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 INTERMEDIATES USED IN THE PREPARATION OF RIFAPENTINE

We, ARENE LIFE SCIENCES PRIVATE LIMITED,
a company incorporated under the companies act, 1956 having address at
#3 - 58, S.R.Chambers, Ramachandrapuram, Hyderabad - 502 032,
Telangana, INDIA.

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 the preparation of intermediate compounds used in the preparation of Rifapentine.

The present invention specifically relates to an improved process for the preparation of intermediate compounds of formula (I) used in the preparation of Rifapentine or its pharmaceutically acceptable salts.
Formula (I)

The present invention also specifically relates to an improved process for the preparation of intermediate compounds of formula (II) used in the preparation of Rifapentine or its pharmaceutically acceptable salts.
Formula (II)

The present invention also relates to an improved process for the preparation of intermediate compound of formula (Ia) used in the preparation of Rifapentine or its pharmaceutically acceptable salts.
Formula (Ia)

The present invention more specifically relates to an improved process for the preparation of intermediate compound of formula (IIa) used in the preparation of Rifapentine or its pharmaceutically acceptable salts.

Formula (IIa)

The present invention also relates to use of intermediate compounds in the preparation of Rifapentine or its pharmaceutically acceptable salts having the following structure of Formula (III).
Formula (III)

BACKGROUND OF THE INVENTION
Rifapentine is rifamycin derivative in which a cyclopentyl ring is substituted for a methyl group on the piperazinyl moiety, resulting a more lipophilic drug. The rifamycins exert their antibiotic activity by forming a stable complex with the DNA-dependent RNA polymerase of susceptible bacteria, suppressing the initiation of chain formation in RNA synthesis.

Chemically Rifapentine is known as 3-[[(4-cyclopentyl-1-piperazinyl)imino]methyl]­ rifamycin or

3-[N-(4-Cyclopentyl-1-piperazinyl)formimidoyl]rifamycin or

5,6,9,17,19,21-hexahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-8-[N-(4-cyclopentyl-1-piperazinyl)-formimidoyl]­2,7-(epoxypentadeca[1,11,13] trienimino)naphtho[2,1-b]furan-1,11(2H)-dione 21-acetate, and has the the following chemical structure.

US 3,342,810 disclose various Rifamycin SV derivatives that show a high degree of antibacterial activity, especially antitubercular activity, and low toxicity. US 4,002,752 disclose the condensation of Intermediate compound, 1-amino-(4-cyclopentyl-1-piperazine), with Rifamycin SV that produce Rifapentine, has broad spectrum of antibacterial utility and low toxicity. The process for the preparation of Rifapentine disclosed in this patent is as shown below:

The disadvantages associated with the above process are formation of genotoxic alkyl halides as well as Nitroso intermediates which might get carried forward into the final API. Catalytic reduction of nitroso group may lead to further cleavage of highly reactive hydrazine N-N bond that results poor yield of final product. In general, N-amino aza-aliphatic cyclic compounds are useful intermediates in the synthesis of pharmaceutical chemicals and such compounds are obtained by reduction of the corresponding N-nitroso derivatives using LiAlH4 in Et2O or THF (J. Org. Chem., 2000, 65, 2723) and TiCl3 in H2O.(J. Org. Chem., 1984, 49, 3470). However, high reactivity of hydrazine N-N bond may further cleave under catalytic hydrogenation leading to poor yield. Hence, in order to avoid the catalytic reduction process to improve yield, environmental friendly and purity of the compound, the development of selective method for the synthesis of 1-amino-(4-cyclopentyl-1-piperazine is needed.

