WO2021117057A1 - Polymorph of n-ethyl-1-(3-(trifluoromethyl)phenyl)propan-2-amine hydrochloride and process for preparation thereof - Google Patents

Polymorph of n-ethyl-1-(3-(trifluoromethyl)phenyl)propan-2-amine hydrochloride and process for preparation thereof Download PDF

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WO2021117057A1
WO2021117057A1 PCT/IN2020/051009 IN2020051009W WO2021117057A1 WO 2021117057 A1 WO2021117057 A1 WO 2021117057A1 IN 2020051009 W IN2020051009 W IN 2020051009W WO 2021117057 A1 WO2021117057 A1 WO 2021117057A1
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compound
formula
ethyl
crystalline form
propan
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PCT/IN2020/051009
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French (fr)
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Nagaraju Chakilam
Ramprasad Achampeta Kodanda
Pradeep Rebelli
Anil Kumar MUTYALA
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Maithri Drugs Pvt Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to crystalline form of N-ethyl-l-(3-(trifluoro methyl) phenyl) propan-2-amine hydrochloride compound of formula- 1, which is represented by the following structural formula:
  • the present invention also relates to process for the preparation of compound of formula- 1.
  • N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride is known as Fenfluramine Hydrochloride, was launched in 1963 by Servier in France and in 1973 by Wyeth in US for the treatment of obesity. However, it was withdrawn from the market in 1997 due to heart valve disease.
  • Zogenix Inc. a global pharmaceutical company has developed a low dose oral solution for the treatment of seizures associated with Dravet syndrome in patients 2 years of age and older.
  • the FDA has approved it on 25-June-2020 with the brand name FINTEPLA ® .
  • US3198833 (herein after designate as US’833) first reported Fenflurmine hydrochloride as product and process for preparation thereof.
  • Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
  • a single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA”, or differential scanning calorimetry - “DSC”), X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum.
  • TGA thermogravimetric analysis -
  • DSC differential scanning calorimetry -
  • Discovering new salts and new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
  • New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional salts and solid state forms of Fenfluramine Hydrochloride.
  • the present invention provides a crystalline form of fenfluramine hydrochloride and process for preparation thereof .
  • the first aspect of the present invention is to provide crystalline form of N-ethyl-l-(3-(tri fluoromethyl)phenyl)propan-2-amine hydrochloride compound of formula- 1, herein after designated as crystalline form-M of Fenfluramine hydrochloride.
  • the second aspect of the present invention is to provide a process for the preparation of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula- 1.
  • the third aspect of the present invention is to provide a process for preparation of N- ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula- 1
  • Figure 1 Illustrates the PXRD pattern of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula- 1 according to example -8.
  • Figure 2 Illustrates the PXRD pattern of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula- 1 according to example -9.
  • Figure 3 Illustrates the DSC thermogram of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl) propan-2-amine hydrochloride compound of formula- 1.
  • Figure 4 Illustrates the TGA thermogram of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl) propan-2-amine hydrochloride compound of formula- 1.
  • Figure 5 Illustrates the IR of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl) propan-2-amine hydrochloride compound of formula- 1.
  • suitable solvent refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, tri ethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2- dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl
  • the first aspect of the present invention provides crystalline Form-M of N-ethyl-l-(3- (trifluoromethyl) phenyl)propan-2-amine hydrochloride compound of formula- 1.
  • the crystalline Form-M of the present invention is characterized by its powder X-Ray diffraction pattern having peaks at about 6.53, 8.97, 12.28, 13.14, 13.94, 14.51, 17.26, 18.49, 19.63, 19.91, 22.42, 22.77, 24.07, 24.76, 25.18, 25.83, 26.48, 27.23, 28.15, 29.90, 31.83, 32.54, 33.91, 39.38, 42.17 & 44.11 ⁇ 0.2° 2Q.
  • the said crystalline form-M is further characterized by its powder X-Ray diffraction pattern substantially in accordance with figure- 1, by its DSC thermograph shown in figure-3.
  • the second aspect of the present invention is to provide a process for the preparation of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula- 1; comprising of: a) Suspending the compound of formula- la or 1 in suitable solvent, b) stirring the solution obtained in step-a) at suitable temperature, c) isolating the compound obtained is step-b) as crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride.
  • step-a) the suitable solvent selected from a hydrocarbon, chlorinated, polar aprotic, polar protic, ether, nitrile, ketone, ester, water, alcohol and mixture thereof; the suitable temperature is 15-100°C;
  • the preferred embodiment of the present invention is to provide a process for the preparation of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula- 1; comprising of: a) suspending the compound of formula- 1 in a mixture of ethyl acetate and water, b) stirring the solution obtained in step-a) at 60-70°C, c) filtering the solution obtained is step-b) at 60-70°C, d) cooling the solution obtained in step-c) and filtering as crystalline Form-M of N-ethyl-l-(3- (trifluoro methyl) phenyl)propan-2-amine hydrochloride.
  • the preferred embodimate of the present invention fenfluramine hydrochloride purification in ethylacete, alcohol, ketone and other solvents are know in the art. However, purification / crystallization of compound of formula- 1 using a mixture of water an organic solvent provides improved filterability with improved colour and free flowing crystals .
  • the preferred solvents are ester, ketone, alcohol, nitirle, polar aprotic, ether and water or mixture thereof.
  • the preferred embodimate of the present invention crystalline form-M of compound of formula- 1 obtained according to present process having particle size of D(0.9) ⁇ 50 mp, D(10) ⁇ 10 Giveaway, D(50) ⁇ 15 mp; preferably D(0.9) ⁇ 25 mp; D(10) ⁇ 4 mp; D(50) ⁇ 9 mp;
  • the third aspect of the present invention is to provide a process for preparation of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula- 1, comprising of : a) Reacting the compound of formula-2
  • the suitable solvent in step-a) b) c) d) is selected from a hydrocarbon, chlorinated, polar aprotic, polar protic, ether, nitrile, ketone, ester, water, alcohol and mixture thereof;
  • step-a) Cone. HC1, NaNC , prop-l-en-2-yl acetate, sodium acetate or potassium acetate, CuCl;
  • step-b) is selected from distillation, fractional distillation, column separation; wherein step-c) the suitable reagent is ethylamine or ethylamine hydrochloride, sodium hydroxide, potassium hydroxide, suitable reducing reagent is selected form sodium borohydride, sodium triacetoxy borohydride, sodiumcyanoborohydride, lithium aluminium hydride, Ray-Ni under 3 ⁇ 4 gas, Pd/C under 3 ⁇ 4 gas;
  • the preferred embodiment of the present invention is to provide a process for preparation of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula- 1, comprising of : a)Reacting the compound of formula-2
  • Formula-4 b) purifying the compound obtained in step-a) by fractional distillation method, c) condensation of the compound obtained in step- a) or b) with ethylamine hydrochloride, in presence sodium hydroxide in methanol to the obtained imine compound , reducing the obtained compound in-situ under hydrogen gas atmosphere in presence of Pd/C in methanol followed by acidification using isopropyl alcohol HC1 to provide the compound of formula- la . d) stirring the compound of formula-la in a mixture of ethyl acetate and water at 65-75°C, e) isolating the compound obtained in step-d) to provide the compound of formula- 1.
  • Another embodiment of the present invention is to provide a process for the preparation of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula- 1, comprising of : a)condensation of the compound of formula-4
  • Another embodiment of the present invention is to provide a process for the preparation of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula- 1, comprising of : a) condensation of the compound of formula-4
  • the crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydro chloride compound of Formula- 1 produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
  • the wet compound was charged in n-heptane (100 mL) and cooled to 10-20°C, slowly added 10 % sodium hydroxide solution (22.5 5 in 225 mL of water) stirred for 45 min. The both layers were separated , the aqueous layer was extracted with n-heptane (100 mL) . The combined organic layer was washed with water (50 mL), brine solution and dried the organic layer over sodium sulfate and concentrated under vacuum at 45 °C, to get the title compound.
  • the organic layer was separated and added n-heptane (625 mL), water (825 mL) and sodium metabisulfite ( 350 g) and stirred for 12 hrs at 25-30 °C.
  • the obtained solid was filtered, washed with n-heptane (250 mL).
  • the wet solid was suspended in n-heptane (250 mL) and adjusted the pH to 9-10 with 10% NaOH solution (450 mL) and stirred for 30 min at 25-30 °C. Separated the both layers and the organic layer was washed with water (2 x 250 mL). The combined organic layer was dried over sodium sulfate and concentrated to get the pure title compound.
  • the reaction mixture was extracted with dichloromethane (2 x 350 mL). The combined organic layer was washed with water (200 mL x 3) and evaporated the solvent to get free base of fenfluramine as colorless oil (57 g).
  • the fenfluramine crude compound (57 g) was diluted with ethyl acetate (450 mL) and cooled to 0-5 °C, adjusted the p H to 1.0 by using isopropyl alcohol hydrochloride and stirred for 30 min. The reaction mixture was warm to 25-30 °C and stirred for 1 hr at the same temperature. The obtained solid was filter and dried at 60-65 °C in hot air oven for 8 hrs to get the title compound. Yield: 61 g.
  • Example-6 Process for preparation of Fenfluramine hydrochloride
  • a round bottom flask was charged with sodium hydroxide (69.24 g), methanol (330 mL) and cooled to 0-5 °C, added ethylamine hydrochloride (141.18 g) and stirred for 30 min at the same temperature.
  • a compound of formula-4 100 g was added to the above reaction mass at 0-5°C and stirred for 3 hr at 20-35°C.
  • the reaction mixture was cooled to -5 to 5°C, charged with 5%- Pd/C (20.0 g in 100 mL of methanol) and stirred for 12 hr under hydrogen pressure ( ⁇ 7 kg ) at 65-75 °C.
  • reaction mixture was charged with water (250 mL), dichloromethane (350 mL) stirred for 20 min. Separated the both layers , the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layer was washed with water (100 mL ) and dried over sodium sulphate and evaporated the solvent to get free base of fenfluramine as colorless oil.
  • the fenfluramine crude compound was diluted with ethyl acetate (1000 mL) and cooled to 0-5 °C, adjusted the p H to 1.0 by using isopropyl alcohol hydrochloride (165 mL) and stirred for 30 min.
  • the reaction mixture was warm to 25-30 °C and stirred for 1 hr at the same temperature. Filtered the obtained solid, washed with ethyl acetate (50 mL) and dried at 60-65 °C in hot air oven for 8 hr to get the title compound.
  • the obtained compound PXRD is similar to the figure -1.
  • Example-12 Purification of compound of formula-1 (Crystalline Form-M)
  • Example-13 Purification of compound of formula-1 (Crystalline Form-M)

Abstract

The present invention relates to a crystalline form of N-ethyl-1-(3-(trifluoro methyl) phenyl) propan-2-amine hydrochloride compound of formula-1, which is represented by the following structural formula. The present invention also relates to process for the preparation of crystalline form of compound of formula-1 and process for the preparation of compound of formula-1.

Description

Field of the Invention:
The present invention relates to crystalline form of N-ethyl-l-(3-(trifluoro methyl) phenyl) propan-2-amine hydrochloride compound of formula- 1, which is represented by the following structural formula:
Figure imgf000002_0001
Formula- 1
The present invention also relates to process for the preparation of compound of formula- 1.
Background of the Invention:
N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride is known as Fenfluramine Hydrochloride, was launched in 1963 by Servier in France and in 1973 by Wyeth in US for the treatment of obesity. However, it was withdrawn from the market in 1997 due to heart valve disease.
Zogenix Inc., a global pharmaceutical company has developed a low dose oral solution for the treatment of seizures associated with Dravet syndrome in patients 2 years of age and older. The FDA has approved it on 25-June-2020 with the brand name FINTEPLA®.
The US3198833 (herein after designate as US’833) first reported Fenflurmine hydrochloride as product and process for preparation thereof. The US’833 isolated fenfluramine free base having boiling point as 108-112°C and Fenfluramine HC1 salt having M.R as 166°C. The process involved in US’833 usage of lithium aluminium hydride reagent, which is pyrophoric in nature, not suitable for industrial scale.
However, there is a need for an alternative preparative routes which for example, use reagents that are less expensive and easier to handle, consume smaller amount of reagents, provide a high yield of product, involve fewer steps, have smaller and / or more eco-friendly waste products, to provide a product of higher purity and quantity. The present invention describes an improved process for the preparation of compound of formula- 1 over the existing processes.
There are various processes reported for the preparation of Fenfluramine hydrochloride, but not disclosed any polymorphs or crystalline forms in the prior art.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
Discovering new salts and new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional salts and solid state forms of Fenfluramine Hydrochloride.
The present invention provides a crystalline form of fenfluramine hydrochloride and process for preparation thereof .
Brief Description :
The first aspect of the present invention is to provide crystalline form of N-ethyl-l-(3-(tri fluoromethyl)phenyl)propan-2-amine hydrochloride compound of formula- 1, herein after designated as crystalline form-M of Fenfluramine hydrochloride.
The second aspect of the present invention is to provide a process for the preparation of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula- 1. The third aspect of the present invention is to provide a process for preparation of N- ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula- 1
Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula- 1 according to example -8.
Figure 2: Illustrates the PXRD pattern of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula- 1 according to example -9.
Figure 3: Illustrates the DSC thermogram of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl) propan-2-amine hydrochloride compound of formula- 1.
Figure 4: Illustrates the TGA thermogram of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl) propan-2-amine hydrochloride compound of formula- 1.
Figure 5: Illustrates the IR of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl) propan-2-amine hydrochloride compound of formula- 1.
Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, tri ethylene glycol dimethyl ether, anisole, 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), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chlorinated solvents” such as dichloromethane, dichloroethane, chloroform, carbontetra chloride, dichlorobenzene and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone 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, 2-nitroethanol, 2-fluoroethanol, 2,2,2- trifluoroethanol, ethylene glycol, 2-methoxyethanol, 1,2-ethoxyethanol, di ethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, di ethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
The first aspect of the present invention provides crystalline Form-M of N-ethyl-l-(3- (trifluoromethyl) phenyl)propan-2-amine hydrochloride compound of formula- 1. The crystalline Form-M of the present invention is characterized by its powder X-Ray diffraction pattern having peaks at about 6.53, 8.97, 12.28, 13.14, 13.94, 14.51, 17.26, 18.49, 19.63, 19.91, 22.42, 22.77, 24.07, 24.76, 25.18, 25.83, 26.48, 27.23, 28.15, 29.90, 31.83, 32.54, 33.91, 39.38, 42.17 & 44.11 ± 0.2° 2Q. The said crystalline form-M is further characterized by its powder X-Ray diffraction pattern substantially in accordance with figure- 1, by its DSC thermograph shown in figure-3.
The second aspect of the present invention is to provide a process for the preparation of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula- 1; comprising of: a) Suspending the compound of formula- la or 1 in suitable solvent, b) stirring the solution obtained in step-a) at suitable temperature, c) isolating the compound obtained is step-b) as crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride.
Wherein step-a) the suitable solvent selected from a hydrocarbon, chlorinated, polar aprotic, polar protic, ether, nitrile, ketone, ester, water, alcohol and mixture thereof; the suitable temperature is 15-100°C;
The preferred embodiment of the present invention is to provide a process for the preparation of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula- 1; comprising of: a) suspending the compound of formula- 1 in a mixture of ethyl acetate and water, b) stirring the solution obtained in step-a) at 60-70°C, c) filtering the solution obtained is step-b) at 60-70°C, d) cooling the solution obtained in step-c) and filtering as crystalline Form-M of N-ethyl-l-(3- (trifluoro methyl) phenyl)propan-2-amine hydrochloride. The preferred embodimate of the present invention fenfluramine hydrochloride purification in ethylacete, alcohol, ketone and other solvents are know in the art. However, purification / crystallization of compound of formula- 1 using a mixture of water an organic solvent provides improved filterability with improved colour and free flowing crystals . The preferred solvents are ester, ketone, alcohol, nitirle, polar aprotic, ether and water or mixture thereof.
The preferred embodimate of the present invention crystalline form-M of compound of formula- 1 obtained according to present process having particle size of D(0.9) < 50 mp, D(10) < 10 ihm, D(50) < 15 mp; preferably D(0.9) < 25 mp; D(10) < 4 mp; D(50) < 9 mp;
The third aspect of the present invention is to provide a process for preparation of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula- 1, comprising of : a) Reacting the compound of formula-2
Figure imgf000006_0001
Formula-2 with suitable reagents, solvent to provide compound of formula-3, reacting in-situ with compound of formula- A, with a suitable reagent and solvent to provide compound of formula-4,
Figure imgf000006_0002
Formula-4 b)optionally purifying the compound obtained in step-a) in a suitable solvent (or) any distillation method, c) condensation of the compound obtained in step- a) or b) with suitable reagent, solvent, reducing the obtained compound in-situ with a suitable reagent, solvent to provide the compound of formula- la (or) 1. d) optionally purifying the compound of formula- la in suitable solvent to provide the compound of formula- 1. Wherein the suitable solvent in step-a) b) c) d) is selected from a hydrocarbon, chlorinated, polar aprotic, polar protic, ether, nitrile, ketone, ester, water, alcohol and mixture thereof;
The suitable reagent in step-a) Cone. HC1, NaNC , prop-l-en-2-yl acetate, sodium acetate or potassium acetate, CuCl;
The suitable purification technique in step-b) is selected from distillation, fractional distillation, column separation; wherein step-c) the suitable reagent is ethylamine or ethylamine hydrochloride, sodium hydroxide, potassium hydroxide, suitable reducing reagent is selected form sodium borohydride, sodium triacetoxy borohydride, sodiumcyanoborohydride, lithium aluminium hydride, Ray-Ni under ¾ gas, Pd/C under ¾ gas;
The preferred embodiment of the present invention is to provide a process for preparation of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula- 1, comprising of : a)Reacting the compound of formula-2
Figure imgf000007_0001
Formula-2 with a mixture of NaNC , Con. HC1 in water to provide compound of formula-3, followed by reacting in-situ with compound of formula-A, sodium acetate, water and CuCl in methanol to provide compound of formula-4,
Figure imgf000007_0002
Formula-4 b) purifying the compound obtained in step-a) by fractional distillation method, c) condensation of the compound obtained in step- a) or b) with ethylamine hydrochloride, in presence sodium hydroxide in methanol to the obtained imine compound , reducing the obtained compound in-situ under hydrogen gas atmosphere in presence of Pd/C in methanol followed by acidification using isopropyl alcohol HC1 to provide the compound of formula- la . d) stirring the compound of formula-la in a mixture of ethyl acetate and water at 65-75°C, e) isolating the compound obtained in step-d) to provide the compound of formula- 1. Another embodiment of the present invention is to provide a process for the preparation of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula- 1, comprising of : a)condensation of the compound of formula-4
Figure imgf000008_0001
Formula-4 with suitable reagent, solvent and reducing the obtained compound in-situ with a suitable reagent, solvent and aci difaction using IP A HC1 in solvent to provide compound of formula- la (or) 1, b) optionally purifying the compound of formula- la in suitable solvent to provide compound of formula- 1.
Another embodiment of the present invention is to provide a process for the preparation of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula- 1, comprising of : a) condensation of the compound of formula-4
Figure imgf000008_0002
Formula-4 with ethylamine hydrochloride, in presence sodium hydroxide in methanol, reducing the obtained compound in-situ under hydrogen gas atmosphere in presence of Pd/C in methanol followed by acidification using isopropyl alcohol HC1 to provide the compound of formula- la. b) suspending the compound of formula- la in a mixture of ethyl acetate and water , c) stirring the solution obtained in step-b) at 60-70°C, d) filtering the solution obtained is step-c) at 60-70°C, e) cooling the solution obtained in step-d) and filtering the crystalline Form-M of N-ethyl-l-(3- (tri fluoromethyl) phenyl)propan-2-amine hydrochloride. The present invention is described in the schematic representation as follows.
Figure imgf000009_0001
The crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydro chloride compound of Formula- 1 produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
PXRD analysis of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan- 2-amine hydrochloride compound of formula- 1 was carried out using BRUKER D8 ADVANCED/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
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 compound of formula-4
A round bottom flask was charged with water (453 mL), Con. HC1 (371.08 mL) was stirred for 15 min at 0-5 °C. 3-(trifluoromethyl)aniline (200 g) was charged to the above reaction mixture for over 30 min, followed by a solution of NaNC (87 g) in water (200 mL). The reaction mixture was stirred at 0-5 °C for 2 hr to obtain a solution of 3-(trifluoromethyl)diazonium chloride salt compound of formula-3.
An another RBF was charged with prop-l-en-2-yl acetate (248.5 g), methanol (573.2 mL) , NaOAc (101.4 g), water (1640 mL) and CuCl (2.95 g) simultaneously at 25-30 °C and stirred for 15 min. The reaction mass gradually heated to 35-45 °C, added to the above solution of compound of formula-3. The reaction mass was heated to 60-65 °C and stirred for 2.5 hr. The reaction mass was cooled to 25-30°C, added n-Heptane (400 mL) and stirred for 15 min. The organic layer was separated, washed with water (100 mL) and dried the organic layer over sodium sulfate and concentrated under vacuum at 65-70°C, 10 mm Hg to get the title compound. Yield: 160 g
Example-2: Preparation of compound of formula-4
A round bottom flask was charged with water (230 mL), Con. HC1 (190 mL) was stirred for 15 min at 0-5 °C. 3-(Trifluoromethyl)aniline (100 g) was charged to the above reaction mixture for over 30 min, followed by addition of a solution NaNCh (87 g) in water (200 mL) for 2 hr. The reaction mixture was stirred at 0-5 °C for 2 hr to obtain a solution of 3-(trifluoro methyl) diazonium chloride salt compound of formula-3.
An another RBF was charged with prop-l-en-2-yl acetate (124.28 g), methanol (300 mL) , sodium acetate (50.89 g), water (800 mL) and CuCl (1.53 g) simultaneously at 25-30°C and stirred for 15 min. The reaction mass gradually heated to 35-45 °C, added to the above solution of compound of formula-3, was heated to 60-65 °C and stirred for 2.5 hr. The reaction mass was cooled to 25-30°C, added n-heptane (350 mL) and stirred for 15 min. The organic layer was separated, aqueous layer was extracted with n-heptane (300 mL) and separated, the combined layer was washed with water (100 mL) and charged sodium metabisulphate (141.5 g dissolved in 300 mL of water) and stirred for 12 hr at 25-35°C. Filtered the obtained solid, washed with n- heptane (50 mL), the wet solid was suspended in heptane (200 mL) and stirred for 30 min. Filtered the obtain solid, the wet compound was charged in n-heptane (100 mL) and cooled to 10-20°C, slowly added 10 % sodium hydroxide solution (22.5 5 in 225 mL of water) stirred for 45 min. The both layers were separated , the aqueous layer was extracted with n-heptane (100 mL) . The combined organic layer was washed with water (50 mL), brine solution and dried the organic layer over sodium sulfate and concentrated under vacuum at 45 °C, to get the title compound.
Yield: 79.2 g Purity by GC: >99 %
Example-3: Preparation of compound of formula-4
A round bottom flask was charged with water (567 mL), Con. HC1 (463 mL) was stirred for 15 min at 0-5°C. 3-(Trifluoromethyl)aniline (250 g) was charged to the above reaction mixture for over 30 min, followed by a solution of NaNCh (108.75 g) in water (250 mL). The reaction mixture was stirred at 0-5 °C for 1 hr to obtain 3-(trifluoromethyl)diazonium chloride salt compound of formula-3.
An another RBF was charged with prop-l-en-2-yl acetate (310.7 g), methanol (716.5 mL), NaOAc (126.8 g), water (2050 mL) and CuCl (3.75 g) simultaneously at 25-30°C and stirred for 15 min. The reaction mass warm to 40-45°C, added to the above solution of 3-(trifluoromethyl) diazonium chloride salt. The reaction mass was heated to 60-65 °C and stirred for lhr. The reaction mass was cooled to 25-30 °C, added n-heptane (625 mL) and stirred for 15 min. The organic layer was separated and added n-heptane (625 mL), water (825 mL) and sodium metabisulfite ( 350 g) and stirred for 12 hrs at 25-30 °C. The obtained solid was filtered, washed with n-heptane (250 mL). The wet solid was suspended in n-heptane (250 mL) and adjusted the pH to 9-10 with 10% NaOH solution (450 mL) and stirred for 30 min at 25-30 °C. Separated the both layers and the organic layer was washed with water (2 x 250 mL). The combined organic layer was dried over sodium sulfate and concentrated to get the pure title compound.
Yield: 190 g.
Purity by HPLC: >99.5 %
Example-4: Preparation of compound of formula-la.
Around bottom flask was charged with sodium hydroxide (112 g ), methanol (528 mL) stirred at 0-5 °C for 15 min. Ethylamine hydrochloride (225 g) was added to the above reaction mixture at same temperature and stirred for 30 min. A compound of formula-4 (160 g ) was added to the reaction mass at 0-5 °C and stirred for 30 min. Sodium borohydride (28.8 g) was added portion wise to the above reaction mixture keeping the temperature below 10 °C and stirred for 30 min. The reaction mixture was warmed to 20-25°C, stirred for 5 hours. Methanol was distilled off under reduced pressure below 40°C, added water (650 mL), dichloromethane (350 mL) stirred for 15 min. The organic layer was separated, washed with water (200 mL x 3) and the organic layer was evaporated to get Fenfluramine free base as colorless oil (160 g). The obtained Fenfluramine crude compound (160 g) was diluted with ethyl acetate (1200 mL), adjusted the pH upto 1.0 by using isopropyl alcohol hydrochloride (245 mL) at 0-5 °C and stirred for 30 min. The reaction mixture was warmed to 25-30 °C and stirred for 1 hr, the obtained solid was filtered and dried to obtain the title compound.
Yield : 148 g .
Purity by HPLC: >99.9 %
Example-5: Process for preparation of Fenfluramine hydrochloride
Around bottom flask was charged with sodium hydroxide (35 g), methanol (500 mL) and cooled to 0-5 °C, added ethylamine hydrochloride (70.5 g) and stirred for 30 min at the same temperature. A compound of formula-4 (50 g) was added to the above reaction mass at 0-5°C and stirred for 30 min. The reaction mixture was charged with 5%-Pd/C (5.0 g) and stirred for 15 min below 10 °C under hydrogen pressure (10 kg ), gradually heated to 50-55 °C and stirred for 6 hr at same temperature. The reaction mixture was filtered, methanol was evaporated under reduced pressure below 40 °C and charged with water (650 ml). The reaction mixture was extracted with dichloromethane (2 x 350 mL). The combined organic layer was washed with water (200 mL x 3) and evaporated the solvent to get free base of fenfluramine as colorless oil (57 g). The fenfluramine crude compound (57 g) was diluted with ethyl acetate (450 mL) and cooled to 0-5 °C, adjusted the pH to 1.0 by using isopropyl alcohol hydrochloride and stirred for 30 min. The reaction mixture was warm to 25-30 °C and stirred for 1 hr at the same temperature. The obtained solid was filter and dried at 60-65 °C in hot air oven for 8 hrs to get the title compound. Yield: 61 g.
Purity by HPLC > 99.9 %
Example-6: Process for preparation of Fenfluramine hydrochloride
A round bottom flask was charged with sodium hydroxide (69.24 g), methanol (330 mL) and cooled to 0-5 °C, added ethylamine hydrochloride (141.18 g) and stirred for 30 min at the same temperature. A compound of formula-4 (100 g) was added to the above reaction mass at 0-5°C and stirred for 3 hr at 20-35°C. The reaction mixture was cooled to -5 to 5°C, charged with 5%- Pd/C (20.0 g in 100 mL of methanol) and stirred for 12 hr under hydrogen pressure (~7 kg ) at 65-75 °C. Cooled the reaction mixture to 20-30°C, filtered and washed with methanol (100 mL) and evaporated under reduced pressure below 65°C. The reaction mixture was charged with water (250 mL), dichloromethane (350 mL) stirred for 20 min. Separated the both layers , the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layer was washed with water (100 mL ) and dried over sodium sulphate and evaporated the solvent to get free base of fenfluramine as colorless oil. The fenfluramine crude compound was diluted with ethyl acetate (1000 mL) and cooled to 0-5 °C, adjusted the pH to 1.0 by using isopropyl alcohol hydrochloride (165 mL) and stirred for 30 min. The reaction mixture was warm to 25-30 °C and stirred for 1 hr at the same temperature. Filtered the obtained solid, washed with ethyl acetate (50 mL) and dried at 60-65 °C in hot air oven for 8 hr to get the title compound.
The obtained compound PXRD is similar to the figure -1.
Yield: 91.2 g.
Purity by HPLC > 99.9 %
Example-7: Purification of compound of formula-1 (Crystalline Form-M)
A round bottom flask was charged with Fenfluramine Hydrochloride (100 g), ethyl acetate (475 mL) and water (22 mL), was heated to 60-70°C to obtain clear solution and stirred for 45 min. Filtered the reaction mixture at 60-70°C, washed with ethyl acetate (25 mL). The filtrate solution was cooled to 20-30°C and stirred for 2.5 hr at the same temperature. Filtered the obtained solid and dried at 50-55°C in hot air oven for 7 hr to get the title compound.
Yield: 74 g.
Purity by HPLC: >99.8 %
Example-8: Purification of compound of formula-1 (Crystalline Form-M)
A round bottom flask was charged with Fenfluramine Hydrochloride (140 g), ethyl acetate (700 mL) and water (32 mL), was heated to 85-95°C to obtain clear solution and stirred for 30 min at same temperature. Cooled to 25-30°C and stirred for 1 hr at the same temperature. The obtained solid was filtered and dried at 60-65 °C in hot air oven for 8 hr to get the title compound. The PXRD of the compound is depicted in Figure -1.
Yield: 89 g. Purity by HPLC: >99.5 %
Example-9: Purification of compound of formula-1 (Crystalline Form-M)
A round bottom flask was charged with Fenfluramine Hydrochloride (1.0 g), ethanol (10 mL), and heated to 70-75°C, stirred for 40 min at same temperature. The reaction mixture was cooled to 25-30°C and stirred for 40 min. The obtained solid was filtered, washed with ethanol (3 ml) and dried at 60-65 °C in hot air oven for 8 hrs to get the title compound.
The PXRD of the compound is depicted in Figure -2.
Yield: 0.85 g
Example-10 Purification of compound of formula-1 (Crystalline Form-M)
A round bottom flask was charged with Fenfluramine Hydrochloride (50.0 g), isopropyl alcohol (500 mL) and heated to 70-75°C, stirred for 60 min at same temperature. Cooled the reaction mixture to 25-30°C and stirred for 60 min. The obtained solid was filtered, washed with isopropyl alcohol (50 ml) and dried to get the title compound.
Yield: 29.0 g
Example-11: Purification of compound of formula-1 (Crystalline Form-M)
A round bottom flask was charged with Fenfluramine Hydrochloride (10.0 g), methanol (10 mL) and ethyl acetate (100 mL) are heated to 60-65°C, stirred for 35 min at same temperature. Cooled the reaction mixture to 25-30 °C and stirred for 30 min. The obtained solid was filtered and dried to get the title compound.
Yield: 7.0 g
Example-12: Purification of compound of formula-1 (Crystalline Form-M)
Around bottom flask was charged with Fenfluramine Hydrochloride (5.0 g), acetonitrile (50 mL), heated to 80-85°C and stirred for 35 min at same temperature. The reaction mixture was cooled to 25-30°C and stirred for 30 min. The obtained solid was filtered and washed with acetonitrile (150 ml) dried to get the title compound.
Yield: 4.0 g
Example-13: Purification of compound of formula-1 (Crystalline Form-M)
Around bottom flask was charged with Fenfluramine Hydrochloride (10.0 g), n-butanol (50 mL) heated to 80-85°C, stirred for 1 hr at same temperature. Cooled the reaction mixture to 20-30°C and stirred for 45 min. The obtained solid was filtered and washed with n-butanol (10 ml) and dried to get the title compound. Yield: 8.5 g
Example-14: Process for preparation of Fenfluramine
A round bottom flask was charged with compound of formula- 1 (5 g), methylenedi chloride (50 mL) and water (50 mL) stirred for 15 min, adjusted the reaction mixture pH to 10-11 by using 10% NaOH solution and stirred for 30 min at 0-10 °C. The reaction mixture was heated to 25-30
°C, separated the organic layer, washed with water (2 x 50 ml). The organic layer was dried over sodium sulfate and evaporated to get the title compound.
Yield: 3.2 g
Purity by HPLC: 99.9%

Claims

We claims:
1. A crystalline Form-M of N-ethyl-l-(3-(trifluoromethyl) phenyl)propan-2-amine hydrochloride compound of formula- 1, is characterized by its powder X-Ray diffraction pattern having peaks at about 6.53, 8.97, 12.28, 13.14, 13.94, 14.51, 17.26, 18.49, 19.63, 19.91, 22.42, 22.77, 24.07, 24.76, 25.18, 25.83, 26.48, 27.23, 28.15, 29.90, 31.83, 32.54, 33.91, 39.38, 42.17 & 44.11 ± 0.2° 2Q.
2. The said crystalline form-M according to claim 1 is further characterized by its powder X-Ray diffraction pattern substantially in accordance with figure- 1, by its DSC thermograph shown in figure- 3.
3. A process for the preparation of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl) propan-2-amine hydrochloride compound of formula- 1; comprising of: a) Suspending the compound of formula- 1 in suitable solvent, b) stirring the solution obtained in step-a) at suitable temperature, c) isolating the compound obtained is step-b) as crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride.
4. A process for the preparation of crystalline Form-M according to claim 3 wherein step-a) the suitable solvent selected from hydrocarbon, polar aprotic, polar protic, ether, nitrile, ketone, ester, chlorinated, water, alcohol and mixture thereof; the suitable temperature is 15-100°C;
5. A process for the preparation of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl) propan-2-amine hydrochloride compound of formula- 1; comprising of: a) Suspending the compound of formula- 1 in mixture of ethyl acetate and water, b) stirring the solution obtained in step-a) at a 60-70°C, c) filtering the solution obtained is step-b) at 60-70°C, d) cooling the solution obtained in step-c) and filtering the crystalline Form-M of N-ethyl-l-(3- (trifluoro methyl) phenyl)propan-2-amine hydrochloride.
6. A process for the preparation of N-ethyl-l-(3-(trifluoro methyl) phenyl)propan-2-amine hydro chloride compound of formula- 1, comprising of : a)condensation of the compound of formula-4
Figure imgf000017_0001
Formula-4 with ethylamine hydrochloride in presence of sodium hydroxide in methanol , reducing the obtained compound in-situ under hydrogen gas atmosphere in presence of Pd/C in methanol followed by acidification using isopropyl alcohol HC1 to provide the compound of formula- la , b) stirring the compound of formula-la in a mixture of ethyl acetate and water at 65-75°C, c) isolating the compound obtained in step-b) to provide the compound of formula- 1.
7. A process for preparation of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl) propan-2-amine hydrochloride compound of formula- 1, comprising of : a) Reacting the compound of formula-2
Figure imgf000017_0002
Formula-2 with suitable reagents, solvent to provide compound of formula-3 followed by reacting in-situ with compound of formula- A, with a suitable reagent and solvent to provide compound of formula-4,
Figure imgf000017_0003
Formula-4 b) optionally purifying the compound obtained in step-a), c) condensation of the compound obtained in step- a) or b) with suitable reagent, solvent further reducing the obtained compound in-situ with a suitable reagent, solvent to provide the compound of formula- la (or) 1. d) optionally purifying the compound of formula- la in suitable solvent to provide the compound of formula- 1. Wherein the suitable solvent in step-a) b) c) d) is selected from hydrocarbon, polar aprotic, polar protic, ether, nitrile, ketone, ester, chlorinated, water, alcohol and mixture thereof;
The suitable reagent in step-a) Cone. HC1, NaNC , prop-l-en-2-yl acetate, sodium acetate or potassium acetate, CuCl;
The suitable purification technique in step-b) is selected from distillation, fractional distillation, column separation; wherein step-c) the suitable reagent is ethylamine or ethylamine hydrochloride, sodium hydroxide, potassium hydroxide, suitable reducing reagent is selected form sodium borohydride, sodium triacetoxy borohydride, sodiumcyanoborohydride, lithium aluminium hydride, Ray-Ni under ¾ gas, Pd/C under ¾ gas;
8. A process for preparation of crystalline Form-M of N-ethyl-l-(3-(trifluoro methyl) phenyl) propan-2-amine hydrochloride compound of formula- 1, comprising of : a)Reacting the compound of formula-2
Figure imgf000018_0001
Formula-2 with a mixture of NaNC , Con. HC1 in water to provide compound of formula-3, followed by reacting in-situ with compound of formula- A, in presence of sodium acetate, water and CuCl in methanol to provide compound of formula-4,
Figure imgf000018_0002
Formula-4 b)purifying the compound obtained in step-a) by fractional distillation method, c) condensing the compound obtained in step- a) or b) with ethylamine hydrochloride, in presence of sodium hydroxide in methanol, reducing the obtained compound in-situ under hydrogen gas atmosphere in presence of Pd/C in methanol followed by acidification using isopropyl alcohol HC1 to provide the compound of formula- la. d) suspending the compound of formula- la in mixture of ethyl acetate and water, e) stirring the solution obtained in step-d) at a 60-70°C, f) filtering the solution obtained is step-e) at 60-70°C, g) cooling the solution obtained in step-f) and filtering the crystalline Form-M of N-ethyl-l-(3- (trifluoro methyl) phenyl)propan-2-amine hydrochloride.
9. The compound of formula- 1 obtained according to any of preceding claims having purity > 95%, preferably > 99.9 % by HPLC.
10. The crystalline form-P of compound of formula- 1 obtained according to any preceding claims having particle size of D(0.9) < 50 mp, D(10) < 10 mp, D(50) < 15 mp; preferably D(0.9) < 25 mp; D(10) < 4 mp; D(50) < 9 mp;
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Citations (2)

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US20170174613A1 (en) * 2015-12-22 2017-06-22 Zogenix International Limited Fenfluramine compositions and methods of preparing the same
US20180208543A1 (en) * 2017-01-26 2018-07-26 Frau Pharma S.R.L. New method for synthesis of fenfluramine, and new compositions comprising it

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Publication number Priority date Publication date Assignee Title
US20170174613A1 (en) * 2015-12-22 2017-06-22 Zogenix International Limited Fenfluramine compositions and methods of preparing the same
US20180208543A1 (en) * 2017-01-26 2018-07-26 Frau Pharma S.R.L. New method for synthesis of fenfluramine, and new compositions comprising it

Non-Patent Citations (1)

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Title
CAIRA M R: "Crystalline polymorphism of organic compounds", TOPICS IN CURRENT CHEMISTRY, vol. 198, 1 January 1998 (1998-01-01), BERLIN, DE, pages 163 - 208, XP008166276, Retrieved from the Internet <URL:https://link.springer.com/chapter/10.1007/3-540-69178-2_5.> DOI: 10.1007/3-540-69178-2_5 *

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