WO2013186792A2 - Process for the preparation of (5-methyl-2-oxo-l,3-dioxoi-4-vl)methvl 2- ethoxv-l-{[2'-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-vl)biphenyi-4-vl]methyl}- lh-benzimidazole-7-carboxyiate and its salts - Google Patents

Process for the preparation of (5-methyl-2-oxo-l,3-dioxoi-4-vl)methvl 2- ethoxv-l-{[2'-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-vl)biphenyi-4-vl]methyl}- lh-benzimidazole-7-carboxyiate and its salts Download PDF

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WO2013186792A2
WO2013186792A2 PCT/IN2013/000367 IN2013000367W WO2013186792A2 WO 2013186792 A2 WO2013186792 A2 WO 2013186792A2 IN 2013000367 W IN2013000367 W IN 2013000367W WO 2013186792 A2 WO2013186792 A2 WO 2013186792A2
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Srinivasan Thirumalai Rajan
Chakilam Nagaraju
Achampeta Kodanda Ramprasad
Karamala Rama Subba Reddy
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Msn Laboratories Limited
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Abstract

The present invention relates to processes for the preparation of (5-methyl-2-oxo- l,3- dioxol-4-yl)methyl 2-ethoxy- 1 - { [2'-(5-oxo-4,5-dihydro- 1,2,4-oxadiazol-3-yl)biphenyl-4- yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1, its potassium salt compound of formula- la and polymorphs thereof.

Description

Process for the preparation of (5-methyl-2-oxo-l,3-dioxoI-4-yl)methyl 2- ethoxy-l-{[2'-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-yl)biphenyI-4-yl]methyl}- lH-benzimidazole-7-carboxyIate and its salts
Related Applications:
This application claims the benefit of priority of our Indian patent application numbers 2306/CHE/2012 filed on 1.1th June 2012 and 918/CHE/2013 filed on 4th March 2013 and 1895/CHE/2013 filed on 29* April 2013 and 2399/CHE/2013 filed on 31st May 2013 and 2475/CHE/2013 filed on 06th June 2013 which are incorporated herein by reference.
Field of the Invention:
The present invention provides processes for the preparation of (5-methyl-2-oxo-l,3- dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4- yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1, its potassium salt compound of formula- la and polymorphs thereof.
Figure imgf000002_0001
Formula- 1 Formula- la
The present invention also provides novel intermediate compounds useful for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula- 1 and its pharmaceutically acceptable salts.
Background of the Invention:
(5-Methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl-2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4- oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate (commonly known as Azilsartan medoxomil) is developed by Takeda pharmaceuticals and is marketed under the trade name Edarbi. It was approved by USFDA on 25tn Feb 2011 and EMEA on 7th Dec 201 1 for the treatment of high blood pressure in adults.
Azilsartan medoxomil and salts thereof are imbibed with properties such as strong and long lasting angiotensin-II antagonistic activity and hypotensive action, which is useful as an agent for the prophylaxis or treatment of circulatory diseases such as hypertension, cardiac diseases (cardiac hypertrophy, cardiac failure, cardiac infarction and the like), nephritis, stroke and insulin sensitizing activity, useful for treatment of metabolic diseases such as diabetes and the like. Azilsartan medoxomil is the prodrug of 2-ethoxy-l-([2'-(5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)biphenyl-4-yl]methyl)-lH-benzimidazole-7-carboxylic acid.
Methods of preparing benzimidazole derivatives useful as angiotensin-II receptor antagonists such as Azilsartan medoxomil and salts thereof are described in US 5,243,054 (herein after referred as US'054 patent). The US'054 patent describes several synthetic routes for preparing Azilsartan. According to one of the synthetic process, Azilsartan is prepared by the synthetic route as depicted below in scheme-A. The compound-Ill is prepared by reacting compound-I with ethyl chloroformate (ECC) to obtain compound-II which on refluxing in xylene undergoes cyclization to provide compound-Ill. Azilsartan was prepared by hydrolysis of compound-Ill in presence of lithium hydroxide. However, the above technique includes purification using column chromatography, which is tedious, expensive and hence it is not suggestible on commercial scale.
Sc
Figure imgf000003_0001
Azilsartan The other processes disclosed in US'054 involve multistep process for the preparation of Azilsartan and Azilsartan medoxomil. Also, these processes give the product in low yield. Hence these processes are commercially/economically not viable. Further, Journal of Medicinal Chemistry 1996, 39, 5228-5235 discloses a method for production of Azilsartan based on reaction scheme-B as depicted below. This includes reaction of compound-I with 2-ethylhexyl chloroformate (EHC) to prepare compound IV and refluxing the obtained compound in the presence of xylene solvent to induce cyclization reaction thus forming compound-Ill as shown in reaction scheme-B. Hydrolysis of compound-Ill using sodium hydroxide produces Azilsartan.
Sche
Figure imgf000004_0001
Conventional technologies used for the preparation of Azilsartan as described above involves the usage of xylene as a solvent, which is carcinogenic and harmful to human body. Further, when xylene is removed through vacuum distillation after completion of the reaction, difficulties may be encountered in relation to generation of xylene waste which is hard to treat and/or dispose. Furthermore, since the reaction is conducted at a high temperature, impurities may formed, which deteriorate the purity and yield of the product. The cyclization reaction using xylene results in low yield (23%) of compound- III which in turn decreases the yield of Azilsartan.
Azilsartan medoxomil, its pharmaceutically acceptable salts and processes for their preparation is specifically disclosed in US7157584B2. It discloses a process for preparation of Azilsartan medoxomil which comprises of reacting the compound of formula V (disodium salt of Azilsartan) with 4- chloromethyl-5-methyl-l,3-dioxol-2-one in dimethyl formamide provides Azilsartan medoxomil in a very low yield (14 %) (Scheme C). This is mainly due to the formation of dimer impurity in higher yields, i.e., in approximately 50% yield.
Scheme-C:
Figure imgf000005_0001
(Lower yields)
Hence there is a significant need in the art to develop a novel or improved process for the preparation of Azilsartan medoxomil and its salts, which overcomes all the problems of the prior-art processes and gives the product in higher yield with better purity.
Polymorphs are distinct solids having the same molecular formula yet having distinct advantageous physical properties compared to other polymorphic forms of the same compound. The difference in the physical properties of different polymorphic forms results from the orientation and intermolecular interactions of adjacent molecules in the bulk solid.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphic forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption and solid state NMR spectrum. One polymorphic form may give rise to thermal behavior different from that of another polymorphic form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermo gravimetric analysis (TGA) and differential scanning calorimetry (DSC) as well as content of solvent in the polymorphic form, which have been used to distinguish polymorphic forms. Brief description of the Invention:
The first aspect of the present invention is to provide a process for the preparation of (5- methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1 and its potassium salt compound of formula- 1 a.
The second aspect of the present invention is to provide a process for the preparation of (5-methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt compound of formula- la, comprising of treating the (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1 with potassium tert.butoxide in a suitable solvent.
The third aspect of the present invention is to provide a process for the preparation of methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate compound of formula- 10, comprising of deprotecting the methyl 2-(tert-butoxycarbonyl((2'-cyanobiphenyl-4- yl)methyl)amino)-3-nitrobenzoate compound of formula-9 by treating it with a suitable boc- deprotecting agent in a suitable solvent.
The fourth aspect of the present invention is to provide a process for the preparation of methyl 3-amino-2-((2'-cyanobiphenyl-4-yl)methylamino)benzoate compound of formula-1 1, comprising of reducing the methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate compound of formula- 10 with a suitable reducing agent in a suitable solvent.
The fifth aspect of the present invention is to provide a process for the preparation of (5- methyl-2-oxo-l ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula- 1.
The sixth aspect of the present invention is to provide a novel crystalline polymorph of 2- ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - IH-benzimidazole -7-carboxylic acid compound of formula-2.
The seventh aspect of the present invention is to provide a novel crystalline polymorph of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula- 1. The eighth aspect of the present invention is to provide amorphous form of (5-methyl-2- oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl- 4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula- 1.
The ninth aspect of the present invention is to provide a novel crystalline polymorph of (5-methyl-2-oxo-l ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt of formula- la.
The tenth aspect of the present invention is to provide a process for the preparation of amorphous form of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro- l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1.
The eleventh aspect of the present invention is to provide a process for the purification of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l- {[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt compound of formula- la.
The twelfth aspect of the present invention is to provide a process for the preparation of 2-ethoxy- 1 -((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzimidazole-7- carboxylic acid compound of formula- 16, comprising of treating the methyl l-((2'- cyanobiphenyl-4-yl)methyl)-2-ethoxy-lH-benzimidazole-7-carboxylate compound of formula- 12 with hydroxylamine hydrochloride in presence of a suitable base in a suitable solvent or mixture of solvents to provide 2-ethoxy- l-((2'-(N'-hydroxy carbamimidoyl)biphenyl-4- yl)methyl)-lH-benzimidazole-7-carboxylic acid compound of formula- 16. The thirteenth aspect of the present invention is to provide a process for the preparation of 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H- benzimidazole-7-carboxylic acid compound of formula-2, comprising of reacting the 2-ethoxy- 1- ((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzimidazole-7-carboxylic acid compound of formula- 16 with a suitable cyclization agent in presence of a suitable base in a suitable solvent to provide 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4- yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2. The fourteenth aspect of the present invention is to provide an improved process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-{[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula- 1 and its potassium salt compound of formula- la.
