FORM-2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]
A novel process for preparation of N-carbamate of 3-oxopiperazine
APPLICANT:
CALYX CHEMICALS AND PHARMACEUTICALS LTD. 2, Marwah's Complex, Sakivihar Road, Sakinaka, Andheri (E), Mumbai-400 072, Maharashtra, India
Indian Company incorporated under the Companies Act 1956
The following specification particularly describes the invention and the manner in which it is performed.

FIELD OF INVENTION
The present invention relates to a novel one pot process for the preparation of N-carbamate of 3-oxopiperazine, particularly benzyl-3-oxopiperazine-l-carboxylate and tert-butyl-3-oxopiperazine-l-carboxylate, from ethylene diamine.
BACKGROUND OF INVENTION
Many chemical entities as disclosed in prior art like US20110207704 (Compound A),
WO2011044001 (Compound B), WO2009158394, WO2010090716,
WO2009098000, WO2008107176, WO2008076356, WO2008076754 (Compound
C), WO2009038974, WO2009078992, WO2008147831, WO2008008375
(Compound D), WO2007138351, WO2007002559, WO2007011809,
WO2007016496, WO2007122410, WO2007009741, WO200705 7742,
WO2006047504, WO2006002099, WO2006046031, WO2006047504,
WO2006002099, WO2005108391, WO2011140488 (Compound 1),
WO2011137049, WO2011121137 (Compound 2), WO2011062853 (Compound 3),
WO2011050284 (Compound 4), WO2011054841, WO2011053705,
WO2011041713, WO2011048082, WO2011026241, WO2011044001,
WO2010149684, WO2010138589, WO2010056875, WO2010131022,
WO2009145856, WO2009158394, WO2010039947 have shown promising activity against obesity, metabolic disorder, AIDS, cancer, cardiovascular disorder, tumor, rheumatoid arthritis, ACC-related disorders, allergic rhinitis, hypertension, Alzheimer's, schizophrenia, diabetes, pain, epilepsy and many more conditions.
These chemical entities have 3-oxopiperazine fragment which is build up using starting material N-carbamate of 3-oxopiperazine having formula I,


wherein, R represents a benzyl group or a tert-butyl group.
Also journal articles like Tetrahedron (2010), 66(18), 3370-3377; Bioorganic and Medicinal Chemistry Letters (2008), 18(22), 5904-5908; Journal of Medicinal Chemistry (2007), 50(26), 6706-6717; Bioorganic and Medicinal Chemistry Letters (2004), 14(9), 2073-2078; Bioorganic and Medicinal Chemistry Letters (2003), 13(4), 723-728; Journal of Medicinal Chemistry (2003), 46(5), 681-684; Bioorganic and Medicinal Chemistry Letters (2002), 12(6), 919-922; Bioorganic and Medicinal Chemistry Letters (2002), 12(7), 1103-1107; Journal of Medicinal Chemistry (1990), 33(9), 2590-5; Bioorganic and Medicinal chemistry letters (2011), 21(12), 3809-3812 have revealed chemical entities showing pharmaceutical activity which are prepared from N-carbamate of 3-oxopiperazine, particularly benzyl-3-oxopiperazine-1-carboxylate or tert-butyl-3-oxopiperazine-l-carboxylate.
Following are some of the structures of compounds having pharmaceutical activity prepared from benzyl-3-oxopiperazine-l-carboxylate



Some of the compounds prepared from tert-butyl-3-oxopiperazine-l-carboxylate have following structures

Hence, it can be concluded from above prior art that in building up all these chemical entities 3-oxopiperazine fragment is very important and therefore the demand for the starting material like N-carbamate of 3-oxopiperazine has increased. However, not many processes for preparation of this starting material are known in the prior art. Inventors of the present invention have successfully found out a novel, simple and industrially viable process for preparation of N-carbamate of 3-oxopiperazine.
OBJECT OF INVENTION
An object of the present invention is to provide a novel one pot process for the preparation of N-carbamate of 3-oxopiperazine from ethylene diamine. In particular the present invention relates to one pot process for the preparation of benzyl-3-oxopiperazine-1-carboxylate and tert-butyl-3-oxopiperazine-l-carboxylate.
Another object of the present invention is to provide a novel one pot process to yield highly pure N-carbamate of 3-oxopiperazine, particularly benzyl-3-oxopiperazine-l-carboxylate and tert-butyl-3-oxopiperazine-l-carboxylate.

