WO2019167085A1 - Process for the preparation of (s)-2-[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]amino propanamide methanesulfonate - Google Patents

Process for the preparation of (s)-2-[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]amino propanamide methanesulfonate Download PDF

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WO2019167085A1
WO2019167085A1 PCT/IN2019/050180 IN2019050180W WO2019167085A1 WO 2019167085 A1 WO2019167085 A1 WO 2019167085A1 IN 2019050180 W IN2019050180 W IN 2019050180W WO 2019167085 A1 WO2019167085 A1 WO 2019167085A1
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safinamide
solvents
formula
compound
methyl
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PCT/IN2019/050180
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French (fr)
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Thirumalai Rajan Srinivasan
Eswaraiah Sajja
Venkata Panakala Rao Gogulapati
Shyam Kiranbabu GANDHAM
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Msn Laboratories Private Limited, R&D Center
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Publication of WO2019167085A1 publication Critical patent/WO2019167085A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups

Definitions

  • the present invention relates to an improved process for the preparation of (S)-2- [[4- [(3-fluorophenyl)methoxy]phenyl]methyl]aminopropanamide methanesulfonate compound of formula- la, represented by the following structural formula:
  • Safinamide brand name Xadago is a drug used as an add-on treatment for Parkinson's disease during "off episodes; it has monoamine oxidase B inhibiting and other methods of action. It was approved in Europe in 2015 and in the United States in 2017.
  • Safinamide has been developed by Newron Pharmaceuticals SpA as adjunct therapy for the treatment of subjects with idiopathic Parkinson’s disease.
  • US’957 patent discloses process for the preparation of safinamide by reacting glycinamide hydrochloride with 3-fluorobenzyloxybenzaldehyde in the presence of sodium cyanoborohydride in methanol to provide safinamide compound of formula- 1 as a residue which was purified by column chromatography.
  • First embodiment of the present invention provides a process for the preparation of (L')-2-[[4-[(3 -fluorophenyl) methoxy] phenyl] methyl] aminopropanamide methanesulfonate compound of formula- la, comprising:
  • Second embodiment of the present invention provides solid state forms of Safinamide free base.
  • Third embodiment of the present invention provides crystalline from of Safinamide free base, herein after referred as form-M.
  • Fourth embodiment of the present invention provides a process for purification of Safinamide.
  • Fifth embodiment of the present invention provides a process for the preparation of Safinamide mesylate.
  • Figure 1 Illustrates the PXRD pattern of crystalline form-M of Safinamide.
  • suitable base used herein the present invention until unless specified is selected from inorganic bases like“alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like;“alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; ammonia; and organic bases such as “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; triethyl amine, methyl amine, ethyl amine, l,8-diaza bicyclo[5.4.0]undec-7-ene (DBU), l
  • DBU
  • suitable solvent refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methylcyclohexane, m-, o-, or p-xylene, and the like;“ether solvents” such as dimethoxy methane, tetrahydrofuran, l,3-dioxane, l,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, di ethylene glycol diethyl ether, tri ethylene glycol dimethyl ether, t-butyl methyl ether, 1,2- dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl methyl ether, n-hexan
  • solid state forms may include crystalline form, and an amorphous form, also including premixes, co-precipitates, solvates and the like, or a mixture of amorphous and one or more crystalline forms.
  • anti-solvent refers to a liquid that, when combined with a solution of Safinamide, reduces solubility of the Safinamide in the solution, causing crystallization or precipitation in some instances spontaneously, and in other instances with additional steps, such as seeding, cooling, scratching, and/or concentrating.
  • First embodiment of the present invention provides a process for the preparation of (S)-2- [ [4- [(3 -fluorophenyl)methoxy] phenyl] methyl] aminopropanamide methanesulfonate compound of formula- la, comprising:
  • the suitable base in step-a) is selected from organic or inorganic base
  • the suitable solvent in step-a) to step-c) is selected from alcohol solvents, chloro solvents, ester solvents, ketone solvents, nitrile solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents and polar solvent like water or mixture thereof.
  • Second embodiment of the present invention provides solid state forms of Safinamide free base.
  • Third embodiment of the present invention provides crystalline from of Safinamide free base, herein after referred as form-M.
  • the present invention provides crystalline form-M of Safinamide free base is characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 9.8, 13.9, 15.6, 17.8, 20.3, 26.7 and 29.9 ⁇ 0.2 degrees of 2-theta.
  • XRD X-ray powder diffraction
  • the present invention provides crystalline form-M of Safinamide free base is further characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 18.6, 19.8, 22.1, 23.3, 24.9 and 30.3 ⁇ 0.2 degrees of 2-theta.
  • XRD X-ray powder diffraction
  • the crystalline form-M of Safinamide is further characterized by its X-ray powder diffraction (XRD) pattern as illustrated in figure- 1.
  • XRD X-ray powder diffraction
  • Fourth embodiment of the present invention provides a process for purification of Safinamide compound of formula- 1, comprising:
  • a suitable solvent selected from alcohol solvents, chloro solvents, ester solvents, ketone solvents, nitrile solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents and polar solvent like water or mixture thereof.
  • the solution may be filtered to make it particle free.
  • isolating the pure Safinamide can be carried out by any methods known in the art or can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
  • the suitable solvent used in step-a) is selected from alcohol solvents, chloro solvents, ester solvents, ketone solvents, nitrile solvents, ether solvents, polar aprotic solvents and polar solvent like water or mixture thereof.
  • the solution may be filtered to make it particle free.
  • heating the reaction mixture to a suitable temperature ranging from 35°C to the reflux temperature of the solvent used.
  • the solvent used in step-c) is hydrocarbon solvent selected from pentane, n-hexane, n-heptane, cyclohexane, pet ether, toluene, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene.
  • isolating the pure Safinamide can be carried out by any methods known in the art or can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
  • Safinamide compound of formula- 1 is having purity greater than about 99.95% as measured by HPLC.
  • the salt of Safinamide is Safinamide mesylate.
  • the Safinamide mesylate has purity by HPLC of greater than about 99.9 %.
  • Fifth embodiment of the present invention provides a process for the preparation of Safinamide mesylate, comprising: a) Reacting l-(chloromethyl)-3-fluorobenzene compound of formula-2 with 4-hydroxy benzaldehyde compound of formula-3 in a suitable base in the presence or absence of suitable phase transfer catalyst in a suitable solvent to provide 4-((3-fluorobenzyl) oxy)benzaldehyde compound of formula-4,
  • suitable base used in step-a) and b) is selected from organic or inorganic base;
  • the suitable solvent used in step-a) to step-d) is selected from alcohol solvents, chloro solvents, ester solvents, ketone solvents, nitrile solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents and polar solvent like water or mixture thereof.
  • the starting material l-(chloromethyl)-3-fluorobenzene compound of formula-2 and 4-hydroxybenzaldehyde compound of formula-3 used in the present invention can be prepared by any of the prior known process.
  • Safinamide mesylate obtained according to the present invention is having purity greater than 99.5% by HPLC.
  • the present invention provides Safinamide mesylate acid having particle size distribution of D 90 less than about 150 pm, preferably less than about 100 pm; more preferably less than about 50 pm.
  • the process of the present invention is represented schematically as follows:
  • (L')-2-[[4-[(3 -fluoropheny l)methoxy] phenyl] methyl] aminopr opanamide methane sulfonate compound of formula- la produced by the present invention can be micronized or milled using conventional techniques to get the desired particle size to achieve desired solubility profile to suit to pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include, but not limited to ball milling, roller milling and hammer milling. Milling or micronization may be performed before drying, or after the completion of drying of the product.
  • compositions comprising compound of formula- 1 or salts thereof of the present invention.
  • pharmaceutical compositions or “pharmaceutical formulations” include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • P-XRD Method of Analysis PXRD analysis of compounds produced by the present invention were carried out using BRUKER D8 ADVANCE/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
  • PSD method of Analysis Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument.
  • Toluene 250 ml was added to l-(chloromethyl)-3-fluorobenzene (50 gms) at 25- 30°C.
  • 4-Hydroxybenzaldehyde 38.8 gms
  • tetra butyl ammonium bromide 5.83 gms
  • potassium carbonate 43.0 gms
  • Tetrahydrofuran 300 ml was added to (S)-2-aminopropanamide hydrochloride (13.51 gms) at 25-30°C under nitrogen atmosphere and stirred the reaction mixture for 15 minutes.
  • Sodium sulphate (20.0 gms) was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature.
  • Sodium triacetoxy borohydride 54.50 gms was slowly added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature.
  • Particle Size Distribution D(0.l) is 2.0 pm; D(0.5) is 6.3 pm; D(0.9) is 26.6 pm; D[4.3] is 10.9 pm;
  • Toluene (1000 ml) was added to 2-fluorobenzyl chloride (118.38 gms) at 25-30°C.
  • 4- Hydroxybenzaldehyde (100 gms), tetra butyl ammonium bromide (10.55 gms) and potassium carbonate (113.16 gms) was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 105-1 l0°C and stirred for 12 hours at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 15 minutes at the same temperature. Filtered the reaction mixture and washed with toluene. Distilled off the solvent completely from the filtrate under reduced pressure.
  • Toluene (38.0 ml) was added to the obtained compound at 40-45 °C and stirred for 15 minutes at the same temperature. Cooled the reaction mixture to 25-30°C. The reaction mixture was slowly added to n-Hexane (380 ml) at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with n-Hexane. To the obtained compound, toluene (68 ml) was added at 25-30°C and stirred for 15 minutes at the same temperature. N-Hexane (680 ml) was added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with n-Hexane and dried to get the title compound. Yield: 100 gms; M.R: 43-46°C.
  • Tetrahydrofuran 500 ml was added to (S)-2-aminopropanamide hydrochloride (64.77 gms) at 25-30°C under nitrogen atmosphere and stirred the reaction mixture for 15 minutes.
  • Triethyl amine 66.78 gms was added to the reaction mixture at 25-30°C and stirred for 20 minutes at the same temperature.
  • the title compound obtained in example-4 was added to the reaction mixture at 25-30°C.
  • Sodium sulphate 100.84 gms was added to the reaction mixture at 25-30°C. Cooled the reaction mixture to 5-l0°C and stirred for 5 hours at the same temperature.
  • Tetrahydrofuran (1200 ml) was added to the reaction mixture.
  • Particle Size Distribution D(0.l) is 2.3 pm; D(0.5) is 8.0 pm; D(0.9) is 33.0 pm; D[4.3] is 13.6 pm.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to an improved process for the preparation of (S)-2- [[4-[(3-fluorophenyl) methoxy] phenyl] methyl] amino propanamide methanesulfonate compound of formula-1a, represented by the following structural formula: Formula-1a The present invention also relates to novel crystalline form of (S)-2- [[4-[(3-fluorophenyl) methoxy] phenyl] methyl] aminopropanamide methanesulfonate compound of formula-1.

Description

Process for the preparation of (S)-2-rr4-r(3-fluorophenyl)methoxylphenyllmethyllamino propanamide methanesulfonate
Related Application:
This application claims the benefit of priority of our Indian patent application number IN201841007721 filed on 0 Ist March 2018 which is incorporated herein by reference.
Field of the Invention:
The present invention relates to an improved process for the preparation of (S)-2- [[4- [(3-fluorophenyl)methoxy]phenyl]methyl]aminopropanamide methanesulfonate compound of formula- la, represented by the following structural formula:
Figure imgf000002_0001
Formula- la
Background of the Invention:
Safinamide; brand name Xadago is a drug used as an add-on treatment for Parkinson's disease during "off episodes; it has monoamine oxidase B inhibiting and other methods of action. It was approved in Europe in 2015 and in the United States in 2017.
Safinamide has been developed by Newron Pharmaceuticals SpA as adjunct therapy for the treatment of subjects with idiopathic Parkinson’s disease.
Safinamide and its pharmaceutically acceptable salts were disclosed in US5236957 hereinafter referred as US’957.
US’957 patent discloses process for the preparation of safinamide by reacting glycinamide hydrochloride with 3-fluorobenzyloxybenzaldehyde in the presence of sodium cyanoborohydride in methanol to provide safinamide compound of formula- 1 as a residue which was purified by column chromatography.
The said US’957 patent suffers from several disadvantages such as usage of sodium cyanoborohydride which is a major drawback of this reagent is that upon hydrolysis it readily forms the toxic, volatile compound hydrogen cyanide. Further, the said process involves column chromatography which is tedious and time consuming and making the process more economical and not viable for commercial scale production.
Process for the preparation of safinamide described in Journal of medicinal chemistry -1998, vol-4l, pages-579-590 by Pevarello et al., by reacting glycinamide hydrochloride with 3-fluorobenzyloxybenzaldehyde in the presence of sodium cyanoborohydride and molecular sieves to provide safinamide which is isolated by column chromatography, followed by conversion into the corresponding salts by treatment with acids. No information is provided about the enantiomeric and/or chemical purity of safinamide and/or their salts. The method described suffers from many drawbacks which limit its use of process on large scale.
The said process suffers from the following draw backs:
a) Involves the formation of cyano derivatives.
b) Use of powdered molecular sieves which are expensive.
c) Yields of final compound of fromula-l are lower than 70%.
d) Use of large amounts of the solvent employed in the reductive alkylation reaction resulting in the generation of lot of spent and unwanted waste products which are difficult to dispose and can lead to pollution of the environment.
e) Isolation of the final product by column chromatography, which is considered a troublesome and expensive method when carried on large scale preparations.
Hence, in view of above drawbacks there still remains an unmet need to develop an improved process which is cost-effective, environment friendly, commercially viable process which provide final compound of formula- 1 with high yield and purity.
Brief description of the Invention:
First embodiment of the present invention provides a process for the preparation of (L')-2-[[4-[(3 -fluorophenyl) methoxy] phenyl] methyl] aminopropanamide methanesulfonate compound of formula- la, comprising:
a) Reacting 4-(3-fluorobenzyloxy)benzaldehyde with (S)-2-aminopropanamide in the presence of sodium(triacetoxy)borohydride in a suitable base in a suitable solvent to provide (L')-2-[[4-[(3 -fluoropheny l)methoxy] phenyl] methyl] aminopropanamide compound of formula- 1,
b) optionally purifying fS')-2-[[4-[(3-fluorophenyl)methoxy]phenyl] methyl] amino propanamide the compound of formula- 1 using a suitable solvent.
c) treating the compound of formula- 1 with methane sulfonic acid in a suitable solvent to provide (L')-2-[[4-[(3 -fluoropheny l)methoxy] phenyl] methyl] aminopropanamide methane sulfonate compound of formula- la.
Second embodiment of the present invention provides solid state forms of Safinamide free base.
Third embodiment of the present invention provides crystalline from of Safinamide free base, herein after referred as form-M.
Fourth embodiment of the present invention provides a process for purification of Safinamide.
Fifth embodiment of the present invention provides a process for the preparation of Safinamide mesylate.
Brief description of the Drawings:
Figure 1: Illustrates the PXRD pattern of crystalline form-M of Safinamide.
Detailed Description of the Invention:
The term“suitable base” used herein the present invention until unless specified is selected from inorganic bases like“alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like;“alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; ammonia; and organic bases such as “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; triethyl amine, methyl amine, ethyl amine, l,8-diaza bicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithium diiso propylamide (LDA), n-butyllithium, tribenzylamine, isopropylamine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethylamino pyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, l-methylimidazole, 1,2, 4-triazole, l,4-diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.
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, methylcyclohexane, m-, o-, or p-xylene, and the like;“ether solvents” such as dimethoxy methane, tetrahydrofuran, l,3-dioxane, l,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, di ethylene glycol diethyl ether, tri ethylene glycol dimethyl ether, t-butyl methyl ether, 1,2- 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- methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane and the like;“ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, ethylene glycol, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, di ethyleneglycol monoethyl ether, cyclohexanol, or glycerol and the like;“polar solvents” such as water or mixtures thereof.
As used herein the term“solid state forms” may include crystalline form, and an amorphous form, also including premixes, co-precipitates, solvates and the like, or a mixture of amorphous and one or more crystalline forms.
The term“anti-solvent” refers to a liquid that, when combined with a solution of Safinamide, reduces solubility of the Safinamide in the solution, causing crystallization or precipitation in some instances spontaneously, and in other instances with additional steps, such as seeding, cooling, scratching, and/or concentrating. First embodiment of the present invention provides a process for the preparation of (S)-2- [ [4- [(3 -fluorophenyl)methoxy] phenyl] methyl] aminopropanamide methanesulfonate compound of formula- la, comprising:
a) Reacting 4-(3-fluorobenzyloxy)benzaldehyde with (S)-2-aminopropanamide in the presence of sodium(triacetoxy)borohydride in a suitable base in a suitable solvent to provide (L')-2-[[4-[(3 -fluoropheny l)methoxy] phenyl] methyl] aminopropanamide compound of formula- 1,
b) optionally purifying fS')-2-[[4-[(3-fluorophenyl)methoxy]phenyl] methyl] amino propanamide the compound of formula- 1 using a suitable solvent.
c) treating the compound of formula- 1 with methane sulfonic acid in a suitable solvent to provide (L')-2-[[4-[(3 -fluoropheny l)methoxy] phenyl] methyl] aminopropanamide methanesulfonate compound of formula- la.
Wherein, the suitable base in step-a) is selected from organic or inorganic base;
the suitable solvent in step-a) to step-c) is selected from alcohol solvents, chloro solvents, ester solvents, ketone solvents, nitrile solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents and polar solvent like water or mixture thereof.
Second embodiment of the present invention provides solid state forms of Safinamide free base.
Figure imgf000006_0001
Third embodiment of the present invention provides crystalline from of Safinamide free base, herein after referred as form-M.
In the third embodiment, the present invention provides crystalline form-M of Safinamide free base is characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 9.8, 13.9, 15.6, 17.8, 20.3, 26.7 and 29.9 ± 0.2 degrees of 2-theta.
In the third embodiment, the present invention provides crystalline form-M of Safinamide free base is further characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 18.6, 19.8, 22.1, 23.3, 24.9 and 30.3 ± 0.2 degrees of 2-theta.
In an embodiment of the present invention the crystalline form-M of Safinamide is further characterized by its X-ray powder diffraction (XRD) pattern as illustrated in figure- 1.
Fourth embodiment of the present invention provides a process for purification of Safinamide compound of formula- 1, comprising:
a) Suspending Safinamide in a suitable solvent,
b) heating the reaction mixture,
c) isolating pure Safinamide compound of formula- 1.
In the process of the fourth embodiment, suspending Safinamide in a suitable solvent selected from alcohol solvents, chloro solvents, ester solvents, ketone solvents, nitrile solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents and polar solvent like water or mixture thereof. Optionally, the solution may be filtered to make it particle free.
In the process of the fourth embodiment, heating the reaction mixture to a suitable temperature ranging from 35°C to the reflux temperature of the solvent used.
In the process of the fourth embodiment, isolating the pure Safinamide can be carried out by any methods known in the art or can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In an embodiment of the present invention provides a process for purification of Safinamide, comprising:
a) Suspending Safinamide in a suitable solvent,
b) heating the reaction mixture,
c) adding anti-solvent to the reaction mixture,
d) isolating pure Safinamide. In an embodiment of the present invention, the suitable solvent used in step-a) is selected from alcohol solvents, chloro solvents, ester solvents, ketone solvents, nitrile solvents, ether solvents, polar aprotic solvents and polar solvent like water or mixture thereof. Optionally, the solution may be filtered to make it particle free.
In an embodiment of the present invention, heating the reaction mixture to a suitable temperature ranging from 35°C to the reflux temperature of the solvent used.
In an embodiment of the present invention, the solvent used in step-c) is hydrocarbon solvent selected from pentane, n-hexane, n-heptane, cyclohexane, pet ether, toluene, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene.
In an embodiment of the present invention, isolating the pure Safinamide can be carried out by any methods known in the art or can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In an embodiment of the present invention wherein Safinamide compound of formula- 1 is having purity greater than about 99.95% as measured by HPLC.
In an embodiment of the present invention, further comprising converting the Safinamide of formula- 1 into a salt of Safinamide.
In an embodiment of the present invention, wherein the salt of Safinamide is Safinamide mesylate.
In an embodiment of the present invention, wherein the Safinamide mesylate has purity by HPLC of greater than about 99.9 %.
Fifth embodiment of the present invention provides a process for the preparation of Safinamide mesylate, comprising: a) Reacting l-(chloromethyl)-3-fluorobenzene compound of formula-2 with 4-hydroxy benzaldehyde compound of formula-3 in a suitable base in the presence or absence of suitable phase transfer catalyst in a suitable solvent to provide 4-((3-fluorobenzyl) oxy)benzaldehyde compound of formula-4,
b) reacting compound of formula-4 with (S)-2-aminopropanamide hydrochloride compound of formula-5 in the presence of sodium sulphate in sodium (triacetoxy) borohydride / sodium cyanoborohydride in a suitable base in a suitable solvent to provide (S)-2-[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]aminopropanamide compound of formula- 1 ,
c) purifying the compound of formula- 1 using a suitable solvent to provide pure compound of formula- 1 ,
d) treating the compound of formula- 1 with methane sulfonic acid in presence of a suitable solvent to provide S)-2-[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]amino propanamide mesylate compound of formula- la.
In the process of the fifth embodiment, suitable base used in step-a) and b) is selected from organic or inorganic base;
the suitable solvent used in step-a) to step-d) is selected from alcohol solvents, chloro solvents, ester solvents, ketone solvents, nitrile solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents and polar solvent like water or mixture thereof.
The starting material l-(chloromethyl)-3-fluorobenzene compound of formula-2 and 4-hydroxybenzaldehyde compound of formula-3 used in the present invention can be prepared by any of the prior known process.
Safinamide mesylate obtained according to the present invention is having purity greater than 99.5% by HPLC.
In an embodiment, the present invention provides Safinamide mesylate acid having particle size distribution of D90 less than about 150 pm, preferably less than about 100 pm; more preferably less than about 50 pm. The process of the present invention is represented schematically as follows:
Figure imgf000010_0001
Triethylamine, THF
Formula-2
Figure imgf000010_0002
Ethyl acetate
Methane sulfonic acid
Figure imgf000010_0003
Formula-la
(L')-2-[[4-[(3 -fluoropheny l)methoxy] phenyl] methyl] aminopr opanamide methane sulfonate compound of formula- la produced by the present invention can be micronized or milled using conventional techniques to get the desired particle size to achieve desired solubility profile to suit to pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball milling, roller milling and hammer milling. Milling or micronization may be performed before drying, or after the completion of drying of the product.
The invention also encompasses pharmaceutical compositions comprising compound of formula- 1 or salts thereof of the present invention. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
P-XRD Method of Analysis: PXRD analysis of compounds produced by the present invention were carried out using BRUKER D8 ADVANCE/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
PSD method of Analysis: Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument.
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: Preparation of 4-(3-fluorobenzyloxy)benzaldehyde
Toluene (250 ml) was added to l-(chloromethyl)-3-fluorobenzene (50 gms) at 25- 30°C. 4-Hydroxybenzaldehyde (38.8 gms), tetra butyl ammonium bromide (5.83 gms) and potassium carbonate (43.0 gms) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 105-1 l0°C and stirred for 8 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered the reaction mixture and washed with toluene. Distilled off the solvent completely from the filtrate under reduced pressure. Methanol was added to the obtained compound at 25-30°C and stirred for 15 minutes at the same temperature. The reaction mixture was slowly added to a pre-cooled aqueous potassium carbonate at 0-5 °C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with water. N-heptane was added to the obtained wet compound at 25-30°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with n-heptane and dried to get the title compound. Yield: 60.0 gms; M.R: 52-57°C.
Example-2: Preparation of (S)-2-[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]amino propanamide
Tetrahydrofuran (300 ml) was added to (S)-2-aminopropanamide hydrochloride (13.51 gms) at 25-30°C under nitrogen atmosphere and stirred the reaction mixture for 15 minutes. Sodium sulphate (20.0 gms) was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Sodium triacetoxy borohydride (54.50 gms) was slowly added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. 4-(3-fluorobenzyloxy)benzaldehyde (20.0 gms) and tetrahydrofuran (100 ml) was added to the reaction mixture at 25-30°C and stirred for 12 hours at the same temperature. Cooled the reaction mixture to 0-5 °C. Adjusted the pH of the reaction mixture using aqueous sodium hydroxide solution. Filtered the reaction mixture through hyflow bed and washed the bed with ethyl acetate. Extracted the filtrate using ethyl acetate. Distilled off the solvent completed from the organic layer. Toluene (60 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 70-75°C and stirred for 45 minutes at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with toluene and dried to get the title compound.
Yield: 17.0 gms; M.R: l25-l30°C.
Example-3: Preparation of (S)-2-[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]amino propanamide methanesulfonate
Ethyl acetate (2500 ml) was added to (S)-2-[[4-[(3-fluorophenyl)methoxy]phenyl] methyljamino propanamide (100 gms) at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed. Methane sulfonic acid (33.25) was slowly added to the obtained filtrate at 55- 60°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 20-25°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 88.0 gms; M.R: 2l4-2l7°C.
Purity by HPLC: 99.93%; Acid impurity: 0.01%. Chiral Purity by HPLC: 99.94%; R-Isomer: 0.01%.
Particle Size Distribution (PSD): D(0.l) is 2.0 pm; D(0.5) is 6.3 pm; D(0.9) is 26.6 pm; D[4.3] is 10.9 pm;
Example-4: Preparation of 4-(3-fluorobenzyloxy)benzaldehyde
Toluene (1000 ml) was added to 2-fluorobenzyl chloride (118.38 gms) at 25-30°C. 4- Hydroxybenzaldehyde (100 gms), tetra butyl ammonium bromide (10.55 gms) and potassium carbonate (113.16 gms) was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 105-1 l0°C and stirred for 12 hours at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 15 minutes at the same temperature. Filtered the reaction mixture and washed with toluene. Distilled off the solvent completely from the filtrate under reduced pressure. Toluene (38.0 ml) was added to the obtained compound at 40-45 °C and stirred for 15 minutes at the same temperature. Cooled the reaction mixture to 25-30°C. The reaction mixture was slowly added to n-Hexane (380 ml) at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with n-Hexane. To the obtained compound, toluene (68 ml) was added at 25-30°C and stirred for 15 minutes at the same temperature. N-Hexane (680 ml) was added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with n-Hexane and dried to get the title compound. Yield: 100 gms; M.R: 43-46°C.
Example-5: Preparation of (S)-2-[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]amino propanamide
Tetrahydrofuran (500 ml) was added to (S)-2-aminopropanamide hydrochloride (64.77 gms) at 25-30°C under nitrogen atmosphere and stirred the reaction mixture for 15 minutes. Triethyl amine (66.78 gms) was added to the reaction mixture at 25-30°C and stirred for 20 minutes at the same temperature. The title compound obtained in example-4 was added to the reaction mixture at 25-30°C. Sodium sulphate (100.84 gms) was added to the reaction mixture at 25-30°C. Cooled the reaction mixture to 5-l0°C and stirred for 5 hours at the same temperature. Tetrahydrofuran (1200 ml) was added to the reaction mixture. Sodium cyanoborohydride (54.67 gms) was slowly added to the reaction mixture in five lots at 5- l0°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 20 hours at the same temperature. Aqueous sodium carbonate solution was added to the reaction mixture and stirred for 3 hours at 25-30°C. Both the organic and aqueous layers were separated. Distilled off the solvent from the organic layer under reduced pressure. Aqueous layer was extracted twice from ethyl acetate. Ethyl acetate was added to the above reaction mixture. Washed the organic layer with water and then with aqueous sodium chloride solution. Carbon (2.0 gms) was added to the organic layer at 25-30°C and stirred for 20 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed the bed with ethyl acetate. Distilled off the solvent from the filtrate under reduced pressure and co-distilled with ethyl acetate. Yield: 125 gms.
Purity by HPLC: 94.55%, 4-Fluoro impurity: 0.04%; Alcohol impurity: 2.23%; N-alkyl impurity: 0.10%; Dimer impurity: 0.41%; Aldehyde impurity: 0.11%. Chiral Purity by HPLC: 99.20%, R-Isomer: 0.73%; 4-Fluoro impurity: 0.07%;
The PXRD pattern of the obtained compound was depicted in Figure- 1.
Example-6: Purification of (S)-2-[ [4- [(3-fluorophenyl)methoxy] phenyl] methyl] amino propanamide
Acetone (320 ml) and n-Heptane (320 ml) was added to the obtained compound in example-5 at 25-30°C. Heated the reaction mixture to 40-45 °C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the solid, washed with mixture of acetone and n-Heptane to provide the title compound. Yield: 85.0 gms. Purity by HPLC: 99.87%, 4-Fluoro impurity: Not detected; Alcohol impurity: Not detected; N-alkyl impurity: 0.04%; Dimer impurity: 0.02%; Aldehyde impurity: Not detected. Chiral Purity by HPLC: 99.92%, R-Isomer: 0.04%; 4-Fluoro impurity: 0.04%; The PXRD pattern of the obtained compound was depicted in Figure- 1. Example-7: Purification of (S)-2-[ [4- [(3-fluorophenyl)methoxy] phenyl] methyl] amino propanamide
Ethyl acetate (250 ml) and Acetone (250 ml) was added to the obtained compound in example-6 at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 45 minutes at the same temperature. n-Heptane (500 ml) was slowly added to the reaction mixture at 50- 55 °C and stirred for 2 hours at same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with mixture of ethyl acetate, acetone and n-Heptane and dried to provide the title compound.
Yield: 72.0 gms; M.R: l3l.9-l32.2°C. Purity by HPLC: 99.91%, N-alkyl impurity: 0.03%; Dimer impurity: 0.02%. Purity by HPLC: 99.97%, R-Isomer: Not detected%; 4-Fluoro impurity: 0.03%. The PXRD pattern of the obtained compound was depicted in Figure-l. Example-8: Preparation of (S)-2-[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]amino propanamide methanesulfonate
A mixture of (S)-2-[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]aminopropanamide (100 gms) and ethyl acetate (2500 ml) was heated to 50-55°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed the bed with ethyl acetate. A solution containing a mixture of ethyl acetate (200) and methane sulfonic acid (33.25 gms) was added to the reaction mixture at 50-55°C and stirred for 45 minutes at the same temperature. Cooled the reaction mixture to 20-25°C and stirred for 45 minutes at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 88.0 gms:
Purity by HPLC: 99.94%; Acid impurity: 0.02%.
Chiral Purity by HPLC: 99.96%; R-Isomer: 0.01%.
Particle Size Distribution (PSD): D(0.l) is 2.3 pm; D(0.5) is 8.0 pm; D(0.9) is 33.0 pm; D[4.3] is 13.6 pm.

Claims

We Claim:
1. A process for the preparation of fS')-2-[[4-[(3-fluorophenyl)methoxy]phenyl]methyl] amino propanamide methanesulfonate compound of formula- la,
Figure imgf000016_0004
Formula- la
comprising:
a) Reacting 4-(3-fluorobenzyloxy)benzaldehyde compound of formula-2
Figure imgf000016_0001
Formula-2
with (S)-2-aminopropanamide compound of formula-3 or its salts
Figure imgf000016_0002
Formula-3
in presence of sodium(triacetoxy)borohydride / sodium cyanoborohydride in a base to provide (L')-2-[[4-[(3 -fluoropheny l)methoxy] phenyl] methyl] aminopropanamide compound of formula- 1,
Figure imgf000016_0003
Formula- 1
b) optionally purifying (A)-2-[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]aminopropan amide the compound of formula- 1 using a suitable solvent, c) treating the compound of formula- 1 with methane sulfonic acid in a suitable solvent to provide (L')-2-[[4-[(3 -fluoropheny l)methoxy] phenyl] methyl] aminopropanamide methanesulfonate compound of formula- la.
2. The process according to claim 1 wherein, purifying fV)-2-[[4-[(3-fluorophenyl) methoxy]phenyl]methyl]aminopropanamide from a solvent selected from alcohol solvents, ester solvents, ester solvents, hydrocarbon solvents, ketone solvents, ether solvents, nitrile solvents, chloro solvents, water or mixture thereof.
3. Crystalline form-M of Safinamide is characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 9.8, 13.9, 15.6, 17.8, 20.3, 26.7 and 29.9 ± 0.2 degrees of 2- theta.
4. Crystalline form-M of Safinamide according to claim 3 is further characterized by its X- ray powder diffraction (XRD) pattern having peaks at about 18.6, 19.8, 22.1, 23.3, 24.9 and 30.3 ± 0.2 degrees of 2-theta and X-ray powder diffraction (XRD) pattern is illustrated in figure- 1.
5. A process for purification of Safinamide compound of formula- 1, comprising:
a) Providing a solution of Safinamide in a suitable solvent,
b) isolating Safinamide compound of formula- 1.
6. The process as claimed in claim 5 wherein, suspending Safinamide in a suitable solvent is selected from alcohol solvents, chloro solvents, ester solvents, ketone solvents, nitrile solvents, ether solvents, hydrocarbon solvents, polar aprotic solvents and polar solvent like water or mixture thereof; Optionally, the solution can be filtered to make it particle free;
7. A process for purification of Safinamide compound of formula- 1, comprising:
a) Providing a solution of Safinamide in a suitable solvent,
b) adding anti-solvent to the reaction mixture, c) isolating Safinamide compound of formula- 1.
8. The process according to claim 7 wherein, suitable solvent used in step-a) is selected from alcohol solvents, chloro solvents, ester solvents, ketone solvents, nitrile solvents, ether solvents, polar aprotic solvents and polar solvent like water or mixture thereof; Optionally, the solution may be filtered to make it particle free.
9. The process according to claim 7 wherein, anti-solvent used in step-b) is hydrocarbon solvents selected from pentane, n-hexane, n-heptane, cyclohexane, pet ether, toluene, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene.
10. The process according to claim 5 & 7 wherein, isolating pure Safinamide can be carried out by decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
11. The process according to claim 5 & 7 wherein Safinamide compound of formula- 1 is having purity greater than about 99.95% as measured by HPLC.
12. A process according to claim 5 & 7, further comprising converting the Safinamide of formula- 1 into a salt of Safinamide.
13. A process according to claim 12, wherein the salt of Safinamide is Safinamide mesylate.
14. A process according to claim 13, wherein the Safinamide mesylate has purity by HPLC of greater than about 99.9 %.
15. The process according to claim 14, wherein Safinamide mesylate having particle size distribution of D90 less than about 150 pm, preferably less than about 100 pm; more preferably less than about 50 pm.
16. Safinamide mesylate obtained according to claim 1 is useful for the preparation of pharmaceutical composition.
17. A pharmaceutical composition comprising Safinamide mesylate according to claim 1 and a pharmaceutically acceptable carrier or diluent.
PCT/IN2019/050180 2018-03-01 2019-03-01 Process for the preparation of (s)-2-[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]amino propanamide methanesulfonate WO2019167085A1 (en)

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WO2023041209A1 (en) * 2021-09-14 2023-03-23 Zach System Process for the preparation of safinamide

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