DESC:
FIELD OF INVENTION

The present invention relates to a process for preparation of Pitolisant and its pharmaceutically acceptable salt thereof and its intermediates.

BACK GROUND OF THE INVENTION

Pitolisant Hydrochloride is chemically known as 1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine Hydrochloride, which has been approved as a tablet having dosage strength 4.45 MG under the trade name WAKIX®, which is indicated for method of treating excessive daytime sleepiness in patients with narcolepsy. Pitolisant Hydrochloride, which is also known as Tiprolisant and is structurally represented as follows:

Pitolisant as well as its pharmaceutically acceptable salts, hydrates, or hydrated salts, or their optical isomers, racemates, diastereoisomers or enantiomers were disclosed in US 7,169,928 B2 (US ‘928) of Bioprojet Societe Civile. Further, discloses the nontoxic salt of inorganic or organic acids salts such as hydrochloride, hydrobromide, oxalate, succinate and maleate salts of Pitolisant. Further, discloses the synthesis of Pitolisant of Formula I(a) by condensing 3-Piperidinopropanol and 3-(4-chlorophenyl)propyl mesylate in presence of Sodium hydride yields Pitolisant of Formula I(a), which is as shown below:

US ‘928, also discloses the synthesis of Pitolisant oxalate salt, comprising condensing Sodium 3-piperidinopropanol salt with 3-(4-chlorophenyl)propyl mesylate in presence of 15-crown-5 and is further crystallized using oxalic acid from Et2O and ethanol, followed by involves purification using column chromatography.

US 8,207,197 B2 (US ‘197), discloses the Crystalline Pitolisant Hydrochloride salt and the synthesis of Crystalline Pitolisant Hydrochloride. Sodium salt of 3-Piperidinopropanol was condensed with 3-(4-chlorophenyl)propyl mesylate in presence of 15-Crown-5 ether and further purified by column chromatography yields Pitolisant as oil (yield: 75%), followed by HCl salt formation has been carried out using HCl gas in anhydrous EA and is further purified using IPA yields Pitolisant HCl salt (yield: 80%), which is as shown below:


CN 103435575 A of Institute of Toxicology and Drugs, Chinese Academy of Military Medical Sciences, discloses the Synthesis of Pitolisant Hydrochloride. Piperdine was condensed with 1-chloropropanol in presence of K2CO3 in ACN to give 1-Piperidinepropanol, which is further treated with 3-(4-Chloro-phenyl)propyl methane sulfonate salt in presence of sodium hydride in N,N-DMA to give Pitolisant of Formula I(a), further treated with thionyl chloride in ethylacetate & ethanol, followed by purification using Ethylacetate & Isopropanol yields Pitolisant Hydrochloride salt (Yield: 81.3%), which is as shown below:

CN 104447620 B of Ruiyang Pharmaceutical Co., Ltd, discloses the process for the preparation of Pitolisant Hydrochloride, comprising treating piperidine with 1,3-dihalopropane in presence of inorganic base (ex: Na2CO3, NaI, KI) and solvent (ex: DMF, THF or Acetone) to give N-(3-halopropyl)piperidine and is further treated with 3-(4-chlorophenyl)propyl alcohol in presence of a base (ex: NaH, KI) and in a solvent (ex: DMF or DMA), followed by treatment with HCl gas yields Pitolisant Hydrochloride (HPLC purity; 99.7%) which is as shown below:

European Journal of Pharmaceutical Sciences 2001, 13, Pages 249 – 259, discloses the process for the preparation of Pitolisant Oxalate. Piperidine was treated with 1-Chloropropanol in presence of KI gives 1-Piperidinepropanol (Yield: 60%) and is further treated with 3-(4-Chloro-phenyl)propyl methane sulfonate salt in presence of NaH, 15-Crown-5 ether, TBAI in toluene gives Pitolisant as residue and is purified by clolumn chromatography, followed by crystallization with oxalic acid in EA yields Pitolisant Oxalate salt (Yield 56%), which is as shown below:

However, the prior-art process involves the condensation of 3-(Piperidin-1-yl)-propanol or its salt with 3-(4-Chlorophenyl)propyl alcohol or its mesylate salt in the presence of sodium hydride base to prepare Pitolisant and its salt thereof. Sodium hydride is hazard, highly corrosive in nature and hence not suitable for industrial preparations.

