DESC:Field of the Invention:
The present invention relates to crystalline form of N-ethyl-1-(3-(trifluoro methyl) phenyl)
propan-2-amine hydrochloride compound of formula-1, which is represented by the following
5 structural formula:
Formula-1
10
The present invention also relates to process for the preparation of compound of formula-1.
Background of the Invention:
N-ethyl-1-(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
15 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 However, it was withdrawn from the market in 1997 due to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®.
20
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 HCl salt having M.R as 166°C.
The process involved in US’833 usage of lithium aluminium hydride reagent, which is
25 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.
3
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 5 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
10 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
15 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,
20 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 .
25 Brief Description:
The first aspect of the present invention is to provide crystalline form of N-ethyl-1-(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
30 crystalline Form-M of N-ethyl-1-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride
compound of formula-1.
4
The third aspect of the present invention is to provide a process for preparation of Nethyl-
1-(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-1-(5 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-1-(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-1-(3-(trifluoro
10 methyl) phenyl) propan-2-amine hydrochloride compound of formula-1.
Figure 4: Illustrates the TGA thermogram of crystalline Form-M of N-ethyl-1-(3-(trifluoro
methyl) phenyl) propan-2-amine hydrochloride compound of formula-1.
Figure 5: Illustrates the IR of crystalline Form-M of N-ethyl-1-(3-(trifluoro methyl) phenyl)
propan-2-amine hydrochloride compound of formula-1.
15
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,
20 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, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-
dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl
25 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,
30 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-
5
trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or
3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether,
cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or
mixtures thereof.
5
The first aspect of the present invention provides crystalline Form-M of N-ethyl-1-(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, 10 39.38, 42.17 & 44.11
± 0.2° 2?. 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
15 crystalline Form-M of N-ethyl-1-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride
compound of formula-1; comprising of:
a) Suspending the compound of formula-1a 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-1-(3-(trifluoro
20 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
25 preparation of crystalline Form-M of N-ethyl-1-(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,
30 d) cooling the solution obtained in step-c) and filtering as crystalline Form-M of N-ethyl-1-(3-
(trifluoro methyl) phenyl)propan-2-amine hydrochloride.
6
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 5 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 mµ, D(10) <
10 mµ, D(50) < 15 mµ; preferably D(0.9) < 25 mµ; D(10) < 4 mµ; D(50) < 9 mµ;
10
The third aspect of the present invention is to provide a process for preparation of
crystalline Form-M of N-ethyl-1-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride
compound of formula-1, comprising of :
15 a) Reacting the compound of formula-2
Formula-2
with suitable reagents, solvent to provide compound of formula-3, reacting in-situ with
20 compound of formula-A, with a suitable reagent and solvent to provide compound of formula-4,
Formula-4
b)optionally purifying the compound obtained in step-a) in a suitable solvent (or) any distillation
method,
25 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-1a (or) 1.
d) optionally purifying the compound of formula-1a in suitable solvent to provide the compound
of formula-1.
30
7
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) Conc. HCl, NaNO2, prop-1-en-2-yl acetate, sodium acetate or
potassium acetate, CuCl;
The suitable purification technique in step-b) is selected from distillation, fractional 5 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 H2 gas, Pd/C under H2 gas;
10
The preferred embodiment of the present invention is to provide a process for preparation
of crystalline Form-M of N-ethyl-1-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride
compound of formula-1, comprising of :
15 a)Reacting the compound of formula-2
Formula-2
with a mixture of NaNO2, Con. HCl 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
20 provide compound of formula-4,
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
25 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 HCl to provide the compound of formula-1a .
d) stirring the compound of formula-1a 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.
8
Another embodiment of the present invention is to provide a process for the preparation
of N-ethyl-1-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula-1,
comprising of :
a)condensation of the compound of formula-4
5
Formula-4
with suitable reagent, solvent and reducing the obtained compound in-situ with a suitable
reagent, solvent and acidifaction using IPA HCl in solvent to provide 10 compound of formula-1a
(or) 1,
b) optionally purifying the compound of formula-1a in suitable solvent to provide compound of
formula-1.
15 Another embodiment of the present invention is to provide a process for the preparation
of N-ethyl-1-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride compound of formula-1,
comprising of :
a) condensation of the compound of formula-4
20
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 HCl to provide the compound of formula-1a.
25 b) suspending the compound of formula-1a 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-1-(3-
(tri fluoromethyl) phenyl)propan-2-amine hydrochloride.
30
9
The present invention is described in the schematic representation as follows.
5
The crystalline Form-M of N-ethyl-1-(3-(trifluoro methyl) phenyl)propan-2-amine hydro
chloride compound of Formula-1 produced by the present invention can be 10 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.
15
PXRD analysis of crystalline Form-M of N-ethyl-1-(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.
20
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.
25
10
Examples:
Example-1: Preparation of compound of formula-4
A round bottom flask was charged with water (453 mL), Con. HCl (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 NaNO2 (87 g) in water 5 (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-1-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
10 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.
15 Yield: 160 g
Example-2: Preparation of compound of formula-4
A round bottom flask was charged with water (230 mL), Con. HCl (190 mL) was stirred for 15
min at 0-5 °C. 3-(Trifluoromethyl)aniline (100 g) was charged to the above reaction mixture for
20 over 30 min, followed by addition of a solution NaNO2 (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-1-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
25 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
30 300 mL of water) and stirred for 12 hr at 25-35°C. Filtered the obtained solid, washed with nheptane
(50 mL), the wet solid was suspended in heptane (200 mL) and stirred for 30 min.
11
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 5 at 45°C, to get the title
compound.
Yield: 79.2 g
Purity by GC: >99 %
Example-3: Preparation of compound of formula-4
10 A round bottom flask was charged with water (567 mL), Con. HCl (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 NaNO2 (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.
15 An another RBF was charged with prop-1-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 1hr. The
reaction mass was cooled to 25-30 °C, added n-heptane (625 mL) and stirred for 15 min. The
20 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
25 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-1a.
A round bottom flask was charged with sodium hydroxide (112 g ), methanol (528 mL) stirred at
30 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
12
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 5 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
10 and dried to obtain the title compound.
Yield : 148 g .
Purity by HPLC: >99.9 %
Example-5: Process for preparation of Fenfluramine hydrochloride
A round bottom flask was charged with sodium hydroxide (35 g), methanol (500 mL) and cooled
15 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
20 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
25 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
30 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
13
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 5 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
10 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.
15 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.
20 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 %
25 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
30 PXRD of the compound is depicted in Figure -1.
Yield: 89 g.
14
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 5 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)
10 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
15 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.
20 Yield: 7.0 g
Example-12: Purification of compound of formula-1 (Crystalline Form-M)
A round 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
25 (150 ml) dried to get the title compound.
Yield: 4.0 g
Example-13: Purification of compound of formula-1 (Crystalline Form-M)
A round 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
30 and stirred for 45 min. The obtained solid was filtered and washed with n-butanol (10 ml) and
dried to get the title compound.
15
Yield: 8.5 g
Example-14: Process for preparation of Fenfluramine
A round bottom flask was charged with compound of formula-1 (5 g), methylenedichloride (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 5 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:1. A crystalline Form-M of N-ethyl-1-(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, 5 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° 2?.
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 10 figure-3.
3. A process for the preparation of crystalline Form-M of N-ethyl-1-(3-(trifluoro methyl) phenyl) propan-2-amine hydrochloride compound of formula-1; comprising of:
a) Suspending the compound of formula-1 in suitable solvent, 15
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-1-(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 20 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-1-(3-(trifluoro methyl) phenyl) propan-2-amine hydrochloride compound of formula-1; comprising of: 25
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-1-(3-(trifluoro methyl) phenyl)propan-2-amine hydrochloride. 30
17
6. A process for the preparation of N-ethyl-1-(3-(trifluoro methyl) phenyl)propan-2-amine hydro
chloride compound of formula-1, comprising of :
a)condensation of the compound of formula-4
5
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
10 followed by acidification using isopropyl alcohol HCl to provide the compound of formula-1a ,
b) stirring the compound of formula-1a 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-1-(3-(trifluoro methyl) phenyl)
15 propan-2-amine hydrochloride compound of formula-1, comprising of :
a) Reacting the compound of formula-2
Formula-2
with suitable reagents, solvent to provide compound of formula-3 followed by reacting in-situ
20 with compound of formula-A, with a suitable reagent and solvent to provide compound of
formula-4,
Formula-4
b) optionally purifying the compound obtained in step-a),
25 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-1a (or) 1.
d) optionally purifying the compound of formula-1a in suitable solvent to provide the compound
of formula-1.
18
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) Conc. HCl, NaNO2, prop-1-en-2-yl acetate, sodium acetate or
potassium acetate, CuCl;
5 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 H2 gas, Pd/C under H2 gas;
10
8. A process for preparation of crystalline Form-M of N-ethyl-1-(3-(trifluoro methyl) phenyl)
propan-2-amine hydrochloride compound of formula-1, comprising of :
a)Reacting the compound of formula-2
15
Formula-2
with a mixture of NaNO2, Con. HCl 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,
20
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
25 hydrogen gas atmosphere in presence of Pd/C in methanol followed by acidification using
isopropyl alcohol HCl to provide the compound of formula-1a.
d) suspending the compound of formula-1a 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,
19
g) cooling the solution obtained in step-f) and filtering the crystalline Form-M of N-ethyl-1-(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. 5
10. The crystalline form-P of compound of formula-1 obtained according to any preceding claims having particle size of D(0.9) < 50 µm, D(10) < 10 µm, D(50) < 15 µm; preferably D(0.9) < 25 µm; D(10) < 4 µm; D(50) < 9 µm;