FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Complete Specification [See Sections 10 and rule 13]
Title: A Method For Preparation Of N-(3-ethynyIphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine And Salts
Applicant: (a) INTAS Pharmaceuticals Limited
(b) Company Registered under Indian Company ACT
(c) 2nd Floor, Chinubhai Centre, Ashram Road, Ahmedabad 380009 Gujarat, India
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 a process for preparation of pure Erlotinib hydrochloride (I) without using purification process. Also provided are novel salts of Erlotinib and their preparation.
BACKGROUND OF THE INVENTION
Erlotinib (II), chemically named N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy) quinazolin-4-amine, is a epidermal growth factor receptor inhibitor and may be used in treatment of several types of cancers. Erlotinib is represented by the following structural formula

and its first synthesis was disclosed in US 5,747,498 (hereinafter referred as '498). It is sold under brand name Tarceva as its hydrochloride salt.

is reacted with 3-ethylnylaniline (V)
According to the process disclosed in '498 4-chloro-6,7-bis (2-methoxyethoxy) quinazoline (IV)


in a mixture of pyridine and isopropanol to get Erlotinib hydrochloride, which is converted to its free base by reacting with base in chloroform containing 10% methanol. The free base is purified by chromatography and is again converted to Erlotinib hydrochloride by reacting with ethereal hydrochloric acid in presence of chloroform and ether.
There are several reports for preparation of Erlotinib and its pharmaceutically acceptable salts for example US 6,476,040, US 2005/0130995, US 7,148,231, WO 2009/002538, and WO 2010/109443.
US 6,476,040 discloses a process for preparation of Erlotinib which involves reacting sillyl protected quinazoline with 3-ethynylaniline.
US 2005/0130995 disclose reaction of 6,7-bis methoxy quinazoline in presence of POCI3 and triethylamine to obtain Erlotinib hydrochloride with 78.1% purity. The process of US 7,148,231 involves reacting 3-ethynylaniline with quinazoline intermediate in presence of α, α, α-trifluorotoluene.
WO 2007/060691 discloses preparation of pure Erlotinib hydrochloride however the process is very lengthy and comprises converting 6,7-dimethoxy-4-(3H) quinazolinone to corresponding 6,7-dihydroxy compound which is acylated and the resulting product is reacted with 3-ethynylaniline to obtain Erlotinib base as crude. The crude base is purified and then reacted with hydrochloric acid to obtain Erlotinib hydrochloride.

Reacting 4-halo-6,7-bis(2-methoxyethoxy)quinazoline and 3-ethynylamine under acidic conditions is disclosed in WO 2008/122776, the process results in product with purity of about 99.2%.The acidic condition in process of '776 is obtained by adding extra acid than required for the reaction to complete, otherwise the reaction condition of the process disclosed in product patent i.e. '498 is also acidic as hydrochloric acid is generated during the reaction.
WO 2009/002538 discloses a process for preparation of Erlotinib comprising reacting 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline with 3-ethynylaniline in alkali hydroxide and isopropanol.
Process of WO 2010/109443 includes reacting 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile and 3-ethynylamine in presence of triethyl orthophosphate. Erlotinib obtained by above processes needs extra purification either at the base stage or after formation of hydrochloride or both to obtain the product complying with pharmaceutical requirement. It is always desirable to obtain highly pure product with minimum operation as each step involved in process or purification leads to yield loss and also makes the over all process cumbersome.
Salts of Erlotinib including hydrochloride, mesylate, sulphate, oxalate, and maleate have been disclosed in the literature. For example US 5,747,498 exemplifies hydrochloride salt of Erlotinib and generally mentions that compounds disclosed therein can form salts like sulphate, methanesulphonate, benzenesulphonate, citrate, lactate, maleate etc. Erlotinib mesylate is disclosed in WO 99/55683, some other salts such as oxalate, tartarate are disclosed in WO 2008/122776.
Providing new salts of pharmaceutically useful compounds present new opportunity to improve the performance characteristics of a pharmaceutical compound. The

present invention also provides novel pharmaceutically acceptable salts of Erlotinib and process for preparation thereof.
Although several processes are reported for preparation Erlotinib hydrochloride and other pharmaceutically acceptable salts but they suffer from one or more drawback such as low purity which necessitates the extra purification and results in low yield hence there remains a need for simple, cost effective, and industrially viable process for production of Erlotinib or its salts.
Thus the present application provides an improved process to prepare Erlotinib hydrochloride which avoids steps involved in purification and provide highly pure Erlotinib hydrochloride while using simple, safe and commercially viable process. The Erlotinib hydrochloride directly isolated from the reaction mixture is highly pure and complies with the required purity standards thus the present process completely avoids extra purification of Erlotinib base or its salt.
OBJECTS OF THE INVENTION
The main objective of the present invention is to provide a process for preparation of pure Erlotinib hydrochloride.
Another object of the invention is to provide novel salts of Erlotinib and their preparation.
SUMMARY OF THE INVENTION
In one aspect, provided herein is a process to prepare highly pure Erlotinib hydrochloride (I) by reacting 4-chloro-6,7-bis-(2-methoxy-ethoxy)-quinazoline of

formula (IV) with 3-ethynylaniline (V) in presence of water and polar aprotic solvent without using purification process.
In another aspect, provided herein are novel salts of Erlotinib selected from mandelate, succinate, fumarate or camphorsulphonate and process for their preparation.
BRIEF DESCRIPTION OF DRAWING
Fig.1is a characteristic nuclear magnetic resonance (NMR) spectrum of impurity A.
Fig.2 is a characteristic mass spectrum of impurity A.
Fig.3 is a characteristic nuclear magnetic resonance (NMR) spectrum of impurity B.
Fig.4 is a characteristic mass spectrum of impurity B.
Fig.5 is a characteristic nuclear magnetic resonance spectrum (NMR) of erlotinib camphorsulphonate.
Fig.6 is a characteristic nuclear magnetic resonance spectrum (NMR) of erlotinib mandelate.
Fig.7 is a characteristic nuclear magnetic resonance spectrum (NMR) of erlotinib succinate.
Fig. 8 is a characteristic nuclear magnetic resonance spectrum of erlotinib fumarate.

DETAILED DESCRIPTION
Accordingly in one aspect of the present invention there is provided a process to prepare Erlotinib hydrochloride (I) by reacting 3-ethynylaniline (V) with 4-chloro-6,7-bis-(2-methoxyethoxy)quinazoline (IV) in presence of water and polar aprotic solvent.
4-chloro-6,7-bis-(2-methoxyethoxy)quinazoline (IV) can be prepared by reacting 6,7-bis(2-methoxyethoxy)quinazoline-4(3H)-one (III) with oxalyl chloride and the process of present application can be depicted by following reaction scheme:


The polar aprotic solvent used in the above process can be selected from but not limited to group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrollidone, 1,4-dioxane and acetonitrile.
The reaction is carried out at a temperature in the range of 50 °C to reflux temperature of the solvent used. Preferably the reaction is carried out at 70-100 °C temperature. After completion of reaction the reaction mixture can be filtered and to this about 0.05 to 0.3 mole of hydrochloric acid can be added. The Erlotinib hydrochloride thus prepared can be separated by cooling the reaction mixture. The reaction mixture can be cooled to ambient temperature preferably from 25-30 °C or more preferably to 0-10 °C. The highly pure Erlotinib hydrochloride can be recovered by methods such as filtration, filtration under vacuum, centrifugation, decantation, or a combination thereof. The Erlotinib hydrochloride obtained from above process can be dried by any conventional method suitable for the product.
The present process results in highly pure Erlotinib hydrochloride which is directly isolated from the reaction mixture and does not require any purification, thus the present process eliminates the need of extra steps of purification. As used herein highly pure Erlotinib hydrochloride refers to Erlotinib hydrochloride having a purity of at least 99.5% by HPLC, specifically in the range of 99.5-99.9% and more specifically 99.8-99.9% by HPLC.
In an alternative the Erlotinib free base can be isolated from the reaction mixture of 4-chloro-6,7-bis-(2-methoxyethoxy)-quinazoline (IV) and 3-Ethynylaniline (V) by adjusting the pH of the reaction mixture. The pH can be adjusted by using any suitable base. The Erlotinib base thus isolated is highly pure and can be directly used in preparation of salts of Erlotinib. The use of highly pure base eventually leads to obtainment of pure salts of Erlotinib.

According to another aspect, there is provided Erlotinib impurity A having following formula (A).

The Erlotinib impurity A have been identified and synthesized. The impurity A detected and resolved from Erlotinib by HPLC with an RRT of 1.25. The structure of impurity A was deduced with the aid of 'HNMR, IR and mass the parent ion is at and is consistent with the assigned structure.
The erlotinib impurity A disclosed herein is characterized by lH NMR (400MHz)8 (ppm) 3.4 (6H;OCH3); 3.8 (4H;-OCH2-CH2); 4.1(4H;0-CH2); 7.4-11.3 (8H-Ar) and MS:m/z:449.8 (m+1)
According to another aspect, there is provided another impurity B having following structural formula

The impurity B is identified and synthesized by the present inventors. The Erlotinib impurity (B) is detected and resolved from Erlotinib by HPLC with an RRT of 1.21.The structure of impurity B was deduced with the aid of 1H NMR, IR, and mass.

The erlotinib impurity B disclosed herein is characterized by data selected from 1H NMR (400MHz) 3.4 (6H;OCH3); 3.8 (4H;-OCH2.CH2); 4.1(4H;0-CH2); 5.3 (1H, HOCH); 5.8 (1H; CH=CH); 6.7 (1H, CH-CH); 7.2-8.6 (7H) and MS:m/z: 396.1(m+1)
The present inventors have found that impurities A and B are formed as impurity in the synthesis of Erlotinib due to the contamination of key starting material 3-ethynylaniline with 3-bromoaniline and/or 3-vinylaniline. The impurities A and B are formed in the reaction of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline and 3-ethynylaniline to prepare Erlotinib.
The Erlotinib or its salt prepared according to the present process is substantially free of impurity A and B.
According to another aspect, present invention provides novel salts of Erlotinib of formula (VI).

HA represents an acid capable of forming salt
The novel salts of the present invention are acid addition salts specifically salts formed with acids selected from but not limited to mandelic acid, succinic acid, fumaric acid and camphorsulphonic acid.

The erlotinib camphor sulfonate salt disclosed herein is characterized by data selected from 1H NMR (400MHz) 8(ppm) 3.4 (6H;-OCH3,-OCH3), 3.8 (2H; CH2-O-CH3), 3.37 (lH,alkyne), 4.37(-OCH2), 7H (-Ar), 11.3 (1H,-NH).
The erlotinib mandelate salt disclosed herein is characterized by data selected from 1H NMR (400MHz) 5 (ppm) 6H (3.35,-OCH3;O-CH3); 3.78(2H,CH2-0-Ar), 4.24(1H,alkyne), 4.28 (2H,-OCH2-CH2), 5 (1H, -CH-(OH)-COOH), 7.2-8.6 (12H,-Ar).
The erlotinib succinate salt disclosed herein is characterized by data selected from 1H NMR (400MHz) 5 (ppm) 3.45 (6H,-OCH3); 3.77 (4H,-CH2-O-CH3), 4.28(1H, alkylne), 4.32(2H,-CH2-0-Ar), 7.24-8.58 (Ar-), 9.94 (1H, -NH).
The erlotinib fumarate salt disclosed herein is characterized by data selected from 1H NMR (400MHz) 5 (ppm) 3.38 (6H,-OCH3), 3.77 (2H,-CH2-O-CH3), 4.24 (lH,alkyne), 4.32(2H, CH2-O-CH3), 6.65 (2H, CH(COOH)=CH(COOH)), 7.23-8.54 (7H,-Ar),9.82(lH,-NH)
In an embodiment the present invention provides process for preparing pharmaceutically acceptable salts of Erlotinib which comprises of reacting Erlotinib free base with the desired acid in presence of a suitable solvent. Exemplary solvents used for preparation of salt include but not limited to water, an alcohol, a ketone, a chlorinated solvent, a hydrocarbon, a nitrile, an ester, ether, a polar aprotic solvent and mixture thereof.
In one embodiment the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate more specifically methanol.

In one embodiment the reaction to prepare salt of Erlotinib the reaction is carried out at a temperature of about 25 °C to reflux temperature of the solvent used, specifically at about 30 °C to reflux temperature.
The reaction for Erlotinib salt preparation can be carried out for at least 15 minutes and more specifically 20 minutes to 3 hours. The salts thus prepared can be precipitated by lowering the reaction temperature preferably the temperature is lowered below the reaction temperature preferably to ambient temperature more preferably to 10-20 °C. The Erlotinib salt can be isolated from reaction mixture by filtration or any other similar technique known conventionally. The isolated salt can be dried at suitable temperature for desired time.
The Erlotinib salts are isolated as solid in crystalline form these are stable; consistently reproducible and are particularly suitable for bulk production.
In another aspect, the Erlotinib or Erlotinib hydrochloride can be prepared by using the salts of Erlotinib selected from mandelate, succinate, fumarate, camphorsulphonate.
Experimental:
HPLC method for measuring chemical purity of Erlotinib

Chromatographic parameters
Instrument A liquid chromatograph equipped with UV detector
Column Inertsil ODS-3V (250 x 4.6 mm), 5u Make: GL Science or equivalent
Column temperature 40 °C

Wavelength 247 nm
Flow Rate 1.2 mL/ minute
Injection Volume 10µL
Vlobile Phase A Take 1.36 g of potassium dihydrogen phosphate in 1000 mL of water. Add 1.0 mL of Triethylamine. Dissolve and adjust pH to 2.75 ± 0.02 with dilute orthophosphoric acid. Filter and degas the buffer through 0.45 µ filter.
Mobile phase B Acetonitrile
Diluent Water: ACN (50:50)
Gradient Program
Ti Time minute in
s Mobile phase A (% v/v) Mobile phase B (% v/v)
.01 75.0 25.0
10 75.0 25.0
25 55.0 45.0
40 40.0 60.0
50 40.0 60.0
50.1 75.0 25.0
60 75.0 25.0
The following examples are illustrative of the invention but not limitative of the scope thereof:
Examples:
Example 1- Preparation of 4-chIoro-6,7-bis (2-methoxyethoxy)quinazoIine
6,7-bis(2-methoxyethoxy)quinazoline-4(3H)-one (50g); methylene dichloride (350ml) and dimethyl formamide (5ml) were charged in a round bottom flask. To this a mixture of oxalyl chloride (32.5 g) and methylene dichloride (150 ml) is added and the temperature of resulting reaction mixture is increased to 40-45 °C.

The reaction mixture is stirred for 5.0 hours at the same temperature. After completion of reaction the reaction mixture is cooled to 25-30 °C followed by addition of 200 ml water. pH of reaction mixture was adjusted to 7.0-7.5 pH and organic layer was separated. Solvent was distilled of under vacuum and to the residue acetone (300ml) was added. The reaction mass cooled to 5-10 °C the solid thus separated was isolated by filtration and dried to obtain title compound.
Example 2 -Preparation of Erlotinib Hydrochloride
4-chloro-6,7-bis-(2-methoxy-ethoxy)-quinazoline (5.0g) was taken in dimethyl formamide (37.5ml) and water (37.5ml). 3-ethynylaniline was added to the resulting mixture at 20-25 °C. The reaction temperature was increased to 80-90 °C and it was stirred for 2-3 hours at the same temperature. After completion of reaction 0.1 g of activated carbon was added to the reaction mixture, followed by filtration. To the filtrate 0.5 ml concentrated hydrochloric acid was added. The filtrate was cooled to 0-5 °C and maintained at the same for 2-3 hours. Reaction mass was filtered to obtain solid followed by drying to obtain 6.1 g of title product. Purity 99.75%
Example 3- Preparation of Erlotinib free base
4-chloro-6,7-bis-(2-methoxyethoxy)quinazoline (5.0g) and water (250ml) were charged in a round bottom flask reaction mixture was heated to 40-45oC. 3-Ethynylaniline was added to reaction mass at 40-45 oC followed by addition of water (350 ml). Reaction mixture was stirred at 85-90 oC for 2 hours. After completion, reaction mixture was cooled to 20-30 oC and pH was adjusted 7.0-8.0 using 20 % aqueous solution of potassium carbonate. Stirred for 30 minutes at same temperature, filtered, washed with water (100 ml) and dried at 45-50 °C for 6 hours under vacuum to obtain the title compound (yield 95% and Purity 99.39%)

Example 4- Preparation of Erlotinib camphor sulfonate
In a flask Erlotinib base (5g) was taken in methanol (50 ml) and the temperature was increased to 50-55 °C, to this camphor sulphonic acid (2.95 g) in methanol (5ml) was added. The reaction mixture was first cooled to 25-30 °C and then to 10-15 °C. The reaction mixture was stirred at 10-15 °C for 25-30 minutes. Reaction mixture was filtered and solid product was dried to obtain 2.8 g of title compound. Purity 99.82%
Example 5- Synthesis of impurity A
4-chloro-6,7-bis-(2-methoxy-ethoxy)-quinazoline (9.0g) was taken in dimethyl formamide (45 ml) and water (90 ml). 3-bromoaniline (5.1 g) was added to the resulting mixture at 20-25 °C. The reaction temperature was increased to 80-90 °C and it was stirred for 2-3 hours at the same temperature. After completion of reaction, 5 ml concentrated hydrochloric acid was added. Reaction mass was filtered to obtain solid followed by drying to obtain 10.2 g of title product.
Example 6- Synthesis of impurity B
4-chloro-6,7-bis-(2-methoxy-ethoxy)-quinazoline (1.0 g) was taken in water (12 ml). 3-vinylaniline (0.4 g) was added to the resulting mixture at 20-25 °C. The reaction temperature was increased to 85-90 °C and it was stirred for 2-3 hours at the same temperature. After completion of reaction, cool the reaction mass to ambient temperature followed by filtration to obtain solid. The crude impurity was purified in ethyl acetate to obtain 0.3 g of title product.

We claim:
1. A process to prepare Erlotinib or its pharmaceutically acceptable salt

comprising reacting 4-chloro-6,7-bis-(2-methoxy-ethoxy)-quinazoline of formula (IV)

with 3-ehtynyllaniline (V)

in presence of water and polar aprotic solvent.
2. A process as claimed in claim 1, wherein polar aprotic solvent is selected from dimethylformamide, dimethyl acetamide, N-methylpyrrolidone, 1,4-dioxane, acetonitrile or a mixture thereof.
3. Erlotinib salt of formula (VI)


wherein HA is selected from mandelic acid, succinic acid, fumaric acid or camphorsulphonic acid.
4. A process to prepare salts of Erlotinib as claimed in claim 3, wherein the process comprising reacting Erlotinib with acid selected from mandelic acid, fumaric acid or camphorsulphonic acid in presence of solvent.
5. A process as claimed in claim 5, wherein the solvent is selected from alkanol, ketone, hydrocarbon, ether, ester, chlorinated solvent, polar aprotic solvent, water or mixture thereof.
6. Use of salts, as claimed in claim 3, in the preparation of Erlotinib or its hydrochloride salt.