FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention: PURE COMPOUNDS
2. Applicants):

(a) NAME. MYLAN INDIA PRIVATE LIMITED
(b) NATIONALITY: An Indian Company.
(c) ADDRESS; Plot I A/2, M.I.D.C. Industrial Estate, Taloja,
Panvel, District Raigad, Maharashtra-410208, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to the preparation of pure Erlotinib and salts and polymorphs thereof.
BACKGROUND OF THE INVENTION
Erlotinib hydrochloride (1), chemically named as N-(3-ethynylphenyl)-6,7-bis-(2-rneth-oxyethoxy)-4-quinazolinamine monohydrochloride, is an inhibitor of oncogenic and proto-oncogenie protein tyrosine kinases, e.g. epidermal growth factor receptor (EGFR). Erlotinib is therefore useful in the treatment of proliferative disorders and is currently marketed for the treatment of lung cancer and pancreatic cancer.

It has been reported that Erlotinib hydrochloride can exist in different polymorphic forms. The manufacturing process for many pharmaceuticals is hindered by the fact that the organic compound which is the active ingredient can exist in more than one polymorphic form. It is essential in pharmaceutical development to ensure that the manufacturing process for the preparation of the active ingredient affords a single polymorph with a consistent level of polymorphic purity. If the manufacturing process produces a product with varying degrees of polymorphic purity and/or or

where the process does not control polymorphic inter conversion, it could lead to serious problems in dissolution and/or bioavailability in the finished pharmaceutical composition comprising the active ingredient.
Erlotinib hydrochloride is disclosed in patent US 5,747,498 and details of the disclosed method for the preparation of Erlotinib hydrochloride are described in Scheme 1.

4-Chloro-6,7-bis-(2-methoxyethoxy)quinazoline (2) was reacted with 3-ethynylaniline (3) or its hydrochloride salt using various solvents and pyridine as a base to yield Erlotinib hydrochloride (1) which was treated with saturated aqueous NaHC03 to form Erlotinib base (4). The base (4) obtained was purified by extraction

with methanol/chloroform, followed by flash chromatography to afford purified Erlotinib base. The purified base was further treated with hydrochloric acid in the presence of diethyl ether and chloroform to yield Erlotinib hydrochloride. This isolation of purified Erlotinib Base required the use of a lengthy workup process including column chromatography and required the chlorinated solvent, chloroform, which is not particularly suitable for commercial production of pharmaceuticals. Furthermore, the purification by column chromatography is neither economical nor feasible at industrial scale. In addition, substantially pure Erlotinib could not be obtained.
Two crystalline forms of Erlotinib hydrochloride (Polymorph A and Polymorph B), were characterized by XRPD in patent application, WO 01/34574. Erlotinib hydrochloride can be obtained in Form A or in a mixture of polymorph A and B, by refluxing 3-ethynylaniline and 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline in a mixture of toluene and acetonitrile. This afforded Polymorph A or a mixture of polymorph A and B. It was also disclosed that the formation of polymorph A was favored by reducing the amounts of acetonitrile with respect to toluene. Furthermore, Erlotinib hydrochloride Polymorph A can be converted into Polymorph B by refluxing the polymorph A with alcohol/water. Consequently, in the disclosed methods, there was always contamination of form A with form B and vice-versa. In addition, the products of the reaction are not chemically pure and difficult to purify thereafter. Consequently, these methods are not suitable for preparation of commercial quantities of pure Polymorph A.
A process for the preparation of Erlotinib hydrochloride, polymorph E, by condensation reaction of 3-ethynylaniline and 4-chloro-6,7-bis-(2-methoxyethoxy)quinazoline in (a,a,a)-trifluorotoluene and HC1 was disclosed in U.S. Patent application 2004/0162300. Polymorph E was characterized by XRPD, IR and

melting point. However, (a,a,a)-trifluorotoluene is a highly flammable and dangerous solvent for the environment and is not suitable for commercial production. A process for preparation of Erlotinib hydrochloride, Polymorph A by reaction of Erlotinib base with aqueous or gaseous HC1 was disclosed in US 2009/0131665. In this method, toluene, a mixture of toluene and methanol, TBME, ethyl acetate, 1-butanol or MIBK were used as a solvent. However, when DCM, diethyl ether, isopropyl acetate, was used as a solvent, polymorph B was formed. In practice, it has been found that the disclosed methods are inconsistent and afford polymorphic mixtures. In particular, example 1 of US 2009/131665 was repeated and Erlotinib hydrochloride was obtained with only 97% purity. In addition, XRPD analysis showed that the example afforded Form B or mixtures of Forms A and B. Furthermore, several crystallizations of Erlotinib hydrochloride, obtained from repetition of the example, using various solvents and their combinations would not yield a product pure enough to comply with ICH guidelines.
A process for the preparation of a hydrate of Erlotinib hydrochloride comprising crystallization of Erlotinib hydrochloride using water as solvent, preferably in the absence of organic solvent was disclosed in US 20080167327. This patent also disclosed the process to prepare hemihydrate polymorph Form I as well as Form II.
A process for the preparation of Erlotinib Hydrochloride, Polymorph M, N and P by reaction of Erlotinib Base and aqueous or gaseous HC1 dissolved in organic solvents was disclosed in WO 2008/102369.
A process for the preparation of Erlotinib Hydrochloride by condensation reaction of 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline and 3-ethynylaniline in isopropyl alcohol as a solvent and pyridine as a base was disclosed in Molecules Journal (Vol. 11, 286, 2006) but no details on the polymorph were disclosed.

A method for the preparation of Erlotinib hydrochloride polymorph A comprising passing hydrochloride gas onto solid Erlotinib base containing residual amounts of isopropanol was disclosed in WO 2010/040212. However, in practice it was found that the process did not afford chemically or polymorphically pure product. Repetition of example 1 (page 8) of WO 2010/040212 to prepare Erlotinib hydrochloride, by reaction of Erlotinib Base and gaseous HC1 in IPA as a solvent, afforded a mixture of Polymorph A and Polymorph B (as checked by XRPD).
A process for the preparation of acid salt of Erlotinib hydrochloride by reaction of 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline and 3-ethynylaniline or an acid salt of 3-ethynylaniline under acidic conditions to form the corresponding Erlotinib salt was disclosed in US 2010/0094004. In order to complete the reaction, several hours (6 hours) of reflux was required and hence it is not a cost effective process. In addition, in practice it was found.that the process did not afford chemically or polymorphically pure product.
A process for the preparation of Erlotinib base, polymorph Gl, G2 and G3 was disclosed in WO 2009/002538 and WO 2010/05924.


Scheme 2
A method for the preparation of Erlotinib hydrochloride was disclosed in WO 2009/0306377. The method, illustrated in Scheme 2, involves treating 6,7-Dimethoxy-4(3H)-quinazolone (5) with hydrobromic acid or pyridine-hydrochloric acid to afford 6,7-dihydroxy-4(3H)-quinazolone (6), which was diacetylated with acetic anhydride to afford diester (7), which was treated with oxalyl chloride/DMF to afford 4-chloro-6,7-diacetoxyquinazoline (8). Compound (8) was condensed with 3-ethynylaniline to afford N-(3-ethynylphenyl)-6,7-dihydroxy-4-quinazolinamine hydrochloride (9), which was converted into the diol N-(3-ethynylphenyl)-6,7-dihydroxy-4-quinazolinamine (10) by treatment with aqueous ammonia/methanol. The diol (10) was treated with 2-iodo-ethylmethyl ether to yield compound (4) which

on treatment with HC1 afforded Erlotinib hydrochloride (1). However, this preparation of Erlotinib Hydrochloride is a long synthetic route and gives low yields and requires very toxic reagents like pyridine, HBr and controlled reagents like acetic anhydride. Hence, it is not suitable for large scale production.
OBJECTS OF THE INVENTION
The prior art processes described above for the preparation of Erlotinib and its salts have major disadvantages with respect to the formation and removal of process related chemical and polymorphic impurities; poor commercial viability due to use of hazardous reactants; expensive, time consuming separation methods such as column chromatography and/or low yields and purity of final and intermediate products.
As the commercial production of Erlotinib hydrochloride is of great importance, for the treatment of cancer, and in view of the above disadvantages associated with the prior art there is a real need for alternative and improved processes for the preparation of erlotinib hydrochloride which do not involve multiple steps and further eliminates the need for cumbersome purification techniques, particularly for the removal of the chemical and polymorphic impurities. The alternative processes must be economical and high yielding and provide erlotinib and its salts with a high degree of chemical and polymorphic purity.
Therefore, the objective of the present invention is to develop improved and efficient processes for the preparation of Erlotinib base and salts with higher purity and higher yields than in the processes disclosed in the prior art. Another objective is the preparation and purification of Erlotinib hydrochloride Polymorph A, substantially free from Polymorph B and other polymorphs. A further objective is to provide Erlotinib and Erlotinib hydrochloride free of all chemical and polymorphic impurities.

SUMMARY OF THE INVENTION
The present inventors have surprisingly developed new processes which circumvent the problems associated the problems reported in the prior art, as described above, which allow the preparation of Erlotinib base and its salts, such as the hydrochloride salt, with very high chemical and polymorphic purity.
Therefore a first aspect of the present invention provides a process for the preparation of Erlotinib base, or a salt thereof, comprising reacting 4-chloro-6,7-bis-(2-methoxyethoxy)qumazoline and 3-ethynylaniline in a reaction solvent, wherein the reaction mixture does not contain an external acid or base and with the proviso that the reaction solvent is not 2-propanoI.
A second aspect of the present invention provides a process for the preparation of substantially pure Erlotinib base, or a substantially pure salt thereof, comprising reacting 4-chloro-6,7-bis-(2-methoxyethoxy)quinazoline and 3-ethynylaniline in a reaction solvent, wherein the reaction mixture does not contain an external acid or base.
Preferably, the reaction solvent in the first or second aspect of the present invention is a straight chain, branched or cyclic C1 to C6 alcohol, more preferably, the reaction solvent is selected from methanol, ethanol, propanol, 1-butanol or mixtures thereof and most preferably, the reaction solvent is methanol.
Preferably, Erlotinib base is isolated in the process according to the first or second aspects of the present invention.
Preferably, in the process according to the first or second aspects of the present invention, the salt of Erlotinib is the hydrochloride salt.

Preferably, the isolated Erlotinib base is further purified, typically by crystallization from a solvent, wherein the solvent is preferably a straight chain, branched or cyclic C1 to C6 alcohol, wherein the solvent is more preferably selected from methanol, ethanol, propanol, 1-butanol or mixtures thereof and most preferably, the solvent is I-butanol.
A preferred process according to the first or second aspects of the present invention is when the isolated Erlotinib base, which is optionally further purified as described above, is converted into Erlotinib hydrochloride by reaction in a solvent with aqueous HC1 or non-aqueous HC1. Preferably, the solvent is a straight chain, branched or cyclic C1 to C6 alcohol, more preferably, the solvent is selected from methanol, ethanol, propanol, 1-butanol, 1-pentanol or mixtures thereof and most preferably the solvent is 1-pentanol.
Preferably, the Erlotinib hydrochloride obtained by the process according to the first or second aspects of the present invention is further purified by crystallization from a solvent. Preferably, the solvent is a straight chain, branched or cyclic C1 to C6 alcohol, more preferably, the solvent is selected from methanol, ethanol, propanol, 1-butanol, 1-pentanol or mixtures thereof and most preferably, the solvent is 1-pentanol.
Preferably, the Erlotinib hydrochloride is isolated as the Form A polymorph.
Preferably, the reaction mixture is heated in the process according to the first or second aspects of the present invention. Preferably, the reaction mixture is heated at the reflux temperature of the reaction solvent or alternatively, the reaction mixture is heated at 35-40 °C.

Preferably, the crude Erlotinib base is purified by dissolving in 1-butanol, optionally with activated charcoal, at a temperature between 65 °C and 100 °C, more preferably wherein the temperature is between 80-90 °C.
A preferred process according the present invention comprises the preparation of Erlotinib hydrochloride Form A by either crystallization of Erlotinib hydrochloride from a solvent or dissolving Erlotinib base in a solvent and mixing with aqueous or non-aqueous HC1 and crystallization of Erlotinib hydrochloride from the solvent. Preferably, the solvent is a straight chain, branched or cyclic C1 to C6 alcohol, preferably selected from methanol, ethanol, propanol, 1-butanol, 1-pentanol or mixtures thereof. Most preferably the solvent is 1-pentanol.
A third aspect of the present invention provides a process according to the first or second aspects of the present invention wherein the HPLC purity of the Erlotinib base or salt obtained is more than 97%, more preferably more than 98%, more preferably more than 99%, more preferably more than 99.5%, more preferably more than 99.8% and most preferably more than 99.9%. Preferably, in the third aspect of the present invention the salt is the hydrochloride.
A fourth aspect of the present invention provides Erlotinib base or a salt thereof with a HPLC purity of more than 99.0%, more preferably more than 99.5%, more preferably more than 99.8% and most preferably more than 99.9%. Preferably, in the fourth aspect of the present invention the salt is the hydrochloride
In a fifth aspect of the present invention, the Erlotinib hydrochloride Form A polymorph isolated in a process according to the present invention, comprises less than 3%, more preferably less than 2%, more preferably less than 1%, and most preferably less than 0.5% of Erlotonib hydrochloride in Form B or other polymorphic forms.

A sixth aspect of the present invention provides Erlotinib hydrochloride Form A comprising less than 3%, more preferably less than 2%, more preferably less than 1%, most preferably less than 0.5% of Erlotinib hydrochloride in Form B or other polymorphic forms.
A seventh aspect of the present invention provides a pharmaceutical composition comprising Erlotinib according to an aspect of the present invention or when prepared by a process according to an aspect of the present invention. Preferably, the pharmaceutical composition is for the use to treat or prevent a disorder wherein inhibiting protein tyrosine kinases is beneficial. Preferably, the disorder is a cancer and more preferably, the cancer is lung cancer or pancreatic cancer.
Preferably, the pharmaceutical composition according to the seventh aspect of the present invention comprises a combination with one or more other active ingredients or for use in combination with one or more other active ingredients. Preferably, the one or more other active ingredients is an anti cancer drug, preferably gemcitabine.
The term erlotinib as used herein throughout the description and claims means erlotinib and/or any salt, solvate or polymorph thereof, unless otherwise specified.
For the purposes of the present invention, the erlotinib or its salts are "substantially pure" if they comprise less than 3%, preferably less than 2%, preferably less than 1%, preferably less than 0.5%, preferably less than 0.2% and most preferably less than . 0.1 % of chemical impurities and/or polymorphic impurities..

DETAILED DESCRIPTION OF THE INVENTION
Convenient processes for the preparation of chemically pure and polymorphically pure Erlotinib and Erltonib salts, such as the hydrochloride salt, have been provided by the present invention. These processes use mild conditions and low temperatures thus minimizing the occurrence of polymorphic inter conversion and producing Erltonib hydrochloride Form A with very high polymorphic purity.
Preferred embodiments of the processes according to the present invention are described in more detail below.
Preferably, the present invention provides processes for the preparation of Erlotinib hydrochloride comprising reaction of 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline (2) and 3-ethynylaniline (3) in methanol without the use of external acid or base. External acid or base has been used as a catalyst in prior art processes.
The purification of crude Erlotinib base (4) is preferably performed by crystallisation from 1-butanol to afford a product with very high yield and purity with an impurity profile well within ICH guidelines.
The purified base (4) is preferably converted into Erlotinib Hydrochloride (Polymorph A) (1) by crystallisation from 1-pentanol and aqueous HC1, or alternatively gaseous HC1 dissolved in ]-pentanol.
A preferred embodiment of the present invention is illustrated in Scheme 3.
Another preferred embodiment of the present invention provides a process for the preparation of Erlotinib hydrochloride (1) comprising the condensation reaction of 4-chloro-6, 7-bis-(2-methoxyethoxy)-quinazoline (2) and 3-ethynylaniline (3) by

refluxing in a straight chain, branched or cyclic C1 to C6 alcohol solvent without the use of external acid or acid salt of 3-ethynyl aniline or base.

Scheme 3
In another preferred embodiment of the present invention, the crude Erlotinib Hydrochloride (1) obtained is suspended in a solvent, such as methanol, and treated with a base, such as sodium carbonate, to yield crude Erlotinib base (4). If required, an anti solvent, such as water can be added to precipitate the crude Erlotinib base.

The Erlotinib base is typically isolated by known methods such as filtration or
centrifugation.
The base used to isolate the Erlotinib base is preferably sodium carbonate but any
suitable base may be used as an alternative. Preferred alternative bases are selected
from the group consisting of sodium hydroxide, potassium hydroxide, potassium
carbonate, ammonia, pyridine and triethylamine.
Preferably, the purification of crude Erlotinib Base (4) to Pure Erlotinib base (4) was achieved by crystallization from 1-butanol/activated charcoal. Preferably, the purified Erlotinib base is obtained with a HPLC purity >99.9%,
Preferably, the purified Erlotinib base obtained has a water content not more than 5%. The purified Erlotinib base may also be dried at 65-75°C to obtain an anhydrous base.
Preferably, Erlotinib hydrochloride Polymorph Form A is prepared by reaction of the purified Erlotinib Base (4) in a suitable solvent with aqueous HC1 or gaseous HC1. Preferably, the solvent is 1-pentanol. Preferably, the Erlotinib hydrochloride is obtained with a HPLC purity >99.9%.
Preferably, the Erlotinib hydrochloride obtained was substantially pure and free from polymorph B or other polymorphic forms.
A particularly preferred embodiment of the present invention for the preparation of Erlotinib hydrochloride (1) comprises the following steps:
a) Condensation of 4-chloro-6,7-bis-(2-methoxyethoxy)quinazoline (2) and 3-
ethynylaniline (3) in an organic reaction solvent to yield crude Erlotinib
Hydrochloride (1).

b) Treatment of the crude Erlotinib hydrochloride (1) with base, such as sodium carbonate, to yield crude Erlotinib base (4).
c) Crystallisation of the crude Erlotinib Base (4) from 1-butanol to afford pure Erlotinib base (4)
d) Crystallisation of the purified Erlotinib Base (4) with aqueous HC1 in 1-pentanol to afford Erlotinib hydrochloride Form A.
Preferably, in step (a), the reaction solvent is a straight chain, branched or cyclic C1 to C6 alcohol. Most preferably, the solvent is methanol. Preferably, 5 to 50 vol, more preferably 20 vol of solvent is used.
Preferably, the 3-ethynylaniline was added into a solution of 4-chloro-6,7-bis-(2-methoxyethoxy)quinazoline in methanol at 25 to 45 °C and more preferably at 35 to 40°C.
Preferably, after complete addition of 3-ethynylaniline into a solution of 4-chloro-6,7-bis-(2-methoxyethoxy)quinazoline in methanol, the reaction mixture was heated to reflux for 1 to 5 hrs, more preferably 2 to 3 hours.
Preferably, crude Erlotinib Hydrochloride was isolated by filtration at 25-30°C.
Preferably, the base, such as sodium carbonate, was added between 10 to 40°C and more preferably between 25 to 30°C.
If required, the volume of anti solvent, such as water is added preferably at 5 to 15 vol., more preferably 10 volumes.

Preferably, the isolated crude Erlotinib base was dried under reduced pressure at 40 to 80 °C, more preferably 65-70 °C.
Preferably, the dried crude Erlotinib Base has a water content of not more than 30% and more preferably not more than 10% (w/w) determined by KF.
The purification of crude Erlotinib base is preferably achieved by crystallisation from solvents selected from an alcoholic solvent such as methanol, ethanol, propanol, isopropyl alcohol, butanol and 1-pentanol and most preferably 1-butanol.
Most preferably, the purification of crude Erlotinib Base was achieved by crystallistion using 6 to 8 volumes of 1-butanol and activated carbon at 75-80 °C.
The drying of purified Erlotinib Base was preferably performed at a temperature ranging from 50 to 100°C and more preferably 65 to 75°C under reduced pressure ranging from 600 mm Hg to 50 mm Hg to afford Erlotinib base hydrate having a water content of not more than 5% (determined by KF).
In another embodiment of the present invention the purified Erlotinib base obtained is dried at 65-75°C to obtain an anhydrous form of Erlotinib base with a water content of not more than 0.2%.
In a preferred aspect of present invention, Erlotinib base was converted into Erlotinib hydrochloride by using the following sequence:
(i) Erlotinib Base was added into 1-pentanol (ii) Aqueous HC1 was added (iii) The mixture was stirred and

(iv) The resulting solid was isolated
In a preferred embodiment, in step (i), Erlotinib base is added into ] -pentanol at a temperature between 0 to 30 °C, more preferably at a temperature between 5 to 10 °C. Preferably, 1-pentanol is used in the range from 10 to 30 vol. and more preferably 20 vol.
Preferably, in step (ii), hydrochloric acid was slowly added to a solution at a temperature between 0 to 30 °C, more preferably between 5 to 10 °C. The hydrochloric acid used is preferably in the form of aqueous hydrochloric acid or in the form of hydrogen chloride gas or hydrogen chloride dissolved in the 1-pentanol. Preferably, the hydrochloric acid was used between 0.25 vol. to 2 vol. of aq. HC1 and more preferably 0.5 vol. of aq. HC1. Preferably, after hydrochloric acid addition, the reaction was stirred for at least 1 to 3 hours, more preferably for about 1 hour.
Preferably, the Erlotinib hydrochloride was isolated by filtration at a temperature ranging from 0 to 30 °C, more preferably between 5 to 10 °C.
The white crystalline Erlotinib hydrochloride Polymorph A obtained had an impurity profile compliant with ICH guidelines. The HPLC purity obtained was preferably more than 99.5%, more preferably more than 99.8% and most preferably more than 99.9%.
The Erlotinib hydrochloride, crystalline polymorph form A, was characterized by XRPD. The XRPD pattern and 20 values are in good agreement with the Form A characterised in the prior art (eg in document WO 01/34574), although the Form A of the present invention is more pure..
The pharmaceutical composition according to the seventh aspect of the present invention can be a solution or a suspension but is preferably a solid oral dosage form. Preferred oral dosage forms in accordance with the invention include tablets, capsules and the like which, optionally, may be coated if desired. Tablets can be prepared by conventional techniques, including direct compression, wet granulation and dry

granulation. Capsules are generally formed from a gelatine material and can include a conventionally prepared granulate of excipients in accordance with the invention.
The pharmaceutical composition according to the present invention typically comprises one or more conventional pharmaceutically acceptable excipient(s) selected from the group comprising of a filler, a binder, a disintegrant, a lubricant and optionally further comprises at least one excipient selected from colouring agents, adsorbents, surfactants, film formers and plasticizers.
If the solid pharmaceutical formulation is in the form of coated tablets, the coating may be prepared from at least one film-former such as hydroxypropyl methylcellulose, hydroxypropyl cellulose or methacrylate polymers which optionally may contain at least from one plasticizer such as polyethylene glycols, dibutyl sebacate, triethyl citrate, and other pharmaceutical auxiliary substances conventional for film coatings, such as pigments and fillers.
Preferably the pharmaceutical compositions according to the present invention are in unit dosage form comprising Erlotinib in an amount of from 1 mg to 500 mg, such that the amount of Erlotinib administered is from 0.1 mg to 100 mg per Kg per day.
The details of the invention, its objects and advantages are illustrated below in greater detail by non-limiting examples.
EXAMPLES
Example 1
Preparation of Crude Erlotinib base
4-chloro-6,7-bis-(2-methoxyethoxy)quinazoline (50 g, 0.1598 mol) was added to methanol (900 ml, 18 vol.) and the mixture was heated to 35-40°C to obtain a uniform suspension. 3-Ethynylaniline (20.6 g, 0.1758 mol) was mixed with 100 ml (2 vol.) of methanol and added drop wise into the the uniform suspension of 4-chloro-

6,7-bis-(2-methoxyethoxy)quinazoline over a period of 15 min at 35-40°C. The temperature of the reaction mixture was slowly raised to 60-65°C and maintained for 2-3 hours. The reaction was monitored by TLC as well as HPLC. When the 4-chloro-6,7-bis-(2-mefhoxyethoxy)-quinazoline content in the reaction mixture was not more than 3%, the reaction mixture was cooled to 25-30°C and crude Erlotinib hydrochloride was isolated by filtration. The cake was washed with 100 ml (2 vol.) of methanol and suck dried.
The wet cake of crude Erlotinib hydrochloride was added to 500 ml (10 vol.) of methanol under stirring at 25-30°C to obtain a suspension. Sodium carbonate (33.8 g, 0.3197 mol) was added to the mixture at 25-30°C and stirred for one hour at. 25-30°C. 500 ml (10 vol) of water was added to the reaction mixture and stirred for one hour. The crude Erlotinib base was isolated by filtration and suck dried before adding it to 250 ml (5 vol.) of water at 25-30°C and stirred for 30 min. The Erlotinib base was isolated by filtration and washed with 50 ml (1 vol.) of water and suck dried to get 70 g as a wet cake. This wet cake was dried under reduced pressure at 100 mm Hg for 3 hour at 60-65°C to afford 63g of Erlotinib base as an off-white powder.
Molar yield = 91.7% HPLC purity >99%.
Example 2
Further Purification of crude Erlotinib base.
60 g of crude Erlotinib base was added to 480 ml (8 vol.) of 1 -butanol under stirring at 25-30°C. The mixture was heated to 80-85°C to obtain a clear solution and maintained for one hour at 80-90°C. The solution was slowly cooled to 25-30°C and the product was isolated by filtration and washed with 120 ml (2 vol.) of 1-butanol. The wet cake was again added to 360 ml (6 vol.) of 1-butanol and the mixture heated to 80-90°C to obtain a clear solution. 2.7 g Activated charcoal (Norit B) was added into the clear solution and maintained for 1 hour at 80-85°C. The reaction mixture

was filtered through a celite bed at 80-85°C and the celite bed was washed with 1 volume hot 1-butanol. The combined mother liquor was slowly cooled to 25-30°C and stirred for 1 hour. The product was isolated by filtration and washed with 120 ml (2 vol.) of 1-butanol. The purified Erlotinib base was dried at 65-75°C for 8 hours, under reduced pressure 160 mm Hg to afford 35 g as a white powder.
Molar yield = 58.3% HPLC purity 99.9%
Example 3
Preparation of Erlotinib Hydrochloride Polymorph Form A
115 g (0.0295 mol) of Erlotinib base was added to 20 vol. of 1-pentanol at 25-30°C. The mixture was cooled to 5 to 10°C and stirred for 30 min. to obtain a suspension. 57.5 g of aqueous hydrochloric acid was added drop wise at 5-10°C and the mixture stirred for 1 hour. The product was isolated by filtration and washed with 230 ml (2 vol.) of 1-pentanol. The product was dried under reduced pressure (50 mm Hg) at 0-60°C to obtain 113 g of Erlotinib hydrochloride Polymorph A as a white solid. Molar yield= 90% HPLC purity 99.85%
No polymorphic Form B or any other polymorphic form could be detected in the product. (Level of detection 0.5%).

WE CLAIM
1. A process for the preparation of Erlotinib base, or a salt thereof, comprising reacting 4-chloro-6,7-bis-(2-methoxyethoxy)quinazoline and 3-ethynylaniline in a reaction solvent, wherein the reaction mixture does not contain an external acid or base and with the proviso that the reaction solvent is not 2-propanol.
2. A process for the preparation of substantially pure Erlotinib base, or a substantially pure salt thereof, comprising reacting 4-chloro-6,7-bis-(2-methoxyethoxy)quinazoline and 3-ethynylaniline in a reaction solvent, wherein the reaction mixture does not contain an external acid or base.
3. A process according to claim 1 or 2 wherein the reaction solvent is a straight chain, branched or cyclic C1i to C6, alcohol.
4. A process according to claim 3 wherein the reaction solvent is selected from methanol, ethanol, propanol, 1-butanol or mixtures thereof.
5. A process according to claim 4 wherein the reaction solvent is methanol.
6. A process according to any preceding claim wherein the salt of Erlotinib is the hydrochloride salt.
7. A process according to any preceding claim wherein Erlotinib base is isolated.
8. A process according to claim 7 wherein the isolated Erlotinib base is further purified.
9. A process according to claim 8 wherein the isolated Erlotinib base is further purified by crystallization from a solvent.
10. A process according to claim 9 wherein the solvent is a straight chain, branched or cyclic C1 to C6 alcohol.
11. A process according to claim 10 wherein the solvent is selected from methanol, ethanol, propanol, 1 -butanol or mixtures thereof.
12. A process according to claim 11 wherein the solvent is 1-butanol.

13. A process according to claim 7 wherein the isolated Erlotinib base, which is optionally further purified according to claims 8 to 12, is converted into Erlotinib hydrochloride by reaction in a solvent with aqueous HC1 or non-aqueous HC1.
14. A process according to claim 13, wherein the solvent is a straight chain, branched or cyclic C1 to C6 alcohol.
15. A process according to claim 14 wherein the solvent is selected from methanol, ethanol, propanol, l-butanol, 1-pentanol or mixtures thereof.
16. A process according to claim 15 wherein the solvent is 1-pentanol.
17. A process according to claim 6 or claims 13 to 16, wherein the Erlotinib hydrochloride is further purified by crystallization from a solvent.
18. A process according to claim 17 wherein the solvent is a straight chain, branched or cyclic C1 to C6 alcohol.
19. A process according to claim 18 wherein the solvent is selected from methanol, ethanol, propanol, l-butanol, 1-pentanol or mixtures thereof.
20. A process according to claim 19 wherein the solvent is 1-pentanol.
21. A process according to claims 6 or claims 13 to 20 wherein the Erlotinib hydrochloride is isolated as the Form A polymorph.
22. A process according to any preceding claim wherein the reaction mixture is heated.
23. A process according to claim 22 wherein the reaction mixture is heated at the reflux temperature of the reaction solvent.
24. A process according to claim 22 wherein the reaction mixture is heated at 35-40°C.
25. A process according to claim 12 wherein the crude Erlotinib base is dissolved in l-butanol, optionally with activated charcoal, at a temperature between 65°C and 100°C.
26. A process according to claim 25 wherein the temperature is between 80 and 90°C.
27. A process according to any preceding claim wherein the HPLC purity of the Erlotinib base or salt obtained is more than 97%.

28. A process according to claim 27 wherein the HPLC purity of the Erlotinib base or salt obtained is more than 98%.
29. A process according to claim 28 wherein the HPLC purity of the Erlotinib base or salt obtained is more than 99%.
30. A process according to claim 29 wherein the HPLC purity of the Erlotinib base or salt obtained is more than 99.5%,
31. A process according to claim 30 wherein the HPLC purity of the Erlotinib base or salt obtained is more than 99.8%.
32. A process according to claim 31 wherein the HPLC purity of the Erlotinib base or salt obtained is more than 99.9%.
33. A process according to claims 27 to 32 wherein the salt is the hydrochloride.
34. Erlotinib base or a salt thereof with a HPLC purity of more than 99.0%.
35. Erlotinib base or salt thereof according to claim 34 with a HPLC purity of more than 99.5%.
36. Erlotinib base or salt thereof according to claim 35 with a HPLC purity of more than 99.8%.
37. Erlotinib base or salt thereof according to claim 36 with a HPLC purity of more than 99.9%.
38. Erlotinib according to claims 34 to 37 wherein the salt is the hydrochloride.
39. A process for the preparation of Erlotinib hydrochloride Form A comprising crystallization of Erlotinib hydrochloride from a solvent.
40. A process for the preparation of Erlotinib hydrochloride Form A comprising dissolving Erlotinib base in a solvent, mixing with aqueous or non-aqueous HC1 and crystallization of Erlotinib hydrochloride from the solvent.
41. A process according to claim 39 or 40 wherein the solvent is a straight chain, branched or cyclic C1 to C6 alcohol.
42. A process according to claim 41 wherein the solvent is selected from methanol, ethanol, propanol, 1-butanol, 1-pentanol or mixtures thereof.

43. A process according to claim 42 wherein the solvent is 1-pentanol.
44. A process according to claim 21 or claims 39 to 43 wherein the Form A polymorph isolated comprises less than 3% of Erlotonib hydrochloride in Form B or other polymorphic forms.
45. A process according to claim 44 wherein the Form A polymorph isolated comprises less than 2% of Erlotonib hydrochloride in Form B or other polymorphic forms.
46. A process according to claim 45 wherein the Form A polymorph isolated comprises less than 1% of Erlotonib hydrochloride in Form B or other polymorphic forms.
47. A process according to claim 46 wherein the Form A polymorph isolated comprises less than 0.5% of Erlotonib hydrochloride in Form B or other polymorphic forms.
48. Erlotinib hydrochloride Form A comprising less than 3% of Erlotinib hydrochloride in Form B or other polymorphic forms.
49. Erlotinib hydrochloride Form A according to claim 48 comprising less than 2% of Erlotinib hydrochloride in Form B or other polymorphic forms.
50. Erlotinib hydrochloride Form A according to claim 49 comprising less than 1% of Erlotinib hydrochloride in Form B or other polymorphic forms.
51. Erlotinib hydrochloride Form A according to claim 50 comprising less than 0.5% of Erlotinib hydrochloride in Form B or other polymorphic forms.
52. A pharmaceutical composition comprising Erlotinib or a salt thereof according to claims 34 to 38 or 48 to 51 or when prepared by a process according to claims 1 to 33 or 39 to 47.
53. A pharmaceutical composition according to claim 52 for use to treat or prevent a disorder wherein inhibiting protein tyrosine kinases is beneficial.
54. A pharmaceutical composition according to claim 53 wherein the disorder is a cancer.

55. A pharmaceutical composition according to claim 54 wherein the cancer is lung cancer or pancreatic cancer.
56. A pharmaceutical composition according to claims 52 to 55 which comprises a combination with one or more other active ingredients or for use in combination with one or more other active ingredients.
57. A pharmaceutical composition according to claim 56 wherein the one or more other active ingredients is an anti cancer drug.
58. A pharmaceutical composition according to claim 57 wherein the one or more other active ingredients is gemcitabine.