It is yet another object of the present invention to provide simple and industrially viable one pot process for the preparation of benzyl-3-oxopiperazine-l-carboxylate, an important starting material for preparing chemical entities having pharmaceutical activity.
It is yet another object of the present invention to provide simple and industrially scalable one pot processes for the preparation of tert-butyl-3-oxopiperazine-l-carboxylate, an important starting material for preparing chemical entities having pharmaceutical activity.
SUMMARY OF INVENTION
According to an aspect of the present invention, there is provided a novel one pot process for the preparation of N-carbamate of 3-oxopiperazine of formula I, from ethylene diamine

wherein, R represents a benzyl group or a tert-butyl group comprising the steps of
A) reacting ethylene diamine with ethyl bromoacetate in an organic solvent in presence of a base at 25-30°C for 15-30 hours to obtain a reaction mixture
B) refluxing the reaction mixture for 6-10 hours and distilling off excess of solvent and ethylene diamine to obtain yellow-brown residue

C) adding an aqueous base to the yellow-brown residue and cooling the mixture to 15-20°C followed by adding solution of a reagent selected from benzylchloroformate or BOC-anhydride in a water immiscible aprotic solvent
D) stirring the reaction mixture obtained in step C) for 0.5-4 hours and separating an organic and an aqueous layers
E) isolating the desired N-carbamate of 3-oxopiperazine from the organic layer
obtained in step D).
In particular, the present invention relates to a novel one pot process for the preparation of benzyl-3-oxopiperazine-l-carboxylate of formula II (R is benzyl group) and tert-butyl-3-oxopiperazine-l-carboxylate of formula III (R is tert-butyl group).


DETAILED DESCRIPTION OF INVENTION
The present invention relates to a novel one pot process for the preparation of N-carbamate of 3-oxopiperazine from ethylene diamine. N-carbamates of 3-oxopiperazine is represented by formula I,

wherein, R represents a benzyl group or a tert-butyl group.
N-carbamate of 3-oxopiperazine is a starting material used in preparation of many chemical entities which have shown important pharmaceutical activity. These chemical entities are build up in specific reaction conditions, depending on these conditions the present invention gives varied choice of using N-carbamate of 3-oxopiperazine, particularly benzyl-3 -oxopiperazine-1 -carboxylate or tert-butyl-3 -oxopiperazine-1-carboxylate as a starting material for addition of 3-oxopiperazine fragment in the desired chemical entity. If the reaction conditions are acidic in nature then benzyl-3-oxopiperazine-1-carboxylate can be used as a starting material and if the reaction involves hydrogenation then the preferred starting material would be tert-butyl-3-oxopiperazine-l-carboxylate.
Thus, the present invention relates to novel one pot process for the preparation of benzyl-3-oxopiperazine-1-carboxylate of formula II (R is benzyl group) and tert-butyl-3-oxopiperazine-1-carboxylate of formula III (R is tert-butyl group) .


The novel one pot process of the present invention for the preparation of N-carbamate of 3-oxopiperazine of formula I, particularly benzyl-3-oxopiperazine-l-carboxylate (when R is benzyl group) and tert-butyl-3-oxopiperazine-l-carboxylate (when R is tert-butyl group), is as shown in the Scheme I below,

wherein, R represents a benzyl group or a tert-butyl group
In an aspect of the present invention, there is provided a novel one pot process for the preparation of N-carbamate of 3-oxopiperazine of formula I


wherein, R represents a benzyl group or a tert-butyl group comprising steps of
A) reacting ethylene diamine with ethyl bromoacetate in an organic solvent in presence of a base at 25-30°C for 15-30 hours to obtain a reaction mixture
B) refluxing the reaction mixture for 6-10 hours and distilling off excess of solvent and ethylene diamine to obtain yellow-brown residue
C) adding an aqueous base to the yellow-brown residue and cooling the mixture to 15-20°C followed by adding the solution of a reagent selected from benzylchloroformate or BOC-anhydride in a water immiscible aprotic solvent
D) stirring the reaction mixture obtained in step C) for 0.5-4 hours and separating an organic and an aqueous layers
E) isolating the desired N-carbamate of 3-oxopiperazine from the organic layer
obtained in step D).
Thus, in an aspect, the present invention particularly provides one pot process, as described above, for the preparation of benzyl-3-oxopiperazine-l-carboxylate of formula II (R is benzyl group) and tert-butyl-3-oxopiperazine-l-carboxylate of formula III (R is tert-butyl group).
In an embodiment of the present invention, the molar ratio of the ethylene diamine used with respect to ethyl bromoacetate is in the range of 2 to 10, preferably it is 5 to
7.

