Chemically enabled synthesis of 2-amino-4-heteroarylpyrimidines

Article abstract of DOI:10.1016/j.tetlet.2009.03.073

2-Amino-4-heteroarylpyrimidines were initially synthesized by microwave-induced S_NAr reactions of primary alkyl amines and 2-methylsulfonylpyrimidines or 2-chloropyrimidines. Following this methodology, pendant piperidine functionality was elab

Full text of DOI:10.1016/j.tetlet.2009.03.073

Tetrahedron Letters 50 (2009) 2552–2554
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Chemically enabled synthesis of 2-amino-4-heteroarylpyrimidines
*
Paul S. Humphries , Quyen-Quyen T. Do, David M. Wilhite
Pfizer Global R&D, Department of Medicinal Chemistry, 10614 Science Center Drive, San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Amino-4-heteroarylpyrimidines were initially synthesized by microwave-induced SNAr reactions of
primary alkyl amines and 2-methylsulfonylpyrimidines or 2-chloropyrimidines. Following this method-
ology, pendant piperidine functionality was elaborated utilizing silica-bound reagents in microwave-
assisted reductive amination and amide bond formation protocols. These methods proved to be versatile,
efficient, and amenable to parallel synthesis.
Received 24 January 2009
Revised 4 March 2009
Accepted 11 March 2009
Available online 16 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
JNK
c-Jun N-terminal kinase
Pyrazole
Pyrimidine
Piperidine
Reductive amination
Amide bond formation
c-Jun N-terminal kinase-1 (JNK1), a member of the mitogen-
activated protein kinase (MAPK) family, has recently emerged as
an attractive target for diabetes therapy, since JNK1 is believed to
play a key role in linking obesity and insulin resistance.1
As part of an ongoing JNK1 drug discovery program in our lab-
oratories, compounds 1 and 2 were identified from high-through-
put screening (HTS) and possessed promising potency as well as
attractive structural features amenable to optimization by rapid
parallel synthesis (Fig. 1).
Figure 1. Initial hits from high-throughput screening.
Unfortunately, 1 was highly cleared in vitro (human hepato-
cytes and liver microsomes). Metabolite ID studies revealed that
metabolism was occurring exclusively on the alkylamino portion
of the molecule. Our strategy was thus to dramatically reduce
the lipophilicity (ELogD = 4.42) of this hit, whilst maintaining or
improving the ligand efficiency (LE = 0.44).2 More specifically, we
wished to expediently and efficiently vary the alkylamino portion
of the molecule.
The initial route to these targets was via the 2-methylsulfonyl-
pyrimidine intermediate 7. This intermediate was accessed in a
straightforward fashion following the four-step protocol below
(Scheme 1).3 2-Mercapto-4-methyl pyrimidine 3 was alkylated
with iodomethane to afford 2-mercapto-4-methyl pyrimidine 4.4
Deprotonation and reaction of the anion of 4 with methyl 4-chlo-
robenzoate 5 gave ketone 6 in good yield.4 Ketone 6 was initially
treated with dimethylformamide dimethylacetal followed by
hydrazine hydrate yielding the required pyrazole.5 Oxidation of
the methylsulfide intermediate to the required methylsulfonylpyr-
imidine 7 was achieved in a straightforward fashion.6
The final SNAr step was optimized under a variety of conditions,
utilizing cyclopentylamine as our partner of choice.7 Initially, it
was found that performing this reaction in dioxane under micro-
wave irradiation (137 °C, 10 min) afforded the required product
(8, where R = cyclopentyl) in a 77% yield.8 Unfortunately, when
using this protocol with a small test set of amines and amine
hydrochlorides, it was immediately apparent that the heterogene-
ity hindered the reaction progress in some instances. Further opti-
mization showed that this reaction could be performed in 2-
propanol (175 °C, 10 min) with no diminution in yield. Due to
the reagents enhanced solubility and the higher reaction tempera-
ture, this optimized protocol showed greater generality over a
more diverse set of amine monomers. For example, utilizing iso-
propylamine afforded the required product (R = iPr) in 42% yield,
2-fluoroethylamine hydrochloride gave 8 (R = CH2CH2F) in 49%
yield, and cyclobutylamine afforded 8 (R = cyclobutyl) in 56% yield.
* Corresponding author. Address: Pfizer Global R&D, Eastern Point Road, MS
8220-3224, Groton, CT 06340, USA. Tel.: +1 860 705 0559.
E-mail address: phumphri@gmail.com (P.S. Humphries).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.073

P. S. Humphries et al. / Tetrahedron Letters 50 (2009) 2552–2554
2553
Scheme 1. Reagents and conditions: (a) NaOH, H2O, EtOH, MeI, rt, 16 h, 95%; (b) LiHMDS, THF, 0 °C, 2 h, 89%; (c) (MeO)2CHNMe2, PhMe, reflux, 16 h then H2NNH2ÁH2O, EtOH,
i
rt, 2 h, 84%; (d) mCPBA, CH2Cl2, rt, 16 h, 84%; (e) RNH2, PrOH, lW, 175 °C, 30 min.
Unfortunately, a number of amine monomers failed to give any
pure final target, due to either their lack of reactivity (presumably
due to steric hindrance and/or unfavorable electronics) or instabil-
ity under the reaction conditions. For example, tert-butylamine, 1-
methyl-1-phenylpropylamine, and benzhydrylamine all resulted in
no isolable products. We therefore attempted to increase the reac-
tivity of the pyrimidine electrophile by choosing to access these fi-
nal targets via the 2-chloropyrimidine intermediate 11 (Scheme 2).
The initial step of this synthetic route required slow addition (via
syringe pump over 30 min) of chloropyrimidine 9 to LDA at
À78 °C, followed by the addition of methyl 4-chlorobenzoate 5
to give ketone 10 in moderate yield.5 The moderate yield was pri-
marily due to competing addition of diisopropylamine to the
chloropyrimidine moiety and hydrolysis of the reactive chloropyr-
imidine moiety to afford the polar pyrimidinone by-product. Ke-
tone 10 was converted to pyrazole 11 as before, but this time in
moderate yield.5 Brief optimization of the final SNAr step showed
that the reaction could once again be performed in 2-propanol un-
der microwave irradiation (160 °C, 60 min), but this time with
added base and longer reaction times (most likely due to the unre-
active nature of the chosen amines).9 For example, utilizing cis-2-
amino-1-cyclopentanecarboxamide afforded the required product
motif found in compound 1. The synthetic scheme to access these
molecules needed to be flexible enough to vary both the 2-amino-
pyrimidine moiety and the piperidine substitution in an efficient
and expedient manner, in order to rapidly explore the SAR of this
chemical series (Scheme 3).
The initial route to these targets was via the key piperidine
intermediate 15. Weinreb amide 12 was obtained via the method
described by Barton et al.10 2-Mercapto-4-methyl pyrimidine 4
was then coupled with Weinreb amide 12, at low temperature,
to afford ketone 13 in good yield.4 Compound 13 was then con-
verted into the pyrazole and the sulfide was oxidized to sulfone
14 in short order.5,6 Finally, sulfone 14 underwent SNAr reaction
with isopropylamine, followed by Boc deprotection to yield piper-
idine 15. This synthetic route could be performed on large scale,
with only the penultimate SNAr reaction limiting the throughput
of material.
In an effort to functionalize intermediate amine 15, we decided
to explore the use of silica-bound cyanoborohydride-mediated
reductive aminations (Scheme 4).11 Specifically, amine 15 was irra-
diated with a variety of aldehydes in the presence of SiliaBond-cya-
noborohydride at 150 °C for 5 min. The crude reaction mixture was
then subjected to an SPE ‘catch and release’ work-up with SCX car-
tridges.12 This allowed for the products 16 to be isolated in pure
in 29% yield, L-alaninamide hydrochloride gave 8 in 44% yield,
and (S)-b-homoalanine hydrochloride afforded 8 in 41% yield.
Our primary strategy for HTS hit 2 was to remove the 4-pyridyl
moiety, so we decided to replace it with the 2-aminopyrimidine
Scheme 3. Reagents and conditions: (a) LiHMDS, THF, 0 °C, 2 h, 84%; (b)
(MeO)2CHNMe2, PhMe, reflux, 16 h then H2NNH2ÁH2O, EtOH, rt, 2 h, 63%; (c)
Scheme 2. Reagents and conditions: (a) LDA, THF, À78 °C, 16 h, 35%; (b)
(MeO)2CHNMe2, PhMe, reflux, 16 h then H2NNH2ÁH2O, EtOH, rt, 2 h, 45%; (c)
i
mCPBA, CH2Cl2, rt, 16 h, 77%; (d) PrNH2, dioxane, 110 °C, sealed tube, 4 h; (e) HCl,
i
i
RNH2, PrOH, Pr2NEt,
l
W, 160 °C, 60 min.
iPrOH, reflux, 2 h, 34% (two steps).

