Efficient synthesis of novel NK1 receptor antagonists: Selective 1,4-addition of Grignard reagents to 6-chloronicotinic acid derivatives

Article abstract of DOI:10.1021/jo0523666

A new efficient synthesis of two novel classes of NK₁ receptor antagonists, among them befetupitant and netupitant, starting from 6-chloronicotinic acid is described. The introduction of the o-tolyl substituent at C(4) of the pyridine ring was achieved by a one-pot selective 1,4-Grignard addition/oxidation sequence to 6-chloronicotinic acid or a derivative of it. The scope of this addition/oxidation sequence was examined. It was also shown that the carboxylic function can be converted to a methyl amino group by a Hofmann rearrangement followed by reduction. Furthermore, a new high-yielding synthesis of 2-(3,5-bistrifluoromethylphenyl)-2-methyl propionic acid based on the carbonylation of the tertiary alcohol obtained by Grignard addition of 3,5-bis(trifluoromethyl)bromobenzene to acetone was established.

Full text of DOI:10.1021/jo0523666

Efficient Synthesis of Novel NK1 Receptor Antagonists: Selective
1,4-Addition of Grignard Reagents to 6-Chloronicotinic Acid
Derivatives
Fabienne Hoffmann-Emery,*,† Hans Hilpert,‡ Michelangelo Scalone,† and Pius Waldmeier†
F. Hoffmann-La Roche Ltd., Pharmaceuticals DiVision, Safety & Technical Sciences, Synthesis & Process
Research, Grenzacherstrasse 124, CH-4070 Basel, Switzerland, and F. Hoffmann-La Roche Ltd.,
Pharmaceuticals DiVision, DiscoVery Chemistry, Lead Generation, Grenzacherstrasse 124,
CH-4070 Basel, Switzerland
fabienne.hoffmann-emery@roche.com
ReceiVed NoVember 16, 2005
A new efficient synthesis of two novel classes of NK1 receptor antagonists, among them befetupitant
and netupitant, starting from 6-chloronicotinic acid is described. The introduction of the o-tolyl substituent
at C(4) of the pyridine ring was achieved by a one-pot selective 1,4-Grignard addition/oxidation sequence
to 6-chloronicotinic acid or a derivative of it. The scope of this addition/oxidation sequence was examined.
It was also shown that the carboxylic function can be converted to a methyl amino group by a Hofmann
rearrangement followed by reduction. Furthermore, a new high-yielding synthesis of 2-(3,5-bistrifluo-
romethylphenyl)-2-methyl propionic acid based on the carbonylation of the tertiary alcohol obtained by
Grignard addition of 3,5-bis(trifluoromethyl)bromobenzene to acetone was established.
Introduction
anxiety and in the control of chemotherapy-induced nausea and
vomiting.4 Two compound classes such as the nicotinamide 1
and the “inverse nicotinamides” befetupitant (2) and netupitant
(3) have been identified at Roche as potent in vitro and in vivo
NK1 receptor antagonists.5
Neurokinin (NK) receptors belong to the family of G-protein
coupled receptors and are divided into three subtypes: NK1,
NK2, and NK3. The endogenous ligand for the NK1 receptors
is the 11 amino acid neuropeptide substance P.1 Following the
discovery of the first non-peptide NK1 receptor antagonist CP-
96,345,2 a remarkable number of structurally diverse small
molecule NK1 receptor antagonists have been identified by many
pharmaceutical companies in the past decade.3 Recent clinical
trials have demonstrated important therapeutic applications for
NK1 receptor antagonists in the treatment of depression and
The strategy applied by Discovery Chemistry to synthesize
compounds 1-3 and a large number of their congeners relied
on an ortho-metalation-iodination sequence of 2,5-disubstituted
pyridines 5, 9, and 10 followed by a Suzuki coupling to allow
for rapid parallel lead optimization (Schemes 1 and 2). The
n
iodination step required a large excess of BuLi (3-4 equiv),
low temperature (-78 °C), and afforded only moderate yields.
In addition, o-tolylboronic acid used to introduce the aryl moiety
† Safety & Technical Sciences, Synthesis & Process Research.
‡ Discovery Chemistry, Lead Generation.
(1) Almeida, T. A.; Rojo, J.; Nieto, P. M.; Pinto, F. M.; Hernandez, M.;
Martin, J. D.; Candenas, M. L. Curr. Med. Chem. 2004, 11, 2045-2081
and references therein.
(2) (a) Snider, R. M.; Constantine, J. W.; Lowe, J. A., III; Longo, K. P.;
Lebel, W. S.; Woody, H. A.; Drozda, S. E.; Desai, M. C.; Vinick, F. J.;
Spencer, R. W.; Hess, H.-J. Science 1991, 251, 435-437. (b) Lowe, J. A.,
III; Drozda, S. E.; Snider, R. M.; Longo, K. P.; Zorn, S. H.; Morrone, J.;
Jackson, E. R.; McLean, S.; Bryce, D. K.; Bordner, J.; Nagahisa, A.; Kanai,
Y.; Suga, O.; Tsuchiya, M. J. Med. Chem. 1992, 35, 2591-2600.
(3) Albert, J. S. Expert Opin. Ther. Pat. 2004, 14, 1421-1433 and
references therein.
(4) Duffy, R. A. Expert Opin. Emerging Drugs 2004, 9, 9-21 and
references therein.
(5) (a) Bo¨s, M.; Branca, Q.; Galley, G.; Godel, T.; Hoffmann, T.;
Hunkeler, W.; Schnider, P.; Stadler, H. EP1035115, 2000. (b) 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, 1362-1365.
10.1021/jo0523666 CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/09/2006
2000
J. Org. Chem. 2006, 71, 2000-2008

Synthesis of NoVel NK1 Receptor Antagonists
SCHEME 1
SCHEME 2
SCHEME 3
at C(4) of the pyridine ring was rather expensive. By this
approach, 1 was prepared in five linear steps with an overall
yield of 19% and 2 and 3 were prepared in nine steps with an
overall yield of 21% and 15%, respectively. To supply larger
amounts of these compounds for clinical evaluation, a cheaper,
higher yielding, and technically feasible synthesis was therefore
required. Herein, we report a practical and efficient approach
for both compound classes.6
pyridine chemistry shows that nucleophilic addition of orga-
nolithium or magnesium compounds to 3-substituted pyridines
often requires quaternization of the heterocyclic nitrogen, and
the regioselectivity depends on the structure of the nucleophile
and of the substituent.7 1,4-Regioselectivity was enhanced in
alkyl nicotinates by quaternization of the heterocyclic nitrogen
and by the use of organocopper reagents.8 However, the
oxazoline of nicotinic acid led to 1,4-dihydropyridine after
Results and Discussion
We considered introducing the C(4) substituent of compounds
1-3 by treating a 6-chloronicotinic acid derivative with
o-tolylmagnesium chloride to obtain an o-tolylpyridine of
structure 16 (Scheme 3). The subsequent steps toward 1 would
then be straightforward. For 2 and 3, the carboxyl function of
16 should be rearranged to known methylamines 13 and 14. A
new route to the acid chloride 15 starting with cheap bromoben-
zene 17 was also envisaged (vide infra). The well-reported
(7) For reviews on the chemistry of dihydropyridines, see: (a) Eisner,
U.; Kuthan, J. Chem. ReV. 1972, 72, 1-16. (b) Stout, D. M.; Meyers, A. I.
Chem. ReV. 1982, 82, 223-243. For reviews on regioselective substitution,
see: (c) Comins, D. L.; O’Connor, S. AdV. Heterocycl. Chem. 1988, 44,
199-267.
(8) (a) Comins, D. L.; Stroud, E. D.; Herrick, J. J. Heterocycles 1984,
22, 151-157. (b) Shiao, M.-J.; Chia, W.-L.; Shing, T.-L.; Chow, T. J. J.
Chem. Res. (S) 1992, 247. (c) Bennasar, M.-L.; Juan, C.; Bosch, J.
