3-(2,5-Dihydro-1H-pyrrol-2-ylmethoxy)pyridines: Synthesis and analgesic activity

Article abstract of DOI:10.1016/j.bmcl.2005.01.058

We disclose an efficient procedure for the preparation of ethers of 2-substituted 2-hydroxymethylpyrroline and of 2-aminomethyl-3-pyrrolines, involving, as a key step, formation and nucleophilic ring opening of a cyclic sulfamidate. Several new analogs of epibatidine (1) and tebanicline (ABT-594, 2) were prepared and tested for analgesic activity in the mouse formalin model.

Full text of DOI:10.1016/j.bmcl.2005.01.058

Bioorganic & Medicinal Chemistry Letters 15 (2005) 1637–1640
3-(2,5-Dihydro-1H-pyrrol-2-ylmethoxy)pyridines: synthesis
and analgesic activity
Ivan L. Baraznenok,a Emma Jonssona and Alf Claessonb,*
aSyntagon AB, Tallva¨gen 2, Box 2073, SE-15102 So¨derta¨lje, Sweden
bAstraZeneca R&D So¨derta¨lje, Discovery Chemistry, 151 85 So¨derta¨lje, Sweden
Received 8 November 2004; revised 12 January 2005; accepted 24 January 2005
Abstract—We disclose an efficient procedure for the preparation of ethers of 2-substituted 2-hydroxymethylpyrroline and of 2-ami-
nomethyl-3-pyrrolines, involving, as a key step, formation and nucleophilic ring opening of a cyclic sulfamidate. Several new ana-
logs of epibatidine (1) and tebanicline (ABT-594, 2) were prepared and tested for analgesic activity in the mouse formalin model.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Epibatidine (1), an alkaloid isolated from a South
H
N
O
Cl
NH
American frog, is known since 1992 as one of the best
nicotinic acetylcholine receptor (nAChR) ligands identi-
fied so far.1 It is reported to possess analgesic properties
but is also toxic or even lethal at doses only slightly
higher than its effective analgesic dose.2 Over the past
few years, considerable efforts have been directed to-
ward the identification of ligands selective for subtypes
of nAChR and several high affinity compounds have
been reported.3 Among them, 3-pyridyl ethers incorpo-
rating a saturated azacyclic fragment, such as 2-pyrro-
lydinyl or 2-azetidinyl, have been described as orally
available nAChR ligands with potential therapeutic use-
fulness.4 The best member of this series, tebanicline
(ABT-594, 2), was less potent than epibatidine in the
treatment of acute and persistent pain, but displayed a
better separation between motor and analgesic effects.
It was advanced to human clinical trials as a non-opioid
analgesic agent with an efficacy equal to that of mor-
phine5 (Fig. 1).
N
Cl
N
2
1
Figure 1. Potent non-opioid analgesic agents epibatidine (1) and
tebanicline (ABT-594, 2).
addition of an a-methyl has the potential to enhance
in vivo stability and might also change receptor selectiv-
ity so to lower side-effects. Herein we report the prepa-
ration and pharmacological evaluation of these novel
pyridyl ethers.
The synthesis began with the Birch reduction6 of isopro-
pyl ester 3 (Scheme 1). Subsequent treatment with
LiBH4 furnished the racemic pyrrolinemethanol 4 in
55% overall yield. Enantiomerically pure alcohols S-
(À)-4 and R-(+)-4 were prepared according to a litera-
ture procedure7 applying lipase mediated kinetic resolu-
tion of ( )-4. Finally, Mitsunobu coupling of S-4 and
R-4 with 2-chloro-5-hydroxypyridine followed by depro-
tection with equimolar amounts of TosOH in refluxing
ethanol yielded the desired ethers R-5 and S-5 as crystal-
line tosylate salts.