According to another embodiment of the present invention, the base used in step A) of the process is selected from alkali metal carbonates or alkali metal alkoxides wherein alkali metal carbonates like potassium carbonate, sodium carbonate are used and alkali metal alkoxides like sodium ethoxide, sodium methoxide are used, preferably the base used is potassium carbonate.
The molar ratio of the base used in step A) with respect to ethyl bromoacetate is in the range of 0.5 to 2.
The organic solvent used in step A) is selected from aromatic solvent, halogenated aprotic solvent or non-halogenated aprotic solvent wherein the aromatic solvent like toluene, xylene , the halogenated aprotic solvent like methylene chloride, ethylene chloride and the non-halogenated aprotic solvent like tetrahydrofuran, ethylacetate, acetonitrile, dimethylformamide, dimethylsulfoxide and acetone is used, preferably the organic solvent used is toluene.
The amount of organic solvent used with respect to ethyl bromoacetate is in range of 10 to 20 volumes.
According to another embodiment of the present invention, the aqueous base used in step C) of the process is selected from alkali metal carbonates or alkali metal hydroxide wherein alkali metal carbonates like potassium carbonate, sodium carbonate are used and the alkali metal hydroxides like sodium hydroxide, potassium hydroxides are used, preferably the aqueous base used is sodium carbonate.
The molar ratio of the aqueous base used with respect to ethyl bromoacetate is in the range of 1 to 5, preferably 2 to 4.

The amount of water used for preparing aqueous base, is in the range of 5 to 15 volumes with respect to ethyl bromoacetate.
According to yet another embodiment of the present invention, the molar ratio of benzyl chloroformate used in step C) of the process, with respect to ethyl bromoacetate is in the range of 0.5 to 3.
The molar ratio of BOC-anhydride used in step C) of the process, with respect to ethyl bromoacetate is in the range of 0.5 to 3.
The water immiscible aprotic solvent used in step C) of the present invention is selected from ethyl acetate, methylene chloride, tetrahydrofuran and acetonitrile, preferably ethyl acetate is used.
The amount of water immiscible aprotic solvent used is in the range of 5 to 15 volumes with respect to ethyl bromoacetate.
The N-carbamate of 3-oxopiperazine obtained by the process described in present invention has HPLC purity of 99% or more.
In other aspect of the present invention, N-carbamate of 3-oxopiperazine, particularly benzy 1-3-oxopiperazine-1 -carboxylate and tert-buty 1-3-oxopiperazine-1 -carboxylate is prepared by one pot process by avoiding the isolation of 3-oxopiperazine, compound of step A.
In yet another aspect, the scope of the present invention covers the preparation of 3-oxopiperazine by reacting ethylene diamine and ethyl bromoacetate in presence of toluene and potassium carbonate.

The details of the invention provided in the following example are given by the way of illustration only and should not be construed to limit the scope of the present invention
EXAMPLES
Example 1
One pot synthesis of benzvl-3-oxopiperazine-l-carboxylate
To the solution of 3.23 kg of ethylene diamine in 15 liters of toluene was added drop-wise solution of 1.5 kg of ethyl bromoacetate in 7.5 liters of toluene. The mixture was stirred for 22 hours at 25-30°C followed by addition of 1.24 kg of potassium carbonate. The mixture was again stirred for 6 hours at 25-30°C. The mixture was then refluxed at 100-105°C temperature for 8 hours followed by distilling off excess of solvent and ethylene diamine to obtain yellow-brown sticky residue. To the yellow-brown residue was added aqueous sodium carbonate (1.58 kg of sodium carbonate in 15 liters of water) and the mixture was cooled to 15-20°C and stirred for 0.5 hours. To this mixture at 15-20°C was added drop-wise solution of 1.02 kg of benzyl chloroformate in 15 liters of ethyl acetate. The mixture was then stirred at 25-30°C for 2 hours. After completion of reaction, organic and aqueous layers were separated. The organic layer thus obtained was washed with brine and then dried over sodium sulfate. The organic layer was then concentrated up to 7 liters followed by stirring it at 25-30°C for 1 hour. The solid product obtained was filtered and washed with ethyl acetate. The product was dried in oven at 60°C for 5-6 hours. Weight of product obtained: 820 gm Yield: 40% HPLC purity: 99.6%

