Research and development of a novel process for nilotinib: A Bcr-Abl inhibitor

Article abstract of DOI:10.14233/ajchem.2013.14247

In this study, an efficient, economic and novel process for the production of highly pure nilotinib (1), a Bcr-Abl inhibitor in described. The synthesis comprises the chlorination of 4-methyl-3-nitro benzoic acid (2) to get 4-methyl-3-nitro benzoyl chloride (2A). Condensation of compound (2) with 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzeneamine (11) to obtain 4-methyl-N-[3-(4-methyl-1Himidazol- 1-yl-5-(trifluoromethyl)phenyl]-3-nitro- benzamide hydrochloride (3). Reducing compound (3) with stannous chloride (or) raney nickel to obtain 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl-5- (trifluoromethyl)phenyl]-3-amino-benzamide (4). Reaction of compound (4) with cyanamide to obtain 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl-5-(trifluoromethyl) phenyl]-3-guanidino-benzamide (5). Condensation of the compound (5) with 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (8) to obtain nilotinib (1).

Full text of DOI:10.14233/ajchem.2013.14247

Asian Journal of Chemistry; Vol. 25, No. 8 (2013), 4599-4602
http://dx.doi.org/10.14233/ajchem.2013.14247
Research and Development of a Novel Process for Nilotinib: A Bcr-Abl Inhibitor
1,*
1
1
2
K. AMALA , A.K.S. BHUJANGA RAO , R. SREENIVAS and P.K. DUBEY
1Natco Research Centre, B-13, Industrial Estate, Sanath Nagar, Hyderabad, India
2Department of Chemistry, JNTU College of Engineering, kukatpally, Hyderabad, India
*Corresponding author: Fax: +91 40 23710578; Tel: +91 40 23710575; E-mail: amala@natcopharma.co.in
(Received: 30 June 2012; Accepted: 18 February 2013)
AJC-13021
In this study, an efficient, economic and novel process for the production of highly pure nilotinib (1), a Bcr-Abl inhibitor in described. The
synthesis comprises the chlorination of 4-methyl-3-nitro benzoic acid (2) to get 4-methyl-3-nitro benzoyl chloride (2A). Condensation
of compound (2) with 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzeneamine (11) to obtain 4-methyl-N-[3-(4-methyl-1H-
imidazol-1-yl-5-(trifluoromethyl)phenyl]-3-nitro-benzamide hydrochloride (3). Reducing compound (3) with stannous chloride (or) raney
nickel to obtain 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl-5-(trifluoromethyl)phenyl]-3-amino-benzamide (4). Reaction of compound
(4) with cyanamide to obtain 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl-5-(trifluoromethyl)phenyl]-3-guanidino-benzamide (5).
Condensation of the compound (5) with 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (8) to obtain nilotinib (1).
Key Words: Bcr-Abl inhibitor, Chlorination.
after recrystallization with diethyl ether. It was observed that
the yield of compound (9) is low (35 %) taking long time for
completion of reaction (65 h) making the process unviable and
the reaction time is very lengthy, which could be problematic
for commercial scale operation. Further use of diethyl ether is
not adaptable on commercial scale of its high flammable and
volatility. Hydrolysis of compound 9 with aqueous ethanol
yielded 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinylamino]-
benzoic acid (10) after treatment with diethyl ether. Compound
10 on condensation with 5-(4-methyl-1H-imidazol-1-yl)-3-
(trifluoromethyl)-benzeneamine (11) in presence of diethyl-
cyanophosphonate in N,N-dimethylformamide at 60 ºC (12
h) yielded nilotinib base. The whole process is reported for
milligram scale and it involves very expensive and toxic
reagent diethylcyanophosphate.
Another synthetic approach (Fig. 2) reported4 involves
the condensation of methyl ester of 4-methyl-3-[[4-(3-
pyridinyl)-2-pyrimidinylamino]-benzoic acid (12) with 5-(4-
methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzeneamine
(11) in presence of potassium tert-butoxide base and THF
solvent at -20 ºC to -10 ºC. Work-up involves adding sodium
chloride solution to THF, extraction with isopropyl acetate,
separation and washing of isopropyl acetate with 15 % aqueous
sodium chloride solution and distillation of isopropyl acetate
affording nilotinib base after recrystallization with isopropyl
acetate, ethanol and water mixture at -15 ºC to -10 ºC. This
process involves multiple solvents like THF, isopropyl acetate
INTRODUCTION
Nilotinib hydrochloride, (4-methyl-N[3-(4-methyl-1H-
imidazol-1-yl-5-(trifluoromethyl)phenyl]-3-{{4-(3-pyridinyl)-
2-pyrimidinyl]amino]benzamide hydrochloride), a protein
tyrosine inhibitor1,2 is the orally active drug developed by
Novartis, approved in October 2007 by United States Food
and Administration as Tasigna (150 mg) for the treatment of
chronic phase (CP) and accelerated phase (AP) Philadelphia
chromosome positive (Ph+) chronic myelogenous leukemia
(CML) in adult patients resistant or intolerant to prior therapy
that included imatinib. On June 2010 the US Food and Drug
Administration (FDA) granted accelerated approval to nilotinib
hydrochloride monohydrate (Tasigna®) Capsules for the treat-
ment of adult patients with newly diagnosed Philadelphia
chromosome positive chronic myeloid leukemia (Ph+ CML)
in chronic phase (CP-CML). The recommended nilotinib dose
for this indication is 300 mg orally twice daily. The first
synthetic approach (Fig. 1) reported3 for nilotinib (1) involved
in the condensation of 3-amino-4-methyl benzoic acid ethyl
ester (6) with cyanamide followed by treatment with ammo-
nium nitrate to provide 3-[(aminoiminomethyl)amino]-4-
methylbenzoic acid ethyl ester mononitrate (7) (Fig. 1). In
our hands it was observed that the yield of compound (7) is
very low (25-30 %) with low purity (90 %). The condensation
of 7 with 3-dimethylamino)-1-(3-pyridinyl)-2-propen-1-one
(8) in refluxing ethanol for 68 h yielded 4-methyl-3-[[4-(3-
pyridyl)-2-pyrimidinyl]amino]-benzoic acid ethyl ester (9)

4600 Amala et al.
Asian J. Chem.
CH3
NH
CH3
NH2
STEP-1
HCl
EXPERIMENTAL
.HNO3
NH
i
NH2
NH2CN
+
ii.ammonium
nitrate
Melting points were determined on mettler melting point
apparatus, in open capillary tubes and are uncorrected. The
1H NMR (400 MHz) and 13C NMR (400 MHz) spectra were
recorded on a Bruker avance-III 400MHz NMR spectrometer.
Chemical shifts were reported in parts per million (ppm) using
tetramethylsilane as an internal standard and are given in δ
units. The solvent used for NMR spectra is deutero dimethyl
sulfoxide unless otherwise stated. Infrared spectra were taken
on Brucker in potassium bromide pellets unless otherwise
stated. High-resolution 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 60 F254 (Merck) plates using UV light (254 and 366 nm).
The gas chromatography onAgilent Technologies 6890B with
head space was used for analyzing the residual solvents. Common
reagent grade commercially available chemicals were used
without further purification.
cyanamide
(7)
COOC2H5
STEP-2
COOC2H5
(6)
O
N(CH3)2
(8)
N
CH3
CH3
N
N
N
N
NH
NH
STEP-3
NaOH
COOC2H5
COOH
N
N
(10)
(9)
CF3
STEP-4
N
NH2
N
(11)
H3C
CH3
N
NH
N
Process for the preparation of nilotinib (1)
C=O
NH
N
Preparation of 4-methyl-N-[3-(4-methyl-1H-imidazol-
1-yl-5-(trifluoromethyl)phenyl]-3-nitro-benzamide hydro-
chloride (3): To a suspension of 100 g (0.55 mol) of 4-methyl-
3-nitro benzoic acid (2A) in chloroform (1 L) thionyl chloride
131.5 g (1.10 mol) and dimethyl formamide (1 mL) were
added. The reaction mass was heated to reflux temperature
and maintained at the same temperature for 3 h. Solvent chloro-
form was distilled off completely under vacuum and again
500 mL of chloroform was charged and distilled under vacuum
to remove traces of thionyl chloride. The residual 4-methyl-3-
nitro benzoyl chloride (2) was taken directly to the following
condensation step. 5-(4-Methyl-1H-imidazol-1-yl)-3-(trifluoro-
methyl)-benzeneamine (11) 110 g (0.45 mol) was dissolved
in 1 L of chloroform. 4-Methyl-3-nitro benzoyl chloride pre-
pared above was added slowly to the reaction mass at 10-15
ºC for 1 h. The temperature of the reaction mass was raised to
room temperature and maintained for 4 h. The reaction mass
was filtered, washed with chloroform and dried. Yield: 161 g
(87 %). Purity: 99 % (by HPLC). 1H NMR DMSO-d6. Imidazole-
CH3 (3H, 2.18, s) Ar-CH3(3H, 2.61,s), imidazole -CH (1H,
7.48-S), imidazole-CH-(1H, 7.71, m),Ar-H (6H, 7.71-8.628, m),
Ar-amide (1H, 10.8, s). IR was consistent with the proposed
structure.
(1)
CF3
N
CH3
N
Fig. 1. Preparation of nilotinib (Ref. 3)
CH3
N
N
CH3
NH
+
N
NH2
H3C
CH3
N
N
O
O
(11)
(12)
CH3
N
N
NH
C=O
NH
N
(1)
CF3
N
CH3
N
Preparation of 4-methyl-N-[3-(4-methyl-1H-imidazol-
1-yl-5-(trifluoromethyl)phenyl]-3-amino-benzamide (4): To
a chilled solution (10-15 ºC) of stannous chloride 265.6 g (1.18
mol) in 400 mL methanol. 4-Methyl-N-[3-(4-methyl-1H-
imidazol-1-yl-5-(trifluoromethyl)phenyl]-3-nitro-benzamide
hydrochloride (3) 130 g (0.29 mol) obtained from step- (a)
was added during 0.5 h. The reaction mass was maintained at
10-15 ºC for 1 h and heated to reflux temperature and then
brought to room temperature. Purified water (600 mL) was
charged to reaction mass at room temperature and maintained
under stirring for 6-8 h. Reaction mass was filtered, washed
with 1 N HCl. The wet solid was charged into 2 L purified
water, cooled to 10-15 ºC and basified with 4 % aqueous
sodium hydroxide solution. The reaction mass was brought to
room temperature and maintained at the same temperature for
Fig. 2. Synthetic approach of nilotinib (Ref. 4)
and ethanol. Further all these solvents cannot be recovered
and recycled as used as mixed solvents with water thus posing
environmental problems. Subsequently, another reported
process5 follows a reaction sequence similar to that represented
in Fig. 2 involving condensation of the acid chloride of
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinylamino]-benzoic
acid (12) with 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoro-
methyl)benzeneamine (11). This process results in unaccepted
amounts of impurities. Herein, we are reporting an improved,
efficient and environment friendly process for nilotinib (1),
which provides multiple benefits such as safety and increased
throughput with economic advantage over the reported
processes.

Vol. 25, No. 8 (2013)
Research and Development of a Novel Process for Nilotinib: A Bcr-Abl Inhibitor 4601
CH3
2 h, filtered and dried at 50-60 ºC to yield compound (4).Yield:
104 g (80 %). Purity: 99.4 % (by HPLC).
NO2
CH3
CH3
CHCl3
SOCl2
CHCl3
NH2
NO2
NO2
Alternatively compound (4) can be prepared by the
catalytic hydrogenation of compound (3) with raney nickel in
methanol medium as follows: In a hydrogenation kettle 50 g
(0.123 mol) of 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl-5-
(trifluoromethyl)phenyl]-3-nitro-benzamide hydrochloride (3)
obtained from step- (a) was charged into 250 mL methanol.
Raney nickel (20 g) was charged into pressure reactor kettle
and hydrogenated at a hydrogen gas pressure of 60 psi for
22 h. After reaction completion reaction mass was filtered and
washed with methanol. To the filtrate aqueous ammonia solution
(45 mL) was charged and stirred for 0.5 h. Reaction mass was
filtered, washed thoroughly with purified water and dried at
50-60 ºC to yield compound (4). Yield: 35 g (70 %). Purity:
.HCl
C=O
NH
(3)
C=O
C=O
HO
Cl
CF3
N
CH3
(11)
(2)
(2A)
N
(
(
2
2
A
)
)
CF3
N
CH3
N
SnCl
Raney nickel/
Methanol
2
base
CH3
N
N
CH3
NH
CH3
NH2
NMe2
H
N
NH
O
NH2
(8)
C=O
NH
N
N
NH CN
/Concd. HCl
C=O
NH
2
C=O
NH
/base
n-butanol
n-butanol
CF3
N
CH3
CF3
N
CH3
CF3
N
1
CH3
N
99.0 % (by HPLC), MR: 210-212 ºC, H NMR DMSO-d6,
N
N
(4)
(5)
(1)
Ar-CH3(3H , 2.13, s), imidazole-CH3 (3H, 2.18, s),Ar-NH2(2H,
5.14,s), imidazole -CH (1H, 7.104, s), imidazole-CH (1H, 7.11,
m), Ar-H (6H, 7.11-8.29, m) Ar-amide-(1H, 10.46, s), IR was
consistent with the proposed structure.
Fig. 3. Synthetic route of nilotinib
(trifluoromethyl)-benzeneamine (11) is prepared as per the
literature procedure6.
Preparation of 4-methyl-N-[3-(4-methyl-1H-imidazol-
1-yl-5-(trifluoromethyl)phenyl]-3-guanidino-benzamide
(5): To a suspension of 80 g (0.213 mol) of 4-methyl-N-[3-(4-
methyl-1H-imidazol-1-yl-5-(trifluoromethyl)phenyl]-3-
amino-benzamide (4) obtained from step-(b) in 480 mL
n-butanol 20.2 mL of concentrated hydrochloric acid was
added. A solution of 18 g (0.427 mol) of cyanamide in 18 mL
water was added and reaction mass was heated to 90-95 ºC
for 20 h while maintaining pH at 2-3 with concentrated
hydrochloric acid (22 mL). The reaction mass was cooled to
10-15 ºC, filtered and washed with chilled n-butanol. Wet solid
was charged into 1.5 L purified water and, basified with 40 %
aqueous sodium hydroxide solution. The reaction mass was
maintained at room temperature for 2 h, filtered, washed with
water and dried at 60-65 ºC to yield compound (5). Yield:
86.3 g (97 %), purity: 99.1 %, 1H NMR DMSO-d6, imidazole-
CH3 (3H, 2.14, s), Ar-CH3(3H, 2.18, s), Ar-NH-(4H, 3.789, s)
imidazole-CH(1H, 7.24, s), imidazole-CH-(1H, 7.26, m),
Ar-H-(6H, 7.26-8.13, m) Ar-amide-(1H, 10.46, s). IR was
consistent with the proposed structure.
Step-1 consists of chlorination of 4-methyl-3-nitro
benzoic acid (2) to get 4-methyl-3-nitro benzoyl chloride (2A).
Condensation of compound (2A) with 5-(4-methyl-1H-
imidazol-1-yl)-3-(trifluoromethyl)-benzeneamine (11) to
obtain 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl-5-(trifluoro-
