Synthesis of antagonists of muscarinic (M3) receptors

Article abstract of DOI:10.1135/cccc2011017

Several α-hydroxyamides with (2,6-dialkoxyphenoxy)methyl substituents have been prepared and their activities as antagonists of the M₃ muscarinic receptor in guinea pig ileum have been evaluated. N-{1-[(Phenyl)methyl]piperidin-4-yl}-2-{2-[(2,6-dimethoxyphenoxy)-methyl]phenyl} -2-hydroxypropanamide and N-(1-[{6-amino-4-[(1-propylpiperidin-4-yl)methyl]- pyridin-2-yl}methyl]piperidin-4-yl)-2-cyclopentyl-2-hydroxy-2-phenylacetamide were the most potent compounds prepared, the micromolar potency of the latter indicating that it may be worth further investigation.

Full text of DOI:10.1135/cccc2011017

Synthesis of Antagonists of Muscarinic (M3) Receptors
781
SYNTHESIS OF ANTAGONISTS OF MUSCARINIC (M3) RECEPTORS
b
a2
Kenneth J. BROADLEYa1, Robin H. DAVIES , Christine ESCARGUEIL
,
c1
a3
c2,
Alan T. L. LEE , Peter PENSON and Eric J. THOMAS
*
a The Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK;
1
2
3
e-mail: broadleykj@cf.ac.uk, escargueilc@cf.ac.uk, P.Penson@ljmu.ac.uk
Muscagen Limited, 10, North Road, Cardiff, CF10 3DFY, UK; e-mail: daviesRH@cardiff.ac.uk
School of Chemistry, University of Manchester, M13 9PL, UK;
b
c
1
2
e-mail: alan.t.lee@manchester.ac.uk, e.j.thomas@manchester.ac.uk
Received January 21, 2011
Accepted March 16, 2011
Published online June 8, 2011
Dedicated to Professor Pavel Kočovský on the occasion of his 60th birthday in recognition of his
outstanding contributions to the area of organic chemistry.
Several α-hydroxyamides with (2,6-dialkoxyphenoxy)methyl substituents have been pre-
pared and their activities as antagonists of the M3 muscarinic receptor in guinea pig ileum
have been evaluated. N-{1-[(Phenyl)methyl]piperidin-4-yl}-2-{2-[(2,6-dimethoxyphenoxy)-
methyl]phenyl}-2-hydroxypropanamide and N-(1-[{6-amino-4-[(1-propylpiperidin-4-yl)methyl]-
pyridin-2-yl}methyl]piperidin-4-yl)-2-cyclopentyl-2-hydroxy-2-phenylacetamide were the
most potent compounds prepared, the micromolar potency of the latter indicating that it
may be worth further investigation.
Keywords: Muscarinic receptors; Antagonists; Suzuki–Miyaura coupling; α-Hydroxyamides;
Alcohols; Amides; Biological activity; Medicinal chemistry.
Muscarinic receptors participate widely in metabolic processes and their
selective modulation has significance for many therapeutic applications1.
Amongst these, regulation of the M3 receptor, which is found in smooth
muscle, has implications for bladder relaxation and treatment of urinary
tract incontinence2. α-Hydroxyamides, e.g. 1 3 and 2 4, are known to be
potent and selective inhibitors of M3 receptors with useful metabolic stabil-
ities, see Fig. 1. Following ab initio studies of a model of muscarinic recep-
tors based on the structures of the α-helices of an adapted mammalian
bovine rhodopsin receptor, a series of 2-benzazepinones 3 was designed as
differently constrained analogues of the α-hydroxyamides 1 and 2. Repre-
sentative examples were synthesized and evaluated as selective M3 antago-
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 7, pp. 781–801
© 2011 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc2011017

782
Broadley, Davies, Escargueil, Lee, Penson, Thomas:
nists5. Further ab initio modelling subsequently indicated that the incorpo-
ration of a suitably positioned (2,6-dialkoxyphenoxy)methyl substituent
could lead to an improvement in selectivity towards M3 receptors by pro-
viding two points of contact with the moiety at position 151 (Ala, M1, M3,
M5; Val, M2, M4) and led to the design and synthesis of the 2-benzazepin-
one 4 6. The potency of this compound against M3 receptors in guinea pig
ileum was slightly less than that observed for some of the earlier examples,
perhaps due to the loss of conformational flexibility when bound to the re-
ceptor site. It also showed membrane stabilizing properties at higher doses
which suggested that a (2,6-dimethoxyphenyl)methyl substituent in an in-
trinsically potent compound with its expected high selectivity against M2
receptors could provide some advantages6.
F
F
H
OH
OH
O
O
HN
HN
N
N
N
NH2
2
1
MeO
OMe
1,2
OH
O
O
Me OH
O
H
N
H
N
Ar
X
N
N
Ph
0,1
3: X = H, F
4
FIG. 1
Representative antagonists of M3 receptors
It was decided to evaluate analogues of the α-hydroxyamides 1 and 2
with (2,6-dialkoxyphenoxy)methyl substituents at the 2-position in the
benzene ring as selective M3 antagonists. The simpler analogues 5 were
prepared first to check procedures for incorporation of the (2,6-dialkoxy-
phenoxy)methyl substituent. The α-hydroxyamides 6 were then prepared
as analogues of the α-hydroxyamide 2 and finally a bis-[(piperidinyl)-
methyl]pyridine 7 was prepared to check the effect of further elaboration of
the 2-aminopyridine moiety at the 4-position, see Fig. 2.
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 7, pp. 781–801

Synthesis of Antagonists of Muscarinic (M3) Receptors
783
X
RO
OR
MeO
OMe
O
O
Me OH
Me OH
O
O
HN
HN
N
N
N
NH2
5
6
R
N
OH
O
HN
N
N
NH2
7
FIG. 2
α-Hydroxyamides to be evaluated as M3 receptor antagonists
RESULTS AND DISCUSSION
Synthesis of α-Hydroxyamides with (2,6-Dialkoxyphenoxy)methyl
Substituents
The racemic α-hydroxyamides 5a, 5b were synthesized as outlined in
Scheme 1. Following Mitsunobu condensation of the [2-(1-methylethenyl)-
phenyl]methyl alcohol 9 7 with 2,6-dimethoxy- and 2,6-diethoxyphenol
(8a, 8b)8, the resulting ethers 10a, 10b were hydroxylated9 to give the diols
11a, 11b. Oxidation of diol 11a using the Dess–Martin periodinane10 re-
sulted in C–C bond cleavage to the corresponding acetophenone, but oxi-
dation under Swern conditions11 gave the required aldehyde 12a which was
oxidized to the acid 13a using sodium chlorite12. The analogous diethoxy-
phenyl substituted acid 13b was similarly prepared and the two acids cou-
pled with 4-amino-1-[(phenyl)methyl]piperidine to give the α-hydroxy-
amides 5a, 5b.
Having prepared the α-hydroxyamides 5a, 5b, procedures for the incorpo-
ration of an additional substituent into the (2,6-dialkoxyphenoxy)methyl
moiety, and the (6-aminopyridin-2-yl)methyl substituent, were investi-
gated. 4-Bromo- and 4-chloro-2,6-dimethoxyphenols (8c and 8d) were pre-
pared by regioselective demethylation of the 5-bromo- and 5-chloro-
1,2,3-trimethoxybenzenes13,14, and chlorination of 2,6-dimethoxyphenol
gave 3-chloro-2,6-dimethoxyphenol (8e)15. These 2,6-dialkoxyphenols were
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 7, pp. 781–801

784
Broadley, Davies, Escargueil, Lee, Penson, Thomas:
HO
RO
OR
Me
RO
OR
Me
i
O
ii
O
Me OH
RO
OR
OH
OH
8a R = Me
8b R = Et
9
10a: R = Me
10b: R = Et
11a: R = Me
11b: R = Et
iii
RO
OR
RO
OR
O
RO
OR
O
O
v
iv
Me OH
Me OH
Me OH
O
O
O
2
HN
H
OH
3'
2'
N
5'
6'
5a: R = Me
5b: R = Et
13a: R = Me
13b: R = Et
12a: R = Me
12b: R = Et
Reagents and conditions: i, 2,6-dialkoxyphenol, Ph3P, DIAD, r.t., 16 h (10a, 75%; 10b, 43%); ii,
OsO4 (10 mol%), NMO, acetone, water, r.t., (11a, 11b, 93-100%); iii, DMSO, (COCl)2, CH2Cl2,
-78 oC, 30 min, Et3N, r.t., 30 min (12a, 68%; 12b, 50%); iv, 2-methylbut-2-ene, NaOCl2, tBuOH,
water, NaH2PO4, 16 h (13a, 39%; 13b, 61%); v, 4-amino-1-benzylpiperidine, HOBt hydrate,
4-methylmorpholine, DMF, 0 oC, then EDCI.HCl, r.t., 16 h (5a, 88%; 5b, 70%).
SCHEME 1
taken through to the α-hydroxy-acids 13c–13e via a Mitsunobu reaction
with the alcohol 9 followed by hydroxylation and oxidation, see Scheme 2.
The known 2-amino-6-[(4-aminopiperidin-1-yl)methyl]pyridine hydrochlo-
ride (14)4 was then acylated using the hydroxyacids 13a, 13c–13e to give
the racemic α-hydroxyamides 6a, 6c–6e.
Finally, it was decided to investigate the biological activity of α-hydroxy-
amides 7 which are analogous to the [(6-aminopyridin-2-yl)methyl]-
piperidine 2, but with an additional (piperidin-4-yl)methyl substituent at
the 4-position of the pyridine ring. The Suzuki–Miyaura reaction of
N-Boc-4-methylenepiperidine (15) and 4-bromopyridine has been used to
access 4-[(piperidin-4-yl)methyl]pyridine (16), see Scheme 3 16. It was
decided to use this approach for the synthesis of the representative
α-hydroxyamide 7a.
Heating chelidamic acid 17 with phosphorus pentabromide followed by
treatment with methanol gave 4-bromo-2,6-bis(methoxycarbonyl)pyridine
(18), see Scheme 4 17. A Suzuki–Miyura reaction with N-tert-butoxycarbonyl-
4-methylenepiperidine (15)18 then gave the 4-[(piperidin-4-yl)methyl]-
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 7, pp. 781–801

Synthesis of Antagonists of Muscarinic (M3) Receptors
785
X
X
1
1
HO
X
MeO
OMe
Me
Me
MeO
OMe
i
ii
O
O
1
+
Me OH
MeO
OMe
OH
OH
10c X = 4-Br
10d X = 4-Cl
10e X = 3-Cl
11c X = 4-Br
11d X = 4-Cl
11e X = 3-Cl
8c X = 4-Br
8d X = 4-Cl
8e X = 3-Cl
9
iii
X
1
X
MeO
OMe
1
O
H2N
MeO
OMe
Me OH
5'
iv
O
O
3'
+
N
Me OH
N
H
NH2
+
Cl—
HN
O
5'
3'
N
OH
N
NH2
14
6a X = H
13c X = 4-Br
13d X = 4-Cl
13e X = 3-Cl
6c X = 4-Br
6d X = 4-Cl
6e X = 3-Cl
Reagents and conditions: i, 9, 2,6-dialkoxyphenol, Ph3P, DIAD, r.t., 16 h (10c, 73%; 10d, 80%;
10e, 64%); ii, OsO4 (10 mol%), NMO, acetone, water, r.t., (11c, 85%; 11d, 97%; 11e, 85%);
iii, (a) DMSO, (COCl)2, CH2Cl2, -78 oC, 30 min, Et3N, r.t., 30 min (b) 2-methylbut-2-ene, NaOCl2,
tBuOH, water, NaH2PO4, 16 h (13c, 34%; 13d, 69%; 13e, 39%); v, 14, HOBt hydrate,
4-methylmorpholine, DMF, 0 oC, then EDCI.HCl, r.t., 16 h (6a, 44%; 6c, 41%; 6d, 50%; 6e, 22%).
SCHEME 2
pyridine 19. Removal of the tert-butoxycarbonyl group was achieved using
trifluoroacetic acid and nosylation of the resulting amine 20 gave the nosyl
protected piperidine 21 which was also prepared directly from the bromo-
pyridine 18 via a Suzuki–Miyaura reaction using N-nosyl-4-methylene-
piperidine (29). Monohydrolysis of the bis-ester 21 gave the mono-acid 22
which was converted into the tert-butoxycarbonyl protected amine 23 by
a Curtius rearrangement. Reduction of the ester gave alcohol 24 which,
following conversion into its mesylate, gave the 2-[(N-piperidinyl)methyl]-
pyridine 25 by displacement using 4-(tert-butoxycarbonylamino)piperidine.
Selective removal of the nosyl group using thiophenol and potassium car-
Boc
N
9-BBN then
4-bromopyridine, PdCl2(dppf)
77%
N
N
Boc
16
15
SCHEME 3
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 7, pp. 781–801

786
Broadley, Davies, Escargueil, Lee, Penson, Thomas:
bonate provided the free piperidine 26 which was subjected to a reductive
amination using propanal, triacetoxyborohydride and acetic acid to give
the N-propyl derivative 27 19. Treatment with dilute aqueous hydrogen
chloride then gave the amine 28 as its hydrochloride salt and coupling
with the racemic α-hydroxyacid 30 gave the α-hydroxyamide 7a.
Ns
X
N
N
O
Br
ii
v
i
HO2C
N
H
CO2H
MeO2C
N
CO2Me
MeO2C
22 X = CO2H
vi
N
X
MeO2C
N
CO2Me
18
19 X = Boc
20 X = H
21 X = Ns
17
iii
iv
23 X = NHBoc
vii
X
Ns
Me
N
N
N
BocNH
H2N
xi
viii
.4HCl
N
N
N
NHBoc
N
NHBoc
N
NH2
OH
25 X = Ns
26 X = H
24
28
ix
x
27 X = nPr
xii
Me
N
OH
O
OH
OH
O
HN
N
N
Ns
N
NH2
30
7a
29
Reagents and conditions: i, PBr5, 90 oC, 3 h, CHCl3, MeOH (84%); ii, 15 or 29, 9-BBN, THF, heat
under reflux, add 18, K2CO3, Pd(dppf)Cl2.CH2Cl2, r.t. 10 - 15 min (19, 89%; 21, 89%); iii, TFA,
CH2Cl2, r.t., 3 h; iv, NsCl, DMAP, Et3N, CH2Cl2, r.t., 16 h (60% from 19); v, MeOH, CH2Cl2, KOH,
r.t., 16 h (91%); vi, (PhO)2P(O)N3, tBuOH, toluene, Et3N, 100 oC, 16 h (66%); vii, NaBH4, CaCl2,
EtOH, 0 oC, 2 h (97%); viii, Et3N, MsCl, EtOAc, 0 oC, 1 h, then K2CO3, 4-tert-butoxycarbonyl-
aminopiperidine, r.t., 16 h (85%); ix, PhSH, K2CO3, MeCN, r.t., 16 h (96%); x, propanal, AcOH,
NaBH(OAc)3, CH2Cl2, r.t., 16 h (94%); xi, aq. HCl (10%), MeOH, r.t., 24 h; xii, 30, HOBt hydrate,
Et3N, CHCl3, r.t., 30 min, EDCI hydrochloride, r.t., 16 h (53% from 27).
SCHEME 4
Evaluation of the Activities of the α-Hydroxyamides as
Antagonists of Muscarinic Receptors
The α-hydroxyamides 5a, 6a, 6b and 7a were screened for biological activ-
ity as antagonists of the M3 receptor which mediates contractions of the
guinea pig ileum and the M2 receptor which mediates negative chrono-
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Synthesis of Antagonists of Muscarinic (M3) Receptors
787
tropic actions in guinea-pig isolated right atria. Tissues were set up in organ
baths containing Kreb’s bicarbonate buffer gassed with 5% CO2 in oxygen
maintained at 37 °C. Isometric tension was recorded by means of trans-
ducers (Ormed, Welwyn Garden City, Hertfordshire, UK) coupled to a
PowerLab/4SP computer system (AD Instruments, Charlgrove, Oxfordshire,
UK) for data collection. The spontaneous rate of contraction of the right
atria was recorded. The data were analysed using Chart v.4.1.1 software
(AD Instruments, Charlgrove, Oxfordshire, UK). Cumulative concentration-
response curves were obtained for the increases in tension of the ileum and
the reduction in rate of the atria in response to the non-selective
muscarinic agonist methacholine. Concentration responses were obtained
before and repeated in the presence of the compounds dissolved in
dimethyl sulfoxide (DMSO). Control experiments were conducted with
DMSO alone. Responses were plotted as changes in tension or rate. To de-
termine the dose-ratios for any shifts of the concentration-response curves
by the antagonist, curves were plotted as a percentage of the maximum re-
sponse and dose-ratios calculated at the 50% response. Affinities of the an-
tagonists were calculated as the pA2 (pKB) from pA2 = log (DR – 1) – log B
where DR is the dose-ratio and B is the molar concentration of agonist. The
results are summarised in the Table I.
TABLE I
M3 and M2 receptor antagonistic activity of representative hydroxyamides
Compound
M3 (pKB)
M2 (pKB)
5a
8.05 0.09 (n = 6)
<6.0
<5.5 (n = 2)
6a
–
6b
<6.0
–
7a
7.35 0.45 (n = 4)
9.4 0.07 (n = 6)
9.31 (n = 3)
<6.0 (n = 4)
8.72 0.06 (n = 7)
7.22 (n = 3)
Atropine20
Darifenacin
CONCLUSIONS
α-Hydroxyamide 5a showed competitive muscarinic blocking activity
against M3 receptors of guinea pig ileum in the low nanomolar range but
also some membrane stabilizing activity. This latter effect was evident as a
depression of the maximum responses as the concentration was increased,
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 7, pp. 781–801

788
Broadley, Davies, Escargueil, Lee, Penson, Thomas:
a phenomenon associated with antagonism of ion channels and is advanta-
geous provided no arrhythmic effect is observed. This compound also
showed over 100-fold selectivity over atrial M2 receptors. The hydroxy-
amides 6a, 6b showed disappointing biological activity. However, the high
micromolar potency of the α-hydroxyamide 7a and its selectivity for M3
over M2 receptors was promising and may be studied further, the free nitro-
gen in the piperidinyl ring of the [(piperidinyl)methyl]pyridine 26 provid-
ing a site for further elaboration.
EXPERIMENTAL
Flash column chromatography was performed using Merck silica gel (60H; 40–60m, 230–240
mesh). Petrol refers to light petroleum which was redistilled before use and refers to the
fraction boiling between 40 and 60 °C. Tetrahydrofuran was dried over sodium-
benzophenone and was distilled prior to use. Dichloromethane was dried over CaH2 and dis-
tilled before use. Ether refers to diethyl ether. Reactions under non-aqueous conditions were
carried out under an atmosphere of nitrogen or argon.
Electron impact (EI) or chemical ionisation using ammonia (CI) mass spectra were re-
corded using a Fisons VG Trio 200 spectrometer and high resolution mass spectra on a
Kratos Concept IS spectrometer. IR spectra (ν in cm–1) were measured using a Genesis FTIR
spectrometer on NaBr plates as evaporated films. NMR spectra were recorded in deuteriated
chloroform unless otherwise indicated on either a Varian Unity 500 (500 MHz), Varian
INOVA 300 (300 MHz), or a Varian Gemini 200 (200 MHz) spectrometer. Coupling con-
stants (J) are given in Hz and chemical shifts in ppm (δ-scale) relative to tetramethylsilane.
4-Chloro-2,6-dimethoxyphenol (8d)13,14
Aluminium chloride (3.01 g, 22.56 mmol, 7 eq.) was added to 1,2,3-trimethoxy-5-chloro-
benzene (653 mg, 3.22 mmol, 1 eq.) in CH2Cl2 (218 ml) and the mixture was stirred at am-
bient temperature for 4 h. After cooling in an ice bath, aqueous hydrogen chloride (2 M,
100 ml) was added and the resulting mixture was stirred for 10 min. The aqueous layer was
extracted with CH2Cl2 (3 × 100 ml) and the organic extracts were dried (Na2SO4) and con-
centrated under reduced pressure to yield the title compound 8d (608 mg, 100%) as a grey
solid used without further purification. RF 0.09 (50% Et2O/petrol). IR (film): 3405, 3004,
1611, 1590, 1509, 1463, 1455, 1442, 1423, 1362, 1311, 1239, 1213, 1111, 878, 831, 786.
1H NMR (300 MHz, CDCl3): 6.60 s, 2 H (Ar-H); 5.46 br s, 1 H (OH); 3.89 s, 6 H (OCH3).
13C NMR (75 MHz, CDCl3): 147.5, 133.7, 124.6, 105.9, 56.7. MS-CI: 208 (29) [M•+ + 18], 206
(100), 191 (12), 189 (40), 190 (11), 188 (26).
Synthesis of 1,3-Dialkoxy-2-{[2-(1-methylethenyl)phenyl]methoxy}benzenes (10a–10e).
Representative Procedure
Diisopropyl azodicarboxylate (15.12 ml, 76.78 mmol, 3 eq.) was added to the alcohol 9
(3.79 g, 25.59 mmol, 1 eq.), 2,6-alkoxyphenol 8a (7.89 g, 51.4 mmol, 2 eq.) and triphenyl-
phosphine (20.14 g, 76.78 mmol, 3 eq.) in THF (128 ml) at ambient temperature and the
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Synthesis of Antagonists of Muscarinic (M3) Receptors
789
mixture was stirred for 16 h. After concentration under reduced pressure, chromatography
of the residue (5→10–30% Et2O/petrol) gave the benzyl ether 10a.
1,3-Dimethoxy-2-{[2-(1-methylethenyl)phenyl]methoxy}benzene (10a) (5.43 g, 75%): a colour-
less oil, RF 0.38 (30% Et2O/petrol). IR (film): 1639, 1596, 1493, 1477, 1437, 1296, 1254,
1219, 1185, 1111, 773, 734. 1H NMR (300 MHz, CDCl3): 7.74 m, 1 H (Ar-H); 7.37–7.27 m,
2 H (Ar-H); 7.22 m, 1 H (Ar-H); 7.04 t, 3J = 8.4, 1 H (Ar-H); 6.63 t, 3J = 8.4, 2 H (Ar-H);
5.25 dq, J = 2.1, 1.6, 1 H (1′′-H); 5.07 s, 2 H (ArCH2); 4.97 dq, J = 2.1, 1.0, 1 H (1′′-H′);
3.85 s, 6 H (2 × OCH3); 2.15 dd, J = 1.5, 1.0, 3 H (CH3). 13C NMR (75 MHz, CDCl3): 154.2,
144.7, 143.6, 137.6, 134.8, 130.0, 127.8, 127.7, 127.1, 124.0, 115.7, 105.7, 72.5, 56.3, 25.3.
MS-ES–: 591 (36), 307 (100). For C18H20O3Na (M•+ + 23) calculated: 307.1305, found:
307.1306.
1,3-Diethoxy-2-{[(2-(1-methylethenyl)phenyl]methoxy}benzene (10b) (310 mg, 43%): a colour-
less oil, RF 0.58 (50% Et2O/petrol). IR (film): 1593, 1467, 1392, 1299, 1253, 1212, 1120,
1090, 983, 900, 772, 738. 1H NMR (300 MHz, CDCl3): 7.82 m, 1 H (Ar-H); 7.37–7.27 m, 2 H
(Ar-H); 7.23 m, 1 H (Ar-H); 6.99 t, 3J = 8.4, 1 H (Ar-H); 6.61 t, 3J = 8.4, 2 H (Ar-H); 5.26 dq,
J = 2.1, 1.6, 1 H (1′′-H); 5.08 s, 2 H (ArCH2); 5.04–5.00 dq, J = 2.1, 1.0, 1 H (1′′-H′); 4.08 q,
3J = 7.0, 4 H (2 × OCH2CH3); 2.17 dd, J = 1.4, 1.0, 3 H (CH3); 1.46 t, 3J = 7.0, 6 H (2 ×
OCH2CH3). 13C NMR (75 MHz, CDCl3): 153.6, 144.8, 143.7, 138.3, 135.1, 130.3, 127.8,
127.7, 127.1, 123.8, 115.8, 106.8, 72.4, 64.8, 25.5, 15.3. MS-CI: 330 (17) [M•+ + 18], 313
(17), 131 (100). For C20H25O3 (M•+ + H) calculated: 313.1798, found: 313.1794.
5-Bromo-1,3-dimethoxy-2-{[2-(1-methylethenyl)phenyl]methoxy}benzene (10c) (358 mg, 73%;
using 2 eq. of Ph3P and DIAD): a colourless oil, RF 0.61 (30% Et2O/petrol). IR (film): 1638,
1587, 1495, 1462, 1442, 1306, 1226, 1185, 1127, 975, 902, 840, 812, 788, 768. 1H NMR
(300 MHz, CDCl3): 7.73 m, 1 H (Ar-H); 7.36–7.27 m, 2 H (Ar-H); 7.22 m, 1 H (Ar-H); 6.75 s,
2 H (Ar-H); 5.25 dq, J = 2.0, 1.6, 1 H (1′′-H); 5.02 s, 2 H (ArCH2); 4.97 dq, J = 2.1, 1.0, 1 H
(1′′-H′); 3.83 s, 6 H (2 × OCH3); 2.14 dd, J = 1.5, 1.0, 3 H (CH3). 13C NMR (75 MHz, CDCl3):
154.6, 144.6, 143.8, 136.6, 134.4, 130.0, 127.9, 127.8, 127.1, 116.5, 115.8, 109.3, 72.6, 56.5,
25.3. MS-ES+: 382 (28) [M•+ + 18], 380 (30), 365 (11), 363 (9), 131 (100). For C18H23NO379Br
(M•+ + NH4) calculated: 380.0856, found: 380.0857.
5-Chloro-1,3-dimethoxy-2-{[2-(1-methylethenyl)phenyl]methoxy}benzene (10d) (638 mg, 80%;
using 1 eq. of Ph3P and DIAD): a colourless oil, RF 0.64 (50% Et2O/petrol). IR (film): 1590,
1495, 1454, 1413, 1225, 1127, 873, 815, 767. 1H NMR (300 MHz, CDCl3): 7.67 m, 1 H
(Ar-H); 7.32–7.26 m, 2 H (Ar-H); 7.20 m, 1 H (Ar-H); 6.59 s, 2 H (Ar-H); 5.23 dq, J = 2.1, 1.6,
1 H (1′′-H); 5.00 s, 2 H (ArCH2); 4.95 dq, J = 2.1, 1.0, 1 H (1′′-H′); 3.80 s, 6 H (2 × OCH3);
2.12 dd, J = 1.5, 1.0, 3 H (CH3). 13C NMR (75 MHz, CDCl3): 154.3, 144.6, 143.8, 136.1,
134.4, 130.0, 129.2, 127.9, 127.8, 127.1, 115.8, 106.3, 72.6, 56.4, 25.3. MS-CI: 338 (3) [M•+
+
18], 336 (7), 321 (1), 319 (3), 131 (100). For C18H19O335Cl (M•+) calculated: 318.1017, found:
318.1017.
1-Chloro-3-{[2-(1-methylethenyl)phenyl]methoxy}-2,4-dimethoxybenzene (10e) (277 mg, 64%;
using 2 eq. of Ph3P and DIAD): a colourless oil, RF 0.58 (30% Et2O/petrol). IR (film): 1478,
1465, 1439, 1418, 1371, 1297, 1216, 1093, 1013, 981, 900, 794, 760, 698. 1H NMR
(300 MHz, CDCl3): 7.74 m, 1 H (Ar-H); 7.40–7.30 m, 2 H (Ar-H); 7.25 m, 1 H (Ar-H); 7.12
and 6.68 each d, 3J = 9.0, 1 H (Ar-H); 5.28 dq, J = 2.1, 1.6, 1 H (1′′-H); 5.10 s, 2 H (ArCH2);
5.00 dq, J = 2.1, 1.0, 1 H (1′′-H′); 3.94 and 3.85 each s, 3 H (OCH3); 2.12 dd, J = 1.5, 1.0, 3 H
(CH3). 13C NMR NMR (75 MHz, CDCl3): 153.4, 150.8, 144.5, 143.8, 143.0, 134.2, 133.9,
129.9, 128.0, 127.3, 124.4, 120.3, 116.0, 108.3, 73.2, 61.6, 56.4, 25.4. MS-CI: 338 (24) [M•+
+
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Broadley, Davies, Escargueil, Lee, Penson, Thomas:
18], 336 (73), 321 (5), 319 (16), 131 (100). For C18H23NO335Cl (M•+ + NH4) calculated:
336.1361, found: 336.1358.
Synthesis of 2-{2-[(2,6-Dialkoxyphenoxy)methyl]phenyl}propane-1,2-diols (11a–11e).
Representative Procedure
Osmium tetraoxide (483 mg, 1.90 mmol, 10 mole %) followed by N-methylmorpholine N-
oxide (6.68 g, 57.01 mmol, 3 eq.) were added at ambient temperature to the alkene 10a
(5.40 g, 19.00 mmol, 1 eq.) in acetone (304 ml) and water (152 ml). Upon completion of the
reaction (monitored by TLC), saturated aqueous sodium sulfite (150 ml) was added. The
mixture was stirred for 30 min then extracted with EtOAc (4 × 150 ml). The organic extracts
were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give
the product that was used without further purification.
2-{2-[(2,6-Dimethoxyphenoxy)methyl]phenyl}propane-1,2-diol (11a) (6.05 g, 100%): a pale or-
ange oil, RF 0.26 (Et2O). IR (film): 3460, 1597, 1494, 1478, 1372, 1295, 1255, 1210, 1111,
1035, 762. 1H NMR (300 MHz, CDCl3): 7.45 d, 3J = 7.9, 1 H (Ar-H); 7.34 m, 1 H (Ar-H);
7.18 m, 2 H (Ar-H); 7.04 t, 3J = 8.4, 1 H (Ar-H); 6.59 d, 3J = 8.4, 2 H (Ar-H); 5.37 and 5.27
each d, 2J = 10.4, 1 H (ArHCH); 4.75 br s, 1 H (OH); 4.14 and 3.81 each d, 2J = 11.1, 1 H
(HCHOH); 3.81 s, 6 H (2 × OCH3); 2.85 br s, 1 H (OH); 1.66 s, 3 H (CH3). 13C NMR
(75 MHz, CDCl3): 153.7, 145.2, 135.8, 134.4, 133.6, 129.1, 127.4, 127.1, 124.4, 105.4, 77.0,
74.8, 71.9, 56.2, 27.7. MS-ES+: 341 (100) (M•+ + 23). For C18H22O5Na (M•+ + Na) calculated:
341.1359, found: 341.1356.
2-{2-[(2,6-Diethoxyphenoxy)methyl]phenyl}propane-1,2-diol (11b) (412 mg, 93%): a colourless
oil, RF 0.13 (50% Et2O/petrol). IR (film): 3470, 1594, 1468, 1392, 1298, 1254, 1208, 1118,
1090, 1039, 972, 761, 740. 1H NMR (300 MHz, CDCl3): 7.45 d, 3J = 7.9, 1 H (Ar-H);
7.36 ddd, 3J = 7.7, 7.3, 4J = 1.6, 1 H (Ar-H); 7.28 dd, 3J = 7.5, 4J =1.4, 1 H (Ar-H); 7.24 dd,
3J = 7.3, 7.1, 1 H (Ar-H); 7.00 t, 3J = 8.4, 1 H (Ar-H); 6.59 d, 3J = 8.4, 2 H (Ar-H); 5.41 and
5.28 each d, 2J = 10.0, 1 H (ArHCH); 4.13 d, 2J = 11.3, 1 H (HCHOH); 4.13–3.99 m, 4 H (2 ×
OCH2CH3); 3.82 d, 2J = 11.3, 1 H (HCHOH); 1.67 s, 3 H (CH3); 1.46 t, 3J = 7.0, 6 H (2 ×
OCH2CH3). 13C NMR (75 MHz, CDCl3): 153.0, 145.2, 136.4, 134.7, 133.5, 129.0, 127.4,
127.1, 124.2, 106.3, 77.1, 74.7, 71.9, 64.7, 27.8, 15.1. MS-ES+: 369 (100) (M•+ + 23), 347 (5),
329 (4). For C20H26O5Na (M•+ + Na) calculated: 369.1672, found: 369.1684.
2-{2-[(4-Bromo-2,6-dimethoxyphenoxy)methyl]phenyl}propane-1,2-diol (11c) [331 mg, 85%;
after chromatography (50→100% Et2O/petrol)]: a cloudy oil, RF 0.10 (50% Et2O/petrol).
IR (film): 3468, 1589, 1494, 1461, 1442, 1409, 1226, 1186, 1127, 1037, 965, 814, 762, 731.
1H NMR (300 MHz, CDCl3): 7.45 dd, 3J = 8.0, 2J = 1.2, 1 H (Ar-H); 7.35 ddd, 3J = 7.9, 6.9,
4J = 1.9, 1 H (Ar-H); 7.20 ddd, 3J = 7.5, 7.0, 4J = 1.3, 1 H (Ar-H); 7.15 dd, 3J = 7.5, 4J = 1.9,
1 H (Ar-H); 6.72 s, 2 H (Ar-H); 5.34 and 5.25 each d, 2J = 10.4, 1 H (ArHCH); 4.54 s, 1 H
(OH); 4.10 dd, 2J = 11.1, 3J = 4.3, 1 H (HCHOH); 3.83–3.76 m, 7 H (2 × OCH3 and HCHOH);
3.81 dd, 3J = 9.2, 4.4, 1 H (OH); 1.64 s, 3 H (CH3). 13C NMR (75 MHz, CDCl3): 154.1, 145.1,
135.0, 134.2, 133.6, 129.2, 127.4, 127.2, 116.9, 109.2, 77.0, 74.8, 71.8, 56.5, 27.6. MS-ES+:
421 (100) [M•+ + 23], 419 (93), 416 (18), 414 (20), 399 (6), 397 (6), 381 (10), 379 (9). For
C
18H21O579BrNa (M•+ + Na) calculated: 419.0465, found: 419.0461.
2-{2-[(4-Chloro-2,6-dimethoxyphenoxy)methyl]phenyl}propane-1,2-diol (11d) [664 mg, 97%;
after chromatography (40→100% Et2O/petrol]: a white foam, RF 0.13 (50% Et2O/petrol).
IR (film): 3468, 1592, 1496, 1463, 1455, 1445, 1415, 1312, 1226, 1187, 1127, 1037, 873,
817, 763, 733. 1H NMR (300 MHz, CDCl3): 7.42 dd, 3J = 7.9, 4J = 1.0, 1 H (Ar-H); 7.32 td,
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Synthesis of Antagonists of Muscarinic (M3) Receptors
791
3J = 7.8, 7.1, 4J = 1.9, 1 H (Ar-H); 7.17 ddd, 3J = 7.5, 7.0, 4J = 1.2, 1 H (Ar-H); 7.12 dd, 3J =
7.6, 4J = 1.7, 1 H (Ar-H); 6.55 s, 2 H (Ar-H); 5.30 and 5.22 d, 2J = 10.4, each 1 H (ArHCH);
4.08 and 3.77 each d, 2J = 11.3, 1 H (HCHOH); 3.75 s, 6 H (2 × OCH3); 1.61 s, 3 H (CH3).
13C NMR (75 MHz, CDCl3): 153.8, 145.0, 134.4, 134.1, 133.5, 129.6, 129.1, 127.4, 127.1,
106.2, 76.9, 74.8, 71.8, 56.4, 27.6. MS-ES+: 377 (6) [M•+ + 23], 375 (21), 372 (28), 370 (100),
355 (0.3), 353 (1). For C18H25NO535Cl (M•+ + NH4] calculated: 370.1416, found: 370.1413.
2-{2-[(3-Chloro-2,6-dimethoxyphenoxy)methyl]phenyl}propane-1,2-diol (11e) [331 mg, 85%;
after chromatography (50→100% Et2O/petrol)]: a white foam, RF 0.10 (50% Et2O/petrol).
IR (film): 3468, 1580, 1478, 1465, 1418, 1373, 1296, 1230, 1091, 1037, 972, 795, 762.
1H NMR (300 MHz, CDCl3): 7.43 dd, 3J = 7.8, 4J = 1.5, 1 H (Ar-H); 7.35 ddd, 3J = 8.0, 6.9,
4J = 1.8, 1 H (Ar-H); 7.29 dd, 3J = 7.6, 4J = 1.7, 1 H (Ar-H); 7.22 td, 3J = 7.2, 4J = 1.5, 1 H
(Ar-H); 7.10 d, 3J = 9.0, 1 H (Ar-H); 6.61 d, 3J = 9.0, 1 H (Ar-H); 5.43 and 5.38 each d, 2J =
10.4, 1 H (ArHCH); 4.46 s, 1 H (OH); 4.09 dd, 2J = 11.2, 3J = 3.6, 1 H (HCHOH); 3.91 s, 3 H
(OCH3); 3.78 dd, 2J = 11.4, 3J = 2.3, 1 H (HCHOH); 3.75 s, 3 H (OCH3); 2.70 dd, 3J = 8.9, 4.6,
1 H (OH); 1.66 s, 3 H (CH3). 13C NMR (75 MHz, CDCl3): 152.8, 150.5, 144.8, 141.5, 134.3,
133.4, 129.2, 127.4, 127.4, 124.8, 120.5, 108.1, 77.0, 75.1, 71.7, 61.4, 56.3, 27.6. MS-ES+:
377 (35) [M•+ + 23], 375 (100), 372 (3), 370 (9), 355 (0.6), 353 (1). For C18H21O535ClNa
(M•+ + Na) calculated: 375.0970, found: 375.0968.
2-{2-[(2,6-Dimethoxyphenoxy)methyl]phenyl}-2-hydroxypropanal (12a)
Dimethyl sulfoxide (3.60 ml, 50.26 mmol, 4 eq.) in CH2Cl2 (25 ml) was added dropwise to
oxalyl chloride (2.20 ml, 25.13 mmol, 2 eq.) in CH2Cl2 (25 ml) at –78 °C and the mixture
stirred for 30 min before adding the alcohol 11a (4.00 g, 12.56 mmol, 1 eq.) in CH2Cl2
(25 ml). The reaction was stirred for a further 30 min then Et3N (10.50 ml, 75.39 mmol,
6 eq.) was added dropwise and the mixture was allowed to warm to 0 °C and stirred for
30 min. Water (80 ml) was added and the mixture was extracted with CH2Cl2 (3 × 80 ml).
The organic extracts were washed with brine, dried (Na2SO4) and concentrated under re-
duced pressure. Chromatography of the residue (30→70% Et2O/petrol) gave the title com-
pound 12a (2.71 g, 68%) as an orange oil, RF 0.55 (Et2O). IR (film): 3456, 2360, 2342, 1733,
1598, 1494, 1479, 1296, 1256, 1210, 1185, 1111, 773. 1H NMR (300 MHz, CDCl3): 9.84 s,
1 H (CHO); 7.44–7.33 m, 3 H (Ar-H); 7.28 m, 1 H (Ar-H); 7.03 t, 3J = 8.5, 1 H (Ar-H); 6.59 d,
3J = 8.5, 2 H (Ar-H); 5.51 br s, 1 H (OH); 5.19 and 5.13 d, 2J = 10.7, each 1 H (ArHCH);
3.85 s, 6 H (2 × OCH3); 1.77 s, 3 H, s (CH3). 13C NMR (75 MHz, CDCl3): 201.6, 153.7, 139.8,
135.8, 135.5, 133.0, 129.0, 128.3, 127.7, 124.5, 105.4, 80.7, 74.2, 56.2, 24.8. MS-CI: 339
(100) [M•+ + 23]. For C18H20O5Na (M•+ + Na) calculated: 339.1203, found: 339.1204.
2-{2-[(2,6-Diethoxyphenoxy)methyl]phenyl}-2-hydroxypropanal (12b)
Following the procedure outlined for the synthesis of the aldehyde 12a, using dimethyl
sulfoxide (0.44 ml, 5.95 mmol, 5 eq.) in CH2Cl2 (5 ml) and oxalyl chloride (0.31 ml,
3.57 mmol, 3 eq.) in CH2Cl2 (5 ml), the diol 11b (412 mg, 1.19 mmol, 1 eq.) in CH2Cl2
(22 ml) with Et3N (0.99 ml, 7.14 mmol, 6 eq.) gave, after chromatography (20→30%
Et2O/petrol) the title compound 12b (206 mg, 50%) as a pale yellow oil, RF 0.34 (50%
Et2O/petrol). IR (film): 3465, 1734, 1595, 1468, 1372, 1299, 1255, 1208, 1118, 1090, 975,
767, 738. 1H NMR (300 MHz, CDCl3): 9.91 s, 1 H (CHO); 7.46–7.29 m, 4 H (Ar-H); 7.01 t,
3J = 8.4, 1 H (Ar-H); 6.59 d, 3J = 8.4, 2 H (Ar-H); 5.44 br s, 1 H (OH); 5.21 s, 2 H (ArCH2);
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792
Broadley, Davies, Escargueil, Lee, Penson, Thomas:
4.10 m, 4 H (OCH2CH3); 1.80 s, 3 H (CH3); 1.48 t, 3J = 7.0, 6 H (OCH2CH3). 13C NMR
(75 MHz, CDCl3): 201.9, 153.1, 139.9, 136.4, 135.7, 132.9, 129.0, 128.3, 127.7, 124.4, 106.3,
80.8, 74.1, 64.7, 25.0, 15.2. MS-ES+: 367 (60) [M•+ + 23], 345 (22), 327 (16). For C20H24O5Na
(M•+ + Na) calculated: 367.1516, found: 367.1516.
2-{2-[(2,6-Dimethoxyphenoxy)methyl]phenyl}-2-hydroxypropanoic Acid (13a)
2-Methyl-2-butene (105 ml, 209.63 mmol, 30 eq.), sodium chlorite (3.98 g, 44.02 mmol,
6.3 eq.) and sodium dihydrogen phosphate (10.90 g, 69.88 mmol, 10 eq.) were added to the
aldehyde 12a (2.21 g, 6.99 mmol, 1 eq.) in tert-butanol (87 ml) and water (87 ml) and the
mixture stirred for 16 h. Saturated aqueous sodium sulfite (87 ml) was added and the mix-
ture stirred for 30 min then extracted with ethyl acetate (3 × 100 ml). The organic extracts
were dried (Na2SO4) and concentrated under reduced pressure. Chromatography of the resi-
due (50→100% Et2O/petrol) to give the title compound 13a (894 mg, 39%) as a pale yellow
oil, RF 0.39 (Et2O). IR (film): 3438, 1732, 1645, 1598, 1479, 1465, 1419, 1374, 1296, 1257,
1217, 1112, 1092, 1007, 760 and 733. 1H NMR (300 MHz, CDCl3): 7.68 dd, 3J = 7.9, 4J = 1.2,
1 H (Ar-H); 7.41 td, 3J = 7.6, 4J = 1.6, 1 H (Ar-H); 7.30 td, 3J = 7.4, 4J = 1.3, 1 H (Ar-H);
7.23 dd, 3J = 7.5, 4J = 1.6, 1 H (Ar-H); 7.05 t, 3J = 8.4, 1 H (Ar-H); 6.59 d, 3J = 8.4, 2 H (Ar-H);
5.28 and 5.02 each d, 2J = 11.3, 1 H (ArHCH); 3.80 s, 6 H (2 × OCH3); 2.00 s, 3 H (CH3).
13C NMR (75 MHz, CDCl3): 177.7, 153.5, 140.9, 135.2, 134.5, 133.3, 129.3, 128.7, 127.6,
124.8, 105.5, 77.2, 73.9, 56.2, 27.4. MS-ES–: 331 (100) [M•+ – 1]. For C18H19O6 (M•+ – H) cal-
culated: 331.1187, found: 331.1178.
2-{2-[(2,6-Diethoxyphenoxy)methyl]phenyl}-2-hydroxypropanoic Acid (13b)
Following the procedure outlined for the synthesis of the acid 13a, aldehyde 12b (206 mg,
0.60 mmol, 1 eq.), after chromatography (50→60% Et2O/petrol) gave the title compound
13b (132 mg, 61%) as a pale oil, RF 0.11 (50% Et2O/petrol). IR (film): 3434, 1724, 1595,
1468, 1392, 1298, 1254, 1212, 1118, 1090, 737. 1H NMR (300 MHz, CDCl3): 7.69 dd, 3J =
7.9, 4J = 0.7, 1 H (Ar-H); 7.42 td, 3J = 7.5, 4J = 1.7, 1 H (Ar-H); 7.30 ddd, 3J = 7.6, 7.1, 4J =
1.0, 1 H (Ar-H); 7.25 dd, 3J = 7.4, 4J = 1.7, 1 H (Ar-H); 7.01 t, 3J = 8.4, 1 H (Ar-H); 6.57 d, 3J =
8.4, 2 H (Ar-H); 6.30 br s, 1 H (OH); 5.27 and 5.09 each d, 2J = 11.4, 1 H (ArHCH); 4.06 m,
4 H (OCH2CH3); 2.00 s, 3 H (CH3); 1.44 t, 3J = 7.0, 6 H (2 × OCH2CH3). 13C NMR (75 MHz,
CDCl3): 177.2, 152.7, 140.9, 135.4, 134.6, 133.4, 129.4, 128.8, 127.7, 127.8, 106.2, 77.2,
73.9, 64.7, 27.3, 15.0. MS-ES+: 361 (23) [M•+ + 1], 136 (100). For C20H25O6 (M•+ + H) calcu-
lated: 361.1646, found: 361.1656.
N-{1-[(Phenyl)methyl]piperidin-4-yl}-2-{2-[(2,6-dimethoxyphenoxy)methyl]phenyl}-
2-hydroxypropanamide (5a)
A mixture of the hydroxyacid 13a (150 mg, 0.45 mmol, 1.0 eq.), 4-amino-1-benzylpiperidine
(0.9 ml, 0.45 mmol, 1.0 eq.), HOBt hydrate (67 mg, 0.50 mmol, 1.1 eq.) and
4-methylmorpholine (0.199 ml, 1.81 mmol, 4 eq.) in DMF (2.25 ml) was stirred at 0 °C for
30 min then EDCI hydrochloride salt (87 mg, 0.45 mmol, 1.0 eq.) was added. The reaction
mixture was allowed to stir for 16 h at ambient temperature then Et2O (15 ml) was added.
The organic layer was washed with saturated aqueous sodium hydrogen carbonate (15 ml)
and the aqueous phase was extracted with Et2O (3 × 15 ml). The organic extracts were
washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Chromatogra-
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Synthesis of Antagonists of Muscarinic (M3) Receptors
793
phy of the residue (70% EtOAc/petrol; 1% Et3N) gave the title compound 5a (200 mg, 88%)
as a colourless oil, RF 0.54 (10% MeOH/CH2Cl2). IR (film): 3400, 2360, 1660, 1597, 1495,
1478, 1367, 1296, 1255, 1221, 1113 and 744. 1H NMR (300 MHz, C6D6): 7.68 dd, 3J = 7.9,
4J = 1.1, 1 H (Ar-H); 7.34–7.25 m, 4 H (Ar-H and NH); 7.22–7.04 m, 4 H (Ar-H); 6.97 td, 3J =
7.4, 4J = 1.3, 1 H (Ar-H); 6.76 t, 3J = 8.4, 1 H (Ar-H); 6.23 d, 3J = 8.4, 2 H (Ar-H); 5.84 br s,
1 H (OH); 5.66 and 5.22 each d, 2J = 11.4, 1 H (ArHCH); 3.93 m, 1 H (4′-H); 3.24 s, 6 H (2 ×
OCH3); 3.20 s, 2 H (ArCH2N); 2.59–2.43 m, 2 H; 2.06 s, 3 H (CH3); 1.90–1.69 m, 4 H;
1.45–1.26 m, 2 H. 13C NMR (75 MHz, C6D6): 175.1, 153.8, 143.4, 139.5, 136.2, 135.5, 132.7,
129.0, 128.6, 128.4, 128.1, 127.5, 127.1, 124.1, 105.6, 77.5, 73.9, 63.0, 55.6, 52.3, 52.2, 46.6,
32.2, 32.1, 28.5. MS-ES+: 527 (100) [M•+ + 23], 505 (75). For C30H37N2O5 (M•+ + H) calcu-
lated: 505.2697, found: 505.2701.
N-{1-[(Phenyl)methyl]piperidin-4-yl}-2-{2-[(2,6-diethoxyphenoxy)methyl]phenyl}-
2-hydroxypropanamide (5b)
Following the procedure outlined for the synthesis of the amide 5a, the hydroxyacid 13b
(132 mg, 0.37 mmol, 1.0 eq.) and 4-amino-1-benzylpiperidine (0.75 ml, 0.37 mmol, 1.0 eq.)
gave, after chromatography (50→80% EtOAc/petrol; 1% Et3N), the title compound 5b
(137 mg, 70%) as a colourless oil, RF 0.40 (10% MeOH/CH2Cl2). IR (film): 3459, 3399, 1670,
1595, 1493, 1468, 1392, 1367, 1298, 1253, 1207, 1090, 1090, 741. 1H NMR (300 MHz,
C6D6): 7.69 dd, 3J = 7.7, 4J = 1.0, 1 H (Ar-H); 7.38 d, 3J = 8.1, 1 H (NH); 7.32 dd, 3J = 7.5, 4J =
1.4, 1 H (Ar-H); 7.30–7.24 m, 2 H (Ar-H); 7.22–7.07 m, 4 H (Ar-H); 7.01 td, 3J = 7.4, 4J = 1.1,
1 H (Ar-H); 6.81 t, 3J = 8.3, 1 H (Ar-H); 6.30 d, 3J = 8.3, 2 H (Ar-H); 5.78 br s, 1 H (OH); 5.65
and 5.26 each d, 2J = 11.5, 1 H (ArHCH); 3.93 m, 1 H (4′-H); 3.56 m, 4 H (OCH2CH3);
3.20 s, 2 H (ArCH2N); 2.58–2.46 m, 2 H; 2.04 s, 3 H (CH3); 1.91–1.70 m, 4 H; 1.45–1.27 m,
2 H; 1.11 t, 3J = 7.0, 6 H (2 × OCH2CH3). 13C NMR (75 MHz, C6D6): 175.2, 153.1, 143.5,
139.5, 136.8, 135.7, 132.6, 129.0, 128.6, 128.5, 128.4, 128.0, 127.1, 124.0, 106.5, 77.6, 74.0,
64.4, 63.0, 52.3, 46.6, 32.2, 32.0, 28.4, 14.8. MS-ES+: 553 (100) [M•+ + 1]. For C32H41N2O5
(M•+ + H) calculated: 533.3010, found: 533.3018.
Preparation of 2-{2-[(2,6-Dimethoxyphenoxy)methyl]phenyl}-2-hydroxypropanoic Acids (13c–13e).
Representative Procedure
Dimethyl sulfoxide (0.30 ml, 4.18 mmol, 5 eq.) in CH2Cl2 (5 ml) was added dropwise to
oxalyl chloride (0.22 ml, 2.51 mmol, 3 eq.) in CH2Cl2 (11 ml) at –78 °C and the mixture
stirred for 30 min before adding the diol 11c (331 mg, 0.84 mmol, 1 eq.) in CH2Cl2 (7 ml).
The reaction was stirred for a further 30 min then Et3N (0.70 ml, 5.02 mmol, 6 eq.) was
added dropwise and the mixture was allowed to warm to 0 °C and stirred for 30 min. Satu-
rated aqueous ammonium chloride (20 ml) was added and the mixture was extracted with
CH2Cl2 (3 × 20 ml). The organic extracts were washed with brine, dried (Na2SO4) and con-
centrated under reduced pressure to afford the corresponding aldehyde (498 mg) as a yellow
oil used without further purification.
2-Methyl-2-butene (12.50 ml, 25.09 mmol, 30 eq.), sodium chlorite (378 mg, 4.18 mmol,
5 eq.) and sodium dihydrogen phosphate (1.30 g, 8.36 mmol, 10 eq.) were added to the al-
dehyde (330 mg, 0.84 mmol, 1 eq.) in tert-butanol (10.5 ml) and water (10.5 ml). The mix-
ture was stirred for 16 h then saturated aqueous sodium sulfite (11 ml) was added. The
mixture stirred for 30 min then extracted with ethyl acetate (5 × 20 ml). The organic ex-
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794
Broadley, Davies, Escargueil, Lee, Penson, Thomas:
tracts were dried (Na2SO4) and concentrated under reduced presure. Chromatography of the
residue (40→50% Et2O/petrol) gave the product.
2-{2-[(4-Bromo-2,6-dimethoxyphenoxy)methyl]phenyl}-2-hydroxypropanoic acid (13c) (91 mg,
34%): a colourless oil, RF 0.10 (50% Et2O/petrol). IR (film): 3437, 1725, 1589, 1494, 1459,
1409, 1226, 1186, 1127, 815, 761. 1H NMR (300 MHz, CDCl3): 7.63 dd, 3J = 7.9, 4J = 1.2,
1 H (Ar-H); 7.39 ddd, 3J = 7.7, 7.5, 4J = 1.6, 1 H (Ar-H); 7.28 ddd, 3J = 7.5, 7.4, 4J = 1.3, 1 H
(Ar-H); 7.20 dd, 3J = 7.5, 4J = 1.6, 1 H (Ar-H); 6.69 s, 2 H (Ar-H); 5.95 br s, 1 H (OH); 5.21
and 4.98 each d, 2J = 11.3, 1 H (ArHCH); 3.75 s, 6 H (2 × OCH3); 1.96 s, 3 H (CH3).
13C NMR (75 MHz, CDCl3): 177.5, 153.9, 140.8, 134.4, 134.2, 133.3, 129.5, 128.7, 127.6,
117.4, 109.1, 77.2, 74.0, 56.5, 27.4. MS-ES+: 435 (58) [M•+ + 23], 433 (58), 430 (5), 428 (5),
413 (3), 411 (3), 395 (8), 393 (8), 269 (100). For C18H19O679BrNa (M•+ + Na) calculated:
433.0257, found: 433.0253.
2-{2-[(4-Chloro-2,6-dimethoxyphenoxy)methyl]phenyl}-2-hydroxypropanoic acid (13d) (252 mg,
69%; after chromatography using 40→70% Et2O/petrol):
a pale yellow oil, RF 0.09
(50% Et2O/petrol). IR (film): 3441, 1728, 1592, 1496, 1462, 1447, 1414, 1312, 1226, 1186,
1127, 874, 816, 762. 1H NMR (300 MHz, CDCl3): 7.63 dd, 3J = 7.9, 4J = 1.0, 1 H (Ar-H);
7.38 ddd, 3J = 7.7, 7.5, 4J = 1.6, 1 H (Ar-H); 7.27 td, 3J = 7.4, 4J = 1.2, 1 H (Ar-H); 7.18 dd,
3J = 7.5, 4J = 1.5, 1 H (Ar-H); 6.54 s, 2 H (Ar-H); 5.99 br s, 1 H (OH); 5.21 and 4.96 each d,
2J = 11.3, 1 H (ArHCH); 3.74 s, 6 H (2 × OCH3); 1.95 s, 3 H (CH3). 13C NMR (75 MHz,
CDCl3): 177.2, 153.6, 140.8, 134.2, 133.8, 133.3, 130.2, 129.5, 128.7, 127.6, 106.2, 77.2,
74.1, 56.4, 27.4. MS-ES+: 391 (40) [M•+
18H19O635ClNa (M•+ + Na) calculated: 389.0762, found: 389.0763.
2-{2-[(3-Chloro-2,6-dimethoxyphenoxy)methyl]phenyl}-2-hydroxypropanoic acid (13e) (102 mg,
+ 23], 389 (100), 386 (11), 384 (25). For
C
39%): a colourless oil, RF 0.51 (Et2O). IR (film): 3434, 1726, 1582, 1477, 1465, 1419, 1375,
1295, 1231, 1091, 1011, 810. 1H NMR (300 MHz, CDCl3): 7.62 d, 3J = 7.6, 1 H (Ar-H);
7.43–7.29 m 3 H (Ar-H); 7.09 d, 3J = 9.0, 1 H (Ar-H); 6.58 d, 3J = 9.0, 1 H (Ar-H); 5.69 br s,
1 H (OH); 5.27 and 5.15 each d, 2J = 11.3, 1 H (ArHCH); 3.85 and 3.73 each s, 3 H (OCH3);
1.96 s, 3 H (CH3). 13C NMR (75 MHz, CDCl3): 178.1, 152.6, 150.3, 141.0, 140.7, 134.3,
133.0, 129.4, 128.8, 127.6, 125.1, 120.5, 108.1, 77.2, 74.4, 61.5, 56.3 and 27.5. MS-ES+: 391
(39) [M•+ + 23], 389 (100), 386 (2), 384 (7). For C18H19O635ClNa (M•+ + Na) calculated:
389.0762, found: 389.0761.
