Synthesis of a Crizotinib Intermediate via Highly Efficient Catalytic Hydrogenation in Continuous Flow

Article abstract of DOI:10.1021/acs.oprd.0c00302

Kilogram-scale highly selective catalytic hydrogenation of the aryl nitro group in the intermediate of crizotinib has been developed, which adopted continuous-flow technology with prepassivated Raney Ni as a catalyst at room temperature. According to the reaction condition optimization, side reactions such as dehalogenation, debenzylation, and reduction of other unsaturated functional groups were inhibited eminently. Moreover, catalytic hydrogenation of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine (compound I) afforded the desired product (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-2-amine (compound II) with high selectivity (99.9%) and high conversion (99.5%). Finally, high-quality crizotinib was synthesized from intermediate II.

Full text of DOI:10.1021/acs.oprd.0c00302

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Full Paper
Synthesis of Crizotinib Intermediate via Highly
Efficient Catalytic Hydrogenation in Continuous-Flow
Feng Xu, Jianli Chen, Xiaoxuan Xie, Pengfei Cheng, Zhiqun Yu, and Wei-Ke Su
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00302 • Publication Date (Web): 29 Sep 2020
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Synthesis of Crizotinib Intermediate via Highly
Efficient Catalytic Hydrogenation in Continuous-Flow
Feng Xu,† Jianli Chen,† Xiaoxuan Xie,† Pengfei Cheng,† Zhiqun Yu,*† Weike Su*‡
†
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National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients,
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of
Technology, Hangzhou 310014, P.R. China
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‡
Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education,
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P.R. China
* Correspondent. Tel: (+86)57188871038. E-mail: yzq@zjut.edu.cn.
* Correspondent. Tel: (+86)57188320899. E-mail: pharmlab@zjut.edu.cn.
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TOC Graphic:
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2
NH
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Kilogram preparation
N
N
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H2
Cl
F
Cl
catalyst packed bed
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Cl
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NH2
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NO2
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Cl
Cl
NH2
Cl
F
Compound II
Compound I
Crizotinib
Yield >99%, product free of catalyst, no post processing
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Abstract:
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A kilogram scale highly selective catalytic hydrogenation of aryl nitro group in the intermediate
of Crizotinib has been developed which adopted continuous-flow technology with pre-passivated
Raney Ni as catalyst under room temperature. According to the reaction condition optimizing, side
reactions like dehalogenation, debenzylation and reduction of other unsaturated functional groups
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were
inhibited
eminently.
Moreover,
catalytic
hydrogenation
of
(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine (compound I) afforded the desired
product (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-2-amine (compound II) with high
selectivity (99.9%) and high conversion (99.5%). Finally, the high quality Crizotinib was
synthesized from the intermediate II.
Key Words: Chemoselectivity, continuous-flow, catalyst, hydrogenation, Crizotinib.
Introduction
Crizotinib is an ATP competitive multi-target protein kinase and a small molecular inhibitor of
ALK/c-MET/ROS. It is currently considered as the best treatment for advanced Anaplastic
Lymphoma Kinase (ALK)-Positive non-small cell lung cancer (NSCLC).1 According to the
literatures, compound II was obtained by catalytic hydrogenation of compound I (scheme 1), which
was a key intermediate of Crizotinib.1
Among them, the researchers tried to use Fe or Ni as the catalyst to reduce compound I to
compound II.1-3 However, two major problems need to be overcome in the synthesis of compound
II: ① Debenzylation and dehalogenation reactions were carried out during catalytic nitro reduction.
In fact, it was found that the dehalogenated and debenzylated impurities were very difficult to
remove in the product. ② Catalytic hydrogenation was flammable and explosive, and the catalyst
filtration was difficult and dangerous. Therefore, development of an inherent safety and
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environmentally friendly nitro reduction process should be explored.
O
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N
O
Cl
Cl
Cl
O
N
N
B
O
Br
O
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F
F
Cl
Cl
Cl
c
H2N
N
N
yield 98%
yield 80%
H2N
N
O2N
N
yield 75%
II
III
I
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Cl
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d
NH
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yield 80%
Cl
H2N
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H2N
N
N
Crizotinib
IV
(a) H2, sponge-nickel, MeOH, 20-50 oC; (b) (i) NBS, MeCN/CH2Cl2, -15 to -10 oC; (ii) Na2S2O5, KOH, CH2Cl2/water; (c)
PdCl2(dppf) CH2Cl2, Cs2CO3, Bu4NBr, toluene/water, 70 oC; (d) HCl, EtOH/EtOAc/CH2Cl2, 0-5 oC, over 2 h.
Scheme 1. Synthesis of Crizotinib involving intermediate II
In general, the catalytic hydrogenation of aromatic nitro compounds containing functional
groups, such as halogens, benzyl, etc., with high selectivity ( ≥ 99%) is one of the challenge.
According to the reports, the results can be divided into two categories based on class of catalysts:
adopting precious metal catalysts and using novel catalysts with yields in the range of
63%-100%.4-15 However, batch process for catalytic hydrogenation have some safety issues, such as
normally tedious post-processing and poor controllability of product dynamics.
Above all, the research in this field focused on the exploration of catalysts and application of
continuous-flow technology for obtaining highly chemoselective hydrogenations of aromatic nitro
compounds in the last decade.16 Continuous-flow technology had some certain advantages compared
to batch mode, such as inherent safety, high efficiency, good mass and heat transfer.17-19 A key
feature of this enabling technology was the straightforward implementation of heterogeneous
catalysis in a continuous-flow transformation, since the catalyst could be easily immobilized in a
specific region of the flow path.20-26 Although the above reports involved continuous flow reduction
of nitro compounds, the continuous-flow catalytic hydrogenation of compounds containing halogen
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and benzyl with high selectivity and high conversion has not been reported.
During the past decade, our group had put continuous efforts on applying continuous-flow
technology to hazardous reactions, and in this paper a continuous-flow hydrogenation process for the
preparation of compound II from compound I was explored with high selectivity (99.5%) and high
conversion (99.9%).
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Results and Discussions
Reaction process analysis
According to study on the mechanism of nitro-catalyzed hydrogenation in the references, the
direction of catalyst design and the improvement of reaction selectivity and conversion were
indicated.27-33,34 We speculated that there might have two pathways for the reduction of compound I
to compound II (Scheme 2).
Cl
N
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Cat.
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Cl
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Cl
Cat.
H2,
Cl
O
Cl
3
Scheme 2. Proposal reaction process and main by-products
In this work, the application of the packed-bed continuous flow reaction technology was
consisted of three parts: ① The performance of the catalyst was evaluated and investigated in the
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hydrogenation reactor to check its availability in continuous flow reaction. ② The catalyst was
immobilized on continuous flow reactor to obtain a suitable packed-bed continuous flow reactor
through preliminary design and improvement. ③ After the continuous flow reaction system was
setup, the preparation of intermediate II was well explored, including reaction temperature, reaction
time, residence time, solvent, pressure and recovery of catalyst.
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Catalyst performance evaluation
Raney-Ni was selected as catalyst with the characteristics of low cost and high efficiency.
Purchased Raney-Ni was pre-passivated by immersion in an ammonia water solution, and then
applied to the catalytic hydrogenation of compound I. In consideration of the better catalytic activity
of Ni than that of Fe, the hydrogenation reaction was firstly conducted at low temperature.
According to the literatures, reaction rate of catalytic hydrogenation of aryl nitro group was
influenced by solvents, and ethanol has been reported as the best solvent.35,36 In our case, THF was
selected as the solvent due to the poor solubility of compound I in alcohol. After that, passivation
reagents of catalyst were further investigated. As shown in Table 1, aqueous ammonia had the best
effect with the selectivity reaching over 75.8%. The reaction selectivity of unpassivated Raney-Ni
catalyst was only 6.2%, 65.1% for benzylamine passivation and 4.3% for ethylenediamine
passivation, respectively.
Dechlorination (Scheme 2, Comp.7) and dibenzyl (Scheme 2, Comp.6) byproducts were the
main impurities in the reaction adopting unpassivated catalyst. Moreover, when the catalyst was
passivated by using ethylenediamine, benzylamine or aqueous ammonia, the azoxybenzene (Scheme
2, Comp.3) and debenzylated (Scheme 2, Comp.6) byproducts were the main impurities.
Table 1. Screening of catalyst
Entry
Passivation solution
Conversion (%)
Selectivity (%)
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None
100
6.2
75.8
4.3
Aqueous ammonia
Ethylenediamine
Benzylamine
100
100
100
65.1
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Condition: Concentration of compound I is 100 g/L. THF as solvent, temperature at 30 C, reaction time is 1.5 h,
pressure is 2.5 MPa. Selectivity (%) = amount of amine substance/(amount of raw material substance - amount of
raw material remaining substance) ×100%.
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After that, the reaction time was further investigated to confirm whether it was suitable for
continuous-flow reaction. Expected product was obtained and the conversion was higher than
88.0%. However, the selectivity was poor (65.4%) and main byproducts were confirmed as
debenzylated (Comp.6) and azoxybenzene (Comp.3) byproducts. It was found that when the reaction
o
temperature was increased to 25 C and the reaction time was set for 10 min, a slight lower
conversion rate of 84.0% was obtained with an improved selectivity of 74.2%, main impurity was
(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitrosopyridine (Comp.1). When reaction time was
extended to 20 min, the conversion was increased to over 94.7% with a better selectivity of 80.0%.
Further prolonging the reaction time to 30 min resulted in decreased selectivity of 78.0% (Table 2).
It was clearly illustrated that the reaction time significantly influences the conversion rate and
selectivity of the reaction, which indicated that such method was not suitable for large-scale
production. Meanwhile, the side reaction was difficult to restrain.
Table 2. Evaluation of catalyst activity
Entry
Conditions
-8℃，20 h
Conversion (%)
Selectivity (%)
88.0
84.0
94.7
65.4
74.2
80.0
1
2
3
25℃，10 min
25℃，20 min
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95.3
100
78.0
75.8
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25℃，30 min
25℃，40 min
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Condition: Concentration of compound I is 100 g/L. THF as solvent, pressure is 1.0 MPa. Selectivity (%) =
amount of amine substance/(amount of raw material substance - amount of raw material remaining substance)
×100%.
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Based on the characteristics and advantages of continuous flow reaction technology, both the
conversion rate and selectivity of reaction might be improved: 1) The conversion rate of the reaction
can be improved by increasing the effective usage of catalyst. 2) The selectivity of reaction can be
improved by avoiding backmixing of materials. Therefore, it was expected that the catalyst could be
suitable for the development of continuous flow reaction technology in packed-bed for the
preparation of intermediate II.
Continuous flow process
According to the results of trials in batch mode, continuous-flow was applied to avoid side
reactions. Figure 1 was the set of tubular reaction system. Reaction conditions were optimized, THF
as solvent, at room temperature, back pressure was set to 44 psi, total residence time was 4 s, result
with conversion of 96.3%, selectivity of 89.8% acquired. Side reactions were inhibited eminently,
and efficiency also improved. However, there were three unsolved problems: ① Catalyst flows
with reaction mixture to collecting vessel, filtration separation of catalyst and reaction solution was
tedious. The usage of catalyst was also higher than in batch. ② The catalyst and the material were
pressurized into the reactor by high-pressure nitrogen gas ， which were uniformly stirred in the
autoclave. Yet, solid-liquid mixing and feeding device was not convenient in lab-scale or large-scale
manufactory. ③ There was a problem that the catalyst could clog the back pressure valve with the
increasing of the reaction concentration and catalyst dosage.
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Reactor
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Magnetic stirring
Reducing valve Check valve
BPR
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controller
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N2
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I.D.=1.77 mm E.D.=3.2 mm Length=30 m
Material kettle
Figure 1. Original continuous-flow reaction system
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Condition: Concentration of compound I is 4 g/L. THF as solvent, at room temperature, back pressure is set to 44
psi, total flow rate is 10 mL/min, samples are tested by HPLC.
An upgraded continuous-flow system that filled catalyst up in reaction tube was adopted in
order to solve these problems (Figure 2). Autoclave was replaced by normal pressure vessel, high
pressure N2 removed, and materials were pumped into reaction tube. Pre-passivated catalyst filled in
reaction tube and thermostat was added to control reaction temperature.
I
Comp.
in solvent
Reactor
Reducing valve
Check valve
BPR
Mass flow
controller
Product tank
I
Comp. :(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine
H2
Pump
Temperature sensor
Packed-bed reactor
150 mm * 4.6 mm
Low Temperature Thermostat Bath
Figure 2. Upgrade continuous-flow reaction system
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Condition: Concentration of compound I is 4 g/L. THF as solvent, at room temperature, back pressure is set to 44
2
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psi, total residence time is 4 s, samples are tested by HPLC.
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Influence of reaction solvent
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To make the process conditions milder, the original reaction temperature is set to 25 C, and
concentration of compound I is 4 g/L, passivated Raney-Ni as catalyst. The length of the packed-bed
reactor is 150 mm and the diameter is 4.6 mm. Moreover, the selectivity and conversion of the
reaction in various solvents have been systematically studied (As shown in Ref. 1, methanol were
not examined because of its poor solubility at room temperature.) The results showed that the
conversion rates of compound I in ethyl acetate, tetrahydrofuran reached more than 99% (Figure 3).
However, selectivity in more polar solvents was poor, and main byproducts were the dechlorination
product (Comp.7) and 2-aminopyridin-3-ol (Comp.6). The reaction with n-hexane as solvents had a
low conversion rate of 35.5% and a poor selectivity of 5.0%. The reaction with tetrahydrofuran as
solvents had a high conversion rate of 99.1% and a poor selectivity of 32.9%. On the other hand, the
reaction has an excellent conversion rate of over 99.0% and a selectivity of 97.9% by using less
polar solvent dichloromethane. Only small amounts of 2-aminopyridin-3-ol (Comp.6 is 0.02%) and
azoxybenzene (Comp.3 is 0.7%) byproducts were detected. It should be noted that the solvent was
crucial for catalytic hydrogenation of aryl nitro group, not only affect reaction rate, but also related
to the formation of debenzylated side products (decreased to 0.2%).
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Figure 3. Influence of solvent polarity on reaction
Condition: Concentration of compound I is 4 g/L. At room temperature, back pressure is set to 44 psi, total
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residence time is 4 s, samples are tested by HPLC.
Influence of reaction temperature
In order to accelerate the reaction rate and increase the productivity, using dicheloromethane as
the reaction solvent, the selectivity and conversion of the reaction at different temperatures were
systematically studied. As the reaction temperature increasing, conversion and selectivity increased
at first reaching to the maximum, which was conversion of 99.9% and selectivity of 97.9% at 25 oC,
and then selectivity declined (Figure 4). When the reaction temperature was higher than 25 oC, side
reactions were accelerated, resulting in a remarkable decline of selectivity, which contained the
dehalogenated (0.8%) and debenzylated (0.6% and 0.4%) side products. According to optimized the
reaction temperature, the reaction conversion rate could reach to 99.9% and had a better selectivity
(97.9%).
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Figure 4. Influence of temperature on reaction
Condition: Concentration of compound I is 4 g/L. DCM as solvent, back pressure is set to 44 psi,
total residence time is 4 s, samples are tested by HPLC.
Influence of pressure
While running time was prolonged, a new problem came out: Pressure in plunger pump was
increasing over time (excess than 600 psi, the pump’s automatically shut down value), meanwhile,
selectivity and conversion were decreasing. According to further research, the higher the pressure in
the reaction tube, the faster the reaction system was shuted down. The results showed that the high
pressure could crush the physical structure of catalyst, reduced active center and the effective surface
area, therefore the efficiency of reaction reduced. Plus, crushed catalyst increased pressure-drop of
reactor, worsening catalytic efficiency and caused reaction system shut down eventually. It was
respectively the state before and after the use of catalyst (Figure S1). Obviously, catalyst physical
structure was crushed. To deal with this problem, a pressure sensor was added before the reaction
tube to explore a suitable inlet pressure of reactor pressure (Figure 5). Finally, under conditions of
outlet pressure of reactor (back pressure) ≤ 30 psi and inlet pressure of reactor pressure < 95 psi,
physical structure of catalyst could maintain a long time.
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P
150mm * 4.6mm
Low Temperature Thermostat Bath
Figure 5. Advanced packed-bed continuous flow reactor
Condition: Concentration of compound I is 4 g/L. DCM as solvent, at 25 oC, back pressure was set to 30 psi, total
residence time was 4 s, Samples are tested by HPLC.
The relationship between reaction pressure, reaction selectivity and conversion rate were
o
studied under outlet pressure of reactor pressure < 95 psi at 25 C, dichloromethane (DCM) as
solvent. When the reaction pressure was in range of 0 to 60 psi, the conversion rate reached more
than 99.9% (Figure 6). However, reaction pressure had great influence on selectivity of catalytic
hydrogenation. As the pressure increasing, selectivity first increases and then decreases. The reason
may be that when the reaction pressure was greater than 30 psi, the high pressure hydrogen greatly
increased the amount of active hydrogen on the surface of the catalyst, the product was overreacted
to form by-products such as dehalogenation (0.7%) and debenzylation (0.5%). When the reaction
pressure was less than 30 psi, the product was rapidly desorbed from the catalyst surface, and even
some of the material was desorbed from the catalyst surface in the intermediate state. As the solution
flowed into the collector, there was an intermediate in the product. Finally, when the pressure was
set to 30 psi using DCM as solvent at 25 oC, the reaction has the best result with a conversion 99.9%
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and a selectivity of 98.1%.
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Figure 6. Influence of reaction pressure on the reaction
Condition: Concentration of compound I is 4 g/L. DCM as solvent, at 25 oC, total residence time is 4 s, samples are
tested by HPLC.
Influence of concentration
The concentration of raw materials was related to the industrialization feasibility of the process,
and the relationship between concentration, conversion and selectivity was studied. At
concentrations of 80 g/L, 100 g/L and 120 g/L, the selectivity and conversion rates of the
intermediates were 99.8%, 100%, 0.2% (intermediate); 99.5%, 100%, 0.5% (intermediate); 99.4%,
100%, 0.6% (intermediate) all achieved the desired results (Figure 7). Under the existing conditions,
with the increase of concentration, the selectivity gradually decreases (mainly due to the increase of
intermediates) and the conversion rate gradually decreases. When the concentration reached 150 g/L,
both selectivity and conversion rate decreased, indicating that the amount of raw material exceeded
the upper limit of the conversion amount. Therefore, the optimal reaction concentration was 120 g/L,
which was close to the kettle reaction1. Surprisingly, keeping the residence time unchanged, the
substrate concentration was actually increased by 30 times. Presumably in a unit volume of the
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catalyst active sites more than the amount of substrate, and catalytic reaction is completed quickly.
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Figure 7. Influence of concentration on the reaction
Condition: DCM as solvent, at 25 oC, back pressure is set to 30 psi, total residence time is 4 s, samples are tested
by HPLC.
Influence of the residence time
When the reaction residence time was less than 6 s, it was found that the catalyst could not
completely catalytically hydrogenate the raw material on the surface of the catalyst (Figure 8).
Meanwhile, the azoxybenzene were detected in the product with 6.6% (residence time is 2 s). When
the residence time was more than 6 s, the competitive reaction rapidly appeared, substituents such as
halogen and benzyloxy were substituted to produce by-products such as dehalogenation and
debenzylation. Best result, 99.9% conversion and 99.5% selectivity were achieved without
o
complicated post-processing in the condition of reaction temperature of 25 C, DCM as solvent, 30
psi back pressure and 6 s residence time, in which azoxybenzene, dehalogenation and debenzylation
impurities were reduced to 0.01%.
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Figure 8. The influence of the residence time on the reaction
o
Condition: Concentration of compound I is 120 g/L. DCM as solvent, at 25 C, back pressure is set to 30 psi,
samples are tested by HPLC.
Reuse of catalyst
The life cycle of the catalyst was investigated and reached nearly 281h after 3 cycles. The
selectivity was maintained above 99% according to the standard, and the conversion rate should not
be less than 96%. The specific data were shown in Table 3. It was found that the selectivity remains
unchanged, only the conversion rate decreases with the extension of time, and can be recovered after
washing, which should be the inactivation caused by the covering of the product on the catalyst
surface. Until, the pressure increased eminently and physical form of catalyst was destroyed.
Table 3. Catalyst reuse
Number of runs
NO.1
Duration (h)
0→98 h
Conversion (%)
99.9→98.3
Selectivity (%)
>99.0
NO.2
0→93 h
99.6→97.5
>99.0
NO.3
0→90h
99.7→96.6
>99.0
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Comparison of batch and continuous-flow process
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Compared to batch process, packed-bed continuous-flow process has some advantages (Table
4). (1) Based on green chemistry principles and inherent safety conception, it was noted that the
packed-bed technology was intensified, and reaction time was shortened. (2) The catalyst post
processing was simplified in packed-bed, which did not need to filter the discharge, post processing
is simplified, and the reduction reaction solution can be directly used in subsequent synthesis
without post-treatment. According to the method of literature,1 the subsequent synthesis process was
verified and qualified high-quality Crizotinib was obtained (specific operation and data were shown
in the supporting information).
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Table 4. Comparison of batch experiment and continuous-flow process
Reaction attribute
Reaction yield (%)
Reaction time
Batcha
95~98
Advance continuous-flow
＞99.0
6 s
>90 min
25→50
0.35
Temperature (oC)
Pressure (MPa)
25
0.20
None
0.016
Post-treatment
complexity
5.99
Catalyst consumption (wt %)
a Crizotinib intermediate II was obtained using batch reaction from reference 1.
Conclusions
Pre-passivated catalyst was prepared and packed in a reaction tube to build a packed-bed
continuous-flow reaction system. Economic H2 was chose as the hydrogen source, studying on
reaction temperature, solvent, concentration, residence time, back pressure to optimize reaction. At
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room temperature, DCM as solvent, concentration 120 g/L, back pressure of 30 psi, residence time
of 6 s, reaction has 99.9% or above and conversion rate 99.5% or above selectivity. The
dehalogenation and debenzylation impurities are less than 0.01%, and the reduction reaction solution
can be directly used in subsequent synthesis without post-treatment. Moreover, product can be
treated by following process to obtain high quality Crizotinib.
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Experimental section
All chemicals were purchased from commercial sources and used without purification. HPLC
analysis was performed a FULI 2200 high-performance liquid chromatography. HPLC conditions:
C18 chromatographic column; HPLC acetonitrile and 0.1% phosphoric as mobile phase, mobile
phase acetonitrile stayed at 35% for 3 min, from 35% to 45% for 17 min, stayed at 45% for 5 min,
from 45% to 85% for 3 min, stayed at 85% for 2 min, from 85% to 35% for 2 min, and at 35% for
3min; flow rate of mobile phase 1.0 mL/min; detection wavelength at 254 nm.
1. Prepared of catalyst
From the catalyst-containing bottle, weigh 20 g of the type DLAW- Ⅴ (Deqing Donglai
Chemical co. LTD) Raney Ni catalyst (Catalyst particle size is 400-500 mesh), put it in a clean jar,
and wash it with 30 mL of deionized water for 1 min, then use Pasteur dropper to remove deionized
water. Add 30 mL of deionized water again and oscillating washing for 1 min, then remove the
deionized water with a Pasteur dropper, until the deionized water is tested as neutral with a pH test
paper. 20 mL of concentrated ammonia water was added, and the mixture was placed in an
environment of 35-50 oC. The mixture was stirred for 30 min and then stored in a static state for 24
h. The nickel was passivated and ready for use. When the catalyst is reactivated, ethyl acetate is
pumped into the reactor, and the catalyst is continuously washed for about 5 h. Then ammonia is
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slowly pumped into the reactor and circulated for 24 h.
