Simple approach to the synthesis of 3-fluoro pyrazolo[1,5-a]pyrimidine analogues

Article abstract of DOI:10.1016/j.tetlet.2013.03.015

A simple method for the synthesis of novel 3-fluoro pyrazolo[1,5-a] pyrimidine analogues has been developed starting from fluoro acetonitrile and benzoyl chloride. The desired compounds are synthesized from a 3-amino-4-fluoro pyrazole intermediate. The versatility of the approach was demonstrated by the synthesis of a small library of pyrazolo[1,5-a]pyrimidine.

Full text of DOI:10.1016/j.tetlet.2013.03.015

Tetrahedron Letters 54 (2013) 2612–2614
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Simple approach to the synthesis of 3-fluoro pyrazolo[1,5-a]pyrimidine
analogues
Hassen Bel Abed a, Oscar Mammoliti b, Guy Van Lommen b, Piet Herdewijn a,
⇑
a Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
b Galapagos, Laboratory of Medicinal Chemistry, General de Wittelaan L11 A3, B-2800 Mechelen, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple method for the synthesis of novel 3-fluoro pyrazolo[1,5-a]pyrimidine analogues has been devel-
oped starting from fluoro acetonitrile and benzoyl chloride. The desired compounds are synthesized from
a 3-amino-4-fluoro pyrazole intermediate. The versatility of the approach was demonstrated by the syn-
thesis of a small library of pyrazolo[1,5-a]pyrimidine.
Received 24 January 2013
Revised 4 March 2013
Accepted 5 March 2013
Available online 13 March 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Pyrazolo[1,5-a]pyrimidine
Pyrazole
Heterocycle
Cyclization
Pyrazolo[1,5-a]pyrimidine1 analogues have been extensively
studied as kinase inhibitors and several compounds have been
found active such as the B-Raf kinase inhibitor2 1 or the cyclin
dependent kinase inhibitor 23 (Fig. 1).
In addition, this core has shown inhibitory activity towards
other kinases such as Pim. The substitution pattern and the kind
of decoration explored, allowed selectivity towards particular ki-
nases. It has been demonstrated that the pyrazolo[1,5-a]pyrimi-
dine scaffold itself interacts with the hinge region of the ATP
binding site.4
this problem, that is, the introduction of the fluorine at an earlier
stage. In fact, the synthesis of an intermediate containing a fluorine
could be of value for the development of a simple approach to the
synthesis of pyrazolo[1,5-a]pyrimidine derivatives and other re-
lated heterocycles.
The synthetic scheme started with the synthesis of the 3-ami-
no-4-fluoro pyrazole derivative10 6 by using fluoro acetonitrile 4
as the starting material. An acylation reaction was performed at
low temperature with LiHMDS as the base to afford the intermedi-
ate a-fluoro-b-ketonitrile 5 which was used without further puri-
fication in the next step.
In view of previous literature5 describing this structure as po-
tential scaffold to develop a kinase inhibitor, the synthesis of 3-flu-
oro pyrazolo[1,5-a]pyrimidine was considered. This synthesis fits
in our ongoing interest6 to explore new heterocycles for the drug
design project.
Herein, we describe the synthesis of 3-fluoro pyrazolo[1,5-
a]pyrimidine starting from 3-amino-4-fluoro pyrazole. One of the
most common methods for the synthesis of fluorinated pyrazol-
o[1,5-a]pyrimidine is the fluorination of the scaffold directly by
electrophilic fluorination,7 using a reagent like 1-chloromethyl-4-
fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) also
known as Selectfluor 38 (Scheme 1).
The hydrazinolysis of 5 in ethanol to obtain the 3-amino-4-flu-
oro pyrazole 6 is straightforward. The formation11 of the 3-fluoro
pyrazolo[1,5-a]pyrimidine scaffold was realized by condensation
of 6 with diethyl ethoxymethylenemalonate in acetic acid at
100 °C for 10 h to afford pyrazolo[1,5-a]pyrimidine 7 in good yield,
However, such fluorination method is generally low yielding
and has never worked in the case of 7-chloro pyrazolo[1,5-
a]pyrimidine in our hands, in contrast to other halogenations such
as iodination.9 An alternative procedure was envisioned to avoid
⇑
Corresponding author. Tel.: +32 16 337387; fax: +32 16 337340.
E-mail address: piet.herdewijn@rega.kuleuven.be (P. Herdewijn).
Figure 1. Kinase inhibitors based on pyrazolo[1,5-a]pyrimidine.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.015

H. Bel Abed et al. / Tetrahedron Letters 54 (2013) 2612–2614
2613
Table 1
Synthesis of 3-fluoro pyrazolo[1,5-a]pyrimidine derivatives 11 and 14
Entry
Product
Yield (%)
a
70
63
Scheme 1. Electrophilic fluorination of 7-chloro pyrazolo[1,5-a]pyrimidine.
b
c
65
d
60
Scheme 2. Synthesis of 3-fluoro-7-hydroxy-2-phenyl pyrazolo[1,5-a]pyrimidine.
e
58
f
68
58
g
Scheme 3. Synthesis of 3-fluoro pyrazolo[1,5-a]pyrimidine derivatives.
which after saponification with sodium hydroxide gave 8. A final
decarboxylation with Dowtherm A at 230 °C for 5 h, led to the de-
sired intermediate 912,13 (Scheme 2).
h
55
Intermediate 9 was treated in refluxing phosphorus oxychloride
to give the chlorinated derivative 10 which was subjected to nucle-
ophilic substitution with different amines to obtain compound
1114 (Scheme 3). The versatility of this approach was demonstrated
by the synthesis of a small-size library as shown in Table 1.
The amines used during the last step varied from aliphatic
amines, cycloalkyl amines, benzyl amines to heteroaryl amines.
The 3-amino-4-fluoro pyrazole 6 has also been condensed with
(hetero)aryl dimethylamino propenone 13 (obtained from
acetophenone derivatives 12) in refluxing acetic acid to obtain 3-
fluoro-7-(hetero)aryl-2-phenyl-pyrazolo[1,5-a]pyrimidine deriva-
tives 1415 (Scheme 4).
i
j
50
42
In conclusion, we have elaborated a simple approach for the
synthesis of 3-fluoro pyrazolo[1,5-a]pyrimidine derivatives by

2614
H. Bel Abed et al. / Tetrahedron Letters 54 (2013) 2612–2614
7. Kataoka, K.; Suzuki, N.; Kosugi, T.; Imai, M.; Makino, H. Patent WO2004/
076458.
8. (a) Nolte, B.; Sucholeiki, I.; Feuerstein, T.; Gallagher, B. M.; Wu, X. Patent
WO2008/063671.; (b) Dressen, D.; Garofalo, A. W.; Hawkinson, J.; Hom, D.;
Jagodzinski, J.; Marugg, J. L.; Neitzel, L. M.; Pleiss, M. A.; Szoke, B.; Tung, J. S.;
Wone, D. W. G.; Wu, J.; Zhang, H. J. Med. Chem. 2007, 50, 5161–5167.
9. Krasovsky, L. A.; Hartulyari, A. S.; Nenajdenko, V. G.; Balenkova, E. S. Synthesis
2002, 1, 133–137.
10. Cocconcelli, G.; Ghiron, C.; Haydar, S.; Micco, I.; Zanaletti, R. Synth. Commun.
2010, 40, 2547–2555.
11. (a) Nagahara, K.; Kawano, H.; Sasaoka, S.; Ukawa, C.; Hirama, T.; Takada, A. J.
Heterocycl. Chem. 1994, 31, 239–243; (b) Gavrin, L. K.; Lee, A.; Provencher, B. A.;
Massefski, W. W.; Huhn, S. D.; Ciszewski, G. M.; Cole, D. C.; McKew, J. C. J. Org.
Chem. 2007, 72, 1043–1046.
12. Representative procedure for 6: A 1 M solution of LiHMDS in THF (29.4 mL,
29.4 mmol, 2.0 equiv) was added dropwise to a solution of benzoyl chloride
(1.7 mL, 14.68 mmol, 1.0 equiv) and fluoroacetonitrile 4 (0.82 mL, 14.68 mmol,
1.0 equiv) in dry THF (15 mL) cooled to À78 °C under nitrogen. The mixture
was allowed to reach room temperature after 5 h of reaction and quenched
Scheme 4. Synthesis of 3-fluoro-7-(hetero)aryl-2-phenyl pyrazolo[1,5-a]pyrimi-
dine derivatives.
with
a saturated solution of ammonium chloride. The mixture was
concentrated under reduced pressure to afford the desired
a-fluoro-b-
ketonitrile 5 in a form pure enough for the next step.
Hydrazine hydrate (64% in water) (1.4 mL, 29.4 mmol, 2.0 equiv) was added to
a solution of -fluoro-b-ketonitrile 5 (14.68 mmol) in ethanol (20 mL), and the
introducing the fluorine at an earlier stage of the synthesis instead
of using a direct electrophilic fluorination on the pyrazolo[1,5-
a]pyrimidine. The method could be employed to the development
of a small-size library of ‘drug-like’ compounds with different
amines. In a first screening assay, compound 11h showed 71% of
inhibition at 10 lM towards the TGF-b receptor II. The further bio-
logical evaluation of the fluorinated pyrazolo[1,5-a]pyrimidines
obtained in these experiments is ongoing.
a
reaction was heated at reflux for 18 h. The reaction mixture was allowed to
cool to room temperature, and the solvent was evaporated under reduced
pressure. The residue was dissolved in dichloromethane and washed with
water. The organic phase was concentrated to give a crude product, flash
column chromatography on silica gel (ethyl acetate/hexane 90:10) afforded the
desired product 6 as a beige powder (1.3 g, 50%); mp 115–118 °C; 1H NMR
(500 MHz, DMSO-d6): d 11.92 (br s, 1H), 7.66 (d, J = 7.5 Hz, 2H), 7.45 (t,
J = 7.4 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1H), 4.77 (br s, 2H); 13C NMR (125 MHz,
DMSO-d6): d 143.3, 135.9, 134.3, 129.0, 127.9, 126.2, 124.7. 19F NMR (470 MHz,
DMSO-d6):
178.0778.
d
À186.5. HRMS calcd for C9H8FN3 (M+H)+: 178.0775, found:
Acknowledgments
13. Representative procedure for 9: To carboxylic acid 8 (1 g, 3.66 mmol) was added
Dowtherm (10 mL). The suspension was heated to 230 °C for 5 h. The
A
Hassen Bel Abed is indebted to the IWT (Agentschap voor Inno-
vatie door Wetenschap en Technologie) and the Galapagos com-
pany for providing a PhD-scholarship (Baekeland-project 90704).
He is also grateful to Dr. Karim and Dr. Kachare for their kind
suggestions.
reaction mixture was cooled to room temperature, then diluted with hexanes
(30 mL), stirred vigorously, filtered, and dried to obtain the desired product 9
as a light brown powder (0.68 g, 82%); mp 205–208 °C; 1H NMR (500 MHz,
DMSO-d6): d 7.97 (d, J = 7.6 Hz, 2H), 7.75 (d, J = 5.9 Hz, 1H), 7.49 (t, J = 7.6 Hz,
2H), 7.39 (t, J = 7.5 Hz, 1H), 5.48 (d, J = 5.9 Hz, 1H); 13C NMR (125 MHz, DMSO-
d6): d 157.2, 148.0, 136.9, 131.8, 131.7, 128.8, 128.3, 126.5, 92.8. HRMS calcd
for C12H8FN3O (M+H)+: 230.0724, found: 230.0725.
14. Representative procedure for 11a: To
1.0 equiv) in ethanol (10 mL) was added a solution of 70% ethylamine (70% in
water) (48 L, 0.6 mmol, 1.5 equiv), followed by triethylamine (83 L,
a solution of 10 (100 mg, 0.4 mmol,
References and notes
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0.6 mmol, 1.5 equiv) at room temperature. The reaction mixture was
refluxed for 16 h and after completion of the reaction (TLC), the reaction
mixture was allowed to cool to room temperature. Dichloromethane was
added and the organic phase was then washed two times with a saturated
solution of NaHCO3, and one time with brine. It was then dried over Na2SO4,
and concentrated in vacuo. Flash column chromatography on silica gel (ethyl
acetate/hexane 75:25) afforded the desired product 11a as a white powder
(72 mg, 70%); mp 212–216 °C; 1H NMR (500 MHz, DMSO-d6):
d 8.16 (d,
J = 5.3 Hz, 1H), 8.13 (t, J = 5.8 Hz, 1H), 8.04 (d, J = 7.3 Hz, 2H), 7.55 (t, J = 7.6 Hz,
2H), 7.47 (t, J = 7.5 Hz, 1H), 6.22 (d, J = 5.3 Hz, 1H), 3.48 (m, 2H), 1.26 (t,
J = 7.3 Hz, 3H); 13C NMR (125 MHz, DMSO-d6): d 149.8, 146.0, 138.7, 136.9,
135.1, 133.5, 130.6, 129.1, 126.7, 85.5, 36.6, 14.2. HRMS calcd for C14H13FN4
(M+H)+: 257.1197, found: 257.1195.
15. Representative procedure for 14b: To a solution of 3-amino-4-fluoro pyrazole 6
(150 mg, 0.85 mmol, 1 equiv) in acetic acid (5 mL) at room temperature was
added 2-thienyl dimethylamino propenone (170 mg, 0.94 mmol, 1.1 equiv).
The mixture was refluxed for 16 h. The suspension was filtered warm, then
washed several times with ethanol and dried to obtain the desired product 14b
as a yellow powder (105 mg, 42%); mp 233–237 °C; 1H NMR (500 MHz, DMSO-
d6): d 8.61 (d, J = 4.6 Hz, 1H), 8.59 (d, J = 3.8 Hz, 1H), 8.18 (d, J = 5.0 Hz, 1H), 8.13
(d, J = 7.7 Hz, 2H), 7.82 (d, J = 4.6 Hz, 1H), 7.62 (t, J = 7.7 Hz, 2H), 7.52 (t,
J = 7.5 Hz, 1H), 7.43 (t, J = 4.8 Hz, 1H); 13C NMR (125 MHz, DMSO-d6): d 149.0,
139.2, 138.6, 136.2, 135.0, 134.2, 132.5, 130.0, 129.6, 129.3, 129.2, 127.8, 126.6,
104.6. HRMS calcd for C16H10FN3S (M+H)+: 296.0652, found: 296.0659.
6. Bel Abed, H.; Mammoliti, O.; Van Lommen, G.; Herdewijn, P. Tetrahedron Lett.
2012, 53, 6489–6491.