Title:
PROCESS FOR THE PREPARATION OF ANTICANCER DRUG IMATINIB AND NEW ANALOGUES
Background of the Invention and relevant prior art:
The chemical entity N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide methanesulfonate salt, known generically as imatinib mesylate, is a tyrosine kinase inhibitor. It is highly specific for BCR ABL, the enzyme associated with chronic myeloid leukemia and certain forms of acute lymphoblastic leukemia.
WO2004108699 describes the preparation of N-(3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)-4-methylphenyl)-4-(chloromethy) benzamide as a intermediate involves the use of 4-(chloromehthyl)-benzoyl chloride. This reagent, in turn, is synthesized starting with 4-(bromomethyl)-benzoic acid, which is hydrolyzed to 4-(hydroxymethyl)-benzoic acid, followed by conversion to 4-(chloromethyl)-benzoylchloride using thionyl chloride. This sequence of reaction is not only lengthy but also involves use of a corrosive and obnoxious reagent like thionyl chloride.
The prior art synthesis of imatinib in EP0564409 and its equivalent US Patent 5511584 involves the course of reactions as given in scheme-l
2-Amino-4-nitro toluene of formula III is treated with 65% nitric acid to form its nitrate salt, which is condensed with cyanamide solution at reflux temperature for 25 hours to give 2-methyl-5-nitrophenyl guanidine nitrate of formula IV. The product of formula IV is treated with 3-dimethylamino-1-(3-pyridyl)-2-propene-1-one of formula VI in isopropanol and sodium hydroxide to afford the product of formula VII. The product of formula VII in ethyl acetate is hydrogenated with 10% Pd/C at atmospheric pressure to afford N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine of formula VIII. Condensation of the product of formula VIII with the product of formula IX in pyridine for 24 hours resulted in crude product, which is chromatographed over column to obtain imatinib of formula I a.


Scheme -1
While performing the above set of reactions to get imatinib of formula I a of good quality at our research laboratory, we encountered the following difficulties in the process
1) Duration of reaction to produce the product of formula IV is very large (25 hours)
This makes the commercial product time consuming
2) Recovery of the unreacted product of formula III is tedious
3) Use of ether in the commercial scale is not advisable as it is volatile and flammable
4) Hydrogenation of the product of formula IV is carried out using 10% Pd/C making the
process costly and the product, so obtained, is having wide range of melting range
from 170-180°C
5) Use of pyridine in penultimate stage i.e. condensation of the product of formula VIII
and formula IX is not eco-friendly
6) Use of excess of intermediate of formula IX and recovery of intermediate is difficult
as it decomposes

7) Isolation of the product of formula la using column chromatography makes the
process non feasible on commercial basis.
8) Process for the synthesis of the product of formula IX requires five more additional
steps as given in scheme-ll

Scheme-ll
Step I - p-Toluic acid of formula X is esterified with methanol to give the product of formula
XI.
Step II - Bromination of the product of formula XI with N-bromosuccinide affords the product
of
formula XII
Step III - N-Methylpiperazine is reacted with the product of formula XII to yield the compound of
formula XIII
Step IV - Compound of formula XIII is hydrolyzed with aqueous alkali to yield the compound of
formula XIV Step V - Treatment of the compound of formula XIV with thionyl chloride yields the product of
formula IX

Summary of the Invention:
Process for the preparation of imatinib of formula la has been modified by using a new intermediate of formula II. This intermediate has also been used to synthesize new compounds of formula I b to I f. The reactions were conducted keeping in the mind the industrial and echo-friendliness norms. The problems pertaining to safety norms have been minimized. The new compounds have shown significant tyrosine kinase inhibition activity.


Objectives of the present invention
The objective of the present invention is to provide a simple, cost effective and eco-friendly process for the preparation of imatinib base via the new intermediate of formula II.
Another objective of the present invention is to provide a process for the preparation of new intermediate of formula II, which is converted to imatinib base as well as several other analogues.
Yet another objective of the present invention is to provide an improved process for the preparation of the product of formula-ll using products of formulae VIII and IX.
Still another objective of the present invention is to provide simple process for the preparation of new analogues using new intermediate of formula-ll
Yet another objective of the present invention is to provide an economical preparation of imatinib by recovery of compound of formula III.
Still another objective of the present invention is to use proper solvent in step 2 in order to increase the yield of the product of the formula VII and reduce the reaction time.
Yet another objective of the present invention is to reduce the nitro derivative of the formula VII using Raney nickel catalyst which is expected to give better quality product of formula VIII and also to bring economy to the process.
To develop an eco friendly, economical process for the preparation of imatinib base of formula l a, new compounds of formulae I b to If and new compound of formula II, we carried out extensive research work and felt that the approach for modification in the process as given in scheme -1 will be as follows
a) using methanol as solvent in step-l, recovering unreacted product of formula III and
replacing ethanol and diethyl ether with ethyl acetate.
b) using n-butanol in step-ll (scheme-l).
c) using Raney nickel for catalytic hydrogenation in step-Ill (scheme-l).
d) synthesizing the compound of formula XVI (scheme-Ill).
e) synthesizing the new compound of formula II using products of formula VIII and
XVI
f) reducing the number of steps from nine to six.
Our research work on aforesaid points yielded an improved, economical and eco-friendly process for the preparation of imatinib of formulae I a and new analogues of formulae I b to I f. Accordingly the present invention provides an improved process for the preparation of imatinib of formula I a and new analogues of formula I b to I f, which comprises of

a) treatment of 2-amino-4-nitrotoluene of formula III with cyanamide in methanol
containing nitric acid to give a product of formula IV.
b) treatment of the guanidine derivative of formula IV with 3-dimethylamino-1-(3-
pyridyl)-2-propene-1one of formula VI in n-butanol.
c) hydrogenation of the product of formula VII with Raney nickel in methanol to give the
product of formula VIII.
d) reaction of the product of formula VIII, with 4-bromomethyl benzoyl chloride of formula
IX to afford a new intermediate of formula II
e) reaction of the new intermediate of formula II with N-methyl piperazine to give imatinib
base
f) reaction of the new intermediate of formula II with other nucleophiles to give the
products of formulae I b to I f.


Description of the invention:
Considering the shortcomings viz., long durations of reactions, lengthy synthetic protocol, non eco-friendly reagents etc., described for the synthesis of imatinib, the present invention has embarked on a trouble-shooting mission. One of the primary objective is to synthesize imatinib through a new intermediate by which the stages for the synthesis protocol, is reduced. Further objectives are to make the process eco-friendly and economical by using appropriate reagents as well as improving the efficiency of the process.
The preparation of 2-methyl-5-nitrophenyl guanidine nitrate was made more efficient by achieving better yields and improving the recovery of unreacted 2-methyl-5-nitrophenyl guanidine.
The reaction of 2-methyl-5-nitro aniline with cyanamide (50% aqueous) in the presence of nitric acid was studied in alcohols like methanol, ethanol, n-propanol, isopropanol, n-butanol etc., at a temperature of 50-120°C for a duration 10-20 hours. The reaction was preferably conducted in ethanol or methanol. It was more preferably conducted in methanol. The synthesis of guanidine nitrate derivative of formula IV was most preferably carried out in methanol at a temperature of 60-65°C for a duration 12-15 hours.
The product was obtained in about 55-65% yield. This process was made more efficient by recovering unreacted 2-methyl-5-nitro aniline. This was achieved by washing the precipitated guanidine derivative, after isolation, with a suitable solvent, as well as treating the residue obtained from mother liquors with the same type of solvent. The preferred solvents are acetone, acetonitrile, ethylacetate, butylacetate, isopropylacetate, ethanol, methanol, n-propanol, isopropanol etc. It was preferable to use acetone, ethylacetate, isopropyl acetate, methanol etc,. It was more preferable to use solvents like ethyl acetate, isopropyl acetate, methanol etc. A total of about 30-35% of unreacted aniline derivative was recovered and this was pure enough for recycling.
The reaction of guanidine nitrate derivative of formula IV with enaminoketone derivative of formula VI was studied in alkanols like n-propanol, isopropanol, n-butanol, isobutanol, tert. butanol etc., containing bases selected from but not limiting to alkali hydroxides, alkaline earth hydroxides, tetraalkyl ammonium hydroxides etc., at a temperature of 65-120°C for a duration of 4 to 10 hours. It was preferable to conduct the reaction in n-propanol or isopropanol or n-butanol at 80-120°C for a duration of 6-9 hours. These conditions yielded almost quantitative output of pyrimidine derivative of formula VII. The quality of this product was excellent.
The reduction of pyrimidine derivative of formula VII to the corresponding amino derivative of formula VIII was tried with chemical reagents like stannous chloride/HCI and sodium dithionite as well as catalytically using Pd/C or Raney NL It was preferable to adopt catalytic process as the work-up in the chemical method was cumbersome and yields were poor. It was more preferable to perform the hydrogenation using Raney Ni. It was most

