An alternative efficient approach for the synthesis of Fingolimod hydrochloride

Article abstract of DOI:10.1080/00397911.2018.1536788

An efficient process for the synthesis of API Fingolimod Hydrochloride is presented. This proposed synthesis involves simple commercially available octanophenone as a starting material. The route is effective involving seven steps to achieve the target, thus reducing the cycle time, and is cost efficient by 50%. It is an immune modulating drug for the treatment of heart failure and arrhythmias.

Full text of DOI:10.1080/00397911.2018.1536788

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
An alternative efficient approach for the synthesis
of Fingolimod hydrochloride
Krishna Vinigari, Krishna Jonnada, Noorjahan Mohammed & Girija
Mangatayaru Kotu
To cite this article: Krishna Vinigari, Krishna Jonnada, Noorjahan Mohammed & Girija
Mangatayaru Kotu (2019): An alternative efficient approach for the synthesis of Fingolimod
hydrochloride, Synthetic Communications, DOI: 10.1080/00397911.2018.1536788
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https://doi.org/10.1080/00397911.2018.1536788
An alternative efficient approach for the synthesis
of Fingolimod hydrochloride
a,b
a
b
Krishna Vinigari , Krishna Jonnada , Noorjahan Mohammed , and
b
Girija Mangatayaru Kotu
a
Research & Development Centre, IPDO-API, Innovation Plaza, Dr. Reddy’s Laboratories Limited,
b
Hyderabad, Telangana, India; Department of Chemistry, Palamuru University, Mahbubnagar,
Telangana, India
ABSTRACT
ARTICLE HISTORY
An efficient process for the synthesis of API Fingolimod Hydrochloride
is presented. This proposed synthesis involves simple commercially
available octanophenone as a starting material. The route is effective
involving seven steps to achieve the target, thus reducing the cycle
time, and is cost efficient by 50%. It is an immune modulating drug
for the treatment of heart failure and arrhythmias.
Received 7 July 2018
KEYWORDS
Active pharmaceutical
ingredient (API); alternative
process; commercial scale;
ICH purity; robust process
GRAPHICAL ABSTRACT
Introduction
[
1–2]
Fingolimod hydrochloride 1,
a novel synthetic sphingosine analog, is an S1P-recep-
tor modulator that reversibly traps a proportion of lymphocytes in the lymph nodes,
thereby reducing their recirculation in the bloodstream and the central nervous system.
The first synthesis of Fingolimod was reported by Adachi, Fujita, and coworkers in
[
3–4]
1992 from an immune suppressive natural product.
After that, several methods
were reported in the literature for the synthesis of Fingolimod hydrochloride. The
CONTACT Girija Mangatayaru Kotu
kotugirijamangatayaru@gmail.com
Department of Chemistry, Palamuru
University, Raichur Road, Mahbubnagar, Telangana 509001, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
K. VINIGARI ET AL.

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3

4
K. VINIGARI ET AL.
Scheme 3. Alternative process for the synthesis of Fingolimod hydrochloride 1.
Table 1. Optimization for the synthesis of octylbenzene 5.
[
a]
o
[b]
Entry
Reagent
Pd/C
Solvent
Temp ( C)
Yield of 5 (%)
1
2
3
4
5
6
7
MeOH
TFA
AcOH
DCM
DCM
MeOH
DCM
rt
rt
rt
0
0
rt
0
75
–
90
90
–
NaBH
NaBH
4
4
TES/TiCl
TES/TiCl
Rany Ni
4
4
–
–
ZnCl
2
/TES
[a]
Reactions were performed on 10 g scale of 4.
Isolated yields of chromatographically pure product.
[b]
Table 2. Optimization for the synthesis of 2.
[
a]
o
[b]
Entry
Solvent
Temp ( C)
Yield of 2 (%)
1
2
3
4
Acetone
THF
EtOAc
DMF
reflux
50
–
–
rt
rt
rt
85
[
a]
Reactions were performed on 10 g scale of 6.
Isolated yields of chromatographically pure product.
[b]