Further, the prior-art process involves the use of crown ether phase transfer catalysts resulting in an inappropriate industrial process because of its high cost and toxicity. Further, involves the use of toxic solvents such as DMF / DMA and results in formation of NSI’s and hence, the prior-art process is economically not viable process.

Further, Pitolisant obtained according to prior-art process having lower purity and is directly used in the preparation of pharmaceutically acceptable salts of Pitolisant and hence, would require an additional column chromatography and/or a molecular distillation process. Column chromatographic purification is not widely used in the manufacturing processes because of high quantities of solvent needed and may result environmental problems. On the other hand, fractional distillation is not convenient because of its high boiling point and required the distillation equipment, which limits its industrial feasibility.

Further, prior-art process for the preparation of Pitolisant Hydrochloride salt involves the use of HCl gas, which is complicated and unfavorable for industrialized production.

Further, the prior-art process involves the condensation of piperidine with dihalopropane or 1-halopropanol to prepare 3-(Piperidin-1-yl)-1-propanol in presence of inorganic base such as Na2CO3, K2CO3, KI or NaI. However, the present invention involves the condensation of piperidine with 1-halopropanol in absence of base yields 3-(Piperidin-1-yl)-1-propanol, which having higher yield (= 96%) than the prior-art process.

Further, the present inventors have observed that the prior-art process for preparing 3-(Piperidin-1-yl)-1-propanol, comprising condensation of piperidine with 1,3-dihalopropane (ex: 1-bromo-3-chloro propane or 1,3-dichloro propane), which may cause the formation of Genotoxic impurities (GTIs) and difficult to remove the GTIs as per the regulatory guidelines and may leads lower yields (= 94.9%) and purity. Hence, further purification is required and hence this process is not economically viable process.

Further, the present inventors have also observed that 1-(3-halopropyl) piperidine is also a GTI, which was produced during the condensation of piperidine with 1,3-dihalopropane (ex: 1-bromo-3-chloro propane or 1,3-dichloro propane). Further, required multiple purifications for removing the unreacted 1-(3-halopropyl)piperidine in the API.

The presence of unreacted 1-(3-halopropyl) piperidine may cause the formation of acid salt of 1-(3-halopropyl) piperidine during the salt formation of API (Pitolisant Hydrochloride salt), which required multiple purification steps and is difficult to remove the acid salt of 1-(3-halopropyl) piperidine from the final API.

Further, the present inventors have also observed that formation of dimer impurity i.e 1,3-di(piperidin-1-yl)propane during the reaction of piperidine with 1,3-dihalopropane according to the prior-art process.

Further observed that, the dimer impurity was carry-over to the final API (Pitolisant and its salt thereof) and could not be removed completely during the purification of API, which shows the impact on yield and purity and accordingly leads lower yield and lower purity of final product.

In view of the above, there is a need for an industrially applicable and cost-effective process for the preparation of Pitolisant and its pharmaceutically acceptable salt thereof, which is free of GTI’s, dimer impurity as well as NSIs.

OBJECTIVES

An objective of the present invention is to provide a process for the preparation of 3-(Piperidin-1-yl)-1-propanol compound of Formula II, which is free of Genotoxic impurities (GTIs) and can be used in the synthesis of Pitolisant and its salt thereof.

Another objective of the present invention is to provide a process for the preparation of Pitolisant and its salt thereof, which is free of Genotoxic impurities (GTIs) as well as Nitrosamine Impurities (NSI’s) and is economically suitable and industrially viable.

