WO2004108699A1 - Process for the preparation of the anti-cancer drug imatinib and its analogues - Google Patents

Process for the preparation of the anti-cancer drug imatinib and its analogues Download PDF

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WO2004108699A1
WO2004108699A1 PCT/IN2003/000211 IN0300211W WO2004108699A1 WO 2004108699 A1 WO2004108699 A1 WO 2004108699A1 IN 0300211 W IN0300211 W IN 0300211W WO 2004108699 A1 WO2004108699 A1 WO 2004108699A1
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PCT/IN2003/000211
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Amala Kompella
Adibhatla Kali Sathya Bhujanga Rao
Nannapaneni Venkaiah Chowdary
Rachakonda Srinivas
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Natco Pharma Limited
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Abstract

The present invention discloses a process of the manufacture of imatinib of formula (Ia) and its new analogues I (b-d) through the intermediate of formula (II). The mesylate (methane sulfonate ) salt of imatinib base (Ia[(4-(4-methylpiperazin-1-ylmethyl)-N4 [methyl-3-(4-pyridin-3-yl)pyrimidn-2-yl amino)phenyl]benzamide])is a popular life -saving drug to treat chronic myelogenous leukemia (CML).

Description

PROCESS FOR THE PREPARATION OF THE ANTI-CANCER DRUG IMATINIB AND ITS ANALOGUES

The present invention relates to an improved process for the preparation of mesylate (methane sulfonate )salt of imatinib base and its analogues.Mesylate(methane sulfonate ) salt of imatinib base [(4-(4-methylpiperazin-l-ylmethyl)-N-4-[methyl-3-(4-pyridin-3-yl) pyrimidin-2-yl amino) phenyl]benzamide] is a protein tyrosine kinase inhibitor and has the formula (Ia).The new analogues prepared by the process of the present invention are potential protein tyrosine kinase inhibitors and have the formulae (lb) to (Id)

Figure imgf000003_0001
This drug is indicated for the treatment of adult patients with Philadelphia chromosome positive Chronic Myeloid Leukemia (CML) in chronic phase (or) in accelerated phase (or) blast crisis after failure of interferon-alpha therapy. It has also been approved by the FDA to treat Gastro Intestinal Stomal Tumours (GIST)

The preparation of [(4-(4-methylpiperazin-l-ylmethyl)-N-4-[methyl-3-(4-pyridin-3-yl) pyrimidin-2-yl amino)phenyl]benzamide (Imatinib) of formula (la) and the use thereof especially as an antitumour agent is described in EP patent No. 0564 409, (Ger., Assignee : Ciba-Geigy corp.) which was published on 6th October 1993 and in US patent no 55211584 (Assignee : Ciba-Geigy corp; Title : Pyrimidine derivatives and process for the preparation there of ) which was published on 28th May 1996 and in equivalent applications in other countries. [ AU-3569493A (1993); CA-2093203A (1993) etc.]

In EP Patent No. 0564409 and in its equivalent US patent no 55211584 the following route is described .

Figure imgf000005_0001

SCHEME-1 Step-1 : 2-amino-4-nitro toluene of the formula (III) in absolute ethanol is treated with 65% nitric acid to form the nitrate salt followed by condensation with cyanamide solution at reflux temperature for 25 hours. After cooling to 0°C, filtration and washing with 1:1 ethanol : diethylether yielded 2-methyl-5-nitrophenyl guanidine nitrate of the formula (IV).

Step-2 : 2-methyl-5-nitrophenyl guanidine of the formula (IV) obtained in step 1 is taken in isopropanol and treated with 3-dimethylamino-l-(3-pyridyl)-2-propen-l-one of the formula (V) and sodium hydroxide and refluxed for 12 hours. After cooling to 0°C, filtration and washing with isopropanol and methanol yielded N-(2-methyl-5- nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine of the formula (VI)

Step-3 : A suspension of N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine of the formula (VI) obtained in step 2 is taken in ethyl acetate and hydrogenated with 10% Pd-C at normal pressure. The resulting suspension is filtered and the filtrate is concentrated under vacuum to yield a crude product which is recrystallized from methylene chloride to yield N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of the formula (VII).

Step-4 : A solution of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of the formula (Vϋ) obtained in step 3 and 4-(4-methyl-piperazinomethyι)benzoyl chloride of the formula (VIII) taken in pyridine are stirred under nitrogen at room temperature for 23 hours. The resulting reaction mixture is concentrated under high vacuum; water is added and the mixture is filtered. After drying at 80°C under high vacuum, the crude product is made into slurry with methylene chloride & methanol and filtered to yield Imatinib of the formula (la). After separation by chromatography, further amounts of the product was obtained.

When we carried out the above process in our laboratory as per the details provided in the above said patent we observed the following difficulties in carrying out the process.. 1. In step 1 (i) The yield of compound of formula (IV) is very low (20-25%) (ii) Process for the recovery of the starting material of the formula (III) is not given. Without recovery and reuse of compound of the formula (HI), the effective yield of compound of formula (IV) will be less (iii)The Reaction time is very lengthy that is 25 hours, which could be problematic for commercial scale production

(iv)Use of diethylether is not possible on commercial scale production because it is highly flammable and very volatile

2. In step (2) The yield of compound of formula (VI) is low (50%) making the process non economical

3. In step (3)

Required product of formula-(VII) is not formed. High melting compound (170- 180°C) with different infrared spectrum is obtained 4. In step (4) i) Yield of compound of formula (la) employing the intermediate of formula (VIII) is very low (10-20%) thereby making the process uneconomical for commercial production ii) Column chromatography is necessary to isolate product of formula (la) in pure form and Column chromatography technique becomes unpractical on commercial scale. iii) Usage of the obnoxious and foul smelling chemical pyridine as a solvent and its distillation for work-up makes this process to be abandoned on bulk scale, iv) Preparation of formula (VIII) is not disclosed. However it can be prepared by literature methods in five steps as given in scheme 2 v) Preparation of compound of formula (VIII) adds five more steps to the process making the overall synthesis lengthy comprising of nine steps. The known intermediate of formula (VIII) is prepared by conventional methods and is outlined below

Figure imgf000008_0001

COOH COOMe (IX) (X)

STEP-2

Figure imgf000008_0002

(XII) (XI)

STEP-4

Figure imgf000008_0003
(XIII) (VIII)

SCHEME-2

Step-1; P-Toluic acid of the formula (IX) on esterification with methanol yields compound of the formula (X ) Step-2: Compound of the formula (X) on bromination with N-bromo succinimide yields compound of the formula (XI )

Step-3: Compound of the formula(XI) on reaction with N-methyl piperazine yields compound of the formula (XII)

Step-4: Compound of the formula (XII) on hydrolysis with aqueous potassium hydroxide yields compound of the formula (XIII)

Step-5: Compound of the formula (XIII) on chlorination with thionyl chloride yields compound of the formula (VIII)

Summary of invention :

Keeping in view of the difficulties in commercialization of the processes for the preparation of imatinib base and its new analogues disclosed in the above mentioned prior a art patents and considering the importance of these drugs for the society, we aimed our research work towards developing an industrially feasible and cost effective process for the preparation of Imatinib of the formula (la) and its new analogues of the formula (lb) to (Id ).

Objectives of the present invention

The main objective of the present invention is to provide an improved process for the preparation of imatinib base overcoming the difficulties of the hither to known processes.

