"Process For Preparation Of Substituted 3' Hydrazino Biphenyl 3 Carboxylic Acid Compounds"
Abstract:
The present invention provides a process for the preparation of substituted 3'-hydrazino-biphenyl-3-carboxylic acid compounds. The present invention -further provides a process for the preparation of 3'-{N'-[l-(3,4-dimethylphenyl)-3-methyl-5-oxo-1.5-dihydro-pyrazol-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid, its intermediate compounds and pharmaceutical acceptable salts thereof.
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HOUSE NO.409,LANE NO.1,DEVNAGAR,TARAGAD ROAD,AJMER-305001
Specification
FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
"PROCESS FOR PREPARATION OF SUBSTITUTED 3-HYDRAZINO-BIPHENYL-3-CARBOXYLIC ACID COMPOUNDS"
Glenmark Generics Limited an Indian Company, registered under the Indian company's Act 1957 and
having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala, Andheri (East), Mumbai- 400 099
The following specification particularly describes the invention and the manner in which it is to be performed.
PROCESS FOR PREPARATION OF SUBSTITUTED 3-HYDRAZINO-BIPHENYL-3-
CARBOXYLIC ACID COMPOUNDS
PRIORITY
This application claims the benefit to Indian Provisional Applications 2570/MUM/2011 filed
on September 13, 2011, 2898/MUM/2011 filed on October 17, 2011 and 582/MUM/2012
filed on March 5, 2012 entitled "PROCESS FOR PREPARATION OF SUBSTITUTED 3'-
HYDRAZINO-BIPHENYL-3-CARBOXYLIC ACID COMPOUNDS", which are
incorporated herein by reference.
BACKGROUND OF THE INVENTION
Technical Field
The present invention relates to a process for the preparation of substituted 3'-hydrazino-
biphenyl-3-carboxylic acid compounds. The present invention relates to a process for the
preparation of 3'-{N'-[l-(3,4-dimethylphenyl)-3-methyl-5-oxo-l,5-dihydro-pyrazol-4-
ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid, its intermediate compounds and
pharmaceutically acceptable salts thereof.
Description of the Related Art
Eltrombopag. also known as 3'-{N'-[l-(3.4-dimethylphenyl)-3-methyl-5-oxo-l,5-dihydro-
pyrazol-4-y!idene]-hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid is represented by the
structure of formula la.
Eltrombopag olamine, compound of formula II, is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura who have had an insufficient response to corticosteroids, immunogfobufins. or splenectomy. E/trombopag olamine is marketed under the brand name PROMACTA® in the United States (approved in November 2008) and under the brand name REVOLADE® in Europe (approved in March 2010).
Eltrombopag belongs to a class of substituted 3'-hydrazino-biphenyl-3-carboxylic acid compounds of formula I.
United States Patent No. 7160870 (the '870 patent) discloses eltrombopag and its salts. United States Patent No. 7547719 discloses eltrombopag olamine, bisethanolamine salt of eltrombopag. The '870 patent discloses a process for the preparation of eltrombopag as schematically represented by Scheme I.
Scheme 1 The object of the present invention is to provide a novel method, which is more convenient .
and more efficient than the previously known method for the synthesis of substituted 3'-
hydrazino-biphenyl-3-carboxylic acid compounds.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of substituted 3'-hydrazino-
biphenyl-3-carboxylic acid compounds of formula I and salts thereof,
wherein R represents hydrogen, linear or branched C1-6 alkyl, C3-8 cycloalkyl, optionally substituted benzyl, linear or branched alkylalkoxy, tetrahydrofuranyl, tetrahydropyranyl, methyloxybenzyl, trialkylsilyl, acyl, trityl; the process comprising: a) reacting a compound of formula III,
wherein R is as defined above, X is selected from the group consisting of CI, Br, I, wjth a compound of formula IV,
wherein R' represents boronic acid, boronic acid ester or halogen in the presence of a metal
catalyst; and
(b) optionally, deprotecting the compound of formula I.
In another embodiment, the present invention provides a compound of formula III,
wherein X and R are as defined above.
In another embodiment, the present invention provides a compound of formula V,
wherein X, R and R" are as defined above.
In another embodiment, the present invention provides a process for the preparation of eltrombopag, compound of formula la,
and pharmaceutically acceptable salts thereof, the process comprising: (a) reacting 3-bromo-2-methoxyaniline with ethylacetoacetate in the presence of alkali or alkaline earth metal nitrite and inorganic acid to give ethyl 2-[(3-bromo-2-methoxyphenyl)hydrazono]-3-oxobutanoate, compound of formula Va;
(b) reacting the compound of formula Va with 3,4-dimethylphenylhydrazine or salt thereof to give l-(3,4-dimethyIphenyl)-3-methyl-4-(3-bromo-2-methoxyphenyl)hydrazono-5-pyrazolone, compound of formula IIIa;
(c) reacting the compound of formula Ilia with 3-carboxyphenylboronic acid in the presence of a metal catalyst to give 3'-{N'-[l-(3,4-dimethylphenyl)-3-methyl-5-oxo-l,5-dihydro-pyrazol-4-ylidene]hydrazino}-2'-methoxybiphenyl-3-carboxylic acid, compound of formula lb;
(d) deprotecting the compound of formula lb using Lewis acid to give eltrombopag; and optionally, converting to its pharmaceutically acceptable salt.
In another embodiment, the present invention provides a process for the preparation of eltrombopag, a compound of formula la,
the process comprising subjecting the compound of formula I to a deprotection reaction,
wherein R represents linear or branched C1-6 alkyl, C3-8 cycloalkyl, optionally substituted benzyl, linear or branched alkylalkoxy, tetrahydrofuranyl, tetrahydropyranyl, methyloxybenzyl, trialkylsilyl, acyl, trityl.
In another embodiment, the present invention provides use of compound of formula IIIa, Va, or lb in the preparation of eltrombopag or salt thereof.
In another embodiment, the present invention provides an eltrombopag ammonium salt.
