FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PROCESS FOR PREPARING 2-((l,3-DIOXO-l,3-DIHYDRO-ISOINDOL-2-YL) METHYL)-l-PHENYL-CYCLOPROPANECARBOXYLIC ACID
DIETHYLAMIDE"
2. APPLICANT:
(a) NAME: CD?LA LTD.
(b) NATIONALITY: Indian Company incorporated under the
Companies Act, 1956
(c) ADDRESS: Mumbai Central, Mumbai - 400 008, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes 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 preparing 2-((l,3-dioxo-l,3-dihydro-isoindol-2-yl)methyl)-l-phenyl-cyclopropanecarboxylic acid diethylamide and to its application in the synthesis of milnacipran.
BACKGROUND AND PRIOR ART:
Milnacipran is a serotonin - norepinephrine reuptake inhibitor used in the treatment of fibromyalgia and was first disclosed in US 4478836.
2-((l,3-dioxo-l,3-dihydro-isoindol-2-yl)methyl)-l-phenyl-cyclopropanecarboxylic acid diethylamide (Formula I) is an important intermediate in the process for preparing milnacipran.

Various processes for preparing milnacipran are covered in prior art, of which some proceed through the intermediate of formula (I). US 5034541, EP 0377381B1, JP 2007023005 and WO 2010086394 disclose the process for preparation of milnacipran wherein the intermediate of formula (I) is obtained by treating the amide alcohol with thionyl chloride to get the chlorinated amide and then reacting it with a phthalimide, as depicted below in reaction Scheme 1:


EP 0200638B1 and second scheme of JP 2007023005 disclose the following process, depicted in Scheme 2, for preparing compound of formula (I):

In the prior art processes, thionyl chloride is mainly used for converting the alcohol compound into the chloride intermediate. Use of thionyl chloride is known to be unsuitable at industrial scale mainly due to its highly toxic nature.
Hence, an industrial process overcoming the use of thionyl chloride and providing 2-(l,3-
dioxo-l,3-dihydro-isoindol-2-ylmethyl)-l-phenyl-cyclopropane carboxylic acid
diethylamide in a cost-effective, environmentally friendly and safe manner is required.
OBJECT OF THE INVENTION:
The main object of the present invention is to provide an improved process for preparing 2-(l,3-dioxo-l,3-dihydro-isoindol-2-ylmethyl)-l-phenyl-cyclopropanecarboxylic acid diethylamide of formula (I).

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 simple, industrially acceptable and economical process for preparation of 2-((l,3-dioxo-l,3-dihydro-isoindol-2-yl)methyl)-I-phenyl-cyclopropane carboxylic acid diethylamide of formula (I).
In an aspect, the present invention provides an improved process for the preparation of 2-((1,3-dioxo-l ,3-dihydro-isoindol-2-yl)methy])-1 -pheny1-cyclopropane carboxylic acid diethylamide of formula I, which process comprises:
(a) reacting 2-((l,3-dioxo-l,3-dihydro-isoindol-2-yl)methyl)-l-phenyl-cyclopropane carboxylic acid of formula (II) with diethylamine in the presence of a coupling reagent;
(b) separating and isolating the product of formula (I).
In an embodiment, the coupling reagent used in the process of present invention is selected from l-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC), N,N'-diisopropyIcarbodiimide (DIC), l,l'-carbonyldiimidazole (CDI), 0-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), Hydroxybenzotriazole (HOBt) or mixtures thereof.
In another embodiment, the reaction of compound of formula (II) with diethylamine is carried out in the presence of a solvent. The solvent used in this reaction step of the process may be polar aprotic or non-polar. The polar aprotic solvent may be selected from dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide, acetonitrile or dimethyl sulfoxide. The non-polar solvent may be toluene, cyclohexane or diethylether.
For isolating 2-(l,3-dioxo-l,3-dihydro-isoindol-2-ylmethyl)-l-phenyl-cyclopropane carboxylic acid diethylamide the solvent used may be selected from water, n-heptane, diisopropyl ether.

