Regioselective synthesis of an imidazo[4,5-c]pyridine through selective acylation of 3,4-diaminopyridine: Synthesis of CP-885,316

Article abstract of DOI:10.1021/op0502250

CP-885,316 (1), an imidazo[4,5-c]pyridine, 4, was prepared from 3,4-diaminopyridine (9). Two routes were demonstrated using the regioselective introduction of either an acetamide at the 3-position or a tert-butylcarbamate at the 4-position.

Full text of DOI:10.1021/op0502250

Organic Process Research & Development 2006, 10, 257−261
Regioselective Synthesis of an Imidazo[4,5-c]pyridine through Selective
Acylation of 3,4-Diaminopyridine: Synthesis of CP-885,316
Ste´phane Caron,* Nga M. Do, Ruth E. McDermott, and S. Bahmanyar†
Chemical R&D, Pfizer Global R&D, MS-8118D/4002, Groton, Connecticut 06340, U.S.A.
Scheme 1. Potential retrosynthesis of 1
Abstract:
CP-885,316 (1), an imidazo[4,5-c]pyridine, 4, was prepared from
3,4-diaminopyridine (9). Two routes were demonstrated using
the regioselective introduction of either an acetamide at the
3-position or a tert-butylcarbamate at the 4-position.
The benzimidazole1-3 and imidazopyridine4-6 moieties are
important pharmacophores which have proven to be useful
for a number of biologically relevant targets. The preparation
of these compounds is usually straightforward, and a number
of synthetic methods are already available.7-11 We were
recently asked to identify an efficient synthesis of imidazo-
[4,5-c]pyridine (1) which would be amenable to its prepara-
tion on a multikilogram scale. Two retrosyntheses for the
final assembly of 1 involve either the reaction of the
diaminopyridine 2 with a carboxylic acid derivative 3 (Path
A) or the alkylation of imidazo[4,5-c]pyridine, 4, with a
thiazoloimidazole 5 (Path B) as depicted in Scheme 1. The
latter was selected as our last bond-forming step since it
allowed the use of two key intermediates with anticipated
superior stability and handling properties.
Scheme 2. Synthesis of thiazoloimidazole 5
Herein, we report our efforts in the identification
of a scalable route for the preparation of CP-885,316 (1)
which led to the discovery of an unanticipated reversal
in the regioselectivity in the acylation of 3,4-diamino-
pyridine (9) with either acetyl chloride or di-tert-butyl-
dicarbonate.
Discussion
The synthesis of thiazoloimidazole 5 was accomplished
readily by a simple modification of a procedure recently
identified by Liras and co-workers.12 Lithiation at the
2-position of the sulfonamide-protected imidazole 613 and
reaction with thioisocyanate 7 led to formation of thioamide
8 which was not isolated and was cyclized using sulfuric
acid in toluene to afford the desired product in 60% overall
yield (Scheme 2).
The preparation of imidazo[4,5-c]pyridine, 4, proved to
be a more difficult task. While the obvious starting material,
3,4-diaminopyridine (9), is commercially available,14,15 con-
ditions for the regioselective introduction of the ethyl side
* To whom correspondence should be addressed. E-mail: stephane.caron@
pfizer.com.
† Chemical R&D, Pfizer Global R&D-La Jolla, 10578 Science Center Drive,
San Diego, California 92121.
(1) Fellenius, E.; Berglindh, T.; Sachs, G.; Olbe, L.; Elander, B.; Sjostrand, S.
E.; Wallmark, B. Nature 1981, 290, 159-161.
(2) Emery, V. C.; Hassan-Walker, A. F. Drugs 2002, 62, 1853-1858.
(3) Sondhi, S. M.; Singhal, N.; Johar, M.; Reddy, B. S. N.; Lown, J. W. Curr.
Med. Chem. 2002, 9, 1045-1074.
(4) Hodgkin, E. E.; Miller, A.; Whittaker, M. Bioorg. Med. Chem. Lett. 1992,
2, 597-602.
