SOLID DISPERSION OF l-{3-[3-(4-CHLOROPHENYL) PROPOXY] PROPYL} PIPERIDINE, HYDROCHLORIDE WITH HYDROXYPROPYL BETA-CYCLODEXTRIN (HPpCD)"

FIELD OF THE INVENTION

The present invention relates to a novel process for the preparation of amorphous solid dispersion of l-{3-[3-(4-chlorophenyl) propoxy] propyl} piperidine, hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1).

BACKGROUND OF THE INVENTION l-{3-[3-(4-chlorophenyl) propoxy] propyl} piperidine, hydrochloride commonly known as Pitolisant hydrochloride is represented by the following structural formula.

Pitolisant hydrochloride is designed and developed by Harmony Biosciences LLC. It is a histamine-3 (H3) receptor antagonist/inverse agonist which is used in the treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with narcolepsy. Pitolisant hydrochloride is approved by USFDA in Aug 14, 2019, and is being marketed under the brand name WAKIX.

Pitolisant was first disclosed in U.S. Pat. No. 7,169,928. This patent discloses process for the preparation of Pitolisant (la) by reacting 3-(piperidin-l-yl)-propan- l-ol (4) with 3-(4-chlorophenyl) propyl methane sulfonate (5) in the presence of sodium hydride and 15-crown-5 in a dry toluene, followed by purification using column chromatography.

The above process is schematically shown as below:

Scheme 1

The process for the preparation of Pitolisant as described in the prior art suffers from the major disadvantage is the reaction between 3-(piperidin-l-yl) propan- l-ol (4) with 3-(4-chlorophenyl) propyl methane sulfonate (5) is performed under very stringent reaction condition and involves the use of dangerous and explosive alkali metal hydride such as sodium hydride; use of alkali metal hydrides is not advisable for commercial scale operations from safety point of view.

Crystalline Pitolisant hydrochloride and its process for the preparation was first disclosed in U.S. Pat. No. 8,207,197.

Still, there is a significant need in the art for the development of a novel process for the preparation of amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1).

OBJECTIVE OF THE INVENTION

The present invention relates to a novel process for the preparation of amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD (1).

In another objective of the present invention provides a novel process for the preparation of amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1) without isolating Pitolisant hydrochloride.

In another objective of the present invention provides a novel process for the purification of Pitolisant free base (2). In another objective of the present invention provides Pitolisant free base (2) is having purity greater than 99.8%, preferably purity of at least 99.9%.

In further objective of the present invention provides amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1) is having purity greater than 99.8%, preferably purity of at least 99.9%.

SUMMARY OF THE INVENTION

The present invention relates to a novel process for the preparation of amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1).

In another aspect of the present invention provides a novel process for the preparation of amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1) as shown in scheme 2, comprising the steps of: a) reacting l-chloro-4-(chloromethyl) benzene (10) with dimethyl malonate (9) to obtain dimethyl 2-(4-chlorobenzyl) malonate (8), b) hydrolyzing the compound of formula (8) to obtain 2-(4-chlorobenzyl) malonic acid (7), c) decarboxylating the compound of formula (7) to obtain 3-(4-chlorophenyl) propanoic acid (6), optionally purifying to provide pure 3-(4-chlorophenyl) propanoic acid (6), d) reducing the compound of formula (6) with suitable reducing agent in the presence of Lewis acid to obtain 3-(4-chlorophenyl) propan- l-ol of formula (5); e) mesylating the compound of formula (5) with methane sulfonyl chloride to obtain 3-(4-chlorophenyl) propyl methane sulfonate of formula (4) f) reacting the compound of formula (4) with 3-(piperidin-l-yl) propan-l-ol (3) in the presence of base to obtain crude Pitolisant free base (2a); g) purifying crude Pitolisant free base (2a) by acid-base treatment to obtain pure Pitolisant free base (2); and h) converting pure Pitolisant free base (2) to provide Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1).

In another aspect, the compounds of formulae (8), (7) and (4) can be prepared in- situ and proceeds to next steps without further purification.