methyl)phenyl]-3-nitro-benzamide hydrochloride (3). Step-1
condensation has been attempted with solvents such as DMF,
chloroform and isopropanol using different inorganic bases
such as sodium hydroxide, potassium hydroxide and sodium
carbonate.Among these combination, it was found that chloro-
form using potassium hydroxide base at 30-40 ºC provided
the intermediate 3 with quantitative yield and high purity
(99 %).
Step-2 consists of reducing compound (3) with stannous
chloride (or) raney nickel to obtain 4-methyl-N-[3-(4-methyl-
1H-imidazol-1-yl-5-(trifluoromethyl)phenyl]-3-amino-
benzamide (4). The reduction has been attempted using
different reducing agent such as stannous chloride/cond. HCl,
stannous chloride/methanol, Pd-C and raney nickel. Among
these reducing agents stannous chloride/methanol and raney
nickel in methanol medium gave the intermediate 4 with
quantitative yield and high purity (99 %).
Preparation of nilotinib (1): A mixture of 65 g (0.156
mol) of 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl-5-
(trifluoromethyl)phenyl]-3-guanidino-benzamide from step-
(c), 30.0 g (0.171 mol) of 3-dimethylamino-1-(3-pyridyl)-2-
propen-1-one (8) in 650 mL n-butanol was heated at 110-115
ºC for 9 h. The reaction mass was brought to room temperature
and the separated solid (70 g) was filtered off. Wet solid was
leached with hot water (700 mL) and hot methanol (700 mL)
successively. The wet product was dried at 60-65 ºC under
vacuum to yield Nilotinib (1).Yield: 52.1 g (63 %), MR: 235-
Step-3 consists of reaction of compound (4) with cyana-
mide to obtain 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl-5-
(trifluoromethyl)phenyl]-3-guanidino-benzamide (5). This
condensation has been attempted in presence of molar quanti-
ties of acids such as concentrated sulfuric acid, concentrated
hydrochloric acid and concentrated nitric acid employing ethanol,
isopropyl alcohol and n-butanol as solvents. Among these
combinations it was found that using concentrated hydrochloric
acid lot wise in n-butanol solvent at 90-95 ºC yielded interme-
diate 5 with quantitative yield and high purity (99 %).
Step-4 consists of condensation of the compound (5) with
3-dimethylamino-1-(3-pyridyl)-2-propen-1-one (8) to obtain
Nilotinib (1). The condensation has been attempted in solvents
such as ethanol, isopropanol and n-butanol. Among these
solvents n-butanol solvent at 110-115 ºC for 9 h gave nilotinib
(1) with quantitative yield and 99.2 % HPLC purity.
1
236 ºC, Purity: 99.2 % (by HPLC), H NMR DMSO-d6,
Ar-CH3(3H , 2.18, s) imidazole-CH3 (3H, 2.36, s)Ar-NH (1H,
9.17, s) Ar-H (14, 7.44-9.28, m) Ar-amide (1H, 10.61, s). IR
was consistent with the proposed structure.
RESULTS AND DISCUSSION
Preparation of nilotinib (1) (Fig. 3): Critical and cost
contributing intermediate 5-(4-methyl-1H-imidazol-1-yl)-3-

4602 Amala et al.
Asian J. Chem.
Conclusion
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ACKNOWLEDGEMENTS
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The authors thank the Management of Natco Pharma
Limited for encouragement and support. The technical help
from the Analytical department is gratefully acknowledged.