(5) Temple, J. C.; Rose, J. D.; Comber, R. N.; Rener, G. A. J. Med. Chem.
1987, 30, 1746-1751.
(6) Cooper, K.; Fray, M. J.; Parry, M. J.; Richardson, K.; Steele, J. J. Med.
Chem. 1992, 35, 3115-3129.
(7) Preston, P. N. Chem. ReV. 1974, 74, 279-314.
(8) Singh, M. P.; Sasmal, S.; Lu, W.; Chatterjee, M. N. Synthesis 2000, 1380-
1390.
(12) Liras, S. Manuscript in preparation.
(9) Katner, A. S.; Brown, R. F. J. Heterocycl. Chem. 1990, 27, 563-566.
(10) Mederski, W. W. K. R.; Pachler, K. G. R. Tetrahedron 1992, 48, 10549-
10558.
(13) Chadwick, D. J.; Ngochindo, R. I. J. Chem. Soc., Perkin Trans. 1: Org.
Bio-Org. Chem. (1972-1999) 1984, 481-486.
(14) Berner, H.; Reinshagen, H. J. Med. Chem. 1973, 16, 1296-1298.
(15) Chatterjee, S. K.; Jain, P. C.; Anand, N. Indian J. Chem. 1965, 3, 138-
139.
(11) Middleton, R. W.; Wibberley, D. G. J. Heterocycl. Chem. 1980, 17, 1757-
1760.
10.1021/op0502250 CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/31/2006
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Scheme 3. Synthesis of imidazo[4,5-c]pyridine, 4, by
selective acylation at the 3-position
Figure 1. HOMO maps generated for 3,4-diaminopyridine.
The darker the blue contour, the larger the HOMO coefficient
at that site.
Scheme 4. Proposed mechanism for the selective acylation
at the 4-position with tert-butyl dicarbonate
chain at the 3-position needed to be identified. Reductive
amination with acetaldehyde was first attempted but led to
a complex mixture of several products. The second strategy
evaluated was the selective acylation of the 3-amino position.
We reasoned that the 4-position of the pyridine should be
deactivated, thus leaving the 3-position more nucleophilic.16,17
Furthermore, HBTU-mediated coupling of a carboxylic acid
with 9 as been reported.18 Upon treatment of 9 with one
equivalent of acetyl chloride in dimethylacetamide (DMAC),
the hydrochloride salt of the 3-acetylated pyridine 10 was
generated and precipitated from the reaction mixture in 76%
yield. This result is in contrast with what has been reported
with a substoichiometric amount of an acid chloride19 as well
as a benzoyl chloride derivative.20 The choice of solvent for
this reaction proved to be a key contributing factor since it
precipitated the desired product and kept small amounts of
the 4-acetylated and 3,4-diacetylated products in solution.
Amide 10 was reduced to its ethyl derivative 2 with LiAlH4
in THF to provide a 60% yield after crystallization from
toluene.21 Finally, the imidazole was generated in a two-
step process by treatment of dianiline 2 with chloroacetic
anhydride in EtOAc followed by reaction with HCl in
2-propanol to complete the dehydration and salt formation.
Imidazo[4,5-c]pyridine, 4, was isolated in 59% yield as its
hydrochloride salt after crystallization from 2-propanol as
shown in Scheme 3.
analysis24 confirmed that the N-3 nitrogen would be expected
to be more nucleophilic as shown in Figure 1.25
It is clear that the different regioselectivity obtained from
Boc2O is not the outcome of kinetic reactivity at the N-4
center but rather the outcome of a change in reaction
mechanism between the acid chloride and the dicarbonate.
One potential mechanism is depicted in Scheme 4. It is
probable that the acylation still proceeds at the 3-position to
provide intermediate 11. Zwitterion 12 could be generated
after deprotonation of the 4-amino position. The anilide can
then add to the carbonate to provide carbamate 13 and tert-
butylcarbonic acid which decomposes to CO2 and t-BuOH.