In another embodiment, the present invention provides a process for the preparation of
eltrombopag ammonium salt comprising reacting eltrombopag with a source of ammonia.
In another embodiment, the present invention provides a process for the preparation of
eltrombopag olamine comprising reacting eltrombopag or a salt thereof with excess of
ethanolamine without using any additional reaction solvent.
In another embodiment, the present invention provides a process for the preparation of eltrombopag
olamine comprising eltrombopag or a salt thereof with ethanolamine in an aqueous medium.
In another embodiment, the present invention provides a process for the preparation of
eltrombopag olamine comprising reacting eltrombopag ammonium salt with ethanolamine.
In another embodiment, the present invention provides use of eltrombopag ammonium salt in
the preparation of eltrombopag olamine.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure ! is the proton NMR spectrum of ethyl 2-[(3-bromo-2-methoxyphenyl)hydrazono]-3-
oxobutanoate, compound of formula Va.
Figure 2 is the proton NMR spectrum of l-(3,4-dimethylphenyl)-3-methyl-4-(3-bromo-2-
methoxyphenyl)hydrazono-5-pyrazoIone, compound of formula Ilia.
Figure 3 is the proton NMR spectrum of 3'-{-2-[I-(ethoxycarbonyl)-2-
oxopropylidenejhydrazino}'-methoxybiphenylo-carboxylic acid.
Figure 4 is the proton NMR spectrum of eltrombopag ammonium salt as obtained in Example 14c.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of substituted 3'-hydrazino-
biphenyl-3-carboxylic acid compounds of formula I and salts thereof,
wherein R represents hydrogen, linear or branched C1-6 alkyl, C-3-8 cycloalkyl, optionally substituted benzyl, linear or branched alkylalkoxy, tetrahydrofuranyl, tetrahydropyranyl, methyloxybenzyl, trialkylsilyl, acyl, trityl; the process comprising: a) reacting a compound of formula III,
wherein R is as defined above, X is selected from the group consisting of CI, Br, I,
with a compound of formula IV, wherein R' represents boronic acid, boronic acid ester or
halogen in the presence of a metal catalyst; and
(b) optionally, deprotecting the compound of formula I.
In the present application, the term "room temperature" means a temperature of about 25°C to about
30°C. The term "linear or branched C1-6 alkyl" includes groups such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl. The term "C3-8 cycloalkyl" includes groups such as
cyclopropyl. cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. The term "optionally substituted
benzyl" means benzyl which is optionally substituted with halo, alkyl, alkoxy or nitro group wherein
halo includes CI. Br, I; alkyl includes methyl, ethyl, propyl, butyl; alkoxy includes methoxy, ethoxy,
propoxy. The term "linear or branched alkylalkoxy" includes groups such as methylmethoxy,
methylethoxy, ethylethoxy. The term "trialkylsilyl" includes groups such as trimethylsilyl,
triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl. The term "acyl" includes groups such as acetyl,
optionally substituted benzoyl, pivaloyl. The term "optionally substituted benzoyl" means benzoyl
which is optionally substituted with halo or nitro group wherein halo includes CI, Br, I.
In (a) of the above process, the compound of formula III, wherein X and R are as defined
above is reacted with the compound of formula IV; wherein R' is as defined above, in the
presence of a metal catalyst.
In one embodiment, the compound of formula III, wherein X and R are as defined above, is
reacted with the compound of formula IV; wherein R' is boronic acid or boronic acid ester in
the presence of a metal catalyst.
In one preferred embodiment, the compound of formula III, wherein R is C,.6 alkyl, X is Br, is
reacted with the compound of formula IV; wherein R' is boronic acid in the presence of a
metal catalyst.
A suitable metal catalyst includes but is not limited to Pd(PPh3)4, PdCl2(PPh3)2, PdCl2(dppf),
Pd(OAc)2, NiCl2(PPh3)2, PdCl2(dppb). Preferably, the metal catalyst selected is PdCl2(PPh3)2.
The reaction of compound of formula III with compound of formula IV may be carried out in
the presence of base which includes organic base such as triethylamine, N-methylmorpholine,
DBU; inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide,
sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate. Preferably,
the base is selected from inorganic base and more preferably the base is potassium hydroxide.
The reaction of compound of formula 111 with compound of formula IV may be carried out in
the presence of a suitable solvent. The suitable solvent includes but is not limited to ethanol,
methanol. 2-propanol, methyl acetate, ethyl acetate, acetone, ethylmethylketone,
tetrahydrofuran, dioxane, toluene, dimethoxyethane, acetonitrile, dimethylformamide, dimethyl
sulfoxide; water or mixtures thereof. Preferably the solvent selected is ethanol-water mixture.
The reaction of compound of formula III with compound of formula IV may be carried out at a
temperature in the range of about 25°C to about the reflux temperature of the solvent. The reaction
is carried out for a period of about 3 hours to about 40 hours. Preferably the reaction is carried out
at a temperature of about 70°C to about 85°C for a period of about 15 hour to about 30 hours.
In one embodiment, the compound of formula III, wherein X is Br and R is methyl, is reacted
with the compound of formula IV; wherein R' is boronic acid, in the presence of PdCl2(PPh3)2
catalyst and potassium hydroxide as base.
In one embodiment, the compound of formula III, wherein X and R are as defined above, is reacted
with the compound of formula IV; wherein R' is halogen in the presence of a metal catalyst.
A suitable metal catalyst includes but is not limited to Pd(PPh3)4, PdCl2(PPh3)2, NiCl2(PPh3)2,
Ni(PPh3)2. Preferably, the metal catalyst selected is PdCI2(PPh3)2.
In one embodiment, the compound of formula III, wherein R is C1-6 alky!, X is Br is reacted with the
compound of formula IV; wherein R' is halogen selected from the group consisting of CI, Br, I.
In one embodiment, the compound of formula III, wherein X is Br and R is methyl, is reacted
with the compound of formula IV; wherein R' is Br, in the presence of PdCl2(PPh3)2 catalyst.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent
includes but is not limited to ethanol, methanol, 1-propanol, 2-propanol, ethyl acetate,
tetrahydrofiiran, dioxane, acetone, toluene, dimethoxyethane, acetonitrile, dimethylformamide,
dimethyl sulfoxide or mixtures thereof. Preferably the solvent selected is ethanol.
In (b) of the above process, the compound of formula I wherein R=H, is deprotected to give
eltrombopag, compound of formula la.
The deprotection reaction process includes any of the following:
(a) where R is C1-6 alkyl, C3-8 cycloalkyl, the deprotection of the compound of formula I is
performed using protic acid such as hydroiodic acid, hydrobromic acid, hydrobromic
acid/acetic acid, methanesulfonic acid, trifluoroacetic acid; Lewis acid selected from the
group consisting of aluminium chloride, aluminium bromide, aluminium iodide, stannous
chloride, stannous bromide, titanium chloride, boron trifluoride, boron tribromide, boron
trifluoride-dimethylsulfide complex, beryllium chloride, beryllium bromide, zinc chloride,
zinc bromide, trimethylsilylchloride, trimethylsilylbromide, trimethylsilyliodide, lithium
iodide, lithium iodide in refluxing 2,4,6-collidine, pyridine hydrochloride; sulphur compounds such as sodium ethylmercaptide, sodium trimethylsilanethiolate; alkali organomides such as sodium bis(trimethylsilyl)amide and lithium diisopropylamide; or
(b) where R is optionally substituted benzyl, methyloxybenzyl, the deprotection of the
compound of formula I is performed via hydrogenation reaction using hydrogen in the
presence of a metal catalyst; or
(c) where R is linear or branched alkylalkoxy, tetrahydrofuranyl, tetrahydropyranyl, trityl, the deprotection of the compound of formula I is performed using an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid; organic acid such as acetic acid; or
(d) where R is trialkylsilyl, the deprotection of the compound of formula I is performed using acids such as acetic acid or fluorides such as tetrabutylammonium fluoride; or
(e) where R is acyl, the deprotection of the compound of formula I is performed using an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid; inorganic base selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
In one embodiment, the compound of formula I wherein R is methyl is deprotected using
aqueous hydrobromic acid to give eltrombopag, compound of formula la.
The reaction may be carried out at a temperature in the range of about 25°C to about 125°C.
The reaction is carried out for a period of about 2 hours to about 80 hours. Preferably the
reaction is carried out at a temperature of about I I0°C to about I I5°C for a period of about 35
hours to about 65 hours.
In one embodiment, the compound of formula I wherein R is methyl is deprotected using
Lewis acid such as aluminium chloride to give eltrombopag, compound of formula la.
In one embodiment, the compound of formula I wherein R is methyl is deprotected using
Lewis acid such as aluminium chloride to give solid eltrombopag-aluminium complex which
on acid treatment gives eltrombopag, compound of formula la.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent
includes but is not limited to chloroform, dichloromethane, dichloroethane, toluene, xylene,
chlorobenzene, tetrahydrofuran, dioxane, tert-butylmethyl ether, dimethoxyethane. Preferably
the solvent selected is toluene, tetrahydrofuran.
The reaction may be carried out at a temperature in the range of about 20°C to about 125°C.
The reaction is carried out for a period of about 2 hours to about 80 hours. Preferably the
reaction is carried out at a temperature of about 25°C to about 40°C for a period of about 35
hour to about 65 hours to give eltrombopag-aluminium complex.
The eltrombopag-aluminium complex on acid treatment gives eltrombopag, compound of
formula la. The acid used includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, acetic acid. Preferably, the acid used is acetic acid. The reaction may be
carried out in the presence of a suitable solvent. The suitable solvent includes but is not
limited to tetrahydrofuran, methanol, ethanol, 2-propanol. The reaction may be carried out at
a temperature in the range of about 25°C to about 125°C. The reaction is carried out for a
period of about 2 hours to about 80 hours. Preferably the reaction is carried out at a
temperature of about 40°C to about 120°C for a period of about 2 hour to about 24 hours.
In one embodiment, the present invention provides a process for the preparation of compound of
formula 1 wherein R is H, the process comprising reacting compound of formula III wherein R is C1-6
alkyl and X is CI. Br. I. with compound of fonnula IV wherein R' is boronic acid in the presence of a
metal catalyst to give compound of fonnula 1 wherein R is C1-6 alkyl followed by deprotecting the
compound of fonnula 1 wherein R is C1-6 alkyl to give compound of fonnula 1 wherein R is H.
In one embodiment, the present invention provides a process for the preparation of compound
of fonnula I wherein R is H, the process .comprising reacting compound of formula III
wherein R is methyl and X is Br, with compound of formula IV wherein R' is boronic acid in
the presence of PdCl2(PPh3)2 catalyst to give compound of formula I wherein R is methyl
followed by deprotecting the compound of formula I wherein R is methyl using aqueous
hydrobromic acid to give compound of formula I wherein R is H.
In one embodiment, the present invention provides a process for the preparation of compound
of formula I wherein R is H, the process comprising reacting compound of formula III
wherein R is methyl and X is Br, with compound of formula IV wherein R' is boronic acid in
the presence of PdCl2(PPh3)2 catalyst to give compound of formula I wherein R is methyl
followed by deprotecting the compound of formula I wherein R is methyl using Lewis acid
such as aluminium chloride to give compound of formula I wherein R is H.
In one embodiment, the present invention provides a process for isolating eltrombopag from
an aqueous medium.
The present invention provides a compound of formula III,
wherein X and R are as defined above.
In one embodiment, the present invention provides a compound of formula III, wherein X is
Brand R is methyl.
The present invention provides a process for the preparation of compound of formula III which comprises reacting a compound of formula V,
wherein X and R are as defined above and R" represents hydrogen, C1-6 alkyl, with 3,4-dimethylphenylhydrazine or salt thereof to give the compound of formula III. The reaction may be carried out in the presence of alkali metal acetate such as sodium acetate, potassium acetate and the like: potassium carbonate, sodium carbonate. Preferably, alkali metal acetate is used; more preferably, sodium acetate is used.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to acetic acid, methanol, ethanol, 2-propanol or mixtures thereof. Preferably the solvent selected is acetic acid.