To gain further insight into the structure–activity rela-
tionship for 3-pyridyl ethers as nAChR agonists we syn-
thesized a new series of ABT-594 analogs, in which the
azetidine ring was replaced with a 3-pyrroline moiety
and/or modified by the incorporation of an a-methyl
substituent into the aza-ring. We anticipated that the
A similar synthetic strategy was attempted for the prep-
aration of a-methylated pyrroline derivatives. Ester 6
was made according to the literature procedure6 via
the Birch reduction/alkylation of 3 (Scheme 2). Reduc-
tion with LiBH4 gave alcohol 7. Unfortunately, all
Keywords: nAChR; Pyridyl ethers; Cyclic sulfamidates; Tebanicline;
ABT-594.
*
Corresponding author. Tel.: +46 8 5532 7174; fax: +46 8 5532
8892; e-mail: alf.claesson@astrazeneca.se
0960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.01.058

1638
I. L. Baraznenok et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1637–1640
in THF provided the crude aminoalcohol, which was al-
a,b
lowed to react with sulfuryl chloride10 at À78 ꢁC fur-
nishing the desired sulfamidate 9. Stable, crystalline 9
was assembled in four steps in 33% overall yield.11 The
procedure can be readily adapted to a multigram scale.
O
OH
55%
N
Boc
N
Boc
O
3
(+)-4
-
c
Once the sulfamidate 9 was available we focused our
attention on the nucleophilic ring opening. Treatment
of 9 with the sodium salt of 2-chloro-5-hydroxypyridine
followed by hydrolysis using 20% aqueous sulfuric acid
at 80 ꢁC afforded the racemic pyridyl ether 11 in surpris-
ingly good yield (82%).11,12 Interestingly, 11 appeared to
be completely stable under harsh acidic conditions in
contrast to other pyrroline derivatives. Initial attempts
to achieve ring opening of 9 with a nitrogen nucleophile,
namely 3-aminopyridine, were unsuccessful, no reaction
was observed either in the presence of bases or at ele-
vated temperatures. However, this transformation was
accomplished via Boc-protection of 3-aminopyridine
and subsequent treatment with 9 in the presence of
NaH. Deprotection with aqueous sulfuric acid provided
pyrrolylmethyl amine 12 in a reasonably good yield
(65%).
d,e
40-45%
O
OH
N
H
N
Boc
Cl
N
R-5
S-5
R-4 ee 95%
S-4 ee 92%
Scheme 1. Reagents and conditions: (a) Na, NH3, THF, À78 ꢁC; (b)
LiBH4, MeOH, Et2O; (c) vinylacetate, Pseudomonas fluorescens,
t-BuOMe, then (only for S-4) NaOH, H2O; (d) 2-chloro-5-hydroxy-
pyridine, Ph3P, DEAD, THF; (e) TosOH, EtOH.
a
b
OH
3
O
N
Boc
N
Boc
95%
78%
O
7
6
The same methodology was applied to the preparation
of the close ABT-594 analog 20 having a methyl substi-
tuent in the 2-position of the azetidine ring (Scheme 3).
Readily available Boc-protected azetidinecarboxylic
acid 13 was converted into the corresponding ester and
then treated sequentially with LDA and MeI providing
ester 14 in 64% overall yield. After the removal of Boc
with MeSO3H and reduction with LiAlH4, the resultant
aminoalcohol was coupled directly with sulfuryl chlo-
ride providing the bicyclic sulfamidate 15 in moderate
yield. With 15 in hand, we proceeded to the key nucleo-
philic ring opening. The addition of deprotonated 2-
chloro-5-hydroxypyridine to 15 proceeded well giving
the corresponding sulfamic acid 16.
35%
c,d,e
O
N
Boc
N
S
O
O
Cl
N
N
O
8
9
X
N
H
XH
f,g (for 10,11)
or h,f,g (for 12)
Y
Y
N
However, treatment of 16 under the previously devel-
oped reaction conditions (aqueous H2SO4, heating)
failed to generate any of the desired azetidinemethyl
X = O, Y = H (10)
X = O, Y = Cl (11)
X = NH, Y = Cl (12)
65-82%
Scheme 2. Reagents and conditions: (a) Li, NH3, NH(CH2-
CH2OCH3)2, THF, À78 ꢁC, then MeI; (b) LiBH4, MeOH, Et2O; (c)
MeSO3H, CH2Cl2; (d) LiAlH4, THF; (e) SO2Cl2, CH2Cl2, À78 ꢁC; (f)
9, NaH, DMF; (g) 20% H2SO4, 90 ꢁC; (h) Boc2O, DMAP, CH3CN.
