A new route to cevimeline

Article abstract of DOI:10.1016/j.tetlet.2013.03.090

The present work demonstrates a new route for the synthesis of cevimeline in which safe and odorless thiourea is utilized as a thiolating reagent.

Full text of DOI:10.1016/j.tetlet.2013.03.090

Accepted Manuscript
A New Route to cevimeline
Chinmoy Pramanik, Pradip Patil, Sandeep Kotharkar, Narendra K. Tripathy,
Mukund K. Gurjar
PII:
S0040-4039(13)00504-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.03.090
TETL 42716
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
1 October 2012
19 March 2013
22 March 2013
Please cite this article as: Pramanik, C., Patil, P., Kotharkar, S., Tripathy, N.K., Gurjar, M.K., A New Route to
cevimeline, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.03.090
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A New Route to cevimeline
ChinmoyPramanik*, PradipPatil, SandeepKotharkar, Narendra K. Tripathy, and Mukund
K. Gurjar
API R&D Centre, Emcure Pharmaceuticals Ltd., ITBT Park, Phase-II, MIDC, Hinjwadi,
Pune-411057, India
Fax: +91-20-39821445. E-mail: chinmoy.pramanik@emcure.co.in
H
Cl
H
N
Cl
N
N
O
O
O
O
S
S
Cevimeline Hydrochloride ( )

A New Route to cevimeline
Authors:ChinmoyPramanik*, PradipPatil, SandeepKotharkar, Narendra K. Tripathy, and
Mukund K. Gurjar
API R&D Centre, Emcure Pharmaceuticals Ltd., ITBT Park, Phase-II, MIDC, Hinjwadi,
Pune-411057, India
Corresponding author: Fax: +91-20-39821445. E-mail: chinmoy.pramanik@emcure.co.in
Abstract: Thepresent work demonstrates a new route for the synthesis of cevimeline
hydrochloride in which safe and odorless thioureais utilized as athiolating reagent.
Keywords:Cevimeline hydrochloride, spirocyclic compound,Active Pharmaceutical
Ingredients (API), muscarinic agent,thiourea, process development.
Cevimeline hydrochloride (1, Figure 1), chemically known as cis-2-methyspiro(1,3-
oxathiolane-5,3)quiniuclidine, exists as a racemic mixture,an oral muscarinic agent that
has been recently approved for the treatment of xerostomia in the setting of Sjogren’s
syndrome.1Sjogren syndrome is a systemic chronic inflammatory disorder characterized
by xerostomia, anhidrosis, and conjunctivitis sicca due to lymphocytic infiltration
ofexocrine organs, such as salivary, sweat, and lacrimal glands. Cevimeline directly
stimulates M3 receptors in the salivary glands and increases salivary secretion and it lasts
longer (5 h) than for pilocarpine (3 h).It is distributed under the brand name Evoxac(R)
by Daiichi Sankyo (Tokyo, Japan) in the USA, Japan, and Taiwan. Common reported
side effects of this drug includenausea, headache, rhinorrhea, diarrhea, abdominal pain,
and diaphoresis.

H
Cl
N
O
S
Cevimeline Hydrochloride ( , 1)
Figure 1 (Cevimeline Hydrochloride)
A detailed literature study revealed that there are two patent procedures available for the
commercial manufacturing of cevimeline/cevimeline hydrochloride. Fisher et. al.2 started
the process with the ketone 3(Scheme 1), which on epoxidation following the Corey-
Chaykovsky conditions3produced the epoxide 4. Compound 4 on treatment with
hydrogen sulfide followed by cyclization of the resulting thiol5 with acetaldehyde in
presence of BF3.Et2O produced 6 (1:1 cis:trans mixture). Cevimeline hydrochloride (1)
(cis isomer) is resolved from the mixture by successive purifications.
Scheme 1
N
HO
HS
H
H
Cl
Cl
Trimethyl Sulfoxonium
Iodide (1.2 eq)
N
N
H2S, NaOH (4.3 eq)
N
+
N
O
+
H2O, 45oC
2.5 h, 50%
DMSO, NaH(1.1 eq)
50 oC, 2 h, 71%
O
O
HS
4
3
HO
5
H
N
Cl
H
N
Cl
O
1. Acetaldehyde (11.0 eq)
BF3-OEt3 (2.2 eq), DCM
Purification
S
S
O
S
H
N
+
Cl
2. Ether, HCl (g)
62% for two steps
Cevimeline Hydrochloride ( , 1)
O
6
Bratovanov et al.4 (Scheme 2) used the same epoxide (4) but opened the ring with
thioacetic acid which was followed by p-TSA catalyzed thioacetal formation in two steps.
The reported routes suffer major disadvantage with respect to the thiolating agent. In both
the cases, they have used highly hazardous, very foul smelling and difficult to handle
reagents like hydrogen sulfide or thioacetic acid.

Scheme 2
H
CH3COS
CH3COS
N
N
1. p-TSA (3.0 eq)
HO
Isopropanol, reflux 3.5 h
O
O
O
O
Trimethylsulfoxonium
H
Thiolacetic acid
Isopropanol
0 oC to rt 2h
68%
S
iodide (1.24 eq)
Cl
N
+
H
2. Acetaldehyde
diethylacetal (5.0 eq), reflux
3h, 89% for two steps
+
tBuOK (2.24 eq)
0 oC to rt, 16 h, 54%
N
N
O
S
3
HO
4
7
N
H
O
Cl
N
Purification followed
by HCl salt formation
S
O
+
N
S
S
Cevimeline Hydrochloride ( , 1)
O
6 (Cevimeline free base)
(cis/Trans-75:25)
In our continuous efforts to develop improved processes for generic drugs of our interest,
we decided to investigate an alternate route to cevimelinehydrochloride (1).In this case
the basic premise would be to focus on the thiolating agents other than hazardous
hydrogen sulfide or thioacetic acid.Herein we report a convenient, economical, much
greener route (Scheme 3) for the synthesis of cevimeline hydrochloride (1) using
nonhazardous and odorlessreagent thiourea as the thiolating reagent.
The literature procedure4was modified to generate the epoxide intermediate 4starting from
commercially available3-quiniclidinone hydrochloride (3). For example, instead of
adding the epoxidation reagent in one lot, we observed that sequential addition of
trimethylsulfoxonium iodide and potassium tert-butoxide to a suspension of 3-
quiniclidinone hydrochloride (3) in dimethylsulfoxide gave better quality product and
improved yield. Our next concern was the insertion of “sulfur” atom. It is known5 in the
literature that direct opening of epoxide with thiourea preferably gives the three-
membered ‘episulfide’ derivative (Scheme 3) which for our endeavor is an undesired
intermediate.

Hence, we diverted our attention to the indirect route of ‘sulfur’ insertion via the
corresponding halide intermediate.6The epoxide 4wastreated with aqueous HBr in
acetone to give the desired bromohydrinprecursor (8) in good yield (scheme 3).7 The
structure of 8 was substantiated by spectroscopic methods.
Scheme 3
H
Br
N
HO
Br
H
+
Br
N
HBr (48%aqueous sol)
acetone, 0 oC to rt 2h
Br
HO
N
8
H
O
O
Trimethylsulfoxonium
Iodide (1.3 eq)
Cl
N
+
N
N
O
KtBuO (2.4 eq), DMSO
0 oC to rt, 8 h, 70%
Thiourea
S
S
3
+
4
N
Episulfide
We envisaged that under classical conditions8 of bromide replacement with thiourea,
compound 8 would give rise to the isothiourenium intermediate (9, Figure 2) which on
simple hydrolysis with a base should provide the thiol derivative (5).
H
Cl
N
HO
S
H2N
NH2
9
Br
Figure 2 (Isothiourenium Intermediate)

As it turned out, the bromo replacement with thiourea was not a simple proposition and in
fact failed under the reported conditions8even after using high boiling alcohols at elevated
temperature. After several attempts, we concluded that the reaction of the bromo
compound (8) with thiourea could best be achieved in water at reflux temperature for 2 h
(Scheme 4). It is pertinent to mention that all the intermediates in this synthetic sequence
were difficult to monitor by conventional TLC or HPLC techniques due to the lack of
uvchromophores in the structures. Also, monitoring the transformations by using iodine
or staining of the TLC was not satisfactory. We then resorted to monitoring the progress
of the reaction by mass spectral analysis and obtained some interesting results. For
instance, the major observed molecular ion peak after 2 h was at m/z 200 with a small
peak at 174 which corresponds to the desired thiol intermediate (5). Interestingly no peak
was detected for the isothiourenium intermediate 9 expected at m/z 215. After 10 h, the
reaction mixture showed almost complete vanishing of the peak at m/z 200 and at the
same time the peak localized at m/z 174 corresponding to the thiol5became hugely
prominent (Figure-3), along with several additional peaks which could be attributed to
the degradation products.
Figure 3: a) Mass spectrum of the reaction mixture after 2h. b) Mass spectrum of the
reaction mixture after 10 h.
Hence, to avoid the degradation of the reaction mixture on prolonged heating (10 h), we
decided to terminate the reaction after 2 h and isolate the intermediate with m/z 200.
Based on spectral data,9 the thiolactone structure (10) was assigned to this new
intermediate having m/z 200.
Scheme 4

N
NaOH, Water
100 oC, 2h,
Acetaldehyde
diethylacetal (5.0 eq)
p-TSA (3.0 eq), IPA
Br
N
thiourea (1.0 eq)
water, 100 oC, 2h
H
O
N
N
HO
HS
O
S
O
HO
Br
70 oC, 3 h, 50 % for
two steps
Cevimeline(6)
cis/trans-70:30
60 %
S
8
5
10
Thiolactone-intermediate 10 on treatment with NaOH in water under reflux underwent
hydrolysis and afforded the thiol intermediate (5) in 2 h which was taken forward without
isolation and treated with acetaldehyde diethyl acetal following literature procedures4to
obtain the desired cyclized compound 6 (cevimeline-free base with 70:30, cis:trans ratio
as seen in the 1H NMR).
The present route can be useful for the development of commercial manufacturing of
cevimeline hydrochloride.
In conclusion, we have developed a new route to cevimeline using much greener
thiolating agent “thiourea” compared to hydrogen sulfide and thioacetic acid. Another
advantage in this new route is the insitu conversion of the thiol intermediate (5) (which
has a very bad smell) to cevimeline.
Acknowledgment
The authors wish to thank Mr. Samit Mehta, our management andARD group of
Emcure Pharmaceuticals Ltd. for their willing support and constant encouragements.
Supplementary data
Supplementary data (general procedures and spectral data)associated with this article can
be found, in the online version, athttp://dx.doi.org
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9. NMR data is given in the Supplementary data section.