The fifteenth aspect of the present invention is to provide a novel process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-{[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3 -yl)biphenyl-4-yl]methyl } - 1 H-benzimidazole-7-carboxylate compound of formula- 1 and its potassium salt compound of formula- la, comprising of;
a) Reacting the 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of formula- 16 with compound of general formula- 15 in presence of a suitable base in a suitable solvent, optionally in presence of a suitable catalyst, suitable phase transfer catalyst or a suitable condensing agent to provide (5- methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 -((2'-(N'-hydroxycarbamimidoyl)biphenyl- 4-yl)methyl)- 1 H-benzo[d]imidazole-7-carboxylate compound of formula- 17,
b) reacting the compound of formula- 17 with Ν,Ν-carbonyldiimidazole in presence of a suitable base in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- 1-((2'- (N'-hydroxy-N-( 1 H-imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)- 1 H- benzo[d]imidazole-7-carboxylate compound of formula- 18,
c) isolating the compound of formula- 18 as a solid,
d) heating the (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-((2'-(N'-hydroxy-N-(lH- imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole-7- carboxylate compound of formula- 18 in presence of a suitable solvent to provide (5-methyl- 2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula- 1 ,
e) treating the compound of formula- 1 with a suitable potassium source in a suitable solvent to provide its potassium salt compound of formula- la.
The sixteenth aspect of the present invention is to provide a process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-((2'-(N'-hydroxy carbamimidoyl)biphenyl-4- yl)methyl)-lH-benzo[d]imidazole-7-carboxylate compound of formula- 17, comprising of reacting the 2-ethoxy- 1 -((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d] imidazole-7-carboxylic acid compound of formula- 16 with compound of general formula- 15 to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-((2'-(N'-hydroxycarbamimidoyl) biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate compound of formula- 17.
The seventeenth aspect of the present invention is to provide a process for the preparation of (5-methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol- 3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1, comprising of;
a) reacting (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- 1 -((2 '-(N'-hydroxy carbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate compound of formula- 17 with Ν,Ν-carbonyldiimidazole in presence of a suitable base in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-((2'-( '-hydroxy-N-(lH- imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole-7- carboxylate compound of formula- 18,
b) isolating the compound of formula- 18 as a solid,
c) heating the (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'-(N'-hydroxy-N-(lH- imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole-7- carboxylate compound of formula- 18 in presence of a suitable solvent to provide (5-methy}- 2-oxo-l ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1.
The eighteenth aspect of the present invention is to provide a crystalline polymorph of (5- methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- 1 -((2 '-(N'-hydroxycarbamimidoyl)biphenyl-4-yl) methyl)- 1 H-benzo[d]imidazole-7-carboxylate compound of formula- 17.
The nineteenth aspect of the present invention is to provide a crystalline polymorph of (5- methyl-2-oxo- 1 ,3 -dioxol-4-yl)methyl 2-ethoxy- 1 -((2'-(N'-hydroxy-N-( 1 H-imidazole- 1 - carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole-7-carboxylate compound of formula- 18.
The twentieth aspect of the present invention is to provide a crystalline polymorph of (5- methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1- {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1. The twenty first aspect of the present invention is to provide a novel process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula- 1 and its potassium salt compound of formula- 1 a.
The twenty second aspect of the present invention is to provide a process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro- l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1 and its potassium salt compound of formula- la, comprising of;
a) Reacting the 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyI-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid compound of formula-2, with a suitable amine protecting agent optionally in presence of a suitable base in a suitable solvent to provide corresponding intermediate compound of general formula-21,
b) reacting the compound of general formula-21 with compound of general formula- 15 in presence of a suitable base in a suitable solvent optionally in presence of a suitable catalyst, suitable phase transfer catalyst or a suitable condensing agent to provide protected compound of general formula-22,
c) deprotecting the compound of general formula-22 by treating it with a suitable deprotecting agent in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l- {[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7- carboxylate compound of formula- 1,
d) treating the compound of formula- 1 with a suitable potassium source in a suitable solvent to provide its potassium salt compound of formula- la. The twenty third aspect of the present invention is to provide a process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula-1, comprising of reacting the 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2 with an intermediate compound of general formula-23 in presence or absence of a base in a suitable solvent is to provide compound of formula-1. The twenty fourth aspect of the present invention is to provide a process for the preparation of methyl 2-(tert-butoxycarbonyl ((2'-cyanobiphenyl-4-yl)methyl)amino)-3- nitrobenzoate compound of formula-9, comprising of reacting the methyl 2-(tert- butoxycarbonylamino)-3-nitrobenzoate compound of formula-7 with compound of general formula-24 in presence of a suitable base in a suitable solvent optionally in presence of a suitable phase transfer catalyst to provide methyl 2-(tert-butoxycarbonyl ((2'-cyanobiphenyl-4-yl)methyl) amino)-3-nitrobenzoate compound of formula-9.
The twenty fifth aspect of the present invention is to provide a novel process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro- l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1 and its potassium salt compound of formula- la.
The twenty sixth aspect of the present invention is to provide a novel process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro- l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1, comprising of;
a) Reacting the 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of formula- 16 with N,N-carbonyl diimidazole (CDI) in presence or absence of a suitable base in a suitable solvent to provide 2- ethoxy- 1 -((2'-(N'-hydroxy-N-( 1 H-imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl) methyl)- lH-benzo[d]imidazole-7-carboxylic acid compound of formula-25,
b) reacting the compound of formula-25 with compound of general formula- 15 in presence of a suitable base in a suitable solvent, optionally in presence of a suitable phase transfer catalyst, suitable catalyst or a suitable condensing agent to provide (5-methyl-2-oxo-l,3-dioxol-4- yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}- lH-benzimidazole-7-carboxylate compound of formula- 1.
The twenty seventh aspect of the present invention is to provide a novel process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro- l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1, comprising of; Reacting the 2-ethoxy-l-((2'-(TST'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of formula- 16 with a N,N- carbonyldiimidazole (CDI) in presence or absence of a suitable base in a suitable solvent to provide N-((4'-((2-ethoxy-7-( 1 H-imidazole- 1 -carbonyl)- 1 H-benzo[d]imidazol- 1 -yl)methyl) biphenyl-2-yl) (hydro xyimino)methyl)- 1 H-imidazole- 1-carboxamide compound of formula-26,
reacting the compound of formula-26 with 4-(hydroxymethyl)-5-methyl-l,3-dioxol-2-one compound of formula- 15c in presence of a suitable base in a suitable solvent to provide (5- methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1.
The twenty eighth aspect of the present invention is to provide novel intermediate compounds, which are useful in the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2- ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH- benzimidazole-7-carboxylate compound of formula- 1 and its pharmaceutically acceptable salts.
Brief description of the drawings:
Figure-1: Illustrates the X-Ray powder diffraction pattern of crystalline form-M of 2-ethoxy- 1- {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7- carboxylic acid (Formula-2).
Figure-2: Illustrates the X-Ray powder diffraction pattern of crystalline form-S of (5-methyl-2- oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl- 4-yl]methyl} - 1 H-benzimidazole-7-carboxylate (Formula- 1 ).
Figure-3: Illustrates the DSC thermogram of crystalline form-S of (5-methyl-2-oxo-l,3-dioxol- 4-yl)methyl 2-ethoxy-l-{[2,-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH- benzimidazole-7-carboxylate (Formula- 1 ).
Figure-4: Illustrates the X-Ray powder diffraction pattern of amorphous form of (5-methyl-2- oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl- 4-yl]methyl}-lH-benzimidazole-7-carboxylate (Formula-1).
Figure-5: Illustrates the X-Ray powder diffraction pattern of crystalline form-N of (5-methyl-2- oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy-l - {[2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl- 4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt (Formula- la). Figure-6: Illustrates the PXRD pattern of crystalline form-M of (5-methyl-2-oxo-l,3-dioxol-4- yl)methyl 2-ethoxy- 1 -((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d] imidazole-7-carboxylate (Formula- 17).
Figure-7: Illustrates the PXRD pattern of crystalline form-S of (5-methyl-2-oxo-l,3-dioxol-4-yl) methyl 2-ethoxy- 1 -((2'-(N'-hydroxy-N-( 1 H-imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4- yl)methyl)- 1 H-benzo[d]imidazole-7-carboxylate (Formula- 18).
Figure-8: Illustrates the PXRD pattern of crystalline form-L of (5-methyl-2-oxo-l,3-dioxol-4-yl) methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH- benzimidazole-7-carboxylate (Formula- 1).
Figure-9: Illustrates the differential scanning calorimetric (DSC) thermogram of crystalline form-L of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate (Formula-1).
Figure-10: Illustrates the PXRD pattern of crystalline form-M! of (5-methyl-2-oxo-l,3-dioxol-4- yl)methyl 2-ethoxy- 1 -((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d] imidazole-7-carboxylate (Formula- 17).
Detailed description of the Invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, methyl tert-butyl ether, 1,2- dimethoxy ethane, tetrahydrofuran, dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile and the like; "alcoholic solvents" such as methanol, ethanol, n- propanol, iso-propanol, n-butanol, iso-butanol, t-butanol and the like; "polar solvents" such as water; acetic acid or mixtures thereof. The term "suitable base" used in the present invention refers to inorganic bases selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide and the like; ammonia, alkali metal and alkaline earth metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate, calcium acetate and the like; and organic bases like methylamine, dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide (LDA), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), l ,4-diazabicyclo[2.2.2]octane (DABCO), imidazole and the like; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS); n-butyl lithium or mixtures thereof.
The first aspect of the present invention provides a process for the preparation of (5- methyl-2-oxo-l ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1 and its potassium salt compound of formula- la, comprising of;
a) Esterification of 3-nitro phthalic acid com ound of formula-3
Figure imgf000014_0001
Formula-3
with methanol in presence of a suitable esterification catalyst to provide 2- (methoxycarbonyl)-6-nitro benzoic acid of formula-4,
Figure imgf000014_0002
Formula-4
b) treating the compound of formula-4 with thionyl chloride in a suitable solvent to provide methyl 2-(chlorocarbonyl)-3-nitrobenzoate compound of formula-5,
Figure imgf000015_0001
Formula-5
treating the compound of formula-5 in-situ with a suitable azide source in a suitable to provide methyl 2-(azidocarbonyl)- -nitrobenzoate compound of formula-6,
Figure imgf000015_0002
Formula-6
d) treating the compound of formula-6 in-situ with tert.butanol to provide methyl 2-(tert- butoxycarbonylamino)-3-nitrobenz ate compound of formula-7,
Figure imgf000015_0003
Formula-7
condensing the compound of formula-7 with 4'-(bromomethyl)biphenyl-2-carbonitrile compound of formula-8
Figure imgf000015_0004
Formula-8
in presence of a suitable base in a suitable solvent, optionally in presence of a suitable phase transfer catalyst to provide methyl 2-(tert-butoxycarbonyl((2'-eyanobiphenyl-4- yl)methyl)amino)-3-nitrobenzoate compound of formula-9,
Figure imgf000016_0001
Formula-9
f) deprotecting the compound of formula-9 by treating it with a suitable boc-deprotecting agent in a suitable solvent to provide methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3- nitrobenzoate compound of fo
Figure imgf000016_0002
Formula- 10
g) reducing the compound of formula- 10 with a suitable reducing agent in a suitable solvent to provide methyl 3-amino-2-((2'-cyanobiphenyl-4-yl)methylamino)benzoate compound of formula-11,
Figure imgf000016_0003
Formula-11
h) cyclization of compound of formula-11 by treating it with tetraethyl orthocarbonate in a suitable solvent to provide methyl l-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-lH- benzimidazole -7-carboxylate compound of formula- 12,
Figure imgf000017_0001
Formula- 12
i) treating the compound of formula- 12 with hydroxylamine hydrochloride in presence of a suitable base in a suitable solvent to provide methyl 2-ethoxy-l-((2'-(N'- hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzimidazole-7-carboxylate compound of formula-13,
Figure imgf000017_0002
Formula-13
j) cyclization of compound of formual-13 by treating it with a suitable cyclization agent presence of a suitable base in a suitable solvent to provide methyl 2-ethoxy-l-((2'-(5-oxo-4, dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- 1 H-benzimidazole-7-carboxylate compound of formula- 14,
Figure imgf000017_0003
Formula- 14
k) hydrolyzing the compound of formula- 14 in presence of a suitable base in a suitable solvent to provide 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - lH-benzimidazole-7-carboxylic acid compound of formula-2,
Figure imgf000018_0001
Formula-2
1) optionally converting the compound of formula-2 into its disodium salt compound of formula-2 a
Figure imgf000018_0002
Formula-2 a
by treating it with a suitable sodium source in a suitable solvent,
m) condensing the compound of formula-2 or compound of formula-2a with compound of general formula- 15
Figure imgf000018_0003
Formula- 15
wherein, X= CI, Br or OH;
in presence or absence of a suitable base in a suitable solvent, optionally in presence of a suitable catalyst or suitable phase transfer catalyst or a suitable condensing agent to provide (5-methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4- oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula- 1,
n) treating the compound of formula- 1 with a suitable potassium source in a suitable solvent to provide its potassium salt compound of formula- la Wherein, in step-a) the suitable esterification catalyst is selected from thionyl chloride, cone. sulfuric acid and the like;
In step-b) the suitable solvent is selected from chloro solvents, polar-aprotic solvents, hydrocarbon solvents or mixtures thereof;
In step-c) the suitable azide source is selected from alkali metal azides such as sodium azide, potassium azide; diphenylphosphoryl azide, trialkylsilyl azides such as trimethylsilyl azide and the like; the suitable solvent is selected from chloro solvents, polar-aprotic solvents, hydrocarbon solvents, ketone solvents, ether solvents, ester solvents or mixtures thereof;
In step-e) the suitable base is selected from inorganic bases such as alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides and the like; the suitable solvent is selected from polar-aprotic solvents, nitrile solvents, ketone solvents, hydrocarbon solvents, alcoholic solvents, ether solvents, ester solvents or mixtures thereof;
The suitable phase transfer catalyst is selected from tetra alkyl ammonium halide, tetra aryl ammonium halide, (alkyl)m(aryl)4.m ammonium halide, tetra alkyl ammonium hydroxide, tetra aryl ammonium hydroxide, (alkyl)m(aryl)4-m ammonium hydroxide, wherein, the alkyl groups can be same or different in tetra alkyl ammonium halide/hydroxide, (alkyl)m(aryl)4.m ammonium halide/hydroxide; the aryl groups can be same or different in tetra aryl ammonium halide/hydroxide, (alkyl)m(aryl)4-m ammonium halide/ hydroxide, wherein 'm' is between land 3; and alkyl represents CrC8 straight chain or branched chain alkyl, aryl represents substituted or unsubstituted C6-C10 aryl; halide represents chloride, bromide or iodide; hexadecyl tributyl phosphonium bromide, preferably tetrabutyl ammonium bromide;
In step-f) the suitable boc-deprotecting agent is selected from hydrochloric acid, trifluoroacetic acid, methanesulfonic acid, p-toluene sulfonic acid, acetyl chloride in combination with alcohol, tri(Ci-C6 alkyl)silyl halides and the like; the suitable solvent is selected from ketone solvents, chloro solvents, alcoholic solvents, ester solvents, polar solvents, ether solvents or mixtures thereof;
In step-g) the suitable reducing agent is selected from Ni, Raney Ni, Pd/C, Pt/C, Pt02, Fe, Fe in acidic media like HC1, acetic acid, NH4C1; Sn-HCl, stannous chloride (SnCl2), Zn in acidic media like HC1, acetic acid, NH4CI, Zinc dust, sodium borohydride, lithium borohydride, lithium aluminium hydride, sodium aluminium hydride, diborane, hydrazine hydrate, sodium dithionate, sodium sulfide, ammonium sulfide, Na-Hg/H2, borane-tetrahydrofuran and the like; the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, chloro solvents, alcoholic solvents, polar solvents or mixtures thereof;
In step-h) the suitable solvent is acetic acid;
In step-i) the suitable base is selected from organic and inorganic bases; the suitable solvent is selected from polar-aprotic solvents, polar solvents, ether solvents, alcoholic solvents, hydrocarbon solvents or mixtures thereof;
In step-j) the suitable cyclization agent is selected from Ν,Ν-carbonyldiimidazole (CDI), carbonyl-di-l ,2,4-triazole, alkyl and aryl haloformates such as ethyl chloro formate, phenyl chloroformate, benzyl chloro formate, dialkyl, diaryl and alkyl aryl carbonates of the formula Ri- 0-CO-0-R2, wherein "Ri" and "R2" are independently selected from branched or unbranched C\- C alkyl or substituted or unsubstituted phenyl group; and
The suitable base is selected from organic and inorganic bases; the suitable solvent is selected from chloro solvents, ether solvents, ester solvents, alcoholic solvents, polar solvents or mixtures thereof;
In step-k) the suitable base is selected from alkali metal hydroxides, alkali metal alkoxides and alkali metal carbonates; the suitable solvent is selected from alcoholic solvents, polar solvents, ether solvents, hydrocarbon solvents or mixtures thereof;
In step-1) the suitable sodium source is selected from hydroxides, alkoxides, carbonates, bicarbonates and acetates of sodium metal; the suitable solvent is selected from alcoholic solvents, polar solvents, ether solvents, hydrocarbon solvents or mixtures thereof; In step-m) the suitable base is selected from inorganic bases, organic bases or their mixtures; the suitable solvent is selected from nitrile solvents, ketone solvents, chloro solvents, ether solvents, polar solvents, ester solvents, hydrocarbon solvents, polar-aprotic solvents or mixtures thereof;
The suitable catalyst is selected from p-toluenesulfonyl chloride, benzene sulfonyl chloride, methane sulfonyl chloride, ethane sulfonyl chloride, thionyl chloride, oxalyl chloride, acylating agents represented by the formula R-CO-X, wherein "R" represents Ci-C6 straight chain or branched chain alkyl group, such as methyl, ethyl, propyl, tert-butyl and the like, a Ci-C^ alkoxy group such as methoxy, ethoxy, propoxy, isobutyloxy and the like; substituted or unsubstituted phenyl group; "X" represents halogens such as CI, Br & I;
The suitable phase transfer catalyst is same as defined in above step-e);
The suitable condensing agent is selected from Ν,Ν-carbonyldiimidazole (CDI), alkyl and aryl carbodiimides such as Ν,Ν-diisopropylcarbodiimide (DIC), N,N- dicyclohexylcarbodiimide (DCC), 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), ditolylcarbodiimide, carbonyl-di- l,2,4-triazole, alkyl and aryl haloformates such as methyl chloroformate, ethyl chloroformate, phenyl chloroformate, benzyl chloroformate, dialkyl, diaryl and alkyl aryl carbonates of the formula Ri-0-CO-0-R2, wherein "Ri" and "R2" are independently selected from branched or unbranched C 1-C4 alkyl, substituted or unsubstituted phenyl group;
In step-n) the suitable potassium source is selected from potassium 2-ethyl hexanoate, potassium tertbutoxide, potassium bis(trimethylsilyl)amide (KHMDS), potassium hydroxide, potassium carbonate and the like; the suitable solvent is selected ketone solvents, ester solvents, polar-aprotic solvents, hydrocarbon solvents, ether solvents or their mixtures.
A preferred embodiment of the present invention provides a process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l- {[2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula-1 and its potassium salt compound of formula- 1 a, comprising of;
a) Esterification of 3-nitro phthalic acid compound of formula-3 with methanol in presence of thionyl chloride to provide 2-(methoxycarbonyl)-6-nitro benzoic acid of formula-4, b) treating the compound of formula-4 with thionyl chloride in dichloromethane or in a mixture of dichloromethane and catalytic amount of Ν,Ν-dimethylformamide to provide methyl 2-
(chlorocarbonyl)-3-nitrobenzoate compound of formula-5,
c) treating the compound of formula-5 in-situ with sodium azide in dimethyl formamide to provide methyl 2-(azidocarbonyl)-3-nitrobenzoate compound of formula-6,
d) treating the compound of formula-6 in-situ with tert.butanol to provide methyl 2-(tert- butoxycarbonylamino)-3-nitrobenzoate compound of formula-7,
e) condensing the compound of formula-7 with 4'-(bromomethyl)biphenyl-2-carbonitrile compound of formula-8 in presence of potassium carbonate and tetra butyl ammonium bromide in acetone or acetonitrile to provide methyl 2-(tert-butoxycarbonyl((2'- cyanobiphenyl-4-yl)methyl)amino)-3-nitro benzoate compound of formula-9,
f) deprotecting the compound of formula-9 by treating it with trifluoroacetic acid or methane sulfonic acid in dichloromethane to provide methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)- 3-nitrobenzoate compound of formula- 10,
g) reducing the compound of formula- 10 with Raney Ni in ethyl acetate under H2 pressure to provide methyl 3-amino-2-((2'-cyanobiphenyl-4-yl)methylamino)benzoate compound of formula-11,
h) cyclization of compound of formula- 11 by treating it in-situ with tetraethyl orthocarbonate in acetic acid to provide methyl l-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-lH-benzimidazole -7-carboxylate compound of formula- 12,
i) treating the compound of formula- 12 with hydroxylamine hydrochloride in presence of triethyl amine in a mixture of dimethylsulfoxide and tetrahydrofuran to provide methyl 2- ethoxy- 1 -((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzimidazole-7- carboxylate compound of formula- 13,
j) cyclization of compound of formual-13 by treating it with ethyl chloroformate in presence of triethyl amine in tetrahydrofuran to provide methyl 2-ethoxy- l-((2'-(5-oxo-4,5-dihydro- 1,2,4- oxadiazol-3-yl)biphenyl-4-yl)methyl)-lH-benzimidazole-7-carboxylate compound of formula- 14,
k) hydrolyzing the compound of formula- 14 in presence of aq.lithium hydroxide in methanol to provide 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1H- benzimidazole-7-carboxylic acid compound of formula-2,
1) condensing the compound of formula-2 with 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one compound of formula- 15a
Figure imgf000022_0001
Formula- 15a
in presence of sodium bicarbonate and tetrabutyl ammonium bromide in acetone to provide (5-methyl-2-oxo-l ,3-dioxol-4-yl)methyl 2-ethoxy- 1- {[2'-(5-oxo-4,5-dihydro- 1 ,2,4- oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula- 1 ,
m) treating the compound of formula- 1 with potassium 2-ethyl hexanoate or potassium tert.butoxide in acetone or in a mixture of acetone and ethyl acetate to provide its potassium salt compound of formula- la.
The 3-nitro phthalic acid compound of formula-3 used in step-a) of the first aspect can be synthesized by any of the processes known in the art such as Journal of the American Chemical Society, 1925, 47 (7), 1980-1981; Journal of the chemical society, 1914, 105, 2476; Organic Syntheses, Coll. Vol. 1, p.408 (1941); Vol. 7, p.70 (1927) etc.
All the prior reported processes for the preparation of (5-methyl-2-oxo-l,3-dioxol-4- yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH- benzimidazole-7-carboxylate potassium salt compound of formula- la from compound of formula- 1 involves the usage of potassium 2-ethyl hexanoate as a potassium source.
The present inventors earnestly tried different potassium sources such as potassium hydroxide, potassium carbonate and potassium tert.butoxide. We found potassium tert.butoxide as an advantageous source of potassium for this step, which is a simple, commercially available and cost-effective reagent when compared to the conventional potassium 2-ethyl hexanoate.
The second aspect of the present invention provides a process for the preparation of (5- methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt compound of formula- la, comprising of treating the (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo- 4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - lH-benzimidazole-7-carboxylate compound of formula- 1 with potassium tert.butoxide in a suitable solvent selected from ketone solvents, ester solvents, polar-aprotic solvents, hydrocarbon solvents, ether solvents or mixtures thereof.
The amount of potassium tert.butoxide used in this process is in an amount ranging from 0.8-1.7 moles, preferably 0.9 to 1.5 moles per one mole equivalent of compound of formula-1 and the reaction can be carried out at a temperature ranging from -10°C to 60°C, preferably -5°C to 35°C. In this process, potassium bis(trimethylsilyl)amide (KHMDS) can also be used as a potassium source in place of potassium tert.butoxide.
A preferred embodiment of the present invention provides a process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l- {[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt compound of formula- la, comprising of treating the (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo- 4, 5-dihydro- 1 ,2,4-oxadiazol-3 -yl)biphenyl-4-yl]methyl } - 1 H-benzimidazole-7-carboxylate compound of formula- 1 with potassium tert.butoxide in acetone or in a mixture of acetone and ethyl acetate.
The third aspect of the present invention provides a process for the preparation of methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate compound of formula- 10, comprising of deprotecting the methyl 2-(tert-butoxycarbonyl((2'-cyanobiphenyl-4-yl)methyl) amino)-3- nitrobenzoate compound of formula-9 by treating it with a suitable boc-deprotecting agent selected from trifluoroacetic acid, methane sulfonic acid in a suitable solvent selected from chloro solvents, ether solvents, alcoholic solvents, hydrocarbon solvents, ketone solvents, ester solvents, polar-aprotic solvents, polar solvents or mixtures thereof.
The said deprotection is carried out by using 2.0-5.0 mole ratio, preferably 3.0-4.0 mole ratio of boc-deprotecting agent per one mole equivalent of compound of formula-9 and the reaction is carried out at a temperature ranging between 25°C to reflux temperature of the solvent used, preferably at 25-30°C.
p-Toluene sulfonic acid, hydrochloric acid, acetyl chloride, tr^Ct-Ce alkyl)silyl halides can also be used for the deprotection of methyl 2-(tert-butoxycarbonyl((2'-cyanobiphenyl-4-yl) methyl)amino)-3 -nitrobenzoate compound of formula-9.
A preferred embodiment of the present invention provides a process for the preparation of methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate compound of formula-10, comprising of deprotecting the methyl 2-(tert-butoxycarbonyl((2'-cyanobiphenyl-4-yl)methyl) amino)-3 -nitrobenzoate compound of formula-9 by treating it with trifluoroacetic acid or methanesulfonic acid in dichloromethane to provide compound of formula-10. The fourth aspect of the present invention provides a process for the preparation of methyl 3-amino-2-((2'-cyanobiphenyl-4-yl)methylamino)benzoate compound of formula-1 1, comprising of reducing the methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate compound of formula- 10 with a suitable reducing agent selected from Raney Ni, NaBH4, Pd/C under H2 gas pressure in a suitable solvent selected from ester solvents, alcoholic solvents, ether solvents, chloro solvents, hydrocarbon solvents, polar solvents or mixtures thereof to provide compound of formula- 1 1.
A preferred embodiment of the present invention provides a process for the preparation of methyl 3-amino-2-((2'-cyanobiphenyl-4-yl)methylamino)benzoate compound of formula-11, comprising of reducing the methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate compound of formula- 10 with Raney Ni in ethyl acetate under H2 gas pressure to provide compound of formula- 11. The fifth aspect of the present invention provides a process for the preparation of (5- methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula-1, comprising of reacting the 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}- lH-benzimidazole-7-carboxylic acid compound of formula-2 with 4-(chloromethyl)-5-methyl- l,3-dioxol-2-one compound of formula- 15a in presence of a suitable alkali metal bicarbonate in a suitable solvent selected from ketone solvents, polar-aprotic solvents, ester solvents, ether solvents or mixtures thereof optionally in presence of a suitable phase transfer catalyst such as tetra butyl ammonium bromide to provide compound of formula-1. A preferred embodiment of the present invention provides a process for the preparation of
(5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula-1, comprising of reacting the 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}- lH-benzimidazole-7-carboxylic acid compound of formula-2 with 4-(chloromethyl)-5-methyl- l,3-dioxol-2-one compound of formula- 15a in presence of sodium bicarbonate and tetra butyl ammonium bromide in acetone to provide compound of formula-1. The sixth aspect of the present invention provides a novel crystalline form, herein after designated as crystalline form-M of 2-ethoxy-l- {[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2, characterized by its X-Ray powder diffraction pattern having peaks at 9.1, 12.7, 14.9, 15.4, 16.2, 17.9, 18.3, 18.6, 19.3, 19.9, 20.4, 21.4, 21.8, 23.5, 23.9, 25.2, 25.6, 26.7, 28.7 ± 0.2 degrees of 2- theta. The said novel crystalline form-M is further characterized by its PXRD pattern as illustrated in figure- 1.
The seventh aspect of the present invention provides a novel crystalline form, herein designated as crystalline form-S of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5- oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - lH-benzimidazole-7-carboxylate compound of formula- 1, characterized by its X-Ray powder diffraction pattern having peaks at 8.6, 9.8, 13.0, 16.1, 16.8, 17.2, 17.4, 18.5, 19.3, 19.9, 20.6, 21.9, 22.4, 22.9, 23.5, 25.8, 26.3±0.2 degrees of 2-theta and its DSC thermogram having one endotherm at 130°C and another endotherm at 171°C. The novel crystalline form-S is further characterized by its PXRD pattern as illustrated in figure-2 and its DSC thermogram as shown in figure-3.
The eighth aspect of the present invention provides amorphous form of (5-methyl-2-oxo- l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4- yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1 characterized by its PXRD pattern as depicted in figure-4.
The ninth aspect of the present invention provides a novel crystalline form, herein after designated as crystalline form-N of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5- oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt compound of formula- la, characterized by its X-Ray powder diffraction pattern having peaks at 6.2, 6.7, 13.4, 14.1, 14.5, 14.8, 16.0, 18.7, 20.3, 21.4, 22.8, 23.8, 27.6 ± 0.2 degrees of 2-theta. This novel crystalline form-N is further characterized by its PXRD pattern as illustrated in figure-5.
The tenth aspect of the present invention provides a process for the preparation of amorphous form of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3 -yl)biphenyl-4-yl]methyl } - 1 H-benzimidazole-7-carboxylate compound of formula- 1 , comprising of;
a) Condensing the 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid compound of formula-2 or its disodium salt compound of formula-2a with 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one compound of formula- 15a in presence or absence of a base in a suitable solvent to provide (5-methyl-2- oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1, b) treating the compound of formula- 1 in-situ with a suitable potassium source in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5- dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt of formula- la,
c) treating the potassium salt obtained in step-b) in-situ with a suitable acid in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate of formula- 1 , d) isolating the compound of formula- 1 from a suitable solvent to provide amorphous form of compound of formula- 1.
Wherein, in step-a) the suitable solvent is selected from polar-aprotic solvents, ketone solvents, hydrocarbon solvents, chloro solvents, ester solvents or mixtures thereof and the suitable base is selected from inorganic bases;
In step-b) the suitable potassium source is selected from potassium 2-ethyl hexanoate, potassium tert.butoxide, potassium bis(trimethylsilyl)amide (KHMDS), potassium hydroxide and the like; the suitable solvent is selected from ketone solvents, ether solvents, ester solvents or mixtures thereof;
In step-c) the suitable acid is selected from acetic acid and hydrochloric acid; and the suitable solvent is selected form polar solvents, hydrocarbon solvents, alcoholic solvents or mixtures thereof;
In step-d) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ketone solvents, alcoholic solvents, ester solvents or mixtures thereof; preferably hydrocarbon solvents. A preferred embodiment of the present invention provides a process for the preparation of amorphous form of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3 -yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula- 1, comprising of;
a) Condensing the 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4- yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2 or its disodium salt compound of formula-2a with 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one compound of formula-15a in Ν,Ν-dimethylformamide to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H- benzimidazole-7-carboxylate compound of formula- 1,
b) treating the compound of formula- 1 in-situ with potassium 2-ethyl hexanoate in acetone to provide (5-methyl-2-oxo- 1 ,3 -dioxol-4-yl)methyl 2-ethoxy- 1 - { [2'-(5 -oxo-4,5-dihydro- 1,2,4- oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt of formula- la,
c) treating the potassium salt obtained in step-b) in-situ with acetic acid in water to provide (5- methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3- yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1, d) isolating the compound of formula- 1 from cyclohexane to provide amorphous form of compound of formula- 1.
The eleventh aspect of the present invention provides a process for the purification of (5-methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3- yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt compound of formula- 1 a, comprising of;
a) Adding a suitable solvent to (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-{[2'-(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt compound of formula- la,
b) heating the reaction mixture,
c) cooling the reaction mixture,
d) filtering the solid to provide highly pure compound of formula- 1 a. Wherein, the suitable solvent used in step-a) is selected from ester solvents, ketone solvents, ether solvents, alcoholic solvents, chloro solvents or their mixtures; preferably selected from ethyl acetate and methyl isobutyl ketone or mixtures thereof. The twelfth aspect of the present invention provides a process for the preparation of 2- ethoxy- 1 -((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzimidazole-7-carboxylic acid compound of formula- 16,
Figure imgf000029_0001
Formula- 16
comprising of reacting the methyl l-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-lH- benzimidazole-7-carboxylate compound of formula- 12 with hydroxylamine hydrochloride in presence of a suitable inorganic base in a suitable solvent or mixture of solvents to provide 2-ethoxy- 1 -((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzimidazole-7- carboxylic acid compound of formula- 16.
Wherein, the suitable inorganic base is selected from alkali metal carbonates, alkali metal bicarbonates; and the suitable solvent is selected from polar-aprotic solvents, polar solvents, alcoholic solvents or mixtures thereof; preferably a mixture of polar solvents and polar-aprotic solvents.
US5243054A patent disclosed the conversion of cyanobiphenyl compound of formula- 12 to the corresponding amidoxime by treating it with hydroxylamine hydrochloride in presence of sodium methoxide as a base. J. Med. Chem. 1996, 39, 5228-5235 also discloses this step using triethylamine as a base.
When we repeated the same processes in our laboratory, we observed the formation of ester amide impurity at a level of about 30-40% along with the desired methyl 2-ethoxy- 1 -((2 - (N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzimidazole-7-carboxylate (amidoxime methyl ester) product. When the amidoxime acid compound of formula- 16 is prepared by hydrolyzing the obtained amidoxime methyl ester compound, we are ended up with compound of formula- 16 having 30-40 of acid amide impurity.
Figure imgf000030_0001
Ester amide impurity Acid amide impurity
Formation of impurities in such levels greatly impacts the yield, purity and cost of the desired product as well as final product, i.e., Azilsartan medoxomil potassium. In order to remove these impurities, additional purification steps need to be performed which further reduces the yield and increases the cost of the desired product.
The present inventors tried different bases and solvents for the said step, and surprisingly found that the usage of alkali metal carbonate as a base in a solvent system comprising of mixture of polar and polar-aprotic solvents considerably suppresses the formation of said impurities and providing the desired product in high yield with enhanced purity.
The reaction is carried out by employing each of hydroxylamine hydrochloride and alkali metal carbonate in 6.0-9.0 mole ratio, preferably in 7.0-8.0 mole ratio per one mole equivalent of compound of formula- 12, and the solvent system comprises of dimethylsulfoxide and water in the ratio of 1 :0.5-1 respectively.
A preferred embodiment of the present invention provides a process for the preparation of 2-ethoxy- 1 -((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzimidazole-7- carboxylic acid compound of formula- 16, comprising of reacting the methyl l-((2'- cyanobiphenyl-4-yl)methyl)-2-ethoxy-lH-benzimidazole-7-carboxylate compound of formula- 12 with hydroxylamine hydrochloride in presence of sodium carbonate in a mixture of dimethyl sulfoxide and water to provide 2-ethoxy- 1 -((2'-(N'-hydroxycarbamimidoyl)biphenyl-4- yl)methyl)-lH-benzimidazole-7-carboxylic acid compound of formula- 16. The thirteenth aspect of the present invention provides a process for the preparation of 2- ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl } - 1 H- benzimidazole-7-carboxylic acid compound of formula-2, comprising of reacting the 2-ethoxy- 1- ((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzimidazole-7-carboxylic acid compound of formula- 16 with a suitable cyclization agent in presence of a suitable base in a suitable solvent to provide 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4- yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2.
Wherein, the suitable cyclization agent, the suitable base and the suitable solvent are same as defined in step-j) of the first aspect of the present invention;
The cyclization of compound of formula- 16 is carried out by employing 1.0-3.0 mole ratio, preferably 1.5-2.5 mole ratio of the cyclization agent per one mole equivalent of compound of formula- 16. The amount of base used in the said cyclization step is ranging from 1.0-3.0 mole ratio, preferably 1.5-2.0 mole ratio per one mole equivalent of compound of formula- 13, and the reaction is carried out at a temperature ranging between 25°C to reflux temperature of the solvent used; preferably at 25-30°C.
A preferred embodiment of the present invention provides a process for the preparation of 2-ethoxy- 1 - {[2*-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H- benzimidazole-7-carboxylic acid compound of formula-2, comprising of reacting the 2-ethoxy- 1- ((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzimidazole-7-carboxylic acid compound of formula-16 with Ν,Ν-carbonyldiimidazole (CDI) in presence of 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) in dichloromethane to provide 2-ethoxy- 1- {[2'-(5-oxo-4,5-dihydro- l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2.
The fourteenth aspect of the present invention provides an improved process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-{[2'-(5-oxo-4,5-dihydro- l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1 and its potassium salt compound of formula- la, comprising of;
a) Deprotecting the methyl 2-(tert-butoxycarbonyl((2'-cyanobiphenyl-4-yl)methyl)amino)-3- nitrobenzoate compound of formula-9 by treating it with a suitable boc-deprotecting agent in a suitable solvent to provide methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate compound of formula- 10,
b) reducing the compound of formula- 10 with a suitable reducing agent in a suitable solvent to provide methyl 3-amino-2-((2'-cyanobiphenyl-4-yl)methylamino)benzoate of formula- 1 1 , c) reacting the compound of formula- 1 1 with tetraethyl orthocarbonate in a suitable solvent to provide methyl 1 -((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy- 1 H-benzimidazole-7- carboxylate compound of formula- 12,
d) treating the compound of formula- 12 with hydroxylamine hydrochloride in presence of a suitable base in a suitable solvent or mixture of solvents to provide 2-ethoxy-l-((2'-(N'- hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzimidazole-7-carboxylic acid compound of formula- 16,
e) reacting the compound of formula- 16 with a suitable cyclization agent in presence of a suitable base in a suitable solvent to provide 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid of formula-2, f) condensing the compound of formula-2 with compound of general formula- 15 in presence of a suitable base in a suitable solvent, optionally in presence of a suitable catalyst or suitable condensing agent or a suitable phase transfer catalyst to provide (5-methyl-2-oxo-l,3-dioxol- 4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - lH-benzimidazole-7-carboxylate compound of formula- 1,
g) converting the compound of formula- 1 into its potassium salt compound of formula- la by treating it with a suitable potassium source in a suitable solvent.
Wherein, in step-a) the suitable boc-deprotecting agent and the suitable solvent are same as defined in step-f) of the first aspect of the present invention;
In step-b) the suitable reducing agent and the suitable solvent are same as defined in step- g) of the first aspect of the present invention;
In step-c) the suitable solvent is acetic acid;
In step-d) the suitable base is selected from carbonates and bicarbonates of alkali metals, preferably alkali metal carbonates; and the suitable solvent is selected from polar-aprotic solvents, polar solvents, alcoholic solvents or mixtures thereof; preferably a mixture of polar and polar-aprotic solvents; In step-e) the suitable cyclization agent, the suitable base and the suitable solvent are same as- defined in step-j) of the first aspect of the present invention;
In step-f) the suitable base, suitable solvent, suitable catalyst, suitable condensing agent and the suitable phase transfer catalyst are same as defined in step-m) of the first aspect of the present invention;
In step-g) the suitable potassium source and the suitable solvent are same as defined in step-n) of the first aspect of the present invention.
A preferred embodiment of the present invention provides an improved process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro- l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- land its potassium salt compound of formula- la, comprising of;
a) Deprotecting the methyl 2-(tert-butoxycarbonyl((2'-cyanobiphenyl-4-yl)methyl)amino)-3- nitrobenzoate compound of formula-9 by treating it with methanesulfonic acid in dichloromethane to provide methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate compound of formula- 10,
b) reducing the compound of formula- 10 with Raney Ni in ethyl acetate under H2 gas pressure to provide methyl 3-amino-2-((2'-cyanobiphenyl-4-yl)methylamino)benzoate compound of formula-1 1,
c) reacting the compound of formula- 11 with tetraethyl orthocarbonate in acetic acid- to provide methyl 1 -((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy- 1 H-benzimidazole-7-carboxylate compound of formula- 12,
d) treating the compound of formula- 12 with hydroxylamine hydrochloride in presence of sodium carbonate in a mixture of dimethyl sulfoxide and water to provide 2-ethoxy- 1 -((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzimidazole-7-carboxylic acid compound of formula- 16,
e) reacting the compound of formula- 16 with N,N-carbonyldiimidazole (CDI) in presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in dichloromethane to provide 2-ethoxy-l-{[2'- (5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7- carboxylic acid compound of formula-2,
f) condensing the compound of formula-2 with 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one compound of formula- 15a in presence of sodium bicarbonate and tetrabutyl ammonium bromide in acetone to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l- {[2'-(5- oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7- carboxylate compound of formula- 1,
g) treating the compound of formula- 1 with potassium 2-ethyl hexanoate in a mixture of acetone and ethyl acetate to provide its potassium salt compound of formula- la.
Another preferred embodiment of the present invention provides an improved process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro- l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1 and its potassium salt compound of formula- 1 a, comprising of;
a) Reacting the 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzimidazole-7-carboxylic acid compound of formula- 16 with Ν,Ν-carbonyl diimidazole in presence of l,8-diazabicyclo[5.4.0]undec-7-ene in dichloromethane to provide 2-ethoxy-l- {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - lH-benzimidazole-7- carboxylic acid compound of formula-2,
b) condensing the compound of formula-2 with 4-(hydroxymethyl)-5-methyl-l,3-dioxol-2-one compound of formula- 15c
Figure imgf000034_0001
Formula-15c
in presence of p-toluenesulfonyl chloride, 4-dimethylaminopyridine (DMAP) and potassium carbonate in acetone to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5- oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7- carboxylate compound of formula- 1,
c) treating the compound of formula- 1 with potassium 2-ethyl hexanoate in a mixture of acetone and ethyl acetate to provide its potassium salt compound of formula- la.
The fifteenth aspect of the present invention provides a novel process for the preparation of (5-methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - { [2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol- 3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula-1 and its potassium salt compound of formula- la, comprising of;
a) Reacting the 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of formula- 16 with compound of general formula- 15 in presence of a suitable base in a suitable solvent, optionally in presence of a suitable catalyst or suitable phase transfer catalyst or a suitable condensing agent to provide (5-methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 -((2'-(N'-hydroxycarbamimidoyl) biphenyl-4-yl)methyl)-lH-benzo d]imidazole-7-carbox late compound of formula- 17,
Figure imgf000035_0001
Formula-17
b) reacting the (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-((2'-(N'-hydroxy carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole-7-carboxylate compound of formula-17 with Ν,Ν-carbonyldiimidazole in presence of a suitable base in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-((2'-(N'-hydroxy-N-(lH- imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole-7- carboxylate compound of formula- 18,
c) isolating the compound of formula- 18 as a solid,
d) heating the compound of formula- 18 in presence of a suitable solvent to provide (5-methyl-2- oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula-1,
e) treating the compound of formula-1 with a suitable potassium source in a suitable solvent to provide its potassium salt compound of formula- la.
Wherein, in step-a) the suitable base, the suitable solvent, the suitable catalyst, the suitable condensing agent and the suitable phase transfer catalyst are same as defined for step-m) of the first aspect of the present invention; In step-b) the suitable cyclization agent, the suitable base and the suitable solvent are same as defined for step-j) of the first aspect of the present invention;
In step-c) the suitable potassium source and the suitable solvent are same as defined for step-n) of the first aspect of the present invention;
A preferred embodiment of the present invention provides a novel process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-{[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula- 1 and its potassium salt compound of formula- la, comprising of;
a) Reacting the 2-ethoxy- l-((2'-( '-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of formula- 16 with 4-(chloromethyl)-5- methyl-l,3-dioxol-2-one compound of formula-15a in presence of tetra butyl ammonium bromide (TBAB) and sodium carbonate in tetrahydrofuran to provide (5-methyl-2-oxo-l,3- dioxol-4-yl)methyl 2-ethoxy- 1 -((2'-( '-hydroxy carbamimidoyl)biphenyl-4-yl)methyl)- 1H- benzo[d]imidazole-7-carboxylate compound of formula- 17,
b) reacting the compound of formula- 17 with Ν,Ν-carbonyldiimidazole in presence of 4-dimethylaminopyridine in tetrahydrofuran to provide (5-methyl-2-oxo-l,3-dioxol-4-yl) methyl 2-ethoxy- 1 -((2'-(N'-hydroxy-N-( 1 H-imidazole- 1 -carbonyl)carbamimidOyl)biphenyl- 4-yl)methyl)- 1 H-benzo[d]imidazole-7-carboxylate compound of formula- 18,
Figure imgf000036_0001
Formula- 18
c) isolating the compound of formula- 18 as a solid and purifying the compound from a suitable solvent,
d) heating the compound of formula- 18 in presence of a suitable solvent at a suitable temperature to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-{[2'-(5-oxo-4,5- dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate of formula- 1, e) treating the compound of formula- 1 with a suitable potassium source in a suitable solvent to provide its potassium salt compound of formula- 1 a.
Wherein in step-c) and step-d) the suitable solvent is selected from chloro solvents, ether solvents, ester solvents, alcoholic solvents, polar solvents, ketone solvents, nitrile solvents, polar- aprotic solvents, hydrocarbon solvents or mixtures thereof;
In step-d) the suitable temperature is ranging from 25°C to reflux temperature of the solvent;
In step-e) the suitable potassium source and the suitable solvent are same as defined in step-n) of the first aspect of the present invention.
The intermediate compounds of formula- 17 and formula- 18 of the present invention are isolated in the form of solids, which are further utilized in the preparation of highly pure (5- methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1 and its pharmaceutically acceptable salts.
The sixteenth aspect of the present invention provides a process for the preparation of (5- methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-((2'-(N'-hydroxy carbamimidoyl)biphenyl-4-yl) methyl)- lH-benzo[d]imidazole-7-carboxylate compound of formula- 17, comprising of reacting the 2-ethoxy- 1 -((2'-( '-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole-7- carboxylic acid compound of formula- 16 with compound of general formula- 15 in presence of a suitable base in a suitable solvent, optionally in presence of a suitable catalyst or suitable phase transfer catalyst or a suitable condensing agent to provide compound of formula- 17. Wherein, the suitable catalyst, the suitable phase transfer catalyst, the suitable condensing agent, the suitable base and the suitable solvent are same as defined in step-m) of the first aspect of the present invention.
In the present invention, the reaction of compound of formula- 16 with 4-(chloromethyl)- 5-methyl-l,3-dioxol-2-one compound of formula- 15a can be carried out in presence of a phase transfer catalyst and the reaction of compound of formula- 16 with 4-(hydroxymethyl)-5-methyl- l,3-dioxol-2-one compound of formula-15c can be carried out in presence of a suitable catalyst or a suitable condensing agent as defined above. The 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one compound of formula- 15a used in the present invention is commercially available.
The 4-(hydroxymethyl)-5-methyl-l,3-dioxol-2-one compound of formula- 15c used in the present invention is also commercially available or it can be synthesized by any of the conventional methods such as Syn. Commu.22, 9, 1277-1282, 1992.
The seventeenth aspect of the present invention provides a process for the preparation of (5-methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1, comprising of reacting the (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-((2'-(N'-hydroxy carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole-7-carboxylate compound of formula- 17 with Ν,Ν-carbonyldiimidazole in presence of a suitable base in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- 1 -((2'-(N'-hydroxy-N-( lH-imidazole- l-carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate compound of formula- 18 followed by heating the compound of formula- 18 in presence of a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-{[2'-(5-oxo-4,5- dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - lH-benzimidazole-7-carboxylate compound of formula- 1. Wherein, suitable base and the suitable solvent are same as defined in step-j) of the first aspect of the present invention.
The compound of formula- 1 obtained in the seventeenth aspect of the present invention can be optionally converted into its pharmaceutically acceptable salts, preferably its potassium salt by the methods known in the art.
The eighteenth aspect of the present invention provides a crystalline polymorph of (5- methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 -((2'-(N'-hydroxycarbamimidoyl)biphenyl-4- yl)methyl)-lH-benzo[d]imidazole-7-carboxylate compound of formula- 17, herein after designated as crystalline form-M. The crystalline form-M of compound of formula- 17 of the present invention is characterized by its X-Ray powder diffraction pattern having peaks at 10.0, 15.0, 15.3, 17.6, 20.0, 23.8 and 28.4 ± 0.2 degrees of 2Θ values. The said crystalline form-M is further characterized by its X-Ray powder diffraction pattern having peaks at 7.1, 21.1, 24.1 and 25.3 ± 0.2 degrees of 2Θ and is further characterized by its PXRD pattern as illustrated in figure-6.
Another embodiment of the eighteenth aspect of the present invention provides crystalline form-Mi of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'-(N'-hydroxy carbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate compound of formula- 17, characterized by;
i) Its X-Ray powder diffraction pattern having peaks at 5.7, 8.7, 11.8, 14.7, 19.5, 22.8 and 23.5 ± 0.2 degrees of 2Θ, and
ii) its X-Ray powder diffraction pattern substantially in accordance with figure- 10.
The nineteenth aspect of the present invention provides a crystalline polymorph of (5- methyl-2-oxo- 1 ,3 -dioxol-4-yl)methyl 2-ethoxy- 1 -((2'-(N'-hydroxy-N-( 1 H-imidazole- 1 - carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole-7-carboxylate compound of formula- 18, herein after designated as crystalline form-S. The said crystalline form-S is characterized by its X-Ray powder diffraction pattern having peaks at 4.1, 7.0, 7.9, 9.1, 10.6,
13.5, 15.7, 16.3, 17.4, 17.8, 19.0, 22.8, 23.5, 24.4, 28.8 ± 0.2 degrees of 2Θ values. The crystalline form-S of the present invention is further characterized by its X-Ray powder diffraction pattern having peaks at 8.1, 16.9, 19.2, 19.9, 20.3, 21.0, 21.9, 22.3, 24.8, 26.1 and 26.8 ± 0.2 degrees of 2Θ and is further characterized by the PXRD pattern as illustrated in figure-7.
The twentieth aspect of the present invention provides a crystalline polymorph of (5- methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1, herein after designated as crystalline form-L. The crystalline form-L of the present invention is characterized by its X-Ray powder diffraction pattern having peaks at 8.9, 10.6, 11.5, 15.4, 19.7, 20.3, 21.5,
24.6, 25.7, 31.4 and 33.1 ± 0.2 degrees of 2Θ. The crystalline form-L of the present invention is further characterized by its X-Ray powder diffraction pattern having peaks at 4.4, 9.3, 17.9, 18.1, 18.6, 19.2, 19.9, 22.4, 22.8, 23.8 ± 0.2 degrees of 2Θ as illustrated in figure-8 and its differential , scanning calorimetric (DSC) thermogram as shown in figure-9. The twenty first aspect of the present invention provides a novel process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro- l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1 and its potassium salt compound of formula- la, comprising of;
a) Treating the 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of formula- 16 with a suitable amine protecting agent optionally in presence of a suitable base in a suitable solvent to provide compound of general formula- 19
Figure imgf000040_0001
Formula- 19
wherein 'P' represents amine protecting group;
b) reacting the compound of general formula- 19 with compound of general formula- 15 in presence of a suitable base in a suitable solvent, optionally in presence of a suitable catalyst, suitable phase- transfer catalyst or a suitable condensing agent to provide compound of general formula-20,
Figure imgf000040_0002
Formula-20
wherein 'P' represents amine protecting group;
c) treating the compound of general formula-20 with a suitable deprotecting agent in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'-(N'- hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate compound of formula- 17, d) reacting the compound of formula- 17 with Ν,Ν-carbonyldiimidazole in presence of a suitable base in a suitable solvent to provide (5-methyl-2-Oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'- (N'-hydroxy-N-( 1 H-imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)- 1 H- benzo[d]imidazole-7-carboxylate compound of formula- 18,
e) isolating the compound of formula- 18 as a solid,
f) heating the compound of formula- 18 in presence of a suitable solvent at a suitable temperature to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5- dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1,
g) treating the compound of formula- 1 with a suitable potassium source in a suitable solvent to provide its potassium salt compound of formula- la.
A preferred embodiment of twenty first aspect of the present invention provides a novel process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo- 4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula- 1 and its potassium salt compound of formula- la, comprising of;
a) Treating the 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of formula- 16 with di-tert-butyl dicarbonate in presence of a suitable base in a suitable solvent to provide l-((2'-(N-(tert-butoxycarbonyl)- N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-2-ethoxy- 1 H-benzo[d]imidazole-7- carboxylic acid compound of formula- 19a,
Figure imgf000041_0001
Formula- 19a
b) reacting the compound of formula- 19a with 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one compound of formula- 15a in presence of a suitable base in a suitable solvent, optionally in presence of a suitable phase transfer catalyst to provide (5-methyl-2-oxo-l,3-dioxol-4-yl) methyl l-((2'-(N-(tert-butoxycarbonyl)-N'-hydroxy carbamimidoyl)biphenyl-4-yl)methyl)-2- ethoxy-lH-benzo[d]imidazole-7-carboxylate compound of formula-20a,
Figure imgf000042_0001
Formula-20a
c) treating the compound of formula-20a with a suitable boc-deprotecting agent in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'-(N'- hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate compound of formula- 17,
d) reacting the compound of formula- 17 with Ν,Ν-carbonyldiimidazole in presence of a suitable base in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'- (N'-hydroxy-N-( 1 H-imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)- 1 H- benzo[d]imidazole-7-carboxylate compound of formula- 18,
e) isolating the compound of formula- 18 as a solid,
f) heating the compound of formula- 18 in presence of a suitable solvent at a suitable temperature to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5- dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1,
g) treating the compound of formula- 1 with a suitable potassium source in a suitable solvent to provide its potassium salt compound of formula- 1 a.
Wherein, in step-a) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates and organic bases; the suitable solvent is selected from nitrile solvents, ketone solvents, chloro solvents, ether solvents, polar solvents, ester solvents, hydrocarbon solvents, polar-aprotic solvents or mixtures thereof;
In step-b) the suitable base, the suitable phase transfer catalyst and the suitable solvent are same as defined step-m) of the first aspect of the present invention; In step-c) the suitable boc-deprotecting agent and the suitable solvent are same as defined in step-f) of the first aspect of the present invention;
In step-d) the suitable cyclization agent, the suitable base and the suitable solvent are same as defined for step-j) of the first aspect of the present invention;
In step-e) the suitable potassium source and the suitable solvent are same as defined for step-n) of the first aspect of the present invention.
Another embodiment of the twenty first aspect of the present invention provides a process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo- 4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - lH-benzimidazole-7-carboxylate compound of formula- 1 , comprising of;
a) Reacting the 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of formula- 16 with ethyl chloro formate optionally in presence of a suitable base in a suitable solvent to provide 2-ethoxy-l-((2'-(N'- (ethoxycarbonyloxy)carbamimidoyl)biphenyl-4-yl)methyl)- lH-benzo[d]imidazole-7- carboxylic acid compound of formula-27,
b) reacting the compound of formula-27 with compound of general formula- 15 in presence of a suitable base in a suitable solvent, optionally in presence of a suitable phase transfer catalyst, suitable catalyst or a suitable condensing agent to provide (5-methyl-2-oxo-l,3-dioxol-4- yl)methyl 2-ethoxy-l-((2'-(N'-(ethoxycarbonyloxy)carbamimidoyl)biphenyl-4-yl) methyl)- lH-benzo[d]imidazole-7-carboxylate compound of formula-28,
c) heating the compound of formula-28 in a suitable solvent at a suitable temperature optionally in presence of suitable base to provide compound of formula- 1. The twenty second aspect of the present invention provides a process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yi)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol- 3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1 and its potassium salt compound of formula- 1 a, comprising of;
a) Reacting the 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid compound of formula-2 with a suitable amine protecting agent optionally in presence of a base in a suitable solvent to provide compound of general formula-21
Figure imgf000044_0001
Formula-21
wherein 'P' represents amine protecting group;
b) reacting the compound of general formula-21 with compound of general formula- 15 in presence of a suitable base in a suitable solvent, optionally in presence of a suitable catalyst, suitable phase transfer catalyst or a suitable condensing agent to provide compound of general formula-22,
Figure imgf000044_0002
Formula-22
wherein 'P' represents amine protecting group;
c) deprotecting the compound of general formula-22 by treating it with a suitable deprotecting agent in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-
{[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7- carboxylate compound of formula- 1,
d) treating the compound of formula- 1 with a suitable potassium source in a suitable solvent to provide its potassium salt compound of formula- la.
In the present invention, the amine protecting group or N-protecting group 'P' is selected from but not limited to tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz), 9- fluorenylmethyloxy carbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate group, p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), 3,4-dimethoxy benzyl (DMPM), tosyl (Ts), trifluoroacetyl (TFA) group and the like. The suitable amine protecting agent is selected such that it is capable of protecting the nitrogen atom with any of the above mentioned amine protecting groups.
Suitable amine protecting agent is selected from but not limited to di-tert.butyl dicarbonate (DIBOC), benzyl chloroformate, fluorenylmethyloxy carbonyl chloride (FMOC chloride), acetyl chloride, acetic anhydride, benzoyl halides, benzyl halides, tosyl halides, tosyl anhydrides, alkyl trifluoroacetates such as methyl trifluoroacetate, ethyl trifluoroacetate, isopropyl trifluoroacetate, vinyl trifluoroacetate, trifluoroacetic acid, trifluoroacetyl chloride and the like.