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2. General batch reaction procedure
Take clean 25 mL
a
high
pressure
autoclave
and
weigh
2
g
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3-[[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethyl]oxy]-2-nitropyridine in it, 0.01 g of pre-passivated
catalyst was added, 20 mL of tetrahydrofuran was added, and magnetons were added and sealed.
Pump vacuum, then filled with nitrogen, vacuum again, repeat three times, try to replace the air in
the reactor with nitrogen. Thereafter, the mixture was stirred in a 38 oC water bath for 30 min. After
o
the completion of the mixing, the reactor was placed in an ice machine pre-frozen to -10 C and
o
cooled to -8.0 C. At low temperature, fill hydrogen to pressure of 0.3 MPa, release hydrogen to
atmospheric pressure, and repeat three times. Finally, the hydrogen pressure was filled to 2.5 MPa,
sealed, and the reaction was stirred at a temperature of 30 oC at a speed of 700 - 800 rpm to keep the
reaction pressure constant. After about 1.5 h of reaction, the progress of the reaction was monitored
by HPLC until the reaction was completed.
3. Continuous-flow reaction procedure
3.1 Loading of reaction column
A clean internal HPLC column with a diameter of 4.6 mm and a length of 150 mm is taken. One
end is sealed with a sieve plate, and the passivated catalyst solid 4.1 g is gradually added from the
other end, and the unconfined end is sleeved with a high pressure vacuum tube, and the compacted
catalyst is continuously blown with nitrogen gas, and the pressure of nitrogen gas reaches 0.5 MPa.
After the catalyst is compacted, a void is generated in the reaction column, and the passivated
catalyst is continuously filled, and the nitrogen compaction process is repeated until the reaction
column is completely filled, and both ends are sealed with a sealing nut for use.
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3.2 Reaction process
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1000g of compound I was weighed and placed in a flask, and 8.34 L of dichloromethane was
added. Solution, seal the bottle mouth with plastic wrap to prevent solvent evaporation, insert the
pipette of the plunger pump below the level of the raw material, and place the packed-bed reactor in
a 25 °C water bath. The back pressure valve creates a back pressure of 30 psi, the pressure sensor
and temperature sensor were ready for power. The mass flow meter in the hydrogen line was
connected to the power supply, and the check valve was ready. Open the plunger pump, set the
residence time to 6 s, maintain the hydrogen pressure at 0.72 - 0.83 MPa (amount of H2: amount of
comp. 1 was about 5 : 1), maintain the plunger pump pressure at 75 - 81 psi, sample test by HPLC,
the conversion rate was over 99.0%, and the selectivity was over 99.0%.
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o
(R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine: Light yellow solid, m.p.:108-109 C
(ref.[1], mp: 109 oC) 1H NMR (400 MHz, DMSO-d6) δ/ppm 7.57 (dd, J = 9.0, 5.0 Hz, 1H), 7.54-7.41
(m, 2H), 6.72-6.59 (m, 1H), 6.41 (dd, J = 7.8, 5.0 Hz, 1H), 5.98 (q, J = 6.6 Hz, 1H), 5.69 (s, 2H),
1.79 (d, J = 6.6 Hz, 3H). HR-MS[ESI]: C13H11Cl2FN2O for [M+H]+, Calculated 301.0232, found
301.0233.
Supporting Information
Experimental procedures for Crizotinib and copies of 1HNMRand MS spectra for all compounds and
HPLC of compound II.
Acknowledgment
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The authors would like to acknowledge the financial support from Zhejiang Provincial Key R&D
Project (No. 2018C03074 & 2020C03006) and the Natural Science Foundation of Zhejiang Province
(No. LQ20B060006).
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50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment