FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"PROCESS FOR THE PREPARATION OF ERLOTINIB HYDROCHLORIDE"
2. APPLICANTS:
(a) NAME: MAC CHEM PRODUCTS INDIA PVT. LTD.
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
ACT, 1956
(c) ADDRESS: 304, Town Centre, Andheri-kurla Road, Andheri (E),
Mumbai-400059, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in
24 JUL2008
which it is to be performed.



Technical field of invention
The present invention relates to a synthetic process for the preparation of hydrochloride salt of N-(3-ethynylpheny()-6,7-bis(2-methoxyethoxy)-4-quinazolinamine (Erlotinib Hydrochloride), which is useful for the treatment of non-small cell lung cancer and pancreatic cancer.
Background of the invention
N-(3-ethynylphenyI)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride (Erlotinib Hydrochloride, trade name: Tarceva) is known as a selective inhibitor of epidermal growth factor receptor (EGFR) protein-tyrosine kinase, and currently, it is used clinically for the treatment of non-small cell lung cancer and pancreatic cancer.

Erlotinib Hydrochloride
The synthetic route of Erlotinib Hydrochloride is mainly reported by Schnur, Rodney C. from Pfizer Inc. N.Y., USA (US5747498) . Its synthetic process is described as follows:


This synthetic route comprises, reaction of starting material ethyl-3,4-dihydroxybenzoate with 2-bromoethyl methyl ether in the presence of a base; further nitration; reduction step of nitro to amine; followed by cyclization reaction and chlorination, and finally condensation with 3-ethynylaniline to obtain Erlotinib Hydrochloride.
As mentioned in WO2007060691, the main disadvantages of the patent US'498 are:
• The reaction is scale dependent during the nitration of the compound. The product yield and purity decrease with the increase in the scale.
• A highly expensive catalyst is used in the catalytic hydrogenation step, which also requires special equipment.
• Free alkali of the final product goes through column chromatography separation with no report on the yield rate as well as the quality of the final products.
WO20070609 describes new method to synthesize Erlotinib Hydrochloride comprises using 6,7-dimethoxy-4(3H)- quinazolinone as raw material, demethylation at 6,7 sites; acetylation using acetic anhydride to protect hydroxyl group; chlorination at C-4 position in quinazolinone, condensation with 3-ethynylaniline and finally deprotected by deacetylation to obtain dihydroxy compound, and reacted with chloromethyl ethyl ether to obtain Erlotinib.
The drawback of the above process involves firstly the step of demethylation, then protection and finally deprotection step, which increases the reaction process steps and decreases the yield rate virtually.



Objective of the invention
The main object of the present invention is to provide a simple, improved and
industrially feasible synthetic method for the preparation of hydrochloride salt of
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine (Erlotinib
Hydrochloride) by removing the drawbacks of existing prior technologies.
Summary of the invention
The present invention discloses a new improved synthetic process for the preparation of Erlotinib Hydrochloride involving 3,4-dihydroxybenzaldehyde as raw material which comprises reaction of 3,4-dihydroxybenzaldehyde with hydroxylamine hydrochloride to obtain cyano compound; which is further reacted with l-chloro-2-methoxyethane under inorganic or organic base conditions followed by nitration to obtain compound (3); oxidation of cyano group of compound (3) to amido group and reduction of nitro group into amino group to obtain compound (5); which on cyclization to yield 6,7-dimethoxy-3,4- dihydroquinazoline-4-one(6). Finally, chlorination of 6,7-dimethoxy-3,4- dihydroquinazoline-4-one followed by reaction with 3-Ethynylaniline to yield Erlotinib Hydrochloride. All the reaction steps are conducted under controlled conditions.
Detailed description of the invention
The invention will now be described in detail in connection with certain preferred and


optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
Accordingly, in a preferred embodiment, the invention describes a synthetic method for preparation of Erlotinib Hydrochloride which comprises the following steps:
a) reacting 3,4-dihydroxybenzaldehyde with hydroxylamine hydrochloride in a solvent in presence of a dehydrating agent to give compound of formula (1);
b) reacting compound (1) with l-chloro-2-methoxyethane in a solvent under inorganic or organic base conditions in presence of a PTC catalyst to obtain compound (2);
c) nitrating compound (2) in mixed acids to obtain compound (3);
d) oxidizing compound (3) to obtain compound (4);
e) reducing compound (4) in presence of a reducing agent and a catalyst in a solvent to obtain compound (5);
f) cyclizing compound (5) in the presence of a cyclization agent to give compound (6);
g) chlorinating compound (6); followed by reacting with 3-ethynyl-benzenamin to give Erlotinib Hydrochloride.
In step a), the reaction solvent is selected from the group of benzene, methyl benzene, 1,2-dimethylbenzene, N,N-dimethyl formamide or dimethyl sulfoxide; and the dehydrating agent is selected from the group of sodium sulfate anhydrous, magnesium sulfate anhydrous, acetic anhydride or chlorine sulfide. The reaction is conducted in presence of acid catalyst, p-toluene sulphonic acid.
In step b) , the reaction solvent is selected from the group of benzene,methylbenzene,
1,2-dimethylbenzene, N,N-dimethylformarnide or dimethyl sulfoxide; base is selected from the group of inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate; or from the group of organic bases such


as triethyiamine, N,N-diisopropylethyiamine, trimethylamine, tripropylamine or tributylamine; and the catalyst is selected from the group of PTC catalysts such as tetrabutyl ammonium iodide, tetrabutyl ammonium bromide or tetrabutylammoniumchloride.
In step c), mixed acids are selected from the group of acetic acid and nitric acid; sulfuric acid and nitric acid; nitric acid and sublimed nitric acid; acetic acid and sulfuric acid with sublimed nitric acid, or sulfuric acid and fuming nitric acid; the reaction temperature is from 0 to 70°C.
In step d), reaction solvent is selected from the group of N,N-dimetylformamide, dimethyl sulfoxide, methyl alcohol, ethyl alcohol or isopropyl alcohol; oxidizing agent is selected from the group of hydrogen peroxide, tert-butyl hydroperoxide, sodium perborate, potassium tetraborate or benzoyl peroxide, and the optimize options is hydrogen peroxide or sodium perborate.
In step e), reaction solvents is selected from the group of methyl alcohol, ethyl alcohol, propanol or butanol and the optimize option is methyl alcohol or ethyl alcohol;
catalyst is selected from the group of 2-20 % (weight percentage) Pd carbon,
hydrochloric acid or acetic acid; reducing agent is selected from the group of hydrogen, ammonium formate, formamide, formylamine, iron powder, zinc dust or sodium dithionite.
In step f), cyclization agent used is selected from formic acid or formamide or combination thereof.
In step g), chlorinating agent is selected from the group of chlorine sulfide, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride; and the solvent is selected from the group of methylbenzene, dichloromethane, dimethyl sulfoxide, n-hexane or 1,2-dichloroethane,


The synthetic route for preparation of Erlotinib Hydrochloride according to the invention is as depicted below:

The synthetic route for Erlotinib
The advantages of the present invention are as follows:
i) This invention utilizes 3,4-dihydroxybenzaldehyde as raw material thereby avoiding the steps of demethylation, protection and deprotection, thus successfully shorten the synthesis route; ii) Oxidation of cyano group into acidamide then reducing nitro group, which can effectively avoid the risk of overhydrolyzation of nitrile group into acid during cyano group hydrolyzation; iii) First oxidating cyano-group into amides to obtain poor water-soluble solid product to centrifugate, can avoid large amount of solvent extraction, iv) All the reactions are carried out under controlled conditions, v) The method is simple, assuring high yield and is suitable for industrial production. The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.


Examples: Example 1
A) Synthesis of compound 1
To a solution of double distilled methylbenzene (5L) in 10L 4-neck flask, 3,4-dihydroxy benzaldehyde (1kg), hydroxyamine hydrochloride (500g), p-tofuene sulfonic acid (160g) and anhydrous magnesium sulfate (5kg) were added and stirred. Reaction mixture was refluxed for 6 hours, and then cooled to room temperature and filtered. Filtered cake was extracted with hot ethyl acetate and then product was detected by TLC. When the product dissolves completely in ethyl acetate, the combined solution of ethyl acetate was repeatedly washed with saturated salt water, then dried and concentrated, till large amount of product gets separated out. Petroleum ether (2.5L) was added for crystallization. Dried with little petroleum ether to obtain dry compound 1 (800g).
B ) Synthesis of compound 2
Compound I (1kg), chloroethyl methyl ether (2kg), potassium carbonate (3kg), tetrabutyl ammonium iodide (500g) and DMSO (5L) were added to 10L, 4-neck flask and refluxed. The reaction was monitored by TLC, after the completion of reaction the reaction mixture was cooled and poured into ice water (lOL).The reaction mixture was extracted with methylene dichloride, washed with salt water and dried and concentrated to obtain compound 2 (1.6kg).
C) Synthesis of compound 3
A solution of compound 2 (1kg) in acetic acid (5L) was added dropwise into nitric acid (3D , which has been cooled to 0°C. The mixture was controlled at a temperature not above 10°C and stirred till the reaction was completed. The mixture was poured into ice water (50 L) and stirred. A large amount of solid precipitated, which was then centrifuged for 30min, the product was washed, dried and recrystallized using methyl alcohol to obtain compound 3(1.1 kg).
D) Synthesis of compound 4


To a solution of compound 3 (1kg) and potassium carbonate (2kg) in DMSO (2L) , hydrogen peroxide (1L) was added dropwise. After addition, the reaction mixture was poured into ice water (20 L). A large amount of solid was precipitated, which was then centrifuged and dried to obtain compound 4 (0.9kg).
E) Synthesis of compound 5
To a solution of compound 4 (1kg) in methyl alcohol (8L), ammonium formate (1kg) and Pd/C (200g) were added. The mixture was then heated to reflux till the reaction gets completed. The mixture was cooled to room temperature and then filtered. The filtrate was concentrated and the remainant (compound V) was used directly without purification.
F) Synthesis of compound 6
A solution of compound 5 (1kg) in formamide (4L) and formic acid (4L) was refluxed till clear solution was obtained. It was then cooled to room temperature, centrifuged and washed to obtain compound 6 (750g).
G ) Synthesis of Erlotinib
To a solution of chlorine sulfide (20L), compound 6 (1kg) and DMF (50mL) were added respectively, and refluxed. After the solid dissolved, excess chlorine sulfide was removed under vacuum. The mixture was cooled to room temperature and dichloromethane was added. It was further washed with saturated sodium bicarbonate solution, dried and concentrated. Obtained product was used without further purification. To a solution of the product in DMF, 3-ethynyl aniline (550g) was added. The mixture was heated to 100°C. After the reaction was completed, mixture was cooled to 10°C and a large amount of solid was precipitated. It was filtered and the cake was washed with ethyl acetate, and dried to obtain Erlotinib Hydrochloride (1kg). The action spectrum is in consistent with literature data.
Example 2
A ) Synthesis of compound 1
To a solution of double distilled methylbenzene (5L) in 10L 4-neck flask,


3,4-dihydroxybenzaldehyde( 1 kg), hydroxyamine hydrochloride( 1 kg), p-toluene sulfonic acid(lOOg) and anhydrous magnesium sulfate(4kg) were added and stirred. The reaction mixture was refluxed for 16 hours, and then cooled to room temperature, and filtered. Filter cake was extracted with hot ethyl acetate and then product was detected by TLC. When the product dissolves completely in ethyl acetate, the combined solution of ethyl acetate was repeatedly washed with saturated salt water, then dried and concentrated, till large amount of product gets separated out. Petroleum ether (2.5L) was added for crystallization. Dried with little petroleum ether to obtain dry compound 1 (850g). B) Synthesis of compound 2
Compound 1 (1kg), chloroethyl methyl ether (2kg), potassium carbonate (3kg), tetrabutylammonium iodide (l00g) and DMSO (5L) were added to 10L 4-neck flask, heated to reflux. The reaction was monitored by TLC, after the completion of reaction the reaction mixture was cooled and poured into ice water (10L). The reaction mixture was extracted with methylene dichloride, washed with salt water, dried and concentrated to obtain compound 2 (1.5kg).
C ) Synthesis of compound 3
A solution of compound 2 (1kg) in acetic acid (5L) was added dropwise into nitric acid (3D which has been cooled to 0°C. The mixture was controlled at a temperature not above 10°C and stirred till the reaction was completed. The mixture was poured into ice water (50 L) and stirred. A large amount of solid was precipitated, which was then centrifuged for 30mins, the product was washed, dried and recrystallized with ethyl alcohol to obtain compound 3(1.1 kg).
D ) Synthesis of compound 4
To a solution of compound 3 (1kg) and sodium carbonate (500g) in DMSO (5L) , hydrogen peroxide (1.5L) was added dropwise. After addition, the reaction mixture was poured into ice water (20 L). A large amount of solid was precipitated, which was
then centrifuged and dried to obtain compound 4 (1 kg).

E ) Synthesis of compound 5

To a solution of compound 4 (1kg) in ethyl alcohol (8L), ammonium formate (1kg) and Pd/C (500g) were added. The mixture was then heated to reflux till the reaction was completed. The mixture was then cooled to room temperature and then filtered. The filtrate was concentrated and the remainant (compound 5) was used directly without purification.
F ) Synthesis of compound 6
A solution of compound 5 (1kg) in formamide (3L) and formic acid (2L) was refluxed till clear solution was obtained. It was than cooled to room temperature, centrifuged and washed to obtain compound 6 (700g).
G ) Synthesis of Erlotinib
To a solution of chlorine sulfide (20L), compound 6 (1kg) and DMF (l00mL) were added respectively, and then heated to reflux. After the solid dissolved, excess chlorine sulfide was removed under vacuum. The mixture was cooled to room temperature and dichloromethane was added. It was further washed with saturated sodium bicarbonate solution, dried and concentrated. Obtained product was used without further purification. To a solution of the product in DMF, 3-ethynyl aniline (550g) was added. The mixture was heated to 120°C. After the reaction completion, mixture was cooled to 10°C. A large amount of solid was precipitated, filtered and the cake was washed with ethyl acetate, and dried to obtain product Erlotinib Hydrochloride (1kg). The action spectrum is in consistent with literature data.
Example 3
A ) Synthesis of compound 1
To a solution of double distilled methylbenzene (5L) in 10L 4-neck flask, 3,4-dihydroxybenzaldehyde(lkg), hydroxyamine hydrochloride(500g), p-toluene sulfonic acid(160g) and sodium sulfate anhydrous (5kg) were added and stirred. The reaction mixture was refluxed for 6 hours, then cooled to room temperature, and filtered. Filter cake was extracted with hot ethyl acetate and then the product was detected by TLC. When the product dissolves completely in ethyl acetate, the


combined solution of ethyl acetate was repeatedly washed with saturated salt water,
then dried and concentrated, till large amount of product gets separated out. Petroleum
ether (2.5L) was added for crystallization. Dried with little petroleum ether to obtain
dry compound 1 (900g).
B) Synthesis of compound 2
Compound 1 (1kg), chloroethyl methyl ether (2kg), potassium carbonate (5kg),
tetrabutylammonium iodide (300g) and THF (5L) were added to 10L, 4-neck flask
and heated to reflux. The reaction was monitored by TLC, after the completion of
reaction the reaction mixture was cooled and poured into ice water (lOL).The reaction
mixture was extracted with methylene dichloride, washed with salt water and dried
and concentrated to obtain compound 2(1. 5kg).
C ) Synthesis of compound 3
A solution of compound 2 (1kg) in acetic acid (3L) was added dropwise into nitric acid (3L) and sulfuric acid (3D which has been cooled to 0°C. The mixture was controlled at a temperature not above than 20°C and stirred till the reaction was completed. The mixture was poured into ice water (50 L) and stirred. A large amount of solid was precipitated, which was then centrifuged for 30min, the product was washed, dried and recrystallized using methyl alcohol to obtain compound 3(1.1 kg).
D ) Synthesis of compound 4
To a solution of compound 3 (1kg) and potassium carbonate (500g) in DMSO (2L) , hydrogen peroxide (2L) was added dropwise. After addition, the reaction mixture was poured into iced water (20 L). A large amount of solid was precipitated, which was then centrifuged and dried to obtain compound 4 (0.9kg).
E ) Synthesis of compound 5
To a solution of compound 4 (1kg) in methyl alcohol (5L), ammonium formate (1.2kg)
and Pd/C (50g) were added. The mixture was heated to reflux till the reaction was
completed. The mixture was then cooled to room temperature and filtered. The filtrate
was concentrated and the remainant (compound 5) was used directly without
purification.


F ) Synthesis of compound 6
A solution of compound 5 (1kg) in formamide (2L) and formic acid (4L) was heated to reflux till clear solution was obtained. It was than cooled to room temperature, centrifuged and washed to obtain compound 6 (750g).
G ) Synthesis of Erlotinib
To a solution of chlorine sulfide (30L), compound 6 (1kg) and DMF (50mL) were added respectively, and then heated to reflux. After the dissolution of solid, excess chlorine sulfide was moved under vacuum. The mixture was cooled to room temperature and dichloromethane was added. It was further washed with saturated sodium bicarbonate solution, dried and concentrated. Obtained product was used without further purification. To a solution of the product in DMF, 3-ethynyl aniline (550g) was added. The mixture was heated to 100°C A large amount of solid was precipitated. It was filtered and the cake was washed with ethyl acetate, and dried to obtain product Erlotinib Hydrochloride (lkg).The action spectrum is in consistent with literature data.


We claim,
1. A Synthetic method for Erlotinib Hydrochloride, comprises following steps:
i) reacting 3.4-dihydroxybenzaidehyde with hydroxylamine hydrochloride in a solvent in presence of dehydrating agent to give
compound of formula (1) ;
ii) reacting compound (1) with 1 -chloro-2-methoxyethane in a solvent
under inorganic or organic base conditions in presence of a PTC
catalyst to obtain compound (2);' iii) nitrating compound (2) in mixed acids to obtain compound (3); iv) oxidizing compound (3) to obtain compound (4); v) reducing compound (4) in presence of a reducing agent and a
catalyst in a solvent to obtain compound (5); vi) cyclizing compound (5) in the presence of a cyclization agent to
give compound (6); vii) chlorinating compound (6); followed by reacting with
3-ethynyl-benzenamine to give Erlotinib Hydrochloride.
2. The synthesis as claimed in claim 1, wherein the reaction solvent used in step (i) and (ii) is selected from the group of benzene, methylbenzene, 1,2-dimethylbenzene, N,N-dimetylformamide or dimethyl sulfoxide;
3. The synthesis as claimed in claim 1, wherein said dehydrating agent used in step (i) is selected from the group of sodium sulfate anhydrous, magnesium sulfate anhydrous, acetic anhydride or chlorine sulfide.
4. The synthesis as claimed in claim 1, wherein the base used in step (ii) is selected from the group of inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate; or from the group of organic bases such as triethylamine, N,N-diisopropylethylamine, trimethylamine, tripropylamine or tributylamine.
5. The synthesis as claimed in claim 1, wherein said catalyst used in step (ii) is selected from the group of PTC catalysts such as tetrabutyl ammonium iodide,


tetrabutyl ammonium bromide or tetrabutylammoniumchloride.
6. The synthesis as claimed in claim 1, wherein the mixed acids used in step (iii) are selected from the group of acetic acid and nitric acid; sulfuric acid and nitric acid; nitric acid and fuming nitric acid; acetic acid and sulfuric acid with sublimed nitric acid, or sulfuric acid and sublimed nitric acid.
7. The synthesis as claimed in claim 1, wherein step (iii), the reaction is carried out at a temperature ranging from 0°C to 70°C.
8. The synthesis as claimed in claim 1, wherein the reaction solvent used in step (iv) is selected from the group of N,N-dirnetylformamide, dimethyl sulfoxide, methyl alcohol, ethyl alcohol or isopropyl alcohol.
9. The synthesis as claimed in claim 1, wherein said oxidizing agent used in step (iv) is selected from the group of hydrogen peroxide, tert-butyl hydroperoxide, sodium perborate, potassium tetraborate or benzoyl peroxide.
10. The synthesis as claimed in claim 9, wherein oxidizing agent used in step (iv) is hydrogen peroxide or sodium perborate.
11. The synthesis as claimed in claim 1, wherein the reaction solvent used in step (v) is selected from the group of methyl alcohol, ethyl alcohol, propanol, butanol.
12. Synthetic method of claim 11, wherein solvent used in step (v) is methyl alcohol or ethyl alcohol.
13. The synthesis as claimed in claim 1, wherein catalyst used in step (v) is
selected from the group of 2-20 % (weight percentage) Pd carbon,
hydrochloric acid or acetic acid.
14. The synthesis as claimed in claim 1, wherein reducing agent used in step (v) is selected from the group of hydrogen, ammonium formate, formamide, formylamine, iron powder, zinc dust or sodium dithionite.
15. The synthesis as claimed in claim 1, wherein cyclization agent used in step (vi) is formic acid or formamide or combination thereof.
16. The synthesis as claimed in claim 1, wherein chlorination agent used in step


(vii) is selected from the group of chlorine sulfide, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride. 17. The synthesis as claimed in claim 1, wherein solvent used in step (vii) is selected from the group of methylbenzene, dichloromethane, dimethyl sulfoxide, n-hexane or 1,2-dichloroethane.
Dated 16* day of July 2008

MAC CHEM PRODUCTS INDIA PVT. LTD.
Applicant