US 2011/166121 disclose the intermediate cyclopentyl piperazine for the preparation of heterocyclic compound used as a platelet aggregation inhibitor. The process disclosed for the preparation of cyclopentyl piperazine is given below:

However, this process needs multiple steps. Mono Boc protection of piperazine require slow addition of Boc anhydride at low dilution and also results Boc protection at piperazine two N-atoms as impurity. Without Boc protection, the process leads further impurity of dicyclopentyl piperazine. Hence, both are undesirable for purity of compound and yield of the compound. Moreover, this reaction involves the usage of alkyl halides which are genotoxic impurities bound to be found in the final API.

BASF’s GB 1 396 985 (A) discloses the catalytic N-alkylation reaction, which involves the reaction of aliphatic or cycloaliphatic carbonyl compound with secondary amine in the presence of hydrogen and in the presence of hydrogenation catalyst comprising a mixture of Ag and Pd, to obtain an aliphatic or a cycloaliphatic tertiary amine. Koei Chemical’s JP H0514709 B2 (expired) discloses the catalytic hydrogen reduction reaction between piperazine and cyclopentanone in the presence or absence of a solvent and in the presence of a hydrogenation catalyst, Raney-Ni. The process disclosed for the preparation of cyclopentyl piperazine is given below:

This application does not disclose further conversion of N-cyclopentyl piperazine into 1-amino(4-cyclopentyl)-1-piperazine.

Yang et al., Chemistry of Heterocyclic Compounds, 2018, 54(8), 780-783 discloses the reduction of N-nitroso aza-aliphatic cyclocompounds employing zinc in pressurized CO2-H2O medium in presence of hydrogen donors H2O and NH4Cl, as shown below:

In order to avoid the catalytic reduction of nitroso group, amination process is carried out to alkyl substituted piperazine using sodium hypochloride, ammonia and ammonium chloride in the presence of a base.

US 3,254,952 A (expired) discloses the production of hydrazine compounds with amination reaction which comprises reacting a chloramine solution with ammonia / a primary amine / a secondary amine at a temperature between 20 °C and 140° C, in the presence of alkali metal hydroxide. US 7,879,999 B2 also discloses the similar process. The process disclosed for the preparation of secondary amine is given below:

However, this patent application neither enables nor discloses use of cycloalkyl substituted secondary amines for amination.

In order to improve the yield and selective amination, usage of environmental friendly reagents, alkyl halide free, N-nitrosamine impurities free and product purity, different methods have been tried for these two steps of alkylation and amination to come-up with novel amination technique for the preparation of rifapentine intermediate, 1-amino 4-cycopentyl piperazine.

The present inventors have surprisingly found new improved process for rifapentine intermediate synthesis, that involve N-alkylation and N-amination reactions for piperazine carried out simultaneously to avoid metal catalytic reduction process in order to achieve high yield by avoiding further cleavage of highly reactive hydrazine N-N bond. Further, the process does not involve formation of any genotoxic alkyl halides and N-nitrosamine impurities in the final product, i.e., rifapentine. There are very often incidents that rifapentine drug are recalled due to the presence of genotoxic impurities in the product. (10/29/2020: UPDATE - FDA not objecting to rifapentine with CPNP at or below 20 ppm remaining on the market: FDA) https://pubmed.ncbi.nlm.nih.gov/35722783/ )

The process of the present invention not only avoids the use of highly toxic reagents, unstable and/or expensive reagents, but also leads to the desire product, in shorter reaction times and with higher productivity and 98% purity than prior art processes. These features make the process of the invention cost-efficient making the process highly suitable for industrial scale up production.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an improved process for the preparation of intermediate compounds used in the preparation of Rifapentine.

Another objective of the present invention is to provide an improved process for the preparation of intermediate compounds of formula (Ia) used in the preparation of Rifapentine or its pharmaceutically acceptable salts.

Formula (Ia)
Yet another preferred objective of the present invention is to provide an improved process for the preparation of intermediate compound of formula (IIa) used in the preparation of Rifapentine or its pharmaceutically acceptable salts.