O
O
OH
O
c,d,e
a,b
O
N
N
N
64%
S
O
Boc
O
Boc
attempts to achieve coupling of the sterically hindered
alcohol 7 with hydroxypyridines using either Mitsunobu
conditions or via conversion into the corresponding
mesylate or tosylate proved unsuccessful. Also, alcohol
7 was found to be rather unstable in pure form at room
temperature and extremely unstable under mild acidic
conditions.8 Obviously, an alternative approach was
necessary.
15
13
14
f
OH
O
O
NH2
g
N
SO3H
Cl
N
Cl
N
17
16
It is known9 that cyclic sulfamidates, derived from b-
aminoalcohols, permit concomitant protection of the
nitrogen moiety and conversion of the hydroxyl into a
good leaving group. Following suit, deprotection of 6
with MeSO3H and subsequent reduction with LiAlH4
Scheme 3. Reagents and conditions: (a) i-PrOH, EDC, DMAP, CH2-
Cl2; (b) LDA, THF, then MeI; (c) MeSO3H, CH2Cl2; (d) LiAlH4,
THF; (e) SO2Cl2, CH2Cl2, À78 ꢁC; (f) 2-chloro-5-hydroxypyridine,
NaH, DMF; (g) 20% H2SO4, 80 ꢁC.

I. L. Baraznenok et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1637–1640
1639
Acknowledgements
O
OH
Boc
NH
b,c
7%
a
14
We would like to thank to Mr. Carl-Oscar Appelros and
Dr. Sandra Oerther for running the in vivo tests.
N
76%
Cl
N
18
20
References and notes
Scheme 4. Reagents: (a) LiBH4, MeOH, Et2O; (b) 2-chloro-5-hy-
droxypyridine, Ph3P, DEAD, THF; (c) TosOH, EtOH.
1. (a) Spande, T. F.; Garaffo, H. M.; Edwards, M. W.; Yeh,
H. J. C.; Pannell, L.; Daly, J. W. J. Am. Chem. Soc. 1992,
114, 3475; (b) Qian, C.; Li, T.; Shen, T. Y.; Libertine-
Garahan, L.; Eckman, J.; Biftu, T.; Ip, S. Eur. J.
Pharmacol. 1993, 250, R13.
2. (a) Sullivan, J. P.; Bannon, A. W. CNS Drug Rev. 1996, 2,
21; (b) Bonhaus, D. W.; Bley, K. R.; Broka, C. A.;
Fontana, D. J.; Leung, E.; Lewis, R.; Shieh, A.; Wong, E.
H. F. J. Pharmacol. Exp. Ther. 1995, 273, 1199; (c) Rao,
T. S.; Correa, L. D.; Reid, R. T.; Lloyd, G. K.
Neuropharmacology 1996, 35, 393.
ether, affording instead ring-opened product 17. An at-
tempt to deprotect 16 under basic condition (aqueous
NaOH, heating10) was also unsuccessful.
Therefore, we turned our attention to the original route,
involving coupling of pyridinol with the neopentyl-like
alcohol 18 (Scheme 4).
3. For example, see: (a) Bai, D.; Xu, R.; Chu, G.; Zhu, X. J.
Org. Chem. 1996, 61, 4600; (b) Wright, E.; Gallagher, T.;
Sharples, C.; Wonnacott, S. Bioorg. Med. Chem. Lett.
1997, 7, 2867; (c) Badio, B.; Garaffo, H. M.; Plummer, C.
