Effective Laboratory-Scale Preparation of Axitinib by Two CuI-Catalyzed Coupling Reactions

Article abstract of DOI:10.1021/acs.oprd.5b00123

The discovery and development of an efficient synthesis route to axinitib is reported. The first-generation route researched by Pfizer implemented two Pd-catalyzed coupling reactions as key steps. In this work, the development of Heck-type and C-S coupling reactions catalyzed by CuI is briefly described, using an economial and practical protocol. Aspects of this route, such as selecting optimal ligands, solvent, and other conditions, are discussed in detail. The scale-up experiment was carried out to provide more than 300 g of active pharmaceutical ingredients of axitinib in Form XLI with 99.9% purity in 39% yield. In short, we provide a new choice of synthesis route to axitinib, through two copper-catalyzed coupling reactions with good yield.

Full text of DOI:10.1021/acs.oprd.5b00123

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Full Paper
Effective Lab-Scale Preparation of Axitinib
by Two CuI-Catalyzed Coupling Reactions
lihai zhai, Li-Hong Guo, Yang-Hui Luo, Yang Ling, and Bai-Wang Sun
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00123 • Publication Date (Web): 11 Jun 2015
Downloaded from http://pubs.acs.org on June 19, 2015
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Effective Lab-Scale Preparation of Axitinib by Two
CuI-Catalyzed Coupling Reactions
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LiꢀHai Zhai,a,b LiꢀHong Guob, YangꢀHui Luoa, Yang Linga and BaiꢀWang Sun*a
a School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, China.
b Lunan Pharmaceutical Co. LTD, Linyi,276000, Shandong, China.
*Corresponding Author Eꢀmail: chmsunbw@seu.edu.cn; Fax: +86ꢀ025ꢀ52090614; Tel: +86ꢀ025ꢀ
52090614.
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Abstract: The discovery and development of an efficient synthesis route to axinitib is
reported. The firstꢀgeneration route researched by Pfizer, implemented two Pdꢀcatalyzed
coupling reactions as key steps. In this work, the development of Heckꢀtype and CꢀS
coupling reactions catalyzed by CuI is briefly described, using an economic and practical
protocol. Aspects of route, such as selecting ligands, solvent and other conditions are
discussed in detail to obtain the optimal conditions. The scale up experiment was carried
out to provide more than 300 g active pharmaceutical ingredients (API) of axitinib in
Form XLI which was produced with 99.9 % purity in 39 % yield. In short, we provide a
new choice of axitinib synthesis route, through two copperꢀcatalyzed coupling reactions
with good yield.
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Key words: Axinitib, Synthesis, CuIꢀcatalyzed, CꢀS coupling, Heckꢀtype reaction.
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Introduction
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Axitinib, a small molecule indazole derivative chemically known as (E)ꢀNꢀ
Methylꢀ2ꢀ(3ꢀ(2ꢀ(pyridineꢀ2ꢀyl)ꢀvinyl)ꢀ1Hꢀindazolꢀ6ꢀylthio) benzamide developed by
Pfizer was approved in January 2012 by the U.S. FDA with the trade name Inlyta. It
selectively inhibits vascular endothelial growth factor receptors (VEGFR) for the
treatment of renal cell carcinoma.1ꢀ3 There are two generations of synthetic routes of
axinitib developed by Pfizer.4 The key steps are the palladium catalyzed crossꢀcoupling
reactions, which purpose is through the building of CꢀC and CꢀS bonds, to complete the
synthesis axitinib . (Scheme1 and Scheme2)
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Scheme 1 The firstꢀgeneration synthesis route
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Scheme 2 The secondꢀgeneration synthesis route
Palladium was used to catalysis the Heckꢀtype and CꢀS bond coupling reaction to
provide the product of axitinib. Palladium is a very effective catalyst for these
crossꢀcoupling reactions. These reactions have been applied to the synthesis of many
organic compounds, especially those of complex natural products, supermolecule
chemistry, and engineering materials such as conducting polymers, molecular wires, and
liquid crystals.5ꢀ10 However, the high cost and residual of Pd (>25ppm after removing
residual palladium by adsorption and crystallization), may not meet the demand for heavy
metals content in the firstꢀgeneration synthesis of axitinib, which demand for below
10ppm.11,12 For the commercial route, a recrystallization was employed to ensure Pd
levels were below 10 ppm and the formation of the desired solid form (Form XLI).
A considerable body of literatures describing CꢀS crossꢀcoupling and Heckꢀ type
reactions with the application of other metals such as copperꢀ, nickelꢀ, cobaltꢀ, and
ironꢀbased catalytic systems has been reported.6,13ꢀ20 CuI has been used to catalyze the
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CꢀS crossꢀcoupling reaction because of its stability to air and good activity with or
without the assistance of supporting ligands.21ꢀ26 Compared with the above CꢀS
crossꢀcoupling reaction, the application of CuI in the Heckꢀtype reaction is reported less
frequently, but there are some successful examples.27ꢀ30 A copper catalytic systems are
cheaper, and easier to remove the heavy metal residues relative to palladium. In fact, the
heavy metal residual limit of copper is higher than palladium in the API. Considering the
advantages of CuI catalyst in crossꢀcoupling reactions, we wanted to reduce costs and
avoid excessive heavy metal residues in the API. These issues are a great challenge for
palladium catalysts.
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As part of our drive to explore and develop a process for the preparation of axitinib,
we recently initiated a systematic investigation to improve the existing chemical schemes
to enhance the yield and quality of the API. In this report, we discuss our attempts to
develop an efficient process for the preparation of axitinib. The purpose is to offer an
alternative process on the basis of the literatures, and to find a cheaper and effective
transition metal catalysis system.
RESULTS AND DISCUSSION
Our focus is to develop an efficient process for the preparation of axitinib. It focused
on the following two aspects: improving the removal of heavy metals to avoid exceeding
limits in API and improving the yield and quality of intermediates and product.
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At first, we compared the two synthetic routes. The most noteworthy difference
between the two processes is the order of CꢀS and CꢀC bond building. In the
firstꢀgeneration route，6ꢀnitro indazole is the starting material. The iodination reaction,
palladiumꢀcatalyzed Heckꢀtype reaction, nitro reduction, Sandmeyer reaction
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Scheme 3 The synthesis route in this work
and palladiumꢀcatalyzed CꢀS crossꢀcoupling reaction have been performed in turn to
construct the molecular skeleton of axitinib. Finally the target crystal form of API was
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produced by removing THP protection groups and reꢀcrystallization. In the
secondꢀgeneration route, 6ꢀiodoindazole is the starting material. The CꢀS bond was
constructed firstly, followed by iodination reaction and Heckꢀtype reaction to complete
coupling of 2ꢀvinylpyridine. Introduction of 2ꢀvinylpyridine late avoids opportunity for
isomerization of the olefin. Heavy metals were not properly controlled in the initial
version of this route. But, the commercial route managed control of Pd efficiently during
isolation of crude aixitnib and a subsequent reꢀcrystallization to lower Pd below 10 ppm
and to obtain the desired crystal form. Compared with the firstꢀgeneration process, this
route is shorter by avoiding the Sandmeyer reaction in the main synthetic process, but
this can lead to a higher cost of 6ꢀiodoindazole relative to the 6ꢀnitro indazole.
At the same time, early formation of CꢀS bond may lead to the formation of
sulfoxide impurities. In the secondꢀgeneration route, the indazole moiety has been
acylated to avoid side reaction with 2ꢀvinylpyridine and other electrophiles. A THP
protecting group has been used in the firstꢀgeneration route to achieve this goal. Both
routes relied heavily upon removal of residual Pd.
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Our purpose is seeking cheaper and more effective catalytic conditions to replace the
expensive palladium catalyst. We choose the firstꢀgeneration route as the improving base
because of its cheaper raw materials and easier control of impurities. The final synthetic
route is shown in Scheme 3.
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Preparation of (E)-N-Methyl-2-(3-(2-(pyridin-2-yl)-vinyl)-1-(tetrahydropyra-2-yl)
-1H-indazol-6-ylthio) benzamide (compound 6)
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Although palladium showed good activity in the CꢀS coupling reaction, application
of other transition metals as catalyst has a lot of reports. In particular, CuI has been
extensively researched for use in the reaction because of its low price, low toxicity and
stability to air.31ꢀ36 Because there are many successful examples of Cuꢀcatalyzed CꢀS
coupling reactions, CuI has been applied firstly to replace palladium as the CꢀS coupling
reaction catalyst in this work.
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Catalytic tests performed with freshly prepared CuCl and CuBr gave a lower yield
(40ꢀ60 %) than commercially available CuI salt. At the same time, catalytic tests of Cu2O
showed that there is almost no desired product generated. The reaction conditions such as
ligands, solvent, alkali selectivity and CuI amount were considered to optimize the
synthetic process. The optimal reaction conditions are shown in Scheme 4.
Scheme 4 Synthesis route of compound 6
Initially, reactions were performed with no ligand involved. Nꢀmethylpyrrolidinone
(NMP) and potassium carbonate were found to be preferred in previous studies of
copperꢀcatalyzed CꢀN and CꢀO coupling reactions, 37 so we chose these conditions firstly.
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The results showed that the conversion rate is low without ligands involved. The ligand
was added to promote the reaction and improve the conversion rate. O, Oꢀtype, N, Nꢀtype
and N, Oꢀtype ligands are most commonly used. These ligands have been selected to
evaluate the results.
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Figure 1 Molecular structure of the ligand
Table 1 Screening of Ligands for the synthesis of compound 6
Entry
1
Ligand
a
Base
Isolated Yield(%)
67
K2CO3
2
3
b
K2CO3
K2CO3
No base
K2CO3
No base
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
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84
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d
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d
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e
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g
h
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No ligand
10
Reaction conditions: compound 5 (0.01 mol), compound C (0.015 mol), K2CO3 (0.012 mol), CuI (40
mol % to compound 5), ligand (40 mol % to compound 5), solvent NMP (30 mL), 100 °C, 12 h. i: reaction
time is over 24 h . ii: reaction time is 18 h, conversion of compound 5 is 100 %.
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N, Nꢀtype ligands have a number of advantages in copperꢀcatalyzed coupling
reaction when compared with other ligands. These ligands showed good activity, wide
applicability to the substrate and mild reaction conditions, etc. Test results prove this
conclusion (Table 1). Entry 3 and entry 5 were significantly higher than that of other
groups, in addition to the entry 7. Entry 9 provides a moderate yield just below entry 3. N,
N'ꢀDimethylꢀ1, 2ꢀcyclohexanediamine gave a higher yield than 1, 2ꢀcyclohexanediamine
(entry 11). It is interesting to note that in the absence of adding potassium carbonate,
although the reaction time increases, N, N ꢀ type ligands (entry 4 and entry 6) also
achieved moderate yield, this might be because of the basic role of ligand itself.
Depending on the results we chose 1, 10ꢀphenanthroline for further research.
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NMP is the most commonly used and effective solvent for CꢀS coupling reaction, as
verified by the experimental results (Table 2, entry 1). It appeared that by applying NMP
and potassium carbonate, compound 6 was produced in 84 % yield. This yield is higher
than other solvents. The need to use a polar solvent which contains the amide functional
group is highlighted by the screening results presented in Table 2, which show that, DMF
and NMP are excellent solvents for this coupling reaction (entries 1 and 4). The solvents
which contain oxygen atoms such as DMSO, Dimethoxy ethane and Dioxane obtain
similar yield, but below that of NMP and DMF. The findings may be because the
coordination ability of NꢀCu+ is stronger than that of OꢀCu+. The result of entry 7
suggests that water is not a suitable solvent for this reaction. Therefore water content
should be controlled. Although NMP as solvent obtained the highest yield, considering its
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high boiling point, and relatively poor water solubility, we still chose DMF as reaction
solvent which obtains a comparable yield (83 %) to NMP.
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Table 2 Screening of solvents for the synthesis of compound 6
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Entry
Solvent
Isolated Yield (%)
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NMP
DMSO
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66i
Dimethoxy ethane
DMF
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Dioxane
Toluene
H2O
78i
70i
Traceii
53i
MeCN
Reaction conditions: compound 5 (0.01 mol), compound C (0.015 mol), K2CO3
(0.012 mol), CuI (40 mol % to compound 5), 1,10ꢀphenanthroline (40 mol % to
compound 5 ), 100 °C, 12 h. i: refluxing for 23 h. ii: at 80 °C for 18 h.
Table 3 Screening of bases for the synthesis of compound 6
Entry
Base
Isolated Yield (%)
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2
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5
6
K2CO3
Cs2CO3
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76
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75
80
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Na2CO3
TEA (triethylamine)
DIPEA (diisopropylethylamine)
NaOH
Reaction conditions: compound 5 (0.01 mol), compound C (0.015mol), K2CO3
(0.012mol), CuI (40 mol % to compound 5), 1, 10ꢀphenanthroline (40 mol % to compound
5), DMF, 100°C, 12h.
A series of bases were screened. Of the four inorganic bases, potassium carbonate
(82 %) gave similar results to organic base DIPEA (80 %), while cesium carbonate (76 %)
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gave comparable results to triethylamine (75 %). Poorer results were obtained with
sodium carbonate and sodium hydroxide (Table2). Considering economy and safety, we
chose potassium carbonate as base in the reaction system.
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Finally, the amount of CuI catalyst was changed to evaluate the influence to the
isolated yield (Table 4). As showed in the results, lowering the amount of CuI to7.5 mol %
has no impact on the efficiency of the reaction. A 5 % decrease in yield was noticed when
the amount of CuI further reduced to 5 mol %. While the amount of CuI reduced to 2.5
mol %, the yield decreases to 58 %. When the amount of catalyst was reduced to 1.5
mol %, the yield was only 30 % after refluxing for 18 hours. Take into account these
results, the appropriate amount of catalyst is 7.5 mol %.
Table 4 Screening of CuI amount in synthesis of compound 6
Entry
CuI (mol %)
Isolated Yield (%)
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20
15
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78
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30i
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7.5
5
2.5
1.5
Reaction conditions: compound 5 (0.01 mol), compound C (0.015mol), K2CO3
(0.012mol), 1, 10ꢀphenanthroline (1.0 eq to CuI ), DMF, 100°C, 12h. i: refluxing for 18 h
Preparation of (E)-6-nitro-3-(2-pyridin-2-yl-vinyl)-1H-indazole (Compound 3) by
CuI catalyzed Heck reaction
In addition to palladium, other metals especially copper salts have been reported to
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catalyze Heck reaction.27,38ꢀ40 After application of CuI / 1, 10ꢀphenanthroline/ K2CO3
catalyst system on the CꢀS coupling reaction, we tried to catalyze Heckꢀtype reaction
using this catalyst in the synthesis process of axinitib.
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Scheme 5 Attempted synthesis of compound 4
Scheme 6 Attempted synthesis of compound 3
At first, we used the method of the firstꢀgeneration route to protect the imidogen in
indazole with the THP group. Palladium is replaced by CuI as a catalyst used for the
preparation of compound 4 (Scheme5). The result is disappointing. Even if the reaction is
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performed more than 48 hours at 100 °C, only a trace of compound 4 is detected by
HPLC (Method B). We assumed that the electronics of the THP group affect the activity
of the reactants. So we tried to synthesis compound 3 without the protection of the
indazole (Scheme 6). It is noteworthy that the conversion of compound 2 is 100 %, but
the product is not the target compound 3. Rather it is the adduct AM-5.
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Heck reaction is facilitated by an electron deficient group. We designed a new
synthetic route (Scheme7). Analogous to the Pfizer commercial route, the 1ꢀposition
nitrogen atom in indazole was protected by an acetyl group in the process of AMꢀ6
synthesis. Then complete Heck reactions catalyzed by CuI to synthesis AMꢀ7. The result
showed that it is difficult to obtain a single intermediate AMꢀ6 because the acetyl is very
labile. Consequently, Heckꢀtype coupling and removal of the acetyl group complete in
oneꢀpot to provide the intermediate compound 3 in 78 % yield.
Scheme 7 Attempted synthesis of AM-7
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Although the CuI/1, 10ꢀphenanthroline/ K2CO3 catalytic system has shown excellent
reactivity in the synthesis of compounds 3, high load catalyst (40 %) need to be improved.
The influence of the amount of CuI and the choice of ligands were evaluated (Table 5).
As showed in Table 5, 1, 10ꢀphenanthroline is acceptable ligand in a 77 % yield when the
CuI amount was reduced to 13 mol % (entry 3). It is noteworthy that N, Oꢀtype
ligandꢀꢀꢀꢀꢀNꢀmethylglycine provides a 76 % yield when the amount of CuI is 15 mol %
(entry 8).
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Other improvements in the synthetic process of axitinib were verified by the
experiments. Such as , iron powder was replaced with sodium sulfide in the nitro
reduction reaction, the postꢀprocessing methods were improved in Sandmeyer reaction,
such as acetic acid as solvent, sulfuric acid instead of hydrochloric acid and sodium
nitrite is added in solid form to reduce the using of water, these improvements promote
the diazotization reaction. The products directly precipitate in the reaction system. These
improvements have made reaction process with a better operability, and increased the
product yield. In the process of preparation axitinib, pꢀtoluenesulfonic acid is replaced by
hydrochloric acid to deꢀprotect THP group. As the liquid inorganic acid, hydrochloric
acid is more effective.
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Table 5 Screening of ligand and CuI amount in synthesis of compound 3
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7
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CuI
Isolated yield
(%)
CuI
Isolated yield
(%)
Entry Ligand
Entry
Ligand
(mol %)
(mol %)
ci
c
c
c
c
c
f
20ii
15
13
10
7
78
77
77
70
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76
76
70
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11
12
13
14
15
16
17
18
f
f
f
h
h
h
h
h
h
10
7
5
20
15
12.5
10
7.5
5
68
47
26
67
67
65
65
60
31
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1
2
3
4
5
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7
8
9
5
20
15
13
f
f
i: Ligand label is consistent with Figure 1. ii: Ligand is equivalent to CuI; K2CO3, DMF, 100 ℃.
CONCLUSION
In summary, an alternative synthesis of axitinib has been accomplished in total 39%
yield overall on labꢀscale through two coupling reactionsꢀꢀꢀHeckꢀtype reaction and CꢀS
coupling reaction by using CuIꢀ1, 10ꢀphenanthrolineꢀK2CO3 as the catalyst system. The
axitinib produced is free from impurities and meets regulatory requirements with 4ꢀfold
overall yield in comparison with the firstꢀgeneration procedure (9% in Form IV) but falls
short of the second generation yield (50ꢀ58% in Form XLI). 4 This route avoids the use of
Pd and only requires removal of the heavy metal Cu. The efficiency of this catalytic
system has been tested in scaleꢀup experiment. 326.4 g of axitinib API in Form XLI was
produced with 99.9% purity in 39% yield. Residual Cu content was detected to be 2.2
ppm by atomic absorption spectroscopy.
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Palladium is still better than copper in catalytic efficiency. There are more researches
needed to make CuIꢀcatalyzed synthesis routes more competitive. Considering the lower
price, toxicity and appropriate yield, the modified processes evaluated have been shown
to be acceptable from both a product quality and yield standpoint. We provide a choice of
using nonꢀprecious metal catalysisꢀCuI for the production of axinitib.
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EXPERIMENTAL SECTION
General
All of the starting materials, reagents, solvents and 2ꢀvinylpyridine (compound B)
are commercially available and used without further purification, unless otherwise
specified. Two coupling reactions were carried out in dry reaction vessels under an
atmosphere of dry nitrogen, other reactions on common conditions without nitrogen
protection. Melting point was measured by WRDꢀ1B Digital Melting Point Apparatus.
1HNMR and 13CNMR spectra were recorded in DMSOꢀd6 or CDCl3 using AVANCE
AVꢀ300 to 500MHz FT NMR spectrometer. The chemical shifts are reported in δ ppm
relative to TMS. Data are reported as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, and br = broad), coupling constant (Hz),
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and integration. Chemical shifts of protonꢀdecoupled C NMR spectra are reported in
ppm from the central peak of CDCl3 (77.0 ppm), DMSOꢀd6 (39.5 ppm) on the δ scale.
The purity of the key intermediate and final APIs was determined by HPLC. The
immediate purity was assessed by HPLC, using an Agilent 1100 series instrument.
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Table 6 Gradient program for method A
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6
Time ( min )
Mobile phase A ( % )
Mobile phase B ( % )
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0
40
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0
0
40
40
60
90
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100
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Method A: HPLC method for compound 3 is a standard method using gradient on
an Aglient SBꢀC18 column (5ꢁm; 250mm × 4.6mm). Mobile phase solution A was 0.05 %
trifluoroacetic acid in water (v/v), and mobile phase solution B was 0.05 trifluoroacetic
acid in acetonitrile (v/v). Gradient elution was performed as showed in Table 6 with a run
time of 25 min and a reꢀequilibration time of approximately 5 min. The flow rate was 1.0
mL / min and the column temperature was 25 °C. The injection volume was 5 ꢁ L, and
UV detection was performed at 254nm. Sample and standard solutions were prepared in
acetonitrile at a nominal concentration of 0.5mg / mL.
Method B: For compound 4 and 5, the HPLC column and mobile phases were
identical to the compound 3. Gradient elution was performed as showed in Table 7 with a
run time of 51 min and a 4 min reꢀequilibration time. The flow rate was 1.0 mL / min,
and the column temperature was 30 °C. The injection volume was 5 ꢁ L, and UV
detection was performed respectively at 220nm for intermediate 4 and 310nm for
compound 5. Sample and standard solutions were prepared in methanol at a nominal
concentration of 0.5mg / mL.
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Table 7 Gradient program for method B
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Time ( min )
Mobile phase A ( % )
Mobile phase B ( % )
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Method C: HPLC method of Nꢀmethylꢀ2ꢀsulfanyl benzamide (compound C),
compound 6 and final product Axitinib is the same gradient elution method. The column
is an Aglient SBꢀC18 column (5ꢁm; 150mm × 4.6mm). Mobile phase solution A was
0.05 % monopotassium phosphate in water (m/v), and mobile phase solution B was
acetonitrile. Gradient elution was performed as showed in Table 8, with a run time of 39
min and a reꢀequilibration time of approximately 6 min.
Table 8 Gradient program for method C
Time (min)
Mobile phase A (%)
Mobile phase B (%)
0
5
80
80
40
10
10
80
80
20
20
60
90
90
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25
32
38
39
45
The UV detection was performed respectively at 220nm for compound 6,
compound C and 233nm for axitinib. Sample and standard solutions were prepared
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in methanol at a nominal concentration of 0.25mg / mL.
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Preparation of (E)-6-nitro-3-(2-pyridin-2-yl-vinyl)-1H-indazole (Compound 3)
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In a 10 L glass reactor vessel, 6ꢀnitroꢀ1Hꢀindazole (350.0 g, 2.15 mol, 1.0 equiv) and
potassium carbonate (594 g, 4.3 mol, 2.0 equiv) is added in DMF (1.5 L) at the room
temperature (25 °C). Iodine solution (821.9 g dissolved in1 L DMF, 3.23 mol, 1.5 equiv)
was added to reaction solution dropwise over 1ꢀ1.5 hours, while the reaction temperature
could rise to 60 °C. The mixture is agitated for 6 hours until the reaction complete
detected by HPLC. The reaction was quenched with 10 % sodium bisulfite aqueous
solution 6 L (600 g, 5.77 mol, 2.7 equiv). The mixture is agitated for 2 hours to
precipitate solids .Then the slurry is agitated for 2 hours at 10 °C. The solids was filtered,
washed with water (1 L) and dried at 60 °C for 48 hours to provide
3ꢀiodoꢀ6ꢀnitroꢀ1Hꢀindazole as yellow solids (613 g, 97.7 % yield with 96 % purity by
HPLC using the Method A). Mp 245ꢀ 246 °C; 1H NMR (500 MHz, DMSOꢀd6) δ 14.12 (s,
1H), 8.45 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 8.9, 2.0 Hz, 1H), 7.65 (d, J = 8.9 Hz, 1H); 13C
NMR (125 MHz, DMSOꢀd6) δ 146.88, 139.79, 30.29, 122.16, 115.76, 108.09, 94.22.
In the 10 L glass reactor vessel, 3ꢀiodoꢀ6ꢀnitroꢀ1Hꢀindazole (600 g, 2.08 mol, 1.0
equiv) is added to a suspend solution of potassium carbonate (400 g, 3.12 mol, 1.5 equiv)
in N, Nꢀdimethyl formamide (DMF, 4L). The mixture is heated to 60 °C and acetic
anhydride (425 g, 4.16 mol, 2 equiv) is added dropwise for 30 min, then react for 2 hours
until the reaction complete detected by HPLC to obtain 1ꢀacetylꢀ3ꢀiodineꢀ 6ꢀnitro
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indazole, which need not separate from the mixture and applied directly to the Heckꢀtype
reaction. 1, 10ꢀphenanthroline (48.7 g, 0.27mol, 0.13 equiv) is added to the mixture at
60 °C. The solution is bubbling with N2 for 2 hours to remove dissolved oxygen and the
vessel was charged with nitrogen. CuI (34.7 g, 0.27 mol, 0.13 equiv) and 2ꢀvinyl pyridine
(240g, 2.3 mol, 1.1 equiv) are added and the mixture is agitated for 8 hours at 100 °C
until the reaction is complete detected by HPLC. The reaction mixture is stirring for 1
hour after ethanol (2 L) addition at 60 °C, then water (2 L) is slowly charged while
maintaining the temperature at 60 °C. After that, the mixture is stirring for 4 hours at
60 °C to complete deacetylation reaction. The mixture further cooled to 15 °C to
crystallize for 2 hours and then filtered. The solid was added to water(5 L), stirred for 2
hours to dissolve the inorganic salts, then filtered , recrystallized in isopropanol, isolated,
dried in vacuum to afford (E)ꢀ6ꢀnitroꢀ3ꢀ(2ꢀpyridinꢀ2ꢀylꢀ vinyl)ꢀ1Hꢀ indazole as faint
yellow to green yellow solid (431.7 g，78 % yield with 95 % purity by HPLC using
Method A). The product applied directly to the next reaction without further purification.
Mp 308 °C (decomposed). Residual Cu content was determined to be 17.3 ppm by atomic
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absorption spectroscopy. H NMR (400 MHz, DMSOꢀd6) δ 13.99 (s, 1H), 8.66ꢀ8.55 (m,
1H), 8.51ꢀ8.41 (m, 1H), 8.06ꢀ7.96 (m, 1H), 7.92ꢀ7.76 (m, 1H), 7.79ꢀ7.66 (m, 1H), 7.43 (d,
J = 16.4, 8.0 Hz, 1H), 7.35ꢀ7.20 (m, 1H), 6.53 (d, J = 1.7 Hz, 1H), 6.09 (s, 1H), 5.47 (d, J
= 15.3 Hz, 1H), 5.35 (s, 1H). 13C NMR (100 MHz, DMSOꢀd6) δ 155.40, 150.42, 149.96,
145.79, 143.55, 137.26, 129.27, 124.66, 122.95, 122.79, 114.46, 113.89, 93.47
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Preparation of
(E)-6-iodo-3-[2-(pyridin-2-yl)-vinyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole
(Compound 5)
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Compound 3 (426 g, 1.6 mol, 1.0 equiv) react with 2,3ꢀdihydropyran (DHP, 672 g,
8.0 mol, 5equiv) in tetrahydrofuran (4.5 L) in the presence of methanesulfonic acid (24 g,
0.24 mol, 0.15 equiv), the mixture refluxing for 6 hours to complete the reaction detected
by HPLC. The mixture is concentrated, neutralized using Na2CO3 aqueous solution (100
g in 1L water) and filtered to obtain (E)ꢀ6ꢀnitroꢀ3ꢀ [2ꢀ(pyridinꢀ2ꢀyl) ꢀvinyl]ꢀ1ꢀ
(tetrahydroꢀ2Hꢀpyranꢀ2ꢀyl)1Hꢀindazoe as yellowꢀgreen solid (507.6 g, 92 % yield with
96 % purity by HPLC using Method B). Mp 185 °C; MS m/z 351［M + H］+ ; 1H NMR
(500 MHz, Chloroformꢀd) δ 8.85ꢀ8.39 (m, 2H), 8.12 (q, J = 9.0 Hz, 2H), 7.93 (d, J = 16.2
Hz, 1H), 7.83ꢀ7.52 (m, 2H), 7.49 (d, J = 7.8 Hz, 1H), 7.08 (s, 1H), 5.84 (dd, J = 9.2, 2.8
Hz, 1H), 4.06 (d, J = 11.8 Hz, 1H), 3.82 (t, J = 10.9 Hz, 1H), 2.57 (t, J = 11.3 Hz, 1H),
2.35ꢀ2.09 (m, 2H), 1.98ꢀ1.35 (m, 4H); 13C NMR (100 MHz, DMSOꢀd6) δ 168.31, 155.32,
150.01, 142.45, 142.30, 137.34, 136.08, 132.98, 130.76, 130.45, 129.71, 128.24, 126.61,
124.08, 123.12, 122.24, 120.73, 115.18, 26.56.
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(E)ꢀ6ꢀnitroꢀ3ꢀ[2ꢀ(pyridinꢀ2ꢀyl)ꢀvinyl]ꢀ1ꢀ(tetrahydroꢀ2Hꢀpyranꢀ2ꢀyl)ꢀ1Hꢀindazole
(505 g, 1.44 mol, 1.0 equiv ) is dissolved in methanol (3 L) and the aqueous solution of
sodium sulphide (867 g, 3.6 mol, 2.5 equiv, Na2S·9H2O in 2 L H2O) and THF (l L) is
added. The reaction mixture is agitated for 3ꢀ4 hours at 60 °C (until the reaction is
complete detected by HPLC). The insoluble salts are removed by filtering. Water (2 L) is
added to the filtrate under vigorous stirring. Then the mixture is cooled to 0 °C stirring
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for 2 hours. The mixture is filtered , rinsed with a mixture of methanol and water solution
1 L (methanol : water=1:3), the solids dried in vacuum for 24 hours at 45 °C to provide
6ꢀaminoꢀ3ꢀ(E)ꢀ2ꢀpyridinꢀ2ꢀylꢀvinyl)ꢀ1ꢀ (tetrahydropyranꢀ2ꢀyl) ꢀ1Hꢀindazole (455 g, 90 %
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yield with a purity of 97 % by HPLC using Method B). Mp 115ꢀ117 °C; H NMR (500
MHz, Chloroformꢀd) δ 8.73ꢀ8.40 (m, 2H), 8.12 (q, J = 9.0 Hz, 2H), 7.93 (d, J = 16.2 Hz,
1H), 7.72 (t, J = 8.0 Hz, 2H), 7.49 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 5.9 Hz, 1H), 5.84 (d, J
= 9.2, 2.8 Hz, 1H), 4.06 (d, J = 11.8 Hz, 1H), 3.82 (t, J = 10.9 Hz, 1H), 2.57 (t, J = 11.4
Hz, 1H), 2.36ꢀ1.96 (m, 3H), 1.92ꢀ1.39 (m, 4H). 13C NMR (100 MHz, DMSOꢀd6) δ
168.31 , 155.32 , 150.01 , 142.38 (d, J = 15.4 Hz), 137.34 , 136.08 , 132.98 , 130.76 ,
130.45 , 129.71 , 128.24 , 126.61 , 126.01 , 124.08 , 123.12 , 122.24 , 115.18 , 26.56 .
6ꢀaminoꢀ3ꢀ(E)ꢀ2ꢀpyridinꢀ2ꢀylꢀvinyl)ꢀ1ꢀ(tetrahydropyranꢀ2ꢀyl)ꢀ1Hꢀindazole (450 g,
1.4 mol, 1 equiv) dissolved in acetic acid (1.2L) and sulphuric acid (275 g, 2.8 mol, 2
equiv, 98 % diluted sulphuric acid with 1 L water). The sodium nitrite (140 g, 2.03 mol,
1.45 equiv) is added in batches over 2 hours at ꢀ5 °C, the mixture is stirred for 2 hours at
0 °C to provide the diazonium salt solution, reaction is monitored by HPLC. A solution
of potassium iodide (675 g, 4.06 mol, 2.9 equiv) dissolved in water (1.5 L) is added at
0 °C over 1.5 hour. The reaction mixture is agitated for 4 hours at 0 °C until complete
detected by HPLC. Then the mixture is poured into a solution of 50 % aqueous sodium
bisulfite (900 g sodium bisulfite in 1 L water) agitated for 2 hours. The mixture is
filtered , rinsed with water (3×200 mL), the filter cake dried in a vacuum oven for 48
hours at 65 °C to provide (E)ꢀ6ꢀiodoꢀ3ꢀ[2ꢀ(pyridinꢀ2ꢀyl)ꢀvinyl]ꢀ1ꢀ(tetrahydroꢀ2Hꢀpyranꢀ
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2ꢀyl) ꢀ1Hꢀindazole (525.7g , 87 % yield with a purity of 95 % by HPLC using Method B).
The raw product can be refined by slurring with water and filtering through a short silica
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1
gel column to provide a product with purity above 99 % by HPLC. Mp 168ꢀ169 °C; H
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NMR (500 MHz, Chloroformꢀd) δ 8.69ꢀ8.57 (m, 1H), 8.01 (d, J = 1.4 Hz, 1H), 7.86 (d, J
= 16.4 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.68 (td, J = 7.7, 1.8 Hz, 1H), 7.58ꢀ7.49 (m, 2H),
7.47 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.6, 4.8, 1.1 Hz, 1H), 5.68 (d, J = 9.1, 2.8 Hz, 1H),
4.04 (d, J = 11.4, 4.4, 2.5 Hz, 1H), 3.94 ꢀ 3.58 (m, 1H), 2.56 (t, J = 17.7, 10.4, 9.8, 4.2 Hz,
1H), 2.18 (t, J = 9.9, 3.6 Hz, 1H), 2.08 (d, J = 13.6, 3.5 Hz, 1H), 1.96ꢀ1.71 (m, 2H), 1.68
13
(t, J = 7.0 Hz, 1H); C NMR (100 MHz, DMSOꢀd6) δ 155.04, 150.03, 142.25, 142.20,
137.36, 130.91, 130.81, 130.24, 123.73, 123.25, 123.18, 123.11, 121.76, 121.34, 119.87,
84.56, 84.26, 67.08, 29.31, 25.21, 22.60.
Preparation of (E)-N-Methyl-2-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-ylthio)
benzamide (Compound 1, Axitinib).
Preparation of Nꢀmethylꢀ2ꢀsulfanyl benzamide (compound C) (Scheme 8)
2,2`ꢀdithiosalicylic acid (800 g, 2.63 mol, 1 equiv) is dissolved in thionyl chloride
(1000 g, 8.4 mol, 3.2 equiv ) and N, Nꢀdimethyl formamide (DMF, 10 mL) is added. The
mixture refluxing for 4 hours, concentrated in vacuum, recrystallize in nꢀhexane. The
solids are filtered, dried in vacuum to provide 2, 2`ꢀdithiosalicylic acid dichloride (C-1,
850 g in 95 % yield).
The intermediates C-1 (800 g, 2.33 mol, 1 equiv) dissolved in THF (2 L) is bubbled
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with methyl amine gas under agitating at 0°C for over 1 hour until the PH is stable
between 9 and 10, and stirring at room temperature for another 10 hours. The mixture is
poured into water (5 L) and the slurry is filtered. The white solids are washed with water
(3×800 mL), dried in vacuum oven to provide 2,2`ꢀdithioꢀNꢀmethylbenzamide (C-2, 513
g in 75% yield.).
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Scheme 8 The synthesis of compound C
The intermediates Cꢀ2 (480 g, 1.44 mol, 1 equiv) is dissolved in THF (2.5 L). The
solution is cooled to 0 °C, and sodium borohydride (225 g, 5.95mol, 4 equiv) is added in
potions over 4 hours, while controlling the temperature is not higher than 30 °C. After the
reaction complete, water (1 L) and acetic acid (450 mL) are added to the mixture to
quench reaction, then ethyl acetate (4×800 mL) is added to extract the product. Under
nitrogen protection, the organic phase is separated, dried, concentrated to provide
Nꢀmethylꢀ 2ꢀsulfanyl benzamide (compound C) as gray solids. (427.5 g in 89 % yield
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with purity of 94.3 % by HPLC using Method C. Mp 91ꢀ93°C. H NMR (400 MHz,
DMSOꢀd6) δ 8.56 (s, 1H), 7.63 (d, J = 7.4, 2.1 Hz, 1H), 7.43(t, J = 7.6, 2.2 Hz, 1H), 7.30
(t, J = 7.3, 1.9 Hz, 1H), 2.82 (s, 3H).
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Preparation
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benzamide (axitinib)
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Preparation of (E)ꢀNꢀMethylꢀ2ꢀ(3ꢀ(2ꢀ(pyridinꢀ2ꢀyl)ꢀvinyl)ꢀ1ꢀ(tetrahydropyꢀranꢀ2ꢀyl)ꢀ1Hꢀ
indazolꢀ 6ꢀylthio) benzamide (compound 6)
Under nitrogen protection, compound 5 (520 g, 1.2 mol, 1 equiv) dissolved in
DMF (2.5 L), is added to copper iodide (CuI, 17. 3g, 0.09 mol, 0.075 equiv), 1,
10ꢀphenanthroline (16.3 g, 0.09 mol, 0.075 equiv), K2CO3 (200 g, 1.45 mol, 1.2 equiv)
and compound C (301.5 g, 1.8 mol, 2.5 equiv) in turn. The mixture is agitated for 12
hours at 100 °C until the reaction is complete by HPLC. The mixture is cooled to 40 °C
and ethyl acetate (2.5 L) is added and cooled to 20 °C to agitate for 1 hour. Water (5 L) is
added and the mixture is agitated for another 1 hour at 20 °C to provide the slurry of the
product which is filtered and washed with ethyl acetate (1 L), water (800 mL x 3) and
ethyl acetate (500 mL x2) in turn. Brown solids were collected to dry in vacuum for 48
hours at 50 °C to provide compound 6. (463 g in 82 % yield with a purity of 96.8 % by
HPLC using Method C). Residual Cu content was determined to be 13.5 ppm by atomic
absorption spectroscopy. Mp 240 °C, 1H NMR (500 MHz, Chloroformꢀd) δ 8.67ꢀ8.58 (m,
1H), 8.13ꢀ7.78 (m, 3H), 7.78ꢀ7.29 (m, 7H), 7.32ꢀ7.11 (m, 2H), 5.64 (d, J = 25.8, 9.0, 2.8
Hz, 1H), 4.01 (d, J = 13.1 Hz, 0H), 3.92 (d, J = 12.0 Hz, 1H), 3.73 ꢀ 3.58 (m, 1H), 2.98
2.90 (m, 2H), 2.18 ꢀ 2.11 (m, 2H), 2.10 ꢀ 1.97 (m, 2H), 1.62 (q, J = 13.0, 11.9, 6.4 Hz,
13
1H), 1.23 (d, J = 20.7 Hz, 2H); C NMR (100 MHz, DMSOꢀd6) δ 155.49, 149.98,
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148.84, 143.32, 141.65, 137.27, 129.46, 124.62, 122.90, 122.80, 121.58, 114.67, 113.77,
91.58, 84.59, 67.00, 29.22, 25.3, 22.71.
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Preparation of (E)-N-Methyl-2-(3-(2-(pyridin-2-yl)-vinyl)-1H-indazol-6-yl -thiol)
benzamide (axitinib)
Compound 6 (460 g, 0.975mol, 1equiv) and 6N hydrochloric acid (812.5 mL,
4.875 mol, 5 equiv) were added to methanol (2 L) and water (500 mL). The mixture
stirred for 6 hours at 60 °C to complete the reaction detected by HPLC. The mixture is
cooled to 10 °C, and methanol (1 L) and potassium carbonate aqueous solution (1000 g in
1 L water) are added, the mixture is agitated for 8 hours at 30 °C while the color changed
from yellow to white. The mixture is filtered, washed with water (800 mL), ethanol ( 800
mL) and ethyl acetate (2×300 mL) in turn, dried in vacuum at 65 °C for 8 hours to
provide (E)ꢀNꢀMethylꢀ2ꢀ(3ꢀ(2ꢀ(pyridinꢀ2ꢀyl)ꢀvinyl)ꢀ1Hꢀindazolꢀ6ꢀylthio) benzamide
(axitinib) as white solids (342 g in 91 % yield and a purity of 99.65 % by HPLC using
Method C). Mp 222.35 °C. This form is the axitinib monohydrate.
The axitinib monohydrate (340 g) and glacial acetic acid (1.8 L) were added to a
threeꢀnecked flask (3L). The mixture was stirred and heated to 80 °C until the solids
completely dissolved. Then, the reaction solution was slowly added of activated carbon
(10 g) and stirred for 1 hour. The reaction mixture was filtered to remove the activated
carbon, cooled to 20 °C (about 1 °C / min) and stirred to crystallize for 4 hours. The
solids were filtered off and reprocessed using the above method. The solid was then
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suspended in anhydrous ethanol (2 L), and stirred at 85°C for 18 hours. The reaction
mixture was cooled (0.5 ° C / min) with stirring (60 rpm) to 20 ° C. The solids was
filtered off, washed with ethanol, and dried in vacuo at 60 ° C. The product is axitinib
anhydrous crystalline Form XLI (326.4 g in 96 % yield with purity 99.91 %). Residual
Cu content was determined to be 2.2 ppm by atomic absorption spectroscopy. Mp
227.7 °C; 1H NMR (300 MHz, DMSOꢀd6) δ 13.27 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.29
(d, J = 5.4 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 16.4 Hz, 1H), 7.81 (t, J = 7.5 Hz,
1H), 7.66 (d, J = 7.8 Hz, 1H), 7.63 ꢀ 7.44 (m, 3H), 7.29 (p, J = 7.4, 6.6 Hz, 3H), 7.19 (d, J
= 8.5 Hz, 1H), 7.08 (d, J = 7.4 Hz, 1H), 2.78 (d, J = 4.6 Hz, 3H); 13C NMR (75 MHz,
DMSOꢀd6) δ 167.89, 154.86, 149.54, 142.01, 141.86, 136.92, 136.88, 135.67, 132.52,
130.32, 129.99, 129.25, 127.80, 126.15, 125.59, 123.66, 122.68, 122.50, 121.79, 120.29,
114.76, 26.13.
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AUTHOR INFORMATION
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful to Lunan Pharmaceutical Co. LTD. for providing of 6ꢀnitro indazole
on scale, equipment for scaleꢀup experiment and help of the HPLC analysis. This work is
supported by National Natural Science Foundation of China (No. 21241009 and
21371031) and International S&T Cooperation Program of China (No. 2015DFG42240).
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