The starting compound of formula (II) is obtained by following any process known in the art.
In an embodiment, the process of present invention is depicted below in Scheme 3,

Thus the present invention provides an efficient process for preparing 2-(l,3-dioxo-l,3-dihydro-isoindol-2-ylmethyl)-l-phenyl-cyclopropane carboxylic acid diethylamide of formula (I), which is used as an intermediate in the synthesis of milnacipran.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of present invention.
The present invention will now be further illustrated by reference to the following examples, which do not limit the scope of the invention any way.
Example 1:
80g of 2-((l,3-dioxo-l,3-dihydro-isoindol-2-yl)methyl)-l-phenyI-cyclopropanecarboxylic acid and 400ml of dichloromethane was stirred at 20-24°C. To this a solution of 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (85.6g) in dichloromethane (400ml) was added. Reaction mass was cooled and diethyl amine (83.12ml) was added at 15-20°C. Reaction mass was stirred at 23-28°C. Water was added using dropping funnel and the layers were separated. Organic layer was washed with water and distilled under vacuum. pH was adjusted to 0-1 using 50% HCI solution. Ethyl acetate was added and the organic layer was separated. Organic layer was distilled under vacuum. To the residue n-

heptane was added. The contents were stirred, filtered and dried at 40-45°C to give 2-((l,3-dioxo-l,3-dihydro-isoindol-2-yl)methyi)-l-phenyl-cyclopropane carboxylic acid diethylamide (Yield - 68.00%; HPLC purity - 90%).
Example 2:
400ml of dichloromethane was added to 80g of 2-((l,3-dioxo-l,3-dihydro-isoindol-2-yl)methyl)-l-phenyl-cyclopropanecarboxylic acid and contents were stirred at 20-24°C. Solution of 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (87.80g) in dichloromethane (400ml) was added. On cooling, diethyl amine (83.12ml) was added at 15-20°C and contents were stirred at 23-28°C. Water was added using dropping funnel and the layers were separated. Organic layer was washed with water and distilled under vacuum. n-heptane was added and contents were stirred, filtered and dried at 40-45°C to give 2-((l,3-dioxo-l,3-dihydro-isoindol-2-yl)methyI)-l-phenyl-cyclopropane carboxylic acid diethylamide (Yield - 98.47%; HPLC purity - 98%).
Example 3:
200ml of dimethyl formamide was added to 80g of 2-((l,3-dioxo-l,3-dihydro-isoindol-2-yl)methyl)-l-phenyl-cyclopropanecarboxylic acid. Reaction mass was stirred. To the clear solution a 1:1 mixture of l-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride and hydroxybenzotriazole in dimethyl formamide was added. The reaction contents were stirred at 20-24°C and cooled. Diethyl amine was added dropwise and contents were stirred at 23-28°C. After completion of reaction, the reaction mass was quenched with water. The solid obtained was filtered, washed with water and dried at 70-90°C to give 2-((l,3-dioxo-l,3-dihydro-isoindol-2-yl)methyl)-l-phenyl-cyclopropane carboxylic acid diethylamide (Yield - 111.25%; HPLC purity - 98%).
We Claims,

1. A process for preparing 2-(l,3-dioxo-l,3-dihydro-isoindol-2-ylmethyl)-l-phenyl-cyclopropane carboxylic acid diethylamide of formula (I) comprising:
(a) reacting 2-(l,3-dioxo-l,3-dihydro-isoindol-2-ylmethyl)-l -phenyl-cyclopropane carboxylic acid of formula (II) with diethylamine in the presence of a coupling reagent;
(b) separating and isolating the product of formula (I).

2. The process according to claim 1, wherein the coupling reagent is selected from l-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC), N,N'-diisopropylcarbodiimide (DIC), l,l'-carbonyIdiimidazole (CDI), 0-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), Hydroxybenzotriazole (HOBt) or mixtures thereof.
3. The process according to claim 1, wherein the reaction of compound of formula (II) with diethylamine is carried out in the presence of a solvent.
4. The process according to claim 1 and 3, wherein the solvent may be polar aprotic or non -polar.
5. The process according to claim 4, wherein the solvent is selected from dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene, cyclohexane or diethylether.
6. The process according to claim 1, wherein the separation and isolation of 2-(l,3-dioxo -l,3-dihydro-isoindol-2-ylmethyl)-l-phenyl-cyclopropane carboxylic acid diethylamide of formula (1) is carried out using water, n-heptane or diisopropyl ether.

7. The process for preparing milnacipran, which process comprises using 2-((l,3-dioxo-l,3-dihydro-isoindol-2-yl)methyl)-l-phenyl-cyclopropane carboxylic acid diethylamide of formula (1) prepared according to any of the preceding claims.