Formula (IIa)

Still another preferred objective of the present invention is to provide use of intermediate compounds in the preparation of Rifapentine or its pharmaceutically acceptable salts having the following structure of Formula (III).
Formula (III)

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of intermediate compound of formula (II)

Formula (II)

wherein R1 and R2, independently from each other, are hydrogen, a saturated straight or branched alkyl groups having from 1 to 6 carbon atoms, or when taken together, are a saturated straight or branched alkane group having from 5-12 carbon atoms which completes a saturated cyclic ring having from substituted or unsubstituted 5-7 members; with the exception both R1 and R2 are not hydrogen and the process comprises converting the intermediate compound of Formula (I)
Formula (I)

using amination process in suitable solvent to produce the intermediate compound of Formula (II).

In another embodiment the present invention provides an improved process for the preparation of intermediate compound of formula (IIa)
Formula (IIa)

converting the intermediate compound of Formula (Ia)
Formula (Ia)

using sodium hypochloride and ammonia mixture in suitable solvent to produce the intermediate compound of Formula (IIa).

In another embodiment the present invention provides an improved process for the preparation of intermediate compound of formula (II)
Formula (II)

wherein R1 and R2, independently from each other, are hydrogen,a saturated straight or branched alkyl groups having from 1 to 6 carbon atoms, or when taken together, are a saturated straight or branched alkane group having from 5-12 carbon atoms which completes an saturated cyclic ring having from substituted or unsubstituted 5-7 members; with the exception both R1 and R2 are not hydrogen and the process comprises the steps of
a) providing Piperazine of formula (IV)
Formula (IV)

and reacting with compound of Formula (V)
Formula (V)

where R1, R2 represents are as defined above; in the presence of a hydrogenation catalyst and under hydrogen atmosphere, in suitable polar solvent to obtain an intermediate compound of Formula (I),
Formula (I)

b) converting the intermediate compound of Formula (I) using amination process in suitable solvent to produce the intermediate compound of Formula (II).

In another embodiment, the present invention specifically provides an improved process for the preparation of intermediate compound of Formula (IIa)
Formula (IIa)
which comprises :

a) providing piperazine compound of Formula (IV)
Formula (IV)

and reacting with compound of Formula (Va)
Formula (Va)

in the presence of a hydrogenation catalyst and under hydrogen atmosphere, in suitable polar solvent to obtain an intermediate compound of Formula (Ia),

Formula (Ia)

b) converting the intermediate compound of Formula (Ia) using sodium hypochloride and ammonia mixture in suitable solvent to produce the intermediate compound of Formula (IIa).

In yet another embodiment, the present invention specifically provides an improved process for the preparation of intermediate compound of Formula (IIa)
Formula (IIa)
which comprises :

a) providing piperazine compound of Formula (IV)
Formula (IV)

and reacting with compound of Formula (Va)
Formula (Va)

in the presence of a Raney-Ni catalyst in suitable polar solvent and under hydrogen atmosphere at below 4 Kg pressure to obtain an intermediate compound of Formula (Ia),

Formula (Ia)

b) converting the intermediate compound of Formula (Ia) using sodium hypochloride and ammonia mixture in suitable solvent to produce the intermediate compound of Formula (IIa),
Formula (IIa)

In still another embodiment, the present invention also provides an improved process for the preparation of Rifapentine or rifamycin derivatives or its pharmaceutically acceptable salts of Formula (IIIa)

Formula (IIIa)

using compound of formula (II) prepared by a process of the present invention.

In still another embodiment, the present invention provides a process for the preparation of Rifapentine or its pharmaceutically acceptable salts compound of Formula (III).

Formula III

using compound of Formula (IIa) prepared by a process of the present invention.

DETAILED DESCRIPTION OF THE INVENTION
The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

In a specific embodiment, the reaction of compound of Formula (IV) with compound of Formula (V) is carried out in presence of a hydrogenation catalyst, hydrogen atmosphere, and in suitable organic polar solvent. After completion of the reaction, the compound of Formula (I) is added with an base and extracted with an appropriate solvent or mixture of solvents. The reaction may be carried out at a temperature in the range of 0 °C to room temperature for a duration of 1 to 15 hours. Further, N-amination for the compound of formula (I) is carried out using NaOCl, ammonia and NH4Cl in the presence of base at lower temperatures.