preferable to perform the hydrogenation using Raney Ni at a temperature of 25-60°C and 2-4 atmospheres pressure in an alkanol solvents like methanol, ethanol or isopropanol.
One of the important objectives of the present invention is to synthesize imatinib and similar derivatives employing a new intermediate, which will overcome the drawbacks described in the prior art. The synthesis of imatinib, as described in the prior art, is give in scheme-l. This involves use of the product of formula IX, whose synthesis is depicted in scheme II. This not only adds more stages for the synthesis but involves use of corrosive reagents. Apart from that, the conversion of the product of formula XIV to IX does not provide very pure product as this reaction is not homogeneous.
These problems were overcome by adopting sequence of reactions as depicted in scheme - III. The synthesis of the new intermediate of formula - II makes the process for the production of imatinib of formula I a and several other derivatives of formulae I b to I f very easy. The steps involve a) bromination of p-toluic acid to give 4-bromomethyl benzoic acid b) converting 4-bromomethyl benzoic acid to its corresponding acid chloride c) reacting the acid chloride of formula XVI with the pyrimidine derivative of formula VIII to give the new intermediate of formula II. This can be easily converted to imatinib. I a and other derivatives of formulae I b to I f under mild condition.
The conversion of p-toluic acid to 4-bromomethylbenzoic acid was tried with different brominating agents like Br2) NBS, and 1,3-dibromo-5,5-dimethyl hydantoin etc., It was preferable to use NBS as the brominating agent. It was more preferable to perform bromination using NBS in solvents like chloroform, methylene chloride, or dichloroethane in the presence of radical initiators like azobisisobutyronitrile or benzoyl peroxide at 45 to 80° C. 4-Bromomethyl benzoic acid was converted to the corresponding acid chloride using conventional method by reacting with thionyl chloride or oxalyl chloride. The acid chloride of formula XVI was coupled with pyrimidine derivative of formula VIII under very mild conditions. 4-Bromomethyl benzoyl chloride, obtained by the reaction of 4-bromomethyl benzoic acid with thionyl chloride or oxalyl chloride, was used without isolation. This reaction was performed in the solvents like methylene dichloride, chloroform, dichloroethane, ethyl acetate, isopropyl acetate, butyl acetate, acetone or acetonitrile in the presence of a base like triethylamine, diethylisopropyl amine, N-methylmorpholine etc., or inorganic bases like sodium carbonate, potassium carbonate, or cesium carbonate in combination with a phase transfer catalyst like tetra alkyl ammonium halide (TBAB, TBAHS ETC.). The reaction of the products of formulae VIII and XVI was preferably conducted using a mole ratio of 1:1 to 2 at 0 to 30° C for a duration of 6 to 12 hours. The reaction was more preferably conducted using a mole ratio of 1:1.2 of the products of formula VIII and XVI respectively at a temperature of 0 to 30° C for a duration of 8 to 10 hours.

The product of formula II was isolated, purified by conventional methods and characterized.
The product of formula II was reacted with amino derivatives like N-methyl piperazine, S-proline,1,2,3,4-tetrahydroisoquinoline-S-carboxylic acid, isonipecotic acid, 1,2,4-triazole, 2-azabicycio[3.3.0]octane-3-carboxy!ic acid etc., to give products of formulae la to If. This reaction was preferably conducted in solvents like dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone etc., in the presence of bases like sodium carbonate, potassium carbonate, cesium carbonate etc., at 10 to 50° C for a duration of 2 to 6 hours. It was more preferably conducted at a temperature of 20 to 30° C for a duration of 3 to 5 hours. The products were isolated by conventional methods known in the art.
The products I b to I f have been tested for their tyrosine kinase inhibition activity. The preliminary studies have indicated very promising results with some of the compounds showing better activity than imatinib.
Advantages of the present invention :
1. A new intermediate viz., 4-bromomethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-yl
amino)-phenyl] benzamide, which has been synthesized by a short and
economical method, can be converted, not only to imatinib but also to several
other derivatives viz., Ib to I f, showing tyrosine kinase inhibition activity.
2. The reaction duration for different stages have been considerably reduced
compared to durations mentioned in the prior art.
3. Toxic reagent like pyridine is replaced
4. Purification by column chromatography has been eliminated.
5. The process has been modified so as to adhere to eco-friendliness and safety
norms, making this an industrially useful methodology.
The invention is further illustrated by the following examples, which should not be construed
as limiting the scope of the invention
Example-1
Sulphuric acid (650 gms) was cooled to about 0 - 5° C and O-toluidine was added
maintaining a temperature of 0-5° C. Then nitric acid (70%, 80 gm) was added
dropwise to the above solution at 0-5°C. After the addition, the reaction mixture was
stirred at 0 - 5° C for one hour. Subsequently the reaction mass was allowed to

warm up to 25 - 30° C and stirred at that temperature for about 3 hours. The reaction
mass was poured into crushed ice, PH was adjusted to 8 - 9 with 25% ammonia
solution. Separated solid was filtered, washed to neutral PH and later crystallized from
methanol to yield 2-methyl-5-nitroaniline 75%.
Example-2
Nitric acid (70%, 60gms) was added dropwise to a suspension of 2-methyl-5-nitro aniline
(100gms) in methanol (400ml) at 0-5°C. After allowing the temperature to come to 25-30°C,
50% aqueous cyanamide solution (86gms) was added and the reaction mixture was stirred
at reflux for 15 hours. After cooling the reaction mass to 0-5°C, the precipitate was filtered
and washed with methanol/isopropylether/ethylacetate to yield (60%) of 2-methyl-5-nitro
phenyl guanidine nitrate, m.p. 215-220°C
The unreacted 2-methyl- 5- nitroaniline was recovered by concentration of a) mother liquor
obtained from islation of crude 2- methyl-5-nitrophenylguanidine nitrate and b) washings the
crude product of formula IV with ethyl acetate. The recovery was about 35%.
Example-3
A suspension of 2-methyl-5-nitro phenylguanidine nitrate (100gms), 2-dimethylamino-1-(3-
pyridyl)-2-proane-1-one (70gms), n-butanol (600ml) and sodium hydroxide (17gms) was
stirred at reflux for 8 hours. The mass was cooled to 25-30 °C , isopropyl alcohol was
added and cooled to 10-15°C. The solid mass separated was filtered to yield 112gms (93%)
of N-(5-nitro-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine, m.p 194-199°C .
Example-4
To a slurry of N-(5-nitro-2-methylphenyl)-4"(3-pyridyl)"2"pyrimidine amine (100gms) in
methanol (1000ml) was added Raney-nickel (15gms) and stirred under hydrogen atmosphere
for 4 hours. On completion of hydrogen take up , the reaction was processed, the catalyst
was filtered and the filtrate concentrated under vacuum to give 81gms (90%) of N-(5-amino-2-
methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine, m.p. 142-45°C
Example-5
A mixture of para toluic acid (100gms), N-bromo succinimide (135gms) and benzoyi
peroxide 2.0gms in chloroform (1000ml) was heated to reflux for 3-4 hours. The solid,
separated, was filtered and dissolved in ethyl acetate. Ethyl acetate solution was washed with
water, dried over sodium sulphate and solvent removed under vacuum to yield 139gms(88%)
of 4-bromomethyl benzoic acid, m.p.-227-30°c.
Example-6
A mixture of 4-bromethyl benzoic acid (100gms), oxalyl chloride (35gm) and dimethylformamide (10ml) in toluene (1000ml) was stirred at room temperature for 3 hours. Excess of solvent distilled off under vacuum to yield 98.5gms (91%) 4-(bromomethyl)-benzoyl chloride, which was used immediately for next stage

Example-7
To a stirred solution of N-(5-amino-2-methylphenyl)-4-(3--pyridyl)-2-pyrimidineamine (100gms) in chloroform (1500ml) and triethylamine (125ml) was added 4-(bromomethyl)- benzoyl chloride (80gms) in chloroform (150ml) slowly at 0-5 °C during 2 hours. Temperature of the mass was slowly raised to 25-30 °C and maintained for 10 hours. The precipitated solid was filtered, washed with chloroform and water to yield 137gms (80%) of 4-bromomethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide, m.p 299-301°C and proton NMR is as follows