The suitable deprotecting agent is selected based on the protecting group employed. The suitable deprotecting agent is selected from but not limited to acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aq.phosphoric acid, trifluoroacetic acid, methane sulfonic acid; acetyl chloride in combination with alcohols; bases such as alkali metal hydroxides, alkali metal carbonates, cesium carbonate/imidazole, alkali metal bicarbonates, ammonia, ammonium cerium(IV) nitrate (CAN); and organic bases such as methylamine, ethylamine, diethylamine, triethylamine, piperidine; hydrogenating agents such as Pd/C, Pd(OH)2/C (Pearlman's catalyst), palladium acetate, platinum oxide, platinum black, sodium borohydride, Na-liquid ammonia, Raney-Ni, tri(C1-C6)alkylsilanes, triiC Ceialkylsilyl halides and the like; the suitable solvent is selected form ether solvents, ester solvents, chloro solvents, hydrocarbon solvents, polar solvents, polar-aprotic solvents, ketone solvents, alcoholic solvents or mixtures thereof;
The twenty third aspect of the present invention provides a process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l- {[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1, comprising of reacting the 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}- lH-benzimidazole-7-carboxylic acid compound of formula-2 with compound of general formula-23
Figure imgf000045_0001
Formula-23
wherein 'R' represents alkyl or aryl sulfonyl group; in presence or absence of a base in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4- yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1H- benzimidazole-7-carboxylate compound of formula- 1. Wherein, the suitable base and the suitable solvent are same as defined in step-m) of the first aspect of the present invention.
The twenty fourth aspect of the present invention provides a process for the preparation of methyl 2-(tert-butoxycarbonyl ((2'-cyanobiphenyl-4-yl)methyl)amino)-3-nitrobenzoate compound of formula-9, comprising of reacting the methyl 2-(tert-butoxycarbonylamino)-3- nitrobenzoate compound of formula-7 with compound of general formula-24,
Figure imgf000046_0001
Formula-24
wherein 'R' represents alkyl or aryl sulfonyl group;
in presence of a suitable base in a suitable solvent, optionally in presence of a suitable phase transfer catalyst to provide methyl 2-(tert-butoxycarbonyl ((2'-cyanobiphenyl-4-yl)methyl) amino)-3-nitrobenzoate compound of formula-9.
Wherein, the suitable base, the suitable solvent and the suitable phase transfer catalyst are same as defined for step-e) of the first aspect of the present invention.
The compound of formula-9 obtained by the process disclosed in twenty fourth aspect of the present invention can be further converted to compound of formula- 1 according to the process disclosed in any of the prior known processes or by the process as disclosed above.
The compound of general formula-23 used in twenty third aspect of the present invention and the compound of general formula-24 used in twenty fourth aspect of the present invention can be synthesized by reacting the corresponding hydroxy compounds with a suitable alkyl or aryl sulfonyl halides or anhydrides or with a suitable alkyl or aryl sulfonic acids in a suitable solvent. The twenty fifth aspect of the present invention provides a novel process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3 -yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula- 1 and its potassium salt compound of formula- 1 a, comprising of;
a) Reacting the 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of formula- 16 with di-tert-butyl dicarbonate (DIBOC) in presence of a suitable base in a suitable solvent to provide l-((2'-(N-(tert- butoxycarbonyl)-N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-2-ethoxy-lH- benzo[d]imidazole-7-carboxylic acid compound of formula- 19a,
b) reacting the compound of formula- 19a with compound of general formula- 15 in presence of a suitable base in a suitable solvent, optionally in presence of a suitable phase transfer catalyst or suitable catalyst or a suitable condensing agent to provide (5-methyl-2-oxo-l,3- dioxol-4-yl)methyl l-((2'-(N-(tert-butoxycarbonyl)-N'-hydroxycarbamimidoyl)biphenyl-4- yl)methyl)-2-ethoxy- 1 H-benzo[d]imidazole-7-carboxylate compound of formula-20a, c) cyclizing the compound of formula-20a in presence or absence of a suitable catalyst in a suitable solvent to provide (5-methyl-2:oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo- 4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula- 1,
d) treating the compound of formula- 1 with a suitable potassium source in a suitable solvent to provide its potassium salt compound of formula- 1 a.
Wherein, in step-a) the suitable base is selected from organic and inorganic bases; and the suitable solvent is selected from nitrile solvents, chloro solvents, polar solvents, polar-aprotic solvents or mixtures thereof;
In step-b) the suitable base, the suitable solvent, the suitable phase transfer catalyst, suitable catalyst and the suitable condensing agent are same as defined in step-m) of the first aspect of the present invention;
In step-c) the suitable catalyst is selected from organic acids such as acetic acid, citric acid, formic acid, trifluoroacetic acid, methane sulfonic acid, ethane sulfonic acid, toluene sulfonic acid, benzene sulfonic acid, trifluoromethane sulfonic acid,v oxalic acid; or inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, carbonic acid, formic acid; organic and inorganic bases;
The suitable solvent is selected from alcoholic solvents (or) alcoholic solvents in combination with chloro solvents, ether solvents, ester solvents, alcoholic solvents, polar solvents, ketone solvents, nitrile solvents, polar-aprotic solvents, hydrocarbon solvents or mixtures thereof;
In step-d) the suitable potassium source and the suitable solvent are same as defined for step-n) of the first aspect of the present invention. The twenty sixth aspect of the present invention provides a novel process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula- 1, comprising of;
a) Reacting the 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-l H- benzo[d]imidazole-7-carboxylic acid compound of formula- 16 with N,N-carbonyl diimidazole (CDI) in presence or absence of a suitable base in a suitable solvent to provide 2- ethoxy- 1 -((2'-(N'-hydroxy-N-( 1 H-imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl) methyl)- lH-benzo[d]imidazole-7-carboxylic acid compound of formula-25,
Figure imgf000048_0001
Formula-25
b) reacting the compound of formula-25 with compound of general formula- 15 in presence of a suitable base in a suitable solvent, optionally in presence of a suitable phase transfer catalyst, suitable catalyst or a suitable condensing agent to provide (5-methyl-2-oxo-l,3-dioxol-4- yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}- lH-benzimidazole-7-carboxylate compound of formula- 1.
Wherein, in step-a) the suitable base and the suitable solvent are same as defined in step-j) of the first aspect of the present invention; In step-b) the suitable base, the suitable solvent, the suitable catalyst, the suitable condensing agent and the suitable phase transfer catalyst are same as defined in step-m) of the first aspect of the present invention.
A preferred embodiment of the twenty sixth aspect of the present invention provides a process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-{[2'-(5-oxo- 4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula- 1, comprising of;
a) Reacting the 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of formula- 16 with N,N-carbonyl diimidazole (CDI) in presence or absence of a suitable base in a suitable solvent to provide 2-ethoxy- 1 -((2'-(N'-hydroxy-N-( 1 H-imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl) methyl)- lH-benzo[d]imidazole-7-carboxylic acid compound of formula-25,
b) reacting the 2-ethoxy- l-((2'-(N'-hydroxy-N-(l H-imidazole- l-carbonyl)carbamimidoyl) biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylic acid compound of formula-25 with 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one compound of formula- 15a in presence of a suitable base in a suitable solvent optionally in presence of a suitable phase transfer catalyst to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-((2'-(N'-hydroxy-N-(lH- imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole-7- carboxylate compound of formula- 18,
c) isolating the compound of formula- 18 as a solid,
d) optionally purifying the compound of formula- 18 from a suitable solvent,
e) heating the compound of formula- 18 in presence of a suitable solvent at a suitable temperature to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-{[2'-(5-oxo-4,5- dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate of formula- 1.
The twenty seventh aspect of the present invention provides a novel process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-{[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula- 1, comprising of; a) Reacting the 2-ethoxy-l-((2'-(TSI'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d] imidazole-7-carboxylic acid compound of formula- 16 with a Ν,Ν-carbonyldiimidazole (CDI) in presence or absence of a suitable base in a suitable solvent to provide N-((4'-((2-ethoxy-7- ( 1H- imidazole- 1 -carbonyl)- lH-benzo[d]imidazol- 1 -yl)methyl)biphenyl-2-yl)
(hydro xyimino)methyl)- 1 H-imidazole- 1 -carboxamide compound of formula-26,
Figure imgf000050_0001
Formula-26
b) reacting the compound of formula-26 with 4-(hydroxymethyl)-5-methyl-l,3-dioxol-2-one compound of formula- 15c in presence of a suitable base in a suitable solvent to provide (5-methyl-2-oxo- 1 ,3 -dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4- oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1.
Wherein, in step-a) and step-b) the suitable base is selected from organic and inorganic bases; the suitable solvent is selected from ester solvents, ether solvents, chloro solvents, nitrile solvents, polar solvents, ketone solvents, polar-aprotic solvents, hydrocarbon solvents, alcoholic solvents or mixtures thereof.
The compound of formula-26 obtained in step-a) of the twenty seventh aspect of the present invention can be optionally converted into compound of formula-25 by treating it with suitable aqueous inorganic base.
In the present invention, the compound of formula-25 and compound of formula-26 are isolated in the form of solids, and the obtained solids are further utilized for the preparation of highly pure (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-{[2'-(5-oxo-4,5-dihydro-l, 2,4- oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1 and its potassium salt compound of formula- 1 a. The twenty eighth aspect of the present invention provides novel intermediate compounds, which are useful in the preparation of (5-methyl-2-oxo-l ,3-dioxol-4-yl)methyl 2- ethoxy- 1 - { [2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H- benzimidazole-7-carboxylate compound of formula- 1 as well as its pharmaceutically acceptable salts, preferably potassium salt.
The said novel intermediate compounds are represented by the below mentioned
Figure imgf000051_0001
Wherein 'P' represents amine protecting group as defined above. The PXRD analysis of the crystalline and amorphous compounds of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A0 and continuous scan speed of 0.03°/min.
Differential scanning calorimetric (DSC) analysis was performed with Q10 V9.6 Build 290 calorimeter. Samples of about 2 to 3 milligrams held in a closed pan were analyzed at a heating rate of 10° per minute.
The particle size distribution of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'- (5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - lH-benzimidazole-7- carboxylate potassium salt compound of formula- la of the present invention is measured using Malvern Mastersizer 2000 instrument.
The 2-ethoxy- 1 -((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H- benzimidazole-7-carboxylic acid compound of formula- 16 was analyzed by HPLC under the following conditions