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5
Table 3. Optimization for the synthesis of 3.
[
a]
o
[b]
Entry
Reagent
Solvent
Temp ( C)
Yield of 3 (%)
1
2
3
4
5
6
7
8
TEA/(CH
2
O)
n
MeOH
DCM
EtOAc
Toulene
2
H O
Toulene
Toulene
Toulene
rt
rt
rt
rt
rt
rt
rt
rt
65
–
50
85
85
–
K
K
K
K
2
CO
2
CO
2
CO
2
CO
3
3
3
3
/(CH
/(CH
/(CH
/(CH
2
2
2
2
O)
n
n
n
O)
O)
O)
n
O)
O)
NaHCO
NaHCO
3
/(CH
/(CH
2
n
3
2
n
–
–
KOH/(CH
2
O)
n
[
a]
Reactions were performed on 10 g scale of 8.
Isolated yields of chromatographically pure product.
[b]
[
5]
[6]
(
2-aminopropane-1, 3-diol), was synthesized from diethyl acetamidomalonate, nitrodiol,
[7]
or amine moiety. The other lipophilic part of Fingolimod was constructed through
Friedel–Crafts acylation followed by Wolf–Kishner reduction. Luo and coworkers synthe-
[8]
sized Fingolimod by Wittig reaction followed by hydrogenation in good overall yield. Most
[9]
of these methods are expensive and involve the use of hazardous reagents.
In addition, the literature reported the synthesis of Fingolimod hydrochloride 1,
involving many sequential steps, thus making the reported process inefficient. On a
commercial scale, isolation of intermediate products at every step incurs high expenses,
long cycle time and decreased productivity. To address this concept, we developed an
alternative process for the synthesis of Fingolimod hydrochloride 1.
Results and discussions
With an aim to develop an effective synthetic route, we proposed the synthesis starting
with easily accessible raw material, octanophenone (Scheme 1). The reduction of octa-
nophenone with 10% Pd/C in ethanol gave octylbenzene 5, which was further subjected
to Friedel–Crafts acylation with 3-chloropropionyl chloride to afford para substituted
octylbenzene 6. Nitration of 6 was carried out with sodium nitrate in acetone under
reflux condition to get 2 followed by NaBH reduction to afford hydroxyl derivative 7.
4
The alcohol 7 was further reduced to compound 8 using triethylsilane and trifluoroace-
tic acid. Hydroxymethylation of nitro compound 8 using paraformaldehyde gave the 3,
which on hydrogenation gave the free base of Fingolimod. This free base on treatment
with ethanolic HCl afforded the desired Fingolimod hydrochloride 1 in good yield.
Alternatively, the reduction of nitro compound 2 was carried out yielding hydroxy
[
10]
derivative 7 using NaBH4.
It was further subjected to hydroxymethylated using paraf-
ormaldehyde and triethylamine to give the dihydroxymethyl derivative 9. Followed by
reduction of 9 using H , Pd/C afford the desired Fingolimod hydrochloride 1
2
(Scheme 2).
During the examination of feasibility of the synthetic route, the practical hurdle arose
as, the reduction of ocatanophenone 4 to octylbenzene 5 was not reproducible and

