Title of Invention

A PROCESS FOR SYNTHESIS OF [6,7-BIS-(2-METHOXYETHOXY)-QUINAZOLIN-4-YL]-(3-ETHYNYLPHENYL)AMINE HYDROCHLORIDE (ERLOTINIB HYDROCHLORIDE)

Abstract The present invention provides a process for synthesizing [6,7nis(2-methoxyethoxy)quina2olin-4-yl]-(3-ethynylphenyl)amine hydrochloride (Eriotinib Hydrochloride) having the formula
Full Text

FIELD OF INVENTION
The present invention relates to a process for synthesis of [ 6,7-bis-(2-methoxyethoxy) - quinazoline -4- yl]-(3-ethynylphenyl)amine hydrochloride of the formula I.

It is a low molecular weight compound used in the treatment of proliferative neoplastic and malignant diseases including multiple forms of solid tumors and psoriasis. It inhibits epidermal growth factor-tyrosine kinase (EGFR-TKI). Receptor protein tyrosine kinases play a key role in signal transduction pathways that regulates cell division and differentiation. Over expression of certain growth factor receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) as well as human epidemial growth factor receptor (HER-2) leads to cancer. Protein kinase inhibitors particularly phosphorylation inhibitors, have become important targets for selective cancer therapies (Bioorganic & Medicinal chemistry Letters 12, 2893-2897 (2002). Further, it exhibits significant anti-tumor activity in a broad range of solid tumor engrafts in vivo. Clinical toxicology studies have demonstrated good oral bio-availability and in long term oral administration it was well tolerated.

PRIOR ART
As known process for the synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amine hydrochloride, there can be mentioned a method comprising preparation of 6,7-bis(2-methoxyethoxy) quinazolone and then reacting 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline with 3-ethynylaniline under basic conditions such as pyridine or using excess aniline in solvents like isopropanol ( US Patent No. 5,747,498, May 5, 1998), followed by silica gel column chromatographic purification as a free base [6,7-bis- (2-methoxyethoxy) quinazolin -4- yl]-(3-ethynylphenyl) amine and titration of this free base with IM HCl to yield [6,7-bis -(2-methoxyethoxy) quinazolin-4-yl]- (3-ethynylphenyl) amine hydrochloride in 71% final step yield. Further preparation of 4-chloro 6,7-bis(2-methoxyethoxy)quinazoline involved many independent steps like alkylation of ethyl 3,4-dihydroxybenzoate using 2-bromo ethylmethyl ether and potassium carbonate, followed by nitration with nitric acid / acetic acid which yielded ethyl 4,5-bis (2-methoxyethoxy)-2-nitrobenzoate. The resulting nitro compound was then reduced to ethyl-2-amino- 4,5"bis-(2-methoxyethoxy) benzoate by hydrogenation in presence of Pt02 with yielded about 88%. This step involved handling of a combustible gas like hydrogen as well as costly catalyst such as Pots. Further cyclization of ethyl-2"amino-4,5-biS"(2-methoxyethoxy)benzoate has been achieved using ammonium fonnat and formaldehyde at a high temperature of 160-1 GS’'C 6,7-bis-(2-methoxyethoxy)-quinazolone. Treatment of 6,7-bis(2-methoxyethoxy) -quinazoline with oxalylchloride / phosphorous oxy chloride in presence of suitable solvent yielded 4-chloro-6,7-bis-(2"methoxyethoxy)-quinazoline with

yields of 92% and 56% respectively. Thus, multiple steps are involved with usage of several costly reagents like platinum oxide, flammable gas like hydrogen and at very high reaction temperatures. Further the penultimate step product namely [6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl] -(3-ethynylphenyl) amine is purified by silica column chromatography.