Example-8
To a mixture of N-methylpiperazine (21gms) and potassium carbonate(58gms) in dimethylformamide (300ml) was added 4-bromomethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (100gms) and stirred at 25-30°c for 4 hours. This reaction mixture was diluted with water (1000ml) and extracted with chloroform. The organic layer was washed with water and dried over sodium sulphate and solvent was distilled off. The residue was added with ethyl acetate to yield 90gms (86%) of 4-(4-Methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (imatinib) m.p. 205-07°C. Example -9
A mixture of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (8gms) potassium carbonate (12gms) and 4-bromomethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (20gms) was stirred at 30-35° C. On completion of (T.L.C monitor) the reaction, the mixture was diluted with water and the pH was adjusted to 7 with acetic acid. The reaction mass was extracted with chloroform and worked up to give 2-{4-[4-Methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenylcarbamoyl]-benzyl}-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic
acid 18gms (75%), m.p. 177-80°C
Example-10
A mixture of isonipecotic acid (5.4gms), 4-bromomethyl-N-[4-methyl-3-(4-pyridin-3-yl-
pyrimidin-2-ylamino)-phenyl]-benzamide (20gms) and potassium carbonate (12gms) in
dimethyl formamide was stirred at 25-30°c for 4 hours. The reaction mass was diluted with
water and the pH of the solution was adjusted to 7 with acetic acid. It was worked up (as

given in example 9) to give 16gms of 1-{4-[4-methyl-3-(4-pyriclin-3-yl-pyrimidin-2-ylamino)-phenylcarbamoyl]-benzyl}-piperidine-4-carboxylicacid, m.p. 114-118°C . Example-11
A solution of 1,2,4-triazole (4.0gms), 4-bromomethyl»N-[4-methyl-3-(4-pyridin-3-yl-pyrirniclin-2-
ylamino)-phenyl]-benzamide (20gms) and potassium carbonate (11gms) in
dimethylformamide was stirred at 25-30°c for 4 hours. The reaction mass was worked up (as
given in example 8) to give N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-4-
[1,2,4]triazol-1-yimethyl-benzamide 17gms (87%), m.p. 198-202°C
Example-12
A mixture of 4-bromomethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-yiamino)-phenyl]-
benzamide (20gms), octahydro-cyclopenta[b]pyrrole-2-carboxylic acid (5.6gms) and
potassium carbonate (11gms) in dimethyl formamide was stirred at 25-30°c. The reaction
mass was worked up (as given in example
10) to give 2-{4-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenylcarbamoyl]-benzyl}-
octahydro-cyclopenta [c]pyrrole-1-carboxylic acid 17.5gms (76%), m.p. 152-55°C
Example-13
A mixture of L-proline (5gms), 4-bromomethyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-
ylamino)-phenyl]-benzamide (20gms) and potassium carbonate (11gms) in
dimethylformamide was stirred at 25-30° C for 3-4 hours. The reaction mixture was diluted
with water, pH adjusted to 7 with acetic acid and was worked up (as given in example 10) to
give 1-{4-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenylcarbamoyl]-benzyl}-
pyrrolidine-2-carboxylic acid 15gms (65%), m.p. 197-204°C

brominating p-toluic acid
b) chlorinating 4-bromomethyl benzoic acid
4. A process, as claimed in claim 3, wherein bromination of p-toluic acid is carried
out with N-bromosuccinimide or 1,3-dibromo-5,5-dimethyl hydrantoin or n-
bromophthalimide in a chlorocarbon solvent like chloroform or dichloroethane at
60°C to 80°C for 3 to 6 hours
5. A process, as claimed in claim 3, wherein the conversion of 4-bromomethyl
benzoic acid to 4-bromomethyl benzoyl chloride is effected by treatment with
thionyl chloride or oxalyl chloride or phosphorouspentachloride or
phosphorousoxychloride at 20°C to 100°C for a duration of 3 to 5 hours.
6. A process, as claimed in claim 1, wherein the product of formula-l is prepared by
treatment of the product formula-II with the appropriate amino compound in
solvents like dimethylformamide, dimethylacetamide, N-methyl pyrrolidine-2-one,
dimethylsulfoxide, sulfone, 1,2-dimethoxyethane, monoglyme, diglymeetc. using
diisiopropyl ethylamine, N-methylmorpholine, etc or anhydrous potassium
carbonate, sodium carbonate, calcium carbonate etc at 20 °C to 100 °C for 4 to
8 hours
7. A process, as claimed in claim 1, wherein the product of formula-l have shown
promising tyrosine kinase inhibition activity in the preliminary tests.