6
K. VINIGARI ET AL.
reaction time differed with input lot, and in some cases, reactions were completed only
after reloading the catalyst. In order to find out the best optimized reaction conditions
for the synthesis of octylbenzene 5, the reaction was explored under different sets of
reaction conditions and the results are summarized in Table 1. The best yield was
ꢀ
obtained with TES/TiCl in CH Cl at 0 C with 90% yield. Whereas, the other reducing
4
2
2
agents were found to be inferior.
Further, during the transformation of chloro derivative 6 to nitro, compounds 2, 11
were formed in small traces as undesired products.
Hence, the chloro to nitro displacement reaction was explored under various sets of
conditions, as shown in Table 2. The table revealed that the best condition was in
DMF, in which the formation of undesired 11 was highly suppressed.
Also, the formylation step was optimized with respect to various solvents and bases
as shown in Table 3. Among all the screened conditions, the reaction with K CO /par-
2
3
aformaldehyde in toluene at room temperature resulted in very good yield of 85%.
Furthermore, as most of the intermediates involved in the synthesis of Fingolimod hydro-
chloride 1, are either oily or low melting solids, to develop a robust and green process, we
planned an alternative process to avoid the isolation and purification of oily or low melting
intermediates. Thus we present the synthesis of Fingolimod hydrochloride 1, by condensing
original nine stages process into three stages by isolating solids in these three stages.
In the concise process, first step involves a combination of three individual steps into
a single pot resulting in the direct formation of 2 from 4. In this, octylphenone 4 was
ꢀ
reduced with TES/TiCl in CH Cl at 0 C followed by acetylation with 3-chloropro-
4
2
2
pionyl chloride/AlCl to give 6. It was further converted to nitro keto compound 2 with
3
NaNO in DMF. The crude compound 2 was purified with n-hexane to give 70% yield
2
with more than 98.0% purity (Scheme 3).
ꢀ
The nitro keto 2 was reduced with triethylsilane/TiCl in CH Cl at 0 C, followed by
4
2
2
hydroxymethylation under K CO /paraformaldehyde in toluene to deliver product 3
2
3
with 85% yield.
The nitro diol 3 was reduced with 10% Pd/C in MeOH followed by methanolic HCl
addition to get Fingolimod Hydrochloride 1. After formation of salt, the reaction mix-
ture was concentrated up to 1/20th volumes followed by addition of ethyl acetate to
give Fingolimod Hydrochloride 1. The isolated compound 1 was purified with metha-
nol/ethyl acetate to meet ICH quality. The reagents such as Pd/C and TiCl were
4
handled under a nitrogen atmosphere by using personal protective equipments.
Conclusion
In conclusion, we developed an alternative efficient process for the synthesis of
Fingolimod hydrochloride. It has resulted in reduction of 50% cost and cycle time. We

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SYNTHETIC COMMUNICATIONS
7
have demonstrated robustness of the process by scaling up from milligram to plant scale
with greater than 99.80% purity.
Experimental section
General procedures
Commercially available solvents and reagents were used without further purification.
Reversed phased HPLC elutions were performed on a stainless steel column (250 mm
length, 4.6 mm internal diameter and filled with porous silica particles of 5 lm diam-
eter, which are bonded to cyanopropyl group) using acetonitrile and potassium dihydro-
gen orthophosphate buffer (2.72 g of potassium dihydrogen orthophosphate in 1.0 L of
1
water and adjust pH 3.0 with orthophosphoric acid) mixtures. H NMR spectra were
recorded on a Bruker Avance 400 MHz spectrophotometer with a multinuclear BBO
probe with TMS as an internal standard in DMSO-d6/CDCl . Chemical shifts are
3
reported in d scale (ppm). Mass spectra were measured on a PE-SCIEX API-3000 LC/
MS/MS with a Turbo ion spray mass spectrophotometer. IR spectra were recorded on a
Perkin–Elmer spectrum 65 FT-IR spectrophotometer in KBr pellets.
Synthesis of 3-Nitro-(4-octyl-phenyl)-propane-1-one (2)
In a reactor, octanophenone was added (5.0 kg, 24.5 mol) to CH Cl (25 L). The mix-
2
2
ꢀ
ture was cooled at À10 to À5 C and was added to triethylsilane, followed by TiCl (4.9
4
ꢀ
kg, 25.7 mol) in CH Cl (25 L) at À10 to 5 C. The temperature was raised from 0 to 5
2
2
ꢀ
C and stirred for 3–5 h. Progress of the reaction was monitored by TLC, after comple-
tion of the reaction, the mixture was filtered through hyflow bed and washed with
CH Cl (10.0 L). The combined organic layer was transferred to another reactor and
2
2
ꢀ
ꢀ
cooled to À10 C from À5 C. To this was added AlCl (4.25 kg, 1.3 equiv.) followed
3
by 3-chloropropionyl chloride (3.5 kg, 2.7mol) in CH Cl (10.0 L) and stirred for 3–5 h
2
2
ꢀ
at À10 to À5 C. Reaction progress was monitored by HPLC. After completion of reac-
ꢀ
tion, ice cold water was slowly added (50.0 L) at below 15 C and stirred for 1–2 h. The
organic layer was separated, washed with 5% NaHCO solution, brine solution and dis-
3
ꢀ
tilled below 40 C under vacuum to get crude compound 6. To a reactor the crude com-
pound 6, NaNO (2.7 kg, 39.2 mol) in DMF (30.0 L) was added and stirred at 25–35 C
ꢀ
2
for 4–6 h. Reaction progress was monitored by TLC. After completion of the reaction, H O
2
(
2
50.0 L) and EtOAc (50.0 L) were added and the mixture was stirred for 15–30 min at
ꢀ
5–35 C. The organic layer was separated and the aqueous layer was washed with EtOAc
(
10.0L). The combined organic layer was washed with brine (2 Â 50.0 L) and distilled
ꢀ
below 50 C under vacuum to get the crude compound. To the crude compound was
ꢀ
added n-hexane (20.0 L), cooled to À15 to À10 C, and stirred for 45–60 min. The solid
was filtered and washed with chilled n-hexane (5.0 L). Then wet cake followed by MeOH
ꢀ
(
30.0 L) was added into another reactor at 25–35 C. Then the mixture was cooled to À15
ꢀ
to À10 C, stirred for 60 min, filtered and washed with chilled MeOH (5.0 L) to get the
ꢀ
1
compound 2. The solid was dried at 35–40 C under vacuum (5.06 kg, Yield: 71%). H
NMR (400 MHz, CDCl d : 7.84–7.89 (m, 2H), 7.14–7.18 (m, 2H), 4.82–4.89 (m, 2H),
3,
)
3.6–3.64 (m, 2H), 3.62–3.68 (m, 2H), 2.64–2.69 (m, 2H), 1.62–1.66 (m, 2H), 1.22–1.41 (m,