Another objective of the present invention is to provide a process for the preparation of new analogues of imatinib base Another objective of the present invention is to provide an improved process for the preparation of imatinib base and its new analogues using n-butanol as solvent in the step (1) and recovery of unconverted compound of the formula (III) at the end of the reaction thereby enhancing the effective yield of compound of the formula IV( Refer to Scheme- 1 shown above )

Still another objective of the present invention is to provide an improved process for the preparation of imatinib base and its new analogues wherein n-butanol is used as the solvent in step -2 ( Refer to Scheme- 1 )

Another objective of the present invention is to provide an improved process for the preparation of imatinib base and its new analogues wherein ethanol is substituted with methanol, diethyl ether with isopropyl ether in step -1 ( Refer to Shown in Scheme- 1 ) thereby avoiding these very flammable and volatile solvents.

Still another objective of the present invention is to provide an improved process for the preparation of imatinib base and its new analogues wherein stannous chloride dihydrate HC1 is used in step -3 ( Refer to Scheme- 1 ) to carry out reduction of the nitro group thereby obtaining compound of formula (VII)

Still another objective of the present invention is to provide an improved process for the preparation of imatinib base and its new analogues involving the novel intermediate of the formula -(II) (Scheme-3) thereby reducing number of steps.

Yet another objective of the present invention is to provide an improved process for the preparation of novel intermediate of the formula (II) using compound of the formula (XVI) (Scheme-3)

Still another objective of the present invention is to provide an improved process for the preparation of imatinib base and its new analogues which is simple, economical, convenient and useful for industrial production. Yet another objective of the present invention is to provide an improved process for the preparation of imatinib base and its new analogues overcoming the difficulties of the hither to known processes

Accordingly, due to our sustained research work to develop an industrially feasible and economical process for the preparation of Imatinib of formula (la) and its new analogues of the formula (lb) to (Id) , we observed that a promising approach for developing such a process based on the process shown in Scheme 1, would be as follows :

a) Using n-butanol as solvent in step (1) (scheme- 1) recovering the unconverted compound of the formula (III) at the end of the reaction, substituting ethanol with methanol, diethyl ether with isopropyl ether b) Using n-butanol as solvent in step (2) (scheme- 1) c) Using stannous chloride dihydrate HC1 in step (3) (scheme- 1) d) Preparing the compound of the formula (XVI) (scheme-3) e) Preparing the novel compound of the formula (II) (scheme-3) using the compound of the formula (XVI)

Figure imgf000011_0001
f) Reducing the number of steps to seven from nine (from scheme- 1 to the current scheme-3 )

Accordingly, we focused our research on the above mentioned directions and were successful in developing an improved , economical , safe process for the preparation of Imatinib of the formula (la) and its new analogues of the formula (lb) to (Id) Accordingly, the present invention provides an improved process for the preparation of imatinib (la) and its new analogues of the formulae (I b) to (Id) which comprises

Figure imgf000012_0001

(I) Treating 2-amino-4-nitro toluene of the formula (III) in n-butanol with cone, nitric acid in the temperature range 90-95°C during 8to 14 hours to form the nitrate salt of the compound of the formula (III)

(ii) Condensing the resulting compound of the formula III with cyanamide (NH2CN) solution at a temperature in the range of 80 to 116 °C ,

(iii) Cooling the reaction mixture of step (ii) to 0°C ,filtering and washing with methanol, diethyl ether to yield 2-methyl-5-nitrophenyl guanidine nitrate of the formula (IV) iv) Treating the resulting 2-methyl-5-nitrophenyl guanidine of the formula (IV) in n- butanol with 3-dimethylamino-l-(3-pyridyl)-2-propen-l-one of the formula (V) and sodium hydroxide and refluxing the resulting mixture for a period of 10 to 12 hours to form the compound of the formula (VI) . (v) Cooling the mixture obtained in step (iv ) to 0°C, filtering and washing the reaction mixture with a mixture of isopropanol and methanol to yield N-(2-methyl-5- nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine of the formula (VI) (vi) Treating the compound of formula (VI) with stannous chloride/cone. HC1 at 0-5°C for 3 to 4 hours to get compound of formula (VII) (vii)Quenching the reaction mass with 50%sodium hydroxide solution and, extracting with chloroform (viii) Concentration of the chloroform yields N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)- 2-pyrimidineamine of the formula [VII]

(ix) Condensing the compound of the formula (XVI) with the compound of the formula (VII) in chloroform solvent and triethylamine as base at a temperature in the range of 0- 20°C to yield the novel intermediate of the formula (II) and,

(x) Reacting the novel compound of formula (II) with appropriate heterocylic amine in a solvent at a temperature in the range of 20-30°C to yield imatinib of the formula (la) and its novel analogues of formulae (lb) (lc) and (Id)

According to another embodiment of the present invention there is provided a process for the preparation of a new compound of the formula (II) which is an intermediate for the preparation of imatinib (la) and its new analogues of the formulae (I b) to (Id) which

Figure imgf000013_0001
comprises

(I) Treating 2-amino-4-nitro toluene of the formula (III) in n-butanol with cone, nitric acid in the temperature range 90-95°C during 8to 14 hours to form the nitrate salt of the compound of the formula (III)

(ii) Condensing the resulting compound of the formula III with cyanamide (NH2CN) solution at a temperature in the range of 80 to 116 °C

(iii) Cooling the reaction mixture of step (ii) to 0°C filtering and washing with methanol, diethyl ether to yield 2-methyl-5-nitrophenyl guanidine nitrate of the formula

(IV) iv) Treating the resulting 2-methyl-5-nitrophenyl guanidine of the formula (IV) in n- butanol with 3-dimethylamino-l-(3-pyridyl)-2-propen-l-one of the formula (V) and sodium hydroxide and refluxing the resulting mixture for a period of 10 to 12 hours to form the compound of the formula (VI) . (v) Cooling the mixture obtained in step (iv ) to 0°C, filtering and washing the reaction mixture with a mixture of isopropanol and methanol to yield N-(2-methyl-5- nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine of the formula (VI)

(vi) Treating the compound of formula (VI) with stannous chloride/cone. HC1 at 0-5°C for 3 to 4 hours to get compound of formula (VII) (vii)Quenching the reaction mass with 50%sodium hydroxide solution and, extracting with chloroform

(viii) Concentration of the chloroform yields N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-

2-pyrimidineamine of the formula (VII)

(ix) Condensing the compound of the formula (XVI) with the compound of the formula (VII) in chloroform solvent and triethylamine as base at a temperature in the range of 0-

20° C to yield the novel intermediate of the formula (II)

Preparation of the novel intermediate of the formula π is shown in the scheme-3 given below

Figure imgf000015_0001

STEP-2

Figure imgf000015_0002
(XVI) (XV)

INTERMEDIATE

Figure imgf000015_0003

Scheme - 3

The quantity of n-butanol used in step- 1 (Scheme- 1) may be in the range of 5 to 10 times with respect to compound of formula (II), preferably in the range of 6 to 8 volumes. The reaction time employed may be in the range of 8 to 14 hours preferably in the range of 10-12 hours. The reaction mixture temperature may preferably in the range of 90-95°C The quantity of n-butanol used in step-2 (Scheme-l)may be in the range of 5 to 10 times with respect to compound of formula (III), preferably in the range of 6 to 8 volumes. The reflux time may be in the range of 5 to 10 hours preferably in the range of 6 to 8 hours.