Preparation of N-{1-[(6-Aminopyridin-2-yl)methyl]piperidin-4-yl}-
2-{2-[(2,6-dimethoxyphenoxy)methyl]phenyl}-2-hydroxypropanamides (6a, 6c–6e).
Representative Procedure
The hydroxy acid 13a (70 mg, 0.21 mmol, 1.0 eq.), 2-amino-6-(4-aminopiperidinyl)methyl-
pyridine hydrochloride (87 mg, 0.28 mmol, 1.3 eq.), HOBt hydrate (48 mg, 0.35 mmol,
1.7 eq.) and Et3N (0.205 ml, 1.48 mmol, 7 eq.) were stirred in in CHCl3 (4 ml) at 0 °C for 30
min. EDCI·hydrochloride salt (52 mg, 0.27 mmol, 1.3 eq.) was added and the mixture stirred
for 16 h at ambient temperature. EtOAc (15 ml) was added and the organic layer was
washed with saturated aqueous sodium hydrogen carbonate (15 ml). The aqueous phase was
extracted with EtOAc (3 × 15 ml) and the organic extracts were washed with brine, dried
(Na2SO4) and concentrated under reduced pressure. Chromatography of the residue (0→2%
MeOH/CH2Cl2; 1% Et3N) gave the product.
N-{1-[(6-Aminopyridin-2-yl)methyl]piperidin-4-yl}-2-{2-[(2,6-dimethoxyphenoxy)methyl]phenyl}-
2-hydroxypropanamide (6a) (48 mg, 44%): a colourless oil, RF 0.19 (10% MeOH/CH2Cl2).
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Synthesis of Antagonists of Muscarinic (M3) Receptors
795
IR (film): 3390, 1656, 1620, 1598, 1517, 1494, 1476, 1295, 1255, 1109 and 734. 1H NMR
(300 MHz, CDCl3): 7.61 d, 3J = 7.9, 1 H (Ar-H); 7.40–7.27 m, 3 H (Ar-H and NH); 7.18 dd,
3J = 7.6, 7.2, 1 H (Ar-H); 7.13 dd, 3J = 7.5, 4J = 1.6, 1 H (Ar-H); 6.98 dd, 3J = 8.5, 8.4, 1 H
(Ar-H); 6.68 d, 3J = 7.3, 1 H (Ar-H); 6.53 d, 3J = 8.4, 2 H (Ar-H); 6.35 d, 3J = 8.1, 1 H (Ar-H);
5.67 br s, 1 H (OH); 5.26 and 4.93 each d, 2J = 11.1, 1 H (PhHCH); 4.47 br s, 2 H (ArNH2);
3.78 m, 1 H (4′-H); 3.74 s, 6 H (2 × OCH3); 3.43 s, 2 H (ArCH2N); 2.83 m, 2 H; 2.22–2.08
and 1.98–1.92 each m, 2 H; 1.88 s, 3 H (CH3); 1.67–1.46 m, 2 H. 13C NMR (75 MHz, CDCl3):
175.7, 158.4, 157.3, 153.5, 142.5, 138.2, 135.3, 134.5, 133.1, 129.1, 128.0, 127.9, 127.5,
113.5, 107.1, 105.5, 77.3, 73.8, 64.8, 56.2, 52.8, 46.7, 32.2, 32.0, 28.2. MS-ES+: 543 (12)
[M•+ + 23], 521 (100). For C29H37N4O5 (M•+ + H) calculated: 521.2758, found: 521.2776.
N-{1-[(6-Aminopyridin-2-yl)methyl]piperidin-4-yl}-2-{2-[(4-bromo-2,6-dimethoxyphenoxy)methyl]-
phenyl}-2-hydroxypropanamide (6c) (64 mg, 41%): a white gum, RF 0.19 (10% MeOH/CH2Cl2).
IR (film): 3468, 3391, 1659, 1620, 1589, 1514, 1495, 1463, 1409, 1226, 1127, 731. 1H NMR
(300 MHz, CDCl3): 7.62 dd, 3J = 8.0, 4J = 0.9, 1 H (Ar-H); 7.39 dd, 3J = 8.1, 7.4, 1 H (Ar-H);
7.34 ddd, 3J = 7.8, 7.5, 4J = 1.6, 1 H (Ar-H); 7.25–7.17 m, 2 H (Ar-H and NH); 7.12 dd, 3J =
7.5, 4J = 1.5, 1 H (Ar-H); 6.71 d, 3J = 7.3, 1 H (Ar-H); 6.67 s, 2 H (Ar-H); 6.38 d, 3J = 8.2, 1 H
(Ar-H); 5.41 br s, 1 H (OH); 5.25 and 4.88 each d, 2J = 11.4, 1 H (PhHCH); 4.54 br s, 2 H
(ArNH2); 3.82 m, 1 H (4′-H); 3.73 s, 6 H (2 × OCH3); 3.47 s, 2 H (ArCH2N); 2.93–2.80,
2.27–2.14 and 1.98–1.85 each m, 2 H; 1.88 s, 3 H (CH3); 1.68–1.50 m, 2 H. 13C NMR (75
MHz, CDCl3): 175.6, 158.3, 156.7, 153.9, 142.2, 138.4, 134.6, 134.4, 133.0, 129.2, 128.2,
128.0, 117.1, 113.6, 109.2, 107.4, 77.3, 73.8, 64.5, 56.5, 52.7, 46.6, 32.0, 31.9, 28.2. MS-ES+:
623 (4) [M•+ + 23], 621 (4), 601 (100), 599 (100). For C29H36N4O579Br (M•+ + H) calculated:
599.1864, found: 599.1859.
N-{1-[(6-Aminopyridin-2-yl)methyl]piperidin-4-yl}-2-{2-[(4-chloro-2,6-dimethoxyphenoxy)methyl]-
phenyl}-2-hydroxypropanamide (6d) (190 mg, 50%): a white foam, RF 0.19 (10% MeOH/
CH2Cl2). IR (film): 3463, 3390, 3199, 1660, 1621, 1592, 1515, 1496, 1464, 1414, 1226, 1124,
732. 1H NMR (300 MHz, CDCl3) 7.61 d, 3J = 7.9, 1 H (Ar-H); 7.38 dd, 3J = 8.1, 7.3, 1 H
(Ar-H); 7.34 td, 3J = 7.7, 4J = 1.3, 1 H (Ar-H); 7.25–7.16 m, 2 H (Ar-H and NH); 7.11 dd, 3J =
7.5, 4J = 1.2, 1 H (Ar-H); 6.70 d, 3J = 7.3, 1 H (Ar-H); 6.53 s, 2 H (Ar-H); 6.37 d, 3J = 8.2, 1 H
(Ar-H); 5.42 br s, 1 H (OH); 5.24 and 4.87 each d, 2J = 11.3, 1 H (PhHCH); 4.48 br s, 2 H
(ArNH2); 3.83 m, 1 H (4′-H); 3.72 s, 6 H (2 × OCH3); 3.45 s, 2 H (ArCH2N); 2.90–2.78,
2.24–2.10 and 1.98–1.84 each m, 2 H; 1.87 s, 3 H (CH3); 1.66–1.48 m, 2 H. 13C NMR
(75 MHz, CDCl3): 175.6, 158.3, 157.1, 153.7, 142.3, 138.3, 134.4, 134.0, 133.0, 129.8, 129.2,
128.1, 128.0, 113.6, 107.2, 106.2, 77.3, 73.9, 64.7, 56.4, 52.8, 46.7, 32.1, 32.0, 28.2. MS-ES+:
579 (17) [M•+ + 23], 577 (27), 557 (69), 555 (100). For C29H36N4O535Cl (M•+ + H) calculated:
555.2369, found: 555.2370.
N-{1-[(6-Aminopyridin-2-yl)methyl]piperidin-4-yl}-2-{2-[(3-chloro-2,6-dimethoxyphenoxy)methyl]-
phenyl}-2-hydroxypropanamide (6e) (33 mg, 22%): a colourless oil, RF 0.40 (10% MeOH/
CH2Cl2). IR (film): 3352, 1659, 1651, 1619, 1580, 1513, 1464, 1092, 1009. 1H NMR
(300 MHz, CDCl3): 7.64 d, 3J = 7.6, 1 H (Ar-H); 7.42–7.34 and 7.32–7.22 each m, 2 H (Ar-H);
7.18 d, 3J = 8.2, 1 H (NH); 7.08 d, 3J = 9.1, 1 H (Ar-H); 6.70 d, 3J = 7.3, 1 H (Ar-H); 6.59 d,
3J = 9.1, 1 H (Ar-H); 6.38 d, 3J = 8.2, 1 H (Ar-H); 5.31 br s, 1 H (OH); 5.30 and 5.02 each d,
2J = 11.3, 1 H (PhHCH); 4.52 br s, 2 H (ArNH2); 3.83 m, 1 H (4-H); 3.84 and 3.72 each s, 3 H
(OCH3); 3.46 s, 2 H (ArCH2N); 2.84 m, 2 H; 2.27–2.13 and 1.98–1.82 each m, 2 H; 1.89 s,
3 H (CH3); 1.68–1.47 m, 2 H. 13C NMR (75 MHz, CDCl3): 175.5, 158.3, 156.9, 152.6, 150.3,
142.2, 141.2, 138.4, 134.4, 132.8, 129.3, 128.4, 128.0, 125.0, 120.5, 113.6, 108.3, 107.3,
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796
Broadley, Davies, Escargueil, Lee, Penson, Thomas:
77.3, 74.5, 64.6, 61.4, 56.4, 52.7, 46.6, 32.1, 31.9, 28.1. MS-ES+: 579 (2) [M•+ + 23], 577 (6),
557 (72), 555 (100). For C29H36N4O535Cl (M•+ + H) calculated: 555.2369, found: 555.2374.
Dimethyl 4-[(1-tert-Butoxycarbonylpiperidin-4-yl)methyl]pyridine-2,6-dicarboxylate (19)
9-Bicycloboranonane (1.67 ml, 0.5
M in THF, 0.84 mmol, 1.7 eq.) was added to the
4-methylenepiperidine 15 (100 mg, 0.51 mmol, 1.1 eq.) in THF (3.3 ml) and the solution
heated under reflux for 3 h. After cooling to room temperature, water (0.10 ml), DMF
(1.04 ml), K2CO3 (293 mg, 1.38 mmol, 3.0 eq.) and the bromide 18 (126 mg, 0.46 mmol,
1.0 eq.) were added and the resulting mixture degassed under a stream of N2 for 15 min.
Pd(dppf)Cl2·CH2Cl2 (19 mg, 0.02 mmol, 5 mole %) was added and the resulting mixture was
stirred for 10 min. Water (20 ml) was added and the mixture extracted with EtOAc (3 ×
20 ml). The organic extracts were washed with brine, dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue (25→100% Et2O/petrol) gave the title com-
pound 19 (177 mg, 89%) as a white solid, RF 0.32 (Et2O). 1H NMR (300 MHz, CDCl3): 8.11 s,
2 H (Ar-H); 4.10 m, 2 H; 4.03 s, 6 H (2 × CO2CH3); 2.71 d, 3J = 7.2, 2 H (4-CH2); 2.63 m,
2 H; 1.80 m, 1 H (4′-H); 1.59 m, 2 H; 1.45 s, 9 H [C(CH3)3]; 1.30–1.11 m, 2 H. 13C NMR
(75 MHz, CDCl3): 165.5, 155.0, 152.7, 148.47, 128.9, 79.7, 53.5, 43.9, 42.6, 37.6, 32.0, 28.7.
MS-ES+: 393 (65) [M•+ + 1], 216 (30), 177 (12), 160 (48), 116 (100).