All steps of the profess disclosed in US Patent No. 5,747,498 are not only push the manufacturing cost to a higher side but also takes more time. Thus, this known method involves various industrial difficulties.
DETAILS OF THE INVENTION
To obviate the disadvantages of the prior art, the present invention
provides a process for the synthesis of [6,7-bis-(2-methoxyethoxy)-
quinazolin-4-yl]-(3-ethynylphenyl)amine hydrochloride having the
formula I,
1. A process for synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4-
yl]-(3-ethynylphenyl)amine hydrochloride having formula (I)


with substituted ethylmethyl ether in presence of an inert solvent and a base to obtain 3,4-bis( 2-methoxyethoxy) benzaldehyde having formula III,

b) converting compound of the formula III in presence of a base and an organic solvent into 3,4-bis(2-

methoxyethoxy)benzaldoxime of the formula IV and dehydrating the said compound to obtain 4,5-bis(2 methoxyethoxy )-2-benzonitrile having formula V

c) nitrating the compound of the formula V with nitrating agent to obtain 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile having the formula VI


subjecting the compound of the formula VI to nitro reduction, nitrile hydrolysis, formulation and cyclization in one-pot synthesis to obtain 6,7-bis(2-methoxyethoxy)-quinazoline-4-one having formula VII,

treating the compound of the formula VII with an halogenating agent in the presence of solvent to obtain 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline chloride having formula VIII, and

coupling the compound of the formula VIII with an aniline derivative in the presence of a solvent to obtain [6,7-bis-(2-

methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)-amine hydrochloride
The compound of fennel VI in step (d) undergoes nitro reduction and nitrile reduction to give us 2-amino-4,5-bis (2-methoxyethoxy)benzamide having formula VIA ;which

undergoes formulation and cyclization to give us compound of formula VII.
The inert solvent in step (a) is an aprotic solvent selected from aliphatic ketones and substituted amides, preferably dimethyl formamide .
The substitution of the ethylmethylether in step (a) is chloro, bromo, iodo, hydroxy or a methoxy group preferably bromo derivative.
The base in step (a) is alkali or alkaline earth carbonate and hydroxide preferably sodium and potassium carbonate.
The reaction mixture in step (a) is maintained at a temperature from ambient to reflux temperature preferably from 80’ C to lOO’C .
The solvent in step (b) is aliphatic alcohol preferably methanol or isopropanol.

The base in step (b) is organic or inorganic bases wherein the organic base is pyridine, dimethylaminopyridine, or triethylamine and the inorganic bases is sodium acetate or ammonium acetate; the organic base used preferably is pyridine.
The dehydration in step (b) is carried out in the presence of thionyl chloride, phosphorous oxy chloride, propionic anhydride or acetic
anhydride ; preferably acetic anhydride.
The reaction in step (b) is from ambient to reflux temperature from 50° C to 120° C ; preferably reaction is carried out at 110 ° C .
The nitrating agent in step (c) is nitric acid.
The reaction in step (c ) is carried out in the temperature range from 25° C to 50° C ; preferably at 40 ° C .
The compound of formula VIA is prepared from compound of formula VI in step (d) the presence of ,hydrazine hydrate in the presence of the charcoal or ferric chloride and mineral acids such as hydrochloric acid or hydrobromic acid; the solvents used are methanol, ethanol or propanol ; preferably methanol at a temperature range from 30° C to 90° C preferably at 90° C.
The reagents used for preparation of the compound of formula VII from compound of formula VIA in step (d) is formulating agent selected from formic acid, formamidine, triethylorthoformate, methy formate ;preferably

formic acid at a temperature range from 100 C to 150 C preferably at 130° C.
The halogenating agent in step (e) is thionyl chloride, oxalyl chloride or phosphorous oxy chloride preferably thionyl chloride.
The reaction in step (e) is carried out at a temperature range from 30° C to 90° C preferably at 90° C .
The aniline derivative coupled to the compound of formula VIII in step (f) is a 3-ethylynyl derivative.
The solvent in step (f) is aprotic solvent selected from dimethyl formamide, methylene dichloride and ethylene dichloride.
The reaction in step (f) is coupled at a temperature range from 25 C to 110°C preferably at 100°C.
The process of preparation of 6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyI)amine hydrochloride, is substantially as herein described with reference to the foregoing example.
The inert solvent used in step (a) can be selected from halogented solvent
,an ether , an aromatic solvent , and a polar solvent .Examples of such
solvents are methylene chloride, chloroform, carbon tetrachloride,
tetrahydrofuran, 1,4-dioxan,toluene,N,Ndimethylformamide,N-
Ndimethylacetamide, dimethylysulphoxide.acetone and acetonitrile.