Alternatively, proton transfer could occur at the 3-position
which could be followed by nucleophilic attack by the amine
at the 4-position. When the reaction is conducted with an
anhydride such as acetic anhydride, acylation at the 3-posi-
tion was observed. This could be resulting from the fact that
the intermediate analogous to 11 contains an acetate which
is a better leaving group than a carbonate. Additionally, the
3-ethyl carbamate was prepared by reaction of 13 with ethyl
chloroformate and deprotection of the tert-butyl carbamate.
We have not observed migration of the ethyl carbamate to
the 4-position.
An alternative approach was identified when 9 was reacted
with tert-butyl dicarbonate in CH2Cl2. Unexpectedly, the
carbamate was regioselectively introduced at the 4-position
of the pyridine in 78% yield after crystallization from MTBE/
hexanes.22,23 The reversal of the regiochemical outcome
certainly came as a surprise to us. Frontier molecular orbital
(16) Buzas, A.; Canac, F.; Egnell, C.; Freon, P.; Champetier, G. C. R. Seances
Acad. Sci., Ser. C 1966, 262, 658-661.
(17) Matsui, T.; Nagano, M.; Tobitsuka, J.; Oyamada, K. Chem. Pharm. Bull.
1974, 22, 2118-2121.
(18) Burli, R. W.; Jones, P.; McMinn, D.; Le, Q.; Duan, J.-X.; Kaizerman, J.
A.; Difuntorum, S.; Moser, H. E. Bioorg. Med. Chem. Lett. 2004, 14, 1259-
1263.
(19) Sahli, S.; Frank, B.; Schweizer, W. B.; Diederich, F.; Blum-Kaelin, D.;
Aebi, J. D.; Boehm, H.-J.; Oefner, C.; Dale, G. E. HelV. Chim. Acta 2005,
88, 731-750.
With the 4-protected aminopyridine 13 in hand, introduc-
tion of the ethyl side chain at the 3-position through reductive
amination was now possible (Scheme 5). Indeed, the imine
was generated in ethanol with acetaldehyde and reduced with
NaBH4 at 0 °C to ethyl aniline 15. The crude solid thus
obtained could be converted directly to the desired imidazo-
[4,5-c]pyridine, 4, by condensation with chloroacetic anhy-
dride in the presence of a catalytic amount of TFA followed
(20) Barraclough, P.; Iyer, R.; Lindon, J. C.; Williams, J. M. Tetrahedron Lett.
1986, 27, 5997-6000.
(21) The regioselectivity was confirmed by nOe evaluation of the protons of
compound 2.
(22) Barraclough, P.; Collard, D.; Gillam, J.; King, W. R.; Smith, S. J. Chem.
Res. (M) 1996, 2316-2335.
(23) The regioselectivity was confirmed by nOe evaluation of the protons on
compound 15.
(24) Fukui, K. Acc. Chem. Res. 1971, 4, 57-64.
(25) HOMO maps were generated using Spartan, V2.0; Wavefunction, Inc:
Irvine, CA 92612. Details of the calculations can be found in Supporting
Information.
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Scheme 5. Synthesis of Imidazo[4,5-c]pyridine, 4, by
selective carbamate formation at the 4-position
temperature, and stirred overnight. The reaction mixture was
quenched with saturated NH4Cl solution (50 mL) and
extracted with EtOAc (50 mL). The organic phase was
washed with brine (50 mL), dried over Na2SO4, and
concentrated in vacuo to afford 1-dimethylsulfamoyl-1H-
imidazole-2-carbothioic acid (2,2-dimethoxy-ethyl)amide (8)
as a dark-brown oil. The crude material (15.55 g) was
dissolved in toluene (70 mL), and H2SO4 (20 mL) was added.
The resulting reaction mixture was heated to 100 °C and
stirred overnight. H2O (100 mL) was added, and the reaction
mixture was then cooled to room temperature. (Note: If
reaction was cooled prior to addition of H2O, the reaction
mixture solidified.) The layers were separated, and the
aqueous phase was basified with NH4OH (to pH 9). The
basified aq layer was extracted with EtOAc (2 × 100 mL).
The combined organic layers were washed with H2O (100
mL) and brine (100 mL), dried over Na2SO4, filtered, and
concentrated in vacuo to afford a brown, soft solid. The
material was triturated with MTBE (50 mL) and filtered to
afford isolated brown crystals of 2-(1H-imidazol-2-yl)thiazole
Scheme 6. Completion of the Synthesis of CP-885,316 (1)
1
by cyclization with hydrochloric acid in a mixture of i-PrOH
and i-PrOAc. This sequence provided 4 in 53% overall yield
from carbamate 13.
As shown in Scheme 6, completion of the synthesis was
achieved by alkylation of the HCl salt 4 with thiazoloimi-
dazole 5 in a i-PrOH/H2O mixture using KOH as the base
to afford 1 in 78% yield.
(5) (4.34 g, 60%). H NMR (400 MHz, d6-DMSO) δ 7.05
(s, 1), 7.27 (s, 1), 7.72 (d, 1, J ) 3.3 Hz), 7.89 (d, 1, J ) 3.3
Hz), 13.09 (br s, 1). 13C NMR (100 MHz, d6-DMSO) δ
119.71, 120.88, 130.40, 141.71, 143.88, 159.68. IR 3112,
1572, 1492, 1353, 1289, 1107, 937, 776, 731, 617 cm-1.
Anal. calcd for C6H5N3S: C, 47.66; H, 3.33; N, 27.79.
Found: C, 47.72; H, 3.02; N, 27.38.
In conclusion, an efficient, convergent synthesis of CP-
885,316 (1) was exemplified. Two routes to the key imidazo-
[4,5-c]pyridine, 4, were discovered, and conditions for the
selective acylation of either the 3- or 4-position of 3,4-
diaminopyridine were identified. While both synthetic routes
proved to be acceptable for scale-up, the second route
presented is preferable because of the higher throughput, the
avoidance of cryogenic conditions, and a more practical
reducing agent in NaBH4. Further evaluation of the reac-
tion mechanism which led to such regioselectivity is
underway.
N-(4-Amino-pyridin-3-yl)acetamide Hydrochloride (10).
To a solution of the 3,4-diaminopyridine (9) (10.53 g) in
dimethyl acetamide (100 mL) was slowly added acetyl
chloride (6.9 mL), keeping the temperature below 22 °C.
The reaction was stirred at room temperature for 16 h upon
which time cream solids had precipitated. The solids were
filtered, washed with CH2Cl2 (2 × 50 mL), and dried under
vacuum to give N-(4-amino-pyridin-3-yl)acetamide hydro-
1
chloride (10) (13.803 g, 76%). Mp ) 232-234 °C dec. H
NMR (400 MHz, d6-DMSO) δ 2.11 (s, 3), 6.9 (d, 1, J ) 6.6
Hz), 7.99 (d, 2, J ) 6.6 Hz), 8.52 (s, 1), 10.05 (s, 1), 13.56
(s, 1). 13C NMR (100 MHz, d6-DMSO) δ 24.01, 109.88,
120.83, 134.53, 137.09, 154.26. IR 3353, 3187, 2950, 2836,
1651, 1563, 1507, 1372, 1268, 1029, 817, 668, 577 cm-1.
Anal. calcd for C7H10ClN3O: C, 44.81; H, 5.37; N, 22.40.
Found: C, 44.80; H, 5.35; N, 22.18.
N-3-Ethyl-pyridine-3,4-diamine (2). To a slurry of N-(4-
amino-pyridin-3-yl)acetamide hydrochloride (10) (16.27 g)
in THF (165 mL) under N2 was added slowly, via an addition
funnel, a 1.0 M solution of LiAlH4 in THF (260 mL) while
maintaining an internal temperature below 25 °C. The
resulting reaction mixture was stirred at room temperature
for 16 h. The resulting reaction mixture was cooled to 0 °C
and was quenched by addition of solid Na2SO4‚10H2O (50
g). The resulting mixture was warmed to room temperature
and stirred for 2.5 h. The reaction mixture was filtered
through Celite and washed with EtOAc (2 × 50 mL). The
filtrate was concentrated in vacuo and crystallized from
toluene to give N-3-ethyl-pyridine-3,4-diamine (2) (7.10 g,
60%). MP ) 119-121 °C. 1H NMR (400 MHz, d6-DMSO)
δ 1.16 (t, 3, J ) 7.0 Hz), 3.01 (qd, 2, J ) 7.0 Hz, 5.4 Hz),
Experimental Details
Experimental Section. Unless otherwise noted, starting
materials were obtained from commercial suppliers and used
without further purification. Reactions were performed under
a dry N2 atmosphere and monitored using HPLC. Melting
points were measured in open capillary tubes and are
1
uncorrected. H NMR and 13C NMR were measured in
CDCl3 unless otherwise indicated. IR spectra were recorded
as thin films on NaCl plates unless otherwise indicated.
2-(1H-Imidazol-2-yl)thiazole (5). To a solution of imi-
dazole-1-sulfonic acid dimethylamide (6) (8.45 g, 48.2 mmol)
in THF (80 mL) at -78 °C under N2 was added n-BuLi
(21.2 mL of a 2.5 M solution in hexanes, 53.0 mmol) slowly,
while maintaining internal temperature below -65 °C. The
resulting reaction mixture was stirred at -78 °C for 1 h
before 2-isothiocyanato-1,1-dimethoxy-ethane (7) (6.50 mL,
48.2 mmol) was added, while maintaining internal temper-
ature below -65 °C. The resulting reaction mixture was
stirred at -78 °C for 2 h, allowed to warm to room
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3.34 (s, 1), 4.34 (t, 1, J ) 5.2), 5.38 (s, 1), 6.37 (d, 1, J )
5.0), 7.49 (d, 2, J ) 5.0). 13C NMR (100 MHz, d6-DMSO)
δ 15.16, 38.42, 108.41, 131.54, 135.96, 139.98, 142.28. IR
3358, 3243, 2971, 1588, 1519, 1427, 1333, 821, 740 cm-1.
Anal. calcd for C7H11N3: C, 61.29; H, 8.08; N, 30.63.
Found: C, 60.99; H, 8.05; N, 30.84.
to 0 °C, and NaBH4 (2.26 g, 59.74 mmol) was added in three
portions, keeping the temperature below 5 °C. The reaction
was allowed to warm to room temperature and was stirred
for 10 h. The mixture was cooled to 0 °C, and H2O (∼140
mL) was added dropwise, keeping the temperature below 5
°C. CH2Cl2 (100 mL) was added to the mixture followed by
a dropwise addition of a 10% aqueous citric acid until the
pH was neutral. The mixture was stirred for an additional
30 min, and CH2Cl2 (100 mL) was added. The layers were
separated, and the aqueous layer was extracted with CH2-
Cl2. The combined organic extracts were dried over Na2-
SO4, filtered, and concentrated in vacuo to give (3-
(ethylamino)pyridin-4-yl)carbamic acid tert-butyl ester (15)
(5.94 g of crude material, 89% purity, 93% yield). A small
portion of the material was purified by silica gel chroma-
tography (25% MeOH/MTBE) for characterization purposes.
1H NMR (400 MHz, d6-DMSO) δ 1.20 (t, 3, J ) 7.1), 1.46
(s, 9), 3.04-3.11 (m, 2), 5.15 (t, 1, J ) 4.5), 7.54 (d, 1, J )
5.2), 7.76 (d, 1, J ) 5.2), 7.83 (s, 1), 8.67 (s, 1). 13C NMR
(100 MHz, d6-DMSO) δ 14.89, 28.69, 38.30, 80.55, 115.04,
131.71, 133.53, 135.27, 138.84, 153.42. IR 2976, 1734, 1591,
1512, 1242, 1156 cm-1. Anal. calcd for C12H19N3O2:
C, 60.74; H, 8.07; N, 17.71. Found: C, 60.85; H, 7.95; N,
17.61.
2-Chloromethyl-3-ethyl-3H-imidazo[4,5-c]pyridine Hy-
drochloride (4). To a solution of chloroacetic anhydride
(10.30 g) in EtOAc (40 mL) was added in one portion N-3-
ethyl-pyridine-3,4-diamine (2) (2.01 g). After approximately
10 min, bright yellow solids had precipitated. The slurry was
stirred at room temperature under N2 for 16 h. The reaction
slurry was poured into 6 N NaOH (40 mL). The layers were
separated and the organic layer was washed again with 1 N
NaOH. The combined aqueous layers were back extracted
with additional EtOAc (20 mL). The combined organic
phases were then washed with brine, dried over Na2SO4, and
filtered. Concentrated HCl (2 mL) was added and the filtrate
was diluted with i-PrOH (30 mL). All solvents were removed
in vacuo. The resulting yellow soft solid was recrystallized
from i-PrOH to give 2-chloromethyl-3-ethyl-3H-imidazo[4,5-
c]pyridine (4) (2.02 g, 59%). MP ) 218-220 °C decomp.
1H NMR (400 MHz, d6-DMSO) δ 1.41 (t, 3, J ) 7.2), 4.56
(q, 2, J ) 7.2), 5.24 (s, 1), 8.21 (d, 1, J ) 6.6), 8.59 (d, 1,
J ) 6.6), 9.64 (s, 1). 13C NMR (100 MHz, d6-DMSO) δ
15.84, 36.34, 41.01, 117.36, 129.58, 133.20, 133.89, 151.66,
160.25. IR 3046, 2966, 2511, 1640, 1461, 1318, 848 cm-1.
Anal. calcd for C9H11Cl2N3: C, 46.57; H, 4.77; N, 18.10.
Found: C, 46.79; H, 4.71; N, 17.93.
2-Chloromethyl-3-ethyl-3H-imidazo[4,5-c]pyridine Hy-
drochloride (4). To a solution of chloroacetic anhydride
(9.80 g, 57.3 mmol) in CH2Cl2 (44 mL) was added (3-
(ethylamino)pyridin-4-yl)carbamic acid tert-butyl ester (15)
as a crude solid from the previous step (3.39 g, 14.3 mmol).
To the clear, bright-yellow solution was added TFA (0.21
mL, 2.7 mmol). The reaction was stirred at 30 °C for 3 days,
poured into a separatory funnel, and washed with 5 N NaOH
(32.5 mL). The layers were separated, and the organic extract
was washed with 1 N NaOH (22.5 mL) and brine (22.5 mL).
The organic extract was diluted with i-PrOH (22 mL) and
i-PrOAc (74 mL), and concentrated HCl (2.2 mL) was added.
The mixture was concentrated to an orange solid under
reduced pressure, and the product was crystallized from
i-PrOH to afford 2-chloromethyl-3-ethyl-3H-imidazo[4,5-c]-
pyridine hydrochloride (4) (1.78 g, 53%). This product was
(3-Amino-pyridin-4-yl)-carbamic acid tert-butyl ester
(13). To a suspension of 3,4-diaminopyridine (9) (8.35 g,
75 mmol) in CH2Cl2 (75 mL) was added dropwise di-tert-
butyl dicarbonate (16.73 g, 75 mmol) in CH2Cl2. The reaction
was allowed to stir at room temperature overnight. 1N HCl
(86.2 mL) was added dropwise and the organic layer was
separated. The aqueous layer was extracted with CH2Cl2 (75
mL) and the organic extracts were discarded. To the aqueous
layer was added CH2Cl2 (75 mL). The mixture was stirred
and K2CO3 (8.25 g) was added. The resulting pH of the
aqueous layer was 8-9. The layers were separated and the
aqueous layer was extracted with CH2Cl2 (2 × 75 mL). The
organic extracts were combined, dried over Na2SO4, filtered
and concentrated in vacuo. The product was crystallized from
MTBE and hexanes at 0 °C to provide (3-amino-pyridin-4-
yl)-carbamic acid tert-butyl ester (13) as a light-yellow solid
1
identical by H NMR to the product prepared by the acetyl
chloride approach.