SUMMARY OF THE INVENTION

A process for the preparation of Pitolisant and its pharmaceutically acceptable salt thereof of Formula I:

which comprises:
i) condensing 3-halo-1-propanol of Formula A

with piperidine of Formula B

in absence of base to yield 3-(Piperidin-1-yl)-1-propanol of Formula II;

ii) condensing 3-(Piperidin-1-yl)-1-propanol compound of Formula II with 3-(4-Chlorophenyl)propyl methanesulfonate of Formula III

in presence of a base to yield Pitolisant of Formula I(a); and

iii) optionally converting the obtained Pitolisant of Formula I(a) in step (ii) to its pharmaceutically acceptable salt thereof of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Pitolisant and its salt thereof of Formula I, which comprises condensing 3-halo-1-propanol of Formula A with piperidine of Formula B in a solvent selected from the group comprising of halogenated solvents, ethers, hydrocarbons, nitriles or mixture of solvents thereof; in absence of base to yield 3-(Piperidin-1-yl)-1-propanol of Formula II. Condensing the obtained 3-(Piperidin-1-yl)-1-propanol of Formula II with 3-(4-Chlorophenyl)propyl methanesulfonate of Formula III in presence of a base selected from the group comprising of NaOH powder, KOH powder, NaOMe, t-BuOK, NaH and the like; in a solvent selected from the group comprising of halogenated solvents, ketones, ethers, esters, nitriles, polar aprotic solvents or mixture of solvents thereof to yield Pitolisant of Formula I(a); optionally isolating the Pitolisant of Formula I(a) and optionally purifying the obtained Pitolisant Free base of Formula I(a). Optionally converting the obtained Pitolisant of Formula I(a) to Pitolisant salt thereof of Formula I. Wherein, salt is hydrochloride salt.

In another embodiment of the invention, the halogenated solvents are selected from the group comprising of dichloromethane (MDC), ethylene dichloride (EDC), chloroform and the like; alcohols are selected from the group comprising of methanol, ethanol, butanol, t-BuOH, isopropanol and the like; ketones are selected from the group comprising of acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK) and the like; ethers are selected from the group comprising of tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), diethyl ether, isopropyl ether, methyl isobutylether (MIBE), methyl t-butyl ether (MTBE), dioxane and the like; esters are selected from the group comprising of ethyl acetate, isopropyl acetate and the like; hydrocarbons are selected from the group comprising of toluene, xylene and the like; nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, acrylonitrile, Potassium cyanide and the like; Polar aprotic solvents are selected from the group comprising of N,N-dimethylformamide (DMF), dimethylacetamide (DMA), acetonitrile (ACN), dimethylsulfoxide (DMSO) and the like.

In another embodiment of the invention, the base is selected from the group comprising of organic base, inorganic base or mixture thereof; wherein organic base is selected from the group comprising of TEA, pyridine, DMAP, N-Methyl morpholine and the like; inorganic base is selected from the group comprising of Na2CO3, K2CO3, NaH, KH, NaOH, KOH, NaI, KI, t-BuOK and the like;

In another embodiment of the invention, the mixture of solvents means two or more solvents.

In another embodiment of the invention, the mixture of bases means two or more bases.

In another embodiment, obtained compound of Formula II can be optionally isolated and optionally purified by conventional methods.

In another embodiment, obtained Pitolisant of Formula I(a) can be optionally isolated and optionally purified by conventional methods.

In another embodiment, obtained Pitolisant and its pharmaceutically acceptable salt thereof of Formula I can be optionally isolated and optionally purified by conventional methods.

In another embodiment of the invention, Isolation of Pitolisant, its pharmaceutically acceptable salts and its intermediate compounds can be performed by conventional methods such as cooling, removal of solvents, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, filtration, centrifugation and the like.

The present invention provides a process for the preparation of 3-(Piperidin-1-yl)-1-propanol of Formula II, comprising condensing 3-halo-1-propanol of Formula A with Piperidine of Formula B in absence of a base, in a solvent, which leads higher yield (=96%), without formation of GTIs, and hence this process is economically friendly and industrially viable process

The present invention provides a process for the preparation of Pitolisant and its pharmaceutically acceptable salts thereof of Formula (I) comprising condensing 3-(Piperidin-1-yl)-1-propanol of Formula II with 3-(4-Chlorophenyl)propyl methanesulfonate of Formula III in presence of a base such as potassium hydroxide or potassium tert-butoxide, which are non-hazardous and hence industrially suitable, followed by simple isolation techniques and conversion to compound of Formula I, also leads higher yield (=90%) and purity, which process is economically friendly and industrially applicable process.

The Abbreviations used throughout the invention are as follows:
AcOH : Acetic acid
DMF / N,N-DMF : N,N-Dimethyl formamide
DMAP : Dimethylamino pyridine
Et2O : Diethyl ether
EA / EtOAc : Ethyl acetate
IPA : Isopropyl alcohol
t-BuOH : tert-butanol
TBAI : Tetrabutylammonium iodide
K2CO3 : Potassium carbonate
KHCO3 : Potassium bicarbonate
KI : Potassium iodide
KOH : Potassium hydroxide
KOtBu / t-BuOK : Potassium tert-butoxide
MsCl : Methanesulfonyl chloride
NaOH : Sodium hydroxide
NMP : N-methylpyrrolidinone
NaH : Sodium hydride
NaI : Sodium iodide
Na2CO3 : Sodium carbonate
NaHCO3 : Sodium bicarbonate
N,N-DMA : N,N-Dimethyl acetamide
SOCl2 : Thionyl chloride
TEA : Triethylamine

The invention of the present application will be explained in more detail with reference to the following examples, which should not be construed as limiting the scope of the invention in any manner.

Examples
Reference Example: Preparation of Pitolisant HCl
Distilled 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine (1.0 kg) and anhydrous ethyl acetate (4.5 kg) are transferred to a 10-L glass vessel fitted with a cooling bath and a gas inlet. A stream of gaseous hydrogen chloride is bubbled in the reaction mixture at 20-25°C. The pH of the solution is checked by taking a 0.5 mL sample of the reaction mixture and diluting it with 5 mL of deionized water. The final pH must be about 3-4. The mixture is cooled to -10°C.-(-12°C.) and stirred at this temperature for 1 h. The precipitate is filtered by using a sintered glass filter and washed with 0.5 L of anhydrous ethyl acetate previously cooled to 0-5°C. The product is dried in a vacuum oven at 50° C. for a minimum period of 12 hours. The resulting crude 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine monohydrochloride weighs 1.10 kg.
Purification
A mixture of the above-described crude, 3.98 kg of anhydrous ethyl acetate and 0.35 kg of i-propanol is heated slowly at 55-60°C. in a 10-L glass vessel fitted with a heating and cooling system. When the solution has been completed, it is filtered through a heat-isolated sintered glass filter, keeping the temperature at 55-60°C. The solution is transferred to a 10 L glass vessel and the mass is slowly cooled to 0-5°C. for about 1 hour. The mixture is stirred at this temperature for 1 hour and the precipitate is filtered through a sintered glass filter. The solid is washed with a mixture of 1.6 kg of anhydrous ethyl acetate and 0.14 kg of i-propanol cooled at 0-5°C. The solid is dried in a vacuum oven at 50°C. for a minimum period of 12 hours. M.p. 117-119°C.

Example 1: Preparation of 3-(Piperidin-1-yl)-1-propanol
To the 3-Chloro-1-propanol (100 gm), added Piperidine (189 gm) and toluene (300 ml). Heated the reaction mixture at 95 – 105°C and stirred for 10 hours to 11 hours. The obtained reaction mixture was cooled to 25 – 35°C, followed by filtration and washed with toluene (100 ml). Distilled off toluene completely under vacuum at below 60°C to yield 3-(Piperidin-1-yl)-1-propanol.
Yield: 145 gm (96%)
Purity: 99.4% by GC
Dimer Impurity Content: 0.02%

Example 2: Preparation of 3-(4-Chlorophenyl)propyl methanesulfonate
To the 3-(4-Chlorophenyl)propanoic acid (100 gm), added toluene (300 ml) & borane THF (596 ml) slowly at 25 – 35°C for 40 minutes to 60 minutes. The reaction mixture was stirred for 1 hour to 1 hour 30 minutes at 25 – 35°C. Added Dil.HCl (dissolving 20 ml of Conc.HCl in 80 ml of water) at 25 – 35°C and stirred the reaction mixture for 30 minutes to 50 minutes at 25 – 35°C. Added water (700 ml) to the reaction mixture and stirred for 15 minutes. The layers were separated and added toluene (100 ml) to the aqueous layer, combined the toluene later and washed with sodium bicarbonate solution followed by distillation to remove THF and water. The obtained reaction mass was cooled to 25 – 35°C, added DMAP (10 gm), TEA (65 gm) and MsCl (75 gm), followed by stirring for 1 hour to 1 hour 30 minutes at 25 – 35°C. Added water (200 ml) and stirred for 15 minutes at 25 – 35°C, added Dil.HCl and washed with aq.NaHCO3 solution & water (100 ml). Activated carbon (5 gm) was added and stirred for 10 minutes at 25 – 35°C, followed by filtration and washed with toluene (100 ml). Concentrate under vacuum below 50°C and added cyclohexane (300 ml). The reaction mass was heated to 45 – 50°C, cooled to 5 – 15°C and stirred for 45 minutes to 60 minutes at to 5 – 15°C. The obtained solid was filtered, washed with cyclohexane (50 ml) and dried under vacuum at 25 – 35°C for 8 hours to 10 hours to yield 3-(4-Chlorophenyl)propylmethanesulfonate.
Yield: 115 gm (86%)
Purity: 98.32% by HPLC

Example 3: Preparation of Pitolisant
To the KOH powder (55 gm), added DMSO (500 ml), 3-(Piperidin-1-yl)-1-propanol (100 gm) at 25 – 35°C. Stirred the reaction mass for 40 minutes to 60 minutes, added 3-(4-Chlorophenyl)propyl methanesulfonate solution (prepared by dissolving 3-(4-Chlorophenyl)propyl methanesulfonate (200 gm) in DMSO (200 ml)) slowly for 45 minutes to 60 minutes and stirred for 5 hours to 6 hours at 25 – 35°C. Added water (600 ml), extracted the product in toluene layer and the layer were separated. Cooled to 10 – 20°C, added HCl solution and stirred for 15 minutes to 20 minutes at 25 – 35°C. The layers were separated, washed with toluene (300 ml) and adjusted the aqueous layer pH to 11 – 12 with NaOH solution and extracted the product into Toluene layer, concentration under vacuum below 60°C to yield Pitolisant Free base.
Yield: 165 gm (80%)
Purity: 98.46% by HPLC
Dimer Impurity Content: 0.07%

Example 4: Preparation of Pitolisant
To the 3-(Piperidin-1-yl)-1-propanol (100 gm), added DMSO (500 ml), t-BuOK (95 gm) at 25 – 35°C and stirred for 30 minutes to 45 minutes. To the obtained reaction mixture, added 3-(4-Chlorophenyl)propyl methanesulfonate solution (prepared by dissolving 3-(4-Chlorophenyl)propyl methanesulfonate (200 gm) in DMSO (200 ml)) at 25 – 35°C slowly for 45 minutes to 60 minutes and stirred for 5 hours to 6 hours at 25 – 35°C. Added water (600 ml), extracted the product into toluene layer and layers were separated. Cooled to 10 – 20°C, added HCl solution and stirred for 15 minutes to 20 minutes at 25 – 35°C. The layers were separated, washed with toluene (300 ml) and adjusted the pH to 11 – 12 with NaOH solution and the extracted the product in to Toluene layer, concentration under vacuum below 60°C to yield Pitolisant Free base.
Yield: 170 gm (82%)
Purity: 97.97% by HPLC
Dimer Impurity Content: 0.06%

Example 5: Preparation of Pitolisant
To the 3-(Piperidin-1-yl)-1-propanol (100 gm), added DMSO (500 ml), NaH (95 gm) at 25 – 35°C and stirred for 30 minutes to 45 minutes. To the obtained reaction mixture, added 3-(4-Chlorophenyl)propyl methanesulfonate solution (prepared by dissolving 3-(4-Chlorophenyl)propyl methanesulfonate (200 gm) in DMSO (200 ml)) at 25 – 35°C slowly for 45 minutes to 60 minutes and stirred for 5 hours to 6 hours. Added water (600 ml), extracted the product into Toluene layer and layers were separated. Cooled to 10 – 20°C, added HCl solution and stirred for 15 minutes to 20 minutes at 25 – 35°C. The layers were separated, washed with toluene (300 ml) and adjusted the pH to 11 – 12 with NaOH solution and extracted the product into Toluene layer, concentration under vacuum below 60°C to yield Pitolisant Free base.
Yield: 165 gm (79%)
Purity: 98.58% by HPLC
Dimer Impurity Content: 0.10%

Example 6: Preparation of Pitolisant
To the 3-(Piperidin-1-yl)-1-propanol (5 gm), DMSO (25 ml), added NaOH powder (1.96 gm), added 3-(4-Chlorophenyl)propyl methanesulfonate solution (prepared by dissolving 3-(4-Chlorophenyl)propyl methanesulfonate (10 gm) in DMSO (10 ml)) at 25 – 35°C. Stirred the reaction mass for 5 hours at 25 – 35°C and maintained for 10 hours to 15 hours, added water (30 ml), toluene (20 ml) and stirred for 10 minutes. Added HCl and cooled to 20 – 35°C. Adjusted the pH to 11 to 12 with NaOH solution, added toluene (20 ml) and stirred for 10 minutes. Filtered through hyflo bed and washed with toluene (20 ml), then distilled under vacuum below 60°C to yield Pitolisant Free base.
Yield: 6.0 gm (58%)
Purity: 95.98% by HPLC
Dimer Impurity Content: 0.06%

Example 7: Preparation of Pitolisant Hydrochloride
To the Pitolisant (100 gm), added EA (250 ml) and the reaction mass was cooled to 5 – 15°C. To the obtained reaction mass, added HCl in EA (90 ml) and stirred for 60 minutes to 70 minutes. The obtained solid was filtered and washed with EA (100 ml). The obtained wet solid, added EA (400 ml) and heated to 60 – 70°C and stirred for 10 minutes. Allowed to cool the reaction mixture to 25 – 35°C and stirred for 45 minutes to 60 minutes. The obtained solid was filtered and washed with EA (100 ml), then dried in vacuum oven below 60°C for 10 hours to 12 hours to yield Pitolisant Hydrochloride.
Yield: 100 gm (90%)
Purity: 99.85% by HPLC
Dimer Impurity Content: 0.06%
,CLAIMS:We Claim:

1. A process for the preparation of Pitolisant and its pharmaceutically acceptable salt thereof of Formula I:

which comprises:
i) condensing 3-halo-1-propanol of Formula A

with piperidine of Formula B

in absence of base to yield 3-(Piperidin-1-yl)-1-propanol of Formula II;

ii) condensing 3-(Piperidin-1-yl)-1-propanol compound of Formula II with 3-(4-Chlorophenyl)propyl methanesulfonate of Formula III

in presence of a base to yield Pitolisant of Formula I(a);

iii) optionally converting the obtained Pitolisant of Formula I(a) in step (ii) to its pharmaceutically acceptable salt thereof of Formula (I).

2. The process as claimed in claim 1, wherein solvent used in step i) is selected from the group comprising of halogenated solvents, ethers, hydrocarbons, nitriles or mixture of solvents thereof.

3. The process as claimed in claim 1, wherein base used in step ii) is selected from the group comprising of KOH powder, NaOH powder, t-BuOK, NaH and the like.

4. The process as claimed in claim 1, wherein solvent used in step ii) is selected from the group comprising of halogenated solvents, ketones, ethers, esters, nitriles, polar aprotic solvents or mixture of solvents thereof.

5. The process as claimed in claim 1, wherein acid used in conversion step iii) is Hydrochloride.