A facile total synthesis for large-scale production of imatinib base

Article abstract of DOI:10.1021/op300212u

An efficient, economic process has been developed for the production of imatinib with 99.99% purity and 50% overall yield from four steps. Formation and control of all possible impurities is described. The synthesis comprises the condensation of N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine with 4-(4-methylpiperazinomethyl)benzoyl chloride in isopropyl alcohol solvent in the presence of potassium carbonate to yield imatinib base.

Full text of DOI:10.1021/op300212u

Subscriber access provided by CHAPMAN UNIV
Full Paper
A Facile Total synthesis for Large-scale production of Imatinib Base
Amala Kompella, AKS Bhujanga Rao, Pulla Reddy Muddasani,
Sreenivas Rachakonda, Venugopala krishna Gampa, and Pramod Dubey
Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 16 Oct 2012
Downloaded from http://pubs.acs.org on October 20, 2012
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 free 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 accessible to all
readers and 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.
Organic Process Research & Development 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 28
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
A Facile Total synthesis for Large-scale production of
Imatinib Base
Amala Kompella,*,† Bhujanga Rao Kalisatya Adibhatla,*,† Pulla Reddy
Muddasani,† Sreenivas Rachakonda,† Venugopala Krishna Gampa,†
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
And Pramod Kumar Dubey §
*, † Natco research centre, Bꢀ13, Industrial estate, Sanath Nagar, Hyderabad, India
§ Department of chemistry, JNTU College of engineering, Kukatpally, Hyderabad, India
Abstract: An efficient, economic process has been developed for the production of Imatinib with 99.99%
purity and 50% overall yield from four steps. Formation and control of all possible impurities is described.
The synthesis comprises the condensation of Nꢀ(5ꢀaminoꢀ2ꢀmethylphenyl)ꢀ4ꢀ(3ꢀpyridinyl)ꢀ2ꢀ
pyrimidineamine with 4ꢀ(4ꢀmethylpiperazino methyl) benzoyl chloride in Isopropanol solvent in the
presence of potassium carbonate to yield imatinib base.
Keywords: BcrꢀAbl inhibitor, imatinib, Imatinib mesylate.
Abbreviations: Chronic Myelogenous Leukemia (CML), Gastrointestinal Stromal Tumors (GISTs), U.S.
Food and Drug Administration (US FDA), Glass Lined Reactor (GLR)
1. INTRODUCTION
Imatinib mesylate (Gleevec, (4ꢀ(4ꢀmethylpiperazinꢀ1ꢀylmethyl)ꢀNꢀ4ꢀ[methylꢀ3ꢀ(4ꢀpyridinꢀ3ꢀyl)pyrimidinꢀ2ꢀyl
amino)phenyl]benzamide methane sulfonate, (Figure 1) is known as an inhibitor of tyrosine kinases and
is indicated for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumors
(GISTs).1 It was approved by the U.S. Food and Drug Administration (US FDA) on 7 November 2001.In
recent years research concerning imatinib has increased over the years in particular due to its positive
effects on those patients with chronic myeloid leukemia. But, the method for synthesis of imatinib has
been rarely reported.
The first synthetic pathway for Imatinib was described by Zimmermann in 1993(Scheme 1).2 This
synthetic approach involved the reaction of 2ꢀaminoꢀ4ꢀnitrotoluene (2) with 65% nitric acid to form its
nitrate salt which was condensed with aqueous solution of cyanamide to give guanidine nitrate
intermediate (3). Intermediate (3) was condensed with the 3ꢀdimethylaminoꢀl ꢀ(3ꢀpyridyl)ꢀ2ꢀpropenꢀl –one
(4) in the presence of sodium hydroxide solution in isopropanol to form a nitro pyrimidine intermediate(5).
Nitro pyrimidine (5) was then reduced using 50 times by volume of ethyl acetate as solvent and palladium
on carbon as catalyst to yield Nꢀ(5ꢀaminoꢀ2ꢀmethylphenyl)ꢀ4ꢀ(3ꢀpyridinyl)ꢀ2ꢀpyrimidineamine(6). The
amine intermediate (6) was condensed with 4ꢀ(4ꢀmethylꢀ piperazinomethyl)ꢀbenzoyl chloride (7) in
pyridine to give crude imatinib, which was then purified by column chromatography. The yields were not
mentioned for the steps in the synthesis shown in Zimmermann’s paper and patent document. We have
found the process described in the above patent to be unsatisfactory, where the yield of nitro intermediate
was found to be only 50%. The nitro intermediate is also found to be contaminated with inorganic
impurities and use of the impure material leads to a very low yield of the final compound i.e. imatinib.
Usage of pyridine as a solvent and purification of the final product by column chromatography are added
disadvantages of the process described in the patent.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 2 of 28
1
2
3
4
5
6
7
8
9
Loiseleur et al.3 described the second synthetic pathway for the preparation of imatinib base (Scheme 2).
This method comprises condensation of 4ꢀ(3ꢀpyridinyl)ꢀ2ꢀpyrimidineamine (8) or a precursor thereof, with
Nꢀ[3ꢀbromoꢀ4ꢀmethylphenyl)ꢀ4ꢀ(4ꢀmethylpiperazinꢀ1ꢀylmethyl)ꢀbenzamide (9). This scheme involved
Pd2(dba) 3CHCl3ꢀcatalyzed CꢀN coupling reaction with the use of organ phosphorous reagent racꢀBINAP
as ligand.
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
However, the shortcomings of this approach is special sonication equipment, as well as tedious
purification of the product by flash chromatography, and separating the desired from the undesired
isomers using reverseꢀphase preparative chromatography and usage of expensive palladium as catalyst.
Amala et al.4 Szakacs et al.5 and Szczepek et al.6 also respectively provided the third synthetic path way,
an improved process based on Loiseleur’s approach (Schemeꢀ 3) . It comprises the condensation of 4ꢀ
methylꢀNꢀ3ꢀ(4ꢀpyridinꢀ3ꢀylꢀpyrimidinꢀ2ꢀyl)benzeneꢀ1,3ꢀdiamine(6)with 4ꢀchloromethylbenzoyl chloride(10)
to yield 4ꢀchloromethylꢀNꢀ{4ꢀmethylꢀ3ꢀ[(4ꢀpyridinꢀ3ꢀyl)ꢀpyrimidinꢀ2ꢀylamino]ꢀphenyl}ꢀbenzamide(11),
followed by its reaction with Nꢀmethylpiperazine.
However shortcoming of these approaches is the use of excess moles of tin(II) chloride /Raney nickel
and hydrazine hydrate reagents for the reduction of nitro pyrimidine intermediate to prepare
corresponding amino compound, Nꢀ(5ꢀaminoꢀ2ꢀmethylphenyl)ꢀ4ꢀ(3ꢀpyridinyl)ꢀ2ꢀpyridineamine(6). Tin (II)
chloride and hydrazine hydrate are not eco friendly reagents posing adverse affect on environment. It
should also be noted that several previous studies have reported the synthesis of imatinib base i. by
employing sodium dithionate for nitro pyrimidine (5) reduction followed by condensation with 4ꢀ(4ꢀmethylꢀ
piperazinomethyl) benzoic acid dihydrochloride in presence of N,Nꢀcarbonyldiimidazole.7 ii. By employing
iron chloride/hydrazine hydrate for nitro pyrimidine (5) reduction followed by condensation with 4ꢀ(4ꢀ
methylꢀ piperazinomethyl) benzoic acid dihydrochloride in presence of N,Nꢀcarbonyldiimidazole.8
However in these processes there was no mention of imatinib base purity.
All the above shortcomings of these processes make them unattractive and economically inefficient at the
industrial level. Further in all these processes there is no mention of genotoxic impurities and their control.
The classification of a compound (impurity) as genotoxic in general means that there are positive findings
in established in vitro and in vivo genotoxicity tests with the main focus on DNA reactive substances that
have a potential for direct DNA damage. For imatinib mesylate two genotoxic impurities, Nꢀ(5ꢀaminoꢀ2ꢀ
methylphenyl)ꢀ4ꢀ(3ꢀpyridinyl)ꢀ2ꢀpyridineamine (6, D6) and 4ꢀChloromethylꢀNꢀ[4ꢀmethylꢀ3ꢀ(4ꢀpyridinꢀ3ꢀylꢀ
pyrimidinꢀ2ꢀylamino)ꢀphenyl]ꢀbenzamide (6A, D9) are reported as per FDA drug review.9 Further daily
dosage of imatinib mesylate is 800mg; therefore the starting material oꢀtoluidine, genotoxic impurity limit
must be below 1.87ppm.10
In view of the stringent quality requirement, we planned to study Scheme 1 in detail and aimed for control
of all the impurities at imatinib base stage.
In Scheme 1 Nꢀ(5ꢀaminoꢀ2ꢀmethylphenyl)ꢀ4ꢀ(3ꢀpyridinyl)ꢀ2ꢀpyridineamine (6) is reacted with 4ꢀ(4ꢀ
methylpiperazinemethyl) benzoyl chloride (7) in the form of a dihydrochloride. This acid chloride (7) is
prepared by the reaction of 4ꢀ(4ꢀmethylpiperazinomethyl) benzoic acid dihydrochloride (14) with thionyl
chloride.
4ꢀ(4ꢀmethylpiperazinomethyl) benzoic acid dihydrochloride was synthesized by Lambardino in
1996(Scheme 4).11 This method employs the condensation of αꢀchloroꢀpꢀtoluic acid with four moles of
Nꢀmethyl piperazine in ethanol under reflux conditions to give 4ꢀ(4ꢀmethylpiperazinomethyl) benzoic acid
dihydrochloride in only 35% yield.
ACS Paragon Plus Environment

Page 3 of 28
Organic Process Research & Development
1
2
3
4
5
6
The low yield may be explained by the simultaneous formation of the following quaternary salt along with
product as a major impurity (14A, Figure 2)
7
8
9
Batchelor et al.12 described the second pathway for the preparation of 4ꢀ(4ꢀmethylpiperazinomethyl)
benzoic acid dihydrochloride (Scheme 5). This method employs the substitution of Nꢀmethyl piperazine
with the primary halide moiety of αꢀbromoꢀtoluic acid methyl ester by heating for 6h in DMF yielding
methyl ester of 4ꢀ(4ꢀmethylpiperazinomethyl) benzoic acid dihydrochloride in only 47% yield. Thus, the
reactions of both the acid and its ester analogs are documented.
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
Subsequently a few more reported processes 13, 14 follow a reaction sequence similar to that represented
in Scheme 4.
Umetsu kazuto15 discloses two step process for the preparation of 4ꢀ(4ꢀmethylpiperazino) methyl
benzoic acid dihydrochloride by the reaction of 1ꢀmethylpiperazine with 4ꢀchloromethylbenzonitrile in
xylene in the presence of potassium carbonate. Hydrolysis of the intermediate product affords 4ꢀ[(4ꢀ
methylꢀ1ꢀpiperazinyl) methyl] benzoic acid dihydrochloride. In this process all intermediates are isolated
for commercial scale operations and dried before using in the next step. Isolation and drying operations
are time consuming and expose the production personnel to solvent vapors, affecting the productivity.
Ivanov et al.7 disclosed three step process for the synthesis of 4ꢀ(4ꢀmethylpiperazino) methyl benzoic
acid dihydrochloride employing methyl pꢀtoluate as starting material with overall yield of 58%. In this
process highly toxic carbon tetrachloride solvent was used for Nꢀbromination step. Sairam et al.16
reported the preparation of 4ꢀ(4ꢀmethylpiperazino) methyl benzoic acid dihydrochloride by the reaction of
pꢀbromomethyl benzonitrile with Nꢀmethylpiperazine followed by basic hydrolysis of the nitrile group and
acidification with hydrochloric acid provided product in 63% yield in two steps. Liu et al.8 reported the
preparation of 4ꢀ(4ꢀmethylpiperazino) methyl benzoic acid dihydrochloride by the reaction of pꢀ
chloromethyl benzonitrile with Nꢀmethylpiperazine followed by acid hydrolysis of the nitrile group with 96%
HPLC purity in two steps. In this paper we report a simple, scalable process for 4ꢀ(4ꢀMethylpiperazino)
methyl benzoic acid dihydrochloride(14) of 99.9% HPLC purity by changing mode of addition of Nꢀmethyl
piperazine to pꢀbromomethyl benzonitrile and hydrolysis conditions to get maximum purity and yield.
In this protocol the preparation of key intermediate 4ꢀ(4ꢀMethylpiperazino) methyl benzoic acid
dihydrochloride(14) comprises of (a) αꢀbromination of pꢀtolunitrile to get 4ꢀbromomethyl benzonitrile(12)
(b) condensation of bromo compound (12) with Nꢀmethyl piperazine in chloroform to get 4ꢀ(4ꢀmethyl
piperazinomethyl benzonitrile (13) (c) in situ., hydrolysis of 4ꢀ(4ꢀmethyl piperazinomethyl)benzonitrile with
concentrated hydrochloric acid to give 4ꢀ[(4ꢀmethylꢀ1ꢀpiperazinyl)methyl]benzoic acid dihydrochloride(14)
of 99.9% purity(Scheme 6)
Highly pure Imatinib base of 99.99% purity is prepared by considering Zimmermann2 route as basis and
thoroughly studying and optimizing parameters thereby making process commercially viable as follows:
(a) reacting 2ꢀmethylꢀ5ꢀnitroaniline with cyanamide in the presence of hydrochloric acid followed by
neutralization to obtain 1ꢀ(2ꢀmethylꢀ5ꢀnitrophenyl)guanidine(3); (b) reacting 3ꢀ(dimethylamino)ꢀ1ꢀ(3ꢀ
pyridinyl)ꢀpropꢀ2ꢀenꢀ1ꢀone(4) with 1ꢀ(2ꢀmethylꢀ5ꢀnitrophenyl)guanidine (3) to obtain Nꢀ(5ꢀnitroꢀ2ꢀ
methylphenyl)ꢀ4ꢀ(3ꢀpyridinyl)ꢀ2ꢀpyridineamine(5); (c) reducing Nꢀ(5ꢀnitroꢀ2ꢀmethylphenyl)ꢀ4ꢀ(3ꢀpyridinyl)ꢀ2ꢀ
pyridineamine(5) in the presence of Raney nickel to obtain Nꢀ(5ꢀaminoꢀ2ꢀmethylphenyl)ꢀ4ꢀ(3ꢀpyridinyl)ꢀ2ꢀ
pyrimidineꢀamine(6); (d) condensing Nꢀ(5ꢀaminoꢀ2ꢀmethylphenyl)ꢀ4ꢀ(3ꢀpyridinyl)ꢀ2ꢀpyrimidineꢀamine(6)
with 4ꢀ(4ꢀMethylpiperazino)methylbenzoyl chloride dihydrochloride(7) in the presence of an inorganic
base (Scheme 7). In thus formed imatinib base all the genotoxic impurities are well controlled by
incorporating extra purification steps.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 4 of 28
1
2
3
4
2. RESULTS AND DISCUSSION
5
6
7
2.1
. Optimization of the process for the preparation of 4-(4-Methylpiperazinomethyl) benzoic acid
dihydrochloride (14)
8
9
2.1.1. New process conditions for the condensation of 4-bromomethyl benzonitrile and N-
methyl piperazine to yield 4-(4-methyl piperazinomethyl) benzonitrile
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
ꢀ
a. Selection of solvent for reaction medium for alpha bromination:
For the alpha bromination of pꢀtolunitrile to prepare 4ꢀbromomethyl benzonitrile (12) detailed
literature search was done. As per literature methods to obtain benzylic bromides are either a
direct bromination using bromine or a free redical bromination using Nꢀbromosuccinimide (NBS).
Photo irradiation is the disadvantage of direct bromination reaction as this technique is not viable
on commercial scale. Carbon tetrachloride has been accepted as general solvent in Nꢀ
bromosuccinimide side chain brominations.17 Water was described as an excellent medium for
free radical reactions,18 due to its remarkable nonꢀreactivity towards radicals (OH bond resistancy
to hemolytic breaking). Unfortunately pꢀtolunitrile was insoluble in water thus, experiment with
water medium was not successful. Methyl formate solvent reported in literature did not seem to
offer any advantage. 19 Cyclohexane and acetic acid solvents were also tried but the reactions
ended up low yielding product. Other solvents comparable with carbon tetrachloride are
chloroform, methylene chloride and benzene. Table 1 shows results for screening of solvents. For
environmental and toxical reasons we optimized chloroform for alpha bromination step. After
reaction completion chloroform layer was water washed distilled and isolated 12 using mixture of
chloroform and hexane. In commercial scale maximum recovery of chloroform was established
and recovered solvent was reused for the same step. The ratio of recovered mixture of
chloroform and hexane was adjusted to 1:4 by the addition of required fresh solvent (Tables 2
and3)
ꢀ
b. Selection of solvent for the condensation of 4-bromomethyl benzonitrile and N-methyl
piperazine to yield 4-(4-methyl piperazinomethyl) benzonitrile
Initial experiments were tried in different solvents like xylene, acetone, isopropanol, DMF and chloroform
using potassium carbonate as base in different experimental conditions. All these experiments resulted in
the formation of the following quaternary salt (13A, Figure 3) as main product. To avoid the formation of
the quaternary salt usage of potassium carbonate was avoided. With water miscible solvents workup
involved number of operations, pouring reaction mass into water, extraction with solvent, distillation and
isolation. Moreover all these solvents resulted in greater amounts of quaternary salt and solvent recovery
is not possible with water miscible solvents. Compared to the case of chloroform lower yields were
observed in all other solvents. To minimize work up water immiscible solvent chloroform was chosen as
medium. After reaction completion water was added and chloroform was removed. Thus chloroform is an
appropriate solvent for the preparation of compound 13. In commercial scale maximum recovery (80%) of
chloroform was established and recovered solvent was reused for the same step (Table 4)
ꢀ
c. Mole ratios study: Molar equivalents of 1, 1.2, 1.5 and 2.8 Nꢀmethyl piperazine (NMP) were
studied with respect to 4ꢀbromomethyl benzonitrile (12) and, finally 2.8 molar equivalents were
optimized to prevent the formation of quaternary salt. The experimental results indicated the
optimum yield and purity obtained with 2.8molar equivalents of Nꢀmethyl piperazine (Table 5)
ꢀ
d. Mode of addition of reagent: In some experiments NMP was dissolved in chloroform and
added to 4ꢀbromomethyl benzonitrile solution. It was found that Nꢀmethyl piperazine dissolution in
chloroform resulted in exothermic reaction (45ꢀ50oC) and further during work up quaternary salt (Figure 3)
formation is noticed affecting the yield of the product. So in the later reactions reverse addition of 4ꢀ
bromomethyl benzonitrile solution to NMP was adopted and optimized to avoid quaternary salt
formation.(Table 6)
2.1.2. Study conducted for hydrolysis of 4-(4-Methyl piperazinomethyl) benzonitrile (13)
ACS Paragon Plus Environment

Page 5 of 28
Organic Process Research & Development
1
2
3
4
5
6
For initial experiments hydrolysis of 4ꢀ(4ꢀMethyl piperazinomethyl) benzonitrile was studied with base
hydrolysis by heating with 10% sodium hydroxide solution, after reaction completion acidification with
concentrated hydrochloric acid to liberate desired acid. It has resulted in 99% purity containing about 1%
inorganic impurities. (Table 7)
7
8
9
For later experiments
acid hydrolysis was studied by taking concentrated hydrochloric acid (10ꢀ15
volumes) as medium. For initial experiments after reaction completion the work up comprised
concentrated hydrochloric acid complete distillation and the desired product 4ꢀ(4ꢀMethylpiperazinomethyl)
benzoic acid dihydrochloride (10) was isolated with different solvents like methanol and isopropanol.
HPLC purity for these experiments was about 99%. Later on antiꢀsolvent like isopropanol was added to
reaction mass to avoid distillation. HPLC purity for these experiments was about 99% with about 80%
yield.
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
Concentrated hydrochloric acid volume was minimized from ten volumes with respect to starting material
to eight volumes and product was isolated from reaction medium by cooling and filtration. Isopropanol is
used for washing purpose as this intermediate solubility is water is very high. Filtration temperature was
fixed as 40ꢀ45oC to get 4ꢀ(4ꢀMethylpiperazinomethyl) benzoic acid dihydrochloride (14) of purity greater
than 99.5% (Table 8)
2.2. Optimization of the process of 4-(4-Methyl-piperazin-1-ylmethyl)-N-{4-methyl-3-[(4-pyridin-3-yl)
pyrimidin-2-ylamino]-phenyl}-benzamide (I, Imatinib base (I))
2.2.1. Preparation of (2-methyl-5-nitrophenyl) guanidine (3):
Preparation of 2ꢀmethyl ꢀ5ꢀnitro phenyl guanidine was studied in laboratory by the condensation of 2ꢀ
methylꢀ5ꢀnitroaniline with different molar equivalents of cyanamide in nꢀButanol solvent with concentrated
hydrochloric acid addition. Formed product 1ꢀ(2ꢀmethylꢀ5ꢀnitrophenyl) guanidine hydrochloride salt was
neutralized using 10% aqueous sodium hydroxide to get (2ꢀmethylꢀ5ꢀnitrophenyl) guanidine (3). The
following parameters were studied thoroughly for optimization of reaction conditions:
:
a. Study of cyanamide moles: 2.0, 2.5 and 3.0 molar equivalents of cyanamide were studied. It was
observed that with 2.0 and 2.5 molar equivalents of cyanamide reaction was incomplete with 5ꢀ10%
unconverted starting material thus the obtained product needed further purifications for the removal of
starting material . Three moles of cyanamide yielded product with good quality and high yield. Based
on this study three molar equivalents of cyanamide were chosen for process development (Table 9).
b. Selection of hydrochloric acid and its mode of addition: In originators process concentrated nitric
acid was added in one lot to 2ꢀmethylꢀ5ꢀnitroaniline to facilitate salt formation. With this condition it
was observed that reaction was incomplete with lot of impurities formation and final realized yield was
35% only. A study has been undertaken to replace concentrated nitric acid and it has been found that
concentrated hydrochloric acid improves yield considerably (up to 85%). Further availability of
concentrated hydrochloric acid to the reaction mass has been increased by its lot wise addition. This
improved yield drastically (98%) and gave product with 99% HPLC purity (Table 10).
2.2.2. Condensation of (2-methyl-5-nitrophenyl) guanidine (3) and (dimethylamino)-1-(3-
pyridinyl)-prop-2-en-1-one (4) :
a. Study of solvents: Solvents like methanol, ethanol, Isopropanol and nꢀbutanol were tried for the
condensation step. It was observed that in methanol, ethanol and isopropanol solvents reaction was
incomplete even after prolonged hours. It was found that nꢀbutanol was the suitable solvent with high
reflux temperature. So, condensation of (2ꢀmethylꢀ5ꢀnitrophenyl) guanidine (3) with 1.1 molar
equivalents of (dimethylamine)ꢀ1ꢀ(3ꢀpyridinyl)ꢀpropꢀ2ꢀenꢀ1ꢀone (4) was studied at nꢀButanol reflux
temperature and the reaction was found to be complete after 9 hours. After reaction completion the
reaction mass was diluted with purified water, filtered and dried to yield Nꢀ(5ꢀnitroꢀ2ꢀmethylphenyl)ꢀ4ꢀ
(3ꢀpyridinyl)ꢀ2ꢀpyrimidineamine (5) with 65ꢀ70%, yield and 99.2ꢀ99.5% purity by HPLC.
2.2.3. Reduction of N-(5-nitro-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine (5): Reduction of
nitro compounds can be achieved by several reagents in solutionꢀphase reactions. Reactions
with metals (usually Fe, Sn and Zn) in the presence of small amounts of acids are the most
vigorous reduction methods. We tried respectively Iron powder/acetic acid, Iron powder/6N
ACS Paragon Plus Environment

Organic Process Research & Development
Page 6 of 28
1
2
3
4
5
6
7
8
9
HCl, Iron powder/30% HCl, 10%PdꢀC/Ethyl acetate, 10%PdꢀC/dimethyl formamide, Stannous
chloride /HCl, Raney nickel/hydrazine and Raney nickel/methanol. The observed results
showed that in experiments with iron powder and hydrochloric acid product was obtained as
oil due to formation of large number of impurities. With 10%PdꢀC/Ethyl acetate or 10%Pdꢀ
C/dimethyl formamide reaction was incomplete after prolonged hydrogenation and formed
product was impure with broad melting range. With PdꢀC of Johnson Mattew grade also same
results were obtained. With Raney nickel/hydrazine we identified a new impurity at about 40%.
On the basis of the LCꢀMS data, this impurity was identified as diazoxy impurity of nitro
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
pyrimidine 5 (Figure-3A). Process has been developed with stannous chloride/HCl
as
reducing agent and this technology was successfully commercialized in 100kgs scale. (Table
11). For batches involving stannous chloride /HCl as reducing agent heavy metal test with limit
of 10 ppm was incorporated at imatinib base stage to ensure that no tin traces were carried
over to the API.
Later on this reduction step was reworked with an aim of minimization of effluents. So, raney
nickel was chosen as reducing agent to meet these objectives and consequently to meet cost
economics.
Nꢀ(5ꢀnitroꢀ2ꢀmethylphenyl)ꢀ4ꢀ(3ꢀpyridyl)ꢀ2ꢀpyrimidineamine (5) was reduced by the catalytic
hydrogenation with Raney nickel to yield Nꢀ(5ꢀaminoꢀ2ꢀmethylphenyl)ꢀ4ꢀ(3ꢀpyridinyl)ꢀ2ꢀ
pyrimidineamine (6) in methanol solvent. The reaction parameters were studied thoroughly to get
product with good quality and yield.
a. Washing of Raney nickel: It was found that washing raney nickel thoroughly with purified
water till pH is < 8.0 is essential for the initiation of the reaction. Without water washing
reaction was not at all initialized.
b. Raney nickel quantity: About 30% (wt/wt) raney nickel was found to be essential for the
completion of reaction> this is based on the observation that with lesser quantities of raney
nickel (10ꢀ20% wt/wt) starting material remained unreacted along with nitroso impurity (Figure
4) formation. Reducing Nꢀ(5ꢀnitroꢀ2ꢀmethylphenyl)ꢀ4ꢀ(3ꢀpyridinyl)ꢀ2ꢀpyridineamine using 30%
Raney nickel (wt/wt) was carried out in methanol.
c. Reaction time: About 45hours reaction time was found to be essential for the completion of
reaction. Further it was also found that with less reaction hours (10ꢀ40) starting material
remained un reacted along with nitroso impurity (Figure 4) formation. Reducing Nꢀ(5ꢀnitroꢀ2ꢀ
methylphenyl)ꢀ4ꢀ(3ꢀpyridinyl)ꢀ2ꢀpyridineamine using 30% Raney nickel (wt/wt) was carried
out in methanol for 45hours. The yield of the reaction is 80% and HPLC purity is 99.4%.
2.3.4 . Study conducted for the condensation of N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-
2- pyrimidine-amine (6) with 4-(4-Methylpiperazino methyl)benzoyl chloride (7) :
a. Study of mole ratios : Condensing Nꢀ(5ꢀaminoꢀ2ꢀmethylphenyl)ꢀ4ꢀ(3ꢀpyridinyl)ꢀ2ꢀ
pyrimidineꢀamine (VI) with 4ꢀ(4ꢀMethylpiperazino methyl)benzoyl chloride(7) in the presence
of an inorganic base to obtain imatinib base(1) is carried out using between about 1 and
about 2 molar equivalents of 4ꢀ(4ꢀMethylpiperazino)methyl benzoyl chloride dihydrochloride
with respect to Nꢀ(5ꢀaminoꢀ2ꢀmethylphenyl)ꢀ4ꢀ(3ꢀpyridinyl)ꢀ2ꢀpyrimidine amine and
optimized as 1.5 molar equivalents. The condensation was studied in presence of excess of
inorganic base using between about 2 and 6 molar equivalents and optimized as 4 molar
equivalents. This optimization is based on completion of reaction, yield and quality of the
obtained imatinib base.
b. Base selection: Inorganic bases like sodium hydroxide, sodium carbonate and sodium
bicarbonate were tried. Sodium carbonate was found to be suitable for the condensation
yielding product was good quality and yield.
c. Solvent(s) selection: Condensation was studied in solvents chloroform and isoPropanol
(IPA) .It was observed that the reaction was going to completion in chloroform solvent after
8hours. In IPA solvent reaction was completed after 2hours. In chloroform solvent medium
purified water was added after reaction complete to move excess potassium carbonate. In
IPA medium product along with potassium carbonate was filtered and slurry washed with
ACS Paragon Plus Environment

Page 7 of 28
Organic Process Research & Development
1
2
3
4
5
6
7
8
purified water to remove excess potassium carbonate. Imatinib base obtained from both the
solvents was purified by in situ.,by salt formation with methane sulfonic acid in aqueous
medium, washing with organic solvent to remove acidic impurities followed by basification ,
extraction, distillation triturating with ethyl acetate and filtration. Finally isoPropanol solvent
was selected for commercialization thereby avoiding chloro hydrocarbon solvent chloroform.
9
Thus condensation of Nꢀ(5ꢀaminoꢀ2ꢀmethylphenyl)ꢀ4ꢀ(3ꢀpyridinyl)ꢀ2ꢀpyrimidineꢀamine (6) with
1.5 molar equivalents of 4ꢀ(4ꢀMethylpiperazino methyl)benzoyl chloride(7) in the presence of four molar
equivalents of potassium carbonate is carried out in Isopropanol solvents yielded imatinib base of about
99% purity (impurity profile: 0.4% 4ꢀ(4ꢀMethylpiperazinomethyl) benzoic acid dihydrochloride, unknown
impurity: 0.3%, impurity D6: 400ꢀ500ppm, oꢀtoluidine: 5ꢀ6 ppm and impurity D9: 0.3ꢀ0.5 ppm ). This on
further purification with insitu., salt formation with methane sulfonic acid and basification with aqueous
sodium hydroxide yielded imatinib base. In thus formed imatinib base all the genotoxic impurities were
controlled in ppm levels. Separate HPLC methods were developed for estimation of genotoxic impurities
and given under experimental section. The yield of the reaction is 75% and HPLC purity is 99.99%. By
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
this process costing of imatinib base is about 300USD
.
3. SUMMARY
A cost effective effective, high yielding , production friendly process for the production of highly pure
imatinib base is described. The present work also describes the processes for the preparation of key
intermediates Nꢀ(5ꢀaminoꢀ2ꢀmethylphenyl)ꢀ4ꢀ(3ꢀpyridinyl)ꢀ2ꢀpyrimidineamine (6) and 4ꢀ(4ꢀ
methylpiperazino methyl) benzoyl chloride (7).
Experimental section:
Melting points were determined on mettler melting point apparatus, in open capillary tubes and are
uncorrected. The 1H NMR (400MHz) and 13C NMR (400 MHz) spectra were recorded on a Bruker
avanceꢀIII 400MHz NMR spectrometer. Chemical shifts were reported in parts per million (ppm) using
tetra methyl silane as an internal standard and are given in δ units. The solvent used for NMR spectra is
deuterodimethyl sulfoxide unless otherwise stated. Infrared spectra were taken on Brucker in potassium
bromide pellets unless otherwise stated. Highꢀresolution mass spectra were obtained with a waters mass
spectrometer. All reactions were monitored by thin layer chromatography (TLC), carried out on 0.2 mm
silica gel 60F254 (Merck) plates using UV light (254 and 366 nm). The gas chromatography on Agilent
Technologies 6890B with head space was used for analyzing the residual solvents. Common reagent
grade commercially available chemicals were used without further purification.
Preparation 1: 4-(4-Methylpiperazinomethyl) benzoyl chloride (7):
Step-A: Preparation of 4-bromomethyl benzonitrile (12):
Pꢀtolunitrile (150.0kg, 1282.0moles), Nꢀbromo succinimide (228.0kg, 1281.0moles), dibenzoyl peroxide
(2.985kg, 12.32moles) and chloroform (900L) were placed into reactor. The reaction mixture was heated
to 60ꢀ65oC for 3.5 hours. The reaction mass was brought to room temperature, washed with water
(2x1180L). Chloroform was distilled under vacuum and to the residue a mixture chloroform (151L) and
hexane (590L) were charged. The slurry was stirred, filtered and washed with hexane. (168.4kg, yield
66.8%, purity by HPLC: 98.5%)
Step-B: 4-(4-Methylpiperazinomethyl) benzoic acid dihydrochloride (14):
Nꢀmethyl piperazine (184.48kg, 1844.83moles) was placed into reactor. 4ꢀbromomethyl benzonitrile
(168.4kg, 859.18moles) was dissolved in chloroform (946L) and added slowly to the reaction mass during
one hour at 20ꢀ25oC. The reaction mass was maintained at room temperature for three hours. After
completion of the reaction, water (1655L) was charged to the reaction mass and chloroform layer was
separated. Chloroform layer was water washed and distilled under vacuum to yield 4ꢀ(4ꢀMethyl
piperazinomethyl) benzonitrile (13, 184.5kg, 99.7% percentage yield) as residual oil.
To the above oil concentrated hydrochloric acid (35%, 1290L) was charged and heated to 90ꢀ95oC for
five hours. After reaction completion the reaction mass was brought to 40ꢀ45oC and filtered at the same
temperature. Filter cake was washed with Isopropanol and dried to yield
4ꢀ(4ꢀMethylpiperazinomethyl) benzoic acid dihydrochloride (198.7kg, 75% percentage yield, 99.9%
HPLC purity)
Melting point: 310ꢀ312oC
ACS Paragon Plus Environment

Organic Process Research & Development
Page 8 of 28
1
2
3
4
5
6
7
8
9
IR (KBr)(cmꢀ1) : 3460, 2927, 2416.5, 1713.9
1H NMR (AV 400 MHZ, DMSOꢀ d6) δ 8.04(d, 2H), 7.61(d, 2H), 4.55(s, 2H), 3.73(m, 8H), 3.03(s, 3H)
Step-C: Preparation of 4-(4-Methylpiperazinomethyl) benzoyl chloride dihydrochloride (14)
A mixture of 4ꢀ(4ꢀMethylpiperazinomethyl) benzoic acid dihydrochloride (198.7kg, 642.23moles) and
thionyl chloride (1816.7kg, 591.53moles) were placed into reactor and heated to 80oC for 24 hours. The
reaction mass was filtered and washed with chloroform to yield
4ꢀ(4ꢀMethylpiperazinomethyl) benzoyl chloride dihydrochloride (198.7kg yield)
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
Preparation 2: 4-(3-pyridinyl)-N-(5-amino-2-methylphenyl)-2-pyrimidine amine (6)
Step-A: 1-(2-Methyl-5-nitrophenyl) guanidine (3)
2ꢀmethylꢀ5ꢀnitroaniline (150.0kg 986.84moles) and nꢀButanol (600L) were charged into reactor.
Concentrated hydrochloric acid (35%, 57L) was added to the reaction mass during 15 minutes. The
reaction mass was stirred for 15minutes and 50% aqueous cyanamide solution (247L, 2940 moles) was
add during 15minutes. The reaction mixture was heated to 90ꢀ95oC and stirred at the same temperature
for four hours and concentrated hydrochloric acid (57L) was added during 15 minutes. The reaction
mixture was further stirred for four hours while maintaining the temperature at 90ꢀ95oC. Concentrated
hydrochloric acid (87L) was added drop wise and the reaction mixture was kept at 90oC for 4hours. The
reaction mass was maintained at the same temperature for a total of 20hours. After the completion of
reaction, the reaction mass was cooled down to 10oC and basified with 10% aqueous sodium hydroxide
solution (1200L). The solid product was filtered, washed with water and dried to afford 1ꢀ(2ꢀmethylꢀ5ꢀ
nitrophenyl) guanidine (189.0kg yield 98.7%. Purity by HPLC: 99%)
Melting point: 136ꢀ140oC
Step-B: N-(5-Nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine (5):
1ꢀ(2ꢀmethylꢀ5ꢀnitrophenyl) guanidine (189.0kg, 974.22moles), 3ꢀdimethylaminoꢀ1ꢀ(3ꢀpyridyl)ꢀ2ꢀpropenꢀ1ꢀ
one (187.5kg, 1065.34moles) and nꢀButanol (1680L) were placed in reactor. The reaction mixture was
heated to 120oC for nine hours and was then brought to room temperature, water (1350L) was added and
the mixture was stirred at room temperature for 3ꢀ4 hours. The precipitated solid was isolated by filtration
and dried to afford 2ꢀ(2ꢀmethylꢀ5ꢀnitroanilino)ꢀ4ꢀ(3ꢀpyridinyl) pyrimidine (221.0kg, yield 81.9%, Purity by
HPLC: 99.9%)
Melting point: 195.6ꢀ195.9oC.
Step-C: N-(5-Amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine (6)
In to a hydrogenation reactor Nꢀ(5ꢀnitroꢀ2ꢀmethylphenyl)ꢀ4ꢀ(3ꢀpyridinyl)ꢀ2ꢀpyridineamine
(50kg, 162.86 moles) and methanol (1000L) were added. Wet Raney's nickel (20kg) was washed
thoroughly with water and charged into hydrogenation kettle. Hydrogenation was conducted at 60psi
for 45hours. The reaction mixture was filtered and washed with methanol (500L). The combined filtrates
were concentrated in vacuum, treated with a mixture of water (250L) and chloroform (500L). The organic
layer was washed with water (3x125L) and distilled under vacuum. Residual solid was brought to room
temperature and ethyl acetate (375L) was charged. The solution was heated to reflux temperature and
cooled down with stirring to 0ꢀ5oC. The crystalline solid was filtered off and washed with chilled ethyl
acetate (25L), dried to afford title compound (37.5kg, yield: 82.7%, Purity by HPLC: 99.40%)
Melting point: 143ꢀ147oC
Preparation 3: 4-(4-Methyl-piperazin-1-ylmethyl)-N-{4-methyl-3-[(4-pyridin-3-yl)pyrimidin-2-
ylamino]-phenyl}-benzamide (I, Imatinib base (I)) :
Nꢀ(5ꢀAminoꢀ2ꢀmethylphenyl)ꢀ4ꢀ(3ꢀpyridinyl)ꢀ2ꢀpyrimidineamine (6, 37.5kg; 135.377mol), potassium
carbonate (112.5kg, 814.0376moles) and Isopropyl alcohol (675L) were charged into reactor and stirred
at room temperature for 15 minutes. 4ꢀ(4ꢀMethylpiperazinomethyl) benzoyl chloride dihydrochloride (7,
65kg, 200mol) was charged to reaction mass, stirred for 15minutes at room temperature and refluxed for
1.5hours. Reaction mass was brought to room temperature, filtered and washed with isopropyl alcohol
(37.5L). Wet filtered compound was slurry washed with water (750L) and dried at 55oC yielded 57.5kg
(86%,HPLC purity 98.7%, Impurity D6: 469 ppm, impurity D9: 0.4 ppm, oꢀtoluidine: 5.6 ppm) of the crude
product as creamꢀcolored crystalline solid.
Into GLR crude imatinib base (57.5kg, 116.467moles) obtained above and water (1150L) were
charged under stirring. Methane Sulfonic acid (16.75kg, 174.55moles) was added slowly and stirred at
room temperature for 30minutes. Reaction mass was washed with chloroform (3x288L) and separated
aqueous layer was basified with 20% sodium hydroxide solution (432L). Aqueous layer was extracted
with chloroform (1x720L, 2x270L). Separated organic layer, washed with water (3x820L) and
ACS Paragon Plus Environment

Page 9 of 28
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
charcoalized. Organic layer was distilled under vacuum and mixture of chloroform (190L) and ethyl
acetate (314L) was charged to the residual mass. Reaction mass was heated to 60oC, maintained
30minutes, brought to 50oC. The solid was filtered, washed with hot ethyl acetate (58L) and dried at 55oC
yielded title compound (55kg, yield 82.3%, HPLC20 purity 99.99%, Impurity D6: 4ppm, impurity D9: Not
detected, oꢀtoluidine: Not detected ) of the desired product as creamꢀcolored crystalline solid.
Melting point: 207ꢀ209oC; IR (KBr, cmꢀ1): 3424.22, 3280.01, 2966, 2928.44, 2795.98, 2695.71, 1647.76,
1575.16, 1451.83, 1416.67, 1374.17, 1351.92, 1290.92, 857.77, 797.12, 702.93, 646.54. 1H NMR (AV
400 MHz, DMSOꢀ d6) δ 10.11(s,1H), 9.28(s,1H), 8.97(s,1H), 8.69 (d,1H), 8.51(d,1H), 8.48(d,1H),
8.08(s,1H), 7.91 (d, 2H), 7.53ꢀ7.42 (m,5H), ,7.21(d,1H) 3.52(s,2H), 2.37 (bs,8H), 2.22 (s,3H), 2.14(s,
3H);13C NMR (AV 400 MHz, DMSOꢀ d6 ) δ 165.43, 161.75,161.21 159.63, 151.49, 148.25, 142.20,137.80,
137.17, 134.64, 133.80, 132.36, 130.22, 128.86, 127.68, 123.98, 117.18, 116.85, 107.73, 61.73, 54.74,
52.62, 45.79, 17.73; ( 24 signals). Anal.Calcd for C29H31N7O: C, 70.55, H, 6.33; N, 19.87. Found: C,
70.13; H, 6.20; N, 19.32.
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
Preparation of quaternary salt (Impurity 13A):
Dimethyl formamide (30ml), 4ꢀbromomethyl benzonitrile (10.0g, 0.050moles) and potassium carbonate
(7.0g, 0.05moles) were charged sequentially into reaction flask. Nꢀmethyl piperazine (5.0g, 0.05moles)
was dissolved in dimethyl formamide (30ml) and added slowly to the reaction mass during 30minutes at
25ꢀ30oC. The reaction mass was maintained at room temperature for two hours and filtered. The filtrate
was distilled under vacuum and the residual dimethyl formamide traces were removed by charging ethyl
acetate and distillation to yield impurity 13A (12g)
Melting point: 120ꢀ123oC; 1H NMR (AV 400 MHz, DMSOꢀ d6): δ 8.04(d, 2H), 7.80(d, 2H), 7.52(d, 2H),
4.81(s, 2H), 3.54(t, 2H), 3.56(t, 2H), 3.74(s, 2H), 3.01(s, 3H), 2.86(t, 2H), 2.73(t, 2H); 13C NMR (AV 400
MHz, DMSOꢀ d6): δ 143.64, 134.29, 132.83, 132.64, 132.46, 132.27, 129.78, 119.016, 118.41, 113.22,
110.14, 66.37, 61.42, 59.84, 59.42, 54.63, 52.44, 45.59, 45.13; IR(KBr, cmꢀ1): 3408, 3093, 2935, 2851,
2223, 1630, 1606, 1506, 1472, 1413, 1351, 1323, 1303, 1265, 1214; MS(m/z): 331(M+ +H)
Preparation of quaternary salt (Impurity 14A):
nꢀButanol (30ml) and 4ꢀ(bromomethyl) benzoic acid (Aldrich make, 5.0g, 0.023moles) were charged into
reaction flask. Nꢀmethyl piperazine (3.5g, 0.0348moles) was dissolved in nꢀButanol (12ml) and added
slowly to the reaction mass during 10minutes at 25ꢀ40oC. The reaction mass was maintained at room
temperature for 12 hours, filtered and washed with nꢀButanol (10ml). Filtered salt was dissolved in 2M
sodium hydroxide solution, acidified with concentrated hydrochloric acid (5ml) and maintained at room
temperature for 2hours. Separated solid was filtered and washed with nꢀButanol (10ml) afforded impurity
14A after drying. Yield: 2.4g
Melting point: 250oC (decom); 1H NMR (AV 400 MHz, DMSOꢀd6): δ 13.30(s, 2H), 8.06(d, 2H), 8.01(d,
2H), 7.72(d, 2H), 4.87(s, 2H), 4.38(s, 2H), 3.76(d,s, 7H), 3.16(s, 4H); 13C NMR (AV 400 MHz, DMSOꢀ
d6): δ 166.85, 166.75, 134.7, 133.72, 132.59, 131.71, 131.47, 129.75, 57.57, 55.81, 44.38; IR(KBr, cmꢀ
1): 3407, 3024, 2635, 1707, 1616, 1475, 1422; MS(m/z): 369(M+ +H)
4. AUTHOR INFORMATION
Corresponding Author
Eꢀmail: amala@natcopharma.co.in; Telephone no: + 91ꢀ 40ꢀ 23710575, Fax: +91ꢀ 40 ꢀ23710578
Acknowledgements
The authors thank the management of Natco pharma limited for encouragement and support. The
technical help from the Analytical department is gratefully acknowledged.
References:
(1)(a) Li, X. Q.; Yang, J.; Chen, X. J.; Liu, J.; Li, H. R.; Li , J.; Zheng, j.; He, Y.; Chen, Z.; Huang, S.
Cancer Genet Cytogenet. 2007, 176, 166. (b) El Hajj Dib, I.; Gallet , M.; Mentaverri, R.; Sévenet, N.;
Brazier, M.; Kamel, S. Eur. J. Pharmacol. 2006, 551, 27.(c) Van Oosterom, A. T.; Judson , J.; Verweij,
ACS Paragon Plus Environment

Organic Process Research & Development
Page 10 of 28
1
2
3
4
5
6
7
8
E.; Stroobants, S.; Donato, D. P. E.; Dimitrijevic, S.; Martens, M.; Webb, A.; Sciot, R.; Van Glabbeke,
M.; Silberman, S.; Nielsen, O. S. Lancet. 2001, 358, 1421. (d) Buchdunger, E.; Cioffi , C. L.; Law, N.;
Stover, D.; OhnoꢀJones, S.; Druker, B. J.; Lydon, N. B. ; J Pharmacol Exp Ther. 2000, 295, 139. (e)
Krystal, G. W.; Honsawek, S.; Litz , J.; Litz Buchdunger.; Clin Cancer Res. 2000,6, 3319.(f) Weisberg,
E.; Griffin, J. D. Blood, 2000, 95, 34981. (g) Druker, B.J.; Lydon, N. B. ; J Clin Invest. 2000, 105, 3.
9
(2) Zimmarmann, J. CAS no. 120:107056, EP Patent 564,409 (1993). (b) Zimmermann, J. CAS no.
125:4681, U.S. Patent 5,521,184(1996) (c) Zimmermann, J.; Buchdunger, E.; Mett , H. ; Meyer, T. ;
Lydon, N.B. ; Traxler, P. Bioorg. Med. Chem. Lett. 1996, P. 1221.
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) Loiseleur, O. ; Kaufmann, D.; Abel, S.; Buerger, H.M. ; Meisenbach, M.; Schmitz, B.; Sedelmeier, G.
CAS no. 139:180080, WO03/066,613(2003).
(4) Amala, K. ; Bhujanga Rao, A.K.S. ; Venkaiah Chowdary, N. CAS no. 142:56339, WO
2004/108699(2004).
(5) Zakacs, S.; Beni, Z. ; Varga, S.; Orfi, Z.; Keri, L.; Noszal, G, B. J. Med. Chem. 2005, P. 249.
(6) Szczepek, W.; Luniewski, W.; Kaczmare, L.; Zagrodzki, B. ;SamsonꢀLazinska, D. ; Szelejewski, M.;
Skarzynski, W. CAS no. 145:103728, U.S. 7674901 (2010).
(7) Ivanov, A.S.; Shishkov, S.V. Monatsh Chem. 2009, P. 619
(8) Liu, H.; Xia, W.; Luo, Y.; Lu, W. Monatsh Chem. 2010, P. 907
(9) NDA 21ꢀ335 Gleevec_pharm_ P2, P. 45
(10) ICHJ harmonized tripartite guideline, Note for guidance on Genotoxicity: A Standard Battery for
Genotoxicity Testing of Pharmaceuticals (CPMP/ICH/174/95, ICHS2B)
(11) Lambardino, J.G. CAS no. 106:50232, U.S. Patent 4,623,486 (1996).
(12) Batchelor, M.J.; Moffat, D.F.C. ; Davis, J.M. ; Hutchings, M.C. CAS no. 106:50232, U.S. Patent
6,57,9983 (2003).
(13) Takezaki, H.; Kitagawa T.; Matsuoka, S. CAS no. 138321295, JP2003119184, (2003).
(14) Takezaki, H. ; Kitagawa, T.; Matsuoka, S. CAS no. 138:321296, JP2003119185, (2003).
(15) Umetsu, K. ; CAS no. 137:370111, JP 2002338558, (2002).
(16) Sairam, P.; Puranik, R.; Keller, AS.; Sasikiran, S.; Veerenderm M.; Parvathi, A. Synth Commun.
2003, P.3597.
(17) Ziegler, K.; Spath, A.; Scoof, E.; Schumann, W.; Winkelmann, E. Justus Liebigs. Ann. Chem. 1952,
P. 80.
(18) Offermann, W.; Vogtle, F. Synthesis 1977, 272ꢀ273.
(19) Shaw, H.; Perlmutter, H. D.; Gu, C. J. Org. Chem. 1997, 236ꢀ237.
(20) HPLC MethodꢀI (for estimation of oꢀtoluidine and impurity D6 in parts per million concentration):
Column: Develosil ODSꢀHGꢀ5, 150x4.6mm, 5ꢁm; flow: 1 mL/min; Mobile phaseꢀ A: buffer solutionꢀA and
ACS Paragon Plus Environment

Page 11 of 28
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
methanol(1:1 v/v); mobile phaseꢀB: buffer solution –A and methanol(4:96 v/v); Diluent: water and
methanol(1:1 v/v); Buffer solutionꢀA preparation: Dissolve 4.56g of octaneꢀ1ꢀsulfonic acid sodium salt in
1000mL of water and adjust pH to 8.0 with diluted sodium hydroxide solution; Reference solutionꢀ1:
Dissolve 10mg each of oꢀtoluidine and impurityꢀD6 in 100ml volumetric flask with diluents. Transfer 0.5mL
of this solution into 50ml volumetric flask and dilute to volume with diluents. Again transfer 2.0mL of this
solution into a 10mL volumetric flask and dilute to volume with diluents; Reference solutionꢀ2: Transfer
0.75 mL of reference solutionꢀ1 into a 10ml volumetric flask and dilute to volume with diluents; test
solution: Dissolve 100mg of test sample in 5ml methanol, sonicate and make up to volume with diluents in
10 mL volumetric flask; Gradient: 0 min: 100% A, 0% B; 15 min: 80% A, 20% B; 40 min: 35% A, 65% B;
42 min: 100% A, 0% B; 50 min: 100% A, 0% B; UV detection: 240 nm.
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
MethodꢀII (for estimation of impurity D9 in parts per million concentration): Column: Develosil ODSꢀHGꢀ3,
150x4.6mm, 3ꢁm; flow: 1 mL/min; Mobile phase: buffer, methanol and acetonitrile in 50:30:20 v/v/v;
Diluents: water and methanol(1:1 v/v); Buffer solution preparation: Dissolve 3.0g of sodium dihydrogen
phosphate dihydrate in 1000mL of water and adjust pH to 2.5 with diluted phosphoric acid; Reference
solutionꢀ1: Dissolve 10mg impurityꢀD9 in 50ml volumetric flask with methanol and acetonitrile mixture
(3:2 v/v). Transfer 1 mL of this solution into a 20 mL volumetric flask and dilute to volume with diluents.
Again transfer 0.5 mL of this solution into a 50 mL volumetric flask and dilute to volume with diluents;
Reference solutionꢀ2: Transfer 3.0 mL of reference solutionꢀ1 into a 10ml volumetric flask and dilute to
volume with diluents; test solution: Dissolve 100mg of test sample in 5ml methanol, sonicate and make up
to volume with diluents in 10 mL volumetric flask;; UV detection: 240 nm.
MethodꢀIII (for estimation of related substances): Column: Develosil ODSꢀHGꢀ5, 150x4.6mm, 5ꢁm; flow: 1
mL/min; Solvent mixture: Mix 300 mL of methanol and 200 mL of acetonitrile. Mobile phase preparation:
Dissolve 1.65g of sodium dihydrogen phosphate dihydrate in 550 mL of water and adjust pH to 8.0 with
triethyl amine and add 450ml of solvent mixture; Test solution: dissolve 50 mg of test sample in 50 mL
volumetric flask with mobile phase. Reference solutionꢀ1: Transfer 1 mL of test solution into 50 mL
volumetric flask and dilute to volume with mobile phase. Transfer 1 mL of this solution into a 20 mL
volumetric flask and dilute to volume with mobile phase. Reference solutionꢀ2: Dissolve 50mg of imatinib
impurity premix in mobile phase in 50 mL volumetric flask (1000 mcg/mL of the imatinib and each 1
mcg/mL of impurities); UV detection: 230 nm.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 12 of 28
1
2
3
4
5
6
7
8
Tables
9
Table 1: Solvent Optimization for the Preparation of 12
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
entry
solvent
temp(oC)
Time(h)
Purity (%)
Yield (%)
1.0
Methyl formate
Watera
32
70
12
6
96
51
2.0
3.0
Acetic acidb
60
80
6
3
4.0
5.0
6.0
6.0
Dichloromethanec
benzene
38
80
80
60
8
3
3
3
97.5
97
60
48
65
Cyclohexane
Chloroform
98.5
a 10% reaction completed; therefore, solid not isolated. b 50% reaction completed; therefore, solid
not isolated. c reaction not initiated; therefore, solid is not isolated.
Table 2: Experimental Results of 12 on commercial scale Using Recovered Chloroform
12 purity
(%)
12 yield
(%)
Solvent purity
(%)
Solvent recovery
(%)
entry
1.0
2.0
98.5
98.7
67
66
99.8
99.7
77
80
ACS Paragon Plus Environment