V The base used in step (a) can be selected from potassium hydoxide, sodium
hydroxide and calcium carbonate.
The nitrating agent in step (c )can be selected from sulphuric acid and potassium nitrate.
The chlorinating agent in step (e) can be selected from solvent such as chloroform, dichloromethane, carbon tetrachloride, 1,4-dioxan, toluene and tetrahydrofuran.
The reaction in step (f) is carried out using 3-ethynyIaniline in a solvent selected from dimethylformamide, chloroform, acetonitrile tetrahydrofuran, 1,4-dioxan and Ci-Ce solvents. Preferably the reaction is carried out under inert atmosphere such as dry nitrogen.
The process of the present invention provides the following distinct advantages over the prior art.
In the process of the present invention, because of unique a one-pot synthesis of quinazoline moiety of step d) higher yields are obtained. No intermediate need to be isolated thus avoiding yield losses and elimination of usage of excess solvents. Also, in situ making of compound of the formula I in step f) helped in getting its higher yields. According to the process of the present invention the overall yield of 4-chloro-6,7-bis (2-methoxyethoxy)quinazoline stood at 71% with respect to the starting material 3,4-dihydoxy benzaldehyde and whereas in the patented process overall yield stood at 65% with respect to starting

material ethyl 3,4-dihydroxybenzoate. Further, it yield obtained from 4-chloro-6,7-bis (2-methoxyethoxy)quinazoline is 75% compared to 71% as reported in the above said patent. Thus, there exists a clear advantage in terms of yields. To summarize, as per the process of present invention the yield is 53% starting from 3,4-dihydroxy benzaldehyde, whereas as per patented procedure the yield is 46% only starting from ethyl 3,4-dihydroxy benzoate.
The usage of costly reducing agent like platinum oxide in reducing nitre compound and higher temperatures used in cyclization of 2-amino-4,5-bis-(2-methoxyethoxy)benzoate are reported in US Patent 5,747,498. Further 4-chloro-6,7 -bis( 2-methoxyethoxy)quinazoline is coupled with suitably substituted aniline in the presence of additional base and isolated product as a free base and purified it by silica column chromatography. Then the free product base is nitrated with ethereal hydrochloric acid to get the product. All these steps involve several independent operations including usage of flammable hydrogen gas and subjecting to silica column chromatographic purifications. In contrast, according to the process of present invention the reduction, formylation, hydrolysis and cyclization operations which involve 4 steps are accomplished in one-pot under mild conditions with less usage of solvents while making 4-chloro-6,7-bis-(2-methoxyethoxy)quinazoline. Secondly, eriotinib hydrochloride preparation is accomplished in one go from 4-chloro 6, 7-bis (2-methoxyetoxy) quinazoline without isolating the free base and purified by crystallization techniques alone.

EXAMPLE
To 3, 4-dihydroxy benzaldehyde of the formula II (25g, 0.1811 mole), potassium carbonate (60g, 0.4347 mole) in N, N-dimethyl forenamed (120ml) was added 2-bromoethylmethyl ether (50.4g, 0.3625 mole). The mixture was stirred at 100°C for 2 hours, cooled to room temperature, filtered inorganic. The clear filtrate was concentrated under vacuum and the residue was dissolved in methylene chloride, washed with water and dried over calcium chloride. Evaporation yielded 3,4-bis (2-methoxyethoxy) benzaldehyde of formula III (45g, 98%).
NMR spectrum (CDCI3): 5 3.46 (s, 6H), 3.81(m, 4H), 4.22 (m, 4H), 7.Q0(d, IH), 7.43(s, IH), 7.45(d, IH) and 9.83(s, IH).
To 3,4-bis(2-methoxyethoxy) benzaldehyde of the formula III (45g, 0.177 mole), hydroxylamine hydrochloride (45g, 0.6521 mole), in methanol (200ml) was added pyridine (52ml, 0.6521 mole). This reaction mixture was stirred at reflux temperature for about 3 hours. Methanol was concentrated under vacuum and the residue was dissolved in ethyl acetate, washed the organic layer with water and dill. HCl, dried over anhydrous sodium sulphate. To the residue obtained after evaporation of ethylacetate was added acetic anhydride (75ml) and heated to 110°C for 4 hours, then cooled the reaction mixture to room temperature, quenched in water and adjusted the P" to 8 with sodium bicarbonate and extracted with methylene chloride. Organic layer was washed with water and dried over calcium chloride. On evaporation of the solvent, a brown liquid i.e. 3,4- bis (2-methoxyethoxy) benzonitrile (42g, 95%) of the formula V.