Example 2
One pot synthesis of tcrt-butvl-3-oxopiperazine-l-carboxvlate
To the solution of 3.23 kg of ethylene diamine in 15 liters of toluene was added drop-wise solution of 1.5 kg of ethyl bromoacetate in 7.5 liters of toluene. The mixture was stirred for 22 hours at 25-30°C followed by addition of 1.24 kg of potassium carbonate. The mixture was again stirred for 6 hours at 25-30°C. The mixture was then refluxed at 100-105°C temperature for 8 hours followed by distilling off excess of solvent and ethylene diamine to obtain yellow-brown sticky residue. To the yellow-brown residue was added aqueous sodium carbonate (1.58 kg of sodium carbonate in 15 liters of water) and the mixture was cooled to 15-20°C and stirred for 0.5 hours. To this mixture at 15-20°C was added drop-wise solution of 2.348 kg of BOC-anhydride in 15 liters of ethyl acetate. The mixture was then stirred at 25-30°C for 2 hours. After completion of reaction, organic and aqueous layers were separated. The organic layer thus obtained was washed with brine and then dried over sodium sulfate. The organic layer was then concentrated up to 7 liters followed by stirring it at 25-30°C for 1 hour. The solid product obtained was filtered and washed with ethyl acetate. The product was dried in oven at 60°C for 5-6 hours. Weight of product obtained: 800 gm Yield: 44.5% HPLC purity: 99%

We claim
1. A novel one pot process for the preparation of N-carbamate of 3-oxopiperazine of formula I

wherein, R represents a benzyl group or a tert-butyl group comprising steps of
A) reacting ethylene diamine with ethyl bromoacetate in an organic solvent in presence of a base at 25-30°C for 15-30 hours to obtain a reaction mixture
B) refluxing the reaction mixture for 6-10 hours and distilling off excess of solvent and ethylene diamine to obtain yellow-brown residue
C) adding an aqueous base to the yellow-brown residue and cooling the mixture to 15-20°C followed by adding the solution of a reagent selected from benzylchloroformate or BOC-anhydride in a water immiscible aprotic solvent
D) stirring the reaction mixture obtained in step C) for 0.5-4 hours and separating an organic layer and an aqueous layer
E) isolating the desired N-carbamate of 3-oxopiperazine from the organic
layer obtained in step D)
2. The process as claimed in claim 1, wherein the desired N-carbamate of 3-oxopiperazine is benzyl-3-oxopiperazine-l-carboxylate of formula II (R is benzyl group) or tert-butyl-3-oxopiperazine-l-carboxylate of formula III (R is tert-butyl
group)


3. The process as claimed in claim 1, wherein the molar ratio of the ethylene diamine
used with respect to ethyl bromoacetate is in the range of 2 to 10, preferably it is 5 to
7
4. The process as claimed in claim 1, wherein the base used in step A) of the process is selected from alkali metal carbonates or alkali metal alkoxides wherein alkali metal carbonates like potassium carbonate, sodium carbonate are used and alkali metal alkoxides like sodium ethoxide, sodium methoxide are used, preferably potassium carbonate is used
5. The process as claimed in claim 1 or 4, wherein the molar ratio of the base used in step A) with respect to ethyl bromoacetate is in the range of 0.5 to 2
6. The process as claimed in claim 1, wherein the organic solvent used is selected from aromatic solvent, halogenated aprotic solvent or non-halogenated aprotic solvent wherein the aromatic solvent like toluene, the halogenated aprotic solvent like methylene chloride, ethylene chloride and the non-halogenated aprotic solvent like

tetrahydrofuran, ethylacetate, acetonitrile, dimethylformamide, dimethylsulfoxide and acetone is used, preferably toluene is used
7. The process as claimed in claim 1 or 6, wherein the amount of the organic solvent used with respect to ethyl bromoacetate is in range of 10 to 20 volumes
8. The process as claimed in claim 1, wherein the aqueous base used in step C) of the process is selected from alkali metal carbonates or alkali metal hydroxide wherein alkali metal carbonates like potassium carbonate, sodium carbonate are used and the alkali metal hydroxides like sodium hydroxide, potassium hydroxides are used, preferably sodium carbonate is used
9. The process as claimed in claim 1 or 8, wherein the molar ratio of the base used in step C) with respect to ethyl bromoacetate is in the range of 1 to 5, preferably 2 to 4
10 The process as claimed in claim 1, wherein the molar ratio of benzyl chloroformate used with respect to ethyl bromoacetate is in the range of 0.5 to 3
11. The process as claimed in claim 1, wherein the molar ratio of BOC-anhydride used with respect to ethyl bromoacetate is in the range of 0.5 to 3
12. The process as claimed in claim 1, wherein the water immiscible aprotic solvent used is selected from ethyl acetate, methylene chloride, tetrahydrofuran and acetonitrile, preferably it is ethyl acetate

13. The process as claimed in claim 1 or 12, , wherein the amount of water immiscible aprotic solvent used is in the range of 5 to 15 volumes with respect to ethyl bromoacetate.