In another aspect of the present invention provides process for the preparation of amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta- Cyclodextrin (HPpCD) (1) from pure Pitolisant free base (2) without isolating Pitolisant hydrochloride, comprising the steps of:

A. dissolving Pitolisant free base (2) in a suitable solvent,

B. cooling the reaction mass to a suitable temperature,

C. adding cone. Hydrochloric acid at a suitable temperature,

D. adding Hydroxypropyl P-cyclodextrin (HPpCD), and

E. stirring and isolating Pitolisant hydrochloride with Hydroxypropyl beta- Cyclodextrin (HPpCD) (1).

In another aspect of the present invention provides a process for the purification of Pitolisant free base (2), comprising the steps of:

1. reacting crude Pitolisant free base (2a) with an acid to obtain acid addition salt of Pitolisant free base (2b),

2. purifying acid addition salt of Pitolisant free base (2b) in a suitable solvent or mixture thereof to obtain pure compound of formula (2b); and

3. neutralizing acid addition salt of Pitolisant (2b) with a base and isolating the compound to provide pure Pitolisant free base (2).

In another aspect of the present invention provides process for the preparation of amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta- Cyclodextrin (HPpCD) (1), comprising the steps of: 1) reducing 3-(4-chlorophenyl) propanoic acid of formula (6) with reducing agent in the presence of Lewis acid to obtain 3-(4-chlorophenyl) propan- l-ol (5);

2) converting the compound of formula (5) to provide Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1).

In another aspect of the present invention provides a process for the preparation of amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta- Cyclodextrin (HPpCD) (1), comprising: i. reacting 3 -(4 -chlorophenyl) propyl methane sulfonate (4) with 3-(piperidin-l- yl) propan- l-ol (3) in the presence of base to obtain Pitolisant free base (2a); and ii. converting Pitolisant free base (2a) to provide Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1).

In another aspect of the present invention provides Pitolisant free base (2) is having purity greater than 99.8%, preferably purity of at least 99.9%.

In further aspect of the present invention provides amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1) is having purity greater than 99.8%, preferably purity of at least 99.9%.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1: X-Ray powder diffraction (XPRD) pattern of amorphous solid dispersion of Pitolisant hydrochloride with hydroxypropyl beta-cyclodextrin (HPpCD) (1) prepared by example 7.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1). In another embodiment of the present invention provides a process for the preparation of amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1), which is illustrated in scheme 2: Scheme-2

In another embodiment, the steps involved in the preparation of amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1) as shown in scheme 2 are as follows:

In an embodiment step a) of the present invention proceeds with reacting 1-chloro- 4-(chloromethyl) benzene (10) with dimethyl malonate (9) to obtain dimethyl 2-(4- chlorobenzyl) malonate (8). The reaction is carried out in the presence of suitable base in a suitable solvent. The suitable base is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, and the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

In an embodiment, the compound of formula (8) of step a) can be prepared in-situ and proceeds to next steps without further purification.

In an embodiment step b) of the present invention proceeds with hydrolysing dimethyl 2-(4-chlorobenzyl) malonate (8) to obtain 2-(4-chlorobenzyl) malonic acid (7). The reaction is carried out in present of suitable base in a suitable solvent. The suitable base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, and the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

In an embodiment, the compound of formula (7) of step b) can be prepared in-situ and proceeds to next steps without further purification.

In an embodiment step c) of the present invention proceeds with decarboxylating 2-(4-chlorobenzyl) malonic acid (7) to obtain 3-(4-chlorophenyl) propanoic acid (6). The reaction is carried out in presence of a suitable acid selected from hydrochloric acid or sulfuric acid, optionally purifying 3-(4-chlorophenyl) propanoic acid (6), wherein the purification process comprises. i. dissolving 3-(4-chlorophenyl) propanoic acid (6) in a suitable solvent. ii. adding an anti-solvent; and iii. isolating 3-(4-chlorophenyl) propanoic acid (6).