NMR (CDCI3): 5 3.45 (s, 6H), 3.79(m, 4H), 4.18(m, 4H), 6.93(d, IH),
7.14(d, lH)and7.26(dd, IH)
To 70% nitric acid (84ml) maintained at 40°C was added 3,4-bis(2-methoxyethoxy) benzonitrile (42g) of the formula V slowly over a period of 2 hours under stirring. After complete addition of the
compound, stirring continued for further an hour, quenched the reaction mass in ice-water, filtered, washed the precipitate with water and dried the material at 50°C to get yellow solid i.e. 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile of the formula VI (44.5g, 90%); m.p. 139-143°C.
NMR (CDCI3): 6 3.45 (s, 6H), 3.82(m, 4H0, 4.30(m, 4H), 7.28(s, IH) and7.85(s, IH).
To a stirred solution of 4,5-bis (2-methoxyethoxy)-2-nitrobenzonitrile (44.5g, 0.1503) of the formula VI, methanol (300ml), and anhydrous ferric chloride (L5g, 0.0092 mole) was added 80% hydrazine hydrate (44.5ml, 0.89 mole) slowly at reflux temperature. After complete addition of hydrazine hydrate, continued refluxing for additional 2 hours. Then cooled the reaction mixture to room temperature and added 35% hydrochloric acid (35ml) slowly in half-an-hour time. Again raised the temperature to 50°C and stirred for further 2 hours. Then removed methanol from under vacuum, adjusted the pH of the reaction mixture to about 8 using sodium bicarbonate. Extracted the material with ethyl acetate, washed the organic layer with water, dried over anhydrous sodium sulphate. On evaporation of the solvent obtained

the product as yellow solid (38g) which was then suspended in ethyl acetate & n-hexane mixture, chilled and filtered to obtain pure compound 6,7-bis (2-methoxyethoxy)-quinazoline-4-one of the formula VII (35.6g,83%); m.p. 103-108°C.
NMR (CDCI3): 6 3.44 (s, 6H), 3.74(m, 4H), 4.10(m, 4H), 5.60(brs, 4H), 6.18(8, IH) and 7.03(s,lH)
To 6,7-bis (2-methoxyethoxy)-quinazoline-4-one (35g, 0.11904mole) and thionyl chloride (570g, 4.8 moles) was added dimethyl formamide (3ml). The reaction mixture was stirred at reflux temperature for about 3 hours. Distilled off excess thionyl chloride, dissolved the residue obtained in methylene dichloride, washed the organic layer with water and dried over calcium chloride. On evaporation of methylene dichloride yielded 4-chloro - 6,7 bis (2-methoxyethoxy) quinazoline (35g, 94%) of the formula VIII.
NMR (CDCI3): 5 3.49 (s, 6H), 3.82 (m, 4H), 4.34 (m, 4H), 7.33(s, IH), 7.42(s, IH) and 8.85 (s,lH).

To a stirred solution of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline (35g, 0.1122 mole) of the formula VHI in dimethyl formamide was added 3-ethynyl aniline( 13.1g, 0.1122mole) and the reaction contents were stirred at 60°C for about an hour. Then cooled the reaction mixture to 10°C, filtered and dried to get the crystalline substance [6,7- bis-(2-methoxyethoxy)quinazolin -4-yl] -(3-ethynyl phenyl) amine hydrochloride of (37g, 75%) having the melting point 228-230°C.
UV, IR, NMR spectral data together with elemental analysis are in complete agreement with those of standard substance.
Preparation 1:
A mixture of 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile (18g, 0.0608mole), methanol (125ml), water (50ml) and anhydrous ferric chloride (O.Sg) was heated to reflux and added 80% hydrazine hydrate (18ml, 0.360mole) slowly over a period of one hour. Stirring continued for further 2 hours and distilled off methanol-water from the reaction mixture. To the reaction mass was added 35% hydrochloric acid (20ml), 85% formic acid (100ml) and water (25ml) and heated the reaction mixture to 140°C while sting for about 4 hours. Distilled off excess of formic acid, hydrochloric acid, dissolved the residue obtained in 40 ml water, adjusted the PH to 8 with sodium bicarbonate and concentrated to get white colored mass (25g). Dissolved the mass in 250 ml methanol and filtered to remove inorganic. Concentrated methanol to get pure material (16g. 90%).