The compound of the formula (XVI) may be prepared by the α-bromination of p-toluic acid of the formula (IX) with N-bromo succinimide in chloroform solvent and benzoyl peroxide as catalyst to yield α-bromo-p-toluic acid of the formula (XIV), hydrolyzing the compound of the formula (XIV) with diluted hydrochloric acid to yield 4-hydroxy methyl benzoic acid of the formula (XV), reacting the compound of the formula (XV) with thionyl chloride to yield 4-chloromethyl benzoyl chloride of the formula (XVI).(Scheme -3)

The compound of the formula VII with sharp melting point (142-143°C) and with 60- 65% yield may be obtained by using stannous chloride dihydrate / cone. HC1 ( in place of H2- Pd/C used in the known method) The number of moles of stannous chloride may be in the range of 3 to 7 preferably in the range of 5 to 6 moles. The volume of concentrated hydrochloric acid may be in the range of 2.5 to 3 volumes. The reaction time may be in the range of 1 to 4 hours preferably in the range of 2 to 3 hours. The concentration of aqueous sodium hydroxide solution used for work-up may be in the range of 20 to 60% preferably in the range of 40 to 50 %

The details of the invention are provided in the Examples given below which are provided to illustrate the invention only and therefore they should not be construed to limit the scope of the invention

Figure imgf000017_0001

ϋb)

) Novel intermediate

Figure imgf000017_0002

US)

■ Novel intermediate

Figure imgf000017_0003
lid)

1 - Novel intermediate

Figure imgf000017_0004

SCHEME-4 Example- 1 : Process for the preparation of Imatinib of the formula (la)

Step-1 The preparation of 2-methyl-5-nitro phenyl guanidine nitrate of the formula (IV)

Figure imgf000018_0001

(III)

(IV) C7H8N2O2 CβHnNδOβ MW :152.0 MW : 257.0

RAW MATERIALS QTY

1. 2-amino-4-nitro toluene (III) 34 Kg

2. Cyanamide solution 14.1 Kg in 14 L DM water

Cone. Nitric acid (69-72%) 14.3 Kg n-Butanol 200 L Isopropyl ether 285 L Methanol 285 L

Procedure : Charged a suspension of 34 Kg of 2-amino-4-nitro toluene in 200 L n-butanol into reactor. 14.3 Kg of cone. Nitric acid is slowly added during half an hour at 25-35°C. 14.1 Kg of cyanamide dissolved in 14 L DM water is charged. Reaction mass is heated to 90- 95°C for 12 hours, cooled to 65-70°C. n-butanol is distilled off not crossing mass temperature 40-50°C to the residual volume of 80 L. Reaction mass is Cooled to 25- 35°C and then cooled to 0-10°C. Charge 235 L isopropyl ether and 235 L methanol are charged at 10°C. Maintained 1 hour at 10-15°C, centrifuged and slurry washed with a mixture of 1:1 isopropyl ether and methanol (100 L). isopropyl ether and methanol mother liquors are kept aside to recover the unreacted starting material 2-amino-4-nitro toluene (III) Centrifuged product is dried at 60-70°C Yield : 22 Kg - 61% (based on recovery of III)

MR : 214-220°C

Purity by HPLC : 99.8%

Recovery of 2-amino-4-nitro toluene of the formula (DD (unreacted starting material). Centrifuged isopropyl ether and methanol mother liquors are distilled to a residual volume of 60 L under vacuum. Cooled the filtrate to 25-35 °C and then cool to 0-5°C. Maintained 3 hours at 0-5°C. Centrifuged and washed with 1:1 chilled mixture of 20 Lts of isopropyl ether and methanol centrifuged and dried the product (III) at 60-70°C Yield : 13.6 Kgs MR 104-107 °C Purity by HPLC : 99.5%

Step-2 The preparation of N-(2-methyl-5-nitro phenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula [VI]

Figure imgf000019_0001

CβHn NδQs 3-Dimethylamϊno-1- C16H13N6O2 (3-pyridyl)-2-propan- 1 -one MW : 257.0 MW : 307.0

RAW MATERIALS QTY

1. 2-methyl-5-nitrophenyl guanidine nitrate (IV) 20 Kg

2. 2-dimethylamino- 1 -(3 -pyridyl)-2-propen- 1 -one (V) 13.6 Kg

3. Sodium hydroxide flakes 3.2 Kg

4. n-Butanol 132 L

5. Isopropyl alcohol 175 L 6. Methanol 85 L Procedure ;

A suspension of 20 Kg of 2-methyl-5-nitrophenyl guanidine nitrate in 132 L n-butanol is charged 13.6 Kg of 2-dimethylamino-l-(3-pyridyl)-2-propen-l-one is charged. 3.2 Kgs of sodium hydroxide flakes are charged. The suspension is heated to reflux and maintained reflux for 10 hours till product separated quantitatively from the reaction mass as heavy mass. As soon as the product separates out the reaction mass cooled to 50-60°C. and charged 117 L of isopropyl alcohol and 57 L of methanol. The reaction mass is cooled to 10°C. Maintained half an hour at 10°C. the mixture centrifuged and washed with a mixture of 58 L Isopropyl ether and 28 L methanol. The product N-(2- methyl-5-nitro phenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula [VI] is dried at 60-70°C Yield : 21 Kg (88%) MR : 193 - 198°C.

Purity by TLC : Single spot.

Step -3 : The preparation of N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula [VII]

Figure imgf000020_0001
VI

CιβHι3N5θ2 C16H15N5 MW: 307.0 MW: 277.0 RAW MATERIALS QTY

1. N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimide amine(VI)18 Kg

2. Stannous chloride dihydrate 70 Kg 3. Cone. Hydrochloric acid 170 L

4. Sodium hydroxide solution (50%) 400 L

5. Carbon 1.0 Kg

6. Hyflow 6.0 Kg

7. Chloroform 700 L 8. Ethyl acetate 30 L

Procedure :

170 L of Cone. Hydrochloric acid is charged into the reactor. 70 Kg of stannous chloride dihydrate is charged. Stirred for 10 minutes. Cooled the reaction mass to 0-5°C. Added compound of the formula (VI) slowly during 3-4 hours at 0-5 °C. reaction mass is brought to 25-35°C. Maintained 1 Vz hour at 25-35°C. Charged 500 Its of DM water to the reaction mass and charged slowly 400 L of 50% sodium hydroxide solution at 25-35°C. Reaction mass is extracted with 2 x 250 L chloroform. The chloroform layer is water wash thoroughly and carbon treatment is given . Distilled off chloroform completely under vacuum and charged 20 L ethyl acetate. Cooled to 0-10°C. Maintained 1 hour at 0- 10°C. Centrifuged and washed with 10 L ethyl acetate to provide N-(5-amino-2- methyl phenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula [VII] Yield : 10 Kg (61.5%) MR : 141-144°C.

Purity by HPLC : 99.8%.