V.; Padgett, W. L.; Daly, J. W. Eur. J. Pharmacol. 1997,
321, 189.
4. (a) Abreo, M. A.; Lin, N.-H.; Garvey, D. S.; Gunn, D. E.;
Hettinger, A.-M.; Wasicak, J. T.; Pavlic, P. A.; Martin, Y.
C.; Donnelly-Roberts, D. L.; Anderson, D. J.; Sullivan, J.
P.; Williams, M.; Arneric, S. P.; Holladay, M. W. J. Med.
Chem. 1996, 39, 817; (b) Koren, A. O.; Horti, A. G.;
Mukhin, A. G.; Gundisch, D.; Kimes, A. S.; Dannals, R.
F.; London, E. D. J. Med. Chem. 1998, 41, 3690; (c) Lee,
J.; Davis, C. B.; Rivero, R. A.; Reitz, A. B.; Shank, R. P.
Bioorg. Med. Chem. Lett. 2000, 10, 1063.
5. (a) Holladay, M. W.; Wasicak, J. T.; Lin, N.-H.; He, Y.;
Ryther, K. B.; Bannon, A. W.; Buckley, M. J.; Kim, D. J.
B.; Decker, M. W.; Anderson, D. J.; Campbell, J. E.;
Kuntzweiler, T. A.; Donnelly-Roberts, D. L.; Piattoni-
Kaplan, M.; Briggs, C. A.; Williams, M.; Arneric, S. P. J.
Med. Chem. 1998, 41, 407; (b) Kesingland, A. C.; Gentry,
C. T.; Panesar, M. S.; Bowes, M. A.; Vernier, J.-M.; Cube,
R.; Walker, K.; Urban, L. Pain 2000, 86, 113.
The latter was prepared in 76% yield by the reduction of
14 with LiBH4. Coupling of 14 under the Mitsunobu
conditions proceeded extremely slowly and resulted in
a very low (less than 15%) conversion of the starting
materials. Deprotection with TosOH afforded only 7%
of the desired ether 20.11 Modification of the reaction
conditions by changing the coupling reagents and their
molar ratio or by increasing the reaction temperature
did not improve the yields.
The compounds were evaluated for analgesic activity in
the mouse formalin model13 using automated video-
based analysis of the behavior. Behavior was analyzed
at two timepoints called phase I and phase II, 0–5 min
and at 15–30 min after injection of formalin. Most of the
compounds affected the general motor behavior of the
animals in such a way that calculation of a true ED50
value for analgesia was impossible (marked as Ôconfound-
ing effectsÕ in the Table 1). Only the reference compound
ABT-594 and the R isomer of 5 gave useful results indi-
cating that R-5 has favorable analgesic properties.
6. Donohoe, T. J.; Guyo, P. M. J. Org. Chem. 1996, 61,
7664.
7. Schieweck, F.; Altenbach, H.-J. Tetrahedron: Asymmetry
1998, 9, 403.
In summary, analogs of epibatidine and ABT-594 were
prepared and tested for analgesic activity. We have
demonstrated the utility of cyclic sulfamidates for the
synthesis of 2-substituted 2-aryloxymethyl- or 2-aryl-
aminomethylpyrrolines in good to excellent yields,
also when nucleophilic substitution takes place at a
neopentyl center.
8. After several weeks at room temperature previously pure 7
contained up to 40% of the single byproduct, which was
identified as 1-(tert-butoxycarbonyl)-2-methylpyrrole. We
did not investigate the mechanism of this transformation.
9. For example, see: (a) Aguilera, B.; Fernandez-Mayoralas,
A. J. Org. Chem. 1998, 63, 2719; (b) Okuda, M.; Tomioka,
K. Tetrahedron Lett. 1994, 35, 4585; (c) Boulton, L. T.;
Stock, H. T.; Raphy, J.; Horwell, D. C. J. Chem. Soc.,
Perkin Trans. 1 1999, 61, 1421.
10. Alker, D.; Doyle, K. J.; Harwood, L. M.; McGregor, A.
Tetrahedron: Asymmetry 1990, 1, 877.
11. Selected procedures and spectral data:
Table 1. Mouse formalin activities for ABT-594 and compounds 5,
10–12. Compound 20 was not tested
3a-methyl-3a,6-dihydro-3H-pyrrolo[1,2-c][1,2,3]oxathiaz-
ole 1,1-dioxide (9). Isopropyl 1-(tert-butoxycarbonyl)-2-
methyl-2,5-dihydro-1H-pyrrole-2-carboxylate (6; 12.5 g,
46 mmol) in CH2Cl2 (150 mL) was cooled to 0 ꢁC, and
methanesulfonic acid (16 mL, 245 mmol) in CH2Cl2
(50 mL) was added dropwise. The reaction mixture was
stirred for 12 h while gradually warming to room temper-
ature. A solution of 1 N HCl (100 mL) was added, the
organic layer was separated and washed with 1 N HCl
(50 mL). Combined aqueous layers were washed with
Et2O (100 mL), basified (pH 8) with solid NaHCO3, and
Compds
Doses given
(sc)
ED50 Ph I,
lmol/kg
ED50 Ph II,
lmol/kg
ABT-594
R-5
S-5
0.4–3.1
0.4–6.3
0.4–6.3
0.4–6.3
0.4–6.3
0.4–6.3
0.4–6.3
0.9
0.8
1.6
1.6
c.e.a
c.e.a
c.e.a
c.e.a
c.e.a
c.e.a
c.e.a
c.e.a
c.e.a
c.e.a
10
(+)-11
(À)-11
12
a c.e.—confounding effects.

1640
I. L. Baraznenok et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1637–1640
extracted with ethyl acetate (5 · 150 mL). The extracts
provided a pale-yellow oil (0.315 g, 82%); 1H NMR
(300 MHz, DMSO-d6): d 8.14 (s, 1H), 7.52 (d, J =
8.3 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.50–7.00 (br s,
1H), 6.06–5.98 (m, 1H), 5.87–5.80 (m, 1H), 4.30–4.18 (m,
2H), 4.10–3.98 (m, 2H), 1.50 (s, 3H); MS (ESI, m/z) calcd
for C11H13ClN2O (M+H+) 225.69, found 225.2 (100),
227.2 (35); HPLC purity over 97% (column Chromolith
Performance RP-18e, 4.6 · 100 mm, mobile phase: gradi-
ent acetonitrile/0.1% TFA (aq), 3 mL/min, 25 ꢁC, 254 nm).
2-Chloro-5-[(2-methylazetidin-2-yl)methoxy]pyridine fuma-
rate (20). To a stirred solution of triphenylphosphine
(12.24 g, 46.7 mmol), 2-chloro-5-hydroxypyridine (1.71 g,
8.49 mmol), and 1-(tert-butoxycarbonyl)-2-(hydroxy-
methyl)-2-methylazetidine (18, 1.10 g, 8.49 mmol) in
THF (50 mL) at 0 ꢁC was added diethyl azodicarboxylate
(6.68 mL, 42.45 mmol) dropwise with stirring. The mix-
ture was allowed to warm to room temperature and stir
for 10 days. The solvent was evaporated, and the residue
was purified by chromatography (silica, heptane/EtOAc
2:1–3:2). The resulting viscous oil (0.24 g, 0.76 mmol) was
dissolved in EtOH (5 mL), treated with TosOH (0.218 g,
1.15 mmol), and the solution was heated to 70 ꢁC for 15 h.
After cooling, the solution was concentrated and diluted
with saturated aqueous K2CO3/ethyl acetate mixture.
Organic layer was separated, aqueous layer extracted
with ethyl acetate (3 · 30 mL), the combined extracts were
dried (K2CO3), filtered, and concentrated under reduced
pressure. Purification of the crude residue by flash
chromatography (CHCl3/MeOH/25% aqueous NH3,
were dried (Na2SO4), filtered, concentrated in vacuo, and
coevaporated two times with toluene.The remaining pale-
yellow oil was dissolved in dry THF (150 mL) and added
dropwise to a suspension of LiAlH4 (2.11 g, 55 mmol) in
Et2O (150 mL). After stirring for 2 h at ambient temper-
ature the reaction was quenched with H2O (12 mL),
filtered, precipitate was suspended in THF (100 mL),
heated to reflux, and filtered again.
Combined filtrates were concentrated under reduced
pressure, residue dissolved in CH2Cl2 (500 mL) and
triethylamine (18.4 mL, 132 mmol), and cooled to
À78 ꢁC. Sulfuryl chloride (3.6 mL, 45 mmol) in CH2Cl2
(200 mL) was added slowly keeping the temperature of the
reaction mixture below À70 ꢁC. The mixture was main-
tained at this temperature for 1 h, allowed to warm to
room temperature and concentrated in vacuo. Flash
chromatography on silica (1:1 heptane/ethyl acetate)
afforded 9 (2.8 g, 35% over the three steps) as a clear oil,
which slowly solidified upon standing in refrigerator, mp
1
41–42 ꢁC; H NMR (300 MHz, CDCl3): d 5.89–5.83 (m,
1H), 5.67–5.60 (m, 1H), 4.59–4.51 (m, 1H), 4.32 (d,
J = 8.5 Hz, 1H), 4.21 (d, J = 8.5 Hz, 1H), 4.15–4.07 (m,
1H), 1.55 (s, 3H); 13C NMR (75 MHz, CDCl3): d 130.75,
126.73, 76.14, 58.14, 25.81.
2-Chloro-5-[(2-methyl-2,5-dihydro-1H-pyrrol-2-yl)meth-
oxy]pyridine (11). Sodium hydride (60% in mineral oil,
0.082 g, 2.06 mmol) was added in one portion to a stirred
and cooled (0 ꢁC) solution of 2-chloro-5-hydroxypyridine
(0.222 g, 1.714 mmol) in DMF (10 mL). The cool bath was
removed, and stirring was continued for 1 h. The solution
was recooled to 0 ꢁC, and 3a-methyl-3a,6-dihydro-3H-
pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide (9) in DMF
(2 mL) was added dropwise. The reaction was stirred at
0 ꢁC for 1 h, and then allowed to warm to the room
temperature during 6 h. Aqueous sulfuric acid (20% v/v,
50 mL) was added, and the resultant mixture was stirred at
80 ꢁC for 3 h, then cooled and basified with saturated
aqueous K2CO3 (pH 10). Mixture was extracted with
CHCl3 (3 · 40 mL), the combined extracts were dried
(K2CO3), filtered, and concentrated under reduced pres-
sure. Purification of the crude residue by flash chroma-
tography (CHCl3/MeOH/25% aqueous NH3, 100:5:0.5)
100:5:0.5–100:10:1) afforded 20 as
a pale-yellow oil
(0.125 g, 7% over the two steps); 1H NMR (300 MHz,
DMSO-d6): d 8.18 (s, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.45
(d, J = 8.3 Hz, 1H), 4.25 (d, J = 10.2 Hz, 1H), 4.10 (d,
J = 10.2 Hz, 1H), 3.74–3.62 (m, 2H), 2.30–2.17 (m, 2H),
1.51 (s, 3H); MS (ESI, m/z) calcd for C10H13ClN2O
(M+H+) 213.68, found 213.2 (100), 215.2 (35); HPLC
purity over 97% (column Chromolith Performance RP-
18e, 4.6 · 100 mm, mobile phase: gradient acetonitrile/
0.1% TFA (aq), 3 mL/min, 25 ꢁC, 254 nm).
12. Enantiomerically pure S-11 and R-11 were prepared by
preparative HPLC resolution of ( )-11.
13. Tjølsen, A.; Berge, O.-G.; Hunskar, S.; Rosland, J. H.;
Hole, K. Pain 1992, 51, 5.