A three-step synthesis of 4-(4-iodo-1H-pyrazol-1-yl)piperidine, a key intermediate in the synthesis of Crizotinib

Article abstract of DOI:10.1016/j.tetlet.2011.12.044

4-(4-Iodo-1H-pyrazol-1-yl)piperidine is a key intermediate in the synthesis of Crizotinib. We report a robust three-step synthesis that has successfully delivered multi-kilogram quantities of the key intermediate. The process includes nucleophilic aromatic substitution of 4-chloropyridine with pyrazole, followed by hydrogenation of the pyridine moiety and subsequent iodination of the pyrazole which all required optimization to ensure successful scale-up.

Full text of DOI:10.1016/j.tetlet.2011.12.044

Tetrahedron Letters 53 (2012) 948–951
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Tetrahedron Letters
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A three-step synthesis of 4-(4-iodo-1H-pyrazol-1-yl)piperidine, a key
intermediate in the synthesis of Crizotinib
⇑
⇑
Steven J. Fussell, Amy Luan , Philip Peach, Gemma Scotney
Department of Chemical Research and Development, Pfizer Limited, Ramsgate Road, Sandwich CT13 9NJ, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
4-(4-Iodo-1H-pyrazol-1-yl)piperidine is a key intermediate in the synthesis of Crizotinib. We report a
robust three-step synthesis that has successfully delivered multi-kilogram quantities of the key interme-
diate. The process includes nucleophilic aromatic substitution of 4-chloropyridine with pyrazole, fol-
lowed by hydrogenation of the pyridine moiety and subsequent iodination of the pyrazole which all
required optimization to ensure successful scale-up.
Received 8 November 2011
Revised 29 November 2011
Accepted 9 December 2011
Available online 16 December 2011
Ó 2011 Published by Elsevier Ltd.
Keywords:
Iodination
Hydrogenation
Nucleophilic aromatic substitution
Palladium
Piperidine
Crizotinib (1) (XALKORIÒ) is a potent and selective anaplastic
lymphoma kinase (ALK) inhibitor that was approved by the US
Food and Drug Administration in August 2011 for the treatment
of locally advanced or metastatic non-small cell lung carcinoma
(NSCLC).1 As a result of the positive results observed during an
early clinical trial, the clinical program was rapidly accelerated
which required extensive route evaluation to enable delivery of
bulk quantities of the clinical candidate.
previously sourced as the corresponding tert-butyl carbamate 5
during the enabling route to make pre-clinical batches of Crizotinib
(1).2 The Boc-protected piperidine 5 has only been reported to be
synthesized via the activation of 4-hydroxy-1-Boc-piperidine (3)
followed by displacement with 4-iodopyrazole (Scheme 2).
This route successfully delivered multi-kilogram amounts of the
target substrate, however it was not suitable for further scale-up
due to the expensive starting material, lengthy work-up, and sig-
nificant formation of the elimination by-product 6 during the dis-
placement reaction.
4-(4-Iodo-1H-pyrazol-1-yl)piperidine (2) is a key intermediate
in the synthesis of Crizotinib (1, Scheme 1). Intermediate 2 was
The unprotected substrate 2 was selected for the commercial
synthetic route as a result of development of the downstream
chemistry. The use of unprotected substrate 2 improved the atom
efficiency for the synthesis of Crizotinib (1) by eliminating the sub-
sequent deprotection step in the enabling route (substrate 7 to 1).
Herein we describe the development and optimization of the syn-
thetic route, via a completely different approach, to the construc-
tion of the pyrazole–piperidine framework (Scheme 2).3 We
initially investigated the shortest route to the target molecule, a
two-step synthesis involving nucleophilic substitution of 4-chloro-
pyridine 8 with 4-iodopyrazole followed by selective reduction of
the pyridine moiety in 9 to furnish the target molecule 2. Although
the conversion of 8 into 9 proceeded in quantitative yield, all the
hydrogenation conditions screened led to dehalogenation of 9.
Therefore, a more stepwise approach was considered whereby a
separate halogenation step would be utilized to incorporate the de-
sired iodine fragment and furnishing a three-step route to the key
intermediate 2.
H
N
N
N
H
N
Cl
F
N
N
N
O
NH2
I
Cl
2
1 Crizotinib
Scheme 1. Crizotinib (1) and key intermediate 4-(4-iodo-1H-pyrazol-1-yl)piperi-
dine (2).
⇑
Corresponding authors. Tel.: +44 1304 644107.
E-mail address: gemma.scotney@pfizer.com (G. Scotney).
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.12.044

S. J. Fussell et al. / Tetrahedron Letters 53 (2012) 948–951
949
O
Existing Route
O
N
O
N
O
N
N
O
O
O
O
New Route
N
N
O
O
HCl
N
N
N
H HCl
N
b
a
+
Cl
F
N
100%
5: 60-66%
6: 10%
N
O
OMs
OH
NH2
N
N
Cl
N
N
I
3
4
5
6
7
H
H
11
10
d
H
N
HCl
N
H
N
HCl
N
d
X
c
N
N
100%
N
N
N
Cl
N
Cl
8
I
I
N
NH2
2
9
O
Cl
F
1
Scheme 2. Reagents and conditions: (a) MsCl (1.4 equiv), Et3N (1.45 equiv), DMAP (0.1 equiv), tert-butyl methyl ether, 0 °C; (b) Method 1: 4-iodopyrazole (0.9 equiv), NaH
(1.1 equiv), DMF, 100 °C, 12 h; Method 2: 4-iodopyrazole (0.9 equiv), Cs2CO3 (1.1 equiv), NMP, 78–82 °C, 6 h; column from 5% EtOAc in heptanes; (c) 4-iodopyrazole
(5.0 equiv), toluene, reflux, 5 h, 60% isolated yield; (d) catalyst: Pd, Pt, PtO2, Rh, or Ru; solvent: AcOH, EtOH, H2O, or toluene/2-PrOH; additive: I2, ZnI2, or HI/H2O, 0% of 2, 100%
of 11.
Table 1
HCl
N
Conditions for the nucleophilic substitution to give 4-(1H-pyrazol-1-yl)pyridine HCl
(10)
HCl
N
Entry Amount of 1H-pyrazole
Solvent
Temp
(°C)
Time
(h)
Yielda
(%)
HCl
N
N+
N
(equiv)
Cl
N+
Cl
1
2
3
4
5
6
7
8
1.0
2.0
3.0
1.2
3.0
3.0
3.0
3.0
Toluene 90
Toluene 90
Toluene 90
EtOAc
EtOAc
MeCN
2-PrOH
H2O
16
16
16
24
24
24
6
52b
86
100
40d
65b
100
97.5e
81f
c
OR
Reflux
N
OR
Reflux
Reflux
Reflux
80
12
13
R = H, Et,
14
6
i
Pr, nBu
a
Reactions were monitored by 1H NMR spectroscopy of crude samples.
Both the starting material, 4-chloropyridine HCl 8 and intermediate 4-pyrazol-
Figure 1. Nucleophilic substitution intermediate 12 and impurities 13 and 14.
b
[1,40]bipyridinyl-1-ylium chloride HCl 12 were present in the reaction mixture.
The nucleophilic substitution in acetonitrile with 3 equiv of 1H-
pyrazole (Table 1, entry 6) gave the best results in terms of conver-
sion, physical properties of the reaction mixture, and simplicity of
isolation. Upon successful completion of the reaction, the mixture
was quenched with 1.0 equiv of Hünig’s base to scavenge the HCl
by-product and the pyridine salt 10 was subsequently isolated by
filtration. Due to solubility differences, this left all of the excess re-
agents and by-products in the mother liquors and hence purged
them from the product 10.
With 10 in hand, the next step involved hydrogenation of the
pyridine moiety. A number of catalysts and solvents were high-
lighted after initial screening to furnish successfully piperidine
11. Side products formed during the hydrogenation were identified
as 1H-pyrazole (16) and piperidine hydrochloride (17); these are
postulated to arise from the elimination and rearomatization of
the partially reduced substrate 15 during the course of the hydro-
genation (Scheme 3).
c
The reaction used 4-chloropyridine (8) as the free base.
Only the intermediate 4-pyrazol-[1,40]bipyridinyl-1-ylium chloride 12 was
d
present in the reaction mixture.
e
Contains 2.5% of 13, R = iPr.
Contains 5% of 13 and 7% of 14, R = H.
f
Nucleophilic aromatic substitution of 4-chloropyridine hydro-
chloride (8) with 1H-pyrazole was initially performed in toluene
(Table 1, entries 1–3). It was clearly shown that the number of
equivalents of 1H-pyrazole utilized in the reaction directly im-
pacted on the extent of conversion and ultimately the yield ob-
tained. By increasing the amount of 1H-pyrazole to 3.0 equiv
(entry 3), intermediate 12 ( Fig. 1) is effectively converted into
two equivalents of the desired product 10 through the reaction
of 1H-pyrazole at the 4-position of the Northern pyridine fragment.
The reaction mixture in toluene was an oily slurry, which posed
potential scale-up issues, therefore a range of further solvents
was subsequently investigated. Reaction in alcoholic solvents and
water resulted in impurities 13 and 14 (Table 1, entries 7 and 8)
ranging from 3% to 50%. In-depth kinetic studies showed that the
formation of such impurities was difficult to control and an alter-
native solution was desirable.
The initial screening experiments highlighted two potentially
useful catalysts, 5% Rh/C 20A and 5% Pd/C 87L and these were used
in subsequent kinetic studies and further development work. Sev-
eral factors were investigated simultaneously and are listed in Ta-
ble 2: catalyst, solvent, catalyst loading, pressure, and reaction

950
S. J. Fussell et al. / Tetrahedron Letters 53 (2012) 948–951
HCl
N
not be avoided as they were generated continuously during the
reaction.
Over the course of our investigation into the hydrogenation of
HCl
N
HCl
NH
HCl
N
N
HN
+
pyridine 10, we noted that the pH of the reaction mixture had a
significant impact on the reaction rate whereby the hydrogenation
started with a pH of 3 and increased to 6 over the course of the
transformation. It was also noted that above pH 6, the rate of the
reaction decreased significantly and a remedial charge of HCl or
acetic acid was necessary to ensure completion of the hydrogena-
tion stage. It was also found that intermediate 12 had a detrimental
effect on the reaction conversion. In fact, the presence of only 2% of
12 was enough to stall the hydrogenation reaction completely and
therefore its levels in 10 needed careful control.
The final step in the sequence involved iodination of piperidine
11 to furnish the target key intermediate 2. This transformation
was initially investigated using isolated 4-(1H-pyrazol-1-yl)piper-
idine 11 di-hydrochloride salt.4 Table 3 indicates that N-iodosuc-
cinimide (entry 1) gave high conversion into the desired product
in a short reaction time of 30 min. Alternative reagents (entries 2
and 3) also provided high conversions but with an increase in
the number of impurities produced in the reaction.5 When using
the mono-hydrochloride salt 11 telescoped from the earlier steps,
additional acid was required to prevent the pH from becoming
too high and causing the reaction to stall (entries 4 and 5). In addi-
tion to the originally used N-iodosuccinimide, alternative iodin-
ation conditions showed promise with excellent conversions and
reaction profiles (entries 6 and 7).
N
N
N
N
10
15
16
17
Scheme 3. Proposed reaction pathway for the formation of 1H-pyrazole (16) and
piperidine hydrochloride (17).
time. Conducting the reaction in water, methanol, and ethanol
showed no significant differences in the reaction rate and product
distribution (entries 1, 4 and 5), whereas reaction in 2-propanol re-
sulted in a significantly slower reaction rate and increased the pro-
duction of the piperidine impurity 17 (entry 6). The rate of
hydrogenation increased with the catalyst loading as seen by com-
paring entries 1 and 9, however the selectivity was not improved.
Increasing the pressure offered little improvement on the reaction
rate and selectivity (entries 1 and 8). Increasing the temperature
failed to increase the rate of reaction but did again result in a sig-
nificant increase in the production of impurity 17 (entries 1 and 7).
An iterative approach allowed us to find optimum conditions for
the formation of piperidine 11 whereby a high catalyst loading,
low temperature, and high pressure in either water or methanol
resulted in excellent levels of conversion into the desired product
with product distributions of 20:1 and 33:1 (entries 10 and 11).
While conducting these two reactions, multiple samples were ta-
ken over the course of the reaction and subsequent analysis
showed that the formation of both impurities 16 and 17 could
During iodination, 1H-pyrazole (16) produced during the
hydrogenation reaction was converted into 4-iodopyrazole (18)
Table 2
Conditions for the hydrogenation of 4-pyrazol-1-yl-piperidine HCl 11
Entry
Solventa
Catalyst
Loadinga (%)
Temp (°C)
Pressure (psi)
Time (h)
Conversion into 11b (%)
Ratio of 11:17b
1
2
3
4
5
6
7
8
9
H2O
H2O
H2O
MeOH
EtOH
2-PrOH
H2O
H2O
H2O
5% Rh/C 20A
5% Pd/C 87L
5% Pd/C 87L
5% Rh/C 20A
5% Rh/C 20A
5% Rh/C 20A
5% Rh/C 20A
5% Rh/C 20A
5% Rh/C 20A
5% Rh/C 20A
5% Rh/C 20A
10
10
5
50
50
50
50
50
50
80
50
50
30
30
150
150
150
150
150
150
200
250
150
250
250
16
40
24
12
16
16
16
12
6
100
94
26
10:1
14:1
N/A
10:1
10:1
7:1
3.6:1
17:1
11:1
20:1
33:1
10
10
10
10
10
20
20
20
100
100
58
100
100
100
100
100
10
11
H2O
MeOH
16
16
a
Hydrogenation was performed in 10 mL/g solvent with respect to 4-(1H-pyrazol-1-yl)pyridine hydrochloride (10).
b
Reaction conversion and selectivity were estimated by 1H NMR spectroscopy.
Table 3
Conditions for the iodination of 4-(1H-pyrazol-1-yl)piperidine HCl (11) at 20 °C
Entry Iodination reagent
Amount of reagent
(equiv)
Additives Amount of additive
(equiv)
Solvent
Time
(h)
Conversiona Total impuritiesa
%
%
1b
2b
3b
N-Iodosuccinimide
1.0
1.0
1.0
None
None
None
—
—
—
H2O
AcOH
AcOH
0.5
16
16
100
100
100
None
30
30
Tetrabutylammonium triiodide
Benzyltrimethyl ammonium
dichloroiodide
4c
5c
N-Iodosuccinimide
1.0
1.0
None
—
H2O, EtOH,
CH2Cl2
H2O
16
32–64
100
1–4
N-Iodosuccinimide
Conc.
HCl
AcOH
Conc.
HCl
1.0
0.5
None
6c
7c
Iodine/30% hydrogen peroxide
Sodium iodide/potassium iodate
0.6/1.0
0.68/0.34
5.0
2.0
H2O
H2O
45–60 100
16 100
None
None
a
The reaction conversion and amount of unknown impurities were determined by GC analysis. Sample preparation included a quench with 2 M NaOH and extraction with
CH2Cl2.
b
Iodination was performed with substrate 11 di-hydrochloride salt.
Iodination was performed with non-isolated substrate 11 hydrochloride aqueous solution from hydrogenation.
c

S. J. Fussell et al. / Tetrahedron Letters 53 (2012) 948–951
951
S
genation support; Suju Mathew for Process Engineering support;
Pieter De Koning, Andrew Derrick, Alan Happe, and Asayuki Kama-
tani for useful discussions and support throughout the project;
Stuart Green, Hayley Jackman, and Stewart Hayes for the support
of this Letter.
H
N
N
N
N
N
N
N
N
I
I
I
19
18
Supplementary data
Figure 2. 4-Iodopyrazole (18) and thiodiamine 19 impurities.
Supplementary data (experimental procedures and spectral
data for new compounds) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2011.12.044.
(Fig. 2) at a rate similar to that of the desired substrate 11. Both by-
products, 4-iodopyrazole (18) and piperidine 17 have solubilities
very different to that of the desired product 2, and consequently,
they were removed during the isolation of 2 by crystallization in
ethyl acetate.
Once the iodination reaction was complete, the mixture was
initially quenched with sodium thiosulfate followed by pH adjust-
ment to pH 12. The desired product 2 was extracted with THF fol-
lowed by solvent replacement into ethyl acetate to enable
crystallization, and isolated by filtration. An overall 73% isolated
yield was obtained over the two steps, whereby hydrogenation
had an in situ 90% conversion and iodination had quantitative con-
version and an 81% isolated yield.
Interestingly, when the iodination mixture was quenched with
sodium thiosulfate, thiodiamine impurity 196 (Fig. 2) was found in
the isolated product at levels up to 10%. This thiodiamine 19 was
later found to be generated when the pH was P8 in the presence
of sodium thiosulfate, and could be converted into the desired
product 2 by exposure to aqueous HCl at 20 °C for 2 h.7 In order
to avoid the formation of 19, sodium sulfite was subsequently used
to quench the iodination reaction mixture.
In conclusion, we have developed a new three-step synthetic
route to 4-(4-iodo-1H-pyrazol-1-yl)piperidine (2), a key intermedi-
ate in the synthesis of Crizotinib (1). It has a number of distinct
advantages over the enabling route including completely eliminat-
ing the formation of unwanted by-product 6. The route has proved
to be easily scalable, robust, and well streamlined. This three-step
synthesis has since successfully been scaled-up on a multi-kilo-
gram scale and has delivered >180 kg of 2 in high purity.
References and notes
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Ruck, R. T.; Zhao, D.; Huffman, M. A. Tetrahedron Lett. 2008, 49, 4026–4028; (c)
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Acknowledgments
We thank Denise Harris and James Hogbin for analytical sup-
port; John Pearce for Process Safety work; John Deering for hydro-