Preparation -2:
To a stirred solution of 85% formic acid (180ml) was added 2-amino-4,5-bis (2-methoxyethoxy) benzamide( 35.6g, 0.1253 mole) and the reaction mixture stirred at 140°C for 4 hours. Distilled off excess of formic acid, dissolved the residue in 100ml water, basified to PH 8 with sodium
bicarbonate and distilled off the water. To the crude material obtained was added 500 ml methanol, heated to reflux, stirred for half-an-hour and filtered. The filtrate was concentrated to get a white solid (35g, 95%)
NMR in D20: 5 3.82(s, 6H), 3.77(m, 4H), 3.98 (m, 4H), 6.44 (s, IH), 6.86 (s, lH)and7.75(s, IH).




We claim, 1) A process for the synthesis of [6,7nis(2-methoxycthoxy) quinazolin-4-yl]-(3-ethynylphenyl) amine hydrochloride having formula (I)

Comprising a) reacting 3,4-dihydroxy benzaldehyde having formula II

with substituted ethylmethyl ether in presence of an inert solvent and a base to obtain 3,4-bis( 2-methoxyethoxy) benzaldehyde having formula HI,


b) converting compound of the formula III in presence of a base and an organic solvent into 3,4-bis(2-

methoxyethoxy)benzaldoxime of the formula IV and dehydrating the said compound to obtain 4,5-bis(2 methoxyethoxy )-2-benzonitrile having formula V
r
c) nitrating the compound of the formula V with nitrating agent to
obtain 4,5"bis(2-methoxyethoxy)-2-nitrobenzonitrile having the formula VI

d) subjecting the compound of the formula VI to nitro reduction,
nitrile hydrolysis, formulation and cyclization in one-pot
synthesis to obtain 6,7-bi3(2-methoxyethoxy)-quinazoline-4-one
having formula VII,


e) treating the compound of the formula VII with an halogenations
agent in the presence of solvent to obtain 4-chloro-6,7-bis(2-
methoxyethoxy)quinazoline chloride having formula VIII, and

f) coupling the compound of the formula VIII with an aniline
derivative in the presence of a solvent to obtain [6,7-bis-(2-
methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)-amine
hydrochloride of formula (I).
2) The process as claimed in claim 1, wherein the compound of
formula VI in step (d) undergoes nitro reduction and nitrile
hydrolysis to provide 2-amino-4,5-bis (2-
methox\ethoxy)benzamide having formula VIA .



The process as claimed in claim 1, wherein the substitution of
the ethylmethylether in step (a) is chloro, bromo, iodo, hydroxy or a methoxy group preferably bromo derivative.
The process as claimed in claim 1, wherein the base in step (a) is alkali or alkaline earth carbonate and hydroxide preferably sodium and potassium carbonate.
The process as claimed in claim 1, wherein the reaction mixture in step (a) is maintained at a temperature from ambient to reflux temperature preferably from 80^ C to 100^ C . The process as claimed in claim 1, wherein the solvent in step (b) is aliphatic alcohol preferably methanol or isopropanol The process as claimed in claim 1, wherein the base in step (b) is organic or inorganic bases wherein the organic base is pyridine, dimethylaminopyridine, or triethylamine and the inorganic bases is sodium acetate or ammonium acetate; the organic base used preferably is pyridine.
The process as claimed in claim 1, wherein the dehydration in (b) is carried out in the presence of thionyl chloride, phosphorous oxy chloride, propionic anhydride or acetic anhydride ; preferably acetic anhydride.

The process as claimed in claim 1, wherein the reaction in step
(b) is from ambient to reflux temperature from 50° C to 120*^ C ;
preferably reaction is carried out at 110 ° C.
The process as claimed in claim 1, wherein the nitrating agent in
step (c) is nitric acid.
The process as claimed in claim 1, wherein tlie reaction in step (c
) is carried out in the temperature range from 25° C to 50 C ;
preferably at 40 ° C .
The process as claimed in claim 2, wherein the compound of
formula VIA is prepared from compound of formula VI in the
presence of ,hydrazine hydrate in the presence of the charcoal or
ferric chloride and mineral acids such as hydrochloric acid or
hydrobromic acid; the solvents used are methanol, ethanol or
propanol ; preferably methanol at a temperature range from 30
C to 90^ C preferably at 90° C.
The process as claimed in claim 1, wherein the reagents used for
preparation of the compound of formula VII from compound of
formula VIA is formulating agent selected from formic
acid,formamidine,triethylorthoformate,methylformate;preferably
formic acid at a temperature range from 100° C to 150 C
preferably at 130° C.
The process as claimed in claim 1 , wherein the halogenations
agent in step (e) is thionyl chloride, oxalyl chloride or
phosphorous oxy chloride preferably thionyl chloride.
The process as claimed in claim 1, wherein the reaction in step
(e) is carried out at a temperature range from 30° C to 90 C
preferably at 90° C .

The process as claimed in claim 1, wherein the anile derivative
coupled to the compound of formula Vin in step (f) is a 3-
ethynyl derivative.
The process as claimed in claim 1, wherein the solvent in step (f)
is aprotic solvent selected from dimethyl formamide,methylene
dichloride and ethylene dichloride.
The process as claimed in claim 1, where the reaction in step (f)
is carried at 25° Cato llO’C preferably all 00 V.
The process of preparation of 6,7-bis-(2-methoxyethoxy)-
quinazolin-4-yl]-(3-ethynylphenyl)amine hydrochloride , is
substantially as herein described with reference to the foregoing
examples.
[6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-
ethynylphenyl)amine hydrochloride wherever prepared by the
process as claimed in any of the preceding claims


Documents:

1483-CHE-2005 AMENDED PAGES OF SPECIFICATION 02-08-2010.pdf

1483-che-2005 amended claims 02-08-2010.pdf

1483-CHE-2005 CORRESPONDENCE 02-08-2010.pdf

1483-che-2005 amended claims 09-11-2010.pdf

1483-che-2005 amended pages of specification 09-11-2010.pdf

1483-CHE-2005 CORRESPONDENCE OTHERS 29-11-2010.pdf

1483-CHE-2005 EXAMINATION REPORT REPLY RECIEVED 09-11-2010.pdf

1483-che-2005-abstract.pdf

1483-che-2005-claims.pdf

1483-che-2005-correspondnece-others.pdf

1483-che-2005-correspondnece-po.pdf

1483-che-2005-description(complete).pdf

1483-che-2005-description(provisional).pdf

1483-che-2005-form 1.pdf

1483-che-2005-form 26.pdf

1483-che-2005-form 3.pdf

1483-che-2005-form 5.pdf

1483-che-2005-other document.pdf


Patent Number 244850
Indian Patent Application Number 1483/CHE/2005
PG Journal Number 52/2010
Publication Date 24-Dec-2010
Grant Date 22-Dec-2010
Date of Filing 17-Oct-2005
Name of Patentee VITTAL MALLYA SCIENTIFIC RESEARCH FOUNDATION
Applicant Address P.B NO 406 K.R ROAD BANGALORE 560 004 KARNATAKA
Inventors:
# Inventor's Name Inventor's Address
1 VENKATESHAPPA CHANDREGOWDA VITTAL MALLYA SCIENTIFIC RESEARCH FOUNDATION P.B NO 406 K.R ROAD BANGALORE 560 004 KARNATAKA
2 GUDAPATI VENKATESWARA RAO VITTAL MALLYA SCIENTIFIC RESEARCH FOUNDATION P.B NO 406 K.R ROAD BANGALORE 560 004 KARNATAKA
3 ANIL KUMAR KUSH VITTAL MALLYA SCIENTIFIC RESEARCH FOUNDATION P.B NO 406 K.R ROAD BANGALORE 560 004 KARNATAKA
4 GOUKANAPALLI CHANDRASEKARA REDDY VITTAL MALLYA SCIENTIFIC RESEARCH FOUNDATION P.B NO 406 K.R ROAD BANGALORE 560 004 KARNATAKA
PCT International Classification Number C07D 521/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA