The present invention relates to a process for the preparation of the active
pharmaceutical ingredient Fingolimod Hydrochloride (I) and its highly pure
intermediate [2-acetamido-2-(acetyloxy methyl)-4-phenylbutyl] acetate(II)
(I) (II)
The present invention also relates to the highly pure intermediate [2-
acetamido-2-(acetyloxy methyl)-4-phenylbutyl] acetate(II) having purity exceeding
98% (by HPLC).
BACKGROUND OF THE INVENTION
Fingolimod hydrochloride (FTY720) has the IUPAC name as 2-amino-2-[2-
(4-octylphenyl) ethyl] propane-l,3-diol hydrochloride and has the following structure:
(I)
Fingolimod is a sphingosine 1-phosphate receptor modulator indicated and
approved for the treatment of relapsing-remitting multiple sclerosis. Fingolimod
hydrochloride capsule with proprietary name 'GILENYA' and strength of 0.50 mg was
approved by USFDA on September 21, 2010 for oral administration.
Fujita et al. US5604229 is the first disclosure of the Fingolimod, its processes and
other related compounds. Patent discloses 2-Amino-1, 3-propanediol compounds of
the formula
wherein R is an optionally substituted straight or branched carbon chain, an optionally
substituted aryl, an optionally substituted cycloalkyl or the like, and R2, R3, R4 and
R5 are the same or different and each is a hydrogen, an alkyl, an aralkyl, an acyl or an
3
alkoxycarbonyl, pharmaceutically acceptable salts thereof and immune suppressants
comprising these compounds as active ingredients. The 2-amino-1, 3-propanediol
compounds disclosed immunosuppressive action and are useful for suppressing
rejection in organ or bone marrow transplantation, prevention and treatment of
autoimmune diseases or as reagents for use in medicinal and pharmaceutical fields.
Kunitomo Adachi et al. in US6214873B1 discloses the preparation of 2-
acetamido-1, 3-diacetoxy-2-(2-phenylethyl) propane also known as [2-acetamido-2-
(acetyloxy methyl)-4-phenylbutyl] acetate(II) from diethyl acetamidomalonate
reacting with 2-phenylethyl bromide in presence of sodium hydride to give diethyl 2-
acetamido-2-(2-phenylethyl) malonate.
Scheme-1: Process as per US6214873B1
On further hydrolysis with lithium aluminum hydride and on acetylation
results in the desired compound. The process involves the use of sodium hydride and
lithium aluminium hydride which are not easy to handle at industrial scale resulting
in the process to be unamenable to commercial scale.
Adachi Kunitomo et al. in JP 4079505 B2 discloses the process of preparation
of 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol from diethyl acetylamide
malonate is reacted with (2-haloethyl) benzene in the presence of a sodium hydride to
obtain diethyl 2-acetylamide-2-phenylethyl malonate.
4
Scheme-2: Process as per JP 4079505 B2
After reducing this with lithium aluminium hydride, further acetylated to 2-
acetylamide-2-acetoxymethyl-4-phenylbutyl acetate, and then an octanoyl group is
introduced. The process involves several number of steps resulting in poor yield.
Chen Xiaoxiang et al. in WO2012031466A1 discloses the process for the
preparation of 2-(p-octylphenylethyl)-2-amino propanediol derivatives involving the
preparation of 2-acetylamino 2-(2-phenylethyl)-1,3-propanediol diacetate from
acetamido malonic acid diethyl ester by reacting with phenylethyliodide in presence
of sodium ethoxide, reducing with lithium aluminium hydride and further acetylating.
5
Scheme-3: Process as per WO2012031466A1
The process involves sodium ethoxide which is to be used when freshly
prepared and the overall yield was observed very low with low purity levels.
Chen Xiaoxiang et al. in CN102887834 A discloses the process of preparation
of 1-[4-[3-amino-4-hydroxy-3-(hydroxymethyl)butyl]phenyl]-1-acetoxime involving
the preparation of 2-acetamido-1, 3-diacetoxy-2-(2-phenylethyl) propane starting
from acetamido diethyl malonate reacting with sodium hydride in presence of
dimethylformamide which on further reduction with sodium borohydride in presence
of ethanol. Reacting N- [1,1-bis (hydroxymethyl) -3-phenylpropyl] acetamide with
acetic anhydride in tetrahydrofuran, triethylamine and DMAP.
6
Scheme-4: Process as per CN102887834 A
The process is for the preparation of impurities relates to Fingolimod
Hydrochloride. The steps are observed to be lengthy and have use of hazardous
reagents which are not usable for bulk production.
Shrawat et al. in US9732030B2 discloses the process of preparation of
fingolimod and its salts involving the process of preparation of 2-acetamido-2-
phenethylpropane-1,3-diyl diacetate starting from the reaction of diethyl acetamido
malonate with phenylethylbromide in presence of sodium metal in ethanol to yield
diethyl-2-acetamido-2(2-phenyl ethyl) malonate on reducing with lithium aluminium
hydride and acetylating with acetic anhydride. More particularly in the step 1 of
example 1, on reproducing entity resulted in a desired regioisomer ratio of not
exceeding 55-70% (by HPLC), whereby the residue obtained was subjecting to purify
by column chromatography over silica gel (230-400 mesh) using an eluent system of
ethyl acetate and hexane. The column purified material was still having purity of not
exceeding of 72-80%. Said material was used for the step-2 reduction whereby the
step-2 product obtained had purity of about 90% (by HPLC).
7
Scheme-5: Process as per US9732030B2
This material was 2 times purified by dissolving in methanol and recrystallized
by low temperature to get a purity of > 99.5%. The disadvantage of the process is that
it was observed the process is very tedious, cumbersome and time consuming method
and has several repeated purifications.
Further, in view of the existence of various literature /information known for
processes related to preparation of Fingolimod hydrochloride, there exists a need of
process/es, which are not only industrially and economically feasible process but also
amenable to scale up and provide improved yields & quality.
Within the large number of methods of preparation of Fingolimod
Hydrochloride and its intermediates, inventors of the present invention have found the
methods, which involve the use of highly pure intermediate [2-acetamido-2-
(acetyloxy methyl)-4-phenylbutyl] acetate(II) is highly efficient and industrially
feasible.
(II)
8
Thus, the inventors of the present application provide a simple and industrially viable
process for the preparation of Fingolimod or its hydrochloride involving the use of
highly pure intermediate [2-acetamido-2-(acetyloxy methyl)-4-phenylbutyl] acetate
(II) by a novel process which is highly efficient and easily up scalable.
SUMMARY OF THE INVENTION
Particular aspects of the present invention relate to the process for the
preparation of the Fingolimod Hydrochloride (I) and its highly pure key intermediate
[2-acetamido-2-(acetyloxymethyl)-4-phenylbutyl]acetate(II).
(I) (II)
comprising the steps of:
a) reacting diethylacetamidomalonate(VI) with phenylethylhalide(V) in
presence of a phase transfer catalyst, base and polar aprotic solvent at temperature
ranging between 80-100°C for a time ranging between 4-8 hours to give diethyl 2-
acetamido-2-phenethylmalonate (IV).
b) reacting diethyl 2-acetamido-2-phenethylmalonate(IV) with aqueous
NaBH4 at temperature ranging between 30-70°C to give N-(1-hydroxy-2-
(hydroxymethyl)-4-phenylbutan-2-yl) acetamide (III).
c) acetylation of N-(1-hydroxy-2-(hydroxymethyl)-4-phenylbutan-2-yl)
acetamide(III) with an acetylating agent in presence of an organic solvent for time
duration ranging between 2-6hrs to give [2-acetamido-2-(acetyloxy methyl)-4-
phenylbutyl] acetate (II).
d) the converting [2-acetamido-2-(acetyloxy methyl)-4-phenylbutyl]
acetate(II) obtained in step c) to get Fingolimod Hydrochloride of formula (I).
In yet another aspect the present invention also relates to a highly pure key
intermediate [2-acetamido-2-(acetyloxy methyl)-4-phenylbutyl] acetate (II) having
purity exceeding 98% (by HPLC).
9
The HPLC method used as per the present invention was performed at column
Intersil ODS-3V (250X4.6) 5μm or equivalent with solvent system of 0.1%
trifluoroacetic acid in acetonitrile at a wavelength of 220nm.
Further particular aspects of the invention are detailed in the description part
of the specification, wherever appropriately desired.
BRIEF DESCRIPTION OF THE DRAWINGS:
FIG. 1 is an illustration of HPLC graph of compound of formula (II).
FIG. 2 is an illustration of HPLC graph of compound of formula (I).
DETAILED DESCRIPTION:
Embodiments according to present invention provides a commercially
amenable process for preparing Fingolimod Hydrochloride, which is stable and
suitable for preparing therapeutic dosage forms and its highly pure key intermediate
[2-acetamido-2-(acetyloxy methyl)-4-phenylbutyl] acetate(II).
(I) (II)
In one embodiment of the present invention, it provides a process for preparing
Fingolimod Hydrochloride (I) comprising of the following steps:
a) reacting diethylacetamidomalonate(VI) with phenylethylhalide(V) in
presence of a phase transfer catalyst, base and polar aprotic solvent at temperature
ranging between 80-100°C for a time ranging between 4-8 hours to give diethyl 2-
acetamido-2-phenethylmalonate (IV).
b) reacting diethyl 2-acetamido-2-phenethylmalonate(IV) with aqueous
NaBH4 at temperature ranging between 30-70°C to give N-(1-hydroxy-2-
(hydroxymethyl)-4-phenylbutan-2-yl) acetamide (III).
c) acetylation of N-(1-hydroxy-2-(hydroxymethyl)-4-phenylbutan-2-yl)
acetamide(III) with an acetylating agent in presence of an organic solvent for time
duration ranging between 2-6hrs to give [2-acetamido-2-(acetyloxy methyl)-4-
phenylbutyl] acetate (II).
10
d) the converting [2-acetamido-2-(acetyloxy methyl)-4-phenylbutyl]
acetate(II) obtained in step c) to get Fingolimod Hydrochloride of formula (I).
Individual steps of the process according to the present invention are detailed herein
below.
In step a), the reaction is performed under nitrogen.
Diethylacetamidomalonate(VI) is dissolved in a polar aprotic solvent i.e. dimethyl
sulfoxide at 25-30°C followed by addition of base selected from cesium carbonate or
lithium carbonate and the phase transfer catalyst for the initiation of the reaction.
The role of base in the condensation reaction was found to be significantly
important.
Inventors found that cesium carbonate works as chemo selective inorganic
base catalyst. It was observed that particularly cesium carbonate and lithium carbonate
as selective catalyst for this step while others alkali carbonates like sodium carbonate
and potassium carbonate were found to be ineffective in performing the reaction.
The phase transfer catalyst used in the present invention is
tetrabutylammonium bromide followed by the addition of phenylethylhalide(V) under
nitrogen atmosphere at 80-100°C specifically at 80-85°C to give diethyl 2-acetamido2-phenethylmalonate (IV).
The phenylethylhalide used in step a) is selected from phenylethylbromide,
phenylethyliodide, phenylethylchloride.
In a particular embodiment, it was phenylethylbromide was used.
The molar ratio of phenylethylbromide used was 1-1.05 about molar ratio with
respect to of diethylacetamidomalonate.
The use of phase transfer catalyst in this step was found to provide reaction a
smoother course resulting in an improved yield.
Inventors observed that a reaction without phase transfer catalyst resulted in
about 20-25% lesser yield. The improve yield by using tetrabutylammonium bromide
as a phase transfer catalyst appears to be owing to by phasic reaction, wherein both
organic and inorganic phase remains in continuous connect during the course of
11
reaction, which appears to be missing in the case of reactions performed without phase
transfer catalyst.
In step b) of the present invention, diethyl 2-acetamido-2-
phenethylmalonate(IV) is treated with aqueous NaBH4 which is found to be more safe
as compared the lithium aluminium hydride used in the prior art.
In the prior art, it is mentioned that reaction may not proceed with sodium
borohydride or may result in low purity and yield as compared to the other reducing
agents such as sodium hydride, lithium aluminium hydride, lithium borohydride.
The inventors of the present invention observed that the addition of solid
sodium borohydride or in anhydrous environment does not move the reaction to
completion however, inventors surprisingly observed that the aqueous solution of
sodium borohydride results in completion of reaction with low impurity profile. The
use of aqueous solution of sodium borohydride is found to be easy to use in scalable
processes. The percentage aqueous solution of sodium borohydride was observed
suitable as about 30-70% w/w in aqueous medium.
The step b) of the present invention is performed in aqueous alcoholic medium
comprising a ratio of alcohol (C1-C3):water mixture is ranging between 1(diethyl 2-
acetamido-2-phenethyl malonate(IV)) :10-15(alcohol) (w/v) and 1(diethyl 2-
acetamido-2-phenethylmalonate(IV)):2-3(water) (w/v).
The alcohol which is used in the aqueous alcoholic medium of step b) is
selected from methanol, ethanol, n-butanol and isopropanol.
In particular embodiment, it was methanol used in the aqueous alcoholic
medium wherein the ratio of methanol: water mixture is ranging between 1(diethyl 2-
acetamido-2-phenethyl malonate(IV)) :10(methanol) (w/v) and 1(diethyl 2-
acetamido-2-phenethylmalonate(IV)):2(water) (w/v).
The inventors have found that the solvent medium needs to be alcoholic for
the reaction to occur in the manner to give desired product. The inventors have
investigated methanol, ethanol, 2-propanol, tetrahydrofuran, pyridine for the step b)
of the present invention.
Reaction in methanol with aqueous solution of sodium borohydride was
observed readily proceed at 30-70°C.
12
In a particular embodiment, Inventors observed that the reaction proceeds to
maximum at 40-60°C temperature range.
In reaction step c) of the present invention, it is preferred under nitrogen the
crude N-(1-hydroxy-2-(hydroxymethyl)-4-phenylbutan-2-yl) acetamide of step is
treated with an acetylating agent in an organic solvent.
The acetylating agent used is selected from acetic anhydride, acetyl chloride,
acetyl bromide.
In a particular embodiment of the present invention the acetylating agent used
is acetic anhydride. The use of acetic anhydride over acetyl chloride or acetyl bromide
is preferred because of less hazardousness and cheaper than the other reagents.
Inventors have observed the reactions in which acetyl chloride or acetyl bromide is
used results in low purity due to formation of large number of byproducts.
The step c) reaction was observed preferably to be performed in an inert
atmosphere with acetic anhydride in pyridine.
From various organic solvent like of pyridine, dichloromethane, chloroform,
tetrahydrofuran, dioxane and toluene, pyridine is found to be more suitable for the
acetylation. Inventors have found the extent of acetylation reaction is less in other
solvents in comparison to pyridine. Pyridine not only work as solvent, it also
accelerates the reaction rate as catalyst.
The step c) of the present invention is performed at 25-30°C for 2-6hrs, more
particularly, for 4hrs.
In presence of pyridine with acetic anhydride, inventors found that the
acetylation occurs at a faster rate and reaction complies in about 4-5hours at 25-30°C.
The isolated product of step c) of the present invention is highly pure
intermediate [2-acetamido-2-(acetyloxy methyl)-4-phenylbutyl] acetate (II) having
purity exceeding 98% (by HPLC).
In step d) of the present invention the isolated highly pure key intermediate
i.e. [2-acetamido-2-(acetyloxy methyl)-4-phenylbutyl] acetate(II) is further converted
to Fingolimod Hydrochloride of formula (I).
13
In another embodiment, the final product Fingolimod HCl obtained by the
processes of the present application may be formulated as solid compositions for oral
administration in the form of capsules, tablets, pills, powders or granules useful in the
treatment or prevention of autoimmune related disorder including multiple sclerosis.
In these compositions, the active product is mixed with one or more pharmaceutically
acceptable excipients. The drug substance can be formulated as liquid compositions
for oral administration including solutions, suspensions, syrups, elixirs and emulsions,
containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or
liquid paraffin.
The compositions for parenteral administration can be suspensions, emulsions
or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol,
polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters,
e.g. ethyl oleate, may be employed. These compositions can contain adjuvants,
especially wetting, emulsifying and dispersing agents. The sterilization may be carried
out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing
agents in the composition, by irradiation or by heating. They may be prepared in the
form of sterile compositions, which can be dissolved at the time of use in sterile water
or any other sterile injectable medium. Pharmaceutically acceptable excipients used
in the compositions comprising highly pure Fingolimod HCl obtained by the process
of the present invention include, but are not limited to diluents such as starch,
pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose,
dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like;
binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the
like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch,
Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as
stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal
silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic
or neutral surfactants, waxes and the like. Other pharmaceutically acceptable
excipients that are of use include but not limited to film formers, plasticizers,
colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives,
antioxidants and the like.
14
Pharmaceutically acceptable excipients used in the compositions derived from
highly pure Fingolimod HCl obtained by the process of the present invention may also
comprise to include the pharmaceutically acceptable carrier used for the preparation
of solid dispersion, wherever utilized in the desired dosage form preparation.
