WO2013156835A1

WO2013156835A1 - An improved process for the preparation of erlotinib hydrochloride form a

Info

Publication number: WO2013156835A1
Application number: PCT/IB2013/000685
Authority: WO
Inventors: Srinivas Simhadri; Arun Gunwanthrao BIRADAR; Venkata Sunil Kumar Indukuri; Seeta Ramanjaneyulu Gorantla; Satyanarayana Chava
Original assignee: Laurus Labs Private Limited
Priority date: 2012-04-16
Filing date: 2013-04-15
Publication date: 2013-10-24

Abstract

The present invention relates to an improved process for the preparation of Erlotinib hydrochloride pure Form A. The present invention also provides a pharmaceutical composition using the erlotinib hydrochloride pure Form A of the invention.

Description

"AN IMPROVED PROCESS FOR THE PREPARATION OF ERLOTINIB HYDROCHLORIDE FORM A"

PRIORITY

This application claims the benefit under Indian Provisional Application No. 1503/CHE/2012, filed on April 16, 2012 entitled "An improved process for the preparation of Erlotinib hydrochloride form A", the contents of which is incorporated by reference herein.

FIELD OF THE INVENTION The present invention generally relates to an improved process for the preparation of Erlotinib hydrochloride, particularly Erlotinib hydrochloride Form A, and pharmaceutical composition containing the same.

BACKGROUND OF THE INVENTION

Erlotinib, a reversible tyrosine kinase inhibitor, acts on the epidermal growth factor receptor is chemically described as 6, 7-bis (2-methoxyethoxy)-4-quinazolin-4-yl]-(3- ethynyl phenyl) amine as represented by Formula I.

Formula I

Erlotinib is marketed as its hydrochloride salt under brand name TARCEVA for the treatment of certain lung cancers and pancreatic cancer. U.S. Patent No. 5,747,498 ("the '498 patent") discloses quinazoline derivatives such as erlotinib and its hydrochloride salt for treating hyper proliferative diseases such as cancers. The '498 patent also discloses a process for the preparation of erlotinib and its hydrochloride salt by reduction of ethyl 4,5-bis-(2-methoxyethoxy)-2-nitrobenzoate with a metal catalyst such as palladium, platinum or nickel, an activated metal with concentrated hydrochloric acid, followed by cyclization with formamide and ammonium formate to obtain 6, 7-bis (2-methoxyethoxy) quinazolin-4-one, which formed corresponding chloro compound (4-chloro-6, 7-bis (2-methoxyethoxy) quinazoline ) with oxalyl chloride. Condensation of the chloro compound with 3-ethynyl aniline in presence of pyridine and isopropanol under reflux conditions to obtain erlotinib freebase as a pale yellow solid, which was isolated by column chromatography. The free base, thus obtained was treated with hydrochloric acid in presence of ether and chloroform to obtain erlotinib hydrochloride with melting point of about 228°C to 230°C. The '498 patent however, does not describe the physical characteristics of the erlotinib free base and its hydrochloride salt so obtained.

The '498 patent discloses the use of highly expensive metal catalyst for example platinum, palladium, an activated metal like zinc with concentrated hydrochloric acid in the nitro reduction and further tedious workup conditions including isolation of free base by chromatography technique, which are not suitable for industrial scale and which in turn result to an increase in the manufacturing cost. The '498 process is depicted in the following reaction scheme:

U.S. Patent publication No. 2010/267949 ("the '949 publication") discloses the reduction of 2-nitro-4, 5-bis (2-methoxy ethoxy) benzoate using sodium hydrosulfite in presence of water, tetrahydrofuran and ammonium hydroxide at reflux temperature. The use of sodium hydrosulfite at high temperatures generates toxic sulfur dioxide gas and is difficult to control, particularly on commercial scale and thus requires more labor and utmost care to use.

The U.S. Patent No. 5,821,246 ("the '246 patent") describes the reduction of 2-nitro-4, 5- bis (2-methoxy ethoxy) benzoate using palladium-on-carbon, cyclohexane and methanol.

U.S. Patent No. 6,900,221 ("the '221 patent") discloses two crystalline polymorphic forms of Erlotinib hydrochloride namely Form A and Form B. The '221 patent cites the Form B is thermodynamically stable compared to Form A. The '221 patent further discloses erlotinib hydrochloride prepared by the process as described in the US'498 was a mixture of polymorphic Form A and Form B. The '221 patent further discloses erlotinib hydrochloride obtained as Form A or a mixture of Form A and Form B, by condensing 3-ethynyl aniline and 4-chloro-6, 7-bis (2-methoxyethoxy) quinazoline in a mixture of toluene and acetonitrile under reflux temperature. The Form B was prepared by recrystallisation of either the Form A or the mixture of Form A and Form B from mixture of ethanol and water. PCT publication WO 2009/24989 ("the '989 publication) discloses the preparation of crystalline polymorph form A substantially free of polymorph form B, which comprises adding hydrochloric acid to a solution of crystalline erlotinib free base in a solvent or a mixture of solvents selected from isopropyl acetate and methyl isobutyl ketone. PCT publication WO 2010/040212 discloses the preparation of erlotinib hydrochloride Form A comprising passing hydrochloride gas to erlotinib base containing about 15% w/w of residual solvent.

PCT publication WO 2011/058525 discloses the preparation of erlotinib hydrochloride Form A by treating erlotinib base in a suitable solvent selected from acetone, methylene chloride or a mixture with hydrogen chloride gas.

PCT publication WO 2009/007984 ("the '984 publication") discloses a process for preparation of erlotinib hydrochloride by condensing 4-chloro-6, 7-bis (2-methoxyethoxy) quinazoline with 3-ethynyl aniline in a mixture of dimethyl sulfoxide and methanol. However, removal of the high boiling solvent dimethyl sulfoxide from the end product would require prolonged period of time at higher temperature, this leads to degradation of the product. Accordingly, extensive purification procedures are required in order to obtain the necessary quality of the end product and results low product yield thereby making the process quite expensive.

The polymorphic Form A processes described in the literature have certain limitations including contamination of Form A with other polymorphic impurities and also hindering the chemical or polymorphic purity.

Despite all prior advances, available methods for synthesizing erlotinib remain labor intensive, time consuming and environmentally unfavorable. Thus, there remains a need for a simple, industrially feasible and scalable process for the synthesis of erlotinib that would avoid the aforementioned difficulties.

Since erlotinib constitutes an important therapeutic agent, additional and improved ways for preparing erlotinib and its salts particularly hydrochloride salt is a great value to pharmaceutical science. An objective is to provide erlotinib hydrochloride Form A which is free of the other known polymorphic forms. The solvent medium and the mode of isolation including the temperatures, sequence of addition of solvents, seeding of the material etc., contribute a significant role in the formation of respective polymorphic forms. Thus the inventors found an improved process for preparing crystal Form A under modified crystallization conditions.

A further objective is to provide an alternate approach for the reduction of ethyl 4, 5-bis (2- methoxyethoxy) 2-nitro benzoate using suitable nitro reducing agents such as stannous chloride. The reported reducing methods are hazardous because of the adsorbed hydrogen will result in pyrophoricity of the reagents, therefore needs a careful handling under inert conditions. Thus there is need in the improvement for the reduction process which will be commercially viable and cost effective.

SUMMARY OF THE INVENTION

The present invention encompasses an improved process for the preparation of erlotinib and its pharmaceutically acceptable salts thereof, particularly erlotinib hydrochloride in polymorphic Form A, which involves nitro reduction using suitable nitro reducing agents such as stannous chloride and selective conditions to crystallize substantially pure Form A crystals such as selection of solvent medium and mode of isolation techniques including the temperatures, sequence of addition of solvents and optional seeding of the material etc. In accordance with one embodiment, the present invention provides a process for the preparation of erlotinib or its pharmaceutically acceptable salts thereof of Formula I,

Formula I comprising: reduction of ethyl 4,5-bis-(2-methoxyethoxy)-2-nitrobenzoate of Formula

with stannous chloride to obtain ethyl 4,5-bis-(2-methoxyethoxy)-2-aminobenzoate of

Formula

In accordance with a second embodiment, the present invention provides an improved process for the preparation of erlotinib or its pharmaceutically acceptable salts thereof,

Formula I

comprising:

a) reduction of ethyl 4,5-bis-(2-methoxyethoxy)-2-nitrobenzoate of Formula,

with stannous chloride to obtain ethyl 4,5-bis-(2-methoxyethoxy)-2-aminobenzoate of Formula,

b) cyclizing the ethyl 4,5-bis-(2-methoxyethoxy)-2-aminobenzoate with formamide to obtain 6, 7-bis (2-methoxyethoxy) quinazolin-4-one of Formula,

c) chlorinating the 6, 7-bis (2-methoxyethoxy) quinazolin-4-one with a chlorinating agent to obtain 4-chloro-6, 7-bis (2-methoxyethoxy) quinazoline of Formula,

d) condensing the 4-chloro-6, 7-bis (2-methoxyethoxy) quinazoline with 3-ethynyl aniline or its hydrochloride salt to obtain erlotinib or a hydrochloride salt thereof,

e) purifying the erlotinib or a hydrochloride salt thereof in an organic solvent; wherein the organic solvent is selected from a C_1-4 alcohol, halogenated hydrocarbons or mixtures thereof. In accordance with a third embodiment, the present invention provides a process for preparation of substantially pure erlotinib hydrochloride polymorph Form A, comprising the steps of:

a) dissolving erlotinib hydrochloride in a first C_1-4 alcohol or a mixture first C_1-4 alcohol and halogenated hydrocarbon solvent at a temperature of about ambient temperature to about reflux temperature,

b) adding step a) solution at ambient temperature to about reflux temperature in to a second C_1-4 alcohol at a temperature of less than about 45°C,

c) cooling the solution to less than 30°C,

d) filtering the erlotinib hydrochloride Form A.

In accordance with a fifth embodiment, the present invention provides a pharmaceutical composition comprising erlotinib hydrochloride polymorph Form A prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawing, which is incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.

Figure 1 is the characteristic powder X-ray diffraction (XRD) pattern of erlotinib hydrochloride Form A. DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for the preparation of erlotinib and its pharmaceutically acceptable salts thereof, particularly erlotinib hydrochloride in polymorphic Form A. The invention provides a large scale process of erlotinib hydrochloride in polymorphic Form A using industrially feasible processes and purification techniques involving nitro reduction using suitable nitro reducing agents such as stannous chloride and selective conditions to crystallize substantially pure Form A crystals such as selection of solvent medium and mode of isolation techniques including the temperatures, sequence of addition of solvents and optional seeding of the material etc.

In one embodiment, the present invention provides an improved process for the preparation of erlotinib or its pharmaceutically acceptable salts thereof,

Formula I

comprising:

a) reduction of ethyl 4,5-bis-(2-methoxyethoxy)-2-nitrobenzoate of Formula,

e) purifying the erlotinib or a hydrochloride salt thereof in an organic solvent; wherein the organic solvent is selected from a C_1-4 alcohol, halogenated hydrocarbons or mixtures thereof.

The starting material ethyl 4,5-bis-(2-methoxyethoxy)-2-nitrobenzoate is known in the art and can be prepared by any known method, for example ethyl 4,5-bis-(2-methoxyethoxy)- 2-nitrobenzoate may be synthesized as disclosed in U.S. Patent No. 5,747,498. Nitro reduction of a) is carried out in presence of a suitable nitro group reducing agent such as stannous chloride in a suitable organic solvent. The molar ratio of the stannous chloride used in the process according to the invention may vary between 2 to 10 moles per mole of ethyl 4,5-bis-(2-methoxyethoxy)-2-nitrobenzoate; preferably about 4 to 7 moles, more preferably about 5 moles.

The reaction temperature should be sufficient to effect conversion of nitro o amino compound. Typically the reaction temperature may be from about ambient temperature to about reflux temperature. Preferably the reaction temperature is about 25°C to about 85°C, more preferably at about 25°C to about 45°C. The reaction may take from about 2 hours to about 12 hours depending upon the amount of catalyst, solvent and temperature chosen.

The suitable organic solvent for the nitro reduction includes but is not limited to alcohols, esters, ketones, amides, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons, cyclic hydrocarbons, nitroalkanes and mixtures thereof. The alcohols include, but are not limited to methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol and the like; esters include, but are not limited to methyl acetate, ethyl acetate, isopropyl acetate and the like; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, N-methyl pyrrolidinone and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform, carbon tetrachloride and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like; cyclic hydrocarbons include, but are not limited to n-hexane, n-heptane, cyclohexane and the like; nitroalkanes include, but are not limited to nitromethane, nitroethane and the like; water and mixtures thereof; preferably the suitable organic solvent is selected form methanol, isopropanol, ethyl acetate, isopropyl acetate, dimethyl formamide, more preferably methanol.

The '498, the '246 patent and the '949 publication disclose use of either expensive or hazardous nitro reducing agents such as platinum, palladium metal or sodium hydrosulfite in reduction of ethyl 4,5-bis-(2-methoxyethoxy)-2-nitrobenzoate. In contrast, the process herein described use inexpensive and comparatively non hazardous reducing agents for example stannous chloride.

Cyclization of the resultant ethyl 4,5-bis-(2-methoxyethoxy)-2-aminobenzoate of aforementioned step b) with formamide and ammonium formate and then chlorinating the resultant 6, 7-bis (2-methoxyethoxy) quinazolin-4-one with oxalyl chloride are is known in the art, for example as disclosed in U.S. Patent No. 5,747,498.

Step d) of the foregoing process may be carried out by condensing the 4-chloro-6, 7-bis (2- methoxyethoxy) quinazoline with 3-ethynyl aniline or its hydrochloride salt in an organic solvent at a suitable temperature to obtain crude erlotinib hydrochloride.

The organic solvent includes but is not limited to C alcohol such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol and the like; preferably isopropanol.

The suitable temperature may be from about ambient temperature to about reflux temperature. Preferably the reaction temperature is about 25°C to about 65°C, preferably at about 25°C to about 45°C. The reaction may take from about 2 hours to about 12 hours. The present invention provides substantially pure polymorphic Form A of erlotinib hydrochloride, obtained by a process comprising providing crude erlotinib hydrochloride as obtained by the process described above, as a starting material or as an intermediate.

Solid state physical properties of ah active pharmaceutical ingredient (API), such as erlotinib hydrochloride, affect the commercial usefulness of the API. Solid state physical properties include, for example, rate of dissolution and/or bioavailabiliy of the API in the finished pharmaceutical composition. Single stable polymorph with a consistent level of polymorphic purity is essential in the API development. If the API has one or more polymorphs and the manufacturing process may gives a polymorph with varying degree of polymorph purity and or where the process does not control polymorphic inter-conversion, it could create troubles in finished pharmaceutical compositions.

It has been reported that erlotinib hydrochloride can exist in different polymorphic forms, for example Form A and Form B of the '221 patent. In the manufacturing process of erlotinib hydrochloride, mixture of Form A and Form B were formed during the routine synthesis. Preparation of a stable single form is influenced by various process factors such as selective solvent medium and the mode of isolation including the temperatures, sequence of addition of solvents, seeding of the material etc. The inventors of the present invention have put efforts to manufacture substantially pure form of erlotinib hydrochloride Form A by adopting various process modifications such as selection of crystallization solvents, reaction temperature and sequence of addition of solvents.

In one embodiment, the present invention provides a process for preparation of substantially pure erlotinib hydrochloride polymorph Form A, comprising the steps of: a) dissolving erlotinib hydrochloride in a first C_1-4 alcohol or a mixture first C_1-4 alcohol and halogenated hydrocarbon solvent at a temperature of about ambient temperature to about reflux temperature,

c) cooling the solution to less than 30°C,

d) filtering the erlotinib hydrochloride Form A. The erlotinib hydrochloride of step a) may be any crystalline or other form of erlotinib hydrochloride, including various solvates and hydrates, as long as erlotinib hydrochloride pure Form A is produced during the process of the invention or erlotinib hydrochloride obtaining an existing solution from a previous processing step. The first C_1-4 alcohol in the foregoing process may be include but is not limited to methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, t-butanol, secondary butanol and the like and mixtures thereof. The halogenated hydrocarbon solvent includes but are not limited to methylene chloride, ethylene chloride, chloroform and the like and mixtures thereof.

In another embodiment, the solvent ratio for mixture of first C_1-4 alcohol and halogenated hydrocarbon solvent is selected from 1:9 or 2:8 or 3:7, preferably 2: 8 or 3:7 and more preferably 3:7. Further the ratio of solvent or mixture of solvents as defined above with second C_1-4 alcohol is selected from 1:1 or 1:2 or 1:3 or vice versa. More preferably the ratio is limited to 1 : 1.

The reaction mixture may be heated to dissolve the crude erlotinib hydrochloride. The temperature suitable for dissolving erlotinib hydrochloride depends on the solvent used and the amount of erlotinib hydrochloride in the solution. Typically, the solution is heated at a temperature of at least about ambient temperature to about reflux temperature, preferably at about 25°C to about 85°C. The solution may be prepared at other suitable temperatures as long as the erlotinib hydrochloride is sufficiently dissolved. Increasing the amount of erlotinib hydrochloride would generally require the use of higher temperatures. Routine experimentation will provide the approximate range of suitable temperatures for a given solvent and amount of erlotinib hydrochloride.

The process includes optional step of filtration in order to remove any extraneous matter present in the solution. The clear solution optionally filtered using any standard filtration techniques known in the art. In another embodiment, the solution of erlotinib hydrochloride in a first C_1-4 alcohol or a mixture first C_1-4 alcohol and halogenated hydrocarbon solvent is maintained at a temperature of about ambient temperature to about reflux temperature, preferably about 30>°C to about 60°C prior to and throughout the addition in to step b).

The step b) of the foregoing process includes addition of step a) of above in to a second C_1-4 alcohol. The second C alcohol includes but is not limited to methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, t-butanol, secondary butanol and the like and mixtures thereof; preferably isopropanol.

In another embodiment, the addition of step a) solution in to a second Ci-4 alcohol is carried out at a temperature of less than about 45°C, preferably less than about 30°C.

In another embodiment, the present invention provides an optional step of addition of seed crystals of erlotinib hydrochloride Form A in to a second CM alcohol of step b) prior to addition of step a) solution.

The step c) of the foregoing process includes cooling the step b) solution to less than about 30°C such that the erlotinib hydrochloride Form A can be isolated by conventional techniques, for example filtration. In the event that stirring is involved for a period of about 30 minutes to about 5 hours, preferably about 3 hours, the temperature during stirring can be less than about 20°C.

The resultant product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 40°C to about 100°C, preferably at about 50°C to about 80°C.

The erlotinib hydrochloride recovered using the process of the present invention is substantially in crystalline Form A. The crystalline erlotinib hydrochloride can be characterized by one or more techniques such as an X-Ray diffraction (XRD) pattern substantially in accordance with Figure.1.

The process of the present invention advantageously provide erlotinib hydrochloride in polymorph Form A in relatively high purity, e.g., a purity of greater than or equal to about 98% as measure by HPLC, preferably greater than or equal to about 99%, and more preferably greater than or equal to about 99.5%; and substantially free of other known polymorphic forms, for example erlotinib hydrochloride Form A of the invention contain less than 1% of polymorph Form B, preferably less than about 0.5%.

The present invention provides erlotinib hydrochloride pure Form A, obtained by the above process, as analyzed using the X-Ray powder diffraction with the conditions described as follows: an X-ray powder Diffractometer equipped with a Cu-anode ([λ] =1.54 Angstrom), X-ray source operated at 30kV, 15 mA and a Ni filter is used to strip K-beta radiation. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=3-45°20; step width=0.020°; and scan speed=2 minute.

In another embodiment, the present invention provides a pharmaceutical composition containing at least the substantially pure erlotinib hydrochloride Form A, prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient. Such pharmaceutical composition may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectable solution, etc.

EXAMPLES:

The following non limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.

EXAMPLE 1: Preparation of EthyI-2-amino-4, 5-bis (2-methoxy ethoxy) benzoate. To a solution of Ethyl-2-nitro-4, 5- bis (2-methoxy ethoxy) benzoate (lOg; 0.0292 mol) in methanol (50mL) , stannous chloride dihydrate (32.85g; 0.145 mol) was added at 25- 35°C.The reaction mixture was stirred over a period of 6-8 hr at 25-35°C.The completion of reaction was monitored by TLC. After the completion of reaction, the reaction mass was distilled off under vacuum at 40-45°C .The residue thus obtained was treated with DM water (200mL).The pH of the reaction mass was adjusted to 6.5-7.5 with 20 % NaOH (~55mL).The reaction mass was filtered off to remove the inorganic content. The filtrate was extracted with ethyl acetate (3x40 mL).The combined organic fractions were collected and distilled off under vacuum at 40-45°C. The residue in ethyl acetate was allowed to cool to 25-30°C and added aqueous hydrochloric acid (3.5mL), stirred further at about 0-5°C to obtain the salt .The reaction mass was filtered off and the wet cake was washed with chilled ethyl acetate (5mL).The resultant compound was suck dried and dried at a temperature about 50-55 C for a period of 4 hours to obtain the desired compound as hydrochloride salt (9g; yield: -90%). EXAMPLE 2: Preparation of 6, 7-bis (2-methoxy ethoxy) quinazolin-4-one

