DESC:FIELD OF INVENTION
The present disclosure relates to a process for the preparation of 1-amino-4-cyclopentylpiperazine.
BACKGROUND OF THE INVENTION AND PRIOR ART
The background information herein below relates to the present disclosure but is not necessarily prior art.
1-amino-4-cyclopentylpiperazine is an important pharmaceutical intermediate and is mainly used for preparing active pharmaceutical ingredients such as Rifamycin, Rifapentine and the like. 1-amino-4-cyclopentylpiperazine is represented as formula (I) below:

(I)
In the current state of the art, 1-amino-4-cyclopentylpiperazine is mostly prepared by reduction method. US4002752A filed in 1976 discloses synthesis of Rifamycin by means of condensing 3-formylrifamycin SV with the aminopiperazine intermediate of the formula , wherein Me is methyl, n is 3-6, g is 0,1,2 and R is lower alkyl. The synthesis of the said aminopiperazine reactant is accomplished by alkylation of N-nitrosopiperazine with an appropriate cycloalkyl bromide or chloride followed by reduction of the nitroso group with LiAlH4 to obtain the corresponding amino derivative. An alternative route involves nitrosation of an N-cycloalkylpiperazine followed by reduction of the nitroso group with LiAlH4.

Further, JPH0514709B2 filed in 1984, recites a process for synthesizing 1-amino-4-cyclopentylpiperazine by subjecting piperazine and cyclopentanone to a catalytic hydrogen reduction in the presence of a hydrogenation catalyst such as 2-50wt% Raney nickel or 0.1-20wt% Pd, in presence or absence of any solvent like toluene, etc.

However, in most of the conventional processes for the preparation of 1-amino-4-cyclopentylpiperazine, nitrosamine (NA)-contaminated substructures (nitroso structures) are found to be produced during reduction or hydrogenation reactions. When such 1-amino- 4-cyclopentylpiperazine is used as an intermediate to prepare the drugs Rifamycin or Rifapentine, then the nitrosamine impurity having highly carcinogenic properties is also carried into the final drug products. Further, it has been found that these nitrosamine impurities are not easy to remove. Therefore, it is required to have the pharmaceutical intermediate 1-amino-4-cyclopentylpiperazine without the formation of the nitrosamine impurity.

Although the prior art CN117186032A discloses the preparation method of the 1-amino-4-cyclopentyl piperazine intermediate without nitrosamine formation, however, such a process essentially employs ethylene oxide during the reaction which is not at all suitable for being used at industrial levels.
Therefore, there is a need to provide a process for the preparation of 1-amino-4-cyclopentylpiperazine that mitigates the aforementioned drawbacks or at least provides a useful alternative.
OBJECTS OF THE PRESENT INVENTION:
Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows:
It is an object of the present disclosure to ameliorate one or more problems of the background or to at least provide a useful alternative.
Another object of the present disclosure is to provide a process for the preparation of 1-amino-4-cyclopentylpiperazine.
Yet another object of the present disclosure is to provide a process for the preparation of 1-amino-4-cyclopentylpiperazine with comparatively better purity and yield.
Still another object of the present disclosure is to provide a simple, cost-effective, and environment-friendly process for the preparation of 1-amino-4-cyclopentylpiperazine.
Yet another object of the present disclosure is to provide a process for the preparation of 1-amino-4-cyclopentylpiperazine that is commercially scalable.
Other objects and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.
SUMMARY OF THE PRESENT INVENTION:
An aspect of the present invention provides an improved process for the preparation of 1-amino-4-cyclopentylpiperazine that comprises the steps of:
a) hydrogenating cyclopentanone with diethanolamine in a first fluid medium in the presence of a catalyst to obtain 2, 2’-(cyclopentylazanediyl) bis (ethan-1-ol) as below:
;
b) chlorinating said 2, 2’-(cyclopentylazanediyl) bis (ethan-1-ol) using a chlorinating agent in a second fluid medium to obtain N, N-bis (2-chloroethyl)cyclopentanamine hydrochloric acid as below:
; and
c) cyclizing said N, N-bis (2-chloroethyl)cyclopentanamine hydrochloric acid using an aqueous hydrazine hydrate (NH2-NH2) in a third fluid medium to obtain 1-amino-4-cyclopentylpiperazine as below:

BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS/ FIGURES:
Figure 1 (a) graphically illustrates the GCHS data that confirms the purity achieved for the synthesized compound I is 95-98%; Figure 1 (b) graphically illustrates the 1H NMR analysis data, confirming the formation of compound I of the present invention; Figure 1 (c) graphically illustrates the GCMS analysis data for the compound I.
Figure 2 (a) graphically illustrates the GCHS data for the process of synthesizing compound II; Figure 2 (b) graphically illustrates the 1H NMR analysis data, confirming the formation of compound II of the present invention; Figure 2 (c) graphically illustrates the GCMS analysis data for compound II.
Figure 3 (a) graphically illustrates the GCHS data for the process of synthesizing the final product 4-cyclopentylpiperazin-1-amine; Figure 3 (b) graphically illustrates the 1H NMR analysis data, confirming the formation of the title compound of the present invention i.e. 4-cyclopentylpiperazin-1-amine; Figure 3 (c) graphically illustrates the GCMS analysis data for the title compound of the present invention i.e. 4-cyclopentylpiperazin-1-amine.
DETAILED DESCRIPTION OF THE INVENTION:
The following description with reference to the accompanying drawings is provided to assist in a comprehensive understanding of exemplary embodiments of the invention. It includes various specific details to assist in that understanding but these are to be regarded as merely exemplary.
The present disclosure relates to a process for the preparation of 1-amino-4-cyclopentylpiperazine represented by formula (I) below:

(I)
Embodiments, of the present disclosure, will now be described herein. Embodiments are provided so as to thoroughly and fully convey the scope of the present disclosure to the person skilled in the art. Numerous details are set forth, relating to specific components, and methods, to provide a complete understanding of embodiments of the present disclosure. It will be apparent to the person skilled in the art that the details provided in the embodiments should not be construed to limit the scope of the present disclosure. In some embodiments, well-known processes, well-known apparatus structures, and well-known techniques are not described in detail.
The terminology used, in the present disclosure, is only for the purpose of explaining a particular embodiment and such terminology shall not be considered to limit the scope of the present disclosure. As used in the present disclosure, the forms "a,” "an," and "the" may be intended to include the plural forms as well, unless the context clearly suggests otherwise. The terms "comprises," "comprising," “including,” and “having,” are open-ended transitional phrases and therefore specify the presence of stated features, integers, steps, operations, elements, modules, units, and/or components, but do not forbid the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. The particular order of steps disclosed in the method and process of the present disclosure is not to be construed as necessarily requiring their performance as described or illustrated. It is also to be understood that additional or alternative steps may be employed.
As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed elements.
Further, as used herein, the term “GCHS” refers to headspace gas chromatography, which is a technique used to analyze volatile organic compounds (VOCs) and their concentrations.
Furthermore, as used herein, the term “GCMS” refers to Gas chromatography-mass spectrometry (GC–MS), which is a technique that combines gas chromatography and mass spectrometry to identify substances in a sample.
The terms first, second, third, etc., should not be construed to limit the scope of the present disclosure as the aforementioned terms may be only used to distinguish one element, component, region, layer, or section from another component, region, layer, or section. Terms such as first, second, third, etc., when used herein do not imply a specific sequence or order unless clearly suggested by the present disclosure.
In the conventional processes for the preparation of 1-amino-4-cyclopentylpiperazine, nitrosamine (NA)-contaminated substructures (N-nitroso derivatives) such as [1-methyl-4-nitrosopiperazine (MNP)], [N-nitroso cyclopentylpiperazine (CPNP)] have been reported to be produced during reduction or hydrogenation reactions. These impurities are highly carcinogenic. When such 1-amino- 4-cyclopentylpiperazine produced along with these harmful substructures is used as an intermediate for preparing important antibiotic drugs like Rifamycin or Rifapentine, then this N-nitrosamine impurity(ies) having highly carcinogenic properties gets carried into these final drug products as well. Further, it has been found that these nitrosamine impurities are not easy to remove. Therefore, it is required to produce the key pharmaceutical intermediate 1-amino-4-cyclopentylpiperazine without the formation of these nitrosamine impurities. Furthermore, some of the conventional processes employ ethylene oxide which is not at all suitable for being used at industrial levels.
The present disclosure thus envisages an improved process for the preparation of 1-amino-4-cyclopentylpiperazine, wherein such toxic nitrosamine impurities are advantageously not formed. The process of the present disclosure is simple, environment-friendly, and economical, and results in improved yield and higher purity of 1-amino-4-cyclopentylpiperazine.