Certain specific aspects and embodiments of the present application will be
explained in more detail with reference to the following example, which is provided
by way of illustration only and should not be construed as limiting the scope of the
invention in any manner.
EXAMPLES
Example 01: Preparation of highly pure intermediate - [2-acetamido-2-
(acetyloxy methyl)-4-phenylbutyl] acetate(II)
Step a: Preparation of diethyl 2-acetamido-2-phenethylmalonate (IV)
Under nitrogen, charge 850ml dimethyl sulfoxide in a 2.0litre round-bottom
flask. Charge 100gm diethylacetamidomalonate(VI) at 25-30°C.Stir the reaction mass
for 10-15minutes. Add 195gm cesium carbonate and tetrabutylammonium bromide
7.5 gm. Stir the reaction mass for 60-90minutes.Gradually, add 90gm phenylethyl
bromide(Va) within a time interval of 60-120 minutes at 25-35°C. After complete
addition of phenylethylbromide, raise the temperature of the reaction mass to 80-
85°C. Maintain under nitrogen for 6 hours at 80-85°C. After reaction completion,
charge 2125ml purified water in a 5.0litre round bottom flask and cool to 0-10°C.
Slowly, charge the reaction mass into pre-cooled water in 50-60minutes at 0-10°C.Stir
the reaction mass for 90-120minutes at 0-10°C. Filter and wash the wet cake with
1litre purified water. Suck dry and unload the wet cake. Further, vacuum dry the wet
cake at 55-55°C for 2-3hours.
15
Charge the dry cake (115gm) in 450ml of isopropyl alcohol in a 2.0 liter round bottom
flask. Slowly, heat the reaction mass to 55-65°C and stir till a clear solution is
observed. Gradually cool to 5-10°C and maintain for 2-2.5hours. Filter and wash with
75ml chilled isopropyl alcohol. Suck dry and unload the wet cake. Dry under vacuum
at 50-60°C for 8-10hours.
Dry weight-95gm
Purity: 98.3% (by HPLC)
Heating weight loss (%): 0.201
Step b: Preparation of N-(1-hydroxy-2-(hydroxymethyl)-4-phenylbutan-2-yl)
acetamide (III)
In 500ml of methanol, charge 50gm of diethyl 2-acetamido-2-
phenethylmalonate (IV) prepared in the above step at 25-30°C. Stir the reaction mass
and cool to 0-5°C. Slowly, charge the solution of sodium borohydride in water (58.9
gm in 100ml purified water) in 30-40minutes at 0-5°C. Raise the temperature of the
reaction mass to 50-60°C and maintain for 4-6hours. Cool to 0-10°C and adjust pH to
7.0 by aqueous hydrochloric acid solution. Raise the temperature of the reaction mass
to 25-30°C and distill out methanol under vacuum at 40-45°C.Charge 300ml purified
water to the residue and extract three times with 500ml ethyl acetate each. Combine
the organic layer and wash with 500ml of 20% of sodium chloride solution. Dry the
organic layer over sodium sulfate and distill out under vacuum at 40-45°C. Proceed
with the residue to the next step.
Weight of the residue: 34.5gm
Purity: 94.56% (by HPLC)
Step c: Preparation of highly pure intermediate- [2-acetamido-2-(acetyloxy
methyl)-4-phenylbutyl] acetate(II)
16
Under nitrogen atmosphere, charge the residue obtained in the step b) in 125ml
of pyridine. Stir the mass till clear solution is observed. Cool to 0-5°C and slowly add
88ml of acetic anhydride in 20-30minutes. Raise the temperature of the reaction mass
to 20-30°C and stir for 5-6hours.After completion of reaction, charge 625ml of
purified water and 625ml of ethyl acetate into the reaction mass. Stir and separate
layers. Wash the aqueous layer again with 625ml of ethyl acetate. Stir and separate
layers. Combine both the organic layers and wash with 375ml of 30% ammonium
chloride solution. Again wash the organic layer with 125ml of purified water, stir and
separate layers. Dry the organic layer over sodium sulfate and filter through hyflo bed.
Distill out the ethyl acetate under vacuum with twice toluene striping of 200ml each
at 40-50°. Charge 250ml toluene to the degas mass and heat to 60-70°. After a clear
solution is observed, gradually cool to 20-30°C and maintain for 2-3hours. Filter and
wash with 50ml X 2 toluene. Suck dry and then vacuum dry the wet cake for 8-10hours
at 50-60°C. Recrystallising the dried material using toluene to get pure material.