8
K. VINIGARI ET AL.
1
3
1
1
2
0H), 1.26–1.29 (m, 10H), 0.86–0.89 (m, 3H) . C NMR (400 MHz, CDCl d): 194.6,
3,
49.8, 133.4, 128.8, 128.6, 128.2, 77.3, 77.0, 76.7, 69.3, 35.9, 34.7, 31.8, 31.0, 29.3, 29.2, 29.1,
2.6, 14.0. IR (KBR): cm 3923, 2922, 1535, 1053,773, 661.
À1
Synthesis of 2-Nitro-2-[2-(4-octyl-phenyl)-ethyl]-propane-1, 3-diol (3)
To a reactor 3-Nitro-(4-octyl-phenyl)-propane-1-one 2 (4.0 kg, 40.8 mol) in CH Cl was
2
2
ꢀ
added and cooled to À10 to 0 C. Triethylsilane (4.0 kg, 34.4 mol) and TiCl (3.92 kg, 20.4
4
ꢀ
mol) in CH Cl (20.0 L) were added to this and the solution was stirred at À10 to À5 C
2
2
for 4–5 h. After completion of reaction (monitored by HPLC), chilled water (40.0 L) below
ꢀ ꢀ
0 C was added and stirred for 1–2 h at 25–35 C. The organic layer was separated and
2
was washed with 5% NaHCO solution (20.0 L), 20% brine solution (20.0) and distilled
3
ꢀ
under vacuum at below 40 C to get the crude compound. The crude compound was dis-
solved in toluene (40.0 L) and transferred to the reactor for next step. To this, paraformal-
ꢀ
dehyde (1.44 kg, 48.0 mol), K CO (3.8 kg, 6.9 mol) was added at 23–27 C and stirred for
2
3
4–6 h. The reaction progress was monitored by HPLC. After completion of the reaction,
solid waste was filtered through Buchner funnel and washed with toluene (8.0 L). Filtered
mother liquor charged into the reactor,and water (40.0 L) followed by EtOAc (8.0 L) were
ꢀ
added and stirred for 1–2 h at 25–35 C. The separated organic layer was washed with 5%
HCl solution (20.0 L) followed by 5% NaHCO (20.0 L) solution and 10% brine solution
3
ꢀ
(
20.0 L) and distilled under vacuum below 45 C. To the crude compound, n-hexane (20.0
ꢀ
L) was added, cooled to 0–5 C and stirred for 45–60 min. The solid material was filtered
and washed with n-hexane (4.0 L). The wet cake was charged into a reactor in toluene
ꢀ
(
20.0 L) and heated to 40–45 C till the formation of a clear solution. The solution was
ꢀ
cooled to 0–5 C and stirred for 45–60 min. The solid material filtered and washed with
toluene (4.0 L). The compound was dried under vacuum at 35–40 C to get compound 3
3.94 kg, Yield: 85.0%). H NMR (400 MHz, CDCl d): 7.0–7.1 (m, 4H), 4.23–4.26 (d, 2 H,
ꢀ
1
(
3,
J:12.4 Hz), 4.02–4.05 (d, 2 H, J:12 Hz), 2.55–2.57 (m, 4H), 2.37–2.38 (b, 2H), 2.17–2.19 (m,
13
2
H), 1.57–1.59 (t, 2 H, J = 7.2Hz), 1.26–1.29 (m, 10H), 0.86–0.89 (m, 3H). C NMR (400
MHz, CDCl , d): 140.4, 138.7, 128.8, 128.5, 95.5, 61.3, 40.4, 40.2, 40.0, 39.8, 39.6, 35.2, 32.2,
3
À1
3
1.7, 31.5, 29.3, 29.1, 29.0, 22.5, 14.4. IR (KBR): cm 3923, 2922, 1535, 1053, 773, 661.
Synthesis of 2-amino-2-(4-octylphenylethyl)propane-1, 3-diol hydrochloride (1)
To an autoclave vessel, 2-amino-2-(4-octylphenylethyl)propane-1,3-diol 3 (3.0 kg), 10% Pd/
C (0.6 kg) were added. The reactants were stirred under hydrogen atmosphere (pressure
2
4
–5 kg/cm ) for 4–6 h. After completion of the reaction (by TLC), the reaction mixture
was filtered through hyflow bed and washed with MeOH (6.0 L). Then methanolic HCl
ꢀ
was added to the filtrate (600 ml) and stirred for 30 min at 25–30 C. The organic layer
ꢀ
was distilled under vacuum at below 50 C till total volume became 1/20th of the original
ꢀ
volume. Ethyl acetate (42.0 L) was then added to the concentrate, cooled to À5 to 0 C
and stirred for 1–2 h. The solid formed was filtered and washed with EtOAc (6.0 L). The
wet solid was charged into a reactor and MeOH (6.0 L) was added and stirred for 15–30
min till the formation of a clear solution. Then EtOAc (42.0 L) was added and stirred at
ꢀ
RT for 45–60 min and then stirred at 0 to 5 C for 1–2 h. The solid compound was filtered

V
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SYNTHETIC COMMUNICATIONS
9
ꢀ
and washed with EtOAc (6.0 L). The compound was dried at 25–30 C under vacuum to
1
get compound 1 (2.12 kg, Yield: 70%). H NMR (400 MHz, DMSO-d d): 7.95 (b, 3H),
6,
7
2
.08–7.12 (q, 4 H, J = 6.4, 6.8 Hz), 5.39–5.41 (t, 2 H, J = 4.4 Hz), 3.5–3.53 (m, 4H),
.5–2.51 (m, 3H), 2.53–2.6(m, 3H), 1.77–1.8(m, 2H), 1.51–1.54 (t, 2 H, J = 6 Hz), 1.24–1.27
13
(m, 10H), 0.84–0.86 (t, 3 H, J = 5.6 Hz); C NMR (400 MHz, DMSO-d , d): 139.7, 138.8,
6
1
2
1
28.2, 128.0, 60.9, 60.3, 40.1, 40.0, 39.9, 39.7, 39.6, 39.2, 39.1, 39.0, 34.7, 33.2, 31.2, 31.0,
8.8, 28.6, 27.9, 22.0, 13.9. DSC: 107.6 C, IR (KBR) cm : 3268, 2923, 1601, 1517, 1242,
070, 864, 824.
ꢀ
À1
Acknowledgments
We thank the management of Dr. Reddy’s Laboratories Ltd. for extending support to the work.
Co-operation from the project colleagues and the analytical department is highly appreciated.
(DRL-IPDO Communication number: IPDO-IPM-0044).
References and notes
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