A facile synthesis of epinastine HCl via dehydroepinastine intermediate

Article abstract of DOI:10.1016/j.tetlet.2019.151451

Epinastine is a second generation histamine H₁ receptor antagonist used as a non-sedative antiallergic drug. When given orally, epinastine poorly penetrates blood-brain barrier (BBB) and appears to be free of cardiac toxicity as compared to other antihistamine drugs. A couple of synthetic approaches for epinastine HCl have been reported so far. They hold several problems such as explosive, highly toxic or expensive reagents. Moreover, they usually do not offer concise synthetic steps. In our synthesis shown here, a commonly used starting material, 6-(chloromethyl)-11H-dibenzo[b,e]azepine is treated with cyanamide to afford dehydroepinastine (14) in significantly high yield, which is subsequently reduced in the presence of aqueous HCl to give epinastine HCl in only two steps (75% overall yield for two steps). The problems associated with the reported processes such as using toxic and dangerous chemicals, lengthy synthetic steps or low overall product yields can be overcome by utilizing this new route. We believe our synthetic scheme might provide a breakthrough to reduce the cost of the production of epinastine HCl.

Full text of DOI:10.1016/j.tetlet.2019.151451

Journal Pre-proofs
A Facile Synthesis of Epinastine HCl via Dehydroepinastine Intermediate
Sang Won Park, Han Eol Kang, Wheesahng Yun, Sang Yeul Lee, Tae-gyu Nam
PII:
S0040-4039(19)31250-X
https://doi.org/10.1016/j.tetlet.2019.151451
TETL 151451
DOI:
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Tetrahedron Letters
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26 September 2019
21 November 2019
25 November 2019
Please cite this article as: Park, S.W., Kang, H.E., Yun, W., Lee, S.Y., Nam, T-g., A Facile Synthesis of Epinastine
HCl via Dehydroepinastine Intermediate, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.
2019.151451
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A Facile Synthesis of Epinastine HCl via Dehydroepinastine Intermediate
Sang Won Park, Han Eol Kang, Wheesahng Yun, Sang Yeul Lee and Tae-gyu Nam*
Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang
University, Ansan, Gyeonggi-do 15588, Republic of Korea
*Corresponding author
Email: tnam@hanyang.ac.kr, Tel: +82-31-400-5807; Fax: +82-31-400-5958
1

Abstract
Epinastine is a second generation histamine H1 receptor antagonist used as a non-
sedative antiallergic drug. When given orally, epinastine poorly penetrates blood-brain barrier
(BBB) and appears to be free of cardiac toxicity as compared to other antihistamine drugs. A
couple of synthetic approaches for epinastine HCl have been reported so far. They hold several
problems such as explosive, highly toxic or expensive reagents. Moreover, they usually do not
offer concise synthetic steps. In our synthesis shown here, a commonly used starting material,
6-(chloromethyl)-11H-dibenzo[b,e]azepine is treated with cyanamide to afford
dehydroepinastine (14) in significantly high yield, which is subsequently reduced in the
presence of aqueous HCl to give epinastine HCl in only two steps (75% overall yield for two
steps). The problems associated with the reported processes such as using toxic and dangerous
chemicals, lengthy synthetic steps or low overall product yields can be overcome by utilizing
this new route. We believe our synthetic scheme might provide a breakthrough to reduce the
cost of the production of epinastine HCl.
Key Words: Epinastine, Dehydroepinastine, Cyanamide, Antihistamine
2

Introduction
Epinastine is a second generation histamine H1 receptor antagonist used as a non-
sedative antiallergic drug. Epinastine hydrochloride has been used as tablets for the treatment
of bronchial asthma, allergic rhinitis and skin diseases with pruritus in adult patients and as
topical ophthalmic solution for allergic conjunctivitis.1-3 When given orally, epinastine poorly
penetrates the blood-brain barrier (BBB) and appears to be free of cardiac toxicity as compared
to other antihistamine drugs such as astemizole and terfenadine.4,5
As a successful active pharmaceutical ingredient (API), a couple of synthetic
approaches for epinastine HCl have been reported so far. The original synthetic scheme began
with the treatment of a commercially available 2-benzylaniline with phosgene to form an
isocyanate intermediate that was converted to 6-morphanthridone or 5,11-dihydro-6H-
dibenzo[b,e]azepin-6-one 2 by an intramolecular Friedel-Crafts acylation (Scheme 1).6
Exposing 2 to phosphorus oxychloride afforded 6-chloromorphanthridine 3, which was
allowed to react with sodium cyanide to give 6-cyanomorphanthridine 4. Both nitrile and imine
functional groups on 4 were simultaneously reduced by lithium aluminum hydride to produce
6-aminomethyl-5,6-dihydromorphanthridine 5. The primary amine on compound 5 reacted
with cyanogen bromide to form N-((5,6-dihydromorphanthridine-6-yl)methyl)cyanamide that
was spontaneously cyclized to provide epinastine HBr salt (6) from which desired epinastine
HCl (1) was afforded via a salt exchange. However, this scheme has several problems in
especially large scale synthesis: a notorious phosgene gas should be avoided in the large scale
synthesis, cyanogen bromide is also a highly volatile and toxic substance, every synthetic step
requires purification, and overall product yield was low.
3

O
NC
Cl
H2N
NH
N
N
COCl2
AlCl3
POCl3
NaCN
2
3
4
NH2
NH
N
N
N
NH2
HBr
NH2
HCl
BrCN
LiAlH4
N
HCl
5
6
Epinastine HCl (1)
Scheme 1. The original synthetic route for Epinastine HCl (1).
In order to address the issues associated with the original scheme, scientists at
Boehringer-Ingelheim developed an improved synthetic route for the key intermediate 5
starting from a known compound 7 (Scheme 2).7 They prepared a chloro compound 7 according
to the literature procedure and converted it to compound 8 through Gabriel synthesis protocol.
The imino group on 8 was reduced under hydrogenation in presence of formic acid to provide
a secondary anime 9, and the hydrazinolysis of the phthalimide of 9 afforded 5, which can be
merged to the original synthetic pathway for epinastine. However, this scheme also has some
problems in that removal of the phthalyl hydrazide byproduct can be troublesome and that toxic
hydrazine is not an ideal reagent in mass production. Besides, treating hydrobromide requires
a special equipment adding an extra cost for synthesis especially in production scale. Since
then, a number of synthetic routes for epinastine have been reported.8-16 Those routes consist
of preparation of compound 5 or N-substituted 5, followed by conversion to N-cyanylation, and
subsequent cyclization to afford epinastine or its N-substituted analogue, and the final treatment
of hydrochloric acid to provide epinastine HCl (1).
4

O
O
Cl
N
N
N
H2, Pd/C
90%
Phthalimide
N
O
NH
O
50%
(reference17)
7
8
9
NH2
NH
N
N
N
NH2
HBr
NH2
HCl
H2NNH2
N
BrCN
76%
HCl
90%
(2 steps)
5
6
1
Scheme 2. Synthetic route in reference 7
Results and Discussion
After a careful examination of reported synthetic routes, we designed a new synthetic
scheme, which might reduce the number of synthetic steps and improve overall yield (Scheme
3). In a new scheme, we predicted that the chloride on compound 7 undergo SN2 displacement
by cyanamide 12 to produce a cyanoamine 13 and the imine functionality on the compound 13
is selectively reduced by a hydride reagent to form a secondary amine intermediate. It is
spontaneously cyclized to an imidazolidin-2-imine that can undergo a tautomerization to
provide epinastine free base 10. Epinastine 10 could be easily converted to its HCl salt (1).
Cyanamide is the key reagent in the new scheme and has desirable features in that it is not only
readily available but also very affordable. A kilogram quantity is available from a common
commercial source for only $97.6 according to SciFinder database.
5

HN
Cl
N
N
NH2
hydride
H2N-CN
N
N
N
10
13
7
Epinastine (
)
Scheme 3. Envisioned synthetic scheme.
In our synthesis, 2-benzylaniline was treated with chloroacetyl chloride to provide an
o
amide 11 in 85% yield.18 Compound 11 was warmed at 120 C in the presence of
polyphosphoric acid and phosphorus oxychloride to provide 7 in 75% yield. When 7 was
allowed to react with cyanamide 12, however, to afford 13 was unsuccessful. As shown in
scheme 4, dehydroepinastine 14 was unexpectedly obtained without giving the expected
product 13 or other cyclized compounds.
Cl
HN
N
N
Cl
NH2
O
NH2
N
N
N
a
c
b
HN
Ph
H2N-CN
12
(
)
13
11
7
14
N
NH2
HCl
d
N
1
(Epinastine HCl)
Scheme 4. Synthesis of epinastine HCl via dehydroepinastine 14 using cyanamide.
reagents and conditions a) Chloroacetyl chloride, pyridine, toluene, 0 oC  r.t., 1.5 h, 85%; b)
polyphosphoric acid, POCl3, 120 oC, 2 h, 90%; c) H2N-CN, conditions (see table 1), 0% ~ 85%;
(d) Pd/C, H2, MeOH, 6 N HCl, 87%
6

The proposed mechanism for 14 would be that the initial SN2 reaction product 13 might
be formed and experience a base-promoted intramolecular cyclization proceeding to give an
imino intermediate that tautomerizes to result in dehydroepinastine 14 (Scheme 5). It is
interesting that HCl salt of 14 is indicated as one of the major impurities of epinastine HCl in
pharmacopeia (impurity A).19 Many pharmaceutical impurities are usually formed in small
amount but hard to remove, still causing costly damage to the purity of API. It will be a
significantly interesting approach to utilize an impurity as a key intermediate for the synthesis,
not trying to minimize its formation.
H
H
H
N
N
N
C
C
Cl
H
N
N
NH
H2N-CN
B
N
N
N
N
7
13
N
NH2
tautomerization
N
14
Scheme 5. Proposed mechanism for compound 14.
Synthetically useful routes for epinastine HCl utilizing the impurity,
dehydroepinastine, have been reported, we envisioned that the olefinic double bond on
imidazole ring of 14 could be selectively reduced to afford desired epinastine and decided to
utilize 14 as the precursor of epinastine in our new synthetic scheme. Accordingly, the
7

optimization study for 14 was performed (Table 1). While a few recent reports exist19,20 on the
synthesis of dehydroepinastine 14, they introduced an oxidative preparation of 14 from
epinastine in order to use it as a standard material for analytical purpose and therefore are not
synthetically useful.
Table 1. Optimization study for 14
Cl
N
NH2
N
N
conditions
+
H2N-CN
12)
(
14
7
Conditions
Entry
Results
12 (eq.)
Base (eq.)
Solvent a
Temp. b
Time
1
2
2.0
-
DMF
130 oC
18 h
decomp.c
decomp.d
10%
2.0
2.0
2.0,
2.0
2.0
3.0
2.0
2.0
2.0
2.0
2.0
K2CO3 (1.5)
DIPEA (1.5)
NaOtBu (1.5)
NaOtBu (1.5)
NaOtBu (1.5)
NaOtBu (1.5)
NaOtBu (1.5)
NaOtBu (1.5)
NaOtBu (1.5)
NaOtBu (1.5)
NaOtBu (1.5)
DMF
DMF
DMF
THF
90 oC
90 oC
90 oC
reflux
reflux
reflux
8 h
8 h
3
4
18 h
17%
5
18 h
15%
6
MeCN
MeCN
DMF
DMF
DCE
18 h
32%
7
12 h
86%
8
MW, 120 oC
MW, 160 oC
MW, 120 oC
MW, 120 oC
MW, 200 oC
30 min.
30 min.
50 min.
50 min.
30 min.
20%
9
29%
10
11
12
Trace
Trace
38%
THF
DMSO
8

13
14
15
16
17
18
19
20
21
22
23
24
2.0
2.0
2.0
3.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
NaOtBu (1.5)
NaOtBu (1.5)
NaOtBu (2.0)
NaOtBu (1.5)
KOtBu (2.0)
Na2CO3,(2.0)
K2CO3,(2.0)
Cs2CO3,(2.0)
KHCO3 (2.0)
NaOH (2.0)
DIPEA (3.0)
NaI (1.0)
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MW, 120 oC
MW, 120 oC
MW, 120 oC
MW, 120 oC
MW, 120 oC
MW, 120 oC
MW, 120 oC
MW, 120 oC
MW, 120 oC
MW, 120 oC
MW, 120 oC
MW, 120 oC
30 min.
30 min.
30 min.
30 min.
30 min.
50 min.
50 min.
50 min.
50 min.
50 min.
50 min.
50 min.
55%
63%
56%
66%
38%
5%
51%
13%
N. R.e
29%
10%
decomp.d
NaI(1.0)/NaOt
Bu(1.5)
25
26
3.0
5.0
MeCN
MeCN
reflux
reflux
18 h
18 h
28%
28%
NaI(3.0)/NaOt
Bu(1.5)
a) Reaction concentration was 0.1 M b) MW = microwave reaction c) decomposition of 7. d)
dechlorinated compound of 7 was observed. e) N.R. = no reaction
At first, compound 7 was treated with 2.0 eq. of 12 in DMF with various conditions
(entries 1–4). When the reaction mixtures were warmed at 90 oC without a base or in presence
of 1.5 eq. K2CO3, only decomposition of 7 was observed (entries 1–2). Addition of mild base
DIPEA to the reaction mixture produced small amount of 14 (10% yield, entry 3). When
o
NaOtBu was used as a base, 14 was obtained in 17% yield at 90 C (entry 4), however, the
9

starting material was almost decomposed when the temperature was raised to 130 oC (data not
shown). Other solvents, such as THF and MeCN, were also tested (entries 5 and 6). While
running the reaction in THF provided a similar result to DMF, the reaction in MeCN afforded
a promising yield (32%). Finally, use of 3.0 eq. of 12 in refluxing MeCN afforded 14 in 85%
yield (entry 7).
In search of alternative reaction conditions, microwave-assisted syntheses were tested.
Microwave reactions generally resulted in better product yields along with cleaner reaction
profiles than thermal counterparts. To find an optimal solvent, compound 7 was treated with
2.0 eq. of 12 and 1.5 eq. of NaOtBu and exposed to microwave reaction conditions in different
solvents (entries 8-14). When running the reaction at 120 oC in DMF (normal abs, 30 min), the
result was similar to that of the thermal condition (20%, entry 8), while producing enhanced
yield of 29% at higher temperature (160 oC) (entry 9). Reactions in DCE and THF produced
only a trace amount of 14 (entries 10–11). However, reactions in DMSO displayed significant
o
o
improvements (38% at 200 C and 55% at 120 C) with inverse dependency on temperature
(entries 12–13). Switching the solvent to MeCN even increased yield to 63% (entry 14).
Doubling of reaction concentration of entry 14 to 0.2 M resulted in ~10% reduction in yield
(data not shown). Varying the amount of the base always resulted in decrease in yield. More
than 1.5 eq. of NaOtBu decreased the yield to 56% (entry 15) and less equivalent decreased the
yield to a greater extent (data not shown). Addition of one more equivalent of cyanamide 12
slightly improved the reaction to afford 66% yield (entry 16) but change of base generally
resulted in poorer yields than NaOtBu except for K2CO3 that afforded 51% yield (entries 17-
23). Finkelstein protocol was also tried, but desired 14 was not formed, but small amount of
dechlorinated compound of 7 was observed. Addition of NaOtBu improved the yields which
were not more than 30% (entry 24-26). With above optimization study, it was evident that
10

reaction time was dramatically reduced through microwave conditions however the best yield
was obtained under refluxing condition. (entry 7).
Once the robust protocol for epinastine precursor 14 was established, a selective
reduction procedure for the C-C double bond on 14 in presence of an imine moiety was
investigated. Metal hydrides such as NaBH4, LiBH4, DIBAL-H and LiAlH4 did not proceed
the reduction and majority of starting material 14 was recovered. Next, compound 14 was
exposed to hydrogenation condition in various solvents. Attempts for hydrogenation of 14 in
MeOH, EtOH, EtOAc, DMF and THF all produced epinastine in quite low yield (<10%). It
was speculated that the primary amine on 14 might be the culprit for the unsuccessful reduction
by poisoning the catalyst. We decided to protonate the amine functional group and
hydrogenation in a mixture of EtOH and aqueous 6 N HCl as a co-solvent afforded the final
compound epinastine HCl. This hydrogenation protocol is beneficial not only for high yield up
to 87% but also for a facile synthesis; it does not require final salt formation or salt exchange
step (Scheme 6).
N
N
NH2
HCl
NH2
N
N
H2, Pd/C
EtOH, 6 N HCl
87%
1
14
(Epinastine HCl)
Scheme 6. Final hydrogenation step toward epinastine HCl (1)
Then, we have explored an alternative route to get to epinastine 10 without association of
palladium-catalyzed reduction (Scheme 7). In this scheme, we hoped to form epinastine 10 in
two step from compound 7 by a reaction of cyanamide with compound 15 as a key step. Imine
group of compound 7 was successfully reduced using NaBH4 to give 15 in 88% yield. However,
11

all attempts including a simple SN2 reaction of 15 with cyanamide 12 and Finkelstein protocol
did not afford epinastine 10 even under refluxing condition. It is probably due to the different
reactivity of methylene group in 7 and 15; a very reactive -chloroimine group in 7 vs. a much
less reactive primary alkyl chloride in 15.
Cl
Cl
N
H2N-CN (3.0 eq.)
NaOtBu (1.5 eq.)
NH2
NaBH4
NH
N
N
//
MeOH
CH3CN, reflux
rt, 9 h, 88%
10
15
7
Scheme 7. Alternative route for epinastine 10 starting from compound 7
In conclusion, a facile and cost-effective synthetic route for epinastine HCl was
developed. From known compound 7, epinastine HCl was prepared in just two synthesis steps.
The problems associated with the reported processes such as using toxic and dangerous
chemicals, long synthetic steps or low overall product yields can be overcome by utilizing this
new route. Selective hydrogenation of an olefin moiety on 2-amino imidazole was achieved by
adding aqueous HCl. Our synthesis scheme might give rise an opportunity to reduce the cost
in mass production of epinastine HCl.
12

Acknowledgement
This research was supported by Research Fund of Hanyang University (HY-2013-P).
13

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14

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Graphical Abstract
N
Cl
N
NH2
NH2
HCl
H2N-CN
N
Pd/C, H2
N
N
EtOH-HCl
7
14
)
Dehydroepinastine (
Epinastine HCl
(75% for two steps)
Highlights
Epinastine, an antiallergic drug, was synthesized efficiently via dehydroepinastine.
Dehydroepinastine was synthesized using cyanamide in high yield.
Epinastine HCl was synthesized in 75% yield in two steps from available intermediate
Declaration of Interest
Authors declare no conflict of interest.
15