A novel approach for the synthesis of Crizotinib through the key chiral alcohol intermediate by asymmetric hydrogenation using highly active Ir-Spiro-PAP catalyst

Article abstract of DOI:10.1016/j.tetlet.2014.01.053

A novel approach for the synthesis of Crizotinib (1) is described. In addition, new efficient procedures have been developed for the preparation of (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (2) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) piperidine-1-carboxylate (4), the key intermediates required for the synthesis of Crizotinib.

Full text of DOI:10.1016/j.tetlet.2014.01.053

Accepted Manuscript
A novel approach for the synthesis of Crizotinib through the key chiral alcohol
intermediate by asymmetric hydrogenation using highly active Ir-Spiro-PAP
catalyst
Jian-Qiang Qian, Pu-Cha Yan, Da-Qing Che, Qi-Lin Zhou, Yuan-Qiang Li
PII:
S0040-4039(14)00087-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.01.053
TETL 44086
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 November 2013
2 January 2014
14 January 2014
Please cite this article as: Qian, J-Q., Yan, P-C., Che, D-Q., Zhou, Q-L., Li, Y-Q., A novel approach for the synthesis
of Crizotinib through the key chiral alcohol intermediate by asymmetric hydrogenation using highly active Ir-Spiro-
PAP catalyst, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.01.053
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Graphical Abstract
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A novel approach for the synthesis of
Crizotinib through the key chiral alcohol
intermediate by asymmetric hydrogenation
using highly active Ir-Spiro-PAP catalyst
Jian-Qiang Qiana, Pu-Cha Yana, Da-Qing Chea, Qi-Lin Zhoub, Yuan-Qiang Lia*

3
Tetrahedron Letters
jo u rn al h ome p ag e : w ww .e lse vie r .c om
A novel approach for the synthesis of Crizotinib
through the key chiral alcohol intermediate by
asymmetric hydrogenation using highly active Ir-
Spiro-PAP catalyst
Jian-Qiang Qiana, Pu-Cha Yana, Da-Qing Chea, Qi-Lin Zhoub, Yuan-Qiang Lia*
a Zhejiang Jiuzhou Pharmaceutical Co. Ltd., Waisha Road 99, Jiaojiang, Taizhou, Zhejiang, 318000, P R China
b Institute and State Key laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
A novel approach for the synthesis of Crizotinib (1) is described. In addition, new efficient procedures
have been developed for the preparation of (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (2) and tert-
Received in revised form
Accepted
butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (4),
the key intermediates required for the synthesis of Crizotinib.
Available online
2012 Elsevier Ltd. All rights reserved.
Keywords:
Keyword_1 Crizotinib
Keyword_2 Asymmetric hydrogenation
Keyword_3 Ir[(R)-DTB-SpiroPAP-3-Me]
Keyword_4 Chiral alcohol
1. Introduction
acetate with pig liver esterase, and the desired chiral alcohol 2
could be produced in 99.7% ee and 50% yield.7 Codexis has
Crizotinib (1) (XALKORI®) is a potent and selective Me-
senchymal epithelial factor/Anaplastic lymphoma kinase (c-
Met/ALK) inhibitor1,2, which has been developed by Pfizer and
was approved by the US FDA in 2011 for the treatment of locally
advanced or metastatic nonsmall-cell lung cancer (NSCLC).
(Figure 1).3
developed an engineered ketoreductase enzyme, which was used
in the asymmetric reduction of 2,6-dichlo-5-fluoroacetophenone
(6) to provide 2 in high selectivity (>99% ee) and efficiency.
Both enzymatic approaches were used in the manufacturing of 2
in multi-kilo scale.8,9
Catalytic asymmetric hydrogenation of ketones is one of the
powerful methods to prepare chiral alcohols, and is considered as
atom economic approach. However, chiral ligands which can be
applied in the manufacturing are still rare, as in the
manufacturing scale, not only high ee, but also a high turnover
number (TON) and turnover frequency (TOF) are required, as the
costs of catalysts are normally key issues in industry scale. As
most of the reported catalysts have TONs lower than 1000 and
cause the high cost of the catalysts which are unsuitable for the
application in industry.10 It is noteworthy that some of the
synthetic chiral catalysts, which are much smaller and simpler
than enzymes, exhibit activities and selectivities comparable to
those of enzymes.11, 12 Zhou et al has recently reported a new type
of chiral iridium catalysts that bearing a spiro pyridine-
aminophosphine ligand, which showed high selectivity and
efficiency for the asymmetric reduction of phenylketone. Among
those catalysts, Ir[(R)-DTB-SpiroPAP-3-Me] (5) can afford the
corresponding chiral alcohol in up to 99.9% ee and with TONs as
high as 4,550,000 in the reduction of acetophenone.13
NH
N N
Cl
N
O
NH2
Cl
F
1
Crizotinib
Boc
N
Cl OH
N
N
O
B
N
HO
Cl
F
O
NH2
2
3
4
Figure 1
In the disclosed synthetic routes, (S)-1-(2,6-dichloro-3-
fluorophenyl)ethanol (2) is a key intermediate, for which lots of
efforts have been carried out to produce this chiral pure alcohol
with high enantioselectivity. However, asymmetric reduction
with well developed boran reagents such as BH3.THF/(R)-
methyl-CBS-oxazaborolidine (cat.)4, (-)-DIPCl5 and NaBH4/
TMSCl/(S)-α,α-diphenylpyrrolidinemethanol6 etc. all gave low
optical purity of the alcohol, and in most of the cases gave low
conversion of the reaction. Kung et al developed a four-step
biotransformation of 2,6-dichloro-5-fluoroacetophenone (6) to
the chiral alcohol 2 via enzymatic hydrolysis of the racemic
On the other hand, the reported route to crizotinib still has
room for improvement in the process perspectives, in which the
nitro compound as intermediate cause safety issue, and using the
iodo intermediate raise the cost concern of the whole process on
manufacturing scale.9,14 Therefore, an alternative synthetic route
with lower cost and safer operation is still desired.
In this article, we report an asymmetric hydrogenation of 2,6-
dichloro-5-fluoroacetophenone (6) to produce the key chiral
alcohol 2 for Crizotinib, by applying highly efficient catalyst
Ir[(R)-DTB-SpiroPAP-3-Me] (5) (Figure 2), and the complete

4
synthesis of an Crizotinib by an alternative approach, which is
considered should be suitable for scaling up.
in 1.5 h (entry 2), and further increasing of tBuOK to 0.08 equiv.
did not result in obvious change (entry 3). When the reaction was
carried out at room temperature (15 oC), full conversion was
achieved within 4 h, giving the alcohol 2 in 99.9% ee (entry 4).
When using 1 atm H2, the hydrogenation reaction rate slowed
down obviously, 62% conversion and 97.8% ee were obtained
within 28 h (entry 5). While increasing the reaction temperature
o
o
to 50 C and 70 C, the conversion rate was increased, and the
reaction could be completed in 1 h (entries 6, 7). When the
hydrogen pressure was increased from 10 atm to 30 and 50 atm at
50 oC with BuOK (0.04 equiv.), the reaction time could be
t
Figure 2
reduced to 40 minutes (entries 8, 9). When the catalyst loading
was lowered to 0.001 mol% (S/C = 100,000), the chiral alcohol 2
could be obtained in 99.5% ee in 100% conversion within 24 h at
2. Results and discussions
o
The asymmetric catalytic hydrogenation of 2,6-dichloro-3-
fluoroacetophenone (6) was carried out by using the extremely
efficient catalyst Ir[(R)-DTB-SpiroPAP-3-Me] (5) (Table 1). The
initial hydrogenation was performed under the conditions
previously applied for the reduction of acetophenone
(substrate/catalyst, S/C = 5000, 10 atm H2, 30 oC) in the presence
of potassium tert-butoxide (0.02 equiv. based on 6 as base (Table
1, entry 1). The reaction was completed in 2.5 h, and 2 was
50 C under the initial hydrogen pressure of 30 atm (entry 10).
This asymmetric hydrogenation condition was considered
suitable for scaling up for manufacturing, as the low catalyst
loading make the cost of the catalyst much lower than the solvent.
The modified condition was carried out in the plant to produce 2
on 100 kg scale per batch and gave consistent results comparable
to the lab scale.15
t
obtained in 99.6% ee with 100% conversion. When BuOK was
increased to 0.04 equivalents, the conversion could be completed
Table 1．Reaction screening for asymmetric hydrogenation of 1-(2,6-dichloro-3-fluorophenyl)ethanonea
Entry
S/Cb
5000
5000
5000
5000
5000
5000
5000
5000
5000
100000
Base (B/Sc)
tBuOK (0.02)
tBuOK (0.04)
tBuOK (0.08)
tBuOK (0.04)
tBuOK (0.04)
tBuOK (0.04)
tBuOK (0.04)
tBuOK (0.04)
tBuOK (0.04)
tBuOK (0.04)
PH2 (atm)
Temp. (oC)
Time (h)
2.5
1.5
Conv. (%)d
100
100
Ee (%)d
99.6 (S)
99.7 (S)
99.6 (S)
99.9 (S)
97.8 (S)
99.6 (S)
99.4 (S)
99.6 (S)
99.6 (S)
99.5 (S)
1
2
3
4
5
6
7
8
9
10
10
10
10
10
1
10
10
30
50
30
30
30
30
15
30
50
70
50
50
50
1.5
4
28
1.0
1.0
40 min
40 min
24.0
100
100
62
100
100
100
100
100
a Reaction: 1-(2,6-dichloro-3-fluorophenyl)ethanone 6 (0.1 mol), tBuOK, anhydrous ethanol (25 mL), catalyst ([Ir((R)-DTB-SpiroPAP-3-Me)]) (5) and H2
were used.
b the mole ratio of substrate to catalyst.
c the mole ratio of base to substrate.
d Determined by chiral HPLC.
Scheme 1. Synthetic route of Crizotinib from chiral alcohol 2. Reaction conditions: (a) bis(trichloromethyl)carbonate (BTC), DCE, pyridine, reflux, 3h, 86%; (b)
Br2, DMF, 0-30 oC, 2 h, 88%; (c) 10% NaOH (aq), 100 oC, 6 h, 90%; (d) (Boc)2O, Et3N, DCM, 20–30 oC, 12 h, 75%; (e) Ph3P, DIAD, THF, 12 h, 20-30 oC, 50%;
(f) Pd(Ph3P)2Cl2, Na2CO3, DMF, H2O, 60 oC, 3 h, 85%; (g) HCl/EtOH, DCM, 20–30 oC, 2 h, 87%.

5
With the enantio pure 2 in hand, the synthesis of crizotinib can
be completed by the route shown in Scheme 1. The synthesis
started with 2-aminopyridin-3-ol (3), which is commercial
available. 3 reacted with bis(trichloromethyl)carbonate (BTC) to
give oxazole compound 7 in 86% yield, in which both amino and
hydroxy groups were protected. Bromination of 7 occurred
regioselectively by reacting with bromine at 0-30 oC to give
bromide 8 as the main product in 88% yield. Hydrolysis of 8 in
boronate intermediate 4 in 80% yield as the white solid. While
using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (16)
for the coupling reaction, the target compound 4 could also be
obtained in 60% yield. (Scheme 3)
In conclusion, we have demonstrated a new approach for the
asymmetric synthesis of Crizotinib (1) with high
enantioselectivity. The key step of this approach is the
asymmetric synthesis of chiral alcohol (S)-1-(2,6-dichloro-3-
fluorophenyl)ethanol 2 through asymmetric hydrogenation of
ketone precursor 6 by using highly efficient and enantioselective
Ir[(R)-DTB-SpiroPAP-3-Me] (5) as catalyst. The asymmetric
hydrogenation was practiced in the pilot plant at 100 kg scale and
2 could be obtained in 99.5% ee with TON of 100,000,15 which
further proves highly efficiency of this type of the catalyst in
producing chiral alcohols.16
o
10% NaOH solution at 100 C to give 9 in 90% yield, followed
by the protection of amino group by Boc group to afford 10 in
75% yield. After coupling of 10 and 2 under Mitsunobu
condition, intermediate 11 could be isolated in 50% yield. Suzuki
coupling of intermediate 11 with boronate
4 by using
Pd(Ph3P)2Cl2 as catalyst in DMF at 60 oC for 3 h, to give Di-Boc
protected compound 12 in 85% yield. Finally, removal of Boc
groups of 12 with HCl in ethanol to produce crizotinib (1) in 87%
yield with 99.5 % ee. It was noted that no racemization occurred
during the above transformation.
References and Notes
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Scheme 2. Original synthetic route of 4 from iodo compound 13. Reaction
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Scheme 3. Synthetic route of 4 through bromide 18. Reaction conditions: (a)
o
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o
o
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In addition, another key intermediate boronate
4 was
previously prepared from the corresponding iodide 13. The
general route can be divided in two classes: Pd-catalyzed
boronation of 13 with pinacol boronate 14,14 or Knochel
procedure of i-PrMgCl assisted coupling reaction of 13 with
pinacol boronate 15 (Scheme 2).9 However, the cost of iodo
compound normally is considered much higher than its bromo
derivatives in process perspective, and in most of the cases of
using iodo compounds for the reaction, the color would be
contained in the product, which needs extra cost for the
purification. As shown in Scheme 3, synthesis of pinacol
boronate intermediate 4 started from pipradrol (17), which was
transformed to its mesylate 18 in 95% yield. Reaction of the
mesylate 18 with 4-bromopyrazole (19), which was previously
deprotonated by sodium hydride, and heating in DMF to give 20
in 55% yield. Reaction of 20 with i-PrMgCl·LiCl generated the
expected Grignard reagent, which was quenched with 2-
methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (15) to yield
12. Other examples of asymmetric hydrogenation of
acetophonone with TONs as high as 1,000,000, see: a) Hu.
A. G.; Ngo. H. L.; Lin, W. B. Org. Lett. 2004, 6, 2937–
2940; b) Li, W.; Sun, X.; Zhou, L.; Hou, G.; Yu, S.; Zhang,
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6
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15. The detailed results of the production of asymmetric
hydrogenation in the pilot plant will disclosed in
somewhere else.
16. Ir[(R)-DTB-SpiroPAP-3-Me] was applied in the
manufacturing of the key chiral intermediate of
Rivastigmine. Yan, P.-C.; Zhu, G.-L.; Xie, J.-H.; Zhang,
X.-D.; Zhou. Q.-L.; Li, Y.-Q.; Shen, W.-H.; Che, D.-Q. Org.
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