Synthesis of Imatinib by C-N Coupling Reaction of Primary Amide and Bromo-Substituted Pyrimidine Amine

Article abstract of DOI:10.1021/acs.oprd.9b00227

A new method for imatinib synthesis is described by using the C-N coupling reaction of 4-(4-methylpiperazine-1-methyl)benzamide with N-(5-bromo-2-tolyl)-4-(3-pyridyl)pyrimidin-2-amine to form imatinib. In this synthetic route, the high efficiency and high selectivity of nano-ZnO as a catalyst is key to the mild hydrolysis of 4-(4-methylpiperazine-1-methyl)benzonitrile into the corresponding amide. The total imatinib yield was 51.3%, and the purity was 99.9%. This simple and effective synthetic pathway avoids gene-impurity production (as classified by the FDA Center for Drug Evaluation and Research), and the synthesis is environmentally friendly with a short reaction time.

Full text of DOI:10.1021/acs.oprd.9b00227

Subscriber access provided by GUILFORD COLLEGE
Full Paper
Synthesis of Imatinib by C–N Coupling Reaction of
Primary Amide and Bromo-Substituted Pyrimidine Amine
cuiling wang, Xiao Bai, Rui Wang, Xudong Zheng, Xiumei Ma, Huan Chen, Yun Ai, Yajun Bai, and Yifeng Liu
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00227 • Publication Date (Web): 31 Jul 2019
Downloaded from pubs.acs.org on July 31, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 27
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Synthesis of Imatinib by C–N Coupling Reaction
of Primary Amide and Bromo-Substituted
Pyrimidine Amine
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cuiling Wang,*† Xiao Bai,† Rui Wang,† Xudong Zheng,† Xiumei Ma,† Huan Chen,† Yun Ai,†‡
Yajun Bai,§ Yifeng Liu║
†College of Life Sciences, Northwest University, Xi’ an 710069, China
‡Xi’an Institute for Food and Drug Control, Xi’an 710054, China
§Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of
Education, College of Chemistry & Materials Science, Northwest University, Xi’an, 710127,
China
║Applied Chemical Institute, Northwest University, Xi’ an 710069, P.R. China
ACS Paragon Plus Environment
1

Organic Process Research & Development
Page 2 of 27
1
2
3
4
TOC figure
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
2

Page 3 of 27
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
ABSTRACT: A new method for imatinib synthesis was described by using the C–N coupling
reaction of 4-(4-methylpiperazine-1-methyl)benzamide with N-(5-bromo-2-tolyl)-4-(3-
pyridyl)pyrimidin-2-amine to form imatinib. In this synthetic route, the high efficiency and high
selectivity of nano-ZnO as a catalyst is key to the mild hydrolysis of 4-(4-methylpiperazine-1-
methyl)benzonitrile into the corresponding amide. The total imatinib yield was 51.3%, and the
purity was 99.9%. This simple and effective synthetic pathway avoids gene-impurity production
(as classified by the FDA Center for Drug Evaluation and Research), and the synthesis is
environmentally friendly with a short reaction time.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
KEYWORDS: Imatinib, Nano-ZnO, C–N coupling reaction, Bromopyrimidine, Piperazine
amide
ACS Paragon Plus Environment
3

Organic Process Research & Development
Page 4 of 27
1
2
3
4
INTRODUCTION
5
6
7
8
Imatinib mesylate is a synthetic tyrosine kinase inhibitor, which is used widely in the
clinical treatment of chronic myeloid leukemia.1-2 Chronic myeloid leukemia is an acquired
myeloproliferative disorder that is characterized by cytogenetic translocation, which forms a
fusion kinase BCR-Abl.3-4 Imatinib(4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-
pyridyl)-2-pyrimidinyl] amino]-phenyl]benzamide)) (1) is the first specific molecular targeting
drug inhibitor of BCR-Abl fusion protein and a first-line therapeutic drug for this type of case.5-6
In recent years, its indications have expanded gradually to the treatment of diffuse cutaneous
mastocytosis and benign prostatic hyperplasia.7
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Because it is a well-established gold-standard drug in the treatment of chronic myeloid
leukaemia, many methods have been developed for the synthesis of imatinib.8-10 The synthetic
route was first proposed by Ciba–Geigy's Zimmermann.8 The Zimmermann route (Method A in
Scheme 1) is the most mainstream synthetic route, and it is converted mainly from aniline (2) to
a guanido-containing compound (3), which is then reduced to a pyrimidineamine (5) by two-step
hydrazine and an enone amine (4). Compound (5) reacts with an acyl chloride (6) to form
imatinib (1). In 2008, we proposed a synthetic imatinib method (Method B in Scheme 2),10 (a)
which uses a new starting material, 2-bromo-4-nitrotoluene (7) and the copper-catalyzed C–N
coupling reaction, followed by a reduction of the nitro group to compound (5) by the N2H4 •
H2O/FeCl3/C system, and finally the target compound (1) is produced. This improved method for
imatinib preparation is less hazardous and more environmentally friendly, and has potential for
industrial application.
ACS Paragon Plus Environment
4

Page 5 of 27
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Zimmermann’s method of synthesis of imatinib
Scheme 2. Our previous imatinib synthetic route
However, additional problems have surfaced in recent years with the increase in clinical
cases of imatinib. The genotoxic impurities in imatinib drugs have raised much attention. Two
ACS Paragon Plus Environment
5

Organic Process Research & Development
Page 6 of 27
1
2
3
4
5
6
7
8
9
impurities in imatinib mesylate, namely, N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-
pyridineamine (5) and 4-chloromethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-yl-amino)-
phenyl]benzamide (10) have been reported by the FDA's Center for Drug Evaluation and
Research. The impurities in imatinib mesylate have potential for direct DNA damage and
toxicity to genes, with genotoxic impurity limit of below 20 ppm (5) and 10 ppm (10),
respectively. In previous reports, these two substances were found mostly as intermediates
(Schemes 1 and 2). Purification to remove two genotoxic impurities is difficult. The most
effective way to resolve this problem is to modify the synthetic route and to avoid the production
of these genotoxic impurities.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In fact, in 2003, the Zimmermann’s inverse synthesis route was designed by Loiseleur et al.
(Methods C and D in Scheme 3).9 Method C consists of 3-nitro-4-methyl aniline (12) as the
starting material, with the first acylation, and then the pyrimidine ring was built. Method D uses
3-bromo-4-methylaniline (15) as the starting material, and the C–N coupling reaction to build
phenylaminopyrimidine,
in
combination
with
two
precious
catalysts:
tris(dibenzylideneacetone)dipalladium (Pd2 (dba) 3) and organophosphorus ligand (+/−)-2,2'-
bis(diphenylphosphine)-1,1'-binaphthyl (rac-BINAP). Both routes do not produce genotoxic
impurities. However, these methods have some shortcomings, such as the poor selectivity of the
acylation reaction, high synthesis costs or long reaction times. Thus, the development of an
effective method for imatinib synthesis is required that avoids the production of these genotoxic
impurities. We designed a new synthetic imatinib route (Scheme 4) by using the C–N coupling
reaction of N-(5-bromo-2-tolyl)-4-(3-pyridyl) pyrimidin-2-amine (17) with 4-(4-
methylpiperazine-1-methyl)benzamide (18) to synthesize imatinib (1). This simple and effective
ACS Paragon Plus Environment
6

Page 7 of 27
Organic Process Research & Development
1
2
3
4
synthetic pathway avoids gene-impurity production (compounds: 5 and 10) and the synthesis is
5
6
environmentally friendly with a short reaction time.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Loiseleur’s methods for imatinib synthesis
ACS Paragon Plus Environment
7

Organic Process Research & Development
Page 8 of 27
1
2
3
4
a
N
H
H
5
6
N
N
N
N
N
7
8
9
K2CO3,CuI,DMEDA
N
N
N
N
HN
N
Br
toluene, sodium ascorbate
H2O, reflux, 24 h
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
N
O
NH2
1
17
18
c
b
4
ZnCl2, EGME
reflux, 4 h
H2O, (CH3)2CHOH, nano ZnO, KOH, reflux, 8 h
N
Cl
N H
N
H
1) CNNH2, CH3OH
HNO3, reflux, 3 h
11
NH2
N
NH2
NaOH
solid grinding
2) NaOH
20
19
Br
CN
Br
21
22
CN
Scheme 4. Newly designed synthetic methods and pathways for imatinib.
RESULTS AND DISCUSSION
According to our designed synthetic route, six steps are required to synthesize imatinib. The
synthesis of N-(5-bromo-2-tolyl)-4-(3-pyridyl)pyrimidin-2-amine (17) and 3-(dimethylamino)-1-
(3-pyridyl)-2-propen-1-one (4) has been reported in the literature. The latter synthesis requires
toluene or xylene as a solvent during the reaction, and the equipment utilization rate is low with a
long reaction time. We obtained satisfactory results by using the solvent-free synthesis of 3-
(dimethylamino)-1-(3-pyridyl)-2-propen-1-one (4). To improve this method, a Vigreux
rectification column needs to be installed on the reaction unit. During the reaction, by-product
methanol that was produced by the reaction was fractionated continuously, the enamine (4) yield
exceeded 95% after 4–6 h. The solid-phase synthesis of 4-(4-methylpiperazine-1-
methyl)benzonitrile (20) and its hydrolysis to amide (18), and the synthesis of imatinib (1) by the
C–N coupling reaction occurred as follows:
ACS Paragon Plus Environment
8

Page 9 of 27
Organic Process Research & Development
1
2
3
4
1. Solid-phase synthesis of 4-(4-methylpiperazine-1-methyl)benzonitrile (20)
5
6
7
8
9
The conventional synthesis of 4-(4-methylpiperazine-1-methyl)benzonitrile (20) was achieved by
a solvent method. Kompella et al.11 used chloroform as a solvent to react N-methyl piperazine
(11) with 4-bromomethyl benzonitrile at room temperature for 4 h to obtain 4-(4-
methylpiperazine-1-methyl)benzonitrile (20). Cheng et al.12 provided chloroform as a solvent in
the presence of sodium carbonate for reaction at 25–30°C for 12 h to yield 4-(4-
methylpiperazine-1-methyl)benzonitrile (20). Umezu et al.13 reported that N-methyl piperazine
(11) was condensed with 4-chloromethyl benzonitrile (19) in the presence of sodium carbonate
in xylene to form 4-(4-methylpiperazine-1-methyl)benzonitrile (20). These methods have many
drawbacks: (a) the use of a large amount of chloroform as a solvent is harmful to the
environment and the operator, and chloroform is a solvent that is restricted in technical guidance
for the research of residual solvents of chemical drugs. The use of chloroform is highly restricted
(if chloroform is used, the solvent residue must be controlled below 0.006%); (b) 4-bromomethyl
benzonitrile is costly and severely toxic, and 4-chloromethyl benzenitrile (19) should be used,
which is affordable and easily available; (c) many by-products result, and the tertiary amine of
N-methyl piperazine (11) reacts easily with chloromethyl group to form quaternary ammonium
hydroxide (23), which converts the nitrile group into carboxylate easily (24) when alkali is added;
and (d) the reaction time is long and the synthesis efficiency is low.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment
9

Organic Process Research & Development
Page 10 of 27
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We used solid-phase organic synthesis to obtain 4-(4-methylpiperazine-1-
methyl)benzonitrile (20) by solid-phase formation of N-methyl piperazine (11) and 4-
chloromethyl benzonitrile (19) in the absence of solvent (Scheme 4, c). The reaction formula is
as follows (see part of Scheme 4):
Certain amounts of 4-chloromethyl benzonitrile (19), N-methyl piperazine (11), and 50%
aqueous sodium hydroxide solution were added to the solid grinding vessel, and after grinding at
room temperature for 30 min under cooling, the reaction mixture was placed in the reactor for
0.5 h. 4-(4-Methylpiperazine-1-methyl)benzonitrile (20) was obtained by extraction, cooling,
crystallization, and filtration with cyclohexane at 70°C, and its yield exceeded 95%. Under
control of the reaction conditions, almost no side reactions occurred. This method is
environmentally friendly, saves time, and produces high yields of target products. Table 1 shows
results from the solid-phase synthesis of 4-(4-methylpiperazine-1-methyl)benzonitrile.
Table 1. Results from solid-phase synthesis of 4-(4-methylpiperazine-1-methyl)benzonitrile
ACS Paragon Plus Environment
10

Page 11 of 27
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Target
products
/g
39.1
40.2
39.6
39.3
39.1
Piperazine Benzonitrile NaOH KOH H2O
Yield
/%
No.
/mol
/mol
/mol
/mol
/mL
1
2
3
4
5
0.2
0.2
0.2
0.2
0.2
0.19
0.19
0.19
0.19
0.19
0.2
0.2
0.2
6
6
6
6
6
90.8
93.4
92.0
91.3
90.8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
0.2
0.2
The excess of N-methyl piperazine (11) relative to 4-chloromethyl benzonitrile (19) allows
for the complete reaction of 4-chloromethyl benzonitrile (19) to avoid difficulties in the removal
of unreacted 4-chloromethyl benzonitrile (19). When the mole ratio of piperazine
(11)/benzonitrile (19)/NaOH or KOH is 0.2:0.19:0.2 regardless of the base, the yields of 4-(4-
Methylpiperazine-1-methyl)benzonitrile (20) were higher (90.8%, 93.4%, 92.0%, 91.3% and
90.8%) (Table 1). Since NaOH or KOH must be moisturized by water for its complete
participation in the reaction, a minimal amount of water was used to moisturize NaOH or KOH.
In this experiment, when 0.2 mol NaOH or KOH was added to the reaction system, 6 mL water
was sufficient to moisturize it. Therefore, the ideal reaction conditions are as follows: the mole
ratio of piperazine (11)/benzonitrile (19)/NaOH or KOH is 0.2:0.19:0.2 with a small amount of
water ensuring a smooth reaction. The results also indicate that sodium and potassium hydroxide
are ideal raw materials, but sodium hydroxide is cheaper and is more suitable.
2. Synthesis of 4-(4-methylpiperazine-1-methyl)benzamide (18) by nitrile (20) hydrolysis
A
method to convert 4-(4-methylpiperazine-1-methyl)phenylnitrile (20) into 4-(4-
methylpiperazine-1-methyl)benzamide (18) has not been reported in previous literature, but an
increased number of reports exist of similar nitriles being converted to amides. Four main
methods exist: (a) acid and alkali hydrolysis.14 The classical hydrolysis method uses a strong acid
and a strong base as a catalyst, which requires a higher reaction temperature, and is prone to
ACS Paragon Plus Environment
11

Organic Process Research & Development
Page 12 of 27
1
2
3
4
5
6
7
8
9
excessive hydrolysis and the formation of by-products. The process yield is low and the by-
product, carboxylic acid, is not removed easily. (b) Oxidation method. During oxidation, nitrile
is converted to amide using hydrogen peroxide as an oxidant. The synthetic pathway for
hydrogen peroxide to oxidize nitrile to yield amide was described by McMaster's group in 1916.
However, the shortcoming of this approach is that the oxidation reaction has a poor selectivity.
In recent years, scientists have tried to improve the reaction results by adding some highly
selective catalysts, such as heteropolyacids.15 (c) Enzymatic catalysis.16,17 The nitrile is
hydrolyzed to the amide by nitrile hydratases. Nitrile hydratases contains two different metal
centers, cobalt and iron. Therefore, the addition of Co2+ and Fe2+ in a bacterial culture has a
strong promoting effect on the enzyme activity. This method has advantages of a high reaction
selectivity, mild conditions, and environmental protection. However, it also has disadvantages of
being more responsive and sensitive to the environment. (d) Transition-metal catalytic hydrolysis.
This approach is a commonly used method for the hydrolysis of nitriles to amides. The metal
ions are mainly Pd, Cu, In, Au, and Ru.18–20 Ma et al.21 reported that the aromatic, fatty, and
heterocyclic nitriles were hydrolyzed smoothly to the corresponding amide in the presence of
acetaldehyde oxime by using NiCl2·6H2O as a catalyst. However, most methods use precious
metals, which increases the reaction cost. Although some methods use inexpensive Cu and Ni,
they are supplemented with a large amount of organic compounds, such as acetaldehyde oxime,
which makes the reaction system more complicated and the product purification more difficult.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We used a combination of high-efficiency and highly selective catalysts: nano-ZnO (15-
25nm, 99.5% metals basis) and KOH to hydrolyze 4-(4-methylpiperazine-1-methyl)benzonitrile
(20) to 4-(4-methylpiperazine-1-methyl)benzoylamide (18) mildly (Scheme 4 c). The reaction
ACS Paragon Plus Environment
12

Page 13 of 27
Organic Process Research & Development
1
2
3
4
conditions are mild and the selectivity is high, so excessive nitrile hydrolysis is controlled
5
6
effectively. The reaction formula is as follows (consider part of Scheme 4):
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
During the reaction, by using isopropanol as solvent, nano-ZnO, KOH or NaOH in a
catalytic amount and with the addition of a theoretical amount of water (based on the moles of
nitrile), 4-(4-methylpiperazine-1-methyl)benzonitrile (20) can be hydrolyzed to 4-(4-
methylpiperazine-1-methyl)benzamide (18) at the isopropanol reflux temperature. The
hydrolysis test results of 4-(4-methylpiperazine-1-methyl)benzonitrile (20) are given in Table 2.
Table 2. Results from synthesis of 4-(4-methylpiperazine-1-methyl)benzamide by nitrile
hydrolysis
Benzonitrile H2O
Nano ZnO KOH
NaOH Benzamide Yield
No.
/mol
0.2
0.2
0.2
0.2
0.2
0.2
/mol
0.2
0.2
0.2
0.2
0.2
0.2
/mol
0.01
0.01
0.01
/mol
0.02
0.02
0.02
0.02
/mol
/g
/%
1
2
3
4
5
6
43.5
42.8
44.0
30.5
40.5
39.1
93.1
91.6
94.2
65.3
86.7
83.7
0.01
0.01
0.02
0.02
The classical hydrolysis method of nitrile to amide uses a strong acid or a strong base as a
catalyst, which is prone to excessive hydrolysis and the formation of by-products carboxylic acid
not removed easily. A good yield was obtained by catalyzing the hydrolysis of 4-(4-
ACS Paragon Plus Environment
13

Organic Process Research & Development
Page 14 of 27
1
2
3
4
5
6
7
8
9
methylpiperazine-1-methyl)benzonitrile (20) by a combination of nano-ZnO and KOH (nano-
ZnO (mol) : KOH (mol) =1: 2). When the mole ratio of benzonitrile (20)/water/nano-ZnO /KOH
is 0.2:0.2:0.01:0.02, 4-(4-methylpiperazine-1-methyl)benzamide (18) was produced in higher
yield (93.1%, 91.6% and 94.2%). In contrast, compound (18) was generated in lower yield
(65.3%) in the absence of nano-ZnO in this reaction system. The synergistic effect of nano-ZnO
is very obvious, but the specific reaction mechanism is still unclear. The catalyst with KOH in
the hydrolysis has a better yield (over 90%) than the NaOH catalysis (about 80% more), which
may be related to the alkaline strength.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3. Synthesis of imatinib (1) based on C–N coupling reaction
The usual C–N coupling reaction is carried out mostly by using an aromatic amine or other more
basic amine and a halogenated aromatic hydrocarbon. In recent years, many reports have been
produced on the C–N coupling reaction of amides,22,23 but because the amide basicity is much
weaker than that of the aromatic amine or pyrimidine amine, the yield of the target product that
is obtained from the C–N coupling reaction with the brominated aromatic hydrocarbon is very
low. Previous methods for synthesizing imatinib (Scheme 2 Method B and Scheme 3 Method D
above) were C–N coupling reactions with pyrimidine amines and brominated aromatic
hydrocarbons,10,24 in which the reaction proceeds easily and the yield was high. In our synthetic
imatinib route (Scheme 4), 4-(4-methylpiperazine-1-methyl)benzamide (18) and N-(5-bromo-2-
methylphenyl)-4-(3-pyridyl)pyrimidine-2-amine (17) reacted according to conventional C–N
coupling reaction conditions, and the obtained imatinib yield was low. Therefore, it is
noteworthy that an increase in the yield of the C–N coupling reaction of this amide becomes a
key issue.
ACS Paragon Plus Environment
14

Page 15 of 27
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
After years of research, we finally resolved this problem. We found that water can promote
this C–N coupling reaction in a non-polar solvent. The use of the antioxidant d-ascorbate can
replace the protection of nitrogen or other inert gases. This simplifies the process equipment and
the difficulty of operation. The results of the C–N coupling-reaction tests as conducted in
accordance with this synthesis method are shown in Table 3.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 3. Results from C–N coupling reaction of pyrimidinyl amine (17) and benzamide (18)
d-
Pyrimidinyl Benzamide H2O
CuI K2CO3 DMED Imatinib
No.
Isoascorbate
/mol
amine /mol /mol
/ml
/mol /mol
/mol
yield /%
1
2
3
4
5
6
0.1
0.1
0.1
0.1
0.1
0.1
0.13
0.13
0.13
0.11
0.13
0.13
5
5
5
5
0.005
0.005
0.005
0.005
0.02 0.2
0.02 0.2
0.02 0.2
0.02 0.2
0.02 0.2
0.02 0.2
0.015
0.015
0.015
0.015
0.015
0.015
83.5
82.8
84.1
80.0
65.4
20.1
0.005
5
When
the
mole
ratio
of
pyrimidinyl
amine
(17)/benzamide
(18)/d-
isoascorbate/CuI/K2CO3/DMED is 0.1:0.13:0.005:0.02:0.2:0.015, imatinib can be synthesized by
a C–N coupling reaction with water (5 mL) with a yield of 83.5%，82.8%，84.1% (Table 3).
We found that water has a significant promoting effect on this C–N coupling reaction in a non-
polar solvent (toluene, xylene). When the solvent was DMF or DMSO, water failed to facilitate
the reaction. The yield of imatinib was obtained in the yiled of 65.4% in the absence of water in
the reaction system (Table 3). The protective effect of the antioxidant d-sodium ascorbate on the
reaction system is also very obvious. Without the protective effect of antioxidant d-sodium
ascorbate, the yield of imatinib was only 20.1%. In addition, it is necessary to add excessive 4-
(4-methylpiperazine-1-methyl)benzamide (18) to the reaction system so that N-(5-bromo-2-
methylphenyl)-4-(3-pyridyl)pyrimidine-2-amine (17) is reacted as completely as possible to
ACS Paragon Plus Environment
15

Organic Process Research & Development
Page 16 of 27
1
2
3
4
5
6
7
8
9
facilitate subsequent imatinib purification. Because the properties of N-(5-bromo-2-
methylphenyl)-4-(3-pyridyl)pyrimidine-2-amine (17) are close to that of imatinib, their
separation is difficult. Whereas 4-(4-methylpiperazine-1-methyl)benzamide (18) has a certain
solubility in hot water, imatinib is completely insoluble in water and can be removed easily from
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
the target product. Elemental analysis of the synthesized imatinib, and IR, MS, and H NMR
spectral analysis, was consistent with the expected structural characterization data. High-
performance liquid chromatography (HPLC) was used to analyze the content, and HPLC-MS
was used to detect the genetoxic impurities (compounds 5 and 10). The content of imatinib that
was obtained by our synthetic method was 99.9% and it did not detect genetic impurities in
imatinib from our new method (data provided in supporting information).
Therefore, the new synthetic route of Scheme 4 was used to couple N-(5-bromo-2-
methylphenyl)-4-(3-pyridyl)pyrimidine-2-amine
(17)
and
4-(4-methylpiperazine-l-
methyl)benzamide (18) with 2-methyl-5-bromoaniline (21) as raw material through the C–N
coupling reaction of amide to produce imatinib (total yield: 51.3%), which did not result in
genetoxic impurities restricted by the FDA.
CONCLUSIONS
A new synthetic imatinib route has been developed by the C–N coupling reaction of 4-(4-
methylpiperazine-1-methyl)benzamide (18) with N-(5-bromo-2-tolyl)-4-(3-pyridyl) pyrimidin-2-
amine (17). The intermediate, 4-(4-methylpiperazine-1-methyl)benzonitrile (20), was obtained
by the reaction of N-methyl piperazine (11) with 4-chloromethyl benzonitrile (19) in solvent-free
conditions at room temperature with a yield of 93.4%. By using a high-efficiency and selective
nano-ZnO catalyst, 4-(4-methylpiperazine-1-methyl)benzonitrile (20) was hydrolyzed mildly
ACS Paragon Plus Environment
16

Page 17 of 27
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
into the corresponding amide (18) with a yield of 94.2%. This synthetic route and process is
simple, environmentally friendly, has a short reaction time, and good selectivity, and the total
yield of imatinib (1) was 51.3% (2-methyl-5-bromoaniline (21) as raw material), with a purity of
99.9%. More importantly, the final product imatinib does not contain genotoxic impurities as
reported by the FDA's Center for Drug Evaluation and Research.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION
General. Melting points were determined on a WRS-1B digital melting-point apparatus
(Shanghai YiCe Instrument Equipment Co., Ltd.), in open capillary tubes, and were uncorrected.
Elemental analyses were performed by Elementar Vario EL III. IR spectra were recorded on a
1
Bruker Equinox-55. H NMR spectra were recorded on a Varian Inova 600 MHz instrument
using DMSO-d6 as a solvent with chemical shifts that were reported relative to tetramethylsilane.
The product purity was analyzed by using an Agilent 1100 HPLC with a DAD detector and a
Zorbax SB-C18 column (250 mm × 4.6 mm, 5 μm), a column temperature of 30°C, a mobile
phase of methanol (0.1% formic acid)-water (50:50), a flow rate of 0.6 mL·min− 1, a detection
wavelength of 254 nm, and an injection volume of 10 μL. Liquid chromatography (LC-MS) was
performed by using an Agilent 1200 HPLC coupled to an Agilent 6520 Quadrupole time-of-
flight mass spectrometer (EI). Flash-column chromatography was performed with silica gel
(100–200 mesh). An imatinib standard sample was purchased from Sigma-Aldrich Life Science
and High Technology Company. ZnO (15-25 nM, 99.5% metals basis, Aladdin Reagent Co.,
Ltd.). All other reagents were used as purchased from commercial suppliers without further
purification. All materials were weighed in air.
General procedure for the synthesis of compounds:
ACS Paragon Plus Environment
17

Organic Process Research & Development
Page 18 of 27
1
2
3
4
3-(Dimethylamino)-1-(3-pyridyl)-2-propen-1-one (4)
5
6
7
8
9
Acetylpyridine (68.6 mL, 0.6 mol) and N,N-dimethylformamide dimethylacetal (94.7 mL, 0.72
mol) were charged into a reaction flask equipped with a mechanical stirrer and a Vigreux column.
The reaction mass was heated slowly with stirring, and the Vigreux column top temperature was
controlled at 65°C. After being maintained for 5 h, the temperature of the reaction mass was
heated gradually to 100°C, and the methanol that was formed in the reaction was distilled off.
The reaction mass was cooled to 80°C, and a mixture of toluene (20 mL) and hexane (10 mL)
was added to the reaction mass, and stirred for 10 min until the liquid reaction mass and solvents
were well mixed. The resultant reaction mass was poured into a beaker, and cooled to room
temperature. The crystalline solid was filtered off under vacuum, and dried at 50–60°C to yield
3-(dimethylamino)-1-(3-pyridyl)-2-propen-1-one as an orange crystal (101.5 g, yield: 96.0%).
Melting point: 81.5–82.2°C (consistent with the literature).25
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5-Bromo-2-methylphenylguanidine (22)
5-Bromo-2-methylaniline (21) (37.4 g, 0.2 mol) and methanol (60 mL) were placed in a reactor
flask with a mechanical stirrer and a dropping funnel. Nitric acid (65%, 10.8 mL, 0.24 mol) was
added dropwise to the reaction mass over 20 min, and the reaction temperature was increased to
60°C. After stirring for 30 min, a 50% aqueous cyanamide solution (11.7 mL, 0.3 mol) was
added dropwise over 40 min. The reaction mixture was heated to the reflux temperature, and
stirred for 1.5 h; then 65% nitric acid (7.2 mL 0.16 mol) was added over 20 min. While the
reaction mixture was stirred for a further 30 min, 50% aqueous cyanamide solution (7.8 mL, 0.2
mol) was added dropwise over 40 min. The reaction mixture was kept at the reflux temperature
for 3 h. After completion of the reaction, the reaction mass was cooled to room temperature. The
ACS Paragon Plus Environment
18

Page 19 of 27
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
solid product was filtered, washed with toluene (20 mL), and dried to yield 5-bromo-2-
methylphenylguanidine nitrate as light-brown granular crystals (46.5 g, yield: 79.9%). Melting
point: 183–184°C. 5-Bromo-2-methylphenylguanidine nitrate and distilled water (150 mL) were
added to a beaker at room temperature with the addition of 130 mL of 5% NaOH aqueous
solution. The reaction mass was stirred for 1 h and filtered to yield a crude product of 5-bromo-
2-methylphenylguanidine. The crude product was recrystallized from toluene to give 5-bromo-2-
methylphenylguanidine as white powder crystals (34.1 g, yield: 74.8%). Melting point: 76–79°C.
Anal. Calcd for C8H10BrN3: C, 42.13; H, 4.42; N, 18.42. Found: C, 42.51; H, 4.18; N, 18.09. IR
(KBr, cm − 1): 3452.4, 3376.8, 3139.1, 2963.8, 2758, 1699.3, 1671.9, 1631.5, 1580.2, 1479.7,
1392.8, 882.08, 797.81. 1H NMR (DMSO-d6, 600 MHz) δ 7.04(d, 1H), 6.96 d, 1H), 6.88(s, 1H),
5.42 bs, 4H), 2.02(s, 3H).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(5-bromo-2-methylphenyl)-4-(3-pyridyl)pyrimidine-2-amine (17)
A reaction flask was charged with 5-bromo-2-methylphenylguanidine (22) (45.6 g, 0.2 mol), 3-
(dimethylamino)-1-(3-pyridyl)-2-propen-1-one (4) (38.8 g, 0.22 mol) and ethylene glycol
monomethyl ether (EGME) (120 mL). The reaction mixture was heated to reflux (~120°C) for 8
h and the reaction mass was cooled to room temperature. The crude product was filtered under
reduced pressure, and the precipitate was washed with 20 mL water on a filter funnel. The
product was recrystallized from toluene to yield 55.6 g (81.5%) of N-(5-bromo-2-methylphenyl)-
4-(pyridin-3-yl)-pyrimidin-2-ylamine (17) as a light-yellow powder. Melting point: 152–156°C.
Anal. Calcd for C16H13BrN4: C, 56.32; H, 3.84; N, 16.42. Found: C, 56.23; H, 3.86; N, 16.51.
MS: 341.0 (M+H), 343.0 (bromine isotope peak), 363.0 (M+Na). IR (KBr, cm−1): 3204.3, 3156.2,
3039.6, 2947, 2892.1, 1581.9, 1533.5, 1454.7, 1421, 1403, 1384, 1337.3, 1294.7, 1024, 990.48,
858.96, 799.05, 710.47, 655, 612.47. 1H NMR (DMSO-d6, 600 MHz) δ 9.26(s, 1H, NH), 9.03(s,
ACS Paragon Plus Environment
19

Organic Process Research & Development
Page 20 of 27
1
2
3
4
5
6
1H), 8.69(d, 1H), 8.54(dd, 1H), 8.41(d, 1H), 7.89(dd, 1H), 7.54–753(m, 1H), 7.48(dd, 1H),
7.22(d, 1H), 7.19(d, 1H), 2.22(s, 3H).
7
8
9
4-(4-Methylpiperazin-1-ylmethyl)-benzonitrile (20)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-Methylpiperazine (22.2 mL, 0.2 mol) and a solution of NaOH (8 g, 0.2 mol) in 6 mL of water
were charged into a 90-mm-diameter ceramic mortar. The reaction mass was ground constantly
in an ice bath, until the liquid became semi-solid. 4-Chloromethylbenzonitrile (19) (28.8 g, 0.19
mol) was added gradually over 30 min, and the temperature of the reaction mass was maintained
below room temperature. Thereafter, the reaction mass remained stationary for 2 h before being
transferred to a beaker that was charged with 30 mL of cyclohexane. The reaction mixture was
heated to 70°C for 10 min. The cyclohexane layer was poured out, and cooled to room
temperature. The product was filtered to give 4-(4-methylpiperazin-1-ylmethyl)-benzonitrile (20)
as white granular crystals (39.1 g, yield: 90.8%). Melting point: 65–68°C. Anal. Calcd for
C13H17N3: C, 72.52; H, 7.96; N, 19.52. Found: C, 72.14; H, 7.48; N, 19.01. IR (KBr, cm− 1):
3042.6, 2941.8, 2798.5, 2788.9, 2223.8, 1606.6, 1504.5, 1455.7, 1369.1, 1351.4, 1318, 1283.7,
1
1162.7, 1141.7, 1010.7, 925.3, 855.4, 809.9. H NMR (DMSO-d6, 600 MHz) δ 7.81(d, 2H),
7.54(d, 2H,), 3.57(s, 2H, CH2), 2.39(bs, 8H), 2.18(s, 3H, CH3).
4-(4-Methylpiperazin-1-ylmethyl)benzamide (18)
A reaction flask was charged with 4-(4-methylpiperazin-1-ylmethyl)benzonitrile (20) (43.1 g, 0.2
mol), isopropyl alcohol (100 mL), water (3.6 mL, 0.2 mol), nano-ZnO (0.81 g, 0.01 mol) and
KOH (1.1 g, 0.02 mol). The reaction mixture was heated to reflux for 6–8 h. After a portion of
isopropyl alcohol had been distilled off, the mother liquor was filtered by hot filtration to remove
the catalyst residue. The reaction mass was poured into a beaker, and brought to room
ACS Paragon Plus Environment
20

Page 21 of 27
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
temperature for 8 h. The precipitated solid was isolated by filtration, and placed into a beaker
charged with 100 mL of distilled water. The mixture was heated to 90°C for 10 min. Hot
filtration was carried out, and the mother liquor was brought to room temperature. The solid
product was filtered, washed with water, and dried to yield 4-(4-methylpiperazin-1-
ylmethyl)benzamide (18) as white granular crystals (43.5 g, yield: 93.1%). Melting point: 156–
159°C. Anal. Calcd for C13H19N3O: C, 66.92; H, 8.21; N, 18.01. Found: C,66.31; H, 7.96; N,
17.92. MS: 234.16 (M+H). IR (KBr, cm−1): 3385.5, 3177, 2937.7, 279.23, 1650.8, 1619.8, 1570,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1457, 1419.5, 1400.7, 1349.7, 1012.9, 852.94, 818.16, 803.3. HNMR (DMSO-d6, 600 MHz) δ
7.89(s, 1H, NH2α), 7.78(d, 2H), 7.31(d, 2H), 7.27(s, 1H, NH2β), 3.45(s, 2H, CH2), 2.31(bs, 8H),
2.11(s, 3H, CH3).
N-(4-Methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-4-((4-methylpiperazin-1-
yl)methyl)benzamide (1)
N-(5-Bromo-2-methylphenyl)-4-(pyridin-3-yl)-pyrimidin-2-ylamine (17) (34.1 g, 0.1 mol), 4-(4-
methylpiperazin-1-ylmethyl)benzamide (18) (30.3 g, 0.13 mol), cuprous iodide (CuI) (3.81 g,
0.02 mol), potassium carbonate (K2CO3) (27.6 g, 0.2 mol), N,N′-dimethylethylenediamine
(DMEDA) (1.32 g, 0.015 mol), sodium d-isoascorbate (0.99 g, 0.005 mol), 5 mL of distilled
water and 300 mL of toluene were charged into a reaction flask. The reaction mixture was stirred
in air for 24 h and the temperature was heated to the reflux temperature. The reaction mass was
returned to room temperature, and maintained for 2 h. The solid product was filtered, washed
with boiling water (100 mL) and toluene (50 mL), and dried at 60°C. The crude product was
purified by recrystallization from ethylene glycol monomethyl ether to yield N-(4-methyl-3-(4-
(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide (1) as
a light-yellow powder (41.2 g, yield: 83.5%. HPLC purity: 99.9%; genotoxic impurity (5) and
ACS Paragon Plus Environment
21

Organic Process Research & Development
Page 22 of 27
1
2
3
4
5
6
7
8
9
(10): not detected; o-toluidine: not detected). Melting point: 206–209°C. Anal. Calcd for
C29H31N7O: C, 70.56; H, 6.33; N, 19.86. Found: C, 70.18; H, 6.45; N, 19.32. MS: 494.3 (M+H).
IR (KBr, cm−1): 3440.8, 3280.7, 3049.8, 2927.8, 2795.4, 1648, 1577.5, 1534.3, 1451.5, 1418.6,
1372.6, 1351.9, 1289.9, 1261.7, 1204.3, 1163, 1009.7, 923.6, 885.72, 856.53, 808.59, 747.49,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
701.43, 646.2. H NMR (DMSO-d6, 600 MHz) δ 10.15(s, 1H, NH), 9.26(s, 1H), 8.96(s, 1H),
8.67(d, 1H), 8.50(d, 1H), 8.46(d, 1H), 8.07(s, 1H), 7.89(d, 2H), 7.51–7.41(m, 5H), 7.19(d, 1H),
3.51(s, 2H), 2.37(bs, 8H), 2.21(s, 3H), 2.13(s, 3H).
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI: xxxxxx. 1H-NMR and IR spectra, MS data for each intermediate. Analysis of the content of
the standard sample from Sigma-Aldrich Company and our synthetic imatinib by HPLC and LC-
MS. (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail address: wangcl@nwu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
ACS Paragon Plus Environment
22

Page 23 of 27
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
We are grateful for support from the Natural Science Foundation of Shaanxi Province (No.
2014JM4095, 2018JM7059), the Xi'an City Science and Technology project (No.
2017085CG/RC048 (XBDX001)), the Shaanxi Province Education Department Key Laboratory
project (No. 16JS110), the Shaanxi Province Key R&D project (No. 2018 SF-077), the NSFC
Enhanced Base Construction projects (No. J1210063), and the Teaching Reform project of the
Northwest University (No. JX17088).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
REFERENCES
(1) (a) Goldman, J. M.; Melo, J. V. Chronic myeloid leukemia-advances in biology and new
approaches to treatment. N. Engl. J. Med. 2003, 349 (15), 1451–1464. (b) O’Brien, S. G.;
Deininger, M. W. Imatinib in patients with newly diagnosed chronic phase chronicmyeloid
leukemia. Semin. Hematol. 2003, 40, 26–30.
(2) Cervantes, F.; Mauro, M. Practical management of patients with chronic myeloid leukemia.
Cancer, 2011,117, 4343–4354.
(3) Apperley, J. F. Chronic myeloid leukaemia, Lancet, 2015, 385, 1447–1459.
(4) (a) Klein, A. d.; Kessel, A. G. V.; Grosveld, G.; Bartram, C. R.; Hagemeijer, A.; Bootsma, D.;
Spurr, N. K.; Heisterkamp, N.; Groffen, J.; Stephenson, J. R. A cellularoncogene is translocated
to the Philadelphia chromosome in chronicmyelocytic leukaemia, Nature, 1982, 300, 765–767.
(b) Baccarani, M.; Pileri, S.; Steegmann, J. L.; Muller, M.; Soverini, S.; Dreyling, M. Chronic
myeloid leukemia: ESMO clinical practice guidelines for diagnosis, treatment and followup. Ann.
Oncol. 2012, 23, vii 72–77.
ACS Paragon Plus Environment
23

Organic Process Research & Development
Page 24 of 27
1
2
3
4
5
6
7
8
9
(5) (a) Druker, B. J.; Tamura, S.; Buchdunger, E.; Ohno, S.; Segal, G. M.; Fanning, S.;
Zimmermann, J.; Lydon, N. B. Effects of a selective inhibitor of the Abl tyrosinekinase on the
growth of Bcr-Abl positive cells, Nat. Med. 1996, 2, 561–566. (b) Druker, B. J.; Talpaz, M.;
Resta, D. J.; Peng, B.; Buchdunger, E.; Ford, J. M.; Lydon, N. B.; Kantarjian, H.; Capdeville, R.;
Ohno-Jones, S.; Sawyers, C. L. Efficacy and safety ofa specific inhibitor of the BCR-ABL
tyrosine kinase in chronic myeloidleukemia, N. Engl. J. Med. 2001, 344, 1031–1037. (c) Carella,
A. M. Imatinib mesylate, a selective inhibitor of BCR–ABL, in chronic myeloid leukemia.
Expert Rev. Anticancer Ther. 2007, 7, 249–251.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(6) (a) Zhang, J.; Adrián, F. J.; Jahnke, W.; Cowan-Jacob, S. W.; Li, A. G.; Iacob, R. E.; Sim, T.;
Powers, J.; Dierks, C.; Sun, F.; Guo, G.R.; Ding, Q.; Okram, B.; Choi, Y.; Wojciechowski, A.;
Deng, X.; Liu, G.; Fendrich, G.; Strauss, A.; Vajpai, N.; Grzesiek, S.; Tuntland, T.; Liu, Y.;
Bursulaya, B.; Azam, M.; Manley, P. W.; Engen, J. R.; Daley, G. Q.; Warmuth, M.; Gray, N. S.
Targeting Bcr–Abl by combining allosteric with ATP-binding-site inhibitors. Nature, 2010, 463,
501–506. (b) Pasica, I.; Liptonb, J. H. Current approach to the treatment of chronic myeloid
leukaemia. Leukemia Research. 2017, 55, 65–78;
(7) (a) Krystal, G. W. Imatinib mesylate (STI571) for myeloid malignancies other than CML.
Leukemia Research. 2004, 28S1: S53–S59. (b) El Hajj Dib, I.; Gallet, M.; Mentaverri, R.;
Spvenet, N.; Brazier, M.; Kamel, S. Imatinib mesylate (Gleevec) enhances mature osteoclast
apoptosis and suppresses osteoclast bone resorbing activity. Eur. J. Pharmacol. 2006, 551, 27–
33.
(8) Zimmermann, J. CAS no. 120:107056, EP Patent 564,409, 1993.
(9) Loiseleur, O.; Kaufmann, D.; Abel, S.; Buerger, H. M.; Meisenbach, M.; Schmitz, B.;
ACS Paragon Plus Environment
24

Page 25 of 27
Organic Process Research & Development
1
2
3
4
Sedelmeier, G. CAS no. 139:180080, WO/2003/066,613, 2003.
5
6
7
8
9
(10) (a) Liu, Y. F.; Wang, C. L.; Bai, Y. J.; Han, N.; Jiao, J. P.; Qi, X. L. A facile total synthesis of
imatinib base and its analogues. Org. Pro. Res. Dev. 2008, 12 (3), 490–495. (b) Kompella, A.;
Adibhatla, B. R. K.; Muddasani, P. R.; Rachakonda, S.; Gampa, V. K.;Dubey, P. K. A facile total
synthesis for large-scale production of imatinib base, Org. Pro. Res. Dev. 2012, 16, 1794–1804.
(c) Heo, Y.; Hyun, D.; Kumar, M. R.; Jung, H. M.; Lee, S. Preparation of copper(II) oxide bound
on polystyrene beads and its application in the aryl aminations: synthesis of imatinib,
Tetrahedron Lett., 2012, 53, 6657–6661. (d) Leonetti, F.; Capaldi, C.; Carotti, A. Microwave-
assisted solid phase synthesis of imatinib, a blockbuster anticancer drug, Tetrahedron Lett. 2007,
48, 3455–3458.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(11) Kishan, K. A.; Sreenivas, R.; Krishna, G. V. G.; Rao, A. K. S. B.; Chowdary, N. V. Processes
for the preparation of imatinib bases and intermediates thereof. Patent WO2013035102, 2013.
(12) Cheng, J. T.; Wei-Ke, S. U.; Bin, X. U. Synthesis of 4-[(4-Methyl-1-
piperazinyl)methyl]benzoic Acid Dihydrochloride HemihyDrate. Guangzhou Chemical Industry.
2011, 39, 9, 106–108.
(13) Umezu, K. Preparation of (4-alkyl-1-piperazinylmethyl)benzoic acid derivatives. Patent
JP2002338558A, 2002.
(14) Jarugu Narasimha, M.; Nidhi, S. Facile and highly selective conversion of nitriles to amides
via indirect acid-catalyzed hydration using TFA or AcOH-H2SO4. J. Org. Chem. 2005, 70 (5),
1926–1929.
(15) Hu, J. H.; Zhou, Y. F.; Li, X. J.; Li, R. X. Study on oxidation of aryl nitriles to amides
ACS Paragon Plus Environment
25

Organic Process Research & Development
Page 26 of 27
1
2
3
4
catalyzed by heteropolyacids in aqueous/organic biphasic system. Chem. Res. Appl. 2008, 20 (4),
5
6
398–402.
7
8
9
(16) Black, G. W.; Gregson, T.; Mcpake, C. B.; Perry, J. J.; Meng, Z. Biotransformation of
nitriles using the solvent-tolerant nitrile hydratase from Rhodopseudomonas palustris CGA009.
Cheminform, 2010, 51 (13), 1639–1641.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(17) Van Pelt, S.; Zhang, M.; Otten, L. G.; Holt, J.; Sorokin, D. Y.; van Rantwijk, F.; Black, G.
W.; Perry, J. J.; Sheldon, R. A. Probing the enantioselectivity of a diverse group of purified
cobalt-centred nitrile hydratases. Org. Biomol. Chem. 2011, 9 (8), 3011–3019.
(18) Kim, E. S.; Kim, H. S.; Kim, J. N. An efficient Pd-catalyzed hydration of nitrile with
acetaldoxime. Tetrahedron Lett. 2009, 50 (24), 2973–2975.
(19) Kim, E. S.; Lee, H. S.; Kim, S. H.; Kim, J. N. An efficient InCl3-catalyzed hydration of
nitriles to amides: acetaldoxime as an effective water surrogate. Tetrahedron Lett. 2010, 51 (12),
1589–1591.
(20) Ma, X.Y.; He, Y.; Hu, Y.L.; Lu, M. Copper(II)-catalyzed hydration of nitriles with the aid of
acetaldoxime. Tetrahedron Lett. 2012, 53 (4), 449–452.
(21) Ma, X.; Ying, H.; Wang, P.; Ming, L. The hydration of nitriles catalyzed by simple transition
metal salt of the fourth period with the aid of acetaldoxime. Appl. Organomet. Chem. 2012, 26
(7), 377–382.
(22) Teo, Y. C.; Yong, F. F.; Ithnin, I. K.; Yio, S. H. T.; Lin, Z. Efficient Manganese/Copper
bimetallic catalyst for N-Arylation of amides and sulfonamides under mild conditions in water.
ACS Paragon Plus Environment
26

Page 27 of 27
Organic Process Research & Development
1
2
3
4
Eur. J. Org. Chem. 2013, 3, 515–524.
5
6
7
(23) Yao, Z.; Wei, X. Amidation of aryl halides catalyzed by the efficient and recyclable Cu2O
8
9
nanoparticles. Chinese J. Chem. 2015, 28 (11), 2260–2268.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(24) Kompella, A.; Adibhatla, B. R. K.; Muddasani, P. R.; Rachakonda, S.; Gampa, V. K.; Dubey,
P. K. A facile total synthesis for large-scale production of imatinib base. Org. Pro. Res. Dev. 2015,
16 (11), 1794–1804.
(25) Bai, Y.-j.; Liu Y.-f.; Zhang, J.; Dang, W.-j.; Jiao, J.-p. Astudy on the synthesisof 3-N, N-
dimethylamino-1-heteroaryl-2-propen-1-one, J. Northwest Univ. (Nat. Sci. Ed.). 2007, 37 (2),
231–234.
ACS Paragon Plus Environment
27