An efficient synthesis of varenicline

Article abstract of DOI:10.1016/j.tetlet.2009.10.107

Synthesis of varenicline the antismoking drug has been achieved in six steps with 10% overall yield. A Diels-Alder reaction, oxidative cleavage of an olefin and reductive amination remain as key steps in the synthesis.

Full text of DOI:10.1016/j.tetlet.2009.10.107

Tetrahedron Letters 51 (2010) 151–152
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient synthesis of varenicline q
Srinivas Pasikanti a,b, D. Srinivasa Reddy a, B. Venkatesham a, P. K. Dubey b, Javed Iqbal a, Parthasarathi Das a,
*
a Discovery Research, Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, AP, India
b Department of Chemistry, JNTU College of Engineering, Kukatpally, Hyderabad 500 085, AP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of varenicline the antismoking drug has been achieved in six steps with 10% overall yield. A
Diels–Alder reaction, oxidative cleavage of an olefin and reductive amination remain as key steps in
the synthesis
Received 15 September 2009
Revised 20 October 2009
Accepted 22 October 2009
Available online 27 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Neuronal nicotinic acetylcholine receptors (nAChRs) belong to a
heterogeneous family of pentameric ligand-gated ion channels
which are differently expressed in many regions of the central ner-
vous system (CNS) and peripheral nervous system.1,2 Agonists and
partial agonists of various subtypes of nicotinic acetylcholine
receptors (nAChRs) are being pursued as potential treatments for
a variety of central nervous system disorders, such as addiction,
pain, depression, schizophrenia, Parkinson’s disease, Alzheimer’s
disease, Attention-deficit hyperactivity disorder (ADHD), and alco-
holism.3–7 Moreover, as the addictive properties of tobacco prod-
ucts are due to the nicotine contained therein, nAChRs also
became important targets for the discovery of medicines for use
presence of ammonium formate in methanol to yield varenicline
1
20 (Scheme 2).
N
N
HN
HN
N
O
Varenicline 1
(-)-Cytisine 2
H
Cl
N
in smoking cessation.8 Varenicline 1 an
a4b2 nAChR partial agonist
N
N
was approved by US FDA as an aid to smoking cessation treatment
in May 2006.9 Varenicline was discovered through the synthesis of
a series of compounds inspired by the natural product (À)-cytisine
2,10 which was previously known to have partial agonist activity at
Me
N
Epibatidine 3
(-)-Nicotine 4
Figure 1. Natural products (2–4) and varenicline (1), ligands that can act as
the a
4b2 nAChR (see Fig. 1).11
neuronal nicotinic acetylcholine receptors.
We herein, wish to report our efforts12 on the synthesis of
varenicline in an efficient manner by using a Diels–Alder reaction,
oxidative cleavage of an olefin and reductive amination as shown
retrosynthetically in Scheme 1.
As per the synthetic plan, our synthesis began with the conver-
sion of 2,3-dimethylpyrazine 10 to its known analogue 2,3-bis-
(dibromomethyl)pyrazine13 8. Followed by NaI-mediated Diels–Al-
der13,14 reaction between 2,3-bis (dibromomethyl)pyrazine 8 and
commercially available norbornadiene 9 to furnish the adduct 7.15
Olefin 7 was converted16 to its corresponding diol 617 with OsO4 in
the presence of NMO. Oxidative cleavage18 of the diol with NaIO4
provided an intermediate dialdehyde. Subsequent reductive amina-
tion with 4-methoxy benzyl amine gave compound PMB-protected
varenicline 5.19 Finally PMB group was removed by Pd/C in the
N
N
N
N
HN
PMBN
1
5
Varenicline
N
N
HO
HO
N
N
7
6
N
CHBr2
CHBr2
+
N
8
q
DRL Publication No. 709.
9
* Corresponding author. Tel.: +91 40 2304 6677; fax: +91 40 2304 5438.
E-mail address: parthads@yahoo.com (P. Das).
Scheme 1. Retrosynthesis of varenicline, 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.107

152
S. Pasikanti et al. / Tetrahedron Letters 51 (2010) 151–152
12. Pasikanti, S.; Reddy, D. S.; Venkatesham, B.; Iqbal, J. Indian Patent Application
N
N
N
CHBr2
CHBr2
N
No. 2355/CHE/2007.
a
b
13. Shepherd, M. K. J. Chem. Soc., Perkin Trans. 1 1986, 1495.
14. Diaz-Ortiz, A.; De la Hoz, A.; Moreno, A.; Prieto, P.; Leon, R.; Herrero, M. A.
Synlett 2002, 2037–2038.
N
8
N
7
10
15. Experimental procedure and spectral data for 7: Sodium iodide was added in
9
small portions over
a period of 2 min to a solution of the 2,3-bis
(dibromomethyl)pyrazine 8 (2.0 g, 4.71 mmol) and norbornadiene 9 (2.16 g,
23.58 mmol) in dry DMF (23 mL) at 60 °C. The mixture was stirred for further
30 min. The reaction mixture was cooled to rt, diluted with EtOAc (46 mL), and
passed through a small pad of Celite. The filtrate was washed with 10% sodium
thiosulfate (3 Â 20 mL), water (2 Â 20 mL), and brine (1 Â 20 mL). The organic
layer was dried (MgSO4) and concentrated in vacuo and the residue was
purified by flash column chromatography (silica gel, EtOAc–hexane, 10:90) to
give 420 mg (46%) of 7 as a white solid. Mp: 120–123 °C; IR (KBr, cmÀ1): 2519,
1708, 1649, 1215, 1182; 1H NMR (400 MHz; DMSO-d6): d = 8.70 (s, 2H), 7.78 (s,
2H), 6.78 (t, J = 1.7 Hz, 2H), 4.08 (t, J = 1.7 Hz, 2H), 2.45–2.43 (m, 1H), 2.32–2.30
(m, 1H); 13C NMR (50 MHz; CDCl3): d = 153.5, 143.2, 142.5, 142.1, 120.3, 66.3,
49.6; Mass (ESI): 195 [M+H]+; HRMS(ESI): calcd for C13H11N2 [M+H]+ 195.0922,
found 195.0931.
HO
HO
N
N
N
d, e
c
PMBN
N
6
5
N
f
HN
N
1
16. Kobayashi, T.; Kobayashi, S. Molecules 2000, 5, 1062–1067.
Varenicline
17. Spectral data of 6: Mp: 143–145 °C; IR (KBr, cmÀ1): 3491, 3124, 2980, 1483,
1359, 1074, 956; 1H NMR (400 MHz; DMSO-d6): d = 8.28 (s, 2H), 7.85 (s, 2H),
5.11 (s, 2H), 3.7 (s, 2H), 3.36 (s, 2H), 2.33 (d, J = 9.4 Hz, 1H), 1.85 (d, J = 9.4 Hz,
1H); 13C NMR (50 MHz; DMSO-d6): d = 148.5, 144.1, 142.3, 120.9, 70.5, 50.3,
41.8; Mass (ESI): 229 [M+H]+; HRMS(ESI): calcd for C13H13N2O2 [M+H]+
229.0977, found 229.0986.
Scheme 2. Reagents and conditions: (a) NBS, CCl4, h
m
, 16 h, 65%; (b) NaI, DMF,
60 °C, 30 min, 46%; (c) NMO, OsO4, acetone/water/t-BuOH, rt, 16 h, 85%; (d) NaIO4,
DCM, silica gel, rt, 30 min; (e) PMBNH2, Na(CN)BH3, methanol, acetic acid, 0 °C to rt,
2 h, 62% for two steps; (f) Pd/C, HCO2NH4, methanol, reflux for 30 min, rt, 24 h, 64%.
18. Perez-Castro, I.; Caamano, O.; Gracia, M. D.; Fernadez, F.; Lopez, C. Synthesis
2007, 9, 1385–1391.
19. Experimental procedure and spectral data for 5: A 0.65 M aq soln of NaIO4
(3.5 mL, 2.14 mmol) was added drop-wise to a vigorously stirred suspension of
chromatography-grade silica gel (3.5 g) in DCM (59 mL). After addition of 6
(350 mg, 1.53 mmol) in DCM (78 mL) to the resulting flaky soln, stirring was
continued for another 30 min and then the mixture was passed through a filter
pad onto a small amount of Na2SO4. The retained silica gel was washed with
DCM (20 mL) and the washings were pooled with filtrate. Removal of the
solvent left the dialdehyde as a solid reddish residue, which was dissolved in
methanol (8 mL). PMB amine (210 mg, 1.53 mmol) in methanol (3 mL)
In summary, total synthesis of varenicline has been achieved in
a total of six steps with 10% overall yield. This procedure can be
scaled up for commercial use.
Acknowledgments
We thank Dr. Reddy’s Laboratories Ltd for their support and
encouragement. Help from the analytical department in recording
spectral data is appreciated.
followed by AcOH (9 lL, 0.15 mmol) was added to the above-mentioned soln
at 0 °C and after stirring at rt for 10 min, Na(CN)BH3 (145 mg, 2.3 mmol) was
added at 0 °C and stirred at rt for 2 h. Methanol was evaporated and the residue
was dissolved in water (15 mL) and extracted with EtOAc (3 Â 15 mL). The
combined organic layers were washed with water (2 Â 15 mL) and brine
(1 Â 15 mL), dried (anhyd MgSO4), and concentrated under reduced pressure.
The crude product was purified by flash chromatography (Silica gel, EtOAc–
hexane, 15:85) to give 315 mg (62%) of 5 as a brown-colored thick liquid. IR
(Neat, cmÀ1): 2947, 2789, 1512, 1244, 1031; 1H NMR (400 MHz; CDCl3):
d = 8.76 (s, 2H), 7.77 (s, 2H), 6.76 (d, J = 8.8 Hz, 2H), 6.65 (d, J = 8.8 Hz, 2H), 3.72
(s, 3H), 3.41 (s, 2H), 3.35 (br s, 2H), 2.80 (d, J = 10.7 Hz, 2H), 2.54 (d, J = 10.3 Hz,
2H), 2.34–2.30 (m, 1H), 1.85 (d, J = 10.7 Hz, 1H); 13C NMR (50 MHz; CDCl3):
d = 158.4, 150.9, 143.4, 143.3, 130.0, 129.4, 120.4, 113.4, 60.9, 57.2, 55.1, 43.1,
41.2; Mass (ESI): 332 [M+H]+; HRMS(ESI): calcd for C21H22N3O [M+H]+
332.1763, found 332.1775.
References and notes
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20. Experimental procedure and spectral data for 1: To a solution of 5 (50 mg,
0.15 mmol) in methanol (2 mL) was added 10% Pd/C (125 mg, 2.5 equiv, wt/
wt), followed by HCO2NH4 (100 mg, 2 equiv, wt/wt), and heated to reflux for
30 min. The reaction mixture was cooled to rt, and allowed to stand for 24 h. It
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flash chromatography (Silica gel, MeOH–CHCl3, 2:98) to give 20 mg (64%) of 1
as a cream-colored solid. Mp: 137–139 °C; IR (KBr, cmÀ1): 3342, 2949, 2924,
2852, 1473, 1354; 1H NMR (400 MHz; CDCl3): d = 8.75 (s, 2H), 7.83 (s, 2H), 3.25
(br s, 2H), 3.15 (d, J = 13.0 Hz, 2H), 2.92 (d, J = 13.0 Hz, 2H), 2.48 (m, 1H), 2.09
(d, J = 8.8 Hz, 1H), 1.82 (br s, 1H); 13C NMR (50 MHz; CDCl3): d = 149.6, 143.5,
143.6, 121.7, 50.5, 43.1, 42.2; Mass (ESI): 212 [M+H]+; HRMS(ESI): calcd for
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