Research and development of an efficient process for the construction of the 2,4,5-substituted pyridines of NK-1 receptor antagonists

Article abstract of DOI:10.1021/op060128m

Roche has identified a 2,4,5-trisubstituted pyridine template for a new class of potent NK₁ receptor antagonists. Previous strategies for construction of the pyridine core of these NK-1 receptor antagonists involved functionalization of a 2,5-disubstituted pyridine. We now report on construction of the pyridine core from commodity components. Shestopalov reported the synthesis of trans-4′-aryl-5′-cyano-1′,2′,3′, 4′-tetrahydro-6′-hydroxy-2′-oxo-1,3′-bipyridinium inner salts from 1-(2-amino-2-oxo-ethyl)pyridinium chloride, aromatic aldehydes, and ethyl cyanoacetate in the presence of a base. Reaction of these salts with phosphorus oxychloride affords 4-aryl-3-cyano-2,6-dichloropyridines. These are efficiently converted to nicotinamide precursors of the Roche NK-1 receptor antagonists by regioselective displacement of one chlorine by an amine, hydrogenolysis of the remaining chlorine, and nitrile hydrolysis.

Full text of DOI:10.1021/op060128m

Organic Process Research & Development 2006, 10, 1157−1166
Research and Development of an Efficient Process for the Construction of the
2,4,5-Substituted Pyridines of NK-1 Receptor Antagonists
Peter J. Harrington,* Dave Johnston, Henk Moorlag, Jim-Wah Wong, L. Mark Hodges, Les Harris,
Gerald K. McEwen, and Blair Smallwood
Roche Colorado Corporation-Boulder Technology Center, 2075 North 55th Street, Boulder, Colorado 80301, U.S.A.
Scheme 1. Discovery Chemistry route from
2-chloro-5-nitropyridine 5 to 2
Abstract:
Roche has identified a 2,4,5-trisubstituted pyridine template for
a new class of potent NK1 receptor antagonists. Previous
strategies for construction of the pyridine core of these NK-1
receptor antagonists involved functionalization of a 2,5-disub-
stituted pyridine. We now report on construction of the pyridine
core from commodity components. Shestopalov reported the
synthesis of trans-4′-aryl-5′-cyano-1′,2′,3′,4′-tetrahydro-6′-hy-
droxy-2′-oxo-1,3′-bipyridinium inner salts from 1-(2-amino-2-oxo-
ethyl)pyridinium chloride, aromatic aldehydes, and ethyl cy-
anoacetate in the presence of a base. Reaction of these salts
with phosphorus oxychloride affords 4-aryl-3-cyano-2,6-dichlo-
ropyridines. These are efficiently converted to nicotinamide
precursors of the Roche NK-1 receptor antagonists by regiose-
lective displacement of one chlorine by an amine, hydrogenolysis
of the remaining chlorine, and nitrile hydrolysis.
Introduction
The tachykinin neuropeptides, substance P (SP), neuro-
kinin A (NKA), and neurokinin B (NKB), are neurotrans-
mitters or neuromodulatory agents. Each of these structurally
related neuropeptides has a preferred receptor: the NK1
receptor for SP, the NK2 receptor for NKA, and the NK3
receptor for NKB. The NK1 and NK2 receptors are widely
distributed in the central nervous system (CNS) and peri-
pheral tissue; NK3 may be more localized in the CNS.
In recent years, many small-molecule NK-1 receptor
antagonists have been identified, and clinical trials have
highlighted their therapeutic potential for treatment of
depression and anxiety and for control of chemotherapy-
induced nausea and vomiting.1 The Roche NK-1 receptor
antagonists are nicotinamides such as 1 and “inverse nico-
tinamides” such as 2-42 (Figure 1).
Previous strategies for construction of antagonists 2-4
involved functionalization of a 2,5-disubstituted pyridine. To
illustrate, the Discovery Chemistry synthesis of 2 (Scheme
1) begins with 2-chloro-5-nitropyridine (5). Morpholine dis-
placement, nitro group reduction, and pivaloylation affords
pivalamide 8. Regioselective lithiation provides access to the
4-iodopyridine 9, which is used in a Suzuki coupling with
an arylboronic acid. Amide hydrolysis, N-methylation via
the methyl carbamate 12a, and acylation with R,R-dimethyl-
3,5-bis(trifluoromethyl)benzeneacetyl chloride (14) complete
the sequence.2b
While the Discovery Chemistry route provided rapid
access to 2, the lithiation required a low temperature (-78
°C) and an excess (3-4 equiv) of butyllithium and the Suzuki
coupling partner was relatively expensive o-tolylboronic acid.
The Process Chemistry group demonstrated that the Dis-
covery Chemistry methyl carbamates such as 12a are also
accessible via Hofmann rearrangement of a nicotinamide
(Scheme 2). 6-Chloronicotinic acid 15 is converted to the
tert-butylamide via the acid chloride. The 4-aryl substituent
is introduced by 1,4-addition of o-tolylmagnesium chloride
followed by dihydropyridine oxidation. After chlorine dis-
placement by morpholine or 1-methylpiperazine, the tert-
butyl group is cleaved, the amide 19 is subjected to Hofmann
rearrangement, and the isocyanate is trapped with methanol.3
While the Process Chemistry route provided larger quan-
tities of the Roche NK-1 receptor antagonists for clinical
evaluation, 6-chloronicotinic acid 15 is a value-added starting
material. 6-Chloronicotinic acid 15 is likely prepared from
6-hydroxynicotinic acid, prepared by microbial oxidation of
* Corresponding author. Telephone: (303)-938-6529. Fax: (303)-938-6590.
E-mail: peter.harrington@roche.com.
(1) (a) Albert, J. S. Expert Opin. Ther. Pat. 2004, 14, 1421. (b) Duffy, R. A.
Expert Opin. Emerging Drugs 2004, 9, 9.
(2) (a) Bo¨s, M.; Branca, Q.; Galley, G.; Godel, T.; Hoffmann, T.; Hunkeler,
W.; Schnider, P.; Stadler, H. EP1035115 (9/13/00). (b) Ballard, T. M.;
Higgins, G. A.; Hoffmann, T.; Poli, S. M.; Sleight, A. EP1103545 (5/30/
01). (c) Hoffmann, T.; Bo¨s, M.; Stadler, H.; Schnider, P.; Hunkeler, W.;
Godel, T.; Galley, G.; Ballard, T. M.; Higgins, G. A.; Poli, S. M.; Sleight,
A. J. Bioorg. Med. Chem. Lett. 2006, 16, 1362.
(3) (a) Hilpert, H.; Hoffmann-Emery, F.; Rimmler, G.; Rogers-Evans, M.; Stahr,
H. W.; Waldmeier, P. EP1103546 (5/30/01). (b) Hoffmann-Emery, F.;
Hilpert, H.; Scalone, M.; Waldmeier, P. J. Org. Chem. 2006, 71, 2000.
10.1021/op060128m CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/26/2006
Vol. 10, No. 6, 2006 / Organic Process Research & Development
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Figure 1. Roche NK-1 receptor antagonists.
Scheme 2. Process Chemistry route from 6-chloronicotinic
acid 15 to 2 and 3
ano-2,6-dihydroxy-4-(2-methylphenyl)pyridine (22b) met
with only limited success.
Shestopalov reported the synthesis of trans-4′-aryl-5′-
cyano-1′,2′,3′,4′-tetrahydro-6-hydroxy-2-oxo-1,3′-bipyridin-
ium inner salts 28 from 1-(2-amino-2-oxoethyl)pyridinium
chloride 23, an aromatic aldehyde 24, and ethyl cyanoacetate
25 in the presence of a base (eq 2).5
We have found that reaction of Shestopalov pyridinium
inner salts such as 28 with phosphorus oxychloride provides
4-aryl-3-cyano-2,6-dichloropyridines 29 which can be ef-
ficiently converted to the nicotinamides 19. The nicotina-
mides 19 can then be converted via the Process Chemistry
route methylamines such as 13 to the Roche NK-1 receptor
antagonists 2, 3, and 4 (Scheme 3). The Shestopalov pyridine
ring construction is detailed in Scheme 4.
nicotinic acid. In addition, the throughput for the 1,4-addition
is poor since o-tolylmagnesium chloride is used in excess
(typically 3-5 equiv) as a 1 M THF solution. Finally, the
dihydropyridine oxidation using manganese dioxide, potas-
sium permanganate, manganese(III) acetate dihydrate, or
DDQ requires a byproduct separation and oxidant regenera-
tion.
