A novel method for preparing Eligulstat through chiral resolution

Article abstract of DOI:10.1016/j.bmcl.2020.127209

Eliglustat is a ceramide glucosyltransferase inhibitor work as first line oral therapy for adults with Gaucher disease type 1 (a rare disease) at present. Although the eliglustat in enantiomerically pure forms is obtained by asymmetric syntheses, the reported methods suffer from many limits when it comes to industrial applications. Therefore, the preparation of a racemic mixture followed by resolution can still be a viable and straightforward alternative, especially when it could be adapted to large scale. Herein, we developed an effective and practical synthetic route to prepare stereoisomers mixture of eliglustat, and a novel chiral resolution method to prepare eliglustat. Using 1,1′-Binaphthyl-2,2′-diyl -hydrogenphosphate (BNDHP) as resolution reagent, optical pure eliglustat (e.e. >99%, 13.97% total yield) could be obtained after recrystallization.

Full text of DOI:10.1016/j.bmcl.2020.127209

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A novel method for preparing Eligulstat through chiral resolution
Jianxun Du, Weiming Chu, Mengmeng Zhang, Chunying Ma, Wenhua Feng
PII:
S0960-894X(20)30309-7
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127209
BMCL 127209
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
7 February 2020
20 April 2020
23 April 2020
Please cite this article as: Du, J., Chu, W., Zhang, M., Ma, C., Feng, W., A novel method for preparing Eligulstat
through chiral resolution, Bioorganic & Medicinal Chemistry Letters (2020), doi: https://doi.org/10.1016/j.bmcl.
2020.127209
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A novel method for preparing Eligulstat
through chiral resolution
Leave this area blank for abstract info.
Jianxun Du,‡ Weiming Chu,‡ Mengmeng Zhang , Chunying Ma, * and Wenhua Feng*
*Department of New Drug Research and Development, Institute of Materia Medica, Peking Union Medical
College & Chinese Academy of Medical Sciences,
OH
H
O
N
C7H15
O
O
N
1)
HCl
spontaneous
crystallization
2) NaHCO3
diastereomers A
diastereomers B
OH
OH
OH
H
N
OH
H
H
H
O
C7
O
O
N
C7H15
O
O
N
C7H15
O
N
C7H15
H1
5
O
O
O
O
O
N
N
O
N
N

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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
A novel method for preparing Eligulstat through chiral resolution
Jianxun Du,‡ Weiming Chu,‡ Mengmeng Zhang , Chunying Ma, * and Wenhua Feng*
*Department of New Drug Research and Development, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences,
100050, Beijing, China. Email:fwh@imm.ac.cn
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Eliglustat is a ceramide glucosyltransferase inhibitor work as first line oral therapy for adults
with Gaucher disease type 1 (a rare disease) at present. Although the eliglustat in
enantiomerically pure forms is obtained by asymmetric syntheses, the reported methods suffer
from many limits when it comes to industrial applications. Therefore, the preparation of a
racemic mixture followed by resolution can still be a viable and straightforward alternative,
especially when it could be adapted to large scale. Herein, we developed an effective and
practical synthetic route to prepare stereoisomers mixture of eliglustat, and a novel chiral
resolution method to prepare eliglustat. Using 1,1'-Binaphthyl-2,2'-diyl -hydrogenphosphate
(BNDHP) as resolution reagent, optical pure eliglustat (e.e. > 99%, 13.97% total yield) could be
obtained after recrystallization.
Available online
Keywords:
Eligustat
Rare disease
Gaucher disease
Chiral resolution
2009 Elsevier Ltd. All rights reserved.
1. Introduction
operations, high cost of chiral reagent, and harsh reaction
conditions, such as non-scalable microwave equipment,
Eliglustat, a small-molecule oral glucosylceramide analogue,
is approved for first-line use in patients with Gaucher disease
type 1, a rare autosomal recessive lysosomal storage disorder in
which the lipid glucosylceramide accumulates in Gaucher cells in
organs including the spleen, liver and bone marrow caused by
enzyme glucosylceramidase deficiency1(Figure 1). Despite the
fascinating biological activity, the price of Eliglustat is rather
high (more than 300 thousands dollars one year). Herein, more
attention has been paid to develop a concise and efficient
synthesis of eliglustat.
extremely high or low temperature and the use of heavy-metal
catalysts (Cu, Ti, etc). Therefore, the preparation of a racemic
mixture followed by resolution can still be a viable and
straightforward alternative, especially when it could be adapted
to large scale. For example, mass production of bedaquiline, an
antituberculosis drug developed by Johnson& Johnson, has been
successfully industrialized by utilizing resolution methods7. In
addition, chiral resolution was also demonstrated to be practical
9
and effective in the preparation of tramadol and ephedrine8,
.
However, as well as we known, the synthesis of eliglustat via
chiral resolution has never been reported before.
The stereocontrolled construction of two contiguous
stereogenic tertiary carbons is the greatest challenge in the
synthesis of Eliglustat. To date, several asymmetric synthetic
methods via introduction of different chiral sources have been
documented. As one of the pioneering works, Genzyme
corporation reported a seven-step synthesis route in which (s)-
OH
O
O
NH
N
O
(+)-2-phenylglycinol was employed as
a
chiral source2.
eliglustat
Subsequently, Husain and Ganem developed a route toward the
key intermediate of eliglustat by utilizing a selective syn-addition
of aryl Grignard reagents to the Garner aldehyde3. In 2015,
another two asymmetric synthesis of eliglustat with high
enantioselectivity were reported by Van den Berg4 and Xu5,
respectively. In 2018, Xie and co-authors achieved the synthesis
of eliglustat in six linear steps with 28.4% overall yield by
utilizing Crimmins aldol reaction6. Recently, the team of Jiancun
Zhang and Zhongqing Wang developed an asymmetric synthesis
with 56.8% overall yield in nine steps7. Although asymmetric
syntheses are preferred for obtaining eliglustat in
enantiomerically pure forms, these methods encounter with many
limits when they are applied in industry, including complicated
Figure 1. the structure of eliglustat
Herein, we would like to introduce our efforts which
developed a new and practical procedure for optical resolution of
(±)-eliglustat with chiral (R)-1,1'-binaphthalene-2,2'-diyl
hydrogenphosphate as resolution agents. Instead of
chromatography, crystallization can be used in the separation and
purification of the synthetic intermediates, which makes it
possible to operate on a large, commercial scale.

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2. Result and Discussion
Another crucial point in scheme 1 is the amination of 2, we
tried to utilize Gabriel Synthesis with potassium phthalimide
transforming 2 to an intermediate. Although this progress was
available and effective, unfortunately, it was hard to cleavage the
intermediate to get product 3 regardless of the acid condition or
base condition and the cleavaged part had a large proportion of
racemization. Delepine reaction is another method which is
usually used for this reaction. The Delepine reaction between 2
and hexamethylenetetramine made a success with 97% yield and
easy separation.
According to the retrosynthetic analysis, a mixture of
eliglustat and its stereoisomers (5) can be obtained in four steps
(Scheme 1). The synthesis commenced with a commercially
available 1,4-benzodioxan-6-yl methyl ketone (1) which was
subjected to sequentially bromination, amination, and acylation
to produce the intermediate 4 with 93% yield. Mannich reaction
of 4 with paraformaldehyde and pyrrolidine, and then reduction
with NaBH4 led to the formation of mixture 5. The ratio of
diastereosiomers A/B was about 1:1 which was determined by
HPLC. However, direct separation of diastereosiomers A from
crude 5 via chromatography was found to be a challeng due to
the little polarity differences. Further optimization lent an
interesting twist that treatment of crude 5 with HCl in water led
to the spontaneous crystallization of diastereomer A (Eligustat
and its enantiomer) hydrochloride salt which can get nearly 50%
total free diastereomer A by further alkalizing with NaHCO3.
The main byproduct of the synthesis presents to be the
byproduct of Mannich reation transforming compound 4 to
compound
5 by self-elimination of mannich base and
hydroxymethylated elimination of compound 4 (see Scheme S3,
in the supporting information). Because the Mannich base is hard
to separate, we reduct it directly without purification. The
byproduct of Mannich reaction can be also reduced by sodium
borohydride and it is easy to separate from the main product.
O
O
O
O
O
O
O
NH2
HCl
With the successful preparation of diastereomer A (rac-
eliglustat), we further studied the chiral resolution of the desired
(1R, 2R) enantiomer eliglustat. Obviously, a suitable chiral
resolving reagent is supposed to be crucial to this separation.
Classical resolution procedures involving the use of well-known
resolving agents such as chiral camphor-10-sulphonic acid,
tartaric acid, and mandelic acid have been available for a long
time. Rene Imhof etal previously described the use of binaphthyl
phosphoric acids in the resolution of 7-phenylquinolizidines.10 In
2002, Periasamy etal reviewed many novel methods of resolving
racemic diols and amino alcohols.11 Inspired by these
encouraging works, a series of commercially available and
commonly methods used acidic resolving agents L1-L6 (Table 2)
were screened for the enantiomer resolution. Firstly,
diastereomers A and resolving agents were mixed and dissolved
in acetone or ethanol for crystallization (Table 2, entries 1-8).
L1-L2 could not yield any precipitated products both in acetone
and ethanol. As for L3, no resolution effect was detected. While,
upon further optimization, a good enantioselectivity (88.5:11.5 dr)
and moderate yield of eliglustat salt was obtained by using bulky
L4 as the resolution regent. To our delight, the yield of product
could be increased to 78% with 95.6:4.3 dr when sterically
bulkier L5 was employed. These results indicated that steric
hinderance effect may be favorable for the resolution of
diastereomers A. Indeed, further optimization with L6 as
resolution regent in acetone showed an excellent resolution effect
Pyridinium tribromide
(CH2)6N4
O
O
Br
HCl, ethanol
1
3
2
OH
*
O
H
N
(2)
O
(1)
H
N
O
O
n-C7H15
O
C7H15 1)(CH2O)n, Pyrrolidine
2) NaBH4
Cl
*
O
O
N
O
CH3COONa
4
5
mixture of (1R,2R)(1S,2S)(1R,1S)(2S,2R)
OH
H
1)
O
O
N
C7H15
HCl
spontaneous
crystallization
O
N
eliglustat
(1R,2R)
2) NaHCO3
+
~ 14% total yield
OH
H
O
N
C7H15
(1S,2S)
O
O
N
Scheme 1. The preparation of rac-eliglustat with four isomers
To get monobrominated 2-bromine-3’,4’-(ethylenedioxy)-
acetophenone, we firstly used bromine as bromide reagent at
room temperature, however it only generated a mixture which
contained 57.5% monobrominated, 20% dibrominated and some
multibrominated product, monitored by LC-MS. And the
mixture can be purified by crystallization in ethyl acetate. Some
experiments have been made to promote the yield such as adding
different equivalent HOAc and reacting at a lower temperature
but they all failed without any meaningful results. Furthermore,
we tried different bromination reagents. NBS had a low activity
of the bromination with trace product. Pyridinium tribromide
showed an almost perfect behavior in this bromination process
with 98% yield (Table 1).
O
O
OH
OH
OH
OH
HO
OH
HO
O
OH
O
HO
OH
, R-Mandelic acid
OH
L2
, D-(-)-Quinic acid
Table 1.The bromination of 3’,4’-(ethylenedioxy)-acetophenone
L1
L3
, D-(+)-Tartaric acid
Entry Reagenta T ℃ HOAc
Solvent
DCM
Yield %
57.5%
59.1%
63.0%
61.2%
5.2%
O
O
O
O
O
O
Ph
OH
O
OH
O
1
2
3
4
5
6
Br2
Br2
25
0
-
O
O
O
P
-
DCM
OH
HO
Ph
HO
O
O
O
O
Br2
0
0.1 eq
DCM
Br2
0
1 eq
DCM
DCM+HOAcb
L4
, D-(+)-DBTA
L5
, D-(+)-DTTA
L6
, (R)-(-)-BNDHP
(95:5). Upon switching to mixed solvents acetone/dimethyl
sulphoxide(2:1), the yield was increased to 65.2%, but a slightly
diminished enantioselectivity was obtained (7.6:92.4). Pleasingly,
the enantioselectivity and yield could be further improved to
97.7:2.3 and 78.7%, respectively, when ethanol was used as
solvent. Changing the amount of L6 to 0.75 equiv or 1.5 equiv
led to lower enantioselectivity and yield both in ethanol or
acetone.
Br2
0
-
-
NBS
NBS
C5H6Br3N
25
25
25
DCM
1.2%
Acetonitrile
MeOH+DCMc 98.1%
5%
7
-
a The reagent equilvalent is 1.05eq.
b HOAc is used to dissolve the sub strate 3’,4’-(ethylenedioxy)-acetophenone.
DCM is dichloromethane. HOAc is acetic acid
c Pyridinium tribromide(C5H6Br3N) can be dissolved well in
MeOH(methanol).
Table 2. Resolution of racemic eliglustat with resolving agentsa