Dimethyl 4-{[1-(2-Nitrobenzenesulfonyl)piperidin-4-yl]methyl}pyridine-
2,6-dicarboxylate (21)
The tert-butyloxycarbonylamine 19 (251 mg, 0.64 mmol) was stirred in CH2Cl2 (4.2 ml) and
trifluoroacetic acid (2.1 ml) for 3 h at ambient temperature. The reaction mixture was con-
centrated under reduced pressure and the residue was washed with saturated aqueous so-
dium bicarbonate (20 ml) and CH2Cl2 (3 × 20 ml). The organic extracts were wash with
brine, dried (MgSO4) and concentrated under reduced pressure to give the amine 20. This
was dissolved in CH2Cl2 (8 ml), and NsCl (170 mg, 0.77 mmol, 1.2 eq.), Et3N (133 µm3,
0.96 mmol, 1.5 eq.) and DMAP (1.6 mg, 2 mole %) were added. The mixture was stirred for
16 h at ambient temperature and water (20 ml) and CH2Cl2 (20 ml) were added. The aque-
ous phase was washed with CH2Cl2 (3 × 20 ml) and the organic extracts were washed with
brine, dried (MgSO4) and concentrated under reduced pressure. Chromatography of the resi-
due (0→10% MeOH/Et2O) gave the title compound 21 (183 mg, 60%) as a white foam, RF
0.09 (Et2O). IR (film): 3091, 1727, 1601, 1549, 1443, 1367, 1250, 1217, 1163, 1126, 998,
940, 913, 852, 781, 748, 734. 1H NMR (300 MHz, CDCl3): 8.12 s, 2 H (Ar-H); 8.00 m, 1 H
(Ar-H); 7.72 m, 2 H (Ar-H); 7.65 m, 1 H (Ar-H); 4.05 s, 6 H (2 × CO2CH3); 3.88 m, 2 H;
2.81–2.68 m, 4 H; 1.90–1.60 m, 3 H; 1.50–1.32 m, 2 H. 13C NMR (75 MHz, CDCl3): 165.5,
152.2, 148.6, 133.9, 131.9, 131.8, 131.2, 128.8, 124.4, 53.5, 46.2, 42.1, 36.8, 31.6. MS-ES+:
500 (100) [M•+ + 23], 495 (23). For C21H23N3O8Na (M•+ + Na) calculated: 500.1098, found:
500.1101.
Alternatively, 9-bicycloboranonane (0.5 M in THF, 10.63 ml, 5.31 mmol, 1.7 eq.) was
added to the 4-methylenepiperidine 29 (1.00 g, 3.54 mmol, 1.1 eq.) in THF (3.3 ml) and the
solution was heated under reflux for 1 h. After cooling to room temperature, water
(0.70 ml), DMF (7.28 ml), K2CO3 (1.34 g, 9.66 mmol, 3.0 eq.) and bromide 18 (883 mg,
42 mmol) were added and the resulting mixture degassed under a stream of N2 for 15 min.
Pd(dppf)Cl2·CH2Cl2 (131 mg, 0.16 mmol, 5 mole %) was added and the resulting mixture
was stirred for 30 min. Water (70 ml) was added and the mixture extracted with EtOAc (3 ×
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Synthesis of Antagonists of Muscarinic (M3) Receptors
797
70 ml). The organic extracts were washed with brine, dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue (0→10% MeOH/Et2O) gave the product 21
(1.37 g, 89%) as a white foam.
6-Methoxycarbonyl-4-{[1-(2-nitrobenzenesulfonyl)piperidin-4-yl]methyl}pyridine-
2-carboxylic Acid (22)
Diester 21 (727 mg, 1.52 mmol, 1 eq.) in CH2Cl2 (17 ml) and MeOH (17 ml) was cooled to
0 °C and KOH pellets (86 mg, 1.52 mmol, 1 eq.) were added. The reaction mixture was
stirred at ambient temperature for 16 h then concentrated under reduced pressure and the
residue was suspended in ethyl acetate. After filtration, the precipitated potassium salt was
dissolved in water (20 ml) and the solution acidified to pH 3 with concentrated aqueous
hydrogen chloride. The solution was extracted with CH2Cl2 (3 × 20 ml) and the organic
extracts were washed with water, brine and dried (MgSO4). Concentration under reduced
pressure gave the title compound 22 (642 mg, 91%) as a white foam, RF 0.20 (10%
MeOH/CH2Cl2). IR (film): 3469, 1729, 1603, 1544, 1438, 1373, 1349, 1244, 1165, 732.
1H NMR (300 MHz, CDCl3): 8.21 and 8.14 each d, 4J = 1.5, 1 H (Ar-H); 8.00 m, 1 H (Ar-H);
7.79–7.69 m, 2 H (Ar-H); 7.65 m, 1 H (Ar-H); 4.06 s, 3 H (CO2CH3); 3.87 m, 2 H;
2.81–2.69 m, 4 H; 1.75 m, 1 H (4′-H); 1.73 m, 2 H; 1.50–1.34 m, 2 H. 13C NMR (75 MHz,
CDCl3): 164.7, 164.2, 153.8, 148.5, 147.0, 134.0, 131.9, 131.8, 131.1, 129.7, 128.9, 127.6,
124.4, 53.5, 46.1, 42.2, 36.8, 31.6. MS-ES+: 464 (12) [M•+ + 1], 454 (100), 445 (74). For
C
20H22N3O8S (M•+ + H) calculated: 464.1122, found: 464.1124.
Methyl 6-tert-Butoxycarbonylamino-4-{[1-(2-nitrobenzenesulfonyl)piperidin-4-yl]methyl}-
pyridine-2-carboxylate (23)
Diphenylphosphoryl azide (510 ml, 2.37 mmol, 1.2 eq.) was added at room temperature to
the acid 22 (914 mg, 1.97 mmol, 1.0 eq.) and Et3N (0.55 ml, 3.94 mmol, 2.0 eq.) in toluene
(11.6 ml) and t-BuOH (1.2 ml) and the mixture heated at 100 °C for 16 h. After being cooled
to room temperature, the reaction mixture was diluted with EtOAc (50 ml). The organic
layer was washed with saturated aqueous sodium hydrogen carbonate (50 ml) and brine,
dried (MgSO4), and concentrated under reduced pressure. Chromatography of the residue
(50→90% Et2O/petrol) gave the title compound 23 (695 mg, 66%) as a white foam, RF 0.46
(Et2O). IR (film): 3219, 1725, 1610, 1571, 1546, 1449, 1432, 1369, 1247, 1161, 912, 733.
1H NMR (300 MHz, CDCl3): 7.99 and 7.72 each m, 2 H (Ar-H); 7.66–7.59 m, 3 H (Ar-H and
ArNH); 4.00 s, 3 H (CO2CH3); 3.92–3.82 m, 2 H; 2.80–2.68 m, 2 H; 2.64 d, 3J = 6.7, 2 H
(4-CH2); 1.78–1.68 m, 3 H; 1.53 s, 9 H [C(CH3)3]; 1.48–1.28 m, 2 H. 13C NMR (75 MHz,
CDCl3): 165.7, 152.8, 152.6, 152.4, 148.6, 146.1, 133.9, 131.9, 131.7, 131.1, 124.3, 121.2,
116.4, 81.6, 53.2, 46.2, 42.4, 36.8, 31.7, 28.4. MS-ES+: 557 (100) [M•+ + 23], 535 (1). For
C
24H30N4O8SNa (M•+ + Na) calculated: 557.1677, found: 557.1687.
[6-tert-Butoxycarbonylamino-4-{[1-(2-nitrobenzenesulfonyl)piperidin-4-yl]methyl}-
pyridin-2-yl]methanol (24)
Sodium borohydride (150 mg, 3.96 mmol, 5 eq.) was added to the ester 23 (423 mg,
0.79 mmol, 1 eq.) and CaCl2 (176 mg, 1.58 mmol, 2 eq.) in EtOH (9 ml). The mixture was
stirred at 0 °C for 2 h then poured into water (20 ml) and extracted with EtOAc (3 × 20 ml).
The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give the
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798
Broadley, Davies, Escargueil, Lee, Penson, Thomas:
title compound 24 (358 mg, 97%) as a white foam, RF 0.12 (Et2O). IR (film): 3364, 3235,
2360, 1725, 1614, 1570, 1545, 1436, 1370, 1232, 1161, 1097, 732. 1H NMR (300 MHz,
CDCl3): 7.99 m, 1 H (Ar-H); 7.72 m, 2 H (Ar-H); 7.68 s, 1 H (Ar-H); 7.63 m, 1 H (Ar-H);
7.48 br s, 1 H (ArNH); 6.72 s, 1 H (Ar-H); 4.65 s, 2 H (CH2O); 3.86 m, 2 H; 2.73 m, 2 H;
2.56 d, 3J = 6.6, 2 H (4′-CH2); 1.79–1.67 m, 3 H; 1.55 s, 9 H [C(CH3)3]; 1.45–1.27 m, 2 H.
13C NMR (75 MHz, CDCl3): 157.6, 152.7, 152.5, 151.5, 148.6, 133.9, 131.9, 131.8, 131.1,
124.3, 116.2, 111.1, 81.6, 64.0, 46.3, 42.6, 36.8, 31.8, 28.5. MS-ES+: 1035 (20), 529 (100)
[M•+ + 23], 507 (1). For C23H30N4O7SNa (M•+ + Na) calculated: 529.1727, found: 529.1730.
4-tert-Butoxycarbonylamino-1-[6-tert-butoxycarbonylamino-4-([{[1-(2-nitrobenzene-
sulfonyl)piperidin-4-yl]methyl}pyridin-2-yl]methyl)piperidine (25)
Methanesulfonyl chloride (0.27 ml, 3.48 mmol, 3.0 eq.) was added to the alcohol 24
(586 mg, 1.16 mmol, 1.0 eq.) and Et3N (0.50 ml, 3.59 mmol, 3.1 eq.) in EtOAc (6.70 ml) and
the mixture stirred at 0 °C for 1 h. Saturated aqueous sodium hydrogen carbonate (50 ml)
was added and the organic layer washed with water and brine, dried (MgSO4), and concen-
trated under reduced pressure to leave the mesylate (682 mg) as a white foam. This was
taken up in CH3CN (7.8 ml) and K2CO3 (497 mg, 3.59 mmol, 3.1 eq.) and 4-tert-butoxy-
carbonylaminopiperidine (255 mg, 1.27 mmol, 1.1 eq.) were added. The mixture was stirred
at room temperature for 16 h then poured into water (50 ml) and extracted with CH2Cl2
(3 × 50 ml). The organic extracts were dried (MgSO4) and concentrated under reduced pres-
sure. Chromatography of the residue (0→5% MeOH/Et2O; 1% Et3N) gave the title compound
25 (682 mg, 85%) as a white foam, RF 0.20 (Et2O). IR (film): 3357, 3209, 1713, 1611, 1569,
1547, 1438, 1368, 1234, 1163, 1047, 937, 736. 1H NMR (300 MHz, CDCl3): 7.99 m, 1 H
(Ar-H); 7.72 and 7.63 each m, 2 H (Ar-H); 7.34 s, 1 H (ArNH); 6.80 s, 1 H (Ar-H); 4.50 br d,
3J = 6.6, 1 H (NH); 3.86 m, 2 H; 3.50 m, 1 H (4-H); 3.47 s, 2 H (2′-CH2); 2.87–2.75 and
2.78–2.67 each m, 2 H; 2.55 d, 3J = 6.7, 2 H (4′-CH2); 2.15 m, 2 H; 1.93 m, 2 H;
1.78–1.66 m, 3 H; 1.57–1.47 m, 2 H; 1.53 and 1.47 each s, 9 H [C(CH3)3]; 1.50–1.25 m, 2 H.