Page 13 of 28
Organic Process Research & Development
1
2
3
4
5
6
3.0
99.8
78
98.5
67
7
8
9
10
11
12
13
14
15
16
Table 3: Experimental Results of 12 on commercial scale Using a Recovered mixture of
Chloroform and hexane (1:4)
12 purity
(%)
12 yield
(%)
Solvent
Solvent recovery
(%)
entry
purity (%)a
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
1.0
2.0
98.5
98.7
67
66
99.7
99.8
77
78
3.0
98.5
67
99.8
77
a Purity of recovered mixture of chloroform and hexane by GC.
Table 4: Experimental Results of 13 on commercial scale Using Recovered Chloroform
13 purity
(%)
13 yield
(%)
Solvent
purity (%)
Solvent recovery
(%)
entry
1.0
99.8
99.7
99.7
76
2.0
3.0
99.8
99.7
99.5
99.5
99.7
99.8
78
80
Table 5: Optimization of N-methyl piperazine mole ratio for condensation of 4-bromomethyl
benzonitrile (8)
N-methyl piperazine Mole
entry
Yield (%)
Purity ( %)
remarks
ratio
1.0
1.2
51.0
96
Yield
is
low
because
of
of
quaternary salt formation
2.0
1.5
49.0
96.9
Yield is low because
quaternary salt formation
ACS Paragon Plus Environment

Organic Process Research & Development
Page 14 of 28
1
2
3
4
5
6
3.0
2.8
94.5
97.4
Yield is high because of
quaternary
salt
Formation
minimization
7
8
9
Table 6: Optimization of mode of addition of N-methyl piperazine (NMP)
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
entry
NMP Mode of addition
Yield (%)
Purity (%)
1.0
2.0
3.0
4.0
Addition of NMP to compound (VIII)
Addition of NMP to compound (VIII)
Addition of Compound(VIII) to NMP
Addition of Compound(VIII) to NMP
82.0
79.0
97.0
97.0
98.5%
98.5%
99.8%
99.7%
Table 7: Hydrolysis of compound (9) with 10% sodium hydroxide solution
entry
Yield (%)
Purity (%)
Residue on ignition (%)
1.0
2.0
3.0
80.0
79.0
80.0
99.0 with 0.18 single impurity
99.2 with 0.17 single impurity
99.3 with 0.18 single impurity
0.7
0.7
0.6
Table 8: Acid hydrolysis of compound (9) with concentrated hydrochloric acid
entry
Yield (%)
Purity (%)
Residue on ignition
Filtration temperature
25ꢀ35oC
1.0
2.0
81.0
79.0
99.12%
99.99%
0.02%
0.01%
40ꢀ45oC
Table 9: Study of cyanamide moles for the condensation of 2-methyl-5-nitroaniline
entry
Cyanamide moles
Yield (%)
Purity (%)
1.0
2.0
3.0
2.0
2.5
3.0
80.0
90.0
98.0
90.0
95.0
98.0
Table 10: Study of mineral acid selection and its mode of addition
entry
Mineral acid
Mode of addition
Yield (%)
Purity (%)
1.0
2.0
3.0
Concd. Nitric acid
One lot
One lot
Lotꢀwise
35.0
87.0
98.0
90.0
98.6
98.8
Concd. Hydrochloric acid
Concd. Hydrochloric acid
ACS Paragon Plus Environment

Page 15 of 28
Organic Process Research & Development
1
2
3
4
5
Table 11: Study of reducing agent for compound (5) reduction
Experimental
entry
Reducing agent
Yield (%)
Purity/Remarks (%)
conditions
6
7
8
9
1.0
Fe powder
acetic acid
Reflux for 4hours
Solid is not
obtained
50% purity with
unconverted starting
material with other
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
2.0
Fe powder
6N HCl
90ꢀ95oC/30 minutes
90ꢀ95oC/2.5hours
77.7
77.5
90% purity with 5%
unconverted starting
material with other
impurities
Fe powder 30% HCl
80% purity with 20%
unconverted starting
material and impurities
3.0
4.0
10% PdꢀC / Ethyl acetate
Solution was not clear
30hours hydrogenation
46.7
Reaction was
incomplete with 20%
starting material and
other impurities.
5.0
6.0
7.0
10% PdꢀC In Ethyl
acetate + DMF
For clear solution
mixture of solvents
taken
Reaction was incomplete
with 10% starting
material and other
impurities.
20hours hydrogenation
Obtained melting
range:106ꢀ115oC
Reported melting range:
140ꢀ142oC
10% PdꢀC DMF
For clear solution
excess DMF taken and
distilled after pdꢀC
filtration
55
Reaction was
incomplete with 10%
starting material and
other impurities.
20hours hydrogenation
Obtained melting
range:106ꢀ115oC
Reported melting range :
140ꢀ142oC
SnCl2/Concd. HCl
Addition at 10oC and
1hour maintenance at
RT
Purity : 99.0
60.0
Obtained melting
range:140ꢀ142oC
Reported melting range :
140ꢀ142oC)
8.0
9.0
Raney nickel/
hydrazine
RT hours
Product not About 50% purity
isolated
with 10% Starting
material and 40%
diazoxy impurity
Raney nickel/Methanol
Hydrogenation for 45
hours
60%
99.5% purity
ACS Paragon Plus Environment

Organic Process Research & Development
Page 16 of 28
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
chemical structure of imatinib base
215x279mm (200 x 200 DPI)
ACS Paragon Plus Environment

Page 17 of 28
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
Reported genotoxic impurities of Imatinib mesylate
215x279mm (200 x 200 DPI)
ACS Paragon Plus Environment

Organic Process Research & Development
Page 18 of 28
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
Structure of impurity 14A
215x279mm (200 x 200 DPI)
ACS Paragon Plus Environment

Page 19 of 28
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
Diazoxy impurity of compound 5 formed in raney nickel/hydrazine reduction
215x279mm (200 x 200 DPI)
ACS Paragon Plus Environment

Organic Process Research & Development
Page 20 of 28
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
Structure of impurity 13A
215x279mm (200 x 200 DPI)
ACS Paragon Plus Environment

Page 21 of 28
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
Nitroso impurity formed in catalytic hydrogenation
215x279mm (200 x 200 DPI)
ACS Paragon Plus Environment

Organic Process Research & Development
Page 22 of 28
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
Zimmermann's route for the preparation of imatinib base
215x279mm (200 x 200 DPI)
ACS Paragon Plus Environment

Page 23 of 28
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
Loiseleur's route for the preparation of imatinib base
215x279mm (200 x 200 DPI)
ACS Paragon Plus Environment

Organic Process Research & Development
Page 24 of 28
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
Amala's/Szczepek's route for the preparation of imatinib base
215x279mm (200 x 200 DPI)
ACS Paragon Plus Environment

Page 25 of 28
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
Lambardino's route for the preparation of 4-(4-methyl piperazinomethyl)benzoic acid dihydrochloride
215x279mm (200 x 200 DPI)
ACS Paragon Plus Environment

Organic Process Research & Development
Page 26 of 28
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
Batchelor's route for the preparation of 4-(4-methyl piperazinomethyl)benzoic acid dihydrochloride
215x279mm (200 x 200 DPI)
ACS Paragon Plus Environment

Page 27 of 28
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
Schematic synthetic procedure for 4-(4-methyl piperazinomethyl)benzoic acid dihydrochloride
215x279mm (200 x 200 DPI)
ACS Paragon Plus Environment

Organic Process Research & Development
Page 28 of 28
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
Schematic synthetic procedure for highly pure imatinib base
215x279mm (200 x 200 DPI)
ACS Paragon Plus Environment