Ethyl-2-amino-4, 5-bis (2-methoxy ethoxy) benzoate (lOOg; 0285 mol) obtained by the process cited in Example No.l, was charged with formamide (226.8 g; 5.035 mol) and ammonium formate (18g) at a temperature about 25-35°C.The temperature of the reaction mass was raised to 140-145°C. After the completion of reaction, water was added (200 mL) followed by stirring with methylene chloride (lOOOmL). The organic fractions was isolated and distilled out at a temperature about 40-45°C. The residue was treated with ethyl acetate filtered and suck dried. The resultant compound was dried under vacuum to obtain the title compound (80g; yield: 80%).

EXAMPLE 3: Preparation of 4-chloro-6, 7-bis (2-methoxyethoxy) quinazoline

6, 7-bis (2-methoxy ethoxy) quinazolin-4-one (lOOg; 0.339 mol) as prepared from process cited in Example No.2, was dissolved in methylene chloride (500mL) containing catalytic dimethylformamide followed by addition of oxalyl chloride (142.3 g; 1.12 mol).The reaction mass allowed to reflux over a period of two hours. The solvent was removed in vacuum and the residue was dissolved in methylene chloride and washed with saturated aqueous sodium carbonate .The organic fraction was concentrated in vacuum to afford solid title compound (95g; yield:90%).

EXAMPLE 4: Preparation of Erlotinib hydrochloride crude

4-chloro-6, 7-bis (2-methoxyethoxy) quinazoline (100 g; 0.319 mol) as prepared from process cited in Example No.3 in Isopropanol (2000mL), stirred under nitrogen at a temperature about 25-35°C.To the above solution, 3-ethynyl aniline hydrochloride (54g; 0.35 lmol) was added and the reaction mass temperature was raised to 40-45°C.The reaction was maintained at 40-45°C for a period about 4 hours. The completion of the reaction was monitored by HPLC. After the completion of reaction, the reaction mass was allowed to cool to 25-35C° and solids thus obtained after stirring, were filtered and washed with isopropanol (500mL). The resultant compound was suck dried and dried under vacuum over a period of 6-8 hrs at 50-55°C to obtain crude erlotinib hydrochloride. (130g; 94%).

EXAMPLE 5: Preparation of Erlotinib hydrochloride Form A

The crude erlotinib hydrochloride (lOOg; 0.232 mol) in methanol (10 L) was heated to reflux, to obtain the clear solution. This reaction mass was filtered at the same temperature without any prior cooling and then washed with 50 mL of hot (~60°C) methanol. The filtrate temperature was maintained at 60-65°C.This reaction mass was slowly added to a precooled solution (less than 30°C) of isopropanol (10 L) seeded with Erlotinib hydrochloride Form A crystal under stirring. The reaction mass was allowed to crystallize under stirring at a temperature about 0-5°C.The reaction mass was filtered off over a stipulated period of time and the wet cake was washed with mixture of chilled isopropanol and methanol (1 :1 ; 100 mL). The resultant compound was suck dried and dried under vacuum over a period of 6-8 hrs at 50-55°C to obtain pure erlotinib hydrochloride Form A (yield: ~ 80% purity by HPLC: > 99.5 %).

EXAMPLE 6: Preparation of Erlotinib hydrochloride Form A

The crude erlotinib hydrochloride (40g) in methanol (360 mL) and methylene chloride (840mL) were stirred at 25 -35 °C to obtain the clear solution .The above reaction mass was filtered and washed with a mixture of methanol (60 mL) and methylene chloride (140mL).The filtrate was added to a solution of isopropanol (1.28 L) seeded with erlotinib hydrochloride Form A crystal under stirring at about 25- 35°C. The reaction mass was allowed to crystallize under stirring at a temperature about 25- 35°C.The reaction mass was filtered off over a stipulated period of time and the wet cake was washed with isopropanol ( 100 mL). The resultant compound was suck dried and dried under vacuum over a period of 6-8 hrs at 50-55°C to obtain pure erlotinib hydrochloride Form A. (yield: ~ 80%; purity by HPLC: > 99.5 %).

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.

Claims

We Claim:

Claim 1 : A process for preparation of erlotinib or its pharmaceutically acceptable salts thereof of Formula I,

with stannous chloride to obtain ethyl 4,5-bis-(2-methoxyethoxy)-2-aminobenzoate of Formula

Claim 2: The process of claim 1, wherein the reduction is carried out in a suitable organic solvent selected from the group consisting of alcohols, esters, ketones, amides, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons, cyclic hydrocarbons, nitroalkanes and mixtures thereof.

Claim 3: The process of claim 2, wherein the suitable organic solvent is methanol.

Claim 4: The process of claim 1, wherein the stannous chloride is about 2 to about 10 moles per mole of ethyl 4,5-bis-(2-methoxyethoxy)-2-nitrobenzoate.

Claim 5: The process of claim 4, wherein the stannous chloride is about 5 moles per mole of ethyl 4,5-bis-(2-methoxyethoxy)-2-nitrobenzoate.

Claim 6: The process of claim 1, wherein the reduction is carried out at a temperature of about 25°C to about 85°C. Claim 7: The process of claim 6, wherein the reduction is carried out at a temperature of about 25°C to about 35°C.

Claim 8: The process of claim 1 , wherein the process further comprises: a) cyclizing the ethyl 4,5-bis-(2-methoxyethoxy)-2-aminobenzoate obtained from the process, of any of claims 1-7; with formamide to obtain 6, 7-bis (2-methoxyethoxy) quinazolin-4-one of Formula,

b) chlorinating the 6, 7-bis (2-methoxyethoxy) quinazolin-4-one with a chlorinating agent to obtain 4-chloro-6, 7-bis (2-methoxyethoxy) quinazoline of Formula,

c) condensing the 4-chloro-6, 7-bis (2-methoxyethoxy) quinazoline with 3-ethynyl aniline or its hydrochloride salt to obtain erlotinib or a hydrochloride salt thereof,

Claim 9: The process of claim 8, wherein the cyclization is carried out in the presence of ammonium formate. Claim 10: The process of claim 8, wherein the chlorinating agent is thionyl chloride, oxalyl chloride and the like.

Claim 11 : The process of claim 8, wherein the process further comprises purifying the erlotinib or a hydrochloride salt thereof in an organic solvent; wherein the organic solvent is selected from a C_1-4 alcohol, halogenated hydrocarbons or mixtures thereof.

Claim 12: The process of claim 11, wherein the organic solvent is selected from a C alcohol such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, t- butanol, secondary butanol and the like; halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform and the like; and mixtures thereof.

Claim 13: The process of claim 11, wherein the erlotinib hydrochloride is isolated as substantially pure crystalline Form A. Claim 14: A process for preparation of substantially pure erlotinib hydrochloride polymorph Form A, comprising the steps of:

a) dissolving erlotinib hydrochloride in a first C_1-4 alcohol or a mixture first C alcohol and halogenated hydrocarbon solvent at a temperature of about ambient temperature to about reflux temperature,

c) cooling the solution to less than 30°C,

d) filtering the erlotinib hydrochloride Form A.

Claim 15: The process of claim 14, wherein the first C alcohol is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, t- butanol, secondary butanol and the like and mixtures thereof.

Claim 16: The process of claim 14, wherein the halogenated hydrocarbon solvent is selected from the group consisting of methylene chloride, ethylene chloride, chloroform and the like and mixtures thereof. Claim 17: The process of claim 14, wherein the first C_1-4 alcohol is methanol and the halogenated hydrocarbon solvent is methylene chloride.

Claim 18: The process of claim 14, wherein the step of dissolving erlotinib hydrochloride is carried at a temperature of about 25°C to about 85°C.

Claim 19: The process of claim 14, wherein the second C alcohol is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, t-butanol, secondary butanol and the like and mixtures thereof. Claim 20: The process of claim 19, wherein the second C_M alcohol is isopropanol.

Claim 21 : The process of claim 14, further comprises step a) solution is maintained at a temperature of about 30°C to about 60°C prior to and throughout the addition in to step b). Claim 22: The process of claim 14, wherein the step a) solution is added in to step b) at a temperature of less than 30°C.

Claim 23: The process of claim 14, further comprises adding seed crystals of erlotinib hydrochloride Form A in to second CM alcohol of step b) prior to addition of step a) solution. Claim 24: A pharmaceutical composition comprising substantially pure erlotinib hydrochloride polymorph Form A, according to any of claims 1-23, and at least one pharmaceutically acceptable excipient.