Step-4 : Preparation of 4-(chloromethyl)-N_-4-methyl-3-[(4-(3-pyridinyl)-2-pyrimidinyl] amino]phenyl benzamide (II)

Figure imgf000022_0001

C16H15N5 C8H6CI20 MW : 277.0 MW : 188.0

Figure imgf000022_0002

C24H20CIN5O MW : 428.5

Raw materials :

N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine (VII) 12.8 Kgs

4-(Chloromethyl)benzoyl chloride (XVI) 10.4 Kgs

Triethylamine 9.3 Kgs

Chloroform 150 Lts

Ethyl acetate 15 Lts Procedure : 80 L chloroform is charged into the reactor 12.8 Kgs of N-(5-amino-2- methylphenyl)-4-(3-pyridyι)~2-pyrimidine of the formula (VII) amine is charged into the reactor. Stirred for 15 minutes to get clear solution 9.3 Kg of triethylamine is charged. To the reaction mass 10.4 Kg of 4-(Chloromethyl)benzoyl chloride dissolved in 70 L chloroform is charged slowly during 4-5 hours at 0-5°C. The compound of the formula (II)is centrifuged and washed with 15 L DM water and 15 L Ethyl acetate, the product is dried at 60-70°C. Yield : 13.9 Kg (70%) MR : 181-183°C. Purity by TLC : Single spot

Step-5 : Preparation of imatinib (la)

e

Figure imgf000023_0001

C24H20CIN5O

MW : 100.0 MW : 428.5

Figure imgf000023_0002
MW : 493.0 Raw materials :

4-(Chloromethyl N-(4-methyl-3 -[(4-3 -pyridyl-2-pyrimidine ]-amino] phenyl benzamide(II) 13.9 Kgs

N-methyl piperazine 9.7Kgs

Dimethyl formamide (DMF) (DMF) 40 Lts

Chloroform 300 Lts

5% aq. Sodium hydroxide solution 200 Lts

Carbon 1.4 Kgs

Ethyl acetate 140 Lts

Procedure : Into the reactor 40 L Dimethyl formamide is charged (DMF) into the reactor 19.7 Kgs of N-methyl piperazine is charged. It is stirred for 15 minutes. 13.9 Kg of compound of formula (IΙ)is charged to the reaction mass slowly during four hours at 20-40°C. Reaction mass is poured into 400 L DM water and stirred for 15 minutes. Reaction mass is extracted with 3 x 100 L chloroform. All chloroform layers are combined and washed with 2 x 100 L 5% aq. Sodium hydroxide solution 2 x 100 Lts DM water. Carbon treatment is given to the chloroform layer. Organic layer Dried over sodium sulfate and distilled off completely under vacuum. 100 Lts Ethyl acetate is charged to the residue and stirred for 15 minutes at 25-35°C. The product of the formula (la)is centrifuged and washed with 40 L Ethyl Acetate. It is dried in oven at 60-70°C Dry wt. : 9.8 Kg (61%) MR : 202-206°C. Purity by HPLC : 99.8%

Example -2 : Preparation of 4-Morpholino -N-[4-methyl-3-[(4-(3-pyridinyl)-2- pyrimidinyl] amino] phenyl benzamide (lb): Step-1 The preparation of 2-methyl-5-nitro phenyl guanidine nitrate (IV)

Figure imgf000025_0001

(III) (IV)

C7H8N2°2 CβHnNβOβ

MW :152.0 MW : 257.0

RAW MATERIALS QTY

1 2-amino-4-nitro toluene (III) 3.4 Kg

2 Cyanamide solution 1.4 Kg in 1.4 L DM water 3 Cone. Nitric acid (69-72%) 1.4 Kg 4 n-Butanol 25 L 5 Isopropyl ether 30 L 6 Methanol 30 L

Procedure :

Charged a suspension of 3.4 Kg of 2-amino-4-nitro toluene in 25 L n-butanol into reactor. 1.4 Kg of cone. Nitric acid is slowly added during half an hour at 25-35°C. 1.4 Kg of cyanamide dissolved in 1.4 L DM water is charged. Reaction mass is heated to 90-95°C for 12 hours, cooled to 65-70°C. n-butanol is distilled off not crossing mass temperature 40-50°C to the residual volume of 80 L. Reaction mass is Cooled to 25-35°C and then cooled to 0-10°C. Charge 25 L isopropyl ether and 25 L methanol are charged at 10°C. Maintained 1 hour at 10-15°C, centrifuged and slurry washed with a mixture of 1:1 isopropyl ether and methanol (10 L). isopropyl ether and methanol mother liquors are kept aside to recover the unreacted starting material 2-amino-4-nitro toluene (III) Centrifuged product is dried at 60-70°C Yield : 2.2 Kg - 61% (based on recovery of III) MR : 215-218°C

Purity by HPLC : 99.80%

Recovery of 2-amino-4-nitro toluene of the formula (HP (unreacted starting material): Centrifuged isopropyl ether and methanol mother liquors are distilled to a residual volume of 60 L under vacuum. Cooled the filtrate to 25-35 °C and then cool to 0-5°C. Maintained 3 hours at 0-5°C. Centrifuged and washed with 1 : 1 chilled mixture of 20 Lts of isopropyl ether and methanol centrifuged and dried the product (El) at 60-70°C Yield : 1.4 Kgs MR 104-107 °C Purity by HPLC : 99.5%

Step-2 The preparation of N-(2-methyl-5-nitro phenyl)-4-(3-pyridyl)-2-pyrimidineamine (VI)

Figure imgf000026_0001

CsHnNsOs 3-Dimethylamino-1- C16H13N6O2 (3-pyridyl)-2-propan-1 -one MW : 257.0 MW : 307.0

RAW MATERIALS QTY

2-methyl-5-nitrophenyl guanidine nitrate (IV) 2 Kg

2-dimethylamino- 1 -(3 -pyridyl)-2-propen- 1 -one (V) 1.36 Kg

Sodium hydroxide flakes 0.3 Kg n-Butanol 16 L

Isopropyl alcohol 18 L

Methanol 10 L Procedure :

A suspension of 2 Kg of 2-methyl-5-nitrophenyl guanidine nitrate in 16 L n-butanol is charged 1.3 Kg of 2-dimethylamino-l-(3-pyridyl)-2-propen-l-one is charged. 0.3 Kgs of sodium hydroxide flakes are charged. The suspension is heated to reflux and maintained reflux for 10 hours till product separated quantitatively from the reaction mass as heavy mass. As soon as the product separates out the reaction mass cooled to 50-60°C. and charged 15 L of isopropyl alcohol and 7 L of methanol. The reaction mass is cooled to 10°C. Maintained half an hour at 10°C. the mixture centrifuged and washed with a mixture of 5 L Isopropyl ether and 3 L methanol. The product N-(2-methyl-5- nitro phenyl)-4-(3-pyridyl)-2-pyrimidineamine (VI) is dried at 60-70° C Yield : 2.0 Kg (84%) MR : 192 - 197°C. Purity by TLC : Single spot.

Step -3 :

The preparation of N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-pyrimidineamine (VII)

Figure imgf000027_0001

Ci6Hi3Nδ0 C16H15N5 MW: 307.0 MW: 277.0 RAW MATERIALS QTY

1. N-(2-methyl-5-nitrophenyl)-4-(3 -pyridyl)-2-pyrimide amine(VI) 1.8 Kg

2. Stannous chloride dihydrate 7.0 Kg Cone. Hydrochloric acid 20 L

Sodium hydroxide solution (50%) 40 L

Carbon 0.1 Kg

Hyflow 0.6 Kg

Chloroform 70 L

Ethyl acetate 3 L

Procedure : 20 L of Cone. Hydrochloric acid is charged into the reactor. 7 Kg of stannous chloride dihydrate is charged. Stirred for 10 minutes. Cooled the reaction mass to 0-5°C. Added compound of the formula (VI) slowly during 2-3 hours at 0-5°C. reaction mass is brought to 25-35°C. Maintained 3 hours at 25-35°C. Charged 500 Its of DM water to the reaction mass and charged slowly 40 L of 50% sodium hydroxide solution at 25-35°C. Reaction mass is extracted with 2 x 35 L chloroform. The chloroform layer is water wash thoroughly and carbon treatment is given . Distilled off chloroform completely under vacuum and charged 2 L ethyl acetate. Cooled to 0-10°C. Maintained 1 hour at 0-

10°C. Centrifuged and washed with 1 L ethyl acetate to provide N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula [VII] Yield : 0.98 Kg (60%) MR : 140-143°C. Purity by HPLC : 99.8%.

Step-4 : Preparation of 4-(chloromethyl)-N-4-methyl-3-[(4-(3-pyridinyl)-2-pyrimidinyl] amino]phenyl benzamide (Et)

Figure imgf000029_0001

C16H15N5 C8H6CI20 MW : 277.0 MW : 188.0

Figure imgf000029_0002

C24H20CIN5O MW : 428.5

Raw materials :

N-(5-amino-2-methylphenyl)-4-(3 -pyridyι)-2-pyrimidine (VII) 1.28 Kgs

4-(Chloromethyl)benzoyl chloride (XVI) 1.04 Kgs

Triethylamine 0.9 Kgs

Chloroform 15 Lts

Ethyl acetate 2 Lts

Procedure : 8 L chloroform is charged into the reactor 1.28 Kgs of N-(5-amino-2- methylphenyl)-4-(3-pyridyl)-2-pyrimidine of the formula (VII) amine is charged into the reactor. Stirred for 15 minutes to get clear solution 0.9 Kg of triethylamine is charged.

To the reaction mass 1.04 Kg of 4-(Chloromethyl)benzoyl chloride dissolved in 7 L chloroform is charged slowly during 2 hours at 0-5°C. The compound of the formula

(II)is centrifuged and washed with 2 L DM water and 2 L Ethyl acetate, the product is dried at 60-70°C.

Yield : 1.35 Kg (68%)

MR : 180-182°C.

Purity by TLC : Single spot

Step-5

Figure imgf000030_0001

C24H20CIN5O MW: 428.5

Figure imgf000030_0002

C2gH3oN602 MW:478.0 Raw materials:

4-(chloromethyl) -N-[4-methyl-3-[(4-(3-pyridinyl)-2-pyrimidinyl] amino] phenyl benzamide (II) 100 gms

Morpholine 61 gms

Dimethyl formamide (DMF) 300 ml

Chloroform 300 ml

5%aq. Sodium hydroxide solution 200 ml carbon 10 gms

Ethyl acetate 300 ml

Procedure

Into the reactor 300 ml Dimethyl formamide is charged (DMF) into the reactor 61 gms morpholine is charged. It is stirred for 15 minutes. lOOgms of compound of formula (II)is charged to the reaction mass slowly during four hours at 20-40°C. Reaction mass is poured into 3 L DM water and stirred for 15 minutes. Reaction mass is extracted with 3 x 100 ml chloroform. All chloroform layers are combined and washed with 2 x 100 ml 5% aq. Sodium hydroxide solution 2 x 100 ml DM water. Carbon treatment is given to the chloroform layer. Organic layer Dried over sodium sulfate and distilled off completely under vacuum. 250 ml Ethyl acetate is charged to the residue and stirred for 15 minutes at 25-35°C. The product (lb)is centrifuged and washed with Ethyl Acetate. It is dried in oven at 60-70°C

Dry wt. : 61.5 gms (55%) MR : 211-213°C. Purity of HPLC: 99.7%

Example-3 . Process for the preparation of 4-piperidino-N-[4-methyl-3-[(4-(3- pyridinyl)-2-pyrimidinyl] amino] phenyl benzamide(lc)

Step-1 The preparation of 2-methyl-5-nitro phenyl guanidine nitrate of the formula (IV)

Figure imgf000032_0001

(III)

(IV) C7H8N202 CBHH NSOS MW : 152.0 MW : 257.0

RAW MATERIALS QTY

2-amino-4-nitro toluene (III) 3.4 Kg Cyanamide solution 1.4 Kg in 1.4 L DM water Cone. Nitric acid (69-72%) 1.4 Kg n-Butanol 20 L Isopropyl ether 30 L Methanol 30 L

Procedure :

Charged a suspension of 3.4 Kg of 2-amino-4-nitro toluene in 20 L n-butanol into reactor. 1.4 Kg of cone. Nitric acid is slowly added during half an hour at 25-35°C. 1.4 Kg of cyanamide dissolved in 1.4 L DM water is charged. Reaction mass is heated to 90-95°C for 14 hours, cooled to 65-70°C. n-butanol is distilled off not crossing mass temperature 40-50°C to the residual volume of 80 L. Reaction mass is Cooled to 25-35°C and then cooled to 0-10°C. Charge 25 L isopropyl ether and 25 L methanol are charged at 10°C. Maintained 1 hour at 10-15°C, centrifuged and slurry washed with a mixture of 1:1 isopropyl ether and methanol (10 L). isopropyl ether and methanol mother liquors are kept aside to recover the unreacted starting material 2-amino-4-nitro toluene (IS) Centrifuged product is dried at 60-70°C Yield : 2.1 Kg - 59% (based on recovery of IQ) MR : 216-219°C Purity by HPLC : 99.9%

Recovery of 2-amino-4-nitro toluene of the formula (UP (unreacted starting material): Centrifuged isopropyl ether and methanol mother liquors are distilled to a residual volume of 60 L under vacuum. Cooled the filtrate to 25-35 °C and then cool to 0-5°C. Maintained 3 hours at 0-5°C. Centrifuged and washed with 1:1 chilled mixture of 20 Lts of isopropyl ether and methanol centrifuged and dried the product (El) at 60-70° C Yield : 1.3 Kgs MR 104-107 °C Purity by HPLC : 99.7%

Step-2 The preparation of N-(2-methyl-5-nitro phenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula [VI]

Figure imgf000033_0001

CsHn NsOs 3-Dimethylamino-1- C16H13N6O2 (3-pyridyl)-2-propan- 1 -one MW : 257.0 MW : 307.0 RAW MATERIALS QTY

1. 2-methyl-5-nitrophenyl guanidine nitrate (IV) 2 Kg

2. 2-dimethylamino-l-(3-pyridyl)-2-propen-l-one (V) 1.36 Kg

3. Sodium hydroxide flakes 0.3 Kg

4. n-Butanol 16 L

5. Isopropyl alcohol 18 L

6. Methanol 10 L ggctcedure :

A suspension of 2 Kg of 2-methyl-5-nitrophenyl guanidine nitrate in 16 L n-butanol is charged 1.3 Kg of 2-dimethylamino-l-(3-pyridyl)-2-propen-l-one is charged. 0.3 Kgs of sodium hydroxide flakes are charged. The suspension is heated to reflux and maintained reflux for 8 hours till product separated quantitatively from the reaction mass as heavy mass. As soon as the product separates out the reaction mass cooled to 50- 60°C. and charged 15 L of isopropyl alcohol and 7 L of methanol. The reaction mass is cooled to 10°C. Maintained half an hour at 10°C. the mixture centrifuged and washed with a mixture of 5 L Isopropyl ether and 3 L methanol. The product N-(2-methyl-5- nitro phenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula [VI] is dried at 60-70°C Yield : 2.0 Kg (85%) MR : 194 - 199°C. Purity by TLC : Single spot.

Step -3 :

The preparation of N-(5-amino-2-methyl ρhenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula [VE]

Figure imgf000035_0001
C16H13N5O2 C16H15N5 MW: 307.0 MW: 277.0

RAWMATERIALS QTY

1. N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimide amine(VI)l .8 Kg

2. Stannous chloride dihydrate 7.0 Kg

3. Cone. Hydrochloric acid 17 L

4. Sodium hydroxide solution (50%) 40 L

5. Carbon 0.1 Kg

6. Hyflow 0.6 Kg

7. Chloroform 70 L

8. Ethyl acetate 3 L

Procedure : 17 L of Cone. Hydrochloric acid is charged into the reactor. 7 Kg of stannous chloride dihydrate is charged. Stirred for 10 minutes. Cooled the reaction mass to 0-5°C. Added compound of the formula (VI) slowly during 2-3 hours at 0-5°C. reaction mass is brought to 25-35°C. Maintained 3 hours at 25-35°C. Charged 500 Its of DM water to the reaction mass and charged slowly 40 L of 50% sodium hydroxide solution at 25-35°C. Reaction mass is extracted with 2 x 50 L chloroform. The chloroform layer is water wash thoroughly and carbon treatment is given . Distilled off chloroform completely under vacuum and charged 2 L ethyl acetate. Cooled to 0-10°C. Maintainedl hour at 0- 10°C. Centrifuged and washed with 1 L ethyl acetate to provide N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula [VII] Yield : 0.97 Kg (60%) M : 140-143°C. Purity by HPLC : 99.7%.

Step-4 : Preparation of 4-(chloromethyl)-N_-4-methyl-3-[(4-(3-pyridinyl)-2-pyrimidinyl] amino]phenyl benzamide (H)

Figure imgf000036_0001

C16H15N5 C8HsCI20 MW : 277.0 MW : 188.0

Figure imgf000036_0002

C24H20CIN5O MW : 428.5 Raw materials :

N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine (VII) 1.28 Kgs

4-(Chloromethyl)benzoyl chloride (XVI) 1.04 Kgs

Triethylamine 0.9 Kgs

Chloroform 15 Lts

Ethyl acetate 2 Lts

Procedure : 8 L chloroform is charged into the reactor 1.28 Kgs of N-(5-amino-2- methylphenyl)-4-(3-pyridyl)-2-pyrimidine of the formula (VII) amine is charged into the reactor. Stirred for 15 minutes to get clear solution 0.9 Kg of triethylamine is charged. To the reaction mass 1.04 Kg of 4-(Chloromethyl)benzoyl chloride dissolved in 7 L chloroform is charged slowly during 3 hours at 5-10°C. The compound of the formula (IΙ)is centrifuged and washed with 2 L DM water and 2 L Ethyl acetate, the product is dried at 60-70°C. Yield : 1.34 Kg (67%) MR : 180-182°C. Purity by TLC : Single spot

Step-5 : Preparation of 4-piρeridino-N-[4-methyl-3-[(4-(3-pyridinyl)-2-pyrimidinyl] amino] phenyl benzamide(lc)

Figure imgf000038_0001

C24H20CIN5O MW: 429.5

Figure imgf000038_0002

C29H30N6O MW:476.0

Raw materials:

4-(chloro methyl -N-[4-methyl-3-[(4-(3-pyridinyl)-2-pyrimidinyl]] aminophenyl benzamide(ll) : 100 gms

Piperidine 63 gms

Dimethyl formamide (DMF) 300 ml

Chloroform 300 ml

5%aq. Sodium hydroxide solution 200ml

Carbon lOgms

Ethyl acetate 300ml

Procedure

Into the reactor 300 ml Dimethyl formamide is charged (DMF) into the reactor 63 gms piperdine is charged. It is stirred for 15 minutes. lOOgms of compound of formula (II) is charged to the reaction mass slowly during four hours at 20-40°C. Reaction mass is poured into 3 L DM water and stirred for 15 minutes. Reaction mass is extracted with 3 x 100 ml chloroform. All chloroform layers are combined and washed with 2 x 100 ml 5% aq. Sodium hydroxide solution 2 x 100 ml DM water. Carbon treatment is given to the chloroform layer. Organic layer Dried over sodium sulfate and distilled off completely under vacuum. 200 ml Ethyl acetate is charged to the residue and stirred for 15 minutes at 25-35°C. The product (lc)is centrifuged and washed with Ethyl Acetate. It is dried in oven at 60-70°C

Dry wt. - 63 gms (57%)

MR - 188-189°C.

Purity (HPLC) : 99.8%

Example-4 Process for the preparation of 4-imidazoyl-N-[4-methyl-3-[(4-(3-pyridinyl)- 2-pyrimidinyl] amino] phenyl benzamide(ld)

Step-1 The preparation of 2-methyl-5-nitro phenyl guanidine nitrate of the formula (IV)

Figure imgf000040_0001

MW :152.0 MW : 257.0

RAWMATERIALS QTY

2-amino-4-nitro toluene (El) 3.4 Kg Cyanamide solution 1.4 Kg in 1.4 L DM water Cone. Nitric acid (69-72%) 1.4 Kg n-Butanol 25 L Isopropyl ether 30 L Methanol 30 L

Procedure :

Charged a suspension of 3.4 Kg of 2-amino-4-nitro toluene in 25 L n-butanol into reactor. 1.4 Kg of cone. Nitric acid is slowly added during half an hour at 25-35°C. 1.4 Kg of cyanamide dissolved in 1.4 L DM water is charged. Reaction mass is heated to 90-95°C for 14 hours, cooled to 65-70°C. n-butanol is distilled off not crossing mass temperature 40-50°C to the residual volume of 80 L. Reaction mass is Cooled to 25-35°C and then cooled to 0-10°C. Charge 25 L isopropyl ether and 25 L methanol are charged at 10°C. Maintained 1 hour at 10-15°C, centrifuged and slurry washed with a mixture of 1:1 isopropyl ether and methanol (10 L). isopropyl ether and methanol mother liquors are kept aside to recover the unreacted starting material 2-amino-4-nitro toluene (III) Centrifuged product is dried at 60-70°C Yield : 2.1 Kg - 59% (based on recovery of IE) MR : 214-220°C Purity by HPLC : 99.85%

Recovery of 2-amino-4-nitro toluene of the formula (HI) (unreacted starting material): Centrifuged isopropyl ether and methanol mother liquors are distilled to a residual volume of 60 L under vacuum. Cooled the filtrate to 25-35 °C and then cool to 0-5°C. Maintained 3 hours at 0-5°C. Centrifuged and washed with 1:1 chilled mixture of 20 Lts of isopropyl ether and methanol centrifuged and dried the product (El) at 60-70°C Yield : 1.3 Kgs MR 103-106 °C Purity by HPLC : 99.6%

Step-2 The preparation of N-(2-methyl-5-nitro phenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula [VI]

Figure imgf000041_0001

CβHn NδOs 3-Dimethylamino-1- O16H13N6O2 (3-pyridyl)-2-propan-1-one MW : 257.0 MW : 307.0

RAWMATERIALS QTY

1. 2-methyl-5-nitrophenyl guanidine nitrate (IV) 2 Kg

2. 2-dimethylamino- 1 -(3 -pyridyl)-^ J-propen -1-one (V) 1.36 Kg

3. Sodium hydroxide flakes 0.3 Kg

4. n-Butanol 13 L

5. Isopropyl alcohol 18 L

6. Methanol 10 L Procedure :

A suspension of 2 Kg of 2-methyl-5-nitrophenyl guanidine nitrate in 13 L n-butanol is charged 1.3 Kg of 2-dimethylamino-l-(3-pyridyl)-2-propen-l-one is charged. 0.3 Kgs of sodium hydroxide flakes are charged. The suspension is heated to reflux and maintained reflux for 10 hours till product separated quantitatively from the reaction mass as heavy mass. As soon as the product separates out the reaction mass cooled to 50-60°C. and charged 15 L of isopropyl alcohol and 7 L of methanol. The reaction mass is cooled to 10°C. Maintained half an hour at 10°C. the mixture centrifuged and washed with a mixture of 5 L Isopropyl ether and 3 L methanol. The product N-(2-methyl-5- nitro phenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula [VI] is dried at 60-70°C Yield : 2.0 Kg (85%) MR : 193 - 197°C. Purity by TLC : Single spot.

Step -3 :

The preparation of N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula [VII]

Figure imgf000042_0001
MW: 307.0 MW: 277.0

RAWMATERIALS QTY

1. N-(2-methyl-5-nitrophenyl)-4-(3 -pyridyl)-2-pyrimide amine(VI) 1.8 Kg 2 Stannous chloride dihydrate 7.0 Kg

3 Cone. Hydrochloric acid 19 L

4 Sodium hydroxide solution (50%) 40 L

5 Carbon 0.1 Kg

6 Hyflow 0.6 Kg

7 Chloroform 70 L

8 Ethyl acetate 3 L

Procedure :

19 L of Cone. Hydrochloric acid is charged into the reactor. 7 Kg of stannous chloride dihydrate is charged. Stirred for 10 minutes. Cooled the reaction mass to 0-5°C. Added compound of the formula (VI) slowly during 2-3 hours at 0-5°C. reaction mass is brought to 25-35°C. Maintained 2 V2 hour at 25-35°C. Charged 500 Its of DM water to the reaction mass and charged slowly 40 L of 50% sodium hydroxide solution at 25-35°C. Reaction mass is extracted with 2 x 50 L chloroform. The chloroform layer is water wash thoroughly and carbon treatment is given . Distilled off chloroform completely under vacuum and charged 2 L ethyl acetate. Cooled to 0-10°C. Maintained 1 hour at 0- 10°C. Centrifuged and washed with 1 L ethyl acetate to provide N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula [VII] Yield : 1.05 Kg (64.5%) MR : 142-144°C. Purity by HPLC : 99.85%.

Step-4 : Preparation of 4-(chloromethyl)-N_-4-methyl-3-[(4-(3-pyridinyl)-2-pyrimidinyl] amino]phenyl benzamide (E)

Figure imgf000044_0001

C16H15N5 C8H6CI20 MW : 277.0 MW : 188.0

Figure imgf000044_0002

C24H20CIN5O

MW : 428.5

Raw materials :

N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine (VII) 1.28 Kgs

4-(Chloromethyl)benzoyl chloride (XVI) 1.04 Kgs

Triethylamine 0.9 Kgs

Chloroform 15 Lts

Ethyl acetate 2 Lts

Procedure : 8 L chloroform is charged into the reactor 1.28 Kgs of N-(5-amino-2- methylphenyl)-4-(3-pyridyl)-2-pyrimidine of the formula (VII) amine is charged into the reactor. Stirred for 15 minutes to get clear solution 0.9 Kg of triethylamine is charged. To the reaction mass 1.04 Kg of 4-(Chloromethyl)benzoyl chloride dissolved in 7 L chloroform is charged slowly during 2 hours at 5-10°C. The compound of the formula

(IΙ)is centrifuged and washed with 2 L DM water and 2 L Ethyl acetate, the product is dried at 60-70°C.

Yield : 1.36 Kg (68%)

MR : 181-183°C.

Purity by TLC : Single spot

Step-5 : Preparation of 4-Imidazolyl-(N-[4-methyl-3-[(4-(3-ρyridinyl)-2-ρyrimidinyl]] aminophenyl benzamide(ld)

Figure imgf000046_0001

C24H20CIN5O MW: 429.5

Figure imgf000046_0002

C27H23N70 MW:460.0

Raw materials:

4- (chloromethyl) -N-[4-methyl-3 -[(4-(3 -pyridinyl)-2-pyrimidinyl] amino]phenyl benzamide(ll) 100 gms

Imidazole 79 gms

Dimethyl formamide (DMF) 300 ml Chloroform 300 ml

5%aq. Sodium hydroxide solution 200ml

Carbon lOgms

Ethyl acetate 300ml

Procedure

Into the reactor 300 ml Dimethyl formamide(DMF) is charged into the reactor 79 gms imidazole is charged. It is stirred for 15 minutes. lOOgms of compound of formula (E)is charged to the reaction mass slowly during four hours at 20-40°C. Reaction mass is poured into 3 L DM water and stirred for 15 minutes. Reaction mass is extracted with 3 x 100 ml chloroform. All chloroform layers are combined and washed with 2 x 100 ml 5% aq. Sodium hydroxide solution 2 x 100 ml DM water. Carbon treatment is given to the chloroform layer. Organic layer Dried over sodium sulfate and distilled off completely under vacuum. 75 ml Ethyl acetate is charged to the residue and stirred for 15 minutes at 25-35°C. The product (ld)is centrifuged and washed with Ethyl Acetate. It is dried in oven at 60-70°C Dry wt. - 48 gms (45%)

MR - 200-207°C.

Example 5. Preparation of 4-(chloromethyl)benzoyl chloride of the formula (XVI) (scheme-3)

Figure imgf000047_0001

C8H802 C8H7Br02 MW : 136.0 MW : 215.0 Step-1 : Preparation of α-bromo-p-toluic acid of the formula (XIV)

Raw materials:

P-toluic acid(IX) 20.8 Kgs N-bromo succinimide 27.4Kgs Benzoyl peroxide 0.370 Kgs Chloroform 200 Lts Ethyl acetate 200 Lts

Procedure

200 Lts Chloroform is charged into the reactor. 27.4 Kgs of N-bromo succinimide is charged. 0.370 Kgs of benzoyl peroxide is charged. Reaction mass is heated to reflux temperature and maintained reflux for2.5-3 hours. Cooled to 25-35°C. the compound of formula (XIV ) is filtered and water washed thoroughly. Ethyl Acetate is charged to the wet material and water washed. Ethyl acetate is distilled off under vacuum to a residual volume of 60-70 L and cooled to 25-35°C. The compound of the formula (XIV) is filtered and washed with a ethyl acetate It is dried at 30-40°C. Dry wt. : 19.7 Kg (60%) MR : 226-230°C. Purity by HPLC : 99.9%

Step-2 : Preparation of (4-Hydroxy methyl)benzoic acid of the formula (XV)

Figure imgf000049_0001

C8H7Br02 C8H8O3 MW : 215.0 MW : 152.0

Raw materials: α-bromop-toluic acid (XIV) 19.6 Kgs cone. HC1 23.5 Lts

Procedure

200 L DM water is charged into the reactor charged 19.6 Kgs of α-bromop-toluic acid

(XIV) is charged . 23.5 L Cone. Hcl is charged. Reaction mass is heated to reflux maintained reflux for 10-12 hours. It is brought to25-35°C . Compound of the formula (XV) is filtered and washed with water Product is dried in oven at 70-80°C Yield . : 10.4 Kg (75%) MR : 176-179°C. Purity by TLC : 98%

Step-3 : Preparation of (4-chloromethyl)benzoyl chloride of the formula (XVI)

Figure imgf000049_0002

C8H803 C8H6CI2O MW : 152.0 MW : 188.0 Raw materials:

(4-chloromethyl)benzoic acid (XV) 10.4 Kgs

Thionyl chloride 23.4 Kgs

Chloroform 100 Lts

DMF l Lts

Toluene 50 Lts

Procedure

100 L chloroform is charged into the reactor. Charged 10.4 Kgs of (4- chloromethyl)benzoic acid (XV) is charged. 1 L DMF is charged slowly. The reaction mass is heated to reflux maintained reflux for 3 hours. Excess thionyl chloride is distilled off completely under vacuum. 2 x 25 L toluene is charged and distilled under vacuum to remove thionyl chloride traces.The residue unloaded and it is to be taken immediately to next stage [ Example- 1-4 ; step-4]

• Advantages of the invention

1. The process involves only fewer steps ( 7 ) as against 9 steps in the known process disclosed in EP 0564409 and US 55211584., thereby making the process simple and cost effective

2. Yields realized are fairly high in all the steps (65-90%) as compared to 20-50% realized by the process disclosed in the above mentioned EP and US patents .

3. Reaction times are fairly low 8-10 hrs at all the steps, as compared to the time 12-25 hours for most of the stages in the process disclosed in the above mentioned EP and US patents

4. Obnoxious and foul smelling, difficult to handle reagents are avoided making the process safe and environmentally safe for application commercially

5. Column chromatography is avoided at all stages which is not practical on commercial scale.. Consequently the process is simple and economical

Claims

We claim.
1. Novel compounds of the formula 1(b) to 1 (d) useful as protein tyrosine kinase
Figure imgf000051_0001
inhibitor
2. Novel intermediate of the formula (II) useful for the preparation of compounds of the formula 1 a to 1 d which are useful as protein tyrosine kinase inhibitor
Figure imgf000051_0002
2. A process for the preparation of Imatinib of the formula (la) and its new analogues of the formula 1(b) to 1 (d) which comprises
Figure imgf000052_0001
(I) Treating 2-amino-4-nitro toluene of the formula (III) in n-butanol with cone, nitric acid to form the nitrate salt of the compound of the formula (IE)
(ii) Condensing the resulting compound of the formula El with cyanamide (NH2CN) solution at a temperature in the range of 80 to 116 °C ,
(iii) Cooling the reaction mixture of step (ii) to 0°C, filtering and washing with methanol, diethyl ether to yield 2-methyl-5-nitrophenyl guanidine nitrate of the formula (IV) iv) Treating the resulting 2-methyl-5-nitrophenyl guanidine of the formula (IV) in n- butanol with 3-dimethylamino-l-(3-pyridyl)-2-propen-l-one of the formula (V) and sodium hydroxide and refluxing the resulting mixture for a period of 10 to 12 hours to yield the compound of the formula VI . (v) Cooling the mixture obtained in step (iv ) to 0°C, filtering and washing the reaction mixture with a mixture of isopropanol and methanol to yield N-(2-methyl-5- nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine of the formula (VI) (vi) Treating the compound of formula (VI) with stannous chloride/cone. HC1 at 0-5°C for 3 to 4 hours to get compound of formula (VII) (vi) Condensing the compound of the formula (XVI) with the compound of the formula (VII) in chloroform solvent and triethylamine as base at a temperature in the range of 10- 20° C to yield the novel intermediate of the formula (II) and, (vii) Reacting the novel compound of formula (II) with appropriate heterocylic amine in a solvent at a temperature in the range of 20-30°C to yield imatinib of the formula (la) and its novel analogues of formulae (lb) (lc) and (Id)
3. A process as claimed in claim 2 wherein the quantity of n-butanol used in step (i) ranges of 5 to 10 times, preferably in the range of 6 to 8 times with respect to compound of the formula (II) used .
4. A process as claimed in claims 1 to 3 wherein the reaction time employed in step (i) ranges from 8 to 14 hours , preferably in the range of 10-12 hours.
5. A process as claimed in claims 1 to 4 wherein the reaction temperature of step (i) ranges fro 90-95°C
6. A process as claimed in claims 1 to 5 wherein the quantity of n-butanol used in step (ii) ranges from 5 to 10 times, , preferably in the range of 6 to 8 times with respect to compound of the formula (IE) used
7. A process as claimed in claims 1 to 6 wherein the reflux time used in step (ii) ranges from 5 to 10 hours, preferably in the range of 6 to 8 hours.
8. A process for the preparation of a new compound of the formula II which is an intermediate for the preparation of imatinib (la) and its new analogues of the formulae (I b) to (Id) which comprises
Figure imgf000054_0001
which comprises
(I) Treating 2-amino-4-nitro toluene of the formula (IE) in n-butanol with cone, nitric acid in the temperature range 90-95°C during 8to 14 hours to form the nitrate salt of the compound of the formula (El)
(ii) Condensing the resulting compound of the formula IE with cyanamide (NH2CN) solution at a temperature in the range of 80 to 116 °C ,
(iii) Cooling the reaction mixture of step (ii) to 0°C filtering and washing with methanol, diethyl ether to yield 2-methyl-5-nitrophenyl guanidine nitrate of the formula (IV) iv) Treating the resulting 2-methyl-5-nitrophenyl guanidine of the formula (IV) in n- butanol with 3-dimethylamino-l-(3-pyridyl)-2-propen-l-one of the formula (V) and sodium hydroxide and refluxing the resulting mixture for a period of 10 to 12 hours to form the compound of the formula VI . (v) Cooling the mixture obtained in step (iv ) to 0°C, filtering and washing the reaction mixture with a mixture of isopropanol and methanol to yield N-(2-methyl-5- nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine of the formula (VI) (vi) Treating the compound of formula (VI) with stannous chloride/cone. HC1 at 0-5°C for 3 to 4 hours to get compound of formula (VE) (vii)Quenching the reaction mass with 50%sodium hydroxide solution and, extracting with chloroform
(viii) Concentration of the chloroform yields N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)- 2-pyrimidineamine of the formula [VII] (ix) Condensing the compound of the formula (XVI) with the compound of the formula (VE) in chloroform solvent and triethylamine as base at a temperature in the range of 0- 20°C to yield the novel intermediate of the formula (E)
9. A process as claimed in claim 8 wherein the quantity of n-butanol used in step (i) ranges of 5 to 10 times, preferably in the range of 6 to 8 times with respect to compound of the formula (E) used .
10. A process as claimed in claims 8 & 9 wherein the reaction time employed in step (i) ranges from 8 to 14 hours , preferably in the range of 10-12 hours.
11. A process as claimed in claims 8 to 10 wherein the reaction temperature of step (i) ranges fro 90-95°C
12. A process as claimed in claims 8 to 11 wherein the quantity of n-butanol used in step (ii) ranges from 5 to 10 times, , preferably in the range of 6 to 8 times with respect to compound of the formula (IE) used
13. A process as claimed in claims 8 to 12 wherein the reflux time used in step (ii) ranges from 5 to 10 hours, preferably in the range of 6 to 8 hours.
14. Novel compounds of the formula 1(b) to 1 (d) useful as protein tyrosine kinase inhibitor substantially as herein described with reference to the Examples lto 4
15. Novel compound of the formula II useful for the preparation of compounds of the formula I a to 1 d substantially as herein described with reference to the Examples 1 to 4
16. A process for the preparation of compounds of the formula 1( a ) to 1 (d) substantially as herein described with reference to the Examples 1 to 4
Figure imgf000056_0001
17. A process for the preparation of novel intermediate of the formula II substantially as herein described with reference to the Examples 1 to 4
PCT/IN2003/000211 2003-06-06 2003-06-06 Process for the preparation of the anti-cancer drug imatinib and its analogues WO2004108699A1 (en)

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