Dry weight: 25gm
HPLC Purity: 99.584%
Example 02: Preparation of highly pure intermediate - [2-acetamido-2-
(acetyloxy methyl)-4-phenylbutyl] acetate(II)
Step a: Preparation of diethyl 2-acetamido-2-phenethylmalonate (IV)
17
Under nitrogen, charge 2125ml dimethyl sulfoxide in a 5.0litre round-bottom
flask. Charge 250gm diethylacetamidomalonate at 25-30°C.Stir the reaction mass for
10-15minutes. Add 487.1 gm cesium carbonate and tetrabutylammonium bromide 19
gm. Stir the reaction mass for 60-90minutes.Gradually, add 224gm phenylethyl
bromide within a time interval of 60-120 minutes at 25-35°C. After complete addition
of phenylethylbromide, raise the temperature of the reaction mass to 80-85°C.
Maintain under nitrogen for 6 hours at 80-85°C. After reaction completion, charge
5300ml purified water in a 10.0litre round bottom flask and cool to 0-10°C. Slowly,
charge the reaction mass into pre-cooled water in 50-60minutes at 0-10°C.Stir the
reaction mass for 90-120minutes at 0-10°C. Filter and wash the wet cake with 2.5litre
purified water. Suck dry and unload the wet cake. Further, vacuum dry the wet cake
at 55-55°C for 6-8hours.
Charge the dry cake (295gm) in 1125ml of isopropyl alcohol in a 2.0 liter
round bottom flask. Slowly, heat the reaction mass to 55-65°C and stir till a clear
solution is observed. Gradually cool to 5-10°C and maintain for 2-2.5hours. Filter and
wash with 190ml chilled isopropyl alcohol. Suck dry and unload the wet cake. Dry
under vacuum at 50-60°C for 8-10hours.
Dry weight-237gm; HPLC purity:
Step b: Preparation of N-(1-hydroxy-2-(hydroxymethyl)-4-phenylbutan-2-yl)
acetamide (III)
In 1000ml of methanol, charge 100gm of diethyl 2-acetamido-2-
phenethylmalonate (IV) prepared in the above step at 25-30°C. Stir the reaction mass
and cool to 0-5°C. Slowly, charge the solution of sodium borohydride in water (118
gm in 200ml purified water) in 30-40minutes at 0-5°C. Raise the temperature of the
reaction mass to 40-60°C and maintain for 3-4hours. Cool the reaction mass to 0-10°C
18
and adjust pH to about 7.0 by aqueous hydrochloric acid solution. Raise the
temperature of the reaction mass to 20-30°C and distill out methanol under vacuum at
40-45°C.Charge 1600ml purified water to the residue and extract three times with
1litre ethyl acetate each. Combine the organic layer and wash with 500ml of 20% of
sodium chloride solution. Dry the organic layer over sodium sulfate and distill out
under vacuum at 40-50°C. Proceed with the residue to the next step.
Step c: Preparation of highly pure intermediate - [2-acetamido-2-(acetyloxy
methyl)-4-phenylbutyl] acetate(II)
Under nitrogen atmosphere, charge the residue obtained in the step b) in 250ml
of pyridine. Stir the mass till clear solution is observed. Cool to 0-5°C and slowly add
176ml of acetic anhydride in 20-30minutes. Raise the temperature of the reaction mass
to 20-30°C and stir for 5-6hours.After completion of reaction, charge 1250ml of
purified water and 1250ml of ethyl acetate into the reaction mass. Stir and separate
layers. Wash the aqueous layer again with 250ml of ethyl acetate. Stir and separate
layers. Combine both the organic layers and wash with 750ml of 30% ammonium
chloride solution. Again wash the organic layer with 250ml of purified water, stir and
separate layers. Dry the organic layer over sodium sulfate and filter through hyflo bed.
Distill out the ethyl acetate under vacuum with twice toluene striping of 200ml each
at 40-50°. Charge 500ml toluene to the degas mass and heat to 60-70°. After a clear
solution is observed, gradually cool to 20-30°C and maintain for 2-3hours. Filter and
wash with 50ml X 2 toluene. Suck dry and then vacuum dry the wet cake for 8-10hours
at 50-60°C. Recrystallising the dried material using toluene to get pure material.