In an embodiment of step c), wherein the suitable solvent used in step i) is selected from “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like; and the anti-solvent used in step ii) is selected from “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, and the like. In an embodiment step d) of the present invention proceeds with reducing 3-(4- chlorophenyl) propanoic acid of formula (6) with a suitable reducing agent to obtain 3-(4-chlorophenyl) propan-l-ol of formula (5). The reaction is carried out in the presence of a suitable Lewis acid in a suitable solvent. The suitable reducing agent is selected from DIBAL, sodium borohydride, potassium borohydride, lithium trisec -butyl borohydride, sodium dihydro-bis-(2-methoxyethoxy) aluminate (Vitride), diisobutylaluminium hydride, lithium aluminum hydride, the suitable Lewis acid is selected from aluminum chloride (A1CL), boron trifluoride etherate (BF3:Et2O), Cone. Sulfuric acid (Cone. H2SO4) etc. and the suitable solvent is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

In an embodiment step e) of the present invention proceeds with mesylating 3-(4- chlorophenyl) propan-l-ol of formula (5) with methane sulfonyl chloride to obtain 3-(4-chlorophenyl) propyl methane sulfonate (4). The reaction is carried out in the presence of organic base in a suitable solvent. The organic base is selected from triethyl amine, methyl amine, ethylamine, isopropyl amine, diisopropylamino, diisopropylethylamine, and the like, and the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

In an embodiment step f) of the present invention proceeds with reacting 3-(4- chlorophenyl) propyl methane sulfonate (4) with 3-(piperidin-l-yl) propan-l-ol (3) to obtain crude Pitolisant free base (2a). The reaction is carried out in the presence of suitable base in a suitable solvent. The suitable base is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, sodium tert-pentoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate and the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

In an embodiment step g) of the present invention proceeds with purifying crude Pitolisant free base (2a) by acid base treatment to obtain pure Pitolisant free base (2). The process involves reacting crude Pitolisant free base (2a) with a suitable acid to obtain acid addition salt of Pitolisant (2b). The acid employed for preparing Pitolisant acid addition salts includes but not limited to formic acid, acetic acid, oxalic acid, propanoic acid, maleic acid, citric acid, phthalic acid, toluene sulfonic acid, naphthalene sulphonic acid, methansulfonic acid, benzenesulfonic acid and the like.

The Pitolisant acid addition salt (2b) can be neutralized to give highly pure Pitolisant free base (2). Generally, the neutralization of acid addition salt carried out in presence of suitable base at a temperature of about 25 to 35 °C. Suitable base that can be used for conversion of Pitolisant acid addition salt (2b) to Pitolisant free base (2) can be inorganic base. Inorganic base includes but are not limited to alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, and the like, and the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

In an embodiment step h) of the present invention proceeds with converting pure Pitolisant free base (2) to amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1) without isolating Pitolisant hydrochloride. In another embodiment of the present invention provides process for the preparation of Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1) from pure Pitolisant free base (2) without isolating Pitolisant hydrochloride, comprising the steps of:

A. dissolving Pitolisant free base (2) in a suitable solvent,

B. cooling the reaction mass to a suitable temperature,

C. adding cone. Hydrochloric acid and raising temperature,

D. adding Hydroxypropyl P-cyclodextrin (HPpCD), and

E. stirring and isolating Pitolisant hydrochloride with Hydroxypropyl beta- Cyclodextrin (HPpCD) (1).

In an embodiment, the suitable solvent used in Step A is “polar solvents” such as water.

In another embodiment of the present invention provides a process for the purification of Pitolisant free base (2), comprising the steps of:

1. reacting crude Pitolisant free base (2a) with an acid to obtain acid addition salt of Pitolisant free base (2b),

2. purifying acid addition salt of Pitolisant free base (2b) in a suitable solvent or mixture thereof to obtain pure compound of formula (2b); and

3. neutralizing acid addition salt of Pitolisant (2b) with a base and isolating the compound to provide pure Pitolisant free base (2).

In another embodiment of the present invention provides a process for the preparation of amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1), comprising the steps of:

1) reducing 3-(4-chlorophenyl) propanoic acid of formula (6) with reducing agent in the presence of Lewis acid to obtain 3-(4-chlorophenyl) propan- l-ol (5);

2) converting the compound of formula (5) to provide Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1). In another embodiment of the present invention provides a process for the preparation of amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1), comprising the steps of: i. reacting 3 -(4 -chlorophenyl) propyl methane sulfonate (4) with 3-(piperidin-l- yl) propan- l-ol (3) in the presence of base to obtain Pitolisant free base (2a); and ii. converting Pitolisant free base (2a) to provide Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1).

In another embodiment of the present invention provides a process for the preparation of 3-(piperidin-l-yl) propan-l-ol (3), which is illustrated in scheme 3:

3-chloropropan-l-ol piperidine

Scheme 3 comprising: dehydrochlorination of piperidine with 3 -chloropropanol to obtain 3- (piperidin-l-yl) propan-l-ol (3); the reaction is carried out in the presence of base, potassium iodide in a suitable solvent The base is selected from sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate and the like, and the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

Pitolisant free base (2) obtained by the above process may be having purity greater than 99.8%, preferably purity of at least 99.9%.

Amorphous solid dispersion of Pitolisant hydrochloride with Hydroxypropyl beta- Cyclodextrin (HPpCD) (1) obtained by the above process may be is having purity greater than 99.8%, preferably purity of at least 99.9%. Substantially pure Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextnn (HPpCD) (1) obtained by the above process is having total impurities not more than 1.0% and each of impurity-A, impurity-B, impurity-C, and impurity-D is not more than 0.15% (w/w), preferably not more than 0.05% (w/w); and impurity-E is not more than 2.0% (w/w), more preferably not more than 0.5% (w/w).

(Impurity-D)

(Impurity-E)

In another embodiment of the present invention provides Pitolisant hydrochloride with Hydroxypropyl beta-Cyclodextrin (HPpCD) (1) obtained according to the present invention has a water content not more than 10.0%, preferably not more than 5%. More preferably not more than 3%.

The powdered x-ray diffractogram (PXRD) of amorphous solid dispersion of Pitolisant hydrochloride (1) in combination with Hydroxypropyl beta cyclodextrin (HPpCD) is shown in figure 1.

As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3 -dioxane, 1,4-dioxane, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene 5 glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, di chloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyro nitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, 15 ethylene glycol, 2- methoxyethanol, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neopentyl alcohol, t-pentyl alcohol, diethylene glycol, monoethyl ether, cyclohexanol, benzyl alcohol or glycerol and the like; “polar solvents” such as water or mixtures thereof.

Various conversions/steps in the processes of the present invention can be carried out in the presence or absence of a solvent or mixture of solvents. The said solvent(s) can be selected from those as described above.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

Example-1: Process for the preparation of 3-(piperidin-l-yl) propan-l-ol (3) 100 g of piperidine, 500 ml of toluene, 260 g of potassium carbonate and 19 g of potassium iodide were taken at 25-30 °C. 116 g of 3-chloropropan-l-ol was added to the reaction mass. The reaction mass temperature was raised to 40-45 °C and stirred for 30-40 minutes. The reaction mass temperature was raised to 108-112°C and stirred for 14-16 hours. After completion of the reaction, the reaction mass was cooled to 25-30°C. The reaction mass was filtered and washed with toluene. The filtrate was distilled off under vacuum to get crude as oily liquid. The crude was purified by fractional distillation to get the titled compound. Yield: 80%; Purity: 99.95%

Example-2: Process for the preparation of 3-(4-chlorophenyl) propanoic acid (6):

160 g of dimethyl malonate (9) and 600 ml of methanol was taken at 25-30 °C. To this 170 ml of sodium methoxide was added at 15-20 °C for 15-20 minutes and stirred for 30-40 minutes. 100 g of l-chloro-4-(chloromethyl) benzene (10) in 50 ml of methanol was added slowly for a period of 30-40 minutes at 5-10 °C. and stirred for 5-6 hours at 25-30°C. After completion of the reaction, the methanol was distilled and cooled to 25-30 °C to obtain crude dimethyl 2-(4- chlorobenzyl) malonate (8). To this, 250 ml of 50 % potassium hydroxide solution was added and stirred for 10-15 minutes. The reaction temperature was raised to 110-115 °C and stirred for 12-14 hours. After completion of the reaction, the reaction mass was cooled to 25-30 °C. 200ml of toluene was added to the reaction mass and stirred for 10-15 minutes at 25-30 °C. Both the layers were separated. The aqueous layer pH was adjusted from 1.0 to 1.5 with cone, hydrochloric acid. The reaction temperature was raised to 140-145 °C and stirred for 14-15 hours. The reaction mass was cooled to 25-30 °C. Filtered the solid and washed with water to obtain crude 3-(4-chlorophenyl) propanoic acid (6). To this crude compound, 500 ml of water was added at 25-30 °C. The reaction temperature was raised to 110-115 °C and stirred for 1-2 hours. The reaction mass was cooled to 25-30°C and stirred. Filtered the solid and dried to obtain dry crude 3-(4-chlorophenyl) propanoic acid (6). To this 500 ml of hexane was added at 25-30 °C and the reaction temperature raised up to 60-65 °C then, 130 ml of ethyl acetate was added and stirred. The reaction mass was cooled to room temperature and cooled to 0-5°C for 1-1.5 hours. Filtered the solid and washed with hexane. The obtained solid was dried at 40-45 °C to get the titled compound.

Yield: 59 %; Purity: 99.95%. Example-3: Process for the preparation of 3-(4-chlorophenyl) propan-l-ol (5): 120 mL of tetrahydrofuran was added to 30 g of sodium borohydride at 25-30 °C and stirred for 20-30 minutes. To this 100 ml of Boron trifluoride etherate (BF3.Et2O) was added slowly to the reaction mass at below 30 °C and stirred for 20-30 minutes. Then the reaction mass was cooled 0-5 °C. To this 100 g of 3-(4- chlorophenyl) propanoic acid (6) was dissolved in 400 ml of tetrahydrofuran was added to the reaction mass at 0-5°C. The reaction mass temperature was raised to 25-30 °C and stirred for 20-30 minutes. Again, the reaction mass temperature raised to 60-75°C and stirred for 2-3 hours. After completion of the reaction, the reaction mass was cooled to 25-30 °C followed by 0-5 °C gradually. Then, 100 ml of methanol and 500 ml of 10 % ammonium chloride solution was added to the reaction mass and stirred for 1 h. Distilled out the tetrahydrofuran from the reaction mass and cooled to 25-30 °C. 200 ml of ethyl acetate was added to the reaction mass and stirred for 10-15 minutes. Both the layers were separated. Aqueous layer was re extracted with ethyl acetate, then combined the organic layers and washed with sodium bicarbonate. The obtained organic layer was dried with sodium sulfate. Filtered the organic layer and distilled off to get oily liquid. Yield: 98%; Purity: 99.95%.

Example-4: Process for the preparation of 3-(4-chlorophenyl) propyl methane sulfonate (4):

100 g of 3-(4-chlorophenyl) propan-l-ol (5) and 500 mL of dichloromethane was taken at 25-30 °C and stirred for 10-15 minutes. To this solution, 80 g of methane sulfonyl chloride was slowly added dropwise and stirred for 10-15 minutes, then cooled the reaction mass to 0-5 °C. 70 g of triethyl amine was slowly added dropwise and stirred. The reaction temperature raised to room temperature and stirred for 2-3 hours. After completion of the reaction, 500 ml of water was slowly added and stirred for 30 minutes. Both the layers were separated. The aqueous layer was re-extracted with 200 ml of dichloromethane. The organic layers were combined and washed with 10% sodium bicarbonate solution. The organic layer was dried with sodium sulfate. Filtered and distilled off the organic layer to get pale yellow to yellow colour semi solid which is used directly in the next step without further purification.

Example-5: Process for the preparation of Pitolisant free base (2a):

200 ml of tetrahydrofuran was added to 65 g of 3-(piperidin-l-yl) propan-l-ol (3) and stirred for 10-15 minutes at 25-30 °C.52 g of sodium tert-pentoxide was added to the reaction mass at 20-30 °C and stirred for 10-15 minutes. The reaction mass temperature was raised to 50-55 °C and stirred for 1 hour, then cooled the reaction mass to 25-30 °C. The obtained mass was slowly added to 145 g of 3- (4-chlorophenyl) propyl methane sulfonate (4) in 140 ml of tetrahydrofuran and stirred for 25-30 minutes at 25-30°C. The reaction mass temperature was raised to 50-55 °C and stirred for 30-40 minutes. 13.55 g of sodium tert-pentoxide was added to the reaction mass at 50-55 °C and stirred for 1 hour. Again 5.35 g of sodium tert-pentoxide was added to the reaction mass and stirred for 2-3 hours. After completion of the reaction, 350 ml of 10% ammonium chloride solution was added to the reaction mass at 0-5 °C and stirred for 15-20 minutes. The reaction mass temperature was raised to 25-30°C. Both the layers were separated. The aqueous layer was re-extracted with 70 ml of methyl tert-butyl ether to obtain crude. The obtained crude was dissolved in 200 ml of methyl tert-butyl ether and cooled to 0-5 °C. The pH of reaction mass was adjusted to 1.0-2.0 with 2N hydrochloric acid and stirred for 10-15 minutes. Both the layers were separated. The aqueous layer was basified with 3N sodium hydroxide to adjust the pH from 11.0-12.0 and stirred for 10-15 minutes. The organic layer was taken and 10.0 g of neutral carbon into the reaction mass was added. The reaction mass was stirred for 10-15 minutes. The reaction temperature was raised to 50-55°C and stirred for 1 h. The reaction mass cooled to room temperature, then filtered the reaction mass and washed with 35 mL of methyl tert-butyl ether. Distilled off the organic layer to ger the crude yellow liquid. 1.2 volumes of ethyl acetate were added to the reaction and cooled to 0 to -10°C. pH of the reaction mass was adjusted up to 3- 4 by adding 1.3 volumes of hydrochloric acid in ethyl acetate and stirred for 1-2 h. The solid material was filtered and washed with 0.3 volumes of chilled ethyl acetate. 1.9 volumes of water were added to the wet material and cooled to 0-5°C. pH adjusted to 11-12 by using sodium hydroxide and stirred for 10-15 min. The reacton temperature raised to room temperature and add 1.25 volumes of methyl tert-butyl ether, then stirred for 15-20 minutes. Both the layers were separated, and aqueous layer was re-extracted with methyl tert-butyl ether. Filtered the organic layer and distilled to get the liquid. Yield: 65%

Example-6: Process for the purification of Pitolisant (2)

1.5 volumes of methanol and 0.96 equivalents of oxalic acid in 3.3 volumes of water was added to the crude Pitolisant free base (2a) at 25-30 °C and stirred for 1-1.5 hour at the same temperature. Cooled the reaction mass to 0-5 °C and stirred for 1- 2 hours at the same temperature. Filtered the solid and washed with water at 25-30 °C and dried under vacuum oven for 6-8 hours to obtain solid. 1:3 ratio of methanol and water was added to the obtain solid. Raised the reaction temperature to 55-60°C and stirred for 20-30 minutes at the same temperature. Cooled the reaction mass gradually to 0-5 °C and stirred for 1 hour. Filtered the solid and washed with water at 25-30 °C. Dried the obtained solid under vacuum for 6-8 hours to get the solid material. 1.5 volumes of methanol were added to the obtained solid material. Raised the reaction temperature up to 55-60 °C. 1.5 volumes of isopropanol were added to the reaction mass and stirred for 20-30 minutes at the same temperature. Cooled the reaction mass gradually to 0-5 °C and stirred for 1 hour. Filtered the solid and washed with isopropanol at 25-30 °C. The obtained solid dried under the vacuum for 6.8 hours to obtain the solid. 4.2 volumes of water were added to the solid. Cooled the reaction mass gradually to 0-5 °C. Basified the reaction mixture using sodium hydroxide to adjust the pH from 11.0-12.0 and stirred for 10-15 minutes. Raised the reaction temperature gradually to 25-30 °C and stirred for 25-30 minutes at the same temperature. 2 volumes of methyl tert-butyl ether were added to the reaction mass and stirred for 15-20 minutes. Layers were separated. The aqueous layer was re-extracted with methyl tert-butyl ether. Dried the organic layer with sodium sulfate. Filtered the organic layer and distilled off the organic layer to get the colour less to yellow reddish liquid. Yield: 37%; Purity: 99.95%.

Example-7: Process for the preparation of solid dispersions of Pitolisant hydrochloride (1) with Hydroxypropyl beta- Cyclodextrin (HPpCD) 100 g of Pitolisant free base (2) and 500 ml of water was taken at room temperature. The reaction mass was cooled 0-5 °C. To this 25 ml of concentrated Hydrochloric acid was added to the reaction mass at 0-5 °C then stirred for 15-20 minutes. The pH of the reaction mass was adjusted to 3.2 to 4.0 by slowly addition of Hydrochloric acid. The reaction mass temperature was raised to 25-30°C. 300 g of Hydroxypropyl P-cyclodextrin (HPpCD) was added and stirred for 20-30 minutes. The reaction mass was passed through 0.2-micron filter. The filtrate was loaded into the freeze dryer and dried to get a title compound. Yield: 92%; Purity: >99.9%