetate and mixtures thereof, the most preferred solvent being ethyl acetate.
The present invention for getting highly pure sulfonamide of formula (2) includes:
1. Reaction of 3-Ethyl- 4-methyl-3-pyrrolidin-2-one with 2-phenylethylisocyanate to obtain [2- (3-Ethyl-4-methyl-2- carbonyl pyrrolidine amido) ethyl] benzene.
2. Reaction of [2- (3-Ethyl-4-methyl-2- carbonyl pyrrolidine amido) ethyl] benzene with chlorosulfonic acid in dichloromethane, yielding 4- [2- (3-Ethyl-4-methyl-2-
4

carbonyl pyrrolidine amido) ethyl] benzene sulfonamide (Ref:US Patent 4379785).
3. The intermediate 4- [2- (3-Ethyl-4-methyI-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide so obtained is then reacted with ammonia in presence of ethyl acetate as solvent and isolating the pure sulfonamide with high purity by simple filtration.
4. Subsequently the pure sulfonamide obtained by the above novel process was reacted with ethyl chloroformate in the presence of triethyl amine and dichloromethane solvent to get sulfonamide ethyl formate. (Ref:US Patent 4379785).
5. Sulfonamide ethyl formate was reacted with trans-4-methyl cycylohexylamine in presence of DMPA to obtain glimepiride, which upon purification from solvent acetone yields highly pure glimepiride with purity greater than 99.7%, single impurity not more than 0.1% and total impurities not more than 0.3%.
The novel aspect of the present invention lies in the synthesis of sulphonamide. Contrary to the earlier processes, it was found that when the reaction of 4- [2- (3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide is carried out with ammonia solution, in solvents rather than aqueous media, the sulfonamide so obtained has a very high purity. By following prior art process normally the sulfonamide obtained has less purity.
Being the key penultimate intermediate it is very essential to have a high purity of
sulfonamide.
If the purity is less, then it necessitates purification as the case is with prior art process.
But when the reaction is carried in solvents like aliphatic acetates such as isoamyl
acetate, isopropyl acetate, butyl acetate, methyl acetate, ethyl acetate and most preferably
ethyl acetate then upon isolation of sulfonamide, the purity is usually greater than 98% by
HPLC and thus eliminates the requirement of purification.
5

As per the present invention, chlrorosulfonylchloride is suspended in ethyl acetate. Chlorosulfonylchloride to solvent ratio is 1: 20 more preferably 1:10 and most preferably 1: 8. Chlorosulfonyl chloride to ammonia is used in molar ratio of preferably 1: 10 and more preferably 1: 8. The reaction is carried out in the range of 30-75°C more preferably 60-70°C and most preferably 65-70°C.
The reaction is taken to completion by heating at above temperature for a period of 1-4 hours and preferably 3hours.
At the end of the reaction the reaction mass is cooled to room temperature and filtered. On filtration, the product sulfonamide obtained is dried. The sulfonamide obtained shows purity greater than 98.5% thereby obviating the need for further purification. The yield varies between. 70-75%.
The yield is also high due to the elimination of purification stages. Subsequently the pure
sulfonamide obtained as per the above novel process is converted into glimepiride by
known prior art processes (US Patent 439785 ) details of which are visible from
examples.
The glimepiride obtained using above sulfonamide is of very high purity. It also
eliminates the need for repeated purifications of glimepiride. The glimepiride obtained
comfortably meets phramcopeial requirements.
The following example, which include preferred embodiment, 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.
Example 1
Process for preparation of sulphonamide and isolation of pure sulphonamide directly
from the reaction mixture:
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l00.0g of 3-Ethyl-4Methyl-3-pyrrolidin-2-one and 138.0g of 2-phenylethylisocyanate mixture was heated at, 145°C for 3 hours. After the completion of reaction the reaction mixture was cooled to 80°C. The product [2- (3-Ethyl-4-methyl-2- carbonyl pyrrolidine amido) ethyl] benzene was precipitated by adding 500ml methanol and isolated by filtration (Ref:US Patent 4379785).
The product [2- (3-Ethyl-4-methyl-2- carbonyl pyrrolidine amido) ethyl] benzene was then dissolved in 650ml of dichloromethane and cooled to -2°C. It was then added to 875.0 gm chlorosulfonic acid and 350ml dichloromethane at -2°C. Reaction was continued at -2°C for 1 hour. The reaction mass was quenched into chilled water. The solvent was distilled off. The product 4- [2- (3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide is isolated by filtration.
The compound 4- [2- (3-Ethyl-4-methyl-2-carbonyl pyrrolidine amido) ethyl] benzene sulfonamide was taken in 500 ml ethyl acetate and 750 ml ammonia. The reaction mass was stirred for 3hours at 65°C and filtered. The sulfonamide obtained was dried at 70°C and showed an HPLC purity of 98.85%. It was then reacted with 11.75 gm of ethyl chloroformate in the presence of triethyl amine and dichloromethane solvent to get Sulfonamide ethyl formate. (Ref:US Patent 4379785).The product so obtained was further treated with 14.4 gm of 4-DMPA and 8.5 gm of trans-4-methyl cyclohexyl amine to obtain glimepiride, which upon purification
from solvent acetone yielded highly pure glimepiride with purity greater than 99.7%, single impurity not more than 0,1% and total impurities not more than 0.3%.
Dated this 31st day of March 2006

7

Documents:

502-mum-2006-abstract(28-3-2007).pdf

502-MUM-2006-ABSTRACT(GRANTED)-(1-9-2011).pdf

502-MUM-2006-CANCELLED PAGES(14-6-2011).pdf

502-mum-2006-claims(28-3-2007).pdf

502-MUM-2006-CLAIMS(AMENDED)-(14-6-2011).pdf

502-MUM-2006-CLAIMS(AMENDED)-(18-1-2011).pdf

502-MUM-2006-CLAIMS(GRANTED)-(1-9-2011).pdf

502-MUM-2006-CLAIMS(MARKED COPY)-(14-6-2011).pdf

502-MUM-2006-CLAIMS(MARKED COPY)-(18-1-2011).pdf

502-mum-2006-correspondence(15-5-2008).pdf

502-MUM-2006-CORRESPONDENCE(IPO)-(5-9-2011).pdf

502-mum-2006-correspondence-received-ver-130406.pdf

502-mum-2006-correspondence-received-ver-310306.pdf

502-mum-2006-correspondence-received-ver-310506.pdf

502-mum-2006-description (provisional).pdf

502-mum-2006-description(complete)-(28-3-2007).pdf

502-MUM-2006-DESCRIPTION(GRANTED)-(1-9-2011).pdf

502-mum-2006-form 1(13-4-2006).pdf

502-mum-2006-form 18(15-5-2008).pdf

502-mum-2006-form 2(28-3-2007).pdf

502-MUM-2006-FORM 2(GRANTED)-(1-9-2011).pdf

502-mum-2006-form 2(title page)-(28-3-2007).pdf

502-MUM-2006-FORM 2(TITLE PAGE)-(GRANTED)-(1-9-2011).pdf

502-MUM-2006-FORM 2(TITLE PAGE)-(PROVISIONAL)-(31-3-2006).pdf

502-MUM-2006-FORM 26(11-4-2007).pdf

502-mum-2006-form 5(28-3-2007).pdf

502-mum-2006-form-1.pdf

502-mum-2006-form-2.doc

502-mum-2006-form-2.pdf

502-mum-2006-form-26.pdf

502-mum-2006-form-3.pdf

502-MUM-2006-OTHER DOCUMENT(14-6-2011).pdf

502-MUM-2006-REPLY TO EXAMINATION REPORT(18-1-2011).pdf

502-MUM-2006-REPLY TO HEARING(14-6-2011).pdf

abstract1.jpg


Patent Number 248857
Indian Patent Application Number 502/MUM/2006
PG Journal Number 36/2011
Publication Date 09-Sep-2011
Grant Date 01-Sep-2011
Date of Filing 31-Mar-2006
Name of Patentee INDOCO REMEDIES LIMITED
Applicant Address Indoco House, 166 C.S.T.Road, Santacruz (East), Mumbai-400 098
Inventors:
# Inventor's Name Inventor's Address
1 VYAS KETAN DHANSUKHLAL Siddachal Phase VI, Building No.24, Flat No.1505-1506 Near Vasant Vihar Pokharan Road No.2 Thane (W) 400601
2 THOMAS SAJI Aangan Co-operative Housing society Plot No.3, Sector-5 Ghansoli, Navi Mumbai 400701
3 PATEL NITIN KUMAR MAGANBHAI Chhapar village Desai street, via.Amalsad, Taluka Gandevi District Navsari Gujarat 396 310
4 UBALE MILIND DIGAMBAR Triveni Housing Society, Plot No.5, Room No.5, Sector-16 New Panvel (West) Navi Mumbai - 410217
5 PANANDIKAR ADITI MILIND Durga Niwas, Nehru Road, Ville Parle, (East), Mumbai-400057
PCT International Classification Number A61K23/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA