Back Ground of the Invention:
Erlotinib (6,7-bis(2-methoxyethoxy)-N-(3-ethynylphenyl)quinazolin-4-amine), in either its hydrochloride or mesylate forms, or in anhydrous and hydrous form, is useful in the treatment hyperproliferative disorders, such as cancers, in humans.

Erlotinib of formula-I is first synthesized by Schnur, Rodney.C. as reported in WO 96/30347 and its equivalent US patent 5,747,498 (1998). The process for the preparation of erlotinib disclosed in WO 96/30347 (US 5747498) is shown in scheme-1.

Scheme-1
The synthesis of erlotinib hydrochloride (IV) is also reported in US 6476040, which is depicted in the scheme-II.

Scheme-2

Another process, as reported in EP1044969 describes the synthesis of erlotinib hydrochloride as shown in scheme-III.

Scheme-3

Summary of the invention

A number of methods are described for the synthesis of erlotinib hydrochloride. A few relevant methods are briefly discussed in the prior art.

The synthesis, as reported in scheme 1, has made use of isopropyl alcohol for the nucleophilic substitution in the presence of a scavenger pyridine at reflux temperature. Erlotinib base has to be isolated and converted to the hydrochloride salt. The process reported scheme 2 and 3 use protected derivatives of 3-ethynylbenzenamine and subsequently protected erlotinib has to be deprotected, after isolation. Again an additional step will be required for purification. Analysing the different routes of syntheses, the following short comings have been observed

a) A number of steps are involved in all the methods of preparation
b) Reaction takes longer time and yields are not very high
c) Reaction required higher temperature
d) Further purification is required to get pure erlotinib

Considering the short comings, as mentioned above, it is imperative to develop a better process

The main objective of the invention is to provide an economically viable process, which uses readily and cheaply available raw materials. Another objective of the invention is to provide an environmentally friendly process.

Keeping in view of all processes referred in the prior art, it is felt that the ideal starting materials will be 6,7-bis(2-methoxyethoxy)-4-chloroquinazoline of formula II and
3-aminophenylacetylene of formula III.

Accordingly a simple, economical and eco-friendly process has been developed by reacting the quinazoline derivative of formula II

Formula-II

with 3-aminophenylacetylene of formula III in the presence of aqueous hydrochloric acid

Formula-III

in water to give 6,7-bis(2-methoxyethoxy)-(3-ethylphenyl)quinanazolin-4-amine hydrochloride viz. erlotinib hydrochloride of formula I.

Formula-I

Advantages of the invention

1. A process in water makes it eco-friendly and economically viable.

2. Temperature (25 to 40OC) makes energy consumption less.

3. The reaction is complete in 3-4 hrs.

Detailed description of the invention

Reaction of 6,7-bis(2-methoxyethoxy)-4-chloroquinazoline of formula II and
3-aminophenylacetylene of formula-III base or hydrochloride was studied in various solvents ranging from aprotic solvent like toluene to aprotic dipolar solvent like acetonitrile. The reaction was also studied in protic solvent like alkanols, aqueous alkanols or water. The initial studies indicated that protic solvent system is better.

Hence the reaction was studied in detail in protic solvent system ranging from pure alkanols to aqueous alkanols to pure water. Reactions were studied with both
3-ethnylbenzenamine as well as its hydrochloride salt. In either case the product obtained, was highly pure.

It was decided to conduct the reaction using 3-ethylnylbenzenamine.

Reaction of the product of formula II with the product of formula III was studied in aqueous alkanol selected from the group consisting of methanol, ethanol and isopropyl alcohol in the presence of concentrated hydrochloric acid. Reactions were performed using different proportions of alkanol and water and temperature ranging from 40 to 90OC. Yields ranged from 70 to 80%.

Reactions were conducted in water. Herein the reactants VIZ., formula II and formula III were reacted in water in the presence of hydrochloric acid. Both the reactants were used in equimolar proportions and hydrochloric acid was used in equal proportion to that of the product of formula III. Reactions were studied at temperature range of 25 to 80OC for 4 to 8 hrs. It was observed that the reaction proceeded smoothly in water at a temperature range of 25 to 40OC in 3 to 4 hrs to give the product of formula I in quantitative yield.
The process described herein yields erlotinib in 99.8% HPLC purity with single impurity not exceeding 0.1%. The product obtained is polymorph B. The XRD of the product is given in figure 1. The process has resulted in achieving the following advantages.

a) The process is economical.
b) The process is eco-friendly.
c) The process yields erlotinib and its salts in high yield and high purity and does not require further purification.
d) The process results in the formation of erlotinib hydrochloride as a polymorph form B.
The following examples exemplify the invention. That should not be construed in limiting the range of application of the invention.

Example 1

In a 100 L glass lined reactor, 1.5 kg of 3-aminophenylacetylene, 1.5 kg of concentrated hydrochloric acid, 3.0 kg of 6,7-bis(2-methoxyethoxy)-4-chloroquinazoline and 36 L of demineralised water were charged at 10-15OC. The contents were stirred for 120-180 minutes at 25-30oC. Thus obtained slurry was filtered, further treated in base/acid and washed with 6.0 L of demineralised water. The wet cake was dried at 45-50oC for 4-5 hours to get 3.95 kg of erlotinib hydrochloride form B having a purity by HPLC > 99.8%

We claim:

01. An economical and eco-friendly process for the preparation of erlotinib in high yield, high purity and polymorphic form B by reacting a product of formula II

Formula-II

with product of formula III

Formula-III

in water containing hydrochloric acid at 25 to 40OC for 2 to 4 hrs.

02. A process, as claimed in claim 1, wherein water used is demineralised.

03. A process, as claimed in claim 1, wherein the reaction is conducted at 25 to 40OC.

04. A process, as claimed in claim 1, wherein the product of formula I is obtained in nearly quantitative yield and with HPLC purity of not less than 99.8%.

Formula I

05. A process wherein erlotinib hydrochloride is obtained as a polymorph B and its XRD is given in figure I.
.