Pyridine Ring Construction
The Shestopalov ring construction shown in Scheme 4 is
the end result of three sequential reactions: Knoevenagel
condensation of aldehyde 24 with methyl cyanoacetate 26,
Michael addition of the pyridinium ylid from 23 to the
condensation product 27, and cyclization of the Michael
adduct.
We now report on an alternative construction of the
Process Chemistry nicotinamides such as 19 from commodity
components. There are many methods for pyridine ring con-
struction, including the Hantzsch, Kro¨hnke, and Guareschi-
Thorpe syntheses. 3-Cyano-2,6-dihydroxy-4-phenylpyridine
(22a) was constructed by a Guareschi-Thorpe synthesis in
1980 (eq 1).4 Ethyl benzoylacetate 20a and cyanoacet-
The Knoevenagel condensation is fast: condensation of
aldehyde 24 and methyl cyanoacetate 26 in isopropanol is
complete in less than 1 h at 25 °C. The Michael addition to
27 is also fast: the Michael adduct precipitates during
triethylamine addition to a mixture of the Knoevenagel
product 27 and pyridinium salt 23 in methanol at 25 °C.
The cyclization is relatively slow, perhaps because of the
limited solubility of the Michael adduct: the precipitate after
6 h at 25 °C consists of a mixture of the Michael adduct
and cyclization product 28.
The pyridinium salt 23 can be prepared by refluxing a
mixture of 2-chloroacetamide and pyridine (1.16 equiv) in
(4) Roch, J.; Mu¨ller, E.; Narr, B.; Nickl, J.; Haarmann, W. US4182887 (1/8/
80).
(5) (a) Shestopalov, A. M.; Litvinov, V. P.; Rodinovskaya, L. A.; Sharanin,
Yu. A. Synthesis 1991, 402. (b) Shestopalov, A. M.; Sharanin, Yu. A.;
Litvinov, V. P. Khim. Geterotsikl. Soedin. 1990, 363. (c) Litvinov, V. P.;
Shestopalov, A. M. Zh. Org. Khim. 1997, 33, 975.
amide 21 are readily available, but the yield is low (42%).
Attempted extension of this method to construction of 3-cy-
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Vol. 10, No. 6, 2006 / Organic Process Research & Development

Scheme 3. Route from Shestopalov pyridinium inner salts
28 to 2, 3, and 4
necessary to maintain a stirrable mixture during the phase/
viscosity changes observed during heatup. The phase/
viscosity changes observed in the RC-1 calorimeter during
heatup using 5 mL of phosphorus oxychloride per g of 28a
are shown in Figure 2.
Regioselective Chlorine Displacement from the 3-Cy-
ano-2,6-dichloropyridine 29 by Amine. Since 3-cyano-2,6-
diaminopyridines are precursors of couplers for the prepa-
ration of azo dyes, the regioselective replacement of one
chlorine of a 3-cyano-2,6-dichloropyridine is well docu-
mented. There are many examples of attack by nonhindered
primary amines at the 2-position and by hindered primary
amines and secondary amines at the 6-position.6 Solvent
polarity often plays a critical role, with attack at the
2-position favored by a decrease in solvent polarity. The
regioselectivity in our reaction of 3-cyano-2,6-dichloropy-
ridine 29a with morpholine is presented in Table 1. The table
Table 1. Regioselectivity in the reaction of 3-cyano-2,6-
dichloro-4-(2-methylphenyl) pyridine 29a with morpholinea
temp
(°C)
product ratiob
30a:regioisomer
solvent
Scheme 4. Shestopalov synthesis of bipyridinium inner salt
28
MeOH
EtOH
EtOH
EtOH
25
25
10:1
12:1
11:1
11:1
14:1
11:1
10:1
7:1
0
-10
-10
-10
-10
-10
-10
-10
EtOH-acetone (1:1)
acetone
CH3CN
MTBE
THF
7:1
EtOAc
5:1
a Conditions: 2.20 equiv of morpholine, 18-22 h. b Determined by 500 MHz
1H NMR.
shows a negligible influence of reaction temperature (in
ethanol) and the expected strong influence of solvent polarity.
We chose to use methanol as solvent: the regioselectivity
in methanol at 25 °C is 10:1, and the desired regioisomer
30a crystallizes from the reaction mixture (78% yield) while
the amine hydrochloride byproduct remains in solution.
The reaction of 3-cyano-2,6-dichloropyridine 29a with
1-methylpiperazine in methanol at 25 °C is also regioselec-
tive (10:1). After dilution of the methanol suspension with
water, 2-chloro-3-cyano-4-(2-methylphenyl)-6-(4-methylpip-
erazinyl)pyridine 30b is isolated in 77% yield. The reaction
of 3-cyano-2,6-dichloropyridine 29c with thiomorpholine in
methanol at 25 °C is also regioselective (10:1). Considerably
less 2-chloro-3-cyano-4-(4-fluoro-2-methylphenyl)-6-(4-thio-
morpholinyl)pyridine 30c is lost to the methanol crystalliza-
tion liquors (88% yield).
Hydrogenolysis and Hydrolysis. Many pyridine ring
construction methods produce 2- or 4-hydroxypyridines.
Replacement of the hydroxyl group by hydrogen via conver-
sion to the chloropyridine and hydrogenolysis is well docu-
mented. Since the hydrogen chloride produced can poison
the catalyst, the hydrogenolysis is often carried out in the
presence of a base. Hydrogenolyses of our 6-amino-2-chloro-
n-butyl acetate. The salt is isolated by cooling the suspension,
filtering, and washing the solid with hexane (92% yield)
(Method A). Alternatively, refluxing 2-chloroacetamide and
pyridine (1.02 equiv) in isopropanol affords a suspension of
pyridinium salt 23 suitable for use in the pyridine ring
construction (Method B). We prefer to avoid the salt isolation
by using Method B. A near-optimal procedure for the ring
construction involves preparation of pyridinium salt 23 in
isopropanol, addition of 1 equiv of methyl cyanoacetate 26,
1 equiv of aldehyde 24, and methanol, and then dropwise
addition of 1.1 equiv of triethylamine. After 24 h, analytically
pure 28 is isolated by filtration and washing with methanol
(89-93%).
Dichloropyridine 29. By returning to the route presented
in Scheme 3, conversion of the inner salt 28a to the
dichloropyridine 29a (82-87% yield) was demonstrated
using 0.64 mL, 1.25 mL, 2.5 mL, and 5 mL of phosphorus
oxychloride per g of 28a at 105-150 °C. While the mixture
becomes homogeneous and the reaction goes to completion
at 135 °C using just 0.64 mL of phosphorus oxychloride
per g of 28a, a greater excess of phosphorus oxychloride is
(6) (a) Fleckenstein, E.; Heinrich, E.; Mohr, R. US4061642 (12/6/77). (b) Lamm,
G.; Dehnert, J. US 3853895 (12/10/74).
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Figure 2. Phase changes during heatup of the salt (28a)-phosphorus oxychloride mixture at (a) 66, (b) 75, (c) 90, and (d) 120 °C.
3-cyanopyridines 30 were accomplished using triethylamine
and palladium hydroxide on carbon in methanol at 25 °C
(93-96%). Side products resulting from overhydrogenation
can be removed after the hydrogenation by an acid wash or
after the nitrile hydrolysis by adsorption on silica.
results in nitrile hydrolysis and ring sulfonation (eq 3). Nearly
A nicotinonitrile can be converted to a nicotinamide with
sulfuric acid,7 aqueous hydroxide,8 basic hydrogen peroxide,9
or potassium trimethylsilanolate.10 We observed that stoi-
chiometry and the presence of a sacrificial solvent are critical
factors in an efficient process using sulfuric acid. To
illustrate, reaction of nitrile 31a with ∼50 equiv of 98%
sulfuric acid at 50 °C for 3 h followed by an aqueous quench
(7) Miyamoto, T.; Egawa, H.; Shibamori, K.-i.; Matsumoto, J.-i. J. Heterocycl.
Chem. 1987, 24, 1333.
(8) Salem, M. A. I.; Madkour, H. M. F.; Soliman, E.-S. A.; Mahmoud, N. F.
H. Heterocycles 2000, 53, 1129.
(9) Humphries, M. J.; Ramsden, C. A. Synthesis 1999, 985.
(10) Merchant, K. J. Tetrahedron Lett. 2000, 41, 3747.
complete conversion to 19a with minimal ring sulfonation
is observed in the reaction of nitrile 31a with 5 to 6 equiv
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Scheme 5. Three alternative sequences from 29a to 19a
Conclusion
One of the most difficult challenges we face in pharma-
ceutical process research and development is to meet all the
short-term clinical supply demands while still pursuing
process improvements for subsequent campaigns at larger
scales. Rapidly approaching clinical supply deadlines for
delivery of 1-10 kg often drive the development of the
Discovery Chemistry route. Subsequent supply deadlines
1-2 years out for delivery of tens to hundreds of kilograms
drive the development of a scaleable and robust Process
Chemistry route. Supply planning for 5-10 years out is
driven by still other priorities: Are the starting materials
readily available in bulk from several suppliers? What will
be the environmental impact of the process reagents, solvents,
and aqueous waste streams? In this report, we described our
efforts to address some long-term supply priorities for the
nicotinamide precursors of several Roche NK-1 receptor
antagonists.
Reaction of a Shestopalov salt 28 with phosphorus
oxychloride is the key step in a new synthesis of the
nicotinamide precursors by pyridine ring construction. The
3-cyano-2,6-dichloropyridines 29 produced are efficiently
converted to the nicotinamide precursors 19 by regioselective
displacement of one chlorine by an amine, hydrogenolysis
of the remaining chlorine, and nitrile hydrolysis. While our
objective was process development for antagonists 2-4, the
versatile ring construction strategy we developed can provide
other nicotinamides with substitution patterns not accessible
when the 4-aryl substituent is derived from an arylboronic
acid or arylmagnesium halide.
of sulfuric acid in toluene at 70 °C after 2 h. We did observe
some toluene sulfonation but did not determine the quantity
of toluenesulfonic acid produced.
Alternative Sequences from 29a to 19a. 3-Cyano-2,6-
dichloropyridine 29a is converted to 6-morpholino-3-pyridi-
necarboxamide 19a in overall 70% yield by three reactions:
a chlorine displacement by morpholine, a chlorine hydro-
genolysis, and a nitrile hydrolysis. These transformations
could potentially be run in a different order (Scheme 5). With
the understanding that there is no precedent for the efficient
hydrogenolysis of one chlorine of a 2,6-dichloropyridine, the
two possible alternative sequences are displacement-hy-
drolysis-hydrogenolysis (via intermediates 30a and 33) and
hydrolysis-displacement-hydrogenolysis (via intermediates
34 and 33).
The displacement-hydrolysis-hydrogenolysis sequence
via intermediates 30a and 33 also affords 6-morpholinylpy-
ridine-3-carboxamide 19a in overall 70% yield. However,
the nitrile hydrolysis to the 2-chloropyridine-3-carboxamide
33 is much slower (5 to 6 equiv of sulfuric acid in toluene
at 70 °C for 120 h) than the nitrile hydrolysis to the pyridine-
3-carboxamide 19a (5 to 6 equiv of sulfuric acid in toluene
at 70 °C for 12 h).
Experimental Section
o-Tolualdehyde 24a is commercially available. Aldehyde
24c has been produced from 3-fluorotoluene by direct
formylation11 and from 2-bromo-5-fluorotoluene by metal-
halogen exchange and aryllithium addition to DMF.12
4-Fluoro-2-methylbenzaldehyde (24c). 2-Bromo-5-fluo-
rotoluene (37.5 mL, 56.1 g, 297 mmol) is dissolved in 500
mL of dry THF, and the solution is cooled to -78 °C under
dry N2. Butyllithium in hexanes (2.5 M) (119 mL, 297 mmol,
1.0 equiv) is added at -75 to -78 °C over 35 min, and the
suspension is stirred at -78 °C for 20 min. Dry N,N-
dimethylformamide (27.6 mL, 26.0 g, 356 mmol, 1.2 equiv)
is added over 26 min at -75 to -78 °C. The resulting
solution is stirred at -78 °C for 60 min and then allowed to
warm to 15 °C over 2 h.
Ammonium chloride (100 g of 15.9% aqueous) is added
over 5 min at 15-20 °C. The solution is concentrated by
fractional distillation (10” 24/40 Vigreux column)(597 mL
collected at 50-61 °C). The distillation pot layers are
separated. The aqueous layer is extracted with 25 mL of
MTBE 3 times. The combined organic layers are washed
with 50 mL of brine and then dried (MgSO4), filtered, and
fractionally distilled (10” 14/20 Vigreux column) (bp 54-
62 °C) to leave 59.3 g of yellow oil. The oil is fractionally
distilled (10” 14/20 Vigreux column) at 60-62 °C (bath 80-
The alternative hydrolysis-displacement-hydrogenolysis
sequence via intermediates 34 and 33 is not competitive. The
hydrolysis to the 2,6-dichloropyridine-3-carboxamide 34 is
very slow using 5 to 6 equiv of sulfuric acid in toluene at
70 °C. We produced amide 34 (75% yield) using neat sulfuric
acid at 100 °C. The displacement reaction with morpholine
(2.1 equiv) in methanol at 25 °C is also slower than the
displacement reaction of the 3-cyano-2,6-dichloropyridine
29a. Reaction of 34 with excess morpholine (10 equiv) in
methanol at reflux does result in complete conversion but
produces a mixture of regioisomers faVoring the wrong
isomer.
(11) Anderson, J. D. O.; Scrivens, W. A. US6300525 (10/9/01).
(12) Robl, J. A. EP044533 (9/4/91).
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100 °C) and 1.6-2.0 mmHg to afford 28.041 g (68.4%) of
24c as a colorless oil.
500 mL of 25 °C methanol, 500 mL of 25 °C toluene, and
500 mL of 25 °C hexanes, and then air-dried 6 h at 25 °C to
afford 285.10 g (93.4%) of 28a as a bright yellow solid.
5′-Cyano-1′,2′,3′,4′-tetrahydro-6′-hydroxy-4′-(2-meth-
ylphenyl)-2′-oxo-1,3′-bipyridinium, Inner Salt 28a (Method
C). A 3000 mL four-necked flask (with a 250 mL pressure
equilibrating addition funnel/dry N2 adapter, septum with a
Teflon-coated thermocouple, Teflon paddle stirrer/glass shaft,
and stopper) is charged with 115.6 mL (120.15 g, 1.0 mol)
of o-tolualdehyde 24a, 87.9 mL (99.09 g, 1.0 mol) of methyl
cyanoacetate 26, the suspension of 172.61 g (1.0 mol) of
pyridinium salt 23 in 300 mL of isopropanol (from pyri-
dinium salt Method B), and 1.7 L of methanol. The addition
funnel is charged with 153.3 mL (111.3 g, 1.1 mol) of
triethylamine. The amine is added over 24 min at 170 rpm
and 20-25 °C (intermittent ice-water bath). The resulting
mixture is stirred at 25-30 °C for 24 h.
The precipitate is suction filtered, washed with 500 mL
of 25 °C methanol, 500 mL of 25 °C toluene, and 500 mL
of 25 °C hexanes, and then air-dried 18 h at 25 °C to afford
284.69 g (93.2%) of 28a as a bright yellow solid, mp 232-
233 °C (dec); 1H NMR (DMSO-d6) δ 9.82 (s, 1H), 8.98 (d,
2H), 8.50 (t, 1H), 8.04 (t, 2H), 7.45 (br, 1H), 7.12 (t, J )
7.0 Hz, 1H), 6.99 (t, J ) 7.0 Hz, 1H), 6.93 (d, J ) 8.0 Hz,
1H), 6.82 (d, J ) 13 Hz, 1H), 6.13 (d, J ) 13 Hz, 1H), 2.08
(s, 3H); 13C NMR (DMSO-d6) δ 166.4, 163.8, 147.3, 145.8,
137.2, 137.0, 128.3, 128.1, 127.5, 126.9, 126.0, 75.3, 53.6,
19.8; IR (KBr) 3625-3300, 3162, 3135, 3045, 2956, 2929,
2168, 1701, 1634, 1600 cm-1. Anal. Calcd for C18H15N2O2:
C, 70.81; H, 4.95; N, 13.76. Found: C, 70.66; H, 5.10; N,
13.80.
5′-Cyano-1′,2′,3′,4′-tetrahydro-6′-hydroxy-4′-(2-methyl-
4-fluorophenyl)-2′-oxo-1,3′-bipyridinium, Inner Salt 28c.
A 1000 mL four-necked flask (with a 50 mL pressure
equilibrating addition funnel/dry N2 adapter, septum with a
Teflon-coated thermocouple, Teflon paddle stirrer/glass shaft,
and stopper) is charged with 28.01 g (203 mmol) of 4-fluoro-
2-methylbenzaldehyde 24c, 17.8 mL (20.1 g, 203 mmol) of
methyl cyanoacetate 26, 35.00 g (203 mmol) of pyridinium
salt 23, and 400 mL of methanol. The addition funnel is
charged with 31.1 mL (22.6 g, 223 mmol) of triethylamine.
The amine is added over 11 min at 170 rpm and 20-25 °C
(intermittent ice-water bath). The resulting mixture is stirred
at 25-30 °C for 24 h.
Methyl 2-Cyano-3-(2-methylphenyl)-2-propenoate 27a.
A 100 mL one-necked round-bottom flask (with a magnetic
stirbar and dry N2 adapter) is charged with 11.6 mL (12.0 g,
100 mmol) of o-tolualdehyde 24a, 8.8 mL (9.9 g, 100 mmol)
of methyl cyanoacetate 26, and 50 mL of isopropanol.
Morpholine (0.50 mL, 0.55 g, 6.3 mmol, 6.3 mol %) is
added, and the mixture was stirred at 20-33 °C for 60 min.
The suspension is diluted with 25 mL of isopropanol. The
precipitate is suction filtered, washed with 10 mL of
isopropanol, and dried in vacuo (17 h at 25 °C and 1 mmHg)
to afford 17.37 g (86.3%) of 27a as a colorless solid.
1-(2-Amino-2-oxoethyl)pyridinium Chloride 23 (Method
A). A 3000 mL four-necked round-bottom flask (with a
reflux condenser/dry N2 adapter, perforated Teflon paddle
stirrer with a glass shaft, septum with a Teflon-coated
thermocouple, and Teflon stopper) is charged with 190.76 g
(2.04 mol) of 2-chloroacetamide, 2.0 L of n-butyl acetate,
and 192 mL (187.8 g, 2.37 mol) of dry pyridine. The
resulting suspension is refluxed (bath 137 °C, pot 119 °C)
at 150 rpm for 24 h. The suspension is cooled to 25 °C. The
precipitate is suction filtered, washed with 500 mL of n-butyl
acetate, washed with 500 mL of hexanes twice, and then
dried in vacuo (17 h at 25 °C and 15 in Hg) to afford 324.05
g (92.0%) of 23 as a beige solid.
1-(2-Amino-2-oxoethyl)pyridinium Chloride 23 (Method
B). A 2000 mL pressure bottle with a paddle stirrer is charged
with 93.51 g (1.00 mol) of 2-chloroacetamide, 300 mL of
isopropanol, and 82.4 mL (80.7 g, 1.02 mol) of pyridine.
The resulting suspension is heated at 110 °C and 150 rpm
for 18 h. The suspension is cooled to 25 °C, and the bottle
is vented.
5′-Cyano-1′,2′,3′,4′-tetrahydro-6′-hydroxy-4′-(2-meth-
ylphenyl)-2′-oxo-1,3′-bipyridinium, Inner Salt 28a (Method
A). A 100 mL two-necked round-bottom flask (with septum
and reflux condenser with dry N2 adapter) is charged with
1.726 g (10.0 mmol) of the pyridinium salt 23, 2.012 g (10.0
mmol) of propenoate 27a, and 20 mL of methanol. Triethyl-
amine (1.55 mL, 1.11 g, 11.0 mmol, 1.10 equiv) is added.
The mixture is refluxed for 1 min and then allowed to cool
to 25 °C and stir for 66 h. The precipitate is suction filtered,
washed with 10 mL of methanol, 10 mL of toluene, and 10
mL of hexanes, and then air-dried for 1 h to afford 2.734 g
(89.5%) of 28a as a bright yellow solid.
The precipitate is suction filtered using a 600 mL coarse
sintered glass funnel. The precipitate is washed with 100
mL of 25 °C methanol, 100 mL of 25 °C toluene, and 100
mL of 25 °C hexanes, and then air-dried 3.5 h at 25 °C to
afford 60.69 g (92.6%) of 28c as a bright yellow solid, mp
5′-Cyano-1′,2′,3′,4′-tetrahydro-6′-hydroxy-4′-(2-meth-
ylphenyl)-2′-oxo-1,3′-bipyridinium, inner salt 28a (Method
B). A 3000 mL four-necked flask (with a 250 mL pressure
equilibrating addition funnel/dry N2 adapter, septum with a
Teflon-coated thermocouple, Teflon paddle stirrer/glass shaft,
and stopper) is charged with 115.6 mL (120.15 g, 1.0 mol)
of o-tolualdehyde 24a, 87.9 mL (99.09 g, 1.0 mol) of methyl
cyanoacetate 26, 172.61 g (1.0 mol) of the pyridinium salt
23, and 2.0 L of methanol. The addition funnel is charged
with 153.3 mL (111.3 g, 1.1 mol) of triethylamine. The amine
is added over 20 min at 170 rpm and 20-25 °C (intermittent
ice-water bath). The resulting mixture is stirred at 25-30
°C for 24 h. The precipitate is suction filtered, washed with
1
236-237 °C (dec); H NMR (DMSO-d6) δ 9.84 (s, 1H),
8.98 (d, J ) 6.0 Hz, 2H), 8.52 (t, J ) 7.5 Hz, 1H), 8.07 (dd,
2H), 7.50 (br, 1H), 6.97 (br t, 7.0 Hz, 1H), 6.80 (dd, J ) 1.5
Hz, J ) 10 Hz, 1H), 6.26 (d, J ) 13 Hz, 1H), 4.81 (d, J )
13 Hz, 1H), 2.08 (br, 3H); 13C NMR (DMSO-d6) δ 166.3,
163.7, 161.2 (d, J ) 241.9 Hz), 147.4, 145.8, 139.9, 133.4,
130.3, 128.5, 126.0, 117.4, 113.7, 75.2, 53.6, 31.4, 19.7; IR
(KBr) 3170, 3130, 3045, 2168, 1703, 1633, 1602, 1577 cm-1.
Elem. Anal. Calcd for C18H14FN3O2: C, 66.87; H, 4.36; F,
1162
•
Vol. 10, No. 6, 2006 / Organic Process Research & Development

5.88; N, 13.00. Found: C, 66.31; H, 4.29; F, 6.05; N, 12.72.
3-Cyano-2,6-dichloro-4-(2-methylphenyl)pyridine 29a.
A mixture of 40.00 g (131.0 mmol) of the pyridinium inner
salt 28a and 50.0 mL (82.3 g, 536 mmol) of phosphorus
oxychloride was heated in a 300 mL Parr bottle at 135 °C
for 10 h.
(d, J ) 21.6 Hz), 114.0 (d, J ) 21.6 Hz), 113.6, 110.4, 20.2
(d, J ) 1.6 Hz); IR (KBr) 3100, 2920, 2230, 1590, 1578,
1566, 1521, 1496 cm-1. Anal. Calcd for C13H7Cl2FN2: C,
55.54; H, 2.51; F, 6.76; N, 9.97. Found: C, 55.32; H, 2.55;
F, 7.02; N, 9.78.
2-Chloro-3-cyano-4-(2-methylphenyl)-6-(4-morpholinyl)-
pyridine 30a. The crude dichloride 29a (194.8 g, 0.740 mol)
and 1100 mL of methanol were added to a 2000 mL three-
necked flask (with a 125 mL pressure-equilibrating addition
funnel/dry N2 adapter, septum with a Teflon-coated thermo-
couple, and Teflon paddle stirrer/glass shaft). The suspension
was cooled to 18 °C (at 200 rpm) using an ice-water bath.
Morpholine (132.3 mL, 132.2 g, 1.52 mol) was charged to
the addition funnel and then added dropwise to the suspen-
sion at 18-22 °C over 45 min. The resulting suspension
was stirred at 20-25 °C for 18 h.
The precipitate was suction filtered, washed with 150 mL
of 25 °C methanol and then with 1000 mL of water, air-
dried for 90 min at 25 °C, and then dried in vacuo (vacuum
oven at 53-57 °C and ∼15 in Hg for 67 h) to afford 182.04
g (78.4%) of 30a as a colorless solid.
An analytical sample was prepared by recrystallization
from isopropanol, mp 152-154 °C; 1H NMR (CDCl3) δ 7.35
(dt, J ) 1.5 Hz, J ) 7.5 Hz, 1H), 7.31-7.28 (m, 1H), 7.26
(dd, J ) 1.5 Hz, J ) 7.5 Hz, 1H), 6.37 (s, 1H), 3.81-3.79
(m, 4H), 3.68-3.66 (m, 4H), 2.25 (s, 3H); 13C NMR (CDCl3)
δ 158.3, 156.9, 153.0, 136.4, 135.1, 130.6, 129.5, 128.4,
126.1, 115.8, 104.7, 97.8, 66.4, 44.8, 19.7; IR (KBr) 2966-
2843, 2216, 1597, 1490 cm-1. Anal. Calcd for C17H16-
ClN3O: C, 65.07; H, 5.14; N, 13.39; Cl, 11.30. Found: C,
65.38; H, 5.28; N, 13.36; Cl, 11.65.
The syrup was cooled to 25 °C, and the bottle was vented.
Methylene chloride (75 mL) was added. The solution was
transferred onto 350 g of ice. Methylene chloride (25 mL)
was used to complete the transfer. During the subsequent
stir time (<1 h), the ice melted, the mixture refluxed briefly,
and the temperature began to drop. The layers were separated.
The aqueous layer was extracted with 25 mL of methylene
chloride twice and then with 50 mL of toluene twice. The
combined extracts were dried (5.0 g Na2SO4) and then
filtered through 15 g of Filtrol on a 60 mL coarse sintered
glass funnel. The flask and cake were washed with 50 mL
of fresh toluene. The combined mother liquors were con-
centrated in vacuo (rotary evaporator at 35 °C and 100-20
mmHg and then vacuum pump at 25 °C and 1 mmHg for 3
h) to afford 28.70 g (83.3%) of 29a as a near colorless solid
(LC assay 100.7 wt %).
An analytical sample was prepared by recrystallization
from isopropanol, mp 129-131 °C; 1H NMR (CDCl3) δ 7.43
(dt, J ) 1.5 Hz, J ) 7 Hz, 1H), 7.37-7.31 (m, 2H), 7.33 (s,
1H), 7.18 (dd, J ) 1.5 Hz, J = 8 Hz, 1H), 2.25 (s, 3H); 13
C
NMR (CDCl3) δ 159.1, 153.9, 153.3, 135.3, 134.1, 131.3,
130.7, 128.8, 126.7, 124.5, 113.7, 110.3, 20.0; IR (KBr)
3087, 2227, 1603, 1569, 1520, 1340 cm-1. Anal. Calcd for
C13H8Cl2N2: C, 59.34; H, 3.06; N, 10.65; Cl, 26.95. Found:
C, 59.00; H, 3.05; N, 10.64; Cl, 27.76.
3-Cyano-2,6-dichloro-4-(4-fluoro-2-methylphenyl)py-
ridine 29c. A mixture of 55.00 g (170.1 mmol) of the
pyridinium inner salt 28c and 65 mL (106.9 g, 697 mmol,
4.1 equiv) of phosphorus oxychloride was heated in a 300
mL Parr bottle at 135 °C for 12 h.
2-Chloro-3-cyano-4-(2-methylphenyl)-6-(4-methylpip-
erazinyl)pyridine 30b. Crude dichloride 29a (78.00 g, 0.296
mol) and 330 mL of methanol were added to a 1000 mL
three-necked flask (with a 125 mL pressure-equilibrating
addition funnel/dry N2 adapter, septum with a Teflon-coated
thermocouple, and Teflon paddle stirrer/glass shaft), and the
suspension was cooled to 18 °C (at 150 rpm) using an ice-
water bath. 1-Methylpiperazine (67.3 mL, 60.78 g, 0.607
mol) was charged to the addition funnel and then added
dropwise to the suspension at 18-22 °C over 15 min. Seed
crystals of 30b were added after 2 h, and the suspension
was stirred at 20-25 °C for an additional 18 h.
Water (165 mL) was added dropwise over 1 h, and the
resulting suspension was stirred at 25 °C for 3 h. The
precipitate was suction filtered, washed with 90 mL of 25
°C 2:1 methanol-H2O and then with 100 mL of water, air-
dried for 78 min at 25 °C, and then dried in vacuo (vacuum
oven at 53-57 °C and ∼15 in Hg for 69 h) to afford 74.19
g (76.6%) of 30b as a beige solid.
An analytical sample was prepared by recrystallization
from isopropanol, mp 116-123 °C; 1H NMR (CDCl3) δ 7.34
(dt, J ) 7.5 Hz, J ) 1.5 Hz, 1H), 7.3-7.25 (m, 2H), 7.14
(dd, J ) 7.5 Hz, J ) 1.5 Hz, 1H), 6.37 (s, 1H), 3.71 (br m,
4H), 2.49 (br t, 4H), 2.35 (s, 3H), 2.25 (s, 3H); 13C NMR
(CDCl3) δ 158.4, 156.9, 153.2, 136.8, 135.4, 130.9, 129.6,
128.7, 126.3, 116.2, 105.0, 97.3, 54.7, 46.3, 44.8, 20.0; IR
(KBr) 2966, 2936, 2846, 2797, 2215, 1592, 1498 cm-1. Anal.
The syrup was cooled to 25 °C, and the bottle was vented.
Methylene chloride (200 mL) was added. The solution was
transferred onto 450 g of ice, and stirring continued until
the ice melted. Methylene chloride (25 mL) was used to
complete the transfer. The layers were separated. The
aqueous layer was extracted with 25 mL of methylene
chloride twice. The aqueous layer was extracted with 125
mL of toluene twice. The combined extracts were filtered
through 15 g of Filtrol on a 60 mL coarse sintered glass
funnel. The flask and cake were washed with 100 mL of
fresh toluene. The combined mother liquors were concen-
trated in vacuo (rotary evaporator at 35 °C and 200-20
mmHg and then vacuum pump at 25 °C and 1 mmHg for
17 h) to afford 39.70 g (83.0%) of 29c as a near colorless
solid.
An analytical sample was prepared by recrystallization
1
from isopropanol, mp 161.5-162.5 °C; H NMR (CDCl3)
δ 7.32 (s, 1H), 7.18 (dd, J ) 5.5 Hz, J ) 8.5 Hz, 1H), 7.08
(dd, J ) 2.5 Hz, J ) 9.5 Hz, 1H), 7.04 (dt, J ) 2.5 Hz, J )
8-8.5 Hz, 1H), 2.26 (s, 3H); 13C NMR (CDCl3) δ 163.9 (d,
J ) 250 Hz), 158.0, 154.0, 153.4, 138.4 (d, J ) 8.4 Hz),
130.8 (d, J ) 8.8 Hz), 130.1 (d, J ) 3.6 Hz), 124.6, 118.2
Vol. 10, No. 6, 2006 / Organic Process Research & Development
•
1163

Calcd for C18H19ClN4: C, 66.15; H, 5.86; N, 17.14; Cl, 10.85.
Found: C, 66.04; H, 6.04; N, 17.11; Cl, 10.94.
The pressure was vented, and the mixture diluted with
40 mL of H2O. The suspension was transferred to a round-
bottom flask using 40 mL of methanol. Methanol was
removed on a rotary evaporator at 35 °C and 60-30 mmHg
(collected 107.5 mL). The resulting suspension was diluted
with 80 mL of toluene and then suction filtered through 2.0
g of celllulose powder on a coarse sintered glass funnel. The
catalyst-celite cake was washed with 10 mL of fresh toluene
3 times. A solution of 2.80 g (70.1 mmol) of sodium
hydroxide in 5 g of H2O was added to the combined mother
liquors. The layers were separated, and the aqueous (pH )
13-14) layer was extracted with 20 mL of toluene 3 times.
The combined organic layers were concentrated in vacuo
(rotary evaporator at 35 °C and 30 mmHg, trituration with
hexanes, and then vacuum pump at 25 °C and ∼1 mmHg
for 22 h) to afford 17.95 g of 31a as a colorless solid (LC
assay 91.8-93.9 wt %) (yield 92.6-94.7%).
An analytical sample was prepared by radial chromatog-
raphy on silica gel followed by recrystallization from
isopropanol, mp 128.5-129.7 °C; 1H NMR (CDCl3) δ 8.48
(s, 1H), 7.35 (dt, J ) 1.5 Hz, J ) 7.5 Hz, 1H), 7.31-7.29
(m, 1H), 7.28-7.26 (m, 1H), 7.16 (dd, J ) 1.5 Hz, J ) 7.5
Hz, 1H), 6.48, (d, 1H), 3.82-3.80 (m, 4H), 3.68-3.66 (m,
4H), 2.25 (s, 3H); 13C NMR (CDCl3) δ 159.6, 154.0, 153.1,
136.8, 135.2, 130.6, 129.2, 128.7, 126.0, 117.9, 106.3, 98.4,
66.5, 44.8, 19.7; IR (KBr) 2967, 2892, 2853, 2210, 1593,
1503, 1444 cm-1. Anal. Calcd for C17H17N3O: C, 73.10; H,
6.13; N, 15.04. Found: C, 73.40; H, 6.18; N, 15.03.
5-Cyano-4-(2-methylphenyl)-2-(4-methylpiperazinyl)-
pyridine 31b. A mixture of 20.00 g (61.19 mmol) of the
chloropyridine 30b, 9.38 mL (6.81 g, 67.3 mmol, 1.1 equiv)
of triethylamine, 25.8 mg of Pd(OH)2 or 190 mg (0.184
mmol, 0.300 mol %) of 20% palladium hydroxide on carbon
[Pearlman’s catalyst, 32.2% LOD], and 80 mL of methanol
was stirred in a 300 mL Parr bottle at 25 °C and 48.3-43.0
psi hydrogen for 10 h.
2-Chloro-3-cyano-4-(4-fluoro-2-methylphenyl)-6-(thio-
morpholino)pyridine 30d. Crude dichloride 29c (32.44 g,
115.4 mmol) and 300 mL of methanol were added to a 500
mL three-necked flask (with a 25 mL pressure-equilibrating
addition funnel/dry N2 adapter, septum with a Teflon-coated
thermocouple, and Teflon paddle stirrer/glass shaft). Thio-
morpholine (23.0 mL, 25.0 g, 242 mmol, 2.10 equiv) was
added dropwise over 22 min, and the resulting suspension
was stirred at 20-25 °C for 18 h. The precipitate was suction
filtered, washed with 30 mL of methanol, and then dried in
vacuo (vacuum pump at 25 °C and 1 mmHg for 24 h) to
afford 35.47 g (88.4%) of 30d as a beige solid.
An analytical sample was prepared by recrystallization
from ethanol, mp 195.3-197.3 °C; 1H NMR (CDCl3) δ 7.13
(dd, J ) 5.5 Hz, J ) 8.5 Hz, 1H), 7.01 (dd, J ) 3.0 Hz, J
) 10 Hz, 1H), 6.97 (dt, J ) 3.0 Hz, J ) 8.5 Hz, 1H), 6.33
(s, 1H), 4.04 (br, 4H), 2.70 (br t, J ) 5.0 Hz, 4H), 2.25 (s,
3H); 13C NMR (CDCl3) δ 163.3 (d, J ) 247 Hz), 157.7,
156.2, 153.4, 138.3 (d, J ) 8.5 Hz), 132.7 (d, J ) 3.1 Hz),
130.5 (d, J ) 8.5 Hz), 117.7 (d, J ) 21.3 Hz), 116.0, 113.4
(d, J ) 21.6 Hz), 105.3, 97.5, 48.1, 27.0, 20.2 (d, J ) 1.6
Hz); IR (KBr) 2219, 1594, 1581, 1502, 1489, 1448, 1432
cm-1. Anal. Calcd for C17H15ClFN3S: C, 58.70; H, 4.35; N,
12.08. Found: C, 58.76; H, 4.43; N, 12.04.
2-Chloro-3-cyano-4-(4-fluoro-2-methylphenyl)-6-(1,1-
dioxo-thiomorpholin-4-yl)pyridine 30c. Oxone (56.18 g,
91.4 mmol) was added to a solution of 26.54 g (76.3 mmol)
of the sulfide 30d in 200 mL of NMP in a 1000 mL three-
necked flask (with a Teflon paddle stirrer, septum with a
Teflon-coated thermocouple, and dry N2 adapter). The
suspension was stirred at 25 °C for 20 h (cool H2O bath).
Water (800 mL) was added, and the suspension was stirred
at 25 °C for 30 min. The precipitate was suction filtered
using a 350 mL coarse sintered glass funnel, slurry-washed
several times with H2O on the funnel, and air-dried 24 h at
25 °C to afford 29.30 g (101.1%) of 30c as a colorless solid.
An analytical sample was prepared by recrystallization
The pressure was vented, and the mixture was diluted with
40 mL of H2O. The suspension was transferred to a round-
bottom flask using 40 mL of methanol. Volatiles were
removed on a rotary evaporator at 35 °C and 60-30 mmHg.
The resulting suspension was diluted with 80 mL of toluene
and then suction filtered through 2.0 g of cellulose powder
on a coarse sintered glass funnel. The catalyst-celite cake
was washed with 10 mL of fresh toluene 3 times. A solution
of 2.80 g (70.1 mmol) of sodium hydroxide in 5 g of H2O
was added to the combined mother liquors. The layers were
separated, and the aqueous (pH ) 13-14) layer was
extracted with 20 mL of toluene 3 times. The combined
organic layers were concentrated in vacuo (rotary evaporator
at 35 °C and 30 mmHg). The residual yellow syrup was taken
up in 100 mL of toluene, washed with dilute HCl (20.5 mL,
20 mL of H2O with 0.5 mL of 12 N HCl), washed with 20
mL of H2O, and then concentrated in vacuo (rotary evapora-
tor at 35 °C and 30 mmHg, trituration with hexanes, and
then vacuum pump at 25 °C and ∼1 mmHg for 21 h) to
afford 16.85 g (94.2%) of 31b as a near-colorless solid.
An analytical sample was prepared by recrystallization
1
from acetonitrile, mp 264-267 °C H NMR (DMSO-d6) δ
7.30 (dd, J ) 5.5-6 Hz, J ) 8.8 Hz, 1 H), 7.26 (dd, J ) 2.5
Hz, J ) 10 Hz, 1H), 7.17 (dd, J ) 2.5 Hz, J ) 8.5-9.0 Hz,
1H), 7.07 (s, 1H), 4.15 (m, 4H), 3.22 (br, 4H), 2.22 (s, 3H);
13C NMR (DMSO-d6) δ 163.1 (d, J ) 244 Hz), 158.2, 155.8,
152.1, 139.1 (d, J ) 8.4 Hz), 133.3 (d, J ) 2.9 Hz), 131.6
(d, J ) 8.8 Hz), 117.6 (d, J ) 21.3 Hz), 116.4, 113.6 (d, J
) 21.3 Hz), 107.9, 97.5, 51.2, 44.1, 20.1; IR (KBr) 2930,
2223, 1588, 1522, 1500, 1494, 1474, 1429, 1125 cm-1. Anal.
Calcd for C17H15ClFN3O2S: C, 53.76; H, 3.98; N, 11.06.
Found: C, 53.76; H, 3.94; N, 11.06.
5-Cyano-4-(2-methylphenyl)-2-(4-morpholinyl)pyri-
dine 31a. A mixture of 20.00 g (63.74 mmol) of the
chloropyridine 30a, 9.77 mL (7.10 g, 70.11 mmol, 1.1 equiv)
of triethylamine, 33.9 mg of Pd(OH)2 or 249 mg (0.242
mmol, 0.379 mol %) of 20% palladium hydroxide on carbon
[Pearlman’s catalyst, 32.2% LOD], and 80 mL of methanol
was stirred in a 300 mL Parr bottle at 25 °C and 48.0-41.3
psi hydrogen for 21 h.
1
from isopropanol, mp 109.5-110.4 °C; H NMR (CDCl3)
1164
•
Vol. 10, No. 6, 2006 / Organic Process Research & Development

δ 8.46 (s, 1H), 7.34 (t, J ) 7 Hz, 1H), 7.30 (d, J ) 7 Hz,
1H), 7.26 (t, J ) 7.5 Hz, 1H), 7.16 (dd, J ) 7.5 Hz, 1H),
6.49 (s, 1H), 3.72 (br t, 4H), 2.50 (t, J ) 5 Hz, 4H), 2.35 (s,
3H), 2.25 (s, 3H); 13C NMR (CDCl3) δ 159.7, 154.0, 153.4,
137.2, 135.5, 130.8, 129.3, 128.9, 126.2, 118.3, 106.6, 98.0,
54.9, 46.4, 44.7, 20.0; IR (KBr) 3019, 2936, 2884, 2848,
2793, 2210, 1607, 1590, 1504 cm-1. Anal. Calcd for
C18H20N4: C, 73.94; H, 6.90; N, 19.16. Found: C, 74.04;
H, 7.03; N, 18.98.
5-Cyano-4-(4-fluoro-2-methylphenyl)-2-(1,1-dioxo-thio-
morpholin-4-yl)pyridine 31c. A 300 mL Parr bottle was
charged with 19.86 g (52.29 mmol) of the crude chloropy-
ridine 30c, 10.9 mL (7.94 g, 78.4 mmol, 1.50 equiv) of
triethylamine, 220 mg of Pd(OH)2 or 1.62 g (1.57 mmol,
3.0 mol %) of 20% palladium hydroxide on carbon [Pearl-
man’s catalyst, 32.2% LOD], and 100 mL of dry DMF. The
suspension was stirred at 25 °C and 48.9-43.2 psi hydrogen
for 25.5 h.
The pressure was vented. The suspension was suction
filtered through 5.0 g of cellulose on a coarse sintered glass
funnel. The catalyst-cellulose cake was washed with 10 mL
of fresh DMF. Water (400 mL) was added to the mother
liquors, and the resulting suspension was stirred at 25 °C
for 30 min. The precipitate was suction filtered, washed
several times with H2O, and air-dried for 3 h at 25 °C to
afford 17.52 g (97.0%) of 31c as a slightly gray solid (97%
conversion).
A 300 mL Parr bottle was charged with 17.31 g of the
crude 31c, 7.3 mL (5.30 g, 52.4 mmol) of triethylamine, 148
mg of Pd(OH)2 or 1.09 g (1.05 mmol) of 20% palladium
hydroxide on carbon [Pearlman’s catalyst, 32.2% LOD], and
100 mL of dry DMF. The suspension was stirred at 25 °C
and 42.5-28.2 psi hydrogen for 23 h.
The pressure was vented. The suspension was suction
filtered through 5.0 g of cellulose on a coarse sintered glass
funnel. The catalyst-cellulose cake was washed with 10 mL
of fresh DMF. Water (400 mL) was added to the mother
liquors, and the resulting suspension was stirred at 25 °C
for 30 min. The precipitate was suction filtered, washed
several times with H2O, and air-dried 5 h at 25 °C to afford
17.04 g (95.5%) of 31c as a colorless solid (100% conver-
sion).
An analytical sample was prepared by recrystallization
from acetonitrile, mp 219.5-220.5 °C; 1H NMR (CDCl3) δ
8.52 (d, J ) 1 Hz, 1H), 7.14 (dd, J ) 5.5 Hz, J ) 8.5 Hz,
1H), 7.04 (dd, J ) 2.5 Hz, J ) 9.5 Hz, 1H), 7.00 (dd, J )
2.5 Hz, J ) 8.5 Hz, 1H), 6.61 (d, J ) 1 Hz, 1H), 4.27 (br
t, 4H), 3.10 (br t, 4H), 2.24 (s, 3H); 13C NMR (CDCl3) δ
163.4 (d, J ) 248 Hz), 157.9, 154.4, 153.6, 138.2 (d, J )
8.0 Hz), 132.5 (d, J ) 3.3 Hz), 130.7 (d, J ) 8.8 Hz), 117.8
(d, J ) 21.6 Hz), 117.2, 113.5 (d, J ) 21.6 Hz), 107.2, 100.6,
51.6, 43.8, 20.2; IR (KBr) 2930, 2217, 1599, 1531, 1494,
1432, 1123, 1117 cm-1. Anal. Calcd for C17H16FN3O2S: C,
59.12; H, 4.67; N, 12.17. Found: C, 59.19; H, 4.69; N, 12.17.
4-(2-Methylphenyl)-6-(4-morpholinyl)-3-pyridinecar-
boxamide 19a (Method A). A suspension of 17.71 g of the
crude nitrile 31a (LC assay 91.8-93.9 wt %), 18 mL of
toluene, and 17.0 mL (33.1 g, 319 mmol) of concentrated
sulfuric acid was heated at 70 °C for 12 h. The suspension
was cooled and then quenched by addition of 100 mL of
cold H2O. Ethyl acetate (100 mL) was added followed by a
solution of 25.5 g (638 mmol) of sodium hydroxide in 50 g
of H2O at 25-30 °C. The layers were separated. The aqueous
layer was extracted 3 times with 50 mL of ethyl acetate.
The combined organic layers were concentrated in vacuo
(rotary evaporator at 35 °C and 70-50 mmHg, trituration
with 25 °C hexanes, and then vacuum pump at 25 °C and 1
mmHg for 17 h) to afford 19.14 g of 19a as a colorless solid
(LC assay 87.7 wt %)(yield 94.9-97%).
An analytical sample was prepared by filtration through
a plug of silica gel and recrystallization from ethyl acetate,
1
mp 144-145.5 °C; H NMR (CDCl3) δ 8.93 (s, 1H), 7.36
(dt, J ) 1.5 Hz, J ) 7.5 Hz, 1H), 7.32-7.29 (m, 2H), 7.21-
7.20 (m, 1H), 6.30 (s, 1H), 5.6 (br, 1H), 5.1 (br, 1H), 3.82-
3.80 (m, 4H), 3.64-3.62 (m, 4H), 2.15 (s, 3H); 13C NMR
(CDCl3) δ 168.0, 160.1, 151.8, 149.5, 139.0, 135.8, 130.7,
129.0, 128.2, 126.5, 117.6, 106.2, 66.6, 45.0, 19.8; IR (KBr)
3462, 3300-3000, 2959, 2854, 1660, 1584, 1491, 1391
cm-1. Anal. Calcd for C17H19N3O2: C, 68.67; H, 6.44; N,
14.13. Found: C, 68.78; H, 6.48; N, 14.11.
4-(2-Methylphenyl)-6-(4-morpholinyl)-3-pyridinecar-
boxamide 19a (Method B). A mixture of 5.00 g (15.1 mmol)
of the 2-chloropyridine-3-carboxamide 33, 2.31 mL (1.68
g, 16.5 mmol, 1.1 equiv) of triethylamine, 6.4 mg of Pd-
(OH)2 or 47 mg (0.0453 mmol, 0.30 mol %) of 20%
palladium hydroxide on carbon [Pearlman’s catalyst, 32.2%
LOD], and 50 mL of methanol was stirred in a 300 mL Parr
bottle at 25 °C and 40.2-31.2 psi hydrogen for 21 h.
The pressure was vented. The suspension was then suction
filtered through 2.0 g of cellulose powder on a coarse sintered
glass funnel. The catalyst-celite cake was washed with 10
mL of methanol twice. Methanol was removed on a rotary
evaporator at 35 °C and 60 mmHg. The residue was taken
up in 25 mL of toluene and 10 mL of H2O. A solution of
660 mg (16.5 mmol) of sodium hydroxide in 2 g of H2O
was added. The layers were separated, and the aqueous layer
was extracted with 10 mL of toluene 3 times. The combined
organic layers were dried (MgSO4), filtered, and concentrated
in vacuo (rotary evaporator at 35 °C and 30 mmHg,
trituration with hexanes, and then vacuum pump at 25 °C
and ∼1 mmHg for 15 h) to afford 4.24 g (94.6%) of 19a as
a colorless solid.