Tetrahedron Lett. 1998, 39, 9275-9278.
(6) These syntheses have been described in patents: Hilpert, H.;
Hoffmann-Emery, F.; Rimmler, G.; Rogers-Evans, M.; Stahr, H. EP1103546,
2001.
J. Org. Chem, Vol. 71, No. 5, 2006 2001

Hoffmann-Emery et al.
SCHEME 4
treatment with organometallic reagents without activation.9 Ethyl
and arylmagnesium bromide were added to the center C(4) of
N-methyl or N-tert-butyl nicotinamide carrying an electron-
withdrawing group at the center C(5) or C(6).10 A good yield
of 4-alkyl or 4-aryl nicotinamide was obtained after oxidation
with NCS. N-(Phenyl)pyridine-3-carboxamide11 and N-(tert-
butyl)pyridine-3-carboxamide12 were reported to undergo 1,4-
addition of organolithium and organomagnesium reagents,
respectively, whereas the corresponding 2- and 4-regioisomers
were deprotonated.
Synthesis of 1. These literature precedents led us to treat
methyl nicotinamide 18 (easily prepared from 6-chloronicotinic
acid (4) via the acid chloride) with o-tolylmagnesium chloride
without further activation. The reaction was clean and gave
presumably a mixture of the dihydropyridines 19 and 20
(Scheme 4), which were unstable upon solvent removal. Thus,
the extraction solution was oxidized with KMnO4 producing
21 in 79% yield after chromatography and 21 was further treated
with N-methylpiperazine affording 6 quantitatively as a crude
product. Alternatively, the solution containing 19 and 20 was
first treated with N-methylpiperazine to form the crude substitu-
tion product 22 in 94% yield, which was oxidized with MnO2
leading to 6 in 81% yield after chromatography. As already
described by Discovery Chemistry, alkylation of 6 with ben-
zylbromide 7 in the presence of KHMDS gave 1 in 74% yield.5a
Thus, the new route delivered 1 in only four steps with an overall
yield of 47%.
tolylpyridine 31 in only a moderate yield of 51% and the same
addition to 30 resulted in a complex mixture (Scheme 5).
Because the methylamide 18, a secondary amide, provided good
results, tert-butylamide 23 and benzylamide 24 were prepared
via the acid chloride of 4. Compounds 23 and 24 both underwent
regioselective addition of o-tolylmagnesium chloride giving
o-tolylpyridine 25 following a one-pot oxidation with DDQ14
in 98% yield after chromatography and o-tolylpyridine 26 after
oxidation with Mn(OAc)3 in 88% yield after chromatography,
respectively. Yields obtained with other oxidants are sum-
marized in Table 1.
Attempts to isolate the addition product after aqueous workup
led to the corresponding pyridone as exemplified for the
benzylamide 24 in eq 1.
The o-tolylpyridines 25 and 26 were heated in neat morpho-
line to yield the crude substitution products 27 and 28 in
quantitative yield. Crude 25 obtained after removal of THF and
precipitation of the salts by trituration in tert-butylmethyl ether
was also treated with morpholine. After an aqueous basic
workup, crude 27 was obtained in 89% yield based on 23.
Cleavage of the tert-butyl group of 27 was best performed in
neat methanesulfonic acid at 100 °C for 5 h giving 95% crude
primary amide 33. The cleavage of the benzyl group of 28 turned
out to be more tedious. Hydrogenolysis resulted in a complex
mixture, whereas heating 28 in methanesulfonic acid and sulfuric
acid (5:1) at 100 °C for 6 h afforded 33 in only 39% yield.
Compound 2 carries a methylamino group at C(3) of the
pyridine ring. Because monoalkylation of amines via direct
alkylation is known to be difficult leading partially to dialkylated
products, monomethylation was reported to be achieved by
converting the amine to the corresponding formimine,15 forma-
Synthesis of 2 and 3. To access the inverse nicotinamides 2
and 3, the same strategy as that for 1 was used to introduce the
aryl substituent at C(4), followed by a Hofmann rearrangement
to convert the carboxylic function at C(3) into an amine.
Performing the Grignard addition/oxidation sequence on primary
amide 30 or on acid 4 offered the shortest route to 2 and 3.
However, the addition of o-tolylmagnesium chloride to 4
followed by a one-pot oxidation with Mn(OAc)313 afforded 4-o-
(9) (a) Meyers, A. I.; Gabel, R. A. Heterocycles 1978, 11, 133-138. (b)
Meyers, A. I.; Gabel, R. A. J. Org. Chem. 1982, 47, 2633-2637.
(10) Schlecker, W.; Huth, A.; Ottow, E.; Mulzer, J. Tetrahedron 1995,
51, 9531-9542.
(11) Epsztajn, J.; Bieniek, A.; Brzezinski, J. Z.; Jozwiak, A. Tetrahedron
Lett. 1983, 24, 4735-4738.
(12) Bonnet, V.; Mongin, F.; Tre´court, F.; Que´guiner, G. J. Chem. Soc.,
Perkin Trans. 1 2000, 4245-4249.
(14) Vanden Eynde, J. J.; Delfosse, F.; Mayence, A.; Van Haverbeke,
Y. Tetrahedron 1995, 51, 6511-6516.
(13) Varma, R. S.; Kumar, D. Tetrahedron Lett. 1999, 40, 21-24.
2002 J. Org. Chem., Vol. 71, No. 5, 2006

Synthesis of NoVel NK1 Receptor Antagonists
SCHEME 5
TABLE 1. Addition of o-Tolylmagnesium Chloride to Nicotinic
mide,16 alkyl imidate,17 or into a carbamate18 followed by a
reduction. Thus, amide 33 was rearranged to the corresponding
methyl carbamate 35, which was reduced to the desired
methylamine 13. The conditions of the Hofmann rearrangement
best run between -5 °C and 0 °C were inspired by the work of
Senanayake.19 The optimal ratio of base to N-bromosuccinimide
has been reported to be 2.5:1. In our case, 1.4 equiv of NBS
and 3.5 equiv of sodium methoxide had to be used to reach
complete conversion. Dichloromethane replaced advantageously
methanol as the solvent, simplifying the workup because no
solvent had to be removed before the extraction and keeping
the yield unchanged at 86% of 35 after crystallization. The
reduction of the methyl carbamate 35 was successfully achieved
using Red-Al20 in toluene at 50 °C for 2 h yielding 81% of
methylamine 13 after crystallization. A portion of 4.7 equiv of
Red-Al was required to achieve complete conversion. Alterna-
tively, 10 equiv of a commercial LiAlH4 solution in THF and
heating at 50 °C for 24 h brought the reduction also to
completion in nearly quantitative crude yield. However, with
solid LiAlH4 in dioxane, the reaction did not take place even at
100 °C.
Acid Derivativesa
yieldb
entry compd
A
B
H
Y
oxidant
KMnO4
(%)
1
2
4
Cl
OH
31 (33)
Mn(OAc)3 31 (51)
NHtBu KMnO4
25 (26)
Mn(OAc)3 25 (46)
DDQ 25 (98)
o-chloranil 25 (82)
23
Cl
Cl
H
3
24
H
NHBn KMnO4
26 (45)
Mn(OAc)3 26 (88)
DDQ
DDQ
26 (66)
39 (86)
41 (84)
27 (44)
44 (55)c
complex
4
5
6
7
8
38
40
42
43
45
Cl
Me
morpholinyl
H
H
H
NEt2
NHtBu DDQ
NHtBu DDQ
Cl
Cl
Cl NHtBu DDQ
Coupling of methylamine 13 with the acid chloride 15 in the
presence of Hu¨nig’s base in dichloromethane gave 2 in 86%
H
H
OMe
mixture21
complex
mixture
9
46
Cl
OtBu
(15) (a) Kessler, P.; Chatrenet, B.; Goeldner, M.; Hirth, C. Synthesis
1990, 1065-1068. (b) Barluenga, J.; Bayo´n, A. M.; Asensio, G. J. Chem.
Soc., Chem. Commun. 1984, 1334-1335.
a The addition was run in THF using 3.0-5.0 equiv. of o-tolylmagnesium
chloride. The mixture was neutralized using AcOH or MeOH, and the
oxidant was added. b Yield of product isolated after chromatography.
c Isolated after digestion; not optimized.
(16) Krishnamurthy, S. Tetrahedron Lett. 1982, 23, 3315-3318.
(17) Crochet, R. A., Jr.; DeWitt, B. C., Jr. Synthesis 1974, 55-56.
(18) (a) Ganesan, A.; Heathcock, C. H. Tetrahedron Lett. 1993, 34, 439-
440. (b) Carbamate prepared by a Hofmann rearrangement: Granados, R.;
Alvarez, M.; Lopez-Calahorra, F.; Salas, M. Synthesis 1983, 329-330.
(19) Senanayake, C. H.; Fredenburgh, L. E.; Reamer, R. A.; Larsen, R.
D.; Verhoeven, T. R.; Reider, P. J. J. Am. Chem. Soc. 1994, 116, 7947-
7948.
yield after crystallization. Thus, 2 was synthesized from 4 in
seven steps and 50% overall yield.
Following an analogous route to that for 2, compound 3 was
prepared from o-tolylpyridine 25 via 29. Alternatively, the
(20) de Keravenant, B. French Patent No. 2.151.568, 1973.
J. Org. Chem, Vol. 71, No. 5, 2006 2003

Hoffmann-Emery et al.
TABLE 2. Addition of Grignard Reagents to 23a
efficient to get pure 54. Thus, a new route to 54 was designed
starting from the less-expensive bromide 17.24 The Grignard
reagent of 17 was generated in Et2O by gentle heating in the
presence of magnesium turnings,25 and acetone was added to
form the crude tertiary alcohol 53 in 98% yield. The carbony-
lation of 53 was first attempted under Koch-Haaf conditions,26
i.e. by generating carbon monoxide in situ by acid-catalyzed
decomposition of formic acid. To prevent rapid loss of carbon
monoxide, the reaction is generally carried out by slow addition
of the substrate (usually an alcohol or an olefin) dissolved in
formic acid to a strong acid (usually sulfuric acid) with slow or
even without stirring. However, because the reaction is diffusion
controlled, reproducibility is usually low. Treatment of 53 with
formic acid in sulfuric acid27 resulted in dimer 57. In neat
trifluoromethanesulfonic acid, which is known to dissolve a
7-fold amount of carbon monoxide compared to sulfuric acid,28
54 was obtained at 0 °C in a yield varying between 11% and
56%. Dimers 57 and 58 were the major side products. Running
the reaction under 1 bar CO did not improve the results. In
methanesulfonic acid, 57 was formed exclusively. In ClSO3H,
ClSO3H/AcOH 1:2, CF3SO3H/CH2Cl2 1:1, or H3PO4, decom-
position or complex mixtures were observed. Because the
concentration of carbon monoxide in the reaction mixture is a
critical factor and the alcohol 53 has a limited stability in the
presence of strong acids, the carbonylation was investigated
under higher CO pressures. Thus, crude 53 was successfully
carbonylated under 30 bar carbon monoxide in dichloromethane
in the presence of trifluoromethanesulfonic acid and 0.5 equiv
of water. Fluorosulfonic acid also promoted the carbonylation
but rendered the isolation of the product more difficult. Other
acids (sulfuric acid, methanesulfonic acid, hydrobromic acid,
hydrochloric acid, and chlorosulfonic acid) induced only
dehydration or decomposition. The use of 0.5 equiv of water
improved the selectivity slightly. Finally, a simple extraction
afforded 54 in 96% yield based on bromide 17 and in >99%
purity. On a larger scale, the carbonylation was conveniently
carried out by adding a solution of 53 in dichloromethane
continuously by a pump to an autoclave containing the trifluo-
romethanesulfonic acid under CO pressure.
yield
(%)
entry
R
oxidant
1
2
3
4
4-F-2-CH3C6H3
4-F-C6H4
I2
49 (81)b
50 (48)c
51 (56)c
no reaction
DDQ
DDQ
DDQ
(CH3)2CHd
2-ClC6H4
a Reactions were run with 3.0 equiv of Grignard. b Yield isolated after
chromatography and crystallization. c Yield isolated after digestion; method
d
not optimized. i-PrMgCl was used.
intermediate primary amide 34 was obtained by conversion of
acid 31 to amide 32 via the corresponding acid chloride and
heating 32 in neat N-methylpiperazine. Hofmann rearrangement
of 34 in the presence of NBS and sodium methoxide gave the
methyl carbamate 36 which was reduced with excess Red-Al
to the methylamine 14. Coupling of 14 with the acid chloride
15 gave 3. Thus, compound 3 was prepared from 4 via 23 in
seven steps and 63% overall yield and via 31 in six steps and
34% overall yield.
Scope of the 1,4-Grignard Addition. To extend the scope
of the 1,4-Grignard addition/oxidation sequence, this reaction
was performed with various derivatives of 6-chloronicotinic acid,
as summarized in Table 1. Tertiary amide 38 also underwent
the addition regioselectively (entry 4). Varying the substituent
at C(6) (entries 5 and 6) led to lower yields with increasing
electron-donating character. An additional chlorine substituent
at C(5) was well tolerated (entry 7). Esters (entries 8 and 9) led
to complex mixtures. Other Grignard reagents also added to
tert-butylamide 23, as shown in Table 2. p-Fluoro-o-tolylmag-
nesium bromide,22 p-fluorophenylmagnesium bromide, and
isopropylmagnesium chloride afforded good to moderate yields
of 49-51, respectively, whereas o-chlorophenylmagnesium
bromide23 unexpectedly did not react at all.
In summary, short and high-yielding syntheses of 2,4-
disubstituted nicotinamide 1 and 2,4-disubstituted inverse nico-
tinamides 2 and 3 starting from 6-chloronicotinic acid have been
described. The o-tolyl group at C(4) was introduced on
secondary nicotinamides 18 and 23 by a regioselective 1,4-
Grignard addition/oxidation sequence to afford the o-tolylpy-
ridines 21 and 25, respectively. 21 was converted in two further
steps into 1, which was thus obtained in four steps from 4 with
Synthesis of Propionic Acid 54. The acid chloride 15 used
in the syntheses of 2 and 3 was obtained by treatment of the
corresponding propionic acid 54 with oxalyl chloride5 (Scheme
6).
The Discovery Chemistry synthesis of 54 employed two
sequential R-methylations of the expensive acetic acid 52
n
performed by deprotonation with BuLi and trapping of the
dianion with 1 equiv of iodomethane. On a small scale, 54 was
obtained in an acceptable quality after crystallization. On a larger
scale, however, the amount of impurities 55 and 56 in the crude
product increased and crystallization was not sufficiently
(24) This synthesis has been described in a patent: Hoffmann-Emery,
F.; Scalone, M.; Spurr, P. WO2002079134, 2002.
(25) During the preparation of this manuscript, formation of this Grignard
i
reagent via Knochel’s procedure (using PrMgCl at low temperature) has
been described. The authors also reported that the formation of this Grignard
failed in THF using magnesium turnings but was successful with granules
or dust: Leazer, J. L., Jr.; Cvetovich, R.; Tsay, F.-R.; Dolling, U.; Vickery,
T.; Bachert, D. J. Org. Chem. 2003, 68, 3695-3698.
(21) The following compounds were isolated by column chromatography:
(26) (a) Haaf, W. Chem. Ber. 1966, 99, 1149-1152; Org. Synth. Coll.,
Vol. V 1973, 739-742. (b) Olah, G. A. Friedel-Crafts and Related
Reactions; Interscience: London, 1964; Vol. III, Part 2, pp 1284-ff. (c)
Falbe, J. Carbon Monoxide in Organic Synthesis; Springer-Verlag: Berlin,
1970; Chapter III. Falbe, J. Carbon Monoxide in Organic Synthesis, 2nd
ed.; Springer-Verlag: Berlin, 1980; Chapter 5.
(27) (a) Takahashi, Y.; Yoneda, N.; Nagai, H. Chem. Lett. 1985, 1733-
1734. (b) Takahashi, Y.; Yoneda, N. Synth. Commun. 1989, 19, 1945-
1954.
(28) Booth, B. L.; El-Fekky, T. A. J. Chem. Soc., Perkin Trans. 1 1979,
2441-2446.
(22) With this Grignard reagent, oxidation with I2 gave a better yield
than that with DDQ. See also ref 6.
(23) Lindholm, A.; Klasson-Wehler, E.; Wehler, T.; Bergman, A. J.
Labelled Compd. Radiopharm. 1987, 24, 1011-1019.
2004 J. Org. Chem., Vol. 71, No. 5, 2006

Synthesis of NoVel NK1 Receptor Antagonists
SCHEME 6
The combined organic extracts were washed with brine (20 mL),
dried (Na2SO4), concentrated under reduced pressure at 40 °C, and
dried under high vacuum at room temperature for 18 h yielding 22
(5.4 g, 94%). A sample was further purified by chromatography
on silica gel using dichloromethane/MeOH 19:1 as eluent yielding
22 as a white powder: mp 136.4-137.1 °C; IR (Nujol) ν 3305,
2925, 2854, 2786, 1619, 1585, 1527, 1460, 1361, 1312, 1288, 1266,
an overall yield of 47%. Compound 25 was converted in four
steps into methylamines 13 and 14 applying a Hofmann
rearrangement/reduction sequence to “invert” the amide. Acy-
lation of 13 and 14 with acid chloride 15 afforded 2 and 3.
Thus, 2 and 3 were prepared from 4 in seven steps with an
overall yield of 50% and 63%, respectively. A selective, high-
yielding, two-step synthesis of the propionic acid 54, the
precursor of 15, was also established.
1
1208, 1149, 997 cm-1; H NMR (400 MHz, CDCl3) δ 7.65 (s,
1H), 7.15 (d, J ) 6.8 Hz, 1H), 7.11-7.04 (m, 2H), 6.98 (d, J )
7.2 Hz, 1H), 5.37 (s br, 1H), 4.24 (m, 1H), 3.48 and 2.23 (2t br, 2
× 4H), 2.76 (d, J ) 4.8 Hz, 3H), 2.69-2.65 (m, 2H), 2.46 (s, 3H),
2.19 (s, 3H); ISP-MS (m/z) 327 (M + H+, 100), 270 (12). Anal.
Calcd for C19H26N4O: C, 69.91; H, 8.03; N, 17.16. Found: C,
69.39; H, 8.03; N, 17.29 (compound is hygroscopic).
N-Methyl-6-(4-methylpiperazin-1-yl)-4-o-tolyl-nicotinamide
(6). 21 (3.2 g, 12.2 mmol) was stirred in N-methylpiperazine (6.7
mL, 60.3 mmol) at 100 °C for 2.5 h. After cooling to room
temperature, the reaction mixture was partitioned between deionized
water (30 mL) and EtOAc (30 mL). The phases were separated,
and the aqueous phase was extracted with EtOAc (2 × 20 mL).
The combined organic extracts were washed with deionized water
(20 mL) and brine (20 mL), dried (Na2SO4), concentrated under
reduced pressure at 40 °C, and dried under high vacuum at room
temperature for 18 h. The residue was purified by column
chromatography on silica gel (160 g) yielding 6 (3.3 g, 83%) as a
beige solid.
Experimental Section
6-Chloro-N-methyl-4-o-tolyl-nicotinamide (21). o-Tolylmag-
nesium chloride (1 M solution in THF, 22.0 mL, 22.0 mmol) was
added over 30 min to a solution of 18 (1.5 g, 8.8 mmol) in THF
(18.0 mL) cooled to 0 °C. The resulting brown solution was stirred
for 2 h at room temperature and cooled to 0 °C, and cold (4 °C)
5% aqueous NH4Cl (30.0 mL, 28.0 mmol) was added over 15 min.
After separation of the phases, the aqueous phase was extracted
with THF (2 × 30 mL). The combined organic extracts were
washed with 5% aqueous NH4Cl (2 × 30 mL), dried (Na2SO4),
and treated at room temperature in four portions with KMnO4 (0.9
g, 5.7 mmol). The suspension was stirred for 5.5 h, filtered, and
concentrated on a rotary evaporator at 35 °C. The residue was
dissolved in CH2Cl2 (4 mL) and purified by chromatography on
silica gel (46 g) using CH2Cl2/MeOH 99:1 as eluent, yielding 1.8
g (79%) of 21 as a light yellow crystalline foam. A sample was
crystallized from EtOH/water yielding 21 as a white powder: mp
102.5-104.5 °C; IR (Nujol) ν 3289, 3062, 2933, 2244, 1643, 1573,
1535, 1493, 1458, 1337, 1315, 1273, 1152, 1096, 909, 854, 758,
723 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.30 (d
br, 1H), 7.45 (s, 1H), 7.31-7.12 (m, 3H), 7.09 (d, J ) 7.6 Hz,
1H), 2.56 (d, J ) 4.8 Hz, 3H), 2.09 (s, 3H); ISP-MS (m/z) 263 (M
+ H+, 27), 262 (13), 261 (M + H+, 100). Anal. Calcd for C14H13-
ClN2O: C, 64.50; H, 5.03; N, 10.74; Cl, 13.60. Found: C, 63.77;
H, 5.32; N, 10.27; Cl, 14.19 (compound is hygroscopic).
6-(4-Methylpiperazin-1-yl)-4-o-tolyl-4,5-dihydropyridine-3-
carboxylic Acid Methylamide (22). o-Tolylmagnesium chloride
(1 M solution in THF, 43.8 mL, 43.8 mmol) was added over 30
min to a solution of 18 (3.0 g, 17.6 mmol) in THF (42 mL) cooled
to 0 °C. The resulting brown solution was stirred for 1 h at room
temperature and cooled to 0 °C, and cold (4 °C) 5% aqueous NH4-
Cl (50.0 mL, 46.7 mmol) was added over 15 min. After phase
separation, the aqueous phase was extracted with THF (2 × 50
mL). The combined organic extracts were washed with 5% aqueous
NH4Cl (2 × 50 mL), dried (Na2SO4), and treated at room
temperature with N-methylpiperazine (9.8 mL, 87.4 mmol). The
suspension was stirred for 2.5 h, and cold 5% aqueous NH4Cl (40.0
mL, 37.4 mmol) was added. The phases were separated, and the
aqueous phase was extracted with dichloromethane (2 × 20 mL).
Alternatively, 22 (1.5 g, 4.6 mmol) dissolved in dichloromethane
(15 mL) was treated at room temperature with MnO2 (5.4 g, 55.1
mmol). The suspension was stirred for 18 h at 65 °C, cooled to
room temperature, filtered, and concentrated under reduced pressure
at 40 °C. The residue was purified by column chromatography on
silica gel (26 g) yielding 6 (1.2 g, 81%) as a beige solid: mp 132.0-
133.0 °C; IR (Nujol) ν 3269, 2927, 2855, 2789, 1625, 1596, 1555,
1491, 1459, 1408, 1377, 1321, 1295, 1229, 1143, 1003, 780 cm-1
;
1H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 7.35-7.27 (m, 3H),
7.20-7.18 (m, 1H), 6.32 (s, 1H), 5.10 (s, 1H), 3.67 and 2.51 (2t,
J ) 5.2 Hz, 2 × 4H), 2.61 (d, J ) 4.8 Hz, 3H), 2.35 (s, 3H), 2.12
(s, 3H); ISP-MS (m/z) 325 (M + H+, 100), 268 (32). Anal. Calcd
for C19H24N4O: C, 70.34; H, 7.46; N, 17.27. Found: C, 69.75; H,
7.39; N, 17.00 (compound is hygroscopic).
N-tert-Butyl-6-chloro-4-o-tolyl-nicotinamide (25). Representa-
tive Procedure for the Grignard Addition/Oxidation Sequence.
o-Tolylmagnesium chloride (1 M solution in THF, 28.2 mL, 28.2
mmol) was added slowly to a stirred solution of 23 (2.0 g, 9.4
mmol) in THF (10 mL) cooled to 0 °C. The resulting brown
suspension was stirred for 3 h at room temperature and for 18 h at
30 °C and cooled to 0 °C. AcOH (2.69 mL, 47.0 mmol) was added
over 15 min followed by DDQ (3.2 g, 14.1 mmol) in one portion,
and after 1 h of stirring at room temperature, the suspension was
poured into half-saturated aqueous Na2CO3 (100 mL) and EtOAc
J. Org. Chem, Vol. 71, No. 5, 2006 2005

Hoffmann-Emery et al.
(100 mL). The precipitate was filtered off and washed with EtOAc
(2 × 20 mL). The phases of the filtrate were separated, and the
aqueous phase was extracted with EtOAc (2 × 50 mL). The
combined organic extracts were washed with deionized water (50
mL) and brine (50 mL), dried (Na2SO4), and concentrated on a
rotary evaporator. The residue was dissolved in CH2Cl2 (10 mL)
and filtered on silica gel (15 g) using EtOAc/n-heptane 1:1 as eluent
yielding 2.8 g (98%) of 25 as a light yellow crystalline foam. A
sample was further purified by column chromatography using
EtOAc/n-hexane 1:9 as eluent yielding 25 as a white powder: mp
117.1-118.1 °C; IR (Nujol) ν 3305, 3066, 3040, 2924, 2854, 1635,
phase was extracted with t-BuOMe (2 × 200 mL). The combined
organic extracts were washed with deionized water (2 × 100 mL).
The combined aqueous phases were brought to pH ) 14 by addition
of 28% aqueous NaOH (300 mL) and extracted with t-BuOMe (400
mL and 2 × 200 mL). These second organic extracts were
combined, washed with deionized water (2 × 200 mL) and brine
(100 mL), dried (Na2SO4), concentrated under reduced pressure,
and dried under high vacuum at 40 °C for 8 h yielding 33 (46.4 g,
95%) as a light beige powder: mp 53.1-56.7 °C; IR (Nujol) ν
3465, 3326, 3178, 2924, 2854, 1662, 1588, 1528, 1489, 1452, 1378,
1
1234, 1117 cm-1; H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H),
1
1585, 1547, 1454, 1390, 1319, 1222, 1087 cm-1; H NMR (400
7.38-7.30 (m, 3H), 7.21-7.19 (m, 1H), 6.30 (s, 1H), 5.40 and
5.09 (2s br, 2 × 1H), 3.81 and 3.63 (2t, J ) 5.0 Hz, 2 × 4H), 2.15
(s, 3H); ISP-MS (m/z) 320 (M + Na+, 6), 298 (M + H+, 100).
Alternatively, 28 (0.5 g, 1.3 mmol) was stirred in methanesulfonic
acid (2.5 mL) and concentrated H2SO4 (0.25 mL) at 100 °C for 1
h. After addition of concentrated H2SO4 (0.25 mL), stirring was
pursued for 22 h at 100 °C. The reaction mixture was cooled to
room temperature and slowly poured onto aqueous saturated Na2-
CO3 (75 mL) cooled with ice. EtOAc (50 mL) was added, and
after vigorous stirring, the phases were separated. The aqueous
phase was saturated with NaCl and extracted with EtOAc (2 × 50
mL). The combined organic extracts were washed with aqueous
saturated Na2CO3 (50 mL) and brine (50 mL), dried (Na2SO4), and
concentrated on a rotary evaporator. The residue was purified by
flash chromatography using CH2Cl2/MeOH 95:5 as eluent yielding
33 (0.15 g, 39%) as a yellow resin.
MHz, CDCl3) δ 8.91 (s, 1H), 7.41 (m, 1H), 7.33 (m, 2H), 7.18 (m,
1
2H), 5.06 (s br, 1H), 2.13 (s, 3H), 1.05 (s, 9H); H NMR (400
MHz, DMSO-d6) δ 8.46 (s, 1H), 7.56 (s, 1H), 7.44 (s, 1H), 7.35-
7.18 (m, 4H), 2.10 (s, 3H), 1.06 (s, 9H); ISP-MS (m/z) 305 (29),
304 (15), 303 (M + H+, 100). Anal. Calcd for C17H19ClN2O: C,
67.43; H, 6.32; N, 9.25. Found: C, 67.18; H, 6.35; N, 9.08.
N-tert-Butyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide (27).
o-Tolylmagnesium chloride (1 M solution in THF, 746 mL, 746
mmol) was added over 20 min to a solution of 23 (40.0 g, 187
mmol) in THF (200 mL) with cooling so that the temperature never
exceeded 20 °C. The resulting dark green fluid suspension was
stirred for 18 h at 30 °C and cooled to 0 °C. Methanol (45.4 mL,
1.1 mol) was added over 30 min, followed, after 10 min, by DDQ
(50.8 g, 224 mmol). After 1 h of stirring at room temperature, the
reaction mixture was concentrated to ca. 450 g under reduced
pressure at 30 °C. The black oil obtained was heated to 50 °C, and
t-BuOMe (800 mL) was added under vigorous stirring. The yellow-
green suspension was refluxed for 30 min, cooled to room
temperature, and stirred for 1 h at room temperature. The precipitate
was filtered off and washed with t-BuOMe (4 × 200 mL), and the
filtrate was concentrated under reduced pressure and dried under
high vacuum at room temperature for 18 h yielding crude 25 (68.5
g). This material (68.0 g) was stirred in morpholine (217.4 mL) at
100 °C for 5 h. After cooling to room temperature, the reaction
mixture was partitioned between deionized water (500 mL) and
EtOAc (500 mL). The phases were separated, and the aqueous phase
was extracted with EtOAc (2 × 500 mL). The combined organic
extracts were washed with deionized water (2 × 500 mL) and brine
(250 mL), dried (Na2SO4), concentrated under reduced pressure,
and dried under high vacuum at room temperature for 18 h yielding
27 (58.7 g, 89% based on 23) as a brown foam: IR (Nujol) ν 3420,
(6-Morpholin-4-yl-4-o-tolylpyridin-3-yl)-carbamic Acid Meth-
yl Ester (35). N-Bromosuccinimide (pract. 97%, 39.7 g, 216.3
mmol) was suspended in CH2Cl2 (230 mL) and cooled to -5 °C,
and sodium methoxide (5.4 M solution in methanol, 100.1 mL,
540.5 mmol) was added over 30 min. The milky fluid suspension
obtained was stirred at -5 °C for 15 h, and then a solution of 33
(45.9 g, 154.4 mmol) in CH2Cl2 (230 mL) was added over 20 min.
The dropping funnel was rinsed with methanol (25 mL). The
reaction mixture was further stirred for 7 h at -5 °C, acidified by
the addition of 1 N aqueous HCl (332 mL), and diluted with CH2-
Cl2 (200 mL). After vigorous stirring, the phases were separated
and the organic phase was washed with deionized water (2 × 400
mL). The aqueous phases were extracted with CH2Cl2 (2 × 200
mL). The combined organic extracts were dried (Na2SO4), con-
centrated under reduced pressure, and dried under high vacuum at
room temperature for 16 h. The residue (53.6 g of orange foam)
was dissolved in CH2Cl2 (53.6 mL) at room temperature under
1
2963, 2922, 2847, 1649, 1582, 1483, 1234, 1211, 1115 cm-1; H
i
NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 7.37-7.35 (m, 1H), 7.33-
7.29 (m, 2H), 7.21-7.18 (m, 1H), 6.30 (s, 1H), 5.00 (s br, 1H),
3.81 and 3.60 (2t, J ) 5.0 Hz, 2 × 4H), 2.13 (s, 3H), 1.03 (s, 9H);
EI-MS (m/z) 353 (M+, 81), 322 (75), 296 (54), 281 (100), 167
(32). Anal. Calcd for C21H27N3O2: C, 71.36; H, 7.70; N, 11.89.
Found: C, 71.14; H, 7.67; N, 11.79.
stirring, and Pr2O (268 mL) was added. After 30 min, n-heptane
(536 mL) was added over 30 min and CH2Cl2 was distilled off at
40 °C under 300 mbar. The suspension was further stirred for 16
h at room temperature and for 2 h at -10 °C and filtered off. The
precipitate was washed with n-heptane cooled to -10 °C (2 × 50
mL) and dried under high vacuum at 40 °C for 16 h yielding 35
(43.2 g, 86%) as a beige powder. Crude 35 (5.2 g of orange foam)
prepared similarly starting from 4.5 g of 33 (14.3 mmol) was
dissolved in EtOAc (26 mL) and n-hexane (26 mL). Alox 1 basic
(5.2 g) was added and after 30 min filtered off. The filter cake was
washed with EtOAc/n-hexane 1:1 (2 × 25 mL). The filtrate was
concentrated in a rotary evaporator at 40 °C and dried under high
vacuum. The residue (4.9 g of orange foam) was dissolved at room
Alternatively, o-tolylmagnesium chloride (1 M solution in THF,
76.0 mL, 76.0 mmol) was added over 15 min to a solution of 42
(5.0 g, 19.0 mmol) in THF (35.0 mL) cooled to 0 °C. The resulting
brown suspension was stirred for 18 h at room temperature and
for 4 h at reflux and cooled to 0 °C. MeOH (4.6 mL) was added
over 25 min, followed by DDQ (12.8 g, 22.8 mmol). After 1 h at
room temperature, the suspension was concentrated under reduced
pressure to a fluid oil (ca. 55 g) and heated to 50 °C, and under
vigorous stirring, t-BuOMe (100 mL) was added. The resulting
suspension was stirred for 16 h at room temperature, and the
precipitate was filtered off and washed with t-BuOMe (4 × 25 mL).
The filtrate was concentrated under reduced pressure. The residue
was purified by column chromatography using EtOAc/n-heptane
1:1 as eluent yielding 27 (2.5 g, 44%) as a brown crystalline foam.
6-Morpholin-4-yl-4-o-tolyl-nicotinamide (33). 27 (58.2 g, 162.5
mmol) was stirred in methanesulfonic acid (115.9 mL, 1.79 mol)
at 100 °C for 5 h. The reaction mixture was poured onto ice-cold
deionized water (580 mL), and t-BuOMe (200 mL) was added.
After vigorous stirring, the phases were separated and the aqueous
i
temperature in CH2Cl2 (5 mL), and Pr2O (25 mL) was added in
one portion. After 30 min of stirring at room temperature, n-heptane
(50 mL) was added over 30 min, CH2Cl2 was distilled off, and the
suspension was stirred for 2 h at 0 °C. The precipitate was filtered
off, washed with n-heptane (20 mL), and dried under 10 mbar at
40 °C for 16 h yielding 35 (3.4 g, 69%) as a yellow powder: mp
125.4-130.5 °C; IR (Nujol) ν 3243, 2922, 2852, 1704, 1606, 1594,
1518, 1466, 1404, 1377, 1251, 1223, 1112, 1075, 954, 778, 751
1
cm-1; H NMR (400 MHz, CDCl3) δ 8.82 (s br, 1H), 7.36-7.27
(m, 3H), 7.12 (d, J ) 7.6 Hz, 1H), 6.43 (s, 1H), 5.89 (s br, 1H),
3.84-3.81 (m, 4H), 3.67 (s, 3H), 3.49-3.46 (m, 4H), 2.12 (s, 3H);
ISP-MS (m/z) 350 (M + Na+, 3), 328 (M + H+, 100), 296 (13).
2006 J. Org. Chem., Vol. 71, No. 5, 2006

Synthesis of NoVel NK1 Receptor Antagonists
Anal. Calcd for C18H21N3O3: C, 66.04; H, 6.47; N, 12.84. Found:
C, 65.64; H, 6.43; N, 12.80.
separated, and the aqueous phase was extracted with EtOAc (2 ×
73 mL). The combined organic extracts were washed with deionized
water (73 mL) and brine (73 mL), dried (Na2SO4), concentrated
under reduced pressure at 40 °C, and dried under high vacuum at
room temperature for 18 h yielding 29 (17.1 g, 97%) as a brown,
thick oil. A sample was purified by column chromatography to give
29 as a beige solid: mp 116.1-117.6 °C; IR (Nujol) ν 3421, 2964,
2937, 2844, 2793, 1655, 1590, 1521, 1490, 1452, 1297, 1239, 1219,
Methyl-(6-morpholin-4-yl-4-o-tolylpyridin-3-yl)-amine (13).
A solution of Red-Al (70% solution in toluene, 80.7 mL, 285 mmol)
and toluene (100 mL) was added over 10 min to a solution of 35
(20.0 g, 61.1 mmol) in toluene (120 mL) with cooling such that
the temperature did not exceed 50 °C. The resulting orange solution
was stirred for 1 h at 50 °C and cooled to 0 °C, and 1 N aqueous
NaOH (160 mL) was added over 15 min (Caution: strongly
exothermic). The phases were separated, and the aqueous phase
(cloudy) was extracted with toluene (2 × 100 mL). The combined
organic extracts were washed with deionized water (2 × 100 mL)
and brine (50 mL), dried (Na2SO4), concentrated under reduced
pressure, and dried under high vacuum at room temperature. The
residue was dissolved in CH2Cl2 (50 mL) at room temperature, and
n-heptane (220 mL) was added. Impurities precipitated as an orange-
brown resin, and the solution was decanted and concentrated under
reduced pressure. The residue was dissolved in n-heptane (48 mL)
at 40 °C, and after about 30 min, a light yellow suspension formed
which was allowed to cool to room temperature and then further
chilled to -10 °C. After 1 h at -10 °C, the precipitate was filtered
off, washed with n-heptane (2 × 20 mL), and dried under high
vacuum at 40 °C for 8 h yielding 13 (14.1 g, 81%) as a light yellow
powder: mp 68.3-76.0 °C; IR (Nujol) ν 3345, 2923, 2854, 1611,
1
1141, 1006 cm-1; H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H),
7.38-7.29 (m, 3H), 7.21-7.19 (m, 1H), 6.32 (s, 1H), 4.99 (s, 1H),
3.66 and 2.51 (2t, J ) 5.2 Hz, 2 × 4H), 2.35 (s, 3H), 2.13 (s, 3H),
1.02 (s, 9H); ISP-MS (m/z) 337 (M + H+, 100), 310 (10). Anal.
Calcd for C22H30N4O: C, 72.10; H, 8.25; N, 15.29. Found: C,
71.85; H, 8.01; N, 15.27.
6-(4-Methylpiperazin-1-yl)-4-o-tolyl-nicotinamide (34). 34 was
obtained from 29 (16.7 g, 45.6 mmol) following the procedure
described to prepare 33 from 27. Using EtOAc as solvent for the
extraction yielded crude 34 (13.3 g, 94%) as a light beige powder.
Alternatively, 32 (1.0 g, 4.1 mmol) was stirred in N-methylpip-
erazine (9.0 mL, 80.1 mmol) at 100 °C for 2 h. The reaction mixture
was concentrated at room temperature under high vacuum, and the
residue was purified by filtration on silica gel (20 g) using CH2Cl2
as eluent yielding 34 (1.2 g, 95%) as a light yellow foam. A sample
was further purified by column chromatography using CH2Cl2/
MeOH 98:2 to 95:5 as eluent yielding 34 as a colorless foam: mp
163.6-164.5 °C; IR (Nujol) ν 3464, 3166, 2926, 2854, 2796, 1662,
1
1503, 1451, 1396, 1376, 1239, 1119, 951 cm-1; H NMR (400
MHz, CDCl3) δ 7.76 (s, 1H), 7.34-7.24 (m, 3H), 7.14 (d, J ) 7.2
Hz, 1H), 6.45 (s, 1H), 3.85-3.83 (m, 4H), 3.40-3.31 (m, 4H),
2.97 (s br, 1H), 2.78 (s, 3H), 2.14 (s, 3H); ISP-MS (m/z) 284 (M
+ H+, 100). Anal. Calcd for C17H21N3O: C, 72.06; H, 7.47; N,
14.83. Found: C, 72.04; H, 7.65; N, 14.58.
1
1589, 1490, 1456, 1378, 1327, 1237, 1141 cm-1; H NMR (400
MHz, CDCl3) δ 8.93 (s br, 1H), 7.38-7.29 (m, 3H), 7.22-7.20
(m, 1H), 6.31 (s, 1H), 5.30 and 5.08 (2s br, 2 × 1H), 3.68 and
2.51 (2t, J ) 5.2 Hz, 2 × 4H), 2.33 (s, 3H), 2.15 (s, 3H); ISP-MS
(m/z) 311 (M + H+, 100), 254 (62). Anal. Calcd for C18H22N4O
(0.4H2O): C, 68.07; H, 7.24; N, 17.64. Found: C, 68.06; H, 7.09;
N, 17.31.
2-(3,5-Bistrifluoromethylphenyl)-N-methyl-N-(morpholin-4-
yl-4-o-tolylpyridin-3-yl)-isobutyramide (2). A solution of 15 (11.8
g, 36.9 mmol) in CH2Cl2 (5.0 mL) was added over 15 min to a
solution of 13 (10.0 g, 35.3 mmol) and iPr2EtN (8.3 mL, 48.3 mmol)
in CH2Cl2 (70 mL) cooled to 0 °C. After 3 h of stirring at 0 °C,
the reaction mixture was poured onto deionized water (80 mL),
and after 30 min of stirring at room temperature, the phases were
separated. The organic phase was washed with deionized water (80
mL), 2% aqueous NaOH (80 mL), deionized water (80 mL), and
5% aqueous NaHCO3 (80 mL). The aqueous phases were separately
extracted with the same portion of CH2Cl2 (40 mL). The combined
organic extracts were dried (Na2SO4) and concentrated to a volume
of 50 mL, filtered on paper, and completely evaporated. The residue
was dissolved in EtOH (100 mL) at 50 °C and concentrated in a
rotary evaporator. The beige foam obtained was dissolved in EtOH
(55 mL) at 50 °C and seeded with some crystals of 2. The resulting
beige suspension was stirred for 2 h at room temperature, for 1 h
at 0 °C, and for 1 h at -20 °C and then filtered (glass filter P3).
The precipitate was washed with EtOH (2 × 10 mL), cooled to
-20 °C, and dried under 25-40 mbar at 50 °C for 2 h, followed
by 16 h at 50 °C under high vacuum yielding 2 (16.3 g, 81%) as
a white powder: mp 128.8-129.9 °C; IR (Nujol) ν 2923, 2855,
1638, 1605, 1594, 1485, 1453, 1375, 1364, 1287, 1266, 1236, 1190,
[6-(4-Methylpiperazin-1-yl)-4-o-tolylpyridin-3-yl]-carbamic Acid
Methyl Ester (36). 36 was obtained from 34 (1.0 g, 3.2 mmol)
following the procedure described to prepare 35 from 33, except
that 34 was dissolved in MeOH. At the end of the workup, the
combined aqueous phases were brought to pH ) 8 by addition of
1 N aqueous NaOH and further extracted with CH2Cl2 (3 × 20
mL). The combined organic extracts were dried (Na2SO4), con-
centrated under reduced pressure, and dried under high vacuum at
room temperature for 16 h yielding 36 (1.08 g, 99%) as a beige
foam: IR (Nujol) ν 3216, 2923, 2853, 1714, 1609, 1598, 1503,
1457, 1224, 1074 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.83 (s br,
1H), 7.37-7.26 (m, 3H), 7.11 (d, J ) 7.6 Hz, 1H), 6.47 (s, 1H),
5.92 (s br, 1H), 3.78 (s br, 4H), 3.68 (s, 3H), 2.89 (s br, 4H), 2.59
(s, 3H), 2.11 (s, 3H); ISP-MS (m/z) 341 (M + H+, 100), 284 (36),
252 (13).
Methyl-[6-(4-methylpiperazin-1-yl)-4-o-tolylpyridin-3-yl]-
amine (14). A solution of Red-Al (70% solution in toluene, 44.82
mL, 158.3 mmol) and toluene (50.0 mL) was added over 10 min
to a solution of 36 (11.0 g, 32.3 mmol) in CH2Cl2 (60.0 mL) cooled
so that the temperature did not exceed 50 °C. The resulting orange
solution was stirred for 1 h at 50 °C and cooled to 0 °C, and 1 N
aqueous NaOH (88.0 mL) was added over 15 min (Caution:
strongly exothermic). The reaction mixture was diluted with EtOAc
(100 mL), and after vigorous stirring, the phases were separated.
The aqueous phase (cloudy) was extracted with EtOAc (2 × 50
mL). The organic extracts were washed with deionized water (2 ×
50 mL) and brine (50 mL), dried (Na2SO4), concentrated in a rotary
evaporator at 40 °C, and dried under high vacuum at room
temperature for 3 h giving an orange resin (10.6 g). This resin was
twice dissolved in 50 mL of CH2Cl2, concentrated in a rotary
evaporator at 40 °C, and then dried under high vacuum at 40 °C
for 4 h yielding 9.8 g of crude 14 (9.8 g, quantitative) as an orange
resin: IR (Nujol) ν 3411, 3022, 2935, 2881, 2795, 2745, 1611,
1
1170, 1124 cm-1; H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H),
7.76 (s, 1H), 7.65 (s, 2H), 7.26 (s br, 4H), 6.50 (s, 1H), 3.82 (m,
4H), 3.52 (m, 4H), 2.56, 2.33, 2.14 (3s br, 6H), 1.50 and 1.33 (2s
br, 6H); ISP-MS (m/z) 588 (M + Na+, 10), 566 (M + H+, 100),
452 (16). Anal. Calcd for C29H29F6N3O2: C, 61.59; H, 5.17; F,
20.16; N, 7.43. Found: C, 61.65; H, 5.22; F, 20.37; N, 7.50.
The mother liquors were evaporated under reduced pressure to
an orange oil, which was crystallized from EtOH/H2O 2:1 at 0 °C
to give a beige powder (2.8 g). This solid was recrystallized from
EtOH at -20 °C yielding 2 (1.0 g, 5%) as an off-white powder of
mp 126.3-127.3 °C.
N-tert-Butyl-6-(4-methylpiperazin-1-yl)-4-o-tolyl-nicotin-
amide (29). 25 (14.6 g, 45.2 mmol) was stirred in N-methylpip-
erazine (43.8 mL, 394 mmol) at 100 °C for 4 h. After cooling to
room temperature, the reaction mixture was partitioned between
deionized water (146 mL) and EtOAc (146 mL). The phases were
1
1501, 1447, 1397, 1246, 1228, 1138, 1010, 953 cm-1; H NMR
(400 MHz, CDCl3) δ 7.75 (s, 1H), 7.33-7.24 (m, 3H), 7.18-7.13
(m, 1H), 6.47 (s, 1H), 3.46-3.38 (m, 4H), 2.94 (s br, 1H), 2.78 (s,
J. Org. Chem, Vol. 71, No. 5, 2006 2007

Hoffmann-Emery et al.
3H), 2.57-2.55 (m, 4H), 2.35 (s, 3H), 2.14 (s, 3H); ISP-MS (m/z)
297 (M + H+, 100), 240 (14).
pressurized with 30 bar of CO, and stirring was started. With the
aid of a membrane pump, a solution of 53 (14.1 g, 51.8 mmol) in
CH2Cl2 (35 mL) was added to the solution in the autoclave under
vigorous stirring at 20 °C and at a flow of 1 mL/min. After stirring
for a further 2 h at 20 °C, the autoclave was vented and the CO
atmosphere was replaced by argon (three cycles of 8 bar argon
venting under vigorous stirring). The reaction mixture was treated
dropwise at 2 °C under stirring with a solution of NaOH (13.2 g,
330 mmol) in water (130 mL). After stirring for 30 min, the organic
phase was separated and extracted with water (10 mL), and the
combined aqueous phases were extracted with CH2Cl2 (3 × 150
mL) and filtered through a sintered glass filter. Addition at 8-12
°C of HCl (11 mL of a 36.5% aqueous solution, 350 mmol) afforded
a suspension which was extracted with CH2Cl2 (2 × 100 mL). The
organic phase was washed with water (100 mL), dried (Na2SO4),
rotary evaporated to dryness, and finally dried under high vacuum
for 5 h providing 54 (15.0 g, 97%) as a pale brown crystalline
solid: mp 105.5-107 °C; IR (Nujol) ν 2923, 1707, 1623, 1464,
2-(3,5-Bistrifluoromethylphenyl)-N-methyl-N-(6-(4-methylpip-
erazin-1-yl)-4-o-tolylpyridin-3-yl)-isobutyramide (3). 3 was ob-
tained from 14 (9.60 g, 32.4 mmol) and 15 (10.90 g, 34.2 mmol)
following the procedure described to prepare 2 from 13 and 15
affording crude 3 (19.6 g). A reference sample of 3 was prepared
by dissolving 2.0 g of crude 3 in iPr2O (20 mL) at room temperature.
After 1 h of stirring at room temperature, the precipitate was filtered
off, washed with iPr2O (2.0 mL), and dried at 40 °C under 25 mbar
for 16 h yielding 3 (1.0 g, 5.3%) with mp ) 159.1-159.8 °C. The
rest (17.6 g) of the crude product was suspended in iPr2O (56 mL)
and stirred at reflux temperature for 30 min. The suspension was
cooled slowly to 0 °C and stirred for 1 h at 0 °C. The precipitate
i
was filtered off, washed with cold (-20 °C) Pr2O (20 mL), and
dried at 50 °C under 25 mbar for 16 h yielding 3 (12.5 g, 67%) as
white crystals: mp 156.2-160.0 °C; IR (Nujol) ν 2925, 2853, 2795,
1647, 1610, 1598, 1500, 1460, 1367, 1277, 1187, 1172, 1149 cm-1
;
1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.75 (s, 1H), 7.66 (s,
2H), 7.27 (s br, 4H), 6.51 (s, 1H), 3.58 (s br, 4H), 2.52 (s br) and
2.35-2.13 (m br, 13H), 1.49 and 1.33 (2s br, 6H); ISP-MS (m/z)
579 (M + H+, 100). Anal. Calcd for C30H32F6N4O: C, 62.28; H,
5.57; F, 19.70; N, 9.68. Found: C, 62.22; H, 5.61; F, 19.60; N,
9.61.
1376, 1279, 1239, 1176, 1136, 900, 845, 684 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 12-10 (broad, 1H), 7.84 (s, 2H), 7.80 (s,
1H), 1.68 (s, 6H); EI-MS (m/z): 300 (M+), 281 (M+ - F), 255
(M+ - COOH), 227 (M+ - COOH - C2H4). Anal. Calcd for
C12H10F6O2: C, 48.01; H, 3.36; F, 37.97. Found: C, 47.99; H, 3.32;
F, 37.90.
2-(3,5-Bistrifluoromethylphenyl)-propan-2-ol (53). For the
formation of the Grignard reagent, an aliquot (10 mL) of a solution
of 17 (150 g, 507 mmol) in Et2O (400 mL) was added to a
suspension of magnesium turnings (16.1 g, 65.9 mmol). After the
reaction had been started by gently heating, the rest of the ethereal
solution was added dropwise over 1 h, during which time the
temperature was kept at ca. 30 °C. Treatment of a sample of the
reaction mixture with water revealed the disappearance of 17. A
solution of acetone (56.0 mL, 762 mmol) in Et2O (100 mL) was
added to the resulting fine suspension over 45 min, and the
temperature was kept between 16 and 22 °C. Addition of 25%
aqueous NH4Cl (110 mL) at ca. 20 °C led to the formation of a
suspension of magnesium salts which were filtered off and washed
with Et2O (3 × 200 mL). After drying (Na2SO4), the filtrate was
rotary evaporated to dryness and finally dried under high vacuum
affording 53 (137 g, 99%) as a yellow crystalline solid: mp 59-
60 °C [lit.29 60.5-61.5 °C] (99.2% pure by GC). This material
was used in the successive carbonylation step without further
purification. An analytically pure sample of 53 was obtained by
crystallization from pentane as a white solid: mp 62.5-63.5 °C;
IR (Nujol) ν 3323, 2921, 2853, 1624, 1467, 1376, 1278, 1117, 962,
2-(3,5-Bistrifluoromethylphenyl)-2-methyl Propionyl Chloride
(15). Oxalyl chloride (8.76 mL, 100.0 mmol) was added slowly to
a stirred suspension of 54 (15.0 g, 50.0 mmol) in CH2Cl2 (127.5
mL) and DMF (0.60 mL) cooled to 0 °C. The reaction mixture
was stirred for 1 h at 0 °C and for 16 h at room temperature and
concentrated in a rotary evaporator at 40 °C. The residue was
dissolved in toluene (60 mL), concentrated under reduced pressure
twice, and dried under high vacuum at room temperature for 2 h
yielding 15 (15.2 g, 96%) as a yellow oil, which was used without
further purification: IR (Nujol) ν 2991, 2944, 1806, 1772, 1632,
1472, 1394, 1372, 1278, 1243, 1188, 1136, 961, 900, 683 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 7.86 (s, 1H), 7.77 (2, 2H), 1.77 (s,
6H); EI-MS (m/z) 299 (2, M+ - F), 271 (6), 255 (100, M+
COCl), 227 (61).
-
Acknowledgment. The authors thank Markus Hohler, Reto
Frey, Christian Haas, Cu¨neyt Kilic, Arthur Meili, Lucia Sutter,
and Guy Zielinski for skillful experimental work, Marcel Althaus
and Jean-Claude Jordan for analytical support, and the Analytical
Services of F. Hoffmann-La Roche Ltd. for providing and
interpreting the physical data of all compounds described. We
thank Paul Spurr, Goesta Rimmler, Helmut Stahr, and Ju¨rg
Bruhin for fruitful discussions. The careful reading of the
manuscript by Martin Karpf, Paul Spurr, and Ulrich Widmer is
gratefully acknowledged.
1
900, 799, 716, 683 cm-1; H NMR (CDCl3, 400 MHz) δ 7.95 (s,
2H), 7.77 (s, 1H), 1.84 (s, 1H), 1.63 (s, 6H); EI-MS (m/z): 257
(M+ - CH3), 253 (M+ - F). Anal. Calcd for C11H10F6O: C, 48.54;
H, 3.70; F, 41.88. Found: C, 48.46; H, 3.73; F, 41.63.
2-(3,5-Bistrifluoromethylphenyl)-2-methyl Propionic Acid
(54). A 185-mL Hastelloy C4 autoclave was charged under an argon
flow with CH2Cl2 (25 mL), triflic acid (22.3 mL, 250 mmol), and
water (0.45 mL, added dropwise). The autoclave was closed and
Supporting Information Available: Experimental procedures
and analytical data of compounds 18, 23, 24, 26, 28, 31, 32, 37-
44, 46-51, and 57. This material is available free of charge via
the Internet at http://pubs.acs.org.
(29) Takeuchi, K.; Kurosaki, T.; Okamoto, K. Tetrahedron 1980, 36,
1557-1563.
JO0523666
2008 J. Org. Chem., Vol. 71, No. 5, 2006