2554
P. S. Humphries et al. / Tetrahedron Letters 50 (2009) 2552–2554
forts on hit compound
1 required target compounds to be
synthesized by microwave-induced SNAr reactions of primary alkyl
amines and 2-methylsulfonylpyrimidines or 2-chloropyrimidines.
Hit-to-lead efforts on hit 2 allowed for pendant piperidine func-
tionality to be elaborated utilizing silica-bound reagents in micro-
wave-assisted reductive amination and amide bond formation
protocols.
Acknowledgements
Scheme 4. Reagents and conditions: (a) RCHO, SiliaBond-cyanoborohydride, AcOH,
DMF, lW, 150 °C, 5 min.
The authors would like to thank Lilian Li for performing the
metabolite ID study on 1 and Shahnaz Ghassemi (Biotage AB) for
technical assistance. We are also grateful to the Discovery Purifica-
tion group for preparative HPLC purification of all final targets de-
scribed in this Letter and John Tatlock and Chris Limberakis for
stimulating discussions and feedback on this manuscript.
References and notes
1. (a) Hirosumi, J.; Tuncman, G.; Chang, L.; Görgün, C. Z.; Uysal, K. T.; Maeda, K.;
Karin, M.; Hotamisligil, G. S. Nature 2002, 420, 333; (b) Bennett, B. L.; Satoh, Y.;
Lewis, A. J. Curr. Opin. Pharmacol. 2003, 3, 420; (c) Wellen, K. E.; Hotamisligil, G.
S. J. Clin. Invest. 2005, 115, 1111.
2. Hopkins, A. L.; Groom, C. R.; Alex, A. Drug Discovery Today 2004, 9, 430.
3. All new compounds were characterized by full spectroscopic data, yields refer
to chromatographed material with purity >95%.
Scheme 5. Reagents and conditions: (a) RCO2H, SiliaBond-carbodiimide, CH2Cl2,
W, 150 °C, 5 min.
l
4. Almansa Rosales, C.; Virgili Bernado, M.; Grima Poveda, P. M. WO 2006/013095
A2, 2006; Chem. Abstr. 2006, 144, 212773.
5. Garcia-Echeverria, C. WO 2005/068452 A1, 2005; Chem. Abstr. 2005, 143,
172889.
6. Uehling, D. E.; Stevens, K. L.; Dickerson, S. H.; Waterson, A. G.; Harris, P. A.;
Sammond, D. M.; Hubbard, R. D.; Emerson, H. K.; Wilson, J. W. WO 2006/
068826 A2, 2006; Chem. Abstr. 2006, 145, 103711.
7. Tavares, F. X.; Boucheron, J. A.; Dickerson, S. H.; Griffin, R. J.; Preugschat, F.;
Thomson, S. A.; Wang, T. Y.; Zhou, H.-Q. J. Med. Chem. 2004, 47, 4716.
8. All microwave-assisted reactions were performed on a Biotage Initiator (http://
www.biotage.com).
9. (a) Luo, G.; Chen, L.; Poindexter, G. S. Tetrahedron Lett. 2002, 43, 5739; (b)
Cherng, Y.-J. Tetrahedron 2002, 58, 887.
10. Barton, P. J.; Butlin, R. J.; Pease, J. E. WO 2005/046685 A1, 2005; Chem. Abstr.
2005, 142, 481954.
11. Silica-bound reagents were purchased from SiliCycle, Inc., http://
www.silicycle.com.
12. Isolute SCX cartridges were purchased from Biotage AB.
form, free from any residual DMF solvent. For example, utilizing
acetaldehyde afforded the required product (R = Me) in 91% yield,
benzaldehyde gave 8 (R = Ph) in 97% yield, and cyclopropanecar-
boxaldehyde afforded 8 (R = cyclopropane) in 94% yield.
Exploration into the use of silica-bound carbodiimide-mediated
amide bond formations was also deemed of interest (Scheme 5).11
Specifically, amine 15 was irradiated with a variety of carboxylic
acids in the presence of SiliaBond-carbodiimide at 150 °C for
5 min to afford amides 17. For example, utilizing isobutyric acid
afforded the required product (R = iPr) in 98% yield, benzoic acid
gave 8 (R = Ph) in 94% yield, and cyclohexanecarboxylic acid affor-
ded 8 (R = cyclohexane) in 97% yield.
In summary, we have successfully developed a number of effi-
cient and versatile routes to 2-amino-4-heteroarylpyrimidines. Ef-