4-(2-Methylphenyl)-6-(4-methylpiperazinyl)-3-pyridi-
necarboxamide 19b. A suspension of the crude nitrile 31b
(16.85 g, 57.6 mmol), 18 mL of toluene, and 27 mL (49.7
g, 507 mmol) of concentrated sulfuric acid was heated at 70
°C for 12 h. The suspension was cooled and then quenched
by addition of 200 mL of cold H2O. Ethyl acetate was added
followed by a solution of 45.6 g (1.14 mol) of sodium
hydroxide in 200 g of H2O at 20-25 °C. Water (200 mL)
was added to dissolve the precipitated salt. The layers were
separated. The aqueous layer was extracted with 100 mL of
ethyl acetate several times. The combined organic layers were
concentrated in vacuo (rotary evaporator at 35 °C and 75
mmHg, trituration with 25 °C hexanes, and then vacuum
pump at 25 °C and 1 mmHg for 17 h) to afford 17.55 g
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1165

(98.1%) of 19b as a colorless solid.
sodium hydroxide in 120 g of H2O at 20-25 °C. The
precipitate was suction filtered. The filtered precipitate was
dried in vacuo (vacuum pump at 25 °C and 1 mmHg for 17
h) to afford 16.83 g (94.8%) of 33 as a colorless solid.
An analytical sample was prepared by recrystallization
from toluene to afford shiny colorless needles, mp 217-
219 °C; 1H NMR (CDCl3) δ 7.28 (dd, 1H), 7.23 (d, J ) 7.0
Hz, 1H), 7.19 (dd, 1H), 7.12 (d, J ) 7.5 Hz, 1H), 6.32 (s,
1H), 5.72 (br, 1H), 5.43 (br, 1H), 3.79 (m, 4H), 3.55 (m,
4H), 2.20 (s, 3H); 13C NMR (CDCl3) δ 167.9, 158.2, 152.4,
146.6, 138.0, 135.5, 130.6, 128.8, 128.5, 125.8, 120.8, 105.7,
66.7, 45.3, 20.3; IR (KBr) 3393, 3197, 2970, 2920, 2900,
2861, 1666, 1607, 1594, 1525 cm-1. Elem. Anal. Calcd for
C17H18ClN3O2: C, 61.54; H, 5.47; N, 12.66. Found: C,
61.65; H, 5.44; N, 12.56.
2,6-Dichloro-4-(2-methylphenyl)-3-pyridinecarboxam-
ide 34. A mixture of 15.00 g (57.0 mmol) of the nitrile 29a
and 15 mL of concentrated sulfuric acid was heated at 100
°C for 3 h. The mixture was cooled and quenched by the
addition of 150 mL of H2O. The suspension was extracted
with ethyl acetate 3 times. The combined organic layers were
washed with 50 mL of H2O twice, dried (MgSO4), filtered,
and concentrated in vacuo (rotary evaporator at 35 °C and
80 mmHg, hexanes trituration, and then vacuum pump at
25 °C and 1 mmHg for 17 h) to afford 11.99 g (74.8%) of
34 as a near-colorless solid.
An analytical sample was prepared by recrystallization
from isopropanol and final recrystallization from toluene-
1
hexanes, mp 127.5-128.5 °C; H NMR (CDCl3) δ 8.92 (s,
1H), 7.35 (m, J ) 1.5 Hz, J ) 7-8 Hz, 1H), 7.31-7.28 (m,
2H), 7.21 (m, 1H), 6.31 (s, 1H), 3.68 (br t, J ) 5 Hz, 4H),
2.51 (t, J ) 5 Hz, 4H), 2.35 (s, 3H), 2.15 (s, 3H); 13C NMR
(CDCl3) δ 168.4, 160.2, 152.1, 149.7, 139.4, 136.0, 130.9,
129.2, 128.4, 126.7, 117.3, 106.5, 55.0, 46.4, 44.8, 20.0; IR
(KBr) 3459, 3324, 3273, 3168, 2967, 2935, 2849, 2795,
1665, 1581 cm-1. Anal. Calcd for C18H22N4O: C, 69.65; H,
7.14; N, 18.05. Found: C, 69.76; H, 7.33; N, 17.92.
4-(4-Fluoro-2-methylphenyl)-6-(1,1-dioxo-thiomorpho-
lin-4-yl)pyridine-3-carboxamide 19c. A mixture of 14.80
g (42.85 mmol) of nitrile 31c, 15 mL of toluene, and 15 mL
(27.6 g, 281 mmol) of concentrated sulfuric acid was heated
in a 500 mL flask (with dry N2 adapter and Teflon stirbar)
at 70 °C for 12 h.
The suspension was cooled and quenched by the addition
of 150 mL of cold H2O. A solution of 22.8 g (570 mmol) of
sodium hydroxide in 200 mL of H2O was added dropwise
at 25-30 °C over 15 min. The precipitate was suction
filtered, washed with H2O, and air-dried for 21 h at 25 °C
to afford 15.68 g (100.7%) of 19c as a colorless solid (2 wt
% toluene remains).
An analytical sample was prepared by recrystallization
from acetonitrile, m.p.235-236 °C; 1H NMR (DMSO-d6) δ
8.38 (s, 1H), 7.36 (br, 1H), 7.13 (dd, J ) 6 Hz, J ) 8.5 Hz,
1H), 7.09-7.07 (m, 2H), 7.02 (dt, J ) 2.5 Hz, J ) 8.5 Hz,
1H), 6.78 (s, 1H), 4.11 (br, 4H), 3.11 (br, 4H), 2.10 (s, 3H);
13C NMR (DMSO-d6) δ 166.9, 160.3 (d, J ) 241 Hz), 155.8,
148.2, 146.3, 136.7 (d, J ) 8.0 Hz), 134.6 (d, J ) 2.8 Hz),
129.1 (d, J ) 8.4 Hz), 121.3, 114.8 (d, J ) 20.8 Hz), 110.8
(d, J ) 20.8 Hz), 107.2, 49.3, 42.1, 18.7; IR (KBr) 3446,
3324, 3147, 1663, 1608, 1575, 1496, 1399, 1372, 1121 cm-1.
Anal. Calcd for C17H18FN3O3S: C, 56.19; H, 4.99; N, 11.56.
Found: C, 56.14; H, 4.99; N, 11.88.
2-Chloro-4-(2-methylphenyl)-6-(4-morpholinyl)-3-py-
ridinecarboxamide 33. A suspension of 16.80 g (53.5 mmol)
of nitrile 30a, 15 mL of toluene, and 14.3 mL (26.2 g, 268
mmol) of concentrated sulfuric acid was heated at 70 °C for
120 h. The suspension was cooled and then quenched by
addition of 160 mL of cold H2O. Isopropyl acetate (150 mL)
was added followed by a solution of 24.46 g (612 mmol) of
An analytical sample was prepared by recrystallization
1
from toluene, mp 154-156 °C; H NMR (CDCl3) δ 7.34
(dt, J ) 1.5 Hz, J ) 7.5 Hz, 1H), 7.27 (d, J ) 7.5 Hz, 1H),
7.23 (t, J ) 8 Hz, 1H), 7.20 (s, 1H), 7.12 (dd, J ) 1 Hz, J
) 7.5 Hz, 1H), 5.76 (br, 1H), 5.53 (br, 1H), 2.18 (s, 3H);
13C NMR (CDCl3) δ 166.0, 153.4, 150.6, 147.4, 135.4, 135.3,
130.9, 129.7, 128.5, 126.1, 124.5, 95.0, 20.4; IR (KBr) 3391,
3303, 3167, 2360, 2350-2340, 1685, 1565, 1525 cm-1.
Elem. Anal. Calcd for C13H10Cl2N2O: C, 55.54; H, 3.59; N,
9.96. Found: C, 55.51; H, 3.57; N, 9.81.
Supporting Information Available
A detailed description of the HPLC method. This material
is available free of charge via the Internet at http://
pubs.acs.org.
Received for review June 27, 2006.
OP060128M
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