3-Ethyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-3H-imi-
dazo[4,5-c]pyridine (CP-885,316) (1). To a solution of
2-(1H-imidazol-2-yl)-thiazole (5) (3.70 kg, 24.4 mol) in
i-PrOH (22 L) was added KOH (3337 g of 85% grade, 50.55
mol) in H2O (28 L). To the mixture was added 2-chloro-
methyl-3-ethyl-3H-imidazo[4,5-c]pyridine hydrochloride (4)-
(4.88 kg, 21.0 mol) in H2O (15.5 L); the reaction mixture
was stirred at room temperature for 16 h, cooled to 0 °C,
filtered, and washed with H2O (4 × 10 L). The solids were
1
(12.24 g, 78%). Mp ) 124-126 °C. H NMR (400 MHz,
d6-DMSO) δ 1.46 (s, 9), 5.08 (bs, 2), 7.50 (d, 1, J ) 5.2),
7.68 (d, 1, J ) 5.4), 7.91 (s, 1), 8.61 (s, 1). 13C NMR (100
MHz, d6-DMSO) δ 28.70, 80.47, 115.21, 131.28, 135.27,
138.41, 138.88, 153.37. IR 2978, 1716, 1588, 1515, 1249,
1154 cm-1. Anal. calcd for C10H15N3O2: C, 57.40; H, 7.23;
N, 20.08. Found: C, 57.50; H, 7.29; N, 20.06.
(3-Ethylamino-pyridin-4-yl)carbamic Acid tert-Butyl
Ester (15). To a solution of (3-amino-pyridin-4-yl)carbamic
acid tert-butyl ester (13) (5 g, 23.89 mmol) in EtOH (119
mL) at 0 °C was added dropwise acetaldehyde (3.35 mL,
58.72 mmol). The mixture was allowed to warm to room
temperature and stirred overnight. The mixture was cooled
1
dried in vacuo to give CP-885,316 (1) (5.16 kg, 79%). H
NMR (400 MHz, CD3OD) δ 1.41 (t, 3, J ) 7.5), 4.55 (q, 1,
J ) 7.5), 6.28 (s, 1), 7.19 (d, 1, J ) 1.2), 7.44 (d, 1, J )
1.2), 7.54 (d, 1, J ) 3.3), 7.55 (d, 1, J ) 1.6), 7.73 (d, 1, J
) 3.3), 8.29 (d, 1, J ) 5.4), 8.91 (s, 1). 13C NMR (125 MHz,
CD2Cl2) δ 15.50, 39.99, 44.22, 114.91, 120.49, 124.06,
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130.40, 133.49, 133.96, 140.64, 142.53, 143.57, 148.13,
152.67, 160.67. IR 3123, 3065, 2976, 1605, 1579, 1497,
1468, 1355, 1280, 1056, 994, 913, 816, 619 cm-1. Anal. calcd
for C15H14N6S: C, 58.05; H, 4.55; N, 27.08; S, 10.33.
Found: C, 58.07; H, 4.51; N, 27.03; S, 10.13.
Supporting Information Available
Cartesian coordinates and details about the calculations.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Received for review November 17, 2005.
OP0502250
Acknowledgment
We acknowledge Robert A. Singer for helpful discussions.
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