RSC Advances
COMMUNICATION
Practical synthesis of fingolimod from diethyl
acetamidomalonate3{
a
b
Bhaskar Kandagatla, Vetukuri Venkata Naga Kali Vara Prasada Raju, Narayana
Received 21st February 2013,
Accepted 3rd May 2013
a
b
b
a
Sravan Kumar, Ganta Madhusudhan Reddy, Katkam Srinivas, Javed Iqbal,
Rakeshwar Bandichhor and Srinivas Oruganti*
b
a
DOI: 10.1039/c3ra40894a
www.rsc.org/advances
A facile six-step synthesis of fingolimod, starting from readily
available and inexpensive starting material diethyl acetamidoma-
lonate, in very good yield is demonstrated.
increased presence of impurities related to the chemistry involved
in the introduction of the N-acetamido-1,3-propanediol moiety.
We therefore decided to install the polar head group first and then
exploit its presence for the synthesis of fingolimod 1 hydrochloride
in an efficient and cost-effective manner (Fig. 2).
Fingolimod (FTY720, Gilenya) 1 is a classic example of a drug
which is inspired by a natural product, in this case myriocin (ISP-
As a part of our ongoing program on scalable and cost-effective
routes for active pharmaceutical ingredients, we were interested in
the synthesis of fingolimod 1 since it is a promising oral drug for
multiple sclerosis. Some of the literature routes had the
disadvantage of including complicated steps which lead to
intermediates as oily substances or various isomeric mixtures.
Consequently, isolation and purification of the intermediate
products by conventional methods such as chromatography
rendered the processes unviable for the large-scale preparation
of 1.
Herein, we report a six step synthesis of fingolimod 1
(Scheme 1) starting from the readily available starting material
diethyl acetamidomalonate 2. Unlike hitherto known routes,
which involved the insertion of the head group at the end, we
decided to start the synthesis from the head group. The first step
involved the alkylation of 2 with phenethylbromide. Due to the
competing nucleophilic substitution vs. elimination during
alkylation reactions with 2, we decided to focus on improving
the alkylation step. An initial screening of a selection of
appropriate bases, solvents and temperatures revealed that
bromide elimination to the styrene was the predominant by-
product under most conditions (Table 1).
1
1), a metabolite of the fungus Isaria sinclairii (Fig. 1). The USFDA
has approved Gilenya (fingolimod) for oral treatment of Multiple
Sclerosis (MS) recently. It is a structural analogue of sphingosine
2–4
that is phosphorylated by sphingosine kinases in cells.
Fingolimod 1 acts as a nonselective agonist of the sphingosine-1
phosphate receptor expressed by lymphocytes, and prevents
lymphocyte emersion from secondary lymphatic organs and their
5
subsequent movement into sites of inflammation. Fingolimod 1
has emerged as a promising oral drug for MS with a significant
6
reduction in relapses observed in patients treated with the drug.
The key challenge in the synthesis of fingolimod [2-amino-2-(4-
octylphenethyl)propane-1,3-diol] 1 is the construction of the
hydrophilic 2-aminopropane-1,3-diol head group and most of
the literature routes have focused on approaches for the
construction of the same. An early synthesis of fingolimod 1 by
Adachi and co workers employed alkylation of diethyl 2-acetami-
domalonate with 1-(2-bromoethyl)-4-octylbenzene to obtain the
Adachi–Fujita intermediate diethyl 2-acetamido-2-(4-octylphe-
7
nethyl)malonate which was then delineated to fingolimod 1.
The other literature syntheses of 1 start from building blocks such
as 4-octylbenzaldehyde or 2-(4-octylphenyl)ethanol, which were
conjugated to the polar head-group derived from diethyl
Nucleophilic substitution of phenethylbromide with consistent
yields and reproducibility was achieved using cesium carbonate as
8
9
acetamidomalonate, TRIS-derivatives or from a bis-aldol addi-
10
tion with 2-aryl substituted ethyl nitrate. One of the problems
with the late stage introduction of the polar head group is the
a
Center for Process Research & Innovation, Dr Reddy’s Institute of Life Sciences,
University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India.
E-mail: soruganti@drils.org
b
API R&D, IPDO-Innovation Plaza, Dr Reddy’s Laboratories Ltd, Bachupally,
Qutubullapur, Hyderabad 500 072, India
3
{
Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra40894a
Dedicated to Dr Kallam Anji Reddy (1940–2013); DRL-IPD Communication No.:
IPDO-IPM-00358.
Fig. 1 Structures of fingolimod 1 and myriocin.
This journal is ß The Royal Society of Chemistry 2013
RSC Adv.