The reaction may be carried out at a temperature in the range of about 25°C to about the reflux temperature of the solvent. The reaction is carried out for a period of about 1 hour to about 10 hours. Preferably the reaction is carried out at about the reflux temperature of the solvent for a period of about 2 hours to about 5 hours.
In one embodiment, the present invention provides a process for the preparation of compound of formula III, the process comprising reacting a compound of formula V with 3,4-dimethylphenylhydrazine or salt thereof to give the compound of formula III, wherein X is Br, R is methyl and R" is ethyl. The present invention provides a compound of formula V,
wherein X, R and R" are as defined above.
In one embodiment, the present invention provides a compound of formula V, wherein X is
Br, R is methyl and R" is ethyl.
The present invention provides a process for the preparation of compound of formula V which
comprises reacting a compound of formula VI or its salt thereof,
wherein X and R are as defined above,
with alky/ acetoacetate or acetoacetic acid in the presence of alkali or alkaline earth metal
nitrite and an inorganic acid in a solvent system to yield the compound of formula V.
The reaction may be carried out in the presence of alkali metal nitrite such as sodium nitrite,
potassium nitrite and the like; alkaline earth metal nitrite such as calcium nitrite and the like.
Preferably, sodium nitrite is used.
The inorganic acid is selected from the group consisting of hydrochloric acid, nitric acid,
sulfuric acid, hydrobromic acid. Preferably, hydrochloric acid is used.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent
includes but is not limited to methanol, ethanol, l-propanol. 2-propanol, water or mixtures
thereof. Preferably the solvent selected is methanol, water, ethanol-water mixture.
The reaction may be carried out at a temperature in the range of about 0°C to about 10°C. The
reaction is carried out for a period of about 2 hours to about 8 hours. Preferably the reaction is
carried out at a temperature about 0°C to about 5°C for a period of about 2 hours to about 6 hours.
In one embodiment, the present invention provides a process for the preparation of compound
of formula V, the process comprising reacting a compound of formula VI with alkyl
acetoacetate in presence of sodium nitrite and hydrochloric acid to yield the compound of
formula V, wherein X is Br, R is methyl and R" is ethyl.
The present invention provides a process for the preparation of eltrombopag, compound of
formula la,
and pharmaceutically acceptable salts thereof, the process comprising: (a) reacting 3-bromo-2~methoxyaniline with ethyl acetoacetate in the presence of alkali or alkaline earth metal nitrite and inorganic acid to give ethyl 2-[(3-bromo-2-methoxyphenyl)hydrazono]-3-oxobutanoate, compound of formula Va;
(b) reacting the compound of formula Va with 3,4-dimethylphenylhydrazine or salt thereof to give l-(3,4-dimethylphenyl)-3-methyl-4-(3-bromo-2-methoxyphenyl)hydrazono-5-pyra2olone, compound of formula Ilia;
(c) reacting the compound of formula IIIa with 3-carboxyphenylboronic acid in the presence of a metal catalyst to give 3'-{N'-[l-(3,4-dimethylphenyl)-3-methyl-5-oxo-l,5-dihydro-pyrazol-4-ylideneJhydrazino}-2'-methoxybiphenyl-3-carboxylic acid, compound of formula lb;
(d) deprotecting the compound of formula lb using Lewis acid to give eltrombopag; and
optionally, converting to its pharmaceutically acceptable salt.
In (a) of the above process. 3-bromo-2-methoxyaniline is reacted with ethylacetoacetate in
presence of alkali or alkaline earth metal nitrite and inorganic acid to give ethyl 2-[(3-bromo-
2-methoxyphenyl)hydrazono]-3-oxobutanoate, compound of formula Va.
The reaction may be carried out in the presence of alkali metal nitrite such as sodium nitrite,
potassium nitrite and the like; alkaline earth metal nitrite such as calcium nitrite and the like.
Preferably, sodium nitrite is used. The inorganic acid is selected from the group consisting of
hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid. Preferably, hydrochloric acid is used. The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to methanol, ethanol, 1-propanol, 2-propanol, water or mixtures thereof. Preferably the solvent selected is methanol, water, ethanol-water mixture. In (b) of the above process, the compound of formula Va is reacted with 3,4-dimethylphenylhydrazine or salt thereof to give l-(3,4-dimethylphenyl)-3-methyl-4-(3-bromo-2-methoxyphenyl)hydrazono-5-pyrazolone, compound of formula IIIa. The reaction may be carried out in the presence of alkali metal acetate such as sodium acetate, potassium acetate and the like; sodium carbonate, potassium carbonate. Preferably, the alkali metal acetate used is sodium acetate. The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to acetic acid, methanol, ethanol or mixtures thereof. Preferably the solvent selected is acetic acid. The reaction may be carried out at a temperature in the range of about 25°C to about the reflux temperature of the solvent. The reaction is carried out for a period of about 1 hour to about 10 hours. Preferably the reaction is carried out at to about the reflux temperature of the solvent for a period of about 2h to about 5h. In (c) of the above process, the compound of formula Ilia with 3-carboxyphenyIboronic acid in presence of metal catalyst to give 3'-{N'-[l-(3,4-dimethylphenyl)-3-methyl-5-oxo-l,5-dihydro-pyrazol-4-ylidene]hydrazino}-2'-methoxybiphenyl-3-carboxylic acid, compound of formula lb. A suitable metal catalyst includes but is not limited to Pd(PPh3)4, PdCI2(PPh3)2. PdCI2(dppf)? Pd(OAc),. NiCI2(PPh,)2. PdCI2(dppb). Preferably, the metal catalyst selected is PdCI2(PPh3)2. The reaction may carried out in the presence of base which includes organic base such as triethylamine, N-methylmorpholine, DBU; inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate. Preferably, the base is selected from inorganic base and more preferably the base is potassium hydroxide. The reaction may carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to ethanol, methanol, 2-propanol, methyl acetate, ethyl acetate, acetone, ethylmethylketone, tetrahydrofuran, dioxane, toluene, dimethoxyethane, acetonitrile, dimethylformamide; water or mixtures thereof. Preferably the solvent selected is ethanol-water mixture. The reaction may be carried out at a temperature in the range of about 25°C to about the reflux temperature of the solvent. The reaction is carried out for a period of about 3 hours to about 40 hours. Preferably the reaction is carried out at a temperature of about 70°C to about 85°C for a period of about 15 hours to about 30 hours. In (d) of the above process, the compound of formula lb is deprotected using Lewis acid to give eltrombopag.
In one embodiment, the compound of formula lb is deprotected using Lewis acid selected from the group consisting of aluminium chloride, aluminium bromide, aluminium iodide, stannous chloride, stannous bromide, titanium chloride, boron trifluoride, boron tribromide, boron
trifluoride-dimethylsulfide complex, beryllium chloride, beryllium bromide, zinc chloride, zinc
bromide, trimethylsilylchloride, trimethylsilylbromide, trimethylsilyliodide.
In one embodiment, the compound of formula lb is deprotected using Lewis acid such as
aluminium chloride to give solid eltrombopag-aluminium complex which on acid treatment
gives eltrombopag. The deprotection reaction process is as discussed supra.
The present invention provides a process for the preparation of eltrombopag, a compound of
formula la, the process comprising subjecting the compound of formula I to a deprotection reaction,
wherein R represents linear or branched C1-6 alkyl, C3-8 cycloalkyl, optionally substituted benzyl, linear or branched alkylalkoxy, tetrahydrofuranyl, tetrahydropyranyl, methyloxybenzyl, trialkylsilyl, acyl, trityl.
In one embodiment, the present invention provides a process for the preparation of eltrombopag comprising subjecting the compound of formula I wherein R is C1-6 alkyl, C3-8 cycloalkyl, to a deprotection reaction using protic acid such as hydroiodic acid, hydrobromic acid, hydrobromic acid/acetic acid, methanesulfonic acid, trifluoroacetic acid; Lev/is acid selected from the group consisting of aluminium chloride, aluminium bromide, aluminium iodide, stannous chloride, stannous bromide, titanium chloride, boron trifluoride, boron tribromide, boron trifluoride-dimethylsulfide complex, beryllium chloride, beryllium bromide, zinc chloride, zinc bromide, trimethylsilylchloride, trimethylsilylbromide, trimethylsilyliodide, lithium iodide, lithium iodide in refluxing 2,4,6-collidine, pyridine hydrochloride; sulphur compounds such as sodium ethylmercaptide, sodium trimethylsilanethiolate; alkali organomides such as sodium bis(trimethylsilyl)amide and lithium diisopropylamide.
In one embodiment, the present invention provides a process for the preparation of eltrombopag, the process comprising subjecting the compound of formula I wherein where R is optionally substituted benzyl, methyloxybenzyl, to a deprotection reaction by hydrogenation using hydrogen in the presence of a metal catalyst.
In one embodiment, the present invention provides a process for the preparation of eltrombopag, the process comprising subjecting the compound of formula I wherein R is
linear or branched alkylalkoxy, tetrahydrofuranyl, tetrahydropyranyl, trityJ, to a deprotection
reaction using an inorganic acid selected from the group consisting of hydrochloric acid,
hydrobromic acid, sulfuric acid, phosphoric acid; organic acid such as acetic acid.
In one embodiment, the present invention provides a process for the preparation of eitrombopag, the
process comprising subjecting the compound of formula I wherein R is trialkylsilyl, to a deprotection
reaction using acids such as acetic acid or fluorides such as tetrabutylammonium fluoride.
In one embodiment, the present invention provides a process for the preparation of eitrombopag,
the process comprising subjecting the compound of formula I wherein R is acyl, to a
deprotection reaction using an inorganic acid selected from the group consisting of hydrochloric
acid, hydrobromic acid, sulfuric acid, phosphoric acid; inorganic base selected from the group
consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate.
In one embodiment, the present invention provides a process for the preparation of
eitrombopag, the process comprising subjecting the compound of formula I wherein R is
methyl, to a deprotection reaction using hydrobromic acid.
In one embodiment, the present invention provides a process for the preparation of
eitrombopag, the process comprising subjecting the compound of formula I wherein R is
methyl, to a deprotection reaction using Lewis acid.
In one embodiment, the present invention provides a process for the preparation of eitrombopag,
compound of formula la, the process comprising deprotecting the compound of formula I
wherein R is methyl, using a Lewis acid such as aluminium chloride to give solid eltrombopag-
aluminium complex, then on acid treatment gives eitrombopag, compound of formula la.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent
includes but is not limited to chloroform, dichloromethane, dichloroethane. toluene, xylene,
chlorobenzene. tetrahydrofuran. dioxane. tert-butylmethyl ether, dimethoxyethane. Preferably
the solvent selected is toluene, tetrahydrofuran.
The reaction may be carried out at a temperature in the range of about 20°C to about 125°C.
The reaction is carried out for a period of about 2 hours to about 80 hours. Preferably the
reaction is carried out at a temperature of about 25°C to about 40°C for a period of about 35
hours to about 65 hours to give eltrombopag-aluminium complex.
The eltrombopag-aluminium complex on acid treatment gives eitrombopag, compound of
formula la. The acid used includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, acetic acid. Preferably, the acid used is acetic acid. The suitable solvent
includes but is not limited to tetrahydrofuran, methanol, ethanol, 2-propanol. The reaction may
be carried out at a temperature in the range of about 25°C to about 125°C. The reaction is carried
out for a period of about 2 hours to about 80 hours. Preferably the reaction is carried out at a
temperature of about 40°C to about 120°C for a period of about 2 hour to about 24 hours.
The present invention provides an eltrombopag-aluminium complex.
The present invention provides a solid eltrombopag-aluminium complex.
The present invention provides use of compound of formula III, or V in the preparation of
eltrombopag or salt thereof.
The present invention provides use of compound of formula I, wherein R represents linear or
branched C1-6 alkyl, C3-8 cycloalkyl, optionally substituted benzyl, linear or branched
alkylalkoxy, tetrahydrofuranyl, tetrahydropyranyl, methyloxybenzyl, trialkylsilyl, acyl, trityl
in the preparation of eltrombopag or salt thereof.
In one embodiment, the present invention provides use of compound of formula IIIa, Va, or lb
in the preparation of eltrombopag and salt thereof.
The present invention provides a process for the preparation of substituted 3'-hydrazino-
biphenyl-3-carboxylic acid compounds of formula 1 and salts thereof,
wherein R represents hydrogen, linear or branched C1-6 alkyl, C3-8 cycloalkyl, optionally substituted benzyl, linear or branched alkylalkoxy, tetrahydrofuranyl, tetrahydropyranyl, methyloxybenzyl, trialkylsilyl, acyl, trityl; the process comprising:
a) reacting a compound of formula VII, wherein R is as defined above and R" represents hydrogen. C1-6 alkyl. with 3,4-dimethylphenylhydrazine or salt thereof to give the compound of formula 1; and
b) optionally, deprotecting the compound of formula I.
In (a) of the above process, the reaction may be carried out in the presence of alkali metal acetate such as sodium acetate, potassium acetate and the like; potassium carbonate, sodium carbonate. Preferably, alkali metal acetate is used; more preferably, sodium acetate is used. The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to acetic acid, methanol, ethanol, 2-propanol or mixtures thereof. Preferably the solvent selected is acetic acid. The reaction may be carried out at a temperature in the range of about 25°C to about the reflux temperature of the solvent. The reaction is carried out for a period of about 1 hour to about 10 hours. Preferably the reaction is carried out at about the reflux temperature of the solvent for a period of about 2h to about 5h.
In one embodiment, the compound of formula VII is reacted with 3,4-dimethylphenylhydrazine or salt thereof to give the compound of formula I, wherein R is methyl and R" is ethyl. In (b) of the above process, the compound of formula 1 wherein R=H, is deprotected to give eltrombopag, compound of formula la. The deprotection reaction process is as discussed supra. In one embodiment, the present invention provides a process for the preparation of compound of formula I wherein R is H, the process comprising reacting compound of formula VII wherein R is C1-6 alkyl and R" is hydrogen, C1-6 alkyl with 3,4-dimethylphenylhydrazine or salt thereof to give the compound of formula I wherein R is C1-6 alkyl followed by deprotecting the compound of formula I wherein R is C1-6 alkyl using aqueous hydrobromic acid, Lewis acid such as aluminium chloride to give compound of formula I wherein R is H. The present invention provides a compound of formula VII,
wherein R represents hydrogen, linear or branched C1-6 alkyl, C3-8 cycloalkyl, optionally
substituted benzyl, linear or branched alkylalkoxy, tetrahydrofuranyl, tetrahydropyranyl,
methyloxybenzyl, trialkylsilyl, acyl, trityl; and R" represents hydrogen, C1-6 alkyl.
In one embodiment, the present invention provides a compound of formula V, wherein R is
methyl and R" is ethyl.
The present invention provides a process for the preparation of compound of formula VII, the
process comprising:
a) reacting a compound of formula VI, wherein X and R are as defined above, with a
compound of formula IV, wherein R' is as defined above,
in the presence of a metal catalyst to give a compound of formula VIII,
wherein R is as defined above; and
h) reacting the compound of formula VIII with alkyl acetoacetate or acetoacetic acid in the presence of alkali or alkaline earth meta! nitrite and an inorganic acid to yield the compound of formula VII. In (a) of the above process, the compound of formula VI, wherein X and R are as defined above, is reacted with the compound of formula IV; wherein R' is boronic acid or boronic acid ester or halogen in the presence of a metal catalyst to give the compound of formula VIII, wherein R is as defined above.
A suitable metal catalyst includes but is not limited to Pd(PPh3)4, PdCl2(PPh3)2, PdCl2(dppf), Pd(OAc)2, NiCl2(PPh3)2, PdCl2(dppb). Preferably, the metal catalyst selected is PdCl2(PPh3)2. The reaction of compound of formula VI with compound of formula IV may be carried out in the presence of base which includes organic base such as triethylamine, N-methylmorpholine, DBU; inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate. Preferably, the base is selected from inorganic base and more preferably the base is potassium hydroxide, potassium carbonate. The reaction of compound of formula VI with compound of formula IV may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to ethanol, methanol. 2-propanol. methyl acetate, ethyl acetate, acetone, ethylmethylketone, tetrahydrofuran, dioxane. toluene, dimethoxyethane, acetonitrile. dimethylformamide, dimethyl sulfoxide; water or mixtures thereof. Preferably the solvent selected is ethanol-water mixture. The reaction of compound of formula VI with compound of formula IV may be carried out at a temperature in the range of about 25°C to about the reflux temperature of the solvent. The reaction is carried out for a period of about 3 hours to about 40 hours. Preferably the reaction is carried out at a temperature of about 70°C to about 85°C for a period of about 15 hour to about 30 hours. In one embodiment, the compound of formula VI, wherein R is C]_6 alkyl, X is Br, is reacted with the compound of formula IV; wherein R' is boronic acid in the presence of a metal catalyst. In one embodiment, the compound of formula VI, wherein X is Br and R is methyl, is reacted with the compound of formula IV; wherein R' is boronic acid, in the presence of PdCl2(PPh3)2 catalyst and potassium carbonate as base.
In one embodiment, the compound of formula VI, wherein R is C1-6 alkyl, X is Br is reacted with the compound of formula IV; wherein R' is halogen selected from the group consisting of CI, Br, I. In (b) of the above process, the reaction may be carried out in the presence of alkali metal nitrite such as sodium nitrite, potassium nitrite and the like; alkaline earth metal nitrite such as calcium nitrite and the like. Preferably, sodium nitrite is used. The inorganic acid is selected from the group consisting of hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid. Preferably, hydrochloric acid is used. The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to methanol, ethanol, 1-propanol, 2-propanol, water or mixtures thereof. Preferably the solvent selected is methanol-water mixture.
In one embodiment, the compound of formula VIII, wherein R is C1-6 alkyl, is reacted with alkyl acetoacetate or acetoacetic acid in presence of sodium nitrite and hydrochloric acid to yield the compound of formula VII, wherein R is C1-6 alkyl and R" is hydrogen. C1-6 alkyl. The present invention provides a process for the preparation of compound of formula VII which comprises reacting a compound of formula V,
wherein X, R and R" are as defined above, with a compound of formula IV, wherein R' is as defined above, in the presence of a metal catalyst to give the compound of formula VII. In one embodiment, the compound of formula V, wherein X and R are as defined above, is reacted with the compound of formula IV; wherein R' is boronic acid or boronic acid ester or halogen in the presence of a metal catalyst.
A suitable metal catalyst includes but is not limited to Pd(PPh3)4, PdCI2(PPh3)2, PdCl2(dppf), Pd(OAc):. NiCl:(PPh:,)2. PdCl2(dppb). Preferably, the metal catalyst selected is PdCI2(PPh3)2. The reaction of compound of formula V with compound of formula IV may be carried out in the presence of base which includes organic base such as triethylamine, N-methylmorphoiine. DBU; inorganic base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate. Preferably, the base is selected from inorganic base and more preferably the base is potassium hydroxide, potassium carbonate. The reaction of compound of formula V with compound of formula IV may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to ethanol, methanol, 2-propanol, methyl acetate, ethyl acetate, acetone, ethyl methyl ketone, tetrahydrofuran, dioxane, toluene, dimethoxyethane, acetonitrile, dimethylformamide, dimethyl sulfoxide; water or mixtures thereof. Preferably the solvent selected is ethanol-water mixture. The reaction of compound of formula V with compound of formula IV may be carried out at a temperature in the range of about 25°C to about the reflux temperature of the solvent. The reaction is carried out for a period of about 3 hours to about 40 hours. Preferably the reaction is carried out at a temperature of about 70°C to about 85°C for a period of about 15 hour to about 30 hours.
In one embodiment, the compound of formula V, wherein R is C1-6 alkyl, X is Br, is reacted with the compound of formula IV; wherein R' is boronic acid in the presence of a metal catalyst.
In one embodiment, the compound of formula V, wherein X is Br and R is methyl, is reacted with the compound of formula IV; wherein R' is boronic acid, in the presence of PdC]2(PPh3)2 catalyst and potassium carbonate as base.
In one embodiment, the compound of formula V, wherein R is C1-6, alky], X is Br is reacted with the compound of formula IV; wherein R1 is halogen selected from the group consisting of CI, Br, I. The present invention provides a process for the deprotection of a compound of formula 111,
wherein R represents linear or branched C1-6 alkyl, C3-8 cycloalkyl, optionally substituted benzyl, linear or branched alkylalkoxy, tetrahydrofuranyl, tetrahydropyranyl, methyloxybenzyl, trialkylsilyl, acyl, trityl, and X is selected from the group consisting of CI, Br, I. The deprotection of compound of formula III may be carried out as described for compound of formula I wherein R=H, as discussed supra.
In one embodiment, the present invention provides a process for the deprotection of the compound of formula III. the process comprising subjecting the compound of formula III wherein R is methyl, (o a deprotection reaction using hydrobromic acid. Lewis acid such as aluminium chloride. The present invention provides an eltrombopag ammonium salt.
The present invention provides an eltrombopag ammonium salt characterized by a proton NMR spectrum having peaks at 8 14.81 (brs,lH), 8.17 (s,lH), 7.80-7.82(m,3H), 7.65-7.68 (d,lH), 7.34-7.42 (m,2H), 7.01-7.07 (m,2H), 6.87 (t,lH), 2.37 (s,3H), 2.22 (s,3H), 2.18 (s,3H). The present invention provides an eltrombopag ammonium salt with ammonia content in the range of about 3.5% to about 8.5%.
The present invention provides an eltrombopag ammonium salt which may be mono-ammonium salt or di-ammonium salt, preferably in crystalline form or amorphous form. The present invention provides a process for the preparation of eltrombopag ammonium salt comprising reacting eltrombopag with a source of ammonia.
A suitable source of ammonia includes but is not limited to ammonia water (aqueous ammonia), ammonium carbonate, ammonia gas, liquid ammonia. Preferably, the source of ammonia selected is ammonia water.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes but is not limited to methanol, ethanol. l-propanol, 2-propanol, 1-butanol, 2-butanol, methyl
acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate, acelone, ethylmethylketone, methyl
isobutyl ketone, chloroform, dichloromethane, dichloroethane. tetrahydrofuran, dioxane, tert-
butylmethyl ether, toluene, xylene, chlorobenzene, dimethoxyethane, acetonitrile,
dimethylformamide; water or mixtures thereof. Preferably the solvent selected is tetrahydrofuran.
The reaction may be carried out at a temperature in the range of about 10°C to about 40°C. The
reaction is carried out for a period of about 1 hour to about 20 hours. Preferably the reaction is carried
out at a temperature of about 20°C to about 35°C for a period of about 1 hour to about 5 hours.
In one embodiment, the present invention provides a process for isolating eltrombopag as an
eltrombopag ammonium salt.
Eltrombopag may be converted to its pharmaceutically acceptable salts such as its
monoethanolamine, bisethanolamine salts. Preferably, eltrombopag is converted to its
bisethanolamine salt namely, eltrombopag olamine, compound of formula II.
In one embodiment, the present invention provides a process for the preparation of
eltrombopag olamine comprising reacting eltrombopag or a salt thereof with excess of
ethanolamine without using any additional reaction solvent.
In one embodiment, the present invention provides a process for the preparation of
eltrombopag olamine comprising reacting eltrombopag or a salt thereof with ethanolamine in
an aqueous medium.
In one embodiment, the present invention provides a process for the preparation of eltrombopag
olamine comprising reacting eltrombopag or a salt thereof with ethanolamine in water.
In one embodiment, the present invention provides a process for the preparation of
eltrombopag olamine comprising reacting eltrombopag or a salt thereof with ethanolamine in
a solvent and isolating eltrombopag olamine by addition of anti-solvent.
The solvent that may be utilized for this step includes, but is not limited to alcohols such as
methanol, ethanol, l-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the
like; ethers such as tert-butylmethyl ether, tetrahydrofuran, dioxane and the like; esters such as
methyl acetate, ethyl acetate, n-propyl acetate, and tert-butyl acetate and the like; ketones such
as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; dimethyl sulfoxide;
dimethyl formamide; dimethyl acetamide; water and mixtures thereof. The anti-solvent that may
be utilized for this step includes, but is not limited to ethers such as diethyl ether, dimethyl
ether, diisopropyl ether, tetrahydrofuran, dioxane; hydrocarbons such as n-hexane, n-heptane,
cyclohexane; water and mixtures thereof; preferably non-polar anti-solvent is used.
The present invention provides a process for the preparation of eltrombopag olamine
comprising reacting eltrombopag ammonium salt with ethanolamine.
In one embodiment, the present invention provides a process for the preparation of
eltrombopag olamine comprising reacting eltrombopag ammonium salt with ethanolamine,
preferably, without using any additional reaction solvent.
In one embodiment, the present invention provides a process for the preparation of
eltrombopag olamine comprising reacting eltrombopag ammonium salt with ethanolamine in
the presence of a solvent.
The solvent that may be utilized for this step includes, but is not limited to methanol, ethanol,
1-propanol, 2-propanol, 1-butanol, 2-butanol, methyl acetate, ethyl acetate, n-propyl acetate,
tert-butyl acetate, acetone, ethylmethylketone, methyl isobutyl ketone, tetrahydrofuran,
dioxane, tert-butylmethyl ether, toluene, dimethoxyethane, acetonitrile, dimethylformamide;
water or mixtures thereof.
The present invention provides use of eltrombopag ammonium salt in the preparation of
eltrombopag olamine.
In one embodiment, the present invention provides a process for the preparation of
eltrombopag olamine. the process comprising: (a) treating a reaction mixture containing
cllrombopag with a base to give eltrombopag salt, and (b) reacting the eltrombopag salt with
ethanolamine to give eltrombopag olamine directly, wherein eltrombopag is formed in-situ in
the reaction. The eltrombopag salt obtained in this step includes, but is not limited to
eltrombopag sodium salt, eltrombopag potassium salt, eltrombopag ammonium salt.
In one preferred embodiment, the present invention provides a process for the preparation of
eltrombopag olamine, the process comprising: (a) treating a reaction mixture containing
eltrombopag with a source of ammonia to give eltrombopag ammonium salt, and (b) reacting
the eltrombopag ammonium salt with ethanolamine to give eltrombopag olamine directly,
wherein eltrombopag is formed in-situ in the reaction.
The present invention provides eltrombopag and a salt thereof, having a compound of formula Ilia
in less than about 0.5%, preferably less than about 0.15%, more preferably less than about 0.05%.
The present invention provides eltrombopag and a salt thereof, having a compound of formula Illb
in less than about 0.5%, preferably less than about 0.15%, more preferably less than about 0.05%).
The present invention provides eltrombopag and a salt thereof, ha.ving a compound of formula lXa in less than about 0.5%, preferably less than about 0.15%, more preferably less than about 0.05%.
The present invention provides eltrombopag and a salt thereof, having a compound of formula IXb in less than about 0.5%, preferably less than about 0.15%, more preferably less than about 0.05%.
The present invention provides substituted 3'-hydrazino-biphenyl-3-carboxylic acid compounds of formula I, salts thereof and intermediate compounds, obtained by the above processes, as characterized and analyzed by following techniques:
A. Proton NMR spectra were recorded in CDC13 and DMSO-d6 using NMR instrument-
Varian 300 MHZ
B. IR spectra were recorded using IR instrument- Perkin Elmer Spectrum One FTIR and all
the samples prepared in KBr.
C. Mass spectra were recorded using instrument- Thermofinnigan, LCQ DECA XP MAX
D. HPLC
E. Melting point
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.
EXAMPLES EXAMPLE 1: Preparation of Ethyl 2-|(3-bromo-2-methoxyphenyl)hydrazono]-3-oxobutanoate
To a solution of 3-bromo-2-methoxyaniline (20g) in IN hydrochloric acid (400mL) was
added a solution of sodium nitrite (7.2g in 720mL of water) at about 0°C to about 5°C under
stirring. The reaction mixture was stirred for about 15 minutes at about 5°C. Then
ethylacetoacetate (12.9g) was added to the reaction mixture and stirred for about 15 minutes
at about 0°C to about 5°C. Sodium bicarbonate solution (27.5g in 300mL water) and ethanol
(400mL) was then added to the reaction mixture. The reaction mixture was allowed to warm
to about room temperature and stirred for about 2 hours. The mixture was filtered, washed
with water (200mL) and dried to get yellowish solid. Yield: 33g; Melting point: 75.9-77.1°C;
Purity (HPLC): 99.12%
IR:3421, 1706, 1684. 1517, 1215, 1093, 980cm"1; Mass: m/z 342.88 [M+] and 344.86 [M+2]
'H NMR (300 MHz in CDC1,): 5 12.86 (s.lH). 7.58-7.61 (dJH), 7.30-7.33 (d.lH), 7.02-7.07
Documents
Application Documents
#
Name
Date
1
2570-MUM-2011-FORM 3(19-09-2014).pdf
2014-09-19
1
2570-MUM-2011-IntimationOfGrant26-11-2019.pdf
2019-11-26
2
2570-MUM-2011-CORRESPONDENCE(19-09-2014).pdf
2014-09-19
2
2570-MUM-2011-PatentCertificate26-11-2019.pdf
2019-11-26
3
2570-MUM-2011-Written submissions and relevant documents (MANDATORY) [14-11-2019(online)].pdf