13C NMR (75 MHz, CDCl3): 157.0, 155.5, 152.7, 151.9, 151.8, 148.6, 133.8, 131.9, 131.7,
131.2, 124.3, 119.4, 110.8, 81.1, 79.5, 64.5, 52.9, 47.9, 46.3, 42.5, 36.9, 32.7, 31.8, 28.7,
28.6. MS-ES+: 711 (100) [M•+ + 23], 689 (21). For C33H49N6O8S (M•+ + H) calculated:
689.3327, found: 689.3339.
4-tert-Butoxycarbonylamino-1-[6-tert-butoxycarbonylamino-4-{[(piperidin-4-yl)methyl]-
pyridin-2-yl}methyl]piperidine (26)
Benzenethiol (0.17 ml, 1.76 mmol, 3 eq.) was added to a suspension of the nosylate 25
(394 mg, 0.58 mmol, 1 eq.) and K2CO3 (316 mg, 2.29 mmol, 4 eq.) in acetonitrile (10 ml).
The mixture was stirred at ambient temperature for 16 h then concentrated under reduced
pressure. The residue was extracted with water (20 ml) and CH2Cl2 (20 ml) and the aqueous
phase extracted with CH2Cl2 (3 × 20 ml). The organic extracts were washed with water and
brine, dried (MgSO4), and concentrated under reduced pressure. Chromatography of the resi-
due (0→30% MeOH/CH2Cl2; 1% Et3N) gave the title compound 26 (276 mg, 96%) as a pale
foam, RF 0.23 (30% MeOH/CH2Cl2). IR (film): 3314, 1712, 1611, 1568, 1520, 1435, 1391,
1367, 1288, 1237, 1163, 1046, 733. 1H NMR (300 MHz, CDCl3): 7.65 d, 4J = 1.0, 1 H (Ar-H);
7.31 s, 1 H (ArNH); 6.82 d, 4J = 1.2, 1 H (Ar-H); 4.49 br d, 3J = 6.6, 1 H (NH); 3.50 m, 1 H
(4-H); 3.49 s, 2 H (2′-CH2); 3.11 m, 2 H; 2.83 m, 2 H; 2.60 m, 2 H; 2.54 d, 3J = 7.0, 2 H
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Synthesis of Antagonists of Muscarinic (M3) Receptors
799
(4′-CH2); 2.16 m, 2 H; 1.99–1.86 m, 2 H; 1.78–1.66 m, 3 H; 1.57–1.47 m, 2 H; 1.55 and 1.48
each s, 9 H [C(CH3)3]; 1.38–1.16 m, 2 H. 13C NMR (75 MHz, CDCl3): 156.8, 155.5, 152.7,
152.3, 151.8, 119.5, 111.0, 81.0, 79.5, 64.5, 52.9, 48.0, 46.0, 43.4, 37.4, 32.7, 32.5, 28.7,
28.5. MS-ES+: 526 (8) [M•+ + 23], 504 (100). For C27H46N5O4 (M•+ + H) calculated: 504.3544,
found: 504.3535.
4-tert-Butoxycarbonylamino-1-[{6-tert-butoxycarbonylamino-4-[(1-propylpiperidin-4-yl)-
methyl]pyridin-2-yl}methyl]piperidine (27)
Sodium triacetoxyborohydride (348 mg, 1.64 mmol, 3 eq.) was added to the amine 26
(276 mg, 0.55 mmol, 1.0 eq.), propionaldehyde (395 µm3, 5.48 mmol, 10.0 eq.), and acetic
acid (35 µm3, 0.60 mmol, 1.1 eq.) in CH2Cl2 (5.5 ml) and the mixture stirred for 16 h. Aque-
ous sodium hydroxide (20 ml, 1 M) was added and the mixture was extracted with CH2Cl2
(4 × 20 ml). The organic extracts were wash with water and brine, dried (MgSO4) and
concentrated under reduced pressure. Chromatography of the residue (0→10% MeOH/Et2O;
1% Et3N) gave the title compound 27 (280 mg, 94%) as a colourless oil, RF 0.37 (30%
MeOH/CH2Cl2). IR (film): 3358, 1713, 1611, 1568, 1519, 1435, 1367, 1288, 1235, 1162,
1046, 733. 1H NMR (300 MHz, CDCl3): 7.64 s, 1 H (Ar-H); 7.33 s, 1 H (ArNH); 6.82 s, 1 H
(Ar-H); 4.49 br d, 3J = 6.8, 1 H (NH); 3.50 m, 1 H (4-H); 3.48 s, 2 H (2′-CH2); 2.99 m, 2 H;
2.83 m, 2 H; 2.55 d, 3J = 6.3, 2 H (4′-CH2); 2.35 m, 2 H (1′′-CH2); 2.16 m, 2 H; 2.06–1.88 m,
4 H; 1.73–1.32 m, 9 H; 1.54 and 1.48 each s, 9 H [C(CH3)3]; 0.93 t, 3J = 7.5, 3 H
(NCH2CH2CH3). 13C NMR (75 MHz, CDCl3): 156.6, 155.5, 152.9, 152.7, 151.7, 119.6, 111.0,
80.9, 79.5, 64.5, 61.4, 54.0, 52.8, 47.9, 43.1, 37.5, 32.7, 32.4, 28.7, 28.5, 20.4, 12.3. MS-ES+:
568 (19) [M•+ + 23], 546 (100). For C30H52N5O4 (M•+ + H) calculated: 546.4014, found:
546.4020.
4-Amino-1-[{6-amino-4-[(1-propylpiperidin-4-yl)methyl]pyridin-2-yl}methyl]piperidine (28)
The bis-tert-butoxycarbonyl amine 27 (280 mg, 0.51 mmol) in methanolic hydrogen chlo-
ride (5.8 ml, 10%) was stirred at room temperature for 24 h. Concentration under reduced
pressure gave the title compound 28 (254 mg, 100%) as a pale highly hygroscopic foam,
m.p. > 350 °C (decomposition). IR (film): 3662, 3332, 1665, 1453, 1395, 1230, 1049, 943,
870. 1H NMR (500 MHz, CD3OD): 7.12 and 6.89 each s, 1 H (Ar-H); 4.46 s, 2 H (2′-CH2);
3.65 m, 2 H; 3.47 m, 3 H; 3.33 m, 2 H; 2.93 m, 4 H; 2.62 d, 3J = 6.0, 2 H (4′-CH2); 2.25 m,
2 H; 2.07 m, 3 H; 1.86 m, 2 H; 1.69 m, 2 H (NCH2CH2CH3); 1.55 m, 2 H; 0.92 t, 3J = 7.3,
3 H (NCH2CH2CH3). 13C NMR (75 MHz, CD3OD): 158.1, 155.1, 135.8, 118.4, 114.7, 58.7,
55.5, 52.6, 51.0, 45.3, 41.1, 33.6, 29.1, 27.1, 17.5, 10.6. MS-ES+: 346 (100). For C20H36N5
(M•+ – H3Cl4) calculated: 346.2965, found: 346.2969.
N-(1-[{6-Amino-4-[(1-propylpiperidin-4-yl)methyl]pyridin-2-yl}methyl]piperidin-4-yl)-
2-cyclopentyl-2-hydroxy-2-phenylacetamide (7a)
The acid 30 (37 mg, 0.17 mmol, 1.3 eq.), amine hydrochloride 28 (64 mg, 0.13 mmol,
1.0 eq.), HOBt hydrate (35 mg, 0.26 mmol, 2.0 eq.) and Et3N (0.15 ml, 1.04 mmol, 10.0 eq.)
in CHCl3 (3.4 ml) were stirred at ambient temperature for 30 min then EDCI hydrochloride
salt (40 mg, 0.21 mmol, 1.6 eq.) was added. The reaction mixture was allowed to stir for
16 h at ambient temperature before EtOAc (15 ml) was added. The organic layer was washed
with saturated aqueous sodium bicarbonate (15 ml) and the aqueous phase was extracted
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800
Broadley, Davies, Escargueil, Lee, Penson, Thomas:
with EtOAc (3 × 15 ml). The organic extracts were washed with brine, dried (Na2SO4) and
concentrated under reduced pressure. Chromatography of the residue (0→20% MeOH/Et2O;
1% Et3N) gave the title compound 7a (38 mg, 53%) as
a pale oil, RF 0.11 (30%
MeOH/CH2Cl2). IR (film): 3393, 1652, 1621, 1567, 1516, 1447, 1376, 1335, 1287, 910, 732.
1H NMR (500 MHz, CDCl3): 7.53 d, 3J = 7.4, 2 H (Ar-H); 7.28–7.16 m, 3 H (Ar-H); 6.40 s, 1 H
(Ar-H); 6.32 d, 3J = 8.2, 1 H (CONH); 6.07 s, 1 H, s (Ar-H); 4.37 br s, 2 H (NH2); 3.64 m, 1 H
(4′-H); 3.31 s, 2 H (2′′-CH2); 3.24 m, 2 H; 3.00–2.86 m, 3 H; 2.72–2.62, 2.32–2.22, 2.10–2.00,
1.93–1.80 and 1.79–1.68 each m, 2 H; 1.66–1.33 m, 14 H; 1.31–1.20 m, 3 H; 0.80 t, 3J = 7.4,
3 H (NCH2CH2CH3). 13C NMR (75 MHz, CDCl3): 173.6, 158.4, 156.7, 151.9, 143.0, 128.6,
127.7, 125.8, 114.9, 107.7, 79.8, 64.6, 53.8, 52.6, 46.7, 42.6, 37.0, 32.1, 31.9, 27.0, 26.9,
26.4, 26.2, 12.2. MS-CI: 570 (19) [M•+ + 23], 548 (100). For C33H50N5O2 (M•+ + H) calcu-
lated: 548.3959, found: 548.3966.
4-Methylene-1-(2-nitrophenylsulfonyl)piperidine (29)
Butyllithium (1.6 M in hexanes, 14.71 ml, 23.74 mmol, 1.5 eq.) was added dropwise to
a suspension of methyltriphenylphosphonium bromide (8.48 g, 23.74 mmol, 1.5 eq.) in
THF (100 ml) at 25 °C. After 30 min, 1-(2-nitrophenylsulfonyl)-4-oxopiperidine (4.50 g,
15.82 mmol, 1.0 eq.) in THF (30 ml) was added and the mixture stirred for 16 h. MeOH was
added and the mixture concentrated under reduced pressure. Chromatography of the resi-
due (10→100% Et2O/petrol) gave the title compound 29 (2.68 g, 60%) as a yellow solid,
m.p. 143–145 °C, RF 0.64 (Et2O). IR (film): 1655, 1588, 1555, 1373, 1344, 1168, 1152, 931,
898, 789, 747, 732. 1H NMR (300 MHz, CDCl3): 8.03 m, 1 H (Ar-H); 7.78–7.68 m, 2 H
(Ar-H); 7.64 m, 1 H (Ar-H); 4.81 s, 2 H (4-CH2); 3.37 and 2.35 each t, 3J = 5.8, 4 H (2 × CH2).
13C NMR (75 MHz, CDCl3): 143.4, 133.9, 132.2, 131.8, 131.1, 124.4, 110.8, 47.8, 34.5.
MS-CI: 300 (16) [M•+ + 18], 283 (9), 253 (100). For C12H15N2O4S (M•+ + H) calculated:
283.0747, found: 283.0742.
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