Dry weight: 40gm. HPLC Purity: 99.58%
Example 03: Preparation of Fingolimod Hydrochloride (I)
19
Step a) Preparation of 2-acetamido-2-(4-octanoylphenethyl) propane-l,3-diyl
diacetate
EDC (200ml) was charged in a four necked RB flask and cooled up to -10°C
to -15°C, and under nitrogen atmosphere. Further Aluminium chloride (33.2g) was
added to the solution and stirred the reaction for 30 min. To this, octanoyl chloride
(26.8ml) was slowly added in an hour and the resulting reaction mixture stirred further
for 1.5 hours, at -10°C to -15°C. A solution of [2-acetamido-2-(acetyloxy methyl)-4-
phenylbutyl] acetate(II) (10g dissolved in 40.0 ml EDC) was slowly added to the
reaction mixture over a period of around 3 hours, maintaining the temperature
between -10°C to -15°C. The reaction mixture was then allowed to come to room
temperature and stirred overnight for 16 hours. After completion of reaction as
confirmed by HPLC, the reaction mixture was slowly poured into chilled water
(200ml) and stirred for 15-20 min. The EDC layer was separated and the aqueous
layer was extracted with EDC (2 x 200 ml). The organic layers were combined,
washed with saturated sodium chloride solution (2 x 50 ml), dried over anhydrous
sodium sulfate (10g), filtered and concentrated under vacuum at temperature below
50°C to get residue. The residue was purified by adding Hexane (200ml) and stirred
the solution for about 2 hours to provide white crystalline solid. The crystalline solid
purified material was filtered and suck dried for to afford 13.0 g title compound. By
this surprising process, no column purification is desired, which is clumsy and time
incurring step.
Yield: 93.52%
Purity (by HPLC): 85.49%
Ortho isomer impurity: 6.280%
Step b) Preparation of 2-acetamido-2-(4-octylphenethyl) propane-l, 3- diyl
diacetate
20
Charged 13g of 2-acetamido-2-(4-octanoylphenethyl) propane-l, 3-diyl
diacetate and ethanol (152.10 ml) in a 2L steel hydrogenation vessel (autoclave),
followed by addition of 10% Pd-C (2.73g). The reaction mixture was hydrogenated
(4kg/cm2 H2 pressure) at RT for 2-3h. The progress of the reaction was confirmed by
HPLC. After completion of the reaction, the reaction mixture was filtered through
hyflo bed & washed with Ethanol (20 ml). The filtrate was concentrated under reduced
pressure below 50°C to give 14.5g of residue. Hexane (98 ml) was added to and stirred
for 2-3 hours at RT. The separated white solid material was filtered to give 8.6g crude
2-acetamido-2-(4-octylphenethyl) propane-l, 3-diyl diacetate compound (HPLC
purity = 97.25%). The obtained crude title compound was taken in methanol (103 ml)
and stirred for 30min at RT to get the clear solution. The solution was then cooled to
0-5°C under stirring maintaining for two hours. The solid obtained was washed with
chilled methanol, filtered and dried at 45°C under vacuum for 2-3 hours, to obtain
6.3g of title compound.
Yield: 50%
Purity (by HPLC): 99.01%
Step c) Preparation of Fingolimod free base
6 gm of 2-acetamido-2-(4-octylphenethyl) propane-l, 3-diyl diacetate was charged in
a three necked RB flask, further added methanol (78 ml) and stirred at room temp till
solution becomes clear. To this slowly added LiOH solution (12.2 g dissolved in 78
ml of DM Water) and then the reaction mixture stirred at reflux for 2-3 hours. The
completion of reaction was monitored by HPLC. The reaction mixture was
concentrated under reduced pressure below 45°C to give residue which was taken in
DM water (42 ml) and extracted twice with ethyl acetate (215 ml and 107.5 ml). The
21
ethyl acetate layers were combined, washed with saturated brine (30ml), dried over
sodium sulfate (21g) and concentrated under vacuum below 45°C. Ethyl acetate (12
ml) was added to residue and cooled the solution to 0-5°C, maintained the temperature
for 2 hours and then filtered to give 3.6 g. Fingolimod free base, which was further
dried under vacuum at 45°C for 6-7 hours.
Yield: 84.6%
Purity (by HPLC): 99. 84%
Step d) Preparation of Fingolimod Hydrochloride
In a three necked round bottom flask Fingolimod free base (3.5 g) was charged to
ethyl acetate (89ml) and reaction stirred at room temperature for 15-20min. The
reaction mixture was slowly heated up to reflux (~70°C) to get a clear solution. A
mixture of 10% IPA-HCl (23 ml) Aqueous IPA-HCl solution was added to the
reaction mixture at 50°Cover 10-15 min till pH 1-2 and resulting solution further
stirred for 30 minutes. The reaction temperature was then cooled to 0-5°C and
maintained for 2-3 hours. The separated solid was filtered & washed with cold ethyl
acetate to get the title compound. The material obtained was dried at 45°C under full
vacuum for 6-7 hours to get 3.4 g of Fingolimod hydrochloride.
Yield: 86.03%
Purity (by HPLC): 99.96%
While the forgoing pages provide a detailed description of the preferred
embodiments of the invention, it is being understood that the summary, description
and examples are illustrative only of the core of the invention and non-limiting in
nature. Furthermore, as many changes can be made to the invention without departing
from the scope of the invention, it is intended that all material contained herein shall
be interpreted as illustrative of the invention and not in a limiting sense.

We Claim,
1. A process for the preparation of Fingolimod Hydrochloride of formula (I):
(I)
comprising of the following steps:
a) reacting diethylacetamidomalonate(VI) with phenylethylhalide(V) in
presence of a phase transfer catalyst, base and polar aprotic solvent at
temperature ranging between 80-100°C for a time ranging between 4-
8 hours to give diethyl 2-acetamido-2-phenethylmalonate (IV).
b) reacting diethyl 2-acetamido-2-phenethylmalonate(IV) with aqueous
NaBH4 at temperature ranging between 30-70°C to give N-(1-
hydroxy-2-(hydroxymethyl)-4-phenylbutan-2-yl) acetamide (III).
c) acetylation of N-(1-hydroxy-2-(hydroxymethyl)-4-phenylbutan-2-yl)
acetamide(III) with an acetylating agent in presence of an organic
solvent for time duration ranging between 2-6hrs to give [2-acetamido2-(acetyloxy methyl)-4-phenylbutyl] acetate (II).
d) the converting [2-acetamido-2-(acetyloxy methyl)-4-phenylbutyl]
acetate(II) obtained in step c) to get Fingolimod Hydrochloride of
formula (I).
2. A process for the preparation of Fingolimod Hydrochloride of formula (I)
according to claim 1, wherein phase transfer catalyst used in step a) is selected
from tetrabutylammonium bromide, benzyltrimethylammonium bromide,
hexyltrimethylammonium bromide.
3. A process for the preparation of Fingolimod Hydrochloride of formula (I)
according to claim 1, wherein phenylethylhalide used in step a) is selected
f~om phenylethylbromide, phenylethyliodide, phenylethylchloride.
4. A process for the preparation of Fingolimod Hydrochloride of formula (I)
according to claim 1, wherein base used in step a) is selected from cesium
carbonate, lithium carbonate.
5. A process for the preparation of Fingolimod Hydrochloride of formula (I)
according to claim 1, wherein polar aprotic solvent used in step a) is.selected
from dimethyl sulfoxide, dimethylformamide, ethyl acetate.
6. A process for the preparation of Fingolimod Hydrochloride of formula (I)
according to claim 1, wherein step b) is . performed in aqueous alcoholic
medium comprising a ratio of alcohol (C1-C3):water mixture is ranging
between !(diethyl 2-acetamido-2-phenethyl malonate(IV)) :10-15(alcohol)
(w/v) and 1 (diethyl 2-acetamido-2-phenethylmalonate(IV)):2-3(water) (w/v).
7. A process for the preparation of Fingolimod Hydrochloride of formula (I)
according to claim 1, wherein acetylating agent used in step c) is selected from
. acetic anhydride, acetyl chloride, acetyl bromide.
8. A process for the preparation of Fingolimod Hydrochloride of formula (I)
according to claim 1, wherein organic solvent used in step c) is selected from
pyridine, dichlororriethane, chloroform, tetrahydrofuran, dioxane, toluene.
9. Highly pure intermediate of compound of formula II
CH20COCH3
&Cl;l2CH2-9-NHCOCH3
· . · .. . CH20COCH3 (II)
having purity exceeding 98% (by HPLC). 1