DESC:FIELD OF THE INVENTION

The field of the invention relates to an improved process for the preparation of vandetanib. In particular, invention relates to a substantially pure vandetanib. More particularly, the invention relates to an improved process for the preparation of vandetanib and its intermediates thereof.

BACKGROUND OF THE INVENTION

The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.

Vandetanib [CAS 443913-73-3] is an anti-cancer drug that is used for the treatment of certain tumors of the thyroid gland. It acts as a kinase inhibitor of a number of cell receptors, mainly the vascular endothelial growth factor receptor (VEGFR), the epidermal growth factor receptor (EGFR), and the RET-tyrosine kinase. The drug was developed by AstraZeneca.

Vandetanib is chemically known as N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine, which has empirical Formula of C22H24BrFN4O2 and it can be structurally represented by Formula (I):

(I)

U.S. Patent No. 7,173,038 (the US ‘038 Patent) discloses vandetanib as a quinazoline derivative, process for its preparation, method of treatment and pharmaceutical composition thereof.

International (PCT) publication Nos. WO 1997/022596, WO 1998/013354, WO 2001/032651, WO 2005/013998, discloses quinazoline derivatives, process for producing an intermediates, pharmaceutical composition and method of treatment thereof.

International (PCT) publication Nos. WO 2007/036713 A2 discloses the processes for preparation and intermediates, useful in the manufacture of the compound 4-(4-bromo-2fluoroanilino)-6-methoxy-7-(l-methylpiperidin-4-ylmethoxy) quinazoline.

Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular Formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid-state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. The polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. For a general review of polymorphs and the pharmaceutical applications of polymorphs, See G. M. Wall, Pharm Manuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J. Pharm. Sci., 58, 911 (1969); and J. K. Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which are incorporated herein by reference.

In view of the above, it is therefore, desirable to provide an improved and efficient process for the preparation of vandetanib with high yield and better impurity profile. The inventors of the present invention have intensively studied to find out the improved process for the preparation of vandetanib, which can be applicable for the large scale production at industrial level having high yield and purity.

SUMMARY OF THE INVENTION

In one general aspect, there is provided a process for the preparation of pure vandetanib of Formula (I)

(I)

the process comprising:
(a) chlorinating a compound of Formula (VII) with chlorinating agent in one or more organic solvents to obtain a compound of Formula (VI),

(VII) (VI)
(b) condensing the compound of Formula (VI) with 4-bromo-2-fluoroaniline to obtain compound of Formula (V),

(V)
(c) deprotecting the compound of Formula (V) with a deprotecting agent in one or more organic solvents and in presence of a base to obtain compound of Formula (IV),

(IV)
(d) condensing the compound of Formula (IV) with Boc-piperidine-4-methanol tosylate in one or more organic solvents to obtain the compound of Formula (III),

(III)
(e) deprotecting the compound of Formula (III) with a deprotecting agent to obtain the compound of Formula (II) or its acid addition salt thereof,

(II)
(f) methylating the compound of Formula (II) or its acid addition salt thereof by a methylating agent to obtain vandetanib of Formula (I’), and

(I’)
g) optionally, purifying the vandetanib of Formula (I) to obtain pure vandetanib of Formula (I)

In another general aspect, there is provided a process for purification of vandetanib of Formula (I’) to obtain pure vandetanib (I).

In another general aspect, there is provided a process for preparation of a crystalline form of vandetanib Formula (I).

In another general aspect, there is provided vandetanib of Formula (I) has a purity of at least about 99%, or of at least about 99.5%, or of at least about 99.8%, or of at least about 99.9%, by area percentage of HPLC.

In another general aspect, there is provided vandetanib of Formula (I) having particle size distributions wherein the 10th volume percentile particle size (D10) of about 100 µm or less, the 50th volume percentile particle size (D50) of about 200 µm or less, or 90th volume percentile particle size (D90) of about 400 µm or less, or any combination thereof.

In another general aspect, there is provided vandetanib of Formula (I) free from one or more of its impurities as determined using high performance liquid chromatography (HPLC).

In another general aspect, there is provided crystalline form of vandetanib of Formula (I) characterized by an X-ray powder diffraction as same as shown in Fig 1.

In another general aspect, there is provided a pharmaceutical composition comprising pure vandetanib of Formula (I) together with one or more pharmaceutically acceptable excipients, carrier or diluents.

BRIEF DESCRIPTION OF THE FIGURES

FIG 1. Illustrates the X-Ray diffraction pattern of the crystalline form of vandetanib (I).
FIG 2. Illustrates the differential scanning calorimetry analysis of vandetanib

DETAILED DESCRIPTION

The above and other objects of the present invention are achieved by the process of the present invention, which leads to an improved process for the preparation of vandetanib of Formula (I) substantially free from one or more of its impurities.

Optionally, the solution, prior to any solids formation, can be filtered to remove any undissolved solids and solid impurities prior to removal of the solvent. Any filtration system and filtration techniques known in the art can be used.

All ranges recited herein include the endpoints, including those that recite a range “between” two values. Terms such as “about”, “generally” and “substantially,” are to be construed as modifying a term or value such that it is not an absolute. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

As used here in the term “obtaining” may include filtration, filtration under vacuum, centrifugation, and decantation for isolation of the product. The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier. The product may be preceded for further reaction with or without isolation and with or without drying in case of the product was isolated.

In one general aspect, there is provided a process for the preparation of pure vandetanib of Formula (I)

(I)
the process comprising:
(a) chlorinating a compound of Formula (VII) with a chlorinating agent in one or more organic solvents to obtain a compound of Formula (VI),

(VII) (VI)
(b) condensing the compound of Formula (VI) with 4-bromo-2-fluoroaniline to obtain a compound of Formula (V),

(V)
(c) deprotecting the compound of Formula (V) with a deprotecting agent in one or more organic solvents and in presence of a base to obtain a compound of Formula (IV),

(IV)
(d) condensing the compound of Formula (IV) with Boc-piperidine-4-methanol tosylate in one or more organic solvents to obtain the compound of Formula (III),

(III)
(e) deprotecting the compound of Formula (III) with a deprotecting reagent to obtain a compound of Formula (II) or its acid addition salt thereof,

(II)
(f) methylating the compound of Formula (II) or its acid addition salt thereof by a methylating agent to obtain vandetanib of Formula (I’); and

(I’)
g) optionally, purifying the vandetanib of Formula (I) to obtain pure vandetanib of Formula (I).

In another general aspect, there is provided a process for purification of vandetanib of Formula (I’) to obtain pure vandetanib (I).

In another general aspect, the invention provides a substantially pure crystalline form of vandetanib (I) is characterized by X-ray powder diffraction pattern having characteristic peak expressed in degrees 2? (±0.2°2?) at about 8.2º, 14.94º, 18.09º, 18.86º, 20.66º, 21.31º, 22.05º, 23.2º, 23.69º and 29.43º (2?).

The substantially pure vandetanib of Formula (I) is further characterized by X-ray powder diffraction pattern having peaks as same as shown in Fig. 1.

The "solvents" is one or more of alcohols comprise methanol, ethanol, n-propanol, isopropanol and n-butanol; the nitriles comprise acetonitrile, propionitrile, butyronitrile and valeronitrile; the ketones comprise acetone, methyl ethyl ketone and methyl isobutyl ketone; the esters comprise ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate; the chlorinated solvents comprise methylene dichloride, chloroform, ethylene dichloride and chlorobenzene; the ethers comprise diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran and dioxane; the amides comprise dimethylformamide, dimethylacetamide and N-methylformamide; and dimethyl sulfoxide.

In another general aspect of the present invention there is provided a chlorinating agent in step (a) comprises thionyl chloride (SOCl3), phosphorous oxychloride (POCl3), phosphorus trichloride (PCl3), and phosphorus pentachloride (PCl5).

In general, the base comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide and ammonia.

In general, the protecting agent in step (d) comprises carbobenzoxy chloride, tert-Butyloxycarbonyl (BOC), 9-Fluorenylmethoxycarbonyl (FMOC), Benzoyl, Benzyl, Carbamate, p-methoxybenzyl, 3,4-Dimethoxybenzyl (DMPM), p-Methoxybenzyl (PMB), p-Methoxyphenyl (PMP), Tosyl (Ts), and Boc-piperidine-4-methanol tosylate (PPM-OTs).

In general deprotecting reagent as used in step (e) comprises dry hydrochloric acid in ethyl acetate, Isopropanol-hydrochloric acid solution and trifluoro acetic acid solution.

In another general aspect, an alkylation of compound of Formula (II) by formic acid and formaldehyde and the reaction was carried out by reductive amination through Eschweiler–Clarke methylation reaction. It also includes use of other methylating agent’s comprises iodomethane, dimethyl sulfate, dimethyl carbonate and methyl triflate.

In another general aspect, there is provided vandetanib of Formula (I) has a purity of at least about 99%, or of at least about 99.5%, or of at least about 99.8%, or of at least about 99.9%, by area percentage of HPLC.

In another general aspect, there is provided vandetanib of Formula (I) having particle size distributions wherein the 10th volume percentile particle size (D10) of about 100 µm or less, the 50th volume percentile particle size (D50) of about 200 µm or less, or 90th volume percentile particle size (D90) of about 400 µm or less, or any combination thereof.

The active ingredient is micronized prior to compression and shearing. Micronisation may be by any available method in the art. Micronization is the process of reducing the average diameter of a solid material's particles, for example by milling or grinding. In one aspect a micronized active is an active ingredient that has been subjected to a mechanical process which applies sufficient force to the active ingredient that the process is capable of breaking coarse particles down to fine particles.

In one aspect micronization of the active ingredient is achieved using one or a combination of the following methods: ball milling, jet milling, jet blending, high-pressure homogenation, or any other milling method.

Ball milling is a milling method used in many of the prior art co-milling processes. Centrifugal and planetary ball milling may also be used.

Jet mills are capable of reducing solids to particle sizes in the low-micron to submicron range. The grinding energy is created by gas streams from horizontal grinding air nozzles. Particles in the fluidised bed created by the gas streams are accelerated towards the centre of the mill, colliding within. The gas streams and the particles carried in them create a violent turbulence and, as the particles collide with one another, they are pulverized.

In another general aspect, there is provided vandetanib of Formula (I) free from one or more of its impurities as determined using high performance liquid chromatography (HPLC).
In another general aspect there is provided pure crystalline form of vandetanib the compound of Formula (I) as same as shown in Fig 1, and X-ray diffraction pattern as depicted herein and after.

In another general aspect, there is provided pharmaceutical composition comprising vandetanib of Formula (I) together with one or more pharmaceutically acceptable excipients, carrier or diluents.

In another general aspect of the present invention there is provided a process for preparation of pure crystalline form of vandetanib.

Powder x-ray diffraction of crystalline vandetanib can be obtained under following conditions;

(i) Characterization by Powder X-ray diffraction

The X-ray powder diffraction spectrum was measured under the following experimental conditions:
Instrument : X-Ray Diffractometer, D/Max-2200/PC
Make : Rigaku, Japan.
X- Ray : Cu/40kv/40mA
Diverging : 10
Scattering Slit : 10
Receiving Slit : 0.15 mm
Monochromator RS : 0.8 mm
Counter : Scintillation Counter
Scan Mode : Continuous
Scan Speed : 3.0000 / Min
Sampling Width : 0.020
Scan Axes : Two Theta / Theta
Scan Range : 2.0000 to 40.0000
Theta Offset : 0.0000

(ii) Characterization by Differential Scanning Calorimetry (DSC)

Analytical method: Differential scanning calorimetric analysis was performed using a Perkin Elmer Diamond DSC control unit and a DSC 300ºC differential scanning calorimeter. 2-5 mg samples were placed in crimped aluminum pans and heated from 50ºC to 300ºC in a liquid nitrogen atmosphere at a heating rate of 10ºC/minute. Zinc-Indium was used as the standard substance.

The invention also encompasses pharmaceutical compositions comprising vandetanib of the invention. As used herein, the term "pharmaceutical compositions" comprises pharmaceutical Formulations comprises tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

In another general aspect, there is provided pharmaceutical composition comprising vandetanib of Formula (I) together with one or more pharmaceutically acceptable excipients, carrier or diluents.

In another general aspect, there is provided pharmaceutical composition comprising vandetanib of Formula (I) free from impurities together with one or more pharmaceutically acceptable carriers, excipients or diluents.

In another general aspect, there is provided process for the preparation of vandetanib of Formula (I) as same as shown in reaction scheme-1.

Scheme-1
Having described the invention with reference to certain preferred embodiments, other embodiments, reaction conditions, temperature control and solvent system may become apparent to one skilled in the art from consideration of the examples provided herein after. The examples are provided as one of the possible way to practice the invention and should not be considered as limitation of the scope of the invention.

EXAMPLES

Example-1: Preparation of 7-(benzyloxy)-4-chloro-6-methoxyquinazoline
In a 5 liter four necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, 6-methoxy-7-benzyloxy quinazoline-4-one (155 g), chloroform (2325 mL),thionyl chloride (139.5 mL) and dimethylformamide (15.5 mL) were heated to reflux. The reaction mixture, after reaction completion, was cooled to 10-15°C and water (1550 mL) was added, stirred and layers were separated. The aqueous layer was extracted with chloroform (465 mL) and the combined organic layer was distilled off completely under reduced pressure. Acetone (775 mL) was added to the residue, cooled to 0-5°C and stirred for 30 minutes. The reaction mass was filtered, washed with acetone and dried to obtain the titled compound (148.5 g).

Example-2: Preparation of 7-benzyloxy-4-(4-bromo-2-fluoroanilino)-6-methoxy quinazoline hydrochloride
In a 3 liter four necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, 7-(benzyloxy)-4-chloro-6-methoxyquinazoline (145 g) and isopropanol (1450 mL) and 4-bromo-2-fluoroaniline (105.35 g) were heated to reflux. The reaction mixture, after reaction completion, was cooled to 0-5°C and stirred for 1 hour. The reaction mass was filtered, washed with isopropanol and dried to obtain the titled compound (228 g).

Example-3: Preparation of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxy quinazoline
In a 3 liter four necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, 7-benzyloxy-4-(4-bromo-2-fluoroanilino)-6-methoxy quinazoline hydrochloride (220 g) and trifluoro acetic acid (440 mL) were heated to reflux. The reaction mixture, after reaction completion, was cooled to 25-35°C and methanol (440 mL) and water (2200 mL) were added. pH of the reaction mixture was adjusted to 8-9 by ammonia. The reaction mass was filtered, washed with water and ethyl acetate and dried to obtain the titled compound (160 g).

Example-4: Preparation of 4-[4-(4-bromo-2-fluoro-phenylamino)-6-methoxy-quinazolin -7-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester
In a 5 liter four necked round bottomed flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (155 g), potassium carbonate (117.5 g) and dimethylformamide (1085 mL) were stirred at 25-30°C for 1 hour and Boc-piperidine-4-methanol tosylate (196.6 g) was added and then heated to 95-105°C. The reaction mixture, after reaction completion, was cooled to 25-35°C and methanol (155 mL) and water (3100 mL) were added and stirred. The reaction mass was filtered, washed with water and dried to obtain the titled compound (221 g).

Example-5: Preparation of (4-bromo-2-fluoro-phenyl)-[6-methoxy-7-(piperidin-4-yl methoxy)-quinazolin-4-yl]-amine
In a 5 liter four necked round bottomed flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, 4-[4-(4-Bromo-2-fluoro-phenylamino)-6-methoxy-quinazolin-7-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (215 g), acetonitrile (3225 mL) and 16.5% isopropanol-HCl (430 mL) were heated to reflux. The reaction mass, after reaction completion, was cooled to 0-5°C and stirred. The mass was then filtered, washed with methyl-t-butyl ether and dried to obtain the titled compound (192.5 g).

Example-6: Preparation of vandetanib
In a 2 liter four necked round bottomed flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, (4-bromo-2-fluoro-phenyl)-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinazolin-4-yl]-amine (180 g), water (540 mL) and liquor ammonia (45 mL) were stirred at 25-35°C for 15-30 min. Formic acid (180 mL) and formaldehyde solution (180 mL) were then added and heated to 95-105°C. The reaction mass, after reaction completion, was cooled to 25-35°C and extracted with dichloromethane (2 X 900 mL). To the aqueous layer dichloromethane (1800 mL) was added and the pH was adjusted to 8-9 using 20% NaOH solution and stirred. Layers were separated and the aqueous layer was extracted with dichloromethane (900 mL). The combined organic layer was distilled off completely under vacuum and acetone (1260 mL) was added to the residue and stirred. The mass was then filtered, washed with acetone and dried to obtain vandetanib (134 g). [Purity by HPLC: 99.72%, water content: 0.24%]

Example 7: Purification of vandetanib
In a 5 liter four necked round bottomed flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, vandetanib (125 g) and methanol (3375 mL) were heated to get clear solution. The solution was given carbon treatment and then 1875 mL solvent was distilled at atmospheric pressure. The remaining mass was then cooled to 0-5°C and filtered, washed with water and dried to obtain vandetanib (110.5 g). [Purity by HPLC: 99.87%, water content: 0.19%]

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
,CLAIMS:We Claim:
1. A process for the preparation of vandetanib of Formula (I)

(I)
the process comprising:
(a) chlorinating a compound of Formula (VII) with a chlorinating agent in one or more organic solvents to obtain a compound of Formula (VI),

(VII) (VI)
(b) condensing the compound of Formula (VI) with 4-bromo-2-fluoroaniline to obtain a compound of Formula (V),

(V)
(c) deprotecting the compound of Formula (V) with a deprotecting agent in one or more organic solvents and in the presence of a base to obtain compound of Formula (IV),

(IV)
(d) condensing the compound of Formula (IV) with Boc-piperidine-4-methanol tosylate in one or more organic solvents to obtain a compound of Formula (III),

(III)
(e) deprotecting the compound of Formula (III) with a deprotecting agent to obtain a compound of Formula (II) or its acid addition salt thereof,

(II)
(f) methylating the compound of Formula (II) or its acid addition salt thereof by a methylating agent to obtain vandetanib of Formula (I’); and

(I’)
g) optionally, purifying the vandetanib of Formula (I’) to obtain pure vandetanib of Formula (I).
2. The process according to claim 1 wherein the chlorinating agent comprises one or more of thionyl chloride (SOCl3), phosphorous oxychloride (POCl3), phosphorus trichloride (PCl3), and phosphorus pentachloride (PCl5).
3. The process according to claim 1 wherein the organic solvents comprises one or more of water, methanol, ethanol, isopropanol, n-butanol, acetone, methylethyl ketone, methylisobutyl ketone, acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methyl pyrrolidone, tetrahydrofuran, 2-methyl tetrahydrofuran, methylene dichloride, ethylene dichloride, chlorobenzene, toluene, xylene and cyclohexane.
4. The process according to claim 1 wherein the base comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide and ammonia.
5. The process according to claim 1 wherein the deprotecting reagent comprises isopropanol-HCl or dry hydrochloric acid in dry hydrochloric acid in ethyl acetate, trifluoroacetic acid and sulfuric acid.
6. The process according to claim 1 wherein methylating agents comprises formic acid, formaldehyde, iodomethane, dimethyl sulfate, dimethyl carbonate and methyl triflate.
7. The process according to claim 1 wherein the purification of vandetanib of Formula (I’), comprising:
a) dissolving vandetanib of Formula (I’) in one or more of C1-4alkyl alcohols, a mixture of a C1-4alkyl alcohols or their mixture and water, C3-6ketones, a mixture of a C3-6 ketones and water, C2-6esters, a mixture of a C2-6esters and water, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl pyrrolidone, C3-6amides, halogenated hydrocarbons, C6-12aromatic hydrocarbons, dimethylsulfoxide, dimethylacetamide to obtain a solution; and
b) crystallizing pure vandetanib by removal of a solvent from the solution.
8. The process according to claim 7 wherein C1-4alkyl alcohols comprises one or more of methanol, n-butanol, ethanol, isopropanol, n-butanol, or mixture thereof.
9. The process according to claim 1 wherein the pure vandetanib has a purity of at least about 99.5% by area percentage of HPLC.
10. The process according to claim 7 wherein vandetanib of Formula (I) is crystalline, characterized by X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2? (±0.2º 2?) at about 8.2º, 14.94º, 18.09º, 18.86º, 20.66º, 21.31º, 22.05º, 23.2º, 23.69º and 29.43º.
11. The crystalline vandetanib according to claim 10 is further characterized by differential scanning calorimetry having major endothermic peak at about 233°±5°C.
12. A pharmaceutical composition comprising the pure vandetanib of Formula (I) according to claim 9 together with one or more pharmaceutically acceptable excipients, carriers and diluents.

Dated this the 16th day of September 2014.

(H. SUBRAMANIAM)
Of SUBRAMANIAM & ASSOCIATES
Attorneys for the Applicants