An embodiment of the present invention provides an improved process for the preparation of 1-amino-4-cyclopentylpiperazine essentially devoid of nitrosamine impurity, that comprises the steps of:
a) hydrogenating cyclopentanone with diethanolamine in a first fluid medium in the presence of a catalyst to obtain 2, 2’-(cyclopentylazanediyl) bis (ethan-1-ol) as below:
;
b) chlorinating said 2, 2’-(cyclopentylazanediyl) bis (ethan-1-ol) using a chlorinating agent in a second fluid medium to obtain N, N-bis (2-chloroethyl)cyclopentanamine hydrochloric acid as below:
; and
c) cyclizing said N, N-bis (2-chloroethyl)cyclopentanamine hydrochloric acid using an aqueous hydrazine hydrate (NH2-NH2) in a third fluid medium to obtain 1-amino-4-cyclopentylpiperazine as below:

Further in accordance with the present invention, in step (a), hydrogenation of cyclopentanone with diethanolamine is carried out in a first fluid medium that is selected from any suitable protic or aprotic solvent, producing 2,2’-(cyclopentylazanediyl)bis(ethan-1-ol). Thus, in this step, the said first liquid medium used can include but is not limited to methanol, ethanol, butanol, isopropanol, and toluene.
The catalyst used in this step (a) can include any metal catalyst and is not limited to palladium on charcoal (Pd/C) or Raney Nickel (Ni).

Further, in accordance with the present invention, in step (b), said 2,2’-(cyclopentylazanediyl)bis(ethan-1-ol) formed is chlorinated by using a chlorinating agent in a second fluid medium to obtain a second reaction mixture comprising N, N-bis (2-chloroethyl) cyclopentanamine hydrochloric acid. The chlorinating agent used in this step can include but is not limited to thionyl chloride, phosphorous chloride, phosphorous oxychloride, and oxalyl chloride.

The second fluid medium used in this step (b) can include but is not limited to dichloromethane. Other known suitable fluid media such as chloroform, and ethylene chloride can also be used here.

Furthermore, in accordance with the present invention, in step (c), said N, N-bis (2-chloroethyl) cyclopentanamine hydrochloric acid is cyclized by using aqueous hydrazine hydrate (aq. NH2-NH2) in a third fluid medium to obtain 1-amino-4-cyclopentylpiperazine. In this step, the third fluid medium can include, but is not limited to ethanol. Other known suitable fluid media such as 2-proponaol, 1-butanol can also be used here.

An exemplary embodiment of the present disclosure further provides the schematic representation of the process for the preparation of 1-amino-4-cyclopentylpiperazine as illustrated in scheme A below:

The process as developed in the present invention thus advantageously results in the formation of the final product i.e. 1-amino-4-cyclopentylpiperazine devoid of any nitrosamine impurity. According to the USFDA (United States Food and Drug Administration), the acceptable intake limits for nitrosamine impurities MNP and CPNP for patients are only 0.16 parts per million (ppm) for MNP in rifampin and 0.1 ppm for CPNP in rifapentine. Therefore, the control strategies in terms of the preventive and corrective actions not only rely on the in-depth chemistry understanding of the nitrosamine formation during synthesis of the key intermediate 1-amino-4-cyclopentylpiperazine, but also depend on the suitable built-in concept of control limit criteria. Therefore, in such a scenario, if these important drugs can be produced without the presence of such harmful nitrosamine impurities, then that would be a significant achievement in this drug development landscape. The same has been successfully achieved by the present invention.

Further, in accordance with the present disclosure, the yield of 1-amino-4-cyclopentylpiperazine is in the range of 75-80%.

Furthermore, the process of the present disclosure employs diethanolamine and cyclopentanone as starting materials which are easily available and economical. Moreover, the currently developed process does not involve the use of any hazardous, toxic reagents like ethylene oxide that are difficult to handle at the industrial level.

The foregoing description of the embodiments has been provided for purposes of illustration and is not intended to limit the scope of the present disclosure. Individual components of a particular embodiment are generally not limited to that particular embodiment but are interchangeable. Such variations are not to be regarded as a departure from the present disclosure, and all such modifications are considered to be within the scope of the present disclosure.
The present disclosure is further described in light of the following non-limiting examples represented through certain experiments, which are set forth for illustration purposes only and not to be construed as limiting the scope of the disclosure. The following experiments are scalable to industrial/ commercial processes.
EXAMPLES:
EXAMPLE 1: Synthesis of Compound I or 2,2'-(cyclopentylazanediyl)bis(ethan-1-ol)
Example 1 illustrates a process for preparation of 2,2'-(cyclopentylazanediyl)bis(ethan-1-ol) [Compound I] from the starting materials cyclpentanone and diethanolamine according to step 1 of scheme A of the present invention.

In a cleaned and dried (10 L) autoclave, methanol (MeOH) (4.0 L, 10 vol) is added, and nitrogen gas is purged in at 25-30°C for 10-15 mins. Diethanolamine (400 g, 3.80 mole, 1.0 eq), cyclopentanone (480 g, 5.70 mole, 1.50 eq), and 10% Pd on Carbon (8.0 g, 2 % w/w) are added into the autoclave under stirring with nitrogen atmosphere at 25-30°C. The autoclave is then fitted and stirred for 5-10 mins at 25-30°C. This reaction mixture is degassed with H2 gas two times, then the autoclave is filled with 100 PSI of H2 gas at 25-30°C. The reaction mass is retained under 100 psi H2 pressure at 30°C for 4-6 hrs and disappearance of the diethanolamine is noted by GCHS data [as illustrated by the accompanying figure 1(a)].
Then the reaction mass from the autoclave is unloaded, followed by filtration through the celite bed under a nitrogen atmosphere and washing of the celite bed is done with MeOH (0.8 L, 2 vol). The collected filtrate mother liquor (MLR) is distilled off (at 45-50 °C) under reduced pressure to yield 650 g (97% yield) of the crude compound I i.e. 2,2'-(cyclopentylazanediyl)bis(ethan-1-ol). The said compound I is found to be pure with only 2-5% presence of unreacted cyclopentanone. Further, it has been observed that when the temperature of this crude product is raised to 85-90°C and nitrogen gas is bubbled in it with the help of a glass pipette for 5hrs, the cyclopentanone content is either not detected or is not more than 1.0 %. Such data is confirmed by GCHS data as illustrated in accompanying Figure 1(b).

Finally, when the reaction mass is cooled down to 25±5°C, and the nitrogen gas purging is stopped and unloaded, then the title compound I of step 1 i.e. 2,2'-(cyclopentylazanediyl)bis(ethan-1-ol) is produced and submitted for further analysis.

Results: Formation of Compound I of step 1 of Scheme A of the present invention is confirmed by the following analytical studies:
a) Accompanying Figure 1(a) graphically illustrates the GCHS data that confirms the above procedure, wherein the crude reaction mass when retained under 100 psi H2 pressure at 30°C for 4-6 hrs., the diethanolamine is found to have disappeared; and further shows that the purity achieved for the synthesized compound I is 95-98 %.
b) The 1H NMR analysis is also conducted and the data has been illustrated in accompanying figure 1 (b) which depicts: 1H NMR (400 MHz, DMSO): d 4.29-4.32 (bs, 2H, 2OH), 3.33-3.40 (t, 4H, 2CH2-O), 2.99-3.07(m, 1H, CH), 2.49-2.52 (t, 4H, 2CH2-N), 1.24-1.70 (m, 8H, 4CH2) ppm; thus, confirming formation of compound I of the present invention.
c) The GCMS analysis is further conducted, and the data is graphically illustrated in accompanying figure 1 (c) which depicts that the GCMS (m/z): calculated for C9H19NO2 is 173.30.

EXAMPLE 2: Synthesis of Compound II or N, N-bis (2-chloroethyl) cyclopentanamine hydrochloric acid
Example 2 illustrates a process for preparation of N,N-bis(2-chloroethyl)cyclopentanamine hydrochloric acid [Compound II] from the said compound I of example 1 above, according to step 2 of scheme A of the present invention.

Procedure:
A cleaned and dried (2 L) round-bottomed flask (RBF) is charged with thionyl chloride (SOCl2,1L, 2.5vol). The temperature is then cooled down to 0-5°C. Next compound I i.e. 2,2'-(cyclopentylazanediyl)bis(ethan-1-ol) of example 1 (400.0 g 2.30 mol, 1.0 eq) is slowly added to the reaction mass dropwise at 0-10°C. Such addition of reagents is exothermic in nature. Next, this reaction vessel is washed with dichloromethane (200 mL, 0.5 vol) and added to the reaction mass. The temperature of this reaction mass is then raised to 30-35°C and maintained for 24 hrs.
At this stage, the disappearance of the compound I [2,2'-(cyclopentylazanediyl) bis(ethan-1-ol)] is noted and the same is confirmed by GCHS data (as illustrated by the accompanying figure 2(a)].
The reaction mass is then concentrated under reduced pressure at 45-50°C to yield 522 g (91.68% yield) of the crude compound II i.e. N, N-bis (2-chloroethyl) cyclopentanamine hydrochloric acid.
Next, the reaction mass is cooled down to 25-30°C, and 2-propoanol (400 mL, 1 Vol) is charged into the reaction mass. Then the reaction mass is heated to 45-50°C and stirred for 1hr. The reaction mass is next cooled down to 35-40 °C, charged with n-heptane (800 mL, 2 Vol), and stirred at 35-40°C for 1hr. This reaction mass is again cooled down to 0-5°C and the same is maintained for 1hr. The solid obtained is then filtered and washed with n-Heptane (800 mL, 2 Vol), followed by suck drying. The filtered solid is then kept under a vacuum tray dryer at 50-55°C for 3 hrs. The compound II of step 2 of scheme A [N,N-bis(2-chloroethyl)cyclopentanamine hydrogen chloride] is thus formed and submitted for complete analytical assessment.

Results: Formation of Compound II of step 2 of Scheme A of the present invention is confirmed by the following analytical studies:
a) Accompanying Figure 2(a) graphically illustrates the GCHS data that confirms the above procedure, wherein the compound I [2,2'-(cyclopentylazanediyl) bis(ethan-1-ol)] which is the main reactant in this reaction is found to have completely disappeared.
b) The 1H NMR analysis is also conducted and the data has been illustrated in accompanying figure 2 (b) which depicts: 1H NMR (400 MHz, DMSO): 11.90 (bs, 1H, HCl), 4.06-4.08 (m, 4H, 2CH2-Cl), 3.75-3.76(m, 1H, CH), 3.49-3.52 (m, 4H, 2CH2-N), 1.50-1.99 (m, 8H, 4CH2) ppm; thus, confirming formation of compound II of the present invention.
c) The GCMS analysis is further conducted, and the data as graphically illustrated in accompanying figure 2 (c) which depicts that the GCMS (m/z): calculated for MF: C9H18Cl3N: is 246.16

EXAMPLE 3: Synthesis of the final compound i.e. the key pharmaceutical intermediate 4-cyclopentylpiperazin-1-amine:
Example 3 illustrates a process for preparation of the final compound i.e. the key pharmaceutical intermediate 4-cyclopentyl piperazin-1-amine from the said compound II of example 2 above, according to step 3 of scheme A of the present invention.

Procedure:
In a cleaned and dried (5L) RBF, ethanol (EtOH;1750.0 mL, 5.0 vol) and aq. hydrazine monohydrate (Aq. NH2-NH2; 455.07 mL, 1.30 Vol, 6.61eq) are added at 20-25ºC. The compound II [N,N-bis(2-chloroethyl)cyclopentamine hydrogen chloride] of example 2 above [350g;1.42 mol, 1.0 eq] is then charged to the reaction vessel, portionwise (4 portions) at 20-25°C. Each of such portions of compound II is added to the reaction vessel in a 5-10 mins time gap and a sudden exothermicity is noted during such addition and the temperature is raised to up to 45°C. The reaction mass is then stirred at 20-25ºC for 20-30 mins, followed by a rise in the temperature of the reaction mass to 45-50°C along with stirring for 2-4 hrs.
At this stage, the disappearance of the compound II [(N,N-bis(2-chloroethyl)cyclopentamine hydrogen chloride)] is noted and the same is confirmed by GCHS data (as illustrated by the accompanying figure 3(a)].
o Sampling procedure: Take 1.0 ml of the above reaction mass and the solvent is distilled off at 45°C under reduce pressure. The crude sample is then submitted to check the content of compound II. The reaction mass is next cooled down to 35ºC and separated the bottom layer (aq. layer). The organic layer is diluted with dichloromethane (3.5 L,10 vol.), stirred at 35ºC for 15-20 mins, and washed with 20% aq. sodium chloride solution (1.5 vol.). The organic and aqueous layers are then separated, and the organic layer is dried over anhydrous sodium sulphate (Na2SO4), filtered and the filtrate is taken for distillation at 45°C under vacuum to afford 260g of crude compound II.

o Crude product purification by high vacuum distillation (HVD): The crude compound II thus obtained above is next transferred into a 500 ml RBF fitted with an HVD set up of glassware. The mass temperature is gradually raised to 135-145°C. Next, the desired compound II i.e. the final intermediate 4-cyclopentylpiperazin-1-amine starts to collate at oil bath temperature 135-145 °C where the vapor temperature is 85°C-100 °C, under the noted vacuum of 700 -720 mm / Hg. The title compound 4-cyclopentyl piperazin-1-amine thus obtained being highly an air and moisture-sensitive product is essentially stored under N2 gas blanketing at 2-8oC. Such sample is submitted for a complete analysis and the following results are obtained.

Results: Formation of the final compound 4-cyclopentylpiperazin-1-amine of step 3 of Scheme A of the present invention (devoid of any nitrosamine impurity) is confirmed by the following analytical data:
a) Accompanying figure 3(a) graphically illustrates the GCHS data that confirms the above procedure, wherein the compound II [(N,N-bis(2-chloroethyl)cyclopentamine hydrogen chloride)] which is the main reactant in this reaction is found to have completely disappeared.
b) The 1H NMR analysis is also conducted and the data has been illustrated in accompanying figure 3 (b) which depicts: 1H NMR (400 MHz, CDCl3): 3.12-3.24 (bs, 2H, N-NH2), 2.62-3.00 (m, 4H, 2CH2-N-NH2), 2.47-2.59 (m, 1H, CH), 2.11-2.45 (m, 4H, 2CH2-N), 1.27-1.82 (m, 8H, 4CH2) ppm; thus, confirming the formation of the title compound of the present invention i.e. 4-cyclopentylpiperazin-1-amine.
c) The GCMS analysis is further conducted, and the data as graphically illustrated in accompanying figure 3 (c) which depicts that the GCMS (m/z): calculated for MF: C9H19N3: is 169.20
TECHNICAL ADVANCEMENT
The present disclosure described hereinabove has several technical advantages including, but not limited to, the realization of a process for the preparation of 1-amino-4-cyclopentylpiperazine, that
• is economical;
• is devoid of toxic reagents;
• does not form toxic impurities, specifically N-nitroso or nitrosamine impurities;
• commercially or industrially scalable; and
• provides 1-amino-4-cyclopentylpiperazine with a comparatively higher purity of 98-99% and a higher yield of 75-80%.
The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.
The foregoing description of the specific embodiments so fully reveals the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.
The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the invention to achieve one or more of the desired objects or results. While certain embodiments of the inventions have been described, these embodiments have been presented by way of example only and are not intended to limit the scope of the inventions. Variations or modifications to the formulation of this invention, within the scope of the invention, may occur to those skilled in the art upon reviewing the disclosure herein. Such variations or modifications are well within the spirit of this invention.
Any discussion of documents, acts, materials, devices, articles, or the like that has been included in this specification is solely for the purpose of providing a context for the disclosure. It is not to be taken as an admission that any or all of these matters form a part of the prior art base or were common general knowledge in the field relevant to the disclosure as it existed anywhere before the priority date of this application. The numerical values given for various physical parameters, dimensions, and quantities are only approximate values and it is envisaged that the values higher than the numerical value assigned to the physical parameters, dimensions, and quantities fall within the scope of the invention unless there is a statement in the specification to the contrary. While considerable emphasis has been placed herein on the specific features of the preferred embodiment, it will be appreciated that many additional features can be added and that many changes can be made in the preferred embodiment without departing from the principles of the disclosure. These and other changes in the preferred embodiment of the disclosure will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation. ,CLAIMS:WE CLAIM:
1. A process for preparation of 1-amino-4-cyclopentylpiperazine of formula I:

(I)
comprising the steps of:
a) hydrogenating cyclopentanone with diethanolamine in a first fluid medium in the presence of a catalyst to obtain 2, 2’-(cyclopentylazanediyl) bis (ethan-1-ol);
b) chlorinating said 2, 2’-(cyclopentylazanediyl) bis (ethan-1-ol) using a chlorinating agent in a second fluid medium to obtain N, N-bis(2-chloroethyl)cyclopentanamine hydrochloric acid; and
c) cyclizing said N, N-bis (2-chloroethyl)cyclopentanamine hydrochloric acid using an aqueous hydrazine hydrate (NH2-NH2) in a third fluid medium to obtain 1-amino-4-cyclopentylpiperazine.

2. The process as claimed in claim 1 is devoid of formation of any toxic nitrosamine impurity.
3. The process as claimed in claim 1, wherein the said first fluid medium of step (a) is selected from any protic or aprotic solvent.
4. The process as claimed in claim 3, wherein the said first fluid medium of step (a) is selected from a group consisting of methanol, ethanol, butanol, isopropanol, and toluene.
5. The process as claimed in claim 1, wherein the said catalyst of step (a) is a metal catalyst.
6. The process as claimed in claim 5, wherein the said catalyst of step (a) is palladium on charcoal (Pd/C) or Raney Ni.
7. The process as claimed in claim 1, wherein the said chlorinating agent of step (b) is selected from a group consisting of thionyl chloride, phosphorous chloride, phosphorous oxychloride, oxalyl chloride.
8. The process as claimed in claim 1, wherein the said second fluid medium of step (b) is selected from a group consisting of dichloromethane, chloroform, ethylene dichloride.
9. The process as claimed in claim 1, wherein the said third fluid medium of step (c) is selected from a group consisting of ethanol, 2-propanol, and butanol.
10. The process as claimed in claim 1 provides 1-amino-4-cyclopentylpiperazine having a purity of 98-99%.
11. The process as claimed in claim 1 provides 1-amino-4-cyclopentylpiperazine having a yield of 75-80 %.

Dated this 21st Day of February 2025

_______________________________
MOHAN RAJKUMAR DEWAN, IN/PA – 25
OF R. K. DEWAN & CO.
AUTHORIZED AGENT OF APPLICANT

TO,
THE CONTROLLER OF PATENTS
THE PATENT OFFICE, AT MUMBAI