In formula (V), R1 and R2 as used herein are selected from hydrogen, the lower saturated straight or branched alkyl groups from 1-6 C atoms used in the present invention is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, tertiary pentyl, hexyl, isohexyl, tert.hexyl wherein R1 and R2 are independent from each other. For R1 and R2 are together represent cyclic ring having from substituted or un-substituted 5-7 members used in the present invention is cyclopentyl, cyclohexyl, cycloheptyl, 2-methyl cyclopentane,

Catalytic hydrogenation as used herein is selected from the reducing agents used in the present invention is selected from Raney-Ni, NaBH4, NaBH3CN, LiAlH4.

The reaction of compound of Formula (IV) with compound of Formula (V) or Formula (Va) is carried out in suitable organic polar solvent. Organic polar solvent as used herein is selected from alcohol solvents, chlorinated solvents, acetic acid, ethanol, isopropanol, dichloroethane, toluene, cyclohexane or its mixture.

The alkylation reaction of compound of Formula (IV) with compound of Formula (V), reagents addition should be done at room temperature, thereafter the temperature is raised from room temperature to 40 0C. After completed the reaction, the reaction mass was taken into water, base and extracted the product using dichloromethane.

N-amination of compound of Formula (I) and Formula (Ia) is carried out using hydrazine preparation process. Sodium hypochloride slowly added to aq. Ammonia at 0 °C and stirring continued for 1 hour. After completion of stirring the reaction mixture slowly added to N-cyclopentyl piperazine 1-2 hours at room temperature and stirred for 2 hrs. The reaction is carried out at lower temperature of 0 °C for a period of 2 to 4 hours. After completion of the reaction, the reaction mass is extracted with dichloromethane.

In yet another embodiment, the addition of NaOCl and ammonia mixture to N-cyclopentyl piperazine used in the present invention is done in the range of 1-2 hours.

In yet another embodiment, the base used in the present invention are not limited to bases inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide.

In yet another embodiment, solvents used in the present invention are selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like; “esters such as ethyl acetate; "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane haloalkanes such as dichloromethane, 1,2-dichloroethane and chloroform, and/or mixtures thereof.

The term “salts” as used herein refers to salts which are known to be non-toxic and are commonly used in the pharmaceutical literature. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenylsubstituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, beta-hydroxybutyrate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, lactate, maleate, hydroxymaleate, malonate, mesylate, nitrate, oxalate, phthalate, phosphate, monohydro genphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propionate, phenylpropionate, salicylate, succinate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like.

In another preferred embodiment, a process for the preparation of compound of Formula (IIa) which yields the compounds with high chemical purity.

In yet another preferred embodiment, the present invention provides use of intermediate compounds of Formula (IIa) in the preparation of Rifapentine or its salts. The intermediates formed in the present invention may or may not be isolated. Any of the above reactions may be carried out in-situ reactions to obtain intermediate compound of Formula (IIa).

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES
Example 1: Preparation of N-cyclopentyl piperazine:
Cyclopentanone (130 g, 1.477 mol) was added to a solution of Piperazine (100 g, 1.162 mol) in methanol (300 L, 3 Vol) at room temperature. To this catalytic amount of acetic acid (1mL) and Raney nickel (15 g, 15% w/w) was added at room temperature. The resulting reaction mass was stirred at 35-40 0C for 12 hours under the hydrogen atmosphere at below 4 kg pressure. The progress of the reaction was monitored by TLC. After completion of reaction, filter the reaction mass over cellite bed and layer was concentrated. The resulting crude residue was taken in water (500 mL, 5 Vol) , 40-50% aq.sodium hydroxide (100 mL) and extracted product using 3 X 500 mL dichloromethane. The combined layer was concentrated to afford the product in 140 g (78%) as yellow oil with more than 97% purity by GC.

Example 2: Preparation of N-cyclohexyl piperazine:
Cyclohexanone (145 g, 1.477 mol) was added to a solution of Piperazine (100 g, 1.162 mol) in methanol (350 mL, 3.5 Vol) at room temperature. To this catalytic amount of acetic acid (1mL) and Raney nickel (15 g, 15% w/w) was added at room temperature. The resulting reaction mass was stirred at 35-40 0C for 12 hours under the hydrogen atmosphere at below 4 kg pressure. The progress of the reaction was monitored by TLC. After completion of reaction, filter the reaction mass over Cellite bed and layer was concentrated. The resulting crude residue was taken in water (500 mL, 5 Vol) , 40-50% aq.sodium hydroxide (100 mL) and extracted product using 3 X 500 mL dichloromethane. The combined layer was concentrated to afford the product in 150 g (80%) as yellow oil with more than 96% purity by GC.

Example 3: Preparation of N-cycloheptyl piperazine:
Cycloheptanone (165.5 g, 1.477 mol) was added to a solution of Piperazine (100 g, 1.162 mol) in methanol (400 mL, 4 Vol) at room temperature. To this catalytic amount of acetic acid (1mL) and Raney nickel (15 g, 15% w/w) was added at room temperature. The resulting reaction mass was stirred at 35-40 0C for 12 hours under the hydrogen atmosphere at below 4 kg pressure. The progress of the reaction was monitored by TLC. After completion of reaction, filter the reaction mass over Cellite bed and layer was concentrated. The resulting crude residue was taken in water (500 mL, 5 Vol) , 40-50% aq.sodium hydroxide (100 mL) and extracted product using 3 X 500 mL dichloromethane. The combined layer was concentrated to afford the product in 174 g (82%) as yellow oil with more than 98% purity by GC.

Example 4: Preparation of N-cyclobutyl piperazine:
Cyclobutanone (103.5 g, 1.477 mol) was added to a solution of Piperazine (100 g, 1.162 mol) in methanol (300 mL, 3 Vol) at room temperature. To this catalytic amount of acetic acid (1mL) and Raney nickel (15 g, 15% w/w) was added at room temperature. The resulting reaction mass was stirred at 35-40 0C for 12 hours under the hydrogen atmosphere at below 4 kg pressure. The progress of the reaction was monitored by TLC. After completion of reaction, filter the reaction mass over Cellite bed and layer was concentrated. The resulting crude residue was taken in water (500 mL, 5 Vol) , 40-50% aq.sodium hydroxide (100 mL) and extracted product using 3 X 500 mL dichloromethane. The combined layer was concentrated to afford the product in 122 g (75%) as yellow oil with more than 95% purity by GC.

Example 5: Preparation of N-cyclopropyl piperazine:
Cyclopropanone (83 g, 1.477 mol) was added to a solution of Piperazine (100 g, 1.162 mol) in methanol (300 mL, 3 Vol) at room temperature. To this catalytic amount of acetic acid (1mL) and Raney nickel (15 g, 15% w/w) was added at room temperature. The resulting reaction mass was stirred at 35-40 0C for 12 hours under the hydrogen atmosphere at below 4 kg pressure. The progress of the reaction was monitored by TLC. After completion of reaction, filter the reaction mass over Cellite bed and layer was concentrated. The resulting crude residue was taken in water (500 mL, 5 Vol) , 40-50% aq.sodium hydroxide (100 mL) and extracted product using 3 X 500 mL dichloromethane. The combined layer was concentrated to afford the product in 113 g (77%) as yellow oil with more than 95% purity by GC.

Example 6: Preparation of N-methyl piperazine:
Paraformaldehyde (45 g, 1.477 mol) was added to a solution of Piperazine (100 g, 1.162 mol) in methanol (300 mL, 3 Vol) at room temperature. To this catalytic amount of acetic acid (1mL) and Raney nickel (15 g, 15% w/w) was added at room temperature. The resulting reaction mass was stirred at 35-40 0C for 12 hours under the hydrogen atmosphere at below 4 kg pressure. The progress of the reaction was monitored by TLC. After completion of reaction, filter the reaction mass over Cellite bed and layer was concentrated. The resulting crude residue was taken in water (500 mL, 5 Vol) , 40-50% aq.sodium hydroxide (100 mL) and extracted product using 3 X 500 mL dichloromethane. The combined layer was concentrated to afford the product in 81 g (70%) as yellow oil with more than 98% purity by GC.

Example 7: Preparation of N-ethyl piperazine:
Acetaldehyde (65 g, 1.477 mol) was added to a solution of Piperazine (100 g, 1.162 mol) in methanol (300 mL, 3 Vol) at room temperature. To this catalytic amount of acetic acid (1mL) and Raney nickel (15 g, 15% w/w) was added at room temperature. The resulting reaction mass was stirred at 35-40 0C for 12 hours under the hydrogen atmosphere at below 4 kg pressure. The progress of the reaction was monitored by TLC. After completion of reaction, filter the reaction mass over Cellite bed and layer was concentrated. The resulting crude residue was taken in water (500 mL, 5 Vol) , 40-50% aq.sodium hydroxide (100 mL) and extracted product using 3 X 500 mL dichloromethane. The combined layer was concentrated to afford the product in 100 g (76%) as yellow oil with more than 98% purity by GC.

Example 8: Preparation of N-isopropyl piperazine:
Acetaldehyde (86 g, 1.477 mol) was added to a solution of Piperazine (100 g, 1.162 mol) in methanol (300 mL, 3 Vol) at room temperature. To this catalytic amount of acetic acid (1mL) and Raney nickel (15 g, 15% w/w) was added at room temperature. The resulting reaction mass was stirred at 35-40 0C for 12 hours under the hydrogen atmosphere at below 4 kg pressure. The progress of the reaction was monitored by TLC. After completion of reaction, filter the reaction mass over Cellite bed and layer was concentrated. The resulting crude residue was taken in water (500 mL, 5 Vol) , 40-50% aq.sodium hydroxide (100 mL) and extracted product using 3 X 500 mL dichloromethane. The combined layer was concentrated to afford the product in 116 g (78%) as yellow oil with more than 98% purity by GC.

Example 9: Preparation of N-isobutyl piperazine:
2-butanone (106 g, 1.477 mol) was added to a solution of Piperazine (100 g, 1.162 mol) in methanol (300 mL, 3 Vol) at room temperature. To this catalytic amount of acetic acid (1mL) and Raney nickel (15 g, 15% w/w) was added at room temperature. The resulting reaction mass was stirred at 35-40 0C for 12 hours under the hydrogen atmosphere at below 4 kg pressure. The progress of the reaction was monitored by TLC. After completion of reaction, filter the reaction mass over Cellite bed and layer was concentrated. The resulting crude residue was taken in water (500 mL, 5 Vol) , 40-50% aq.sodium hydroxide (100 mL) and extracted product using 3 X 500 mL dichloromethane. The combined layer was concentrated to afford the product in 132 g (80%) as yellow oil with more than 98% purity by GC.

Example 10: Preparation of N-cyclopentyl piperazine:
Cyclopentanone (130 g, 1.477 mol) was added to a solution of Piperazine (100 g, 1.162 mol) in Ethanol (300 mL, 3 Vol) at room temperature. To this catalytic amount of acetic acid (1mL) and Raney nickel (15 g, 15% w/w) was added at room temperature. The resulting reaction mass was stirred at 35-40 0C for 12 hours under the hydrogen atmosphere at below 4 kg pressure. The progress of the reaction was monitored by TLC. After completion of reaction, filter the reaction mass over Cellite bed and layer was concentrated. The resulting crude residue was taken in water (500 mL, 5 Vol) , 40-50% aq.sodium hydroxide (100 mL) and extracted product using 3 X 500 mL dichloromethane. The combined layer was concentrated to afford the product in 136 g (76%) as yellow oil with more than 97% purity by GC.

Example 11: Preparation of N-cyclopentyl piperazine:
Cyclopentanone (130 g, 1.477 mol) was added to a solution of Piperazine (100 g, 1.162 mol) in IPA (300 mL, 3 Vol) at room temperature. To this catalytic amount of acetic acid (1mL) and Raney nickel (15 g, 15% w/w) was added at room temperature. The resulting reaction mass was stirred at 35-40 0C for 12 hours under the hydrogen atmosphere at below 4 kg pressure. The progress of the reaction was monitored by TLC. After completion of reaction, filter the reaction mass over Cellite bed and layer was concentrated. The resulting crude residue was taken in water (500 mL, 5 Vol) , 40-50% aq.sodium hydroxide (100 mL) and extracted product using 3 X 500 mL dichloromethane. The combined layer was concentrated to afford the product in 141.5 g (79%) as yellow oil with more than 97% purity by GC.

Example 12: Preparation of N-cyclopentyl piperazine:
Cyclopentanone (130 g, 1.477 mol) was added to a solution of Piperazine (100 g, 1.162 mol) in n-butanol (300 mL, 3 Vol) at room temperature. To this catalytic amount of acetic acid (1mL) and Raney nickel (15 g, 15% w/w) was added at room temperature. The resulting reaction mass was stirred at 35-40 0C for 12 hours under the hydrogen atmosphere at below 4 kg pressure. The progress of the reaction was monitored by TLC. After completion of reaction, filter the reaction mass over Cellite bed and layer was concentrated. The resulting crude residue was taken in water (500 mL, 5 Vol) , 40-50% aq.sodium hydroxide (100 mL) and extracted product using 3 X 500 mL dichloromethane. The combined layer was concentrated to afford the product in 134.5 g (75%) as yellow oil with more than 97% purity by GC.

Example 13: Preparation of N-cyclopentyl piperazine:
Cyclopentanone (130 g, 1.477 mol) was added to a solution of Piperazine (100 g, 1.162 mol) in Ethyl acetate (300 mL, 3 Vol) at room temperature. To this catalytic amount of acetic acid (1mL) and Raney nickel (15 g, 15% w/w) was added at room temperature. The resulting reaction mass was stirred at 35-40 0C for 12 hours under the hydrogen atmosphere at below 4 kg pressure. The progress of the reaction was monitored by TLC. After completion of reaction, filter the reaction mass over Cellite bed and layer was concentrated. The resulting crude residue was taken in water (500 mL, 5 Vol) , 40-50% aq.sodium hydroxide (100 mL) and extracted product using 3 X 500 mL dichloromethane. The combined layer was concentrated to afford the product in 132.5 g (74%) as yellow oil with more than 97% purity by GC.

Example 14: Preparation of N-cyclopentyl piperazine:
Cyclopentanone (130 g, 1.477 mol) was added to a solution of Piperazine (100 g, 1.162 mol) in MDC (300 mL, 3 Vol) at room temperature. To this catalytic amount of acetic acid (1mL) and Raney nickel (15 g, 15% w/w) was added at room temperature. The resulting reaction mass was stirred at 35-40 0C for 12 hours under the hydrogen atmosphere at below 4 kg pressure. The progress of the reaction was monitored by TLC. After completion of reaction, filter the reaction mass over Cellite bed and layer was concentrated. The resulting crude residue was taken in water (500 mL, 5 Vol) , 40-50% aq.sodium hydroxide (100 mL) and extracted product using 3 X 500 mL dichloromethane. The combined layer was concentrated to afford the product in 131 g (73%) as yellow oil with more than 97% purity by GC.

Example-15: Preparation of 4-cyclopentylpiperazine-1-amine:
12% solution of sodium hypochloride (1200 mL) was slowly added to 8.2% aq. ammonia (402 mL) at 0 °C. After stirring the reaction mass for 1 hour, reaction mixture was slowly added to N-cyclopentyl piperazine (100 g, 0.65 mol) at room temperature and stirred for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, 50% aq. Sodium hydroxide (20 mL) added to the reaction mass and extracted with 2X500 mL dichloromethane. The combined layer was concentrated and purified by high vacuum distillation to afford the product as wax like solid 70 g (65%) with more than 98% purity by GC. ,CLAIMS:WE CLAIM
1. An improved process for the preparation of intermediate compound of formula (II)
Formula (II)

wherein R1 and R2, independently from each other, are hydrogen, a saturated straight or branched alkyl groups having from 1 to 6 carbon atoms, or when taken together, are a saturated straight or branched alkane group having from 5-12 carbon atoms which completes a saturated cyclic ring having from substituted or unsubstituted 5-7 members; with the exception both R1 and R2 are not hydrogen and the process comprises converting the intermediate compound of Formula (I)
Formula (I)

using amination process in suitable solvent to produce the intermediate compound of Formula (II).

2. The process as claimed in claim 1, wherein the N-amination of compound of Formula (I) is carried out using hydrazine preparation process.

3. The process as claimed in claim 1, wherein the hydrazine preparation process involves use of Sodium hypochloride and aq. Ammonia.

4. The process as claimed in claim 1, wherein the process comprises preparation of intermediate compound of formula (IIa)
Formula (IIa)

converting the intermediate compound of Formula (Ia)
Formula (Ia)

using sodium hypochloride and ammonia mixture in suitable solvent to produce the intermediate compound of Formula (IIa).

5. The process as claimed in claim 1, wherein the process comprises preparation of intermediate compound of formula (II) which comprises
a) providing Piperazine of formula (IV)
Formula (IV)

and reacting with compound of Formula (V)
Formula (V)

where R1 and R2, independently from each other, are hydrogen, a saturated straight or branched alkyl groups having from 1 to 6 carbon atoms, or when taken together, are a saturated straight or branched alkane group having from 5-12 carbon atoms which completes a saturated cyclic ring having from substituted or unsubstituted 5-7 members; with the exception both R1 and R2 are not hydrogen in the presence of a hydrogenation catalyst and under hydrogen atmosphere, in suitable polar solvent to obtain an intermediate compound of Formula (I),
Formula (I)

b) converting the intermediate compound of Formula (I) using amination process in suitable solvent to produce the intermediate compound of Formula (II).

6. The process as claimed in claim 3, wherein the process comprises preparation of intermediate compound of formula (IIa) which comprises
Formula (IIa)
which comprises :

a) providing piperazine compound of Formula (IV)
Formula (IV)

and reacting with compound of Formula (Va)
Formula (Va)

in the presence of a hydrogenation catalyst and under hydrogen atmosphere, in suitable polar solvent to obtain an intermediate compound of Formula (Ia),
Formula (Ia)

b) converting the intermediate compound of Formula (Ia) using sodium hypochloride and ammonia mixture in suitable solvent to produce the intermediate compound of Formula (IIa).

7. The process as claimed in claims 3 and 4, wherein the hydrogenation catalyst is selected from Raney-Ni, NaBH4, NaBH3CN, LiAlH4.

8. The process as claimed in claims 1 to 7, wherein solvents used are selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like; “esters such as ethyl acetate; "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane; “haloalkanes” such as dichloromethane, 1,2-dichloroethane and chloroform, and/or mixtures thereof.

Dated this Twenty Eighth (28th) day of August, 2023

_________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883