CLIAMS:Claims:

1) A process for the preparation of Erlotinib or its hydrochloride salt of Formula (I)
(I)
comprises the steps of
a) reacting 3,4-dihydroxybenzoic acid with 2-bromo ethyl methyl ether in presence of alkali carbonate, potassium iodide and a solvent, followed by hydrolysis to obtain 3,4-bis(2-methoxyethoxy)benzoic acid;

b) halogenating 3,4-bis(2-methoxyethoxy)benzoic acid, followed by reaction with ammonia to obtain 3,4-bis(2-methoxyethoxy)benzamide;

c) converting 3,4-bis(2-methoxyethoxy)benzamide to obtain 3,4-bis(2-methoxyethoxy) benzonitrile;

d) nitrating 3,4-bis(2-methoxyethoxy)benzonitrile to obtain 4,5-bis(2-methoxy ethoxy)-2-nitrobenzonitrile;

e) reduction of 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile to obtain 4,5-bis(2-methoxy ethoxy)-2-aminobenzonitrile of formula;

f) condensing 4,5-bis(2-methoxyethoxy)-2-aminobenzonitrile with 1,1-dimethoxy trimethyl amine to obtain N'-(4, 5-bis (2-methoxyethoxy)-2-cyanophenyl)-N,N-dimethyl formamidine;

g) N'-(4,5-bis (2-methoxyethoxy)-2-cyanophenyl)-N,N-dimethyl formamidine is reacted with 3-ethynylaniline hydrochloride to obtain Erlotinib; and

h) optionally converting Erlotinib in to its hydrochloride salt.

2) A process for the preparation of Erlotinib or its hydrochloride salt of Formula (I) according to claim 1, wherein in the solvent in step (a) is selected from Ketones (C3-6) or organic solvents (C1-8 alkanes, dimethyl formamide, toluene, xylene) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran, Di-isopropyl ether ) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate) or water or mixtures thereof;

3) A process for the preparation of Erlotinib or its hydrochloride salt of Formula (I) according to claim 1, wherein step (b) halogenating comprises the use of a halogenating agent selected from thionyl chloride, oxalyl chloride, Phosphorous trichloride, Phosphorous pentachloride, Phosphorous oxy chloride.

4) A process for the preparation of Erlotinib or its hydrochloride salt of Formula (I) according to claim 1, wherein step (c) is carried out using reagent selected from Phosphorous oxy chloride, Phosphorous trichloride, Phosphorous pentachloride.
5) A process for the preparation of Erlotinib or its hydrochloride salt of Formula (I) according to claim 1, wherein step (d) nitrating is carried out in presence of nitric acid and an acid selected from sulfuric acid, acetic acid, Formic acid, trifluoro acetic acid.

6) A process for the preparation of Erlotinib or its hydrochloride salt of Formula (I) according to claim 1, wherein step (e) reduction is carried out in presence of metal catalyst such as Iron, Zinc, Tin, Platinum, Palladium; alkali metal dithionate such as potassium dithionate, Sodium dithionate, Barium dithionate.

7) A process for the preparation of Erlotinib or its hydrochloride salt of Formula (I)
(I)
comprises the steps of
a) reacting 3,4-dihydroxybenzoic acid with 2-bromo ethyl methyl ether in presence of alkali carbonate, potassium iodide and a solvent, followed by hydrolysis to obtain 3,4-bis(2-methoxyethoxy)benzoic acid of formula;

b) halogenating 3,4-bis(2-methoxyethoxy)benzoic acid, followed by reaction with ammonia to obtain 3,4-bis(2-methoxyethoxy)benzamide;

c) converting 3,4-bis(2-methoxyethoxy)benzamide to obtain 3,4-bis(2-methoxyethoxy) benzonitrile; and

d) converting 3,4-bis(2-methoxyethoxy) benzonitrile to Erlotinib or its hydrochloride salt.

8) A process for the preparation of Erlotinib or its hydrochloride salt of Formula (I) according to claim 1, wherein in the solvent is selected from alcohol (C1-4) or Ketones (C3-6) or organic solvents (C1-8 alkanes, dimethyl formamide, toluene, xylene) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran, Di-isopropyl ether ) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate) or water or mixtures thereof.

9) A process for the preparation of Erlotinib or its hydrochloride salt of Formula (I) according to claim 1, wherein step (b) halogenating comprises the use of a halogenating agent selected from thionyl chloride, oxalyl chloride, Phosphorous trichloride, Phosphorous pentachloride, Phosphorous oxy chloride.

10) A process for the preparation of Erlotinib or its hydrochloride salt of Formula (I) according to claim 1, wherein step (c) is carried out using reagent selected from Phosphorous oxy chloride, Phosphorous trichloride, Phosphorous pentachloride.

Dated this … th day of … June 2015

Signature:
Dr. A. K Chaturvedi

,TagSPECI: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 an improved process for the preparation Erlotinib or its hydrochloride salt of Formula (I).
(I)

BACKGROUND OF THE INVENTION
Erlotinib hydrochloride (I) is chemically known as N-(3-ethynylphenyl)-6,7-bis(2-methoxy ethoxy)-4-quinazolinamine hydrochloride
(I)
It is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen, and in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer.

Schnur, et al in US5747498 and EP0817775B1 disclose a process for the preparation of Erlotinib free base and its Hydrochloride salt, which follows the pathway as given in the scheme.

N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine (Erlotinib) base is separated chromatographically and converted to the hydrochloride salt in a solvent, such as, chloroform using hydrochloric acid. Though the disclosure provide some acid-addition salt e.g. hydrochloric, hydrobromic, sulphuric, phosphoric, methanesulfonic, benzenesulfonic, trifluoroacetic, citric, lactic or maleic acid, however, it only demonstrates predominately the process for the preparation of erlotinib hydrochloride.

Scheme: Process as disclosed in US5747498
EP1044969B1 provides a process for preparing N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine which involves stirring 4-[3-[[6,7-bis(2-methoxyethoxy)-4-quinazolinyl]amino]phenyl]-2-methyl-3-butyn-2-ol with anhydrous sodium hydroxide and 2-methoxyethanol and heating at reflux for 47 hours. The reaction mixture is cooled to 20 to 25 degree C and concentrated hydrochloric acid is added to it. The resulting mixture is granulated at 20 to 25oC to crystallize the product.

WO 2007/138612 provides a process for preparation of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride which involves treatment in the end with a polar solvent containing hydrochloric acid with Erlotinib free base to provide Erlotinib hydrochloride.

Norris et al in WO 01/34574 and its equivalent US6900221 described polymorphic Forms-A and B of Erlotinib Hydrochloride, and mentioned that the polymorphic form `B` is thermodynamically more stable. This patent, also described that product obtained as per US5747498 was a mixture of polymorphic Forms A and B.
Further, Norris et al in US6900221 also disclosed a method of preparing pure polymorphic Form-B of Erlotinib Hydrochloride (I) that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 6.26, 12.48, 13.39, 16.96, 20.20, 21.10, 22.98, 24.46, 25.14 and, 26.91, which is free of the A polymorph.

Bubendorf et al in US 7148231 and its corresponding International Application published as WO 2004/072049 disclosed a novel polymorph E along with its DSC and XRD characteristics. This crystalline polymorphic form E is prepared particularly in (a,a,a)-trifluoro toluene, which is highly flammable and dangerous for the environment. The solvent is not only expensive solvent but also have inconvenience to handle on industrial scale.

Jyothi Prasad Ramanadham et al in US 20100261738 A1 disclosed other stable polymorphic forms of Erlotinib Hydrochloride designated as Form-M, Form-N and Form-P. These forms were prepared from solvent systems selected from methanol with a solution of Hydrochloride in dry methanol or isopropanol (Form-M); isopropanol with isopropanolic Hydrochloride (Form-N) and methylene chloride with isopropanolic Hydrochloride (Form-P).

Murugesan Balaguru et al in US 20120101272 A1 disclosed Erlotinib trifluoroacetate salt as Form E characterized by a powder XRD pattern comprising peak 2? values at about 6.43±0.2? , 16.73±0.2?, 22.55 ±0.2?, 25.72 ±0.2?, and 26.25±0.2?.

Besides the above disclosures various other disclosures includes US6476040; US2005/0130995; US2006/0154941; US2008/0167327 A1; US2008/0058355 A1; WO 99/55683; WO2003/066602 A1; WO2007/060691; WO 2008/000418 A2; WO2008/012105; WO2008/049645; WO2008/102369; WO 2008/122776; WO2009/002538; WO2009/007984; WO2009/024989; WO 2009/025873 A2; WO2009/025876 A2 dealt with either process or intermediates for Erlotinib.

The present inventors has repeated the above process and found the following disadvantages:
? In most of the patent literature, the rate of reaction is very low, which parallel yield in the formation of by-products, which is tedious for the removal.
? Unwanted reactions are observed during the formation of Erlotinib, as the reaction in carried out at very high temperature
? The conversion of 3,4-bis(2-methoxyethoxy)benzamide to obtain 3,4-bis(2-methoxyethoxy) benzonitrile involves the use of hygroscopic reagent like Phosphorous pentoxide.

In view of the above, to overcome the prior-art problems the present inventors have now developed an improved process for the preparation of Erlotinib Hydrochloride, using industrially feasible and viable process, with the use of industrially friendly solvents, which does not include tedious work up.

Being Erlotinib hydrochloride as an important anticancer therapeutic agent, additional and improved ways of preparing erlotinib hydrochloride salt may be of immense value to pharmaceutical science and the healthcare of cancer patients. Hence, there exists a need in the development of new stable crystalline form and economically viable processes, which may be commercially up scalable, viable, safer for handling, less time consuming and with better and consistent quality parameters.

The present inventors have now developed a new process for the preparation of Erlotinib Hydrochloride (I), which is stable and free from any process related impurities.

SUMMARY OF INVENTION
The main aspect of the present invention relates to a process for the preparation of Erlotinib or its hydrochloride salt of Formula (I)
(I)
comprises the steps of
a) reacting 3,4-dihydroxybenzoic acid with 2-bromo ethyl methyl ether in presence of alkali carbonate, potassium iodide and a solvent, followed by hydrolysis to obtain 3,4-bis(2-methoxyethoxy)benzoic acid;

b) halogenating 3,4-bis(2-methoxyethoxy)benzoic acid, followed by reaction with ammonia to obtain 3,4-bis(2-methoxyethoxy)benzamide;

c) converting 3,4-bis(2-methoxyethoxy)benzamide to obtain 3,4-bis(2-methoxyethoxy) benzonitrile;

d) nitrating 3,4-bis(2-methoxyethoxy)benzonitrile to obtain 4,5-bis(2-methoxy ethoxy)-2-nitrobenzonitrile;

e) reduction of 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile to obtain 4,5-bis(2-methoxy ethoxy)-2-aminobenzonitrile of formula;

f) condensing 4,5-bis(2-methoxyethoxy)-2-aminobenzonitrile with 1,1-dimethoxy trimethyl amine to obtain N'-(4, 5-bis (2-methoxyethoxy)-2-cyanophenyl)-N,N-dimethyl formamidine;

g) N'-(4,5-bis (2-methoxyethoxy)-2-cyanophenyl)-N,N-dimethyl formamidine is reacted with 3-ethynylaniline hydrochloride to obtain Erlotinib; and

h) optionally converting Erlotinib in to its hydrochloride salt.

Another aspect of the present invention relates to a process for the preparation of Erlotinib or its hydrochloride salt of Formula (I)
(I)
comprises the steps of
a) reacting 3,4-dihydroxybenzoic acid with 2-bromo ethyl methyl ether in presence of alkali carbonate, potassium iodide and a solvent, followed by hydrolysis to obtain 3,4-bis(2-methoxyethoxy)benzoic acid of formula;

b) halogenating 3,4-bis(2-methoxyethoxy)benzoic acid, followed by reaction with ammonia to obtain 3,4-bis(2-methoxyethoxy)benzamide;

c) converting 3,4-bis(2-methoxyethoxy)benzamide to obtain 3,4-bis(2-methoxyethoxy) benzonitrile; and

d) converting 3,4-bis(2-methoxyethoxy) benzonitrile to Erlotinib or its hydrochloride salt.

In another aspect of the present invention relates to a process for the preparation of 3,4-bis(2-methoxyethoxy) benzonitrile, which is a useful intermediate in the preparation of Erlotinib or its hydrochloride salt of Formula (I)
(I)
comprises the steps of
a) reacting 3,4-dihydroxybenzoic acid with 2-bromo ethyl methyl ether in presence of alkali carbonate, potassium iodide and a solvent, followed by hydrolysis to obtain 3,4-bis(2-methoxyethoxy)benzoic acid of formula;

b) halogenating 3,4-bis(2-methoxyethoxy)benzoic acid, followed by reaction with ammonia to obtain 3,4-bis(2-methoxyethoxy)benzamide;

c) converting 3,4-bis(2-methoxyethoxy)benzamide to obtain 3,4-bis(2-methoxyethoxy) benzonitrile; and

d) converting 3,4-bis(2-methoxyethoxy) benzonitrile to Erlotinib or its hydrochloride salt.

In another aspect of the present invention relates to an improved process for the preparation of 3,4-bis(2-methoxyethoxy) benzonitrile, which is useful in the preparation of highly pure Erlotinib or its hydrochloride salt.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is an example of X-ray powder diffraction (“XRPD”) pattern of crystalline Erlotinib obtained according the present invention.
Fig. 2 is an example of X-ray powder diffraction (“XRPD”) pattern of crystalline Erlotinib Hydrochloride obtained according the present invention.

DETAILED DESCRIPTION
The main embodiment of the present invention relates to a process for the preparation of Erlotinib or its hydrochloride salt of Formula (I)
(I)

In another embodiment of the present invention relates to a process for the preparation of Erlotinib Hydrochloride comprises reacting 3,4-dihydroxybenzoic acid with 2-bromo ethyl methyl ether in presence of alkali carbonate selected from potassium carbonate, sodium carbonate, ammonium carbonate, barium carbonate, sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, potassium iodide; and a solvent selected from selected from alcohol (C1-4) or Ketones (C3-6) or organic solvents (C1-8 alkanes, dimethyl formamide, toluene, xylene) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran, Di-isopropyl ether ) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate) or water or mixtures thereof; at a temperature ranging from 60-90°C. The obtained reaction mixture was filtered and washed with hot ethyl acetate, followed by distillation of solvent to yield a residue.

The present inventors found that the use of potassium iodide in this reaction will boost –up the reaction and clear conversion is observed, which parallel yields in the formation of highly pure material, which is devoid of by products and process related impurities. Further, the present inventors also observed that the use of potassium iodide in this reaction improves the rate of the reaction.

The residue obtained is dissolved in solvent selected from alcohol (C1-4) or Ketones (C3-6) or organic solvents (C1-8 alkanes, dimethyl formamide, toluene, xylene) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran, Di-isopropyl ether ) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate) or water or mixtures thereof; to the obtained solution, followed by hydrolysis using an alkali solution, by adding the alkali solution slowly at a temperature ranging from 10-15°C to obtain the reaction mixture, and was stirred for 12 to 20 hours at a temperature ranging from 20-40°C. Filtered the material, washed with a solvent and precipitated the solid by adjusting the pH to yield 3,4-bis(2-methoxyethoxy)benzoic acid.
In view of this, the present inventors overcome the prior-art problems and developed an improved process for the preparation of 3,4-bis(2-methoxyethoxy)benzoic acid, using industrially feasible and viable process, with the use of industrially friendly solvents and reagents, which does not include tedious work up.

Halogenating 3,4-bis(2-methoxyethoxy)benzoic acid comprises the use of a halogenating agent selected from thionyl chloride, oxalyl chloride, Phosphorous trichloride, Phosphorous pentachloride, Phosphorous oxy chloride; in presence of a solvent selected Ketones (C3-6) or organic solvents (C1-8 alkanes, dimethyl formamide, toluene, xylene) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran, Di-isopropyl ether ) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate) or mixtures thereof; at a temperature ranging from 20-30°C to obtained an acid halide, the obtained acid halide is reacted with ammonia; in presence of a solvent selected from Ketones (C3-6) or organic solvents (C1-8 alkanes, dimethyl formamide, toluene, xylene) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran, Di-isopropyl ether ) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate); at a temperature ranging from 10-40 °C to obtain 3,4-bis(2-methoxyethoxy)benzamide.

The prior-art process involves the use of high temperature for the formation of amide at a temperature ranging from 210-220 °C, which is tedious and unsafe at bulk scale. Further, if the reaction is carried out at higher temperature, the reactants become hyper active and involves in the formation of byproducts and process related impurities.

The present inventors found that the prior-art amidation processes yields in the formation of process related impurities and is carried forward till the final stage of the reaction and yields Erlotinib or its hydrochloride sale with an impurity content, which does not meet the ICH guidelines.
However, the present inventors now developed a process for amidation 3,4-bis(2-methoxyethoxy)benzoyl halide, using industrial friendly and viable process. The present process also avoids the formation of by-products and process related impurities, parallel yields in the formation of highly pure Erlotinib or its hydrochloride salt.
Converting 3,4-bis(2-methoxyethoxy)benzamide to 3,4-bis(2-methoxyethoxy) benzonitrile by treating 3,4-bis(2-methoxyethoxy)benzamide with a dehydrating agent selected from selected from Phosphorous oxy chloride, Phosphorous trichloride, Phosphorous pentachloride; the reaction was refluxed for 2 hours at a temperature ranging from 70 to 111 °C; . The obtained reaction mixture concentrated to get residue. The residue was dissolved in Ethyl acetate and adjusted the pH between 8 to 9 using saturated NaHCO3 solution. The organic layer was separated and concentrated to obtain 3,4-bis(2-methoxyethoxy) benzonitrile.

It is noted that the prior-art process involves the use of Phosphorous pentoxide, which is highly hygroscopic and difficult to handle at large scale synthesis. Further, it is noted that the prior-art processes involves the use of high temperature for dehydration of 3,4-bis(2-methoxyethoxy)benzamide.

The present inventors surprisingly found that the use of dehydrating agents like Phosphorous oxy chloride, Phosphorous trichloride, Phosphorous pentachloride is quite easy to handle and viable in large scale synthesis also. Further, the present inventors found that the use of dehydrating agents like Phosphorous oxy chloride, Phosphorous trichloride, Phosphorous pentachloride does not involve the use high reaction temperature in between 130-135°C., instead the reaction will complete at low temperatures in between 70-110°C.

Nitrating 3,4-bis(2-methoxyethoxy)benzonitrile in presence of nitric acid and an acid selected from sulfuric acid, acetic acid, Formic acid, trifluoro acetic acid; at temperature ranging from 40-60 °C; for a period of 30 minutes to 1 hour 30 min to obtain 4,5-bis(2-methoxy ethoxy)-2-nitrobenzonitrile.

Reduction of 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile using a reducing agent selected from reduction is carried out in presence of metal catalyst such as Iron, Zinc, Tin, Platinum, Palladium; alkali metal dithionate such as potassium dithionate, Sodium dithionate, Barium dithionate; at a temperature ranging from 40-60 °C for a period of 30 minutes to 2 hours 30 minutes to obtain the reaction mixture. The reaction mixture was heated up to 60-65 °C and Hydrochloric acid was added slowly to the reaction mixture within 30-45 minutes at 60-65 °C. The reaction mixture was cooled to 10-15 °C and pH adjusted to 8-9 using 50% NaOH solution. Ethyl acetate was added, stirred for 30 min and separated the organic layer. The aqueous layer extracted two times with ethyl acetate. The combined organic layer was washed with water and sodium chloride solution. Activated charcoal was added into organic layer and stirred for 30 min at room temperature and filtered through celite bed. The organic layer was concentrated to obtain 4,5-bis(2-methoxyethoxy)-2-aminobenzonitrile.

4,5-bis(2-methoxyethoxy)-2-aminobenzonitrile was reacted with 1,1-dimethoxy trimethyl amine in presence of solvent selected from Toluene, xylene and acid selected from acetic acid, trifluoro acetic acid, formic acid at temperature ranging from 90-120°C for a period of 1hour to 3 hours to obtain a reaction mixture. The reaction mixture was concentrated at 80-85 °C under vacuum to obtain N'-(4, 5-bis (2-methoxyethoxy)-2-cyanophenyl)-N,N-dimethyl formamidine in the form of residue.

N'-(4,5-bis (2-methoxyethoxy)-2-cyanophenyl)-N,N-dimethyl formamidine obtained is reacted with 3-ethynylaniline hydrochloride in presence of an acid selected from acetic acid trifluoro acetic acid, formic acid at temperature ranging from 100 to 140 °C for a period of 30 minutes to 2 hours 30 minutes. After completion of the reaction, the reaction mixture cooled to 45-50°C and water was added. The reaction mixture cooled to 15-20 °C and pH was adjusted to 9-10 by using 25% aqueous ammonia solution. The solid was filtered and dried to obtain Erlotinib as light yellow solid.

The present inventors noticed that the use of 3-ethynylaniline free base, in a liquid stage can oxidized easily at room temperature, which is difficult to handle. The present inventor’s surprisingly found that the use of 3-ethynylaniline hydrochloride, which is solid and easy to handle and can be stored for longer time. Further, the present inventors found that the use of acetic acid in 3.5 volumes also completes the reaction, which is viable at large scale synthesis.

Erlotinib was converted in to its Hydrochloride salt by dissolving charged Erlotinib into mixture of ketone and alcohol solvent at temperature ranging from to 40-65 °C to get clear solution. Activated Carbon was added into the reaction mixture and stirred at 40-65 °C for 30 min. The reaction mixture was filtered through celite. The filtrate was again heated to 60-65 °C to get clear solution and isopranolic hydrochloride was added drop wise for about 30 minute to 1 hour. The reaction mixture was allowed slowly at room temperature and the precipitated solid was filtered to obtain Erlotinib hydrochloride as off-white solid.

Step of combining the Erlotinib free base or salt with a mixture of ketone and alcohol comprise either mixing or suspending or making solution with Erlotinib free base or salt obtained by any process /any form with a readymade or freshly prepared mixture of ketone and alcohol solvent both having individually as well as after mixing – a water content up to less than 0.5% w/w.

In the process of preparing mixed solvent solution, alcohol solvent is selected from C2 to C4 alcohol and ketone solvent may be selected from C3 to C10 ketone. In one of the particular embodiment, C3 alcohol as isopropanol and C6 ketone as methyl isobutyl ketone (MIBK) was used for preparing form SE.

Preparation of mixed solvent solution of ketone and alcohol comprise a mixture of ketone and alcohol solvent having ratio between 30:70 to 70:30 v/v. In one of the particular embodiment, solvent mixture utilized for making Erlotinib Hydrochloride was of alcohol and ketone in ratio of (50:50 v/v).

During combining Erlotinib free base or salt with a mixture of ketone and alcohol, a ratio of Erlotinib free base or salt w.r.t. mixture of ketone and alcohol is important in order to obtain the Erlotinib Hydrochloride to meet, which comprise a range between 1: 30-70 (w/v). More preferably, this range may be 1: 40-60(w/v).

In steps of combining isopropanol and Hydrochloride mixture, it comprises of slow addition of isopropanol (IPA) and Hydrochloride mixture, wherein isopropanol and Hydrochloride mixture prepared earlier by combining Hydrochloride gas and IPA comprises of Hydrochloride strength ranging between 5 to 20% w/v.

After combining this acidic alcohol mixture, the solution may optionally be maintain under stirring for a time ranging between 10-60 minutes in order to retain the maximum hydro chlorination with unreacted erlotinib base present if any. If the process is started with Erlotinib Hydrochloride salt, this step may not be desired and the solution may be subjected to cooling simultaneously.
The step of cooling the mixture may be carried out for the mixture upto about 10-40°C as per need to attain the crystalline material precipitated out with no or minimal possible degradation if any. Simultaneously, it is also essentially required to cool the solution in the successive lower rate of cooling in order to retain the characteristics of Form-SE, while achieving the pure crystal formation.

The process related impurities, including unreacted intermediates, side products, degradation products and other medium dependent impurities, that appears in the impurity profile of the Erlotinib hydrochloride can substantially be removed by the process of the present invention resulting in the formation highly pure Erlotinib, which parallel leads to the formation of highly pure stable Erlotinib hydrochloride.

A substantially pure product having purities more than 99.5% (by HPLC) can be obtained by the process of the present invention. In view of maintaining the equilibrium to the impurity profile compliance, the process requires quality checks, while raising the temperature, wherever required upto 40-70°C.

The product obtained by the present invention is free of process related impurities, including unreacted intermediates, side products, degradation products and other medium dependent impurities. The Erlotinib or its Hydrochloride salt obtained by the process according to the present invention is highly pure having a substantially purity of greater than 99.7% and having total impurities of less than 0.3% selected from A, B, C and/or D

The product may be isolated from the reaction mass by conventional processes including filtering and optional drying, which may be carried out at room temperature for the suitable durations to retain the crystalline polymorphic form characteristics.

Erlotinib hydrochloride obtained according to present invention shall be dried under vacuum to attain water content in the range between 0.1 to 1.0 % w/w.

In yet further another embodiment, it provides that the Erlotinib Hydrochloride obtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules useful in the treatment of hyper-proliferative disorders, such as cancer.

Erlotinib Hydrochloride of the present invention may have one or more advantageous and desirable properties compared to the known Erlotinib Hydrochloride, which are not limited to better stability, solubility and quality parameter leading to improved storage and distribution.

In another embodiment, the Erlotinib Hydrochloride obtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.

The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Pharmaceutically acceptable excipients used in the compositions comprising Erlotinib Hydrochloride of the present application include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Pharmaceutically acceptable excipients used in the compositions derived from Erlotinib Hydrochloride of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.

Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE DEMOSTRATING THE WORKING OF INVENTION

Step-a) Preparation of 3,4-bis(2-methoxyethoxy)benzoic acid
3,4-dihydroxybenzoic acid (100 gm, 0.65 mol), K2CO3 (360.0 gm, 2.60 mol) and KI (50.0 gm, 0.30 mol) was charged into the reaction flask containing DMF (1200 ml) and stirred for 15 min at 25-30 °C. 2-bromo ethyl methyl ether (250.0 ml, 2.66 mol) was added and heated to 80-85 °C. The reaction mixture was stirred for 20 hours. The reaction mixture was filtered and washed with hot ethyl acetate (400.0 ml). The filtrate was distilled out under vacuum at below 85 °C to get residue. Methanol (1050 ml) was added to residue and reaction mixture was cooled to 10-15 °C. KOH solution (110.0 gm, 1.964 mol in 850.0 ml DM water) was added slowly at 10-15 °C and stirred for 18 hours at 25-30 °C. Distilled out the methanol under vacuum at below 50° C. DM water (500 ml) was added at room temperature and stirred for 10 min and washed with ethyl acetate (2 × 350.0 ml). The pH of the aqueous layer was adjusted to 2.5 to 3.0 with 3N HCl (~650.0 ml) at10-15 °C. The reaction mass was allowed to room temperature and stirred for 1 hour at 25-30 °C and filtered the precipitated solid to obtain 3,4-bis(2-methoxyethoxy)benzoic acid as an off-white solid.
Yield: 123.0 gm

Step-b) Preparation of 3,4-bis(2-methoxyethoxy)benzamide:
3,4-bis(2-methoxyethoxy)benzoic acid (100.0 gm, 0.370 mol) was charged in to a reaction flask containing Dichloromethane (1000 ml) at room temperature and DMF (5.0 ml) was added slowly. The reaction mixture was cooled to 0-5 °C and oxalyl chloride (50.0 ml, 0.58 mol) was added slowly in 30 min and stirred at room temperature for 1-2 hrs. The reaction mixture was concentrated to get residue to this added THF (1000 ml). The reaction mixture was cooled to 10-15 °C and ammonia gas was purged to get pH 8-9. The reaction mixture was concentrated and added DM water (500 ml) and stirred at room temperature for 30 min. The solid was filtered and washed with DM water (100 ml) and suck dry for 1 hour to obtain 3,4-bis(2-methoxyethoxy)benzamide.
Yield: 60.0 gm

Step-c) Preparation of 3,4-bis(2-methoxyethoxy)benzonitrile:
3,4-bis(2-methoxyethoxy)benzamide (45 gm, 0.167 mol) and POCl3 (225 ml) was charged in to a reaction flask containing Toluene (450 ml) and refluxed for 2 hrs. The reaction mixture concentrated to get residue. The residue was dissolved in Ethyl acetate (900 ml) and pH adjusted to 8-9 using saturated NaHCO3 solution. The organic layer was separated and concentrated to yield 3,4-bis (2-methoxyethoxy)benzonitrile as yellow solid.
Yield: 33.0 gm

Step-d) Preparation of 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile:
3,4-bis(2-methoxyethoxy)benzonitrile (25.0 gm, 0.0996 mol) obtained as per Step-c) was dissolved in acetic acid (25 ml) and then Nitric acid (50 ml) was added at 0-5 °C and stirred at room temperature for 2 hrs. The reaction mixture was heated to 50-55 °C for 1 hrs and cooled to room temperature. Pre cooled-water (250 ml) was added to reaction mixture to precipitate out the solid, which was filtered and washed with chilled water to obtain 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile as yellow solid.
Yield: 23.0 gm

Step-e) Preparation of 4,5-bis(2-methoxyethoxy)-2-aminobenzonitrile:
4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile (100 gm, 0.337 mol) was charged in to a reaction flask containing DM water (1700 ml) at 25-30 °C and sodium hydrosulfite (235 gm, 1.349 mol) was added slowly to reaction mixture at 25-30 °C. The reaction mixture was heated to 50-55 °C and stirred for 1-2 hours at 50-55 °C. Slowly raise the temperature to 60-65 °C and conc. HCl (208.0 ml) was added slowly to the reaction mass fo 30-45 minutes at 60-65 °C. The reaction mass was cooled to 10-15 °C and PH adjusted to 8-9 with 50% NaOH solution. Ethyl acetate (800ml) was added and stirred for 30 min and separated the organic layer. The aqueous layer extracted two times with ethyl acetate (350 ml). The combined organic layer was washed with DM water (500 ml) and 25% NaCl solution. Activated charcoal (5.0 gm) was added into organic layer and stirred for 30 min at room temperature and filtered through celite bed. The organic layer concentrated to obtain 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile as light yellow solid.
Yield: 84.7 gm
Chromatographic Purity (By HPLC): 96.61%

Step-f) Preparation of N'-(4,5-bis(2-methoxyethoxy)-2-cyanophenyl)-N,N-dimethyl formamidine
4,5-bis(2-methoxyethoxy)-2-aminobenzonitrile (82.0 g, 0.309 mol) and DMF-DMA (82.0 ml, 1.0 vol) was charged in to a reaction flask containing of Toluene (820 ml) and added acetic acid (1.3 ml) slowly at room temperature. The reaction mixture was heated to 105-110 °C for 2 hrs with downward distillation set up to collect the byproduct methanol. The reaction mixture was concentrated at 80-85 °C under vacuum to get residue. The residue proceeded for next stage.

Step-g) Preparation of Erlotinib
3-ethynylaniline hydrochloride (42.3 gm, 0.36 mol) was added to the residue obtained in step-f), acetic acid (287 ml) was charged in to the reaction mixture and heated the reaction mixture to 115-120 °C and stirred the reaction mixture for 2 hrs. The reaction mixture cooled to 45-50°C and added DM water (1230 ml). The reaction mixture was cooled to 15-20 °C and pH was adjusted to 9-10 by using 25% aqueous ammonia solution. The solid was filtered and dried to obtain Erlotinib as light yellow solid. The solid was filtered and purified using isopropyl alcohol and toluene to obtain Erlotinib as light yellow solid.
Yield: 80.0 gm
Chromatographic Purity (By HPLC): 99.73%
PXRD pattern resembles with Fig.1

Example-2
Preparation of Erlotinib hydrochloride
Erlotinib (76.0 gm) was charged into a reaction flask containing mixture of Methyl isobutyl ketone (1900 ml) and isopropyl alcohol (1900 ml) and heated to 60-65 °C for clear dissolution. Activated Carbon was added into the reaction mixture and stirred at 60-65 °C for 30 min. The reaction mixture was filtered through celite-bed. The filtrate was again heated to 60-65 °C for clear solution and IPA-HCl (98.8 ml) was added slowly drop wise for 30 min. The reaction mixture was allowed slowly at room temperature and the precipitated solid was filtered to obtain Erlotinib hydrochloride as off-white solid.
Yield: 77.0 gm
Chromatographic Purity (By HPLC): 99.73%
PXRD pattern resembles with Fig.2

The abovementioned examples, which are provided by way of illustration, should not be construed as limiting the scope of the invention with respect to parameter/s, ingredient/s and quantities used in any manner.