DESC:FIELD OF THE INVENTION
The present invention relates to a process for preparing 1-(3-(3-(4-chlorophenyl)propoxy)propyl) piperidine hydrochloride.
BACKGROUND OF THE INVENTION
1-(3-(3-(4-chlorophenyl)propoxy)propyl)piperidine hydrochloride, also known as Pitolisant Hydrochloride represented by a compound of formula A, is a histamine H3 receptor antagonist developed by Bioprojet Pharma.

Pitolisant Hydrochloride was approved by the European Medicines Agency on March 31, 2016 under the trade name, Wakix®. On August 14, 2019, the U.S. Food and Drug Administration (FDA) approved Harmony Bioscience’s Wakix for the treatment of excessive day time sleepiness in adult patients with narcolepsy.
Several methods are known in the art for the preparation of Pitolisant Hydrochloride (A).
PCT Publication No. WO/2000/006254 discloses the preparation of 1-(3-(3-(4-chlorophenyl)propoxy) propyl)piperidine (Pitolisant base) wherein the process comprises reacting Sodium 3-piperidinopropanolate with 3-(4-chlorophenyl)propylmesylate and 15-crown-5 in toluene. However, this process makes the use of Crown ether which is a highly toxic reagent, expensive and difficult to remove in work-up steps.
PCT Publication No. WO2007/006708 discloses the preparation of Pitolisant base comprising reacting 3-(piperidin-l-yl) propan-l-ol and 3-(4-chlorophenyl) propyl methanesulfonate in the presence of dimethylacetamide. The significant drawback of this process relate to the use of the very expensive reagent 3-(4-chlorophenyl) propyl methanesulphonate and the use of dimethylacetamide, the toxicity of which makes its use inadvisable during the final synthesis steps in the production of an active ingredient. Moreover, mesylate compounds are genotoxic impurities or potential genotoxic impurities.
Chinese Patent Publication No. CN110804026 comprises reacting 3-(4-chlorophenyl)propan-1-ol with 3-(piperidin-1-yl)propionic acid in the presence of a solid super acid to form an intermediate, 3-(4-chlorphenyl) propyl-3-(piperidine-1-yl)propionate, followed by reacting the said intermediate with a reducing agent and a catalyst to obtain Pitolisant Hydrochloride. However, this process makes the use of super acid, reducing agent and catalysts which are expensive and whose disposal causes environmental damage.
Chinese Patent No. CN104447620 discloses the reaction of piperidine with 1,3-dihalopropane to obtain N-(3-halopropyl)piperidine which undergoes nucleophilic substitution reaction with 3-(4-chlorophenyl)propanol using solvents such as dimethylformamide or dimethylacetamide, followed by salification to give Pitolisant hydrochloride. The main drawback of said process is that, the reaction of piperidine with a bis-halogen derivative can lead to the formation of dimeric by-products which are difficult to remove during the work-up steps. A further drawback relates to the use of toxic solvents, such as dimethylformamide or dimethylacetamide, during the next step.
The prior art processes involve the use of expensive, highly toxic raw materials, reagents, or involve complex work-up procedures.
In order to overcome the disadvantages of the prior arts, there is a need to have improved process for preparing Pitolisant hydrochloride with increased safety, efficiency and reasonable cost that can be used on an industrial scale.
OBJECT OF THE INVENTION
The object of the invention is to provide an alternative, cost-efficient process for the preparation of 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine hydrochloride, avoiding the use of expensive and highly toxic crown ethers, thereby rendering the process cost-efficient, resulting in a product with high yield and purity.
It is also an object of the invention to provide a process for preparing 1-[3-[3-(4-chlorophenyl)propoxy]propyl]piperidine hydrochloride, circumventing the use of potentially genotoxic sulfonate esters, thereby rendering a safe and reliable process.
SUMMARY OF THE INVENTION
The present inventors have surprisingly found a novel intermediate for preparing 1-[3-[3-(4-chlorophenyl)propoxy]propyl]piperidine, represented by a compound of formula Va,

Wherein PG denotes a hydroxyl protecting group. Example of hydroxyl protecting group include without limitation, (C1-6 alkyl)-carbonyl, arylcarbonyl, aryl-C1-3-alkyl, allyl, (C1-6-alkyl)silyl groups. In preferred embodiments, PG is pivaloyl group.
The novel intermediate of present invention overcomes the drawbacks of prior art particularly the genotoxic impurities associated with sulfonate esters.
The present invention is advantageous over prior art in that it involves the use of inexpensive, easily available, convenient raw materials and reagents rendering the process cost-efficient and suitable for industrial production.
The present invention provides a process for preparing 1-[3-[3-(4-chlorophenyl)propoxy] propyl]piperidine hydrochloride (A), said process comprises reacting the compound of formula Va with 3-(piperidine-1-yl)propan-1-ol (VI) in the presence of an inorganic base, followed by salifying with hydrogen chloride or hydrochloric acid to yield the compound of formula A.

According to the present invention, the process for preparing the compound of formula Va comprises treating the compound of formula V with a suitable reagent wherein the hydroxyl group is protected in the presence of an organic base.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides improved, cost-effective, industrially viable processes for preparing Pitolisant hydrochloride in high yields and good purity, by way of using novel intermediate compound of formula Va.
None of the prior art processes teaches nor suggests the use of a compound of formula Va of the present invention for the preparation of Pitolisant Hydrochloride.
In one embodiment, the present invention provides an improved process for preparing 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine hydrochloride, represented by compound of formula A, wherein the process comprises the following steps:
(1) Treating 3-(4-chlorophenyl)propan-1-ol (V) with a suitable reagent in the presence of a base and a first solvent, wherein the hydroxyl group is protected to obtain a compound of formula Va;

Wherein PG represents a hydroxyl protecting group selected from (C1-6 alkyl)-carbonyl, arylcarbonyl, aryl-C1-3-alkyl, allyl, (C1-6-alkyl)silyl groups,
(2) Reacting the compound of formula Va with 3-(piperidin-1-yl)propan-1-ol (VI) in the presence of a base and a second solvent to obtain a compound of formula Aa;

(3) Optionally purifying the compound obtained from step (2) in one or more solvents;
(4) Treating the compound obtained from step (3) with hydrogen chloride or hydrochloric acid to form 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine hydrochloride (A).

In Step (1), the suitable reagent is selected from acyl chlorides such as acetyl chloride, propionyl chloride, butyryl chloride, pivaloyl chloride, benzoyl chloride, benzyl chloride; allyl halides; silyl halides such as tri(C1-4-alkyl)silyl halide, tert-butyldimethylsilyl halide, tertbutyldiphenylsilyl halide; and the like. In preferred embodiments, the suitable reagent used is acyl chloride, more preferably pivaloyl chloride.
According to the present invention, the base(s) wherever used is selected from Inorganic bases including without limitation, alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, barium hydroxide, calcium hydroxide, magnesium hydroxide; alkali metal hydride such as sodium hydride; and alkali metal and alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, barium carbonate, calcium carbonate, magnesium carbonate; Organic bases such as triethylamine, ammonia, pyridine, N,N-dimethylpyridine, alkanamines such as methylamine, diethylamine or mixtures thereof.
In preferred embodiments, the base used in Step (1) is triethylamine and the base in Step (2) is sodium hydride.
The process of present invention may be carried out in one or more solvents including without limitation, halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride; hydrocarbon solvents such as n-hexane, n-heptane, n-pentane, cyclohexane; aromatic hydrocarbons such as benzene, toluene, xylene; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol; ester solvents such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate; polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP); ether solvents such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile or mixtures thereof.
In preferred embodiments, the first solvent in Step (1) is dichloromethane and the second solvent in Step (2) is toluene.
In an embodiment, the compound obtained from Step (2) may either be isolated or proceeded to the next step without being isolated. Optionally, the compound obtained from Step (2) may be purified by techniques known in the art in one or more solvents described hereinbefore.
Likewise, each compound obtained in each of the above-mentioned reaction steps may either be isolated or proceeded as such to the next reaction. The crude compounds may be purified from the reaction mixture by, for example, by cooling the reaction mixture, applying an isolation operation of filtration, concentration, extraction and the like, to separate a crude reaction product, and applying a general purification operation such as column chromatography, recrystallization and the like.
Further, the compound obtained from Step (3) is reacted with gaseous hydrogen chloride or hydrochloric acid solution and isolating the compound, 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine hydrochloride i.e. Pitolisant Hydrochloride (A) by precipitation of the solid. In preferred embodiments, gaseous hydrogen chloride is bubbled through the reaction mixture comprising the Pitolisant free base to precipitate the hydrochloride salt. The reaction is carried out a temperature of 0-5oC.
In another embodiment, the process of present invention comprises preparing 3-(4-chlorophenyl) propan-1-ol (V), comprising:
(a) Reacting p-chlorobenzyl chloride (I) with Diethyl malonate (II) to form a compound of formula IIIa, followed by subjecting compound IIIa to base hydrolysis to isolate 2-(4-chlorobenzyl)malonic acid (III);

(b) Subjecting compound III to acid hydrolysis to obtain 3-(4-chlorophenyl)propanoic acid (IV);

(c) Reducing compound IV using a suitable reducing agent in the presence of an acid to obtain 3-(4-chlorophenyl)propan-1-ol (V).

Wherein the solvent(s) used for preparing the compound V, starting from compound I are selected from the group of solvents described hereinbefore.
In an embodiment, p-chlorobenzyl chloride (I) is reacted with Diethyl malonate (II) in the presence of a base and suitable solvent to form compound IIIa, wherein the base and solvent is selected from what have been described earlier in the specification. Preferably, the base used is sodium hydroxide and the solvent used is a polar-aprotic solvent, more preferably dimethyl formamide.
The compounds obtained in each of the above-mentioned reaction steps may either be isolated or proceeded as such to the next reaction without being isolated.
In preferred embodiments, the reaction mixture containing the compound IIIa is subjected to hydrolysis in the presence of a base to form compound III, wherein the base is sodium hydroxide.
Further, the compound III is subjected to acid hydrolysis resulting in the formation of compound IV, wherein the acid is selected from the group consisting of mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, nitric acid, sulfuric acid, phosphoric acid, boric acid, perchloric acid; organic acids such as acetic acid, formic acid, benzoic acid, lactic acid, p-toluene sulfonic acid, oxalic acid, tartaric acid. In preferred embodiments, mineral acid is used, more preferably sulfuric acid.
Compound IV so obtained is reacted with a suitable reducing agent to form compound V, wherein such reduction takes place in the presence of an acid. Examples of acid are described as hereinbefore. Examples of reducing agent include without limitation, sodium borohydride, lithium borohydride, sodium aluminum hydride, lithium aluminum hydride, diisobutylaluminium hydride, diborane, sodium triacetoxyborohydride. In preferred embodiments, the reducing agent is sodium borohydride and the acid used is sulfuric acid.
In another embodiment, the present invention provides a process for preparing 3-(piperidin-1-yl)propan-1-ol of formula VI, said process comprising reacting piperidine with 3-chloropropan-1-ol in the presence of a suitable solvent and a base to obtain 3-(piperidin-1-yl)propan-1-ol of formula (VI).

Wherein the base and solvent are as described hereinbefore. In preferred embodiments, the reaction is carried out in a ketone solvent in the presence of alkali metal carbonate. More preferably potassium carbonate and acetone are used. Additionally, the process comprises use of catalytic amounts of metal iodide selected from sodium iodide and potassium iodide. Preferably, potassium iodide is used.

The above-mentioned embodiments are only to illustrate the technical concept and characteristics of the present invention, and their purpose is to enable those familiar with the art to understand the content of the present invention and implement them accordingly, and cannot limit the protection scope of the present invention. All equivalent changes or modifications made according to the spirit of the present invention should be covered by the protection scope of the present invention.

The present invention shall be further described below in conjunction with examples. The following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention
EXAMPLES:
Example 1: Preparation of 2-(4-chlorobenzyl)malonic acid (III):
To a solution of p-chlorobenzylchloride (6.21 moles) in N,N-dimethylformamide (1100 ml), was added diethylmalonate (6.21 moles) at room temperature (RT) and stirred for few minutes. Sodium hydroxide flakes (6.83 moles) were added portion wise and maintained at same temperature. After the completion of reaction, the reaction mixture (RM) was charged with water (5 vol.) at below 20°C, stirred overnight at RT, followed by addition of Dichloromethane (5 vol.) and stirred for 30 min. The aqueous and organic layers were separated and extracted with dichloromethane (1 vol.). Organic layer extracted with water and washed with sodium chloride solution (2 vol.) and water (1 vol.), dried over sodium sulfate and distilled under vacuum at 40°C to give crude diethyl 2-(4-chlorobenzyl)malonate (IIIa).
Sodium hydroxide solution (16.875 mol) was slowly added to the above crude product at RT for and the RM was heated to reflux. Stirred overnight at reflux temperature (65-80°C). After completion of reaction, RM was cooled to 20°C and Conc. HCl was added to adjust pH. The RM was stirred overnight at RT and maintained at 0±5°C for 60 min. The filtered solid was washed with water (5 vol.) followed by dissolving the obtained solid in dichloromethane (10 vol.) and dried at RT to give pure title compound (Purity by HPLC = 99.13%).

Example 2: Preparation of 3-(4-chlorophenyl)propanoic acid (IV):
To the compound III (3.1 mol) obtained from the Example 1, water was charged followed by addition of 80% sulfuric acid (1600 ml) at RT. Slowly the temperature of RM was raised to 90-95°C, stirred and maintained at same temperature overnight. After the reaction was complete, water (2200 ml) and conc. Sulfuric acid (300 ml) was added to the RM and the temperature was raised to 120°C. The RM was stirred for 8 hrs, then cooled to RT, filtered, washed with water (4000 ml) and dried in hot air oven at 60°C for 5 hrs to give the title compound (Purity by HPLC = 98.57%).

Example 3: Preparation of 3-(4-chlorophenyl)propan-1-ol (V):
To the compound IV (2.92 mol) obtained from Example 2 was added sodium borohydride (5.85 mol) portionwise at RT for 3 hrs. The RM was cooled to below 15°C and slowly added conc. sulfuric acid (2.92 mol). Stirred the RM overnight at RT under N2 atmosphere, slowly added 10% NaOH solution at below 15°C. The aqueous and organic layers were separated and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and water at RT. The combined organic layers dried over sodium sulfate. The solvent was distilled completely under vacuum at 40-45°C to give title compound (Purity by HPLC = 99.01%).

Example 4: Preparation of 3-(piperidin-1-yl)propan-1-ol (VI):
To a solution of 3-chloropropanol (5.28 mol) in acetonitrile (1 L), was added potassium iodide (50 gm) and potassium carbonate (6.34 mol). To the RM, was slowly added piperidine (5.55 mol) at RT, heated to 85-90°C and maintained at same temperature. Filtered the RM, washed with acetonitrile (2 L) and solvent was distilled completely under vacuum at 40°C. To the crude, dichloromethane (1.5 L) and water (1L) was added. The aqueous and organic layers were separated and extracted with dichloromethane (1L). The aqueous layer was washed with saturated sodium bicarbonate solution (1L) and dichloromethane (1L). The combined organic layers dried over sodium sulfate. The solvent was distilled completely under vacuum at 40°C to give title compound (Purity by HPLC = 97.92%).

Example 5: Preparation of 3-(4-chlorophenyl)propyl pivalate (Va):
To a solution of compound V (25 gm) obtained from Example 3 in dichloromethane, was added pivaloyl chloride (25 gm) and stirred for 10 min at RT. The RM was cooled to 0-5°C, followed by addition of triethylamine (30 ml) and dichloromethane, stirred for 10 min. The temperature of the RM was slowly raised to RT and maintained for few hours. After completion of the reaction, water was added and stirred for 10 min. The aqueous and organic layers were separated and extracted with dichloromethane (50 ml). The organic layer was washed with water (100 ml), twice with sodium bicarbonate (100 ml each) and then twice with water (100 ml each). The combined organic layers dried over sodium sulfate. The solvent was distilled completely under vacuum at 45°C to give the title compound (Purity by HPLC = 99.5%).

Example 6: Preparation of 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine hydrochloride (A):
To a mixture of toluene (200 ml) and sodium hydride (4.7~8 gm), compound VI (25 gm) obtained from Example 4 was slowly added under nitrogen atmosphere followed by toluene (100 ml). The RM was stirred at RT for 3 hrs and Compound Va obtained from Example 5 was slowly added to the RM. Under nitrogen atmosphere, the RM was stirred overnight at RT. After completion of the reaction, saturated sodium chloride solution (640 ml) was slowly added portion wise to the RM under N2 atmosphere and stirred for 10 min. The aqueous and organic layers were separated and extracted with toluene (100 ml). The organic layer was washed with saturated NaHCO3 solution (2 × 100 ml) and water (300 ml). The solvent was distilled completely under vacuum at 45°C to give the crude compound. The crude compound was purified by column with 20 % n-hexane and ethyl acetate solvent. The solvent was distilled completely under vacuum at below 45°C to give the free base of the title compound.
The above free base was cooled to 0±5°C. To the RM, HCl gas was purged until solid formed. The filtered solid was washed with ethyl acetate (1.5 vol.) to give the title compound (Purity by HPLC = 99.9%).
,CLAIMS:1. A process for the preparation of 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine hydrochloride represented by a compound of formula (A), comprising the steps of:
(a) reacting 3-(4-chlorophenyl)propan-1-ol represented by a compound of formula (V) with a suitable reagent in the presence of a base and a solvent to obtain a compound of formula (Va);

wherein PG represents a hydroxyl protecting group selected from (C1-6 alkyl)-carbonyl, arylcarbonyl, aryl-C1-3-alkyl, allyl, (C1-6-alkyl)silyl groups,
(b) coupling the compound of formula (Va) with 3-(piperidin-1-yl)propan-1-ol represented by a compound of formula (VI) in the presence of a base and a solvent to obtain a compound of formula (Aa);

(c) Optionally purifying the compound of formula (Aa) in one or more solvents;
(d) Treating the compound of formula (Aa) with hydrogen chloride or hydrochloric acid to form 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine hydrochloride represented by a compound of formula (A).

2. The process as claimed in claim 1, wherein the process for preparing a compound of formula (V) comprises:
(a) reacting p-chlorobenzyl chloride (I) with Diethyl malonate (II) to form a compound of formula IIIa, followed by subjecting compound IIIa to base hydrolysis to isolate 2-(4-chlorobenzyl)malonic acid (III);

(b) subjecting compound III to acid hydrolysis to obtain 3-(4-chlorophenyl)propanoic acid (IV);

(c) reducing compound IV using a suitable reducing agent in the presence of an acid to obtain 3-(4-chlorophenyl)propan-1-ol (V).

3. The process as claimed in claim 1, wherein the process for preparing a compound of formula (VI) comprises:
reacting piperidine with 3-chloropropan-1-ol in the presence of a suitable solvent and a base to obtain 3-(piperidin-1-yl)propan-1-ol of formula (VI).

4. The process as claimed in claim 1, wherein the suitable reagent in step (a) is acyl chlorides selected from acetyl chloride, propionyl chloride, butyryl chloride, pivaloyl chloride, benzoyl chloride, benzyl chloride; allyl halides; silyl halides such as tri(C1-4-alkyl)silyl halide, tert-butyldimethylsilyl halide, tertbutyldiphenylsilyl halide.

5. The process as claimed in claim 1, claim 2 and claim 3, wherein the base used is selected from inorganic bases: alkali metal or alkali earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, barium hydroxide, calcium hydroxide, magnesium hydroxide; alkali metal hydride such as sodium hydride; and alkali metal and alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, barium carbonate, calcium carbonate, magnesium carbonate; organic bases such as triethylamine, ammonia, pyridine, N,N-dimethylpyridine, alkanamines such as methylamine, diethylamine or mixtures thereof;
solvent used is selected from halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride; hydrocarbon solvents such as n-hexane, n-heptane, n-pentane, cyclohexane; aromatic hydrocarbons such as benzene, toluene, xylene; alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol; ester solvents such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate; polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP); ether solvents such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile or mixtures thereof.

6. The process as claimed in claim 2, wherein acid used in step (b) and step (c) is selected from mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, nitric acid, sulfuric acid, phosphoric acid, boric acid, perchloric acid; organic acids such as acetic acid, formic acid, benzoic acid, lactic acid, p-toluene sulfonic acid, oxalic acid, tartaric acid;
the reducing agent used in step (c) is selected from sodium borohydride, lithium borohydride, sodium aluminum hydride, lithium aluminum hydride, diisobutylaluminium hydride, diborane, sodium triacetoxyborohydride.

7. A compound of formula Va;

wherein PG represents a hydroxyl protecting group selected from (C1-6 alkyl)-carbonyl, arylcarbonyl, aryl-C1-3-alkyl, allyl, (C1-6-alkyl)silyl groups,

8. The compound as claimed in claim 7, is defined by a compound of formula Va(i);

9. An improved process for the preparation of 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine hydrochloride (pitolisant hydrochloride) represented by a compound of formula (A), comprising the steps of:
(a) reacting p-chlorobenzyl chloride (I) with Diethyl malonate (II) to form a compound of formula IIIa, followed by subjecting compound IIIa to base hydrolysis to isolate 2-(4-chlorobenzyl)malonic acid (III);

(b) subjecting compound III to acid hydrolysis to obtain 3-(4-chlorophenyl)propanoic acid (IV);

(c) reducing compound IV using sodium borohydride in the presence of an acid to obtain 3-(4-chlorophenyl)propan-1-ol (V);

(d) reacting a compound of formula (V) with pivaloyl chloride in the presence of pyridine and dichloromethane to obtain a compound of formula Va(i);

(e) coupling a compound of formula Va(i) with a compound of formula (VI) in the presence of sodium hydride and toluene to obtain a compound of formula (Aa);

(f) optionally purifying the compound obtained from step (2) in one or more solvents;
(g) treating the compound of formula (Aa) with hydrogen chloride or hydrochloric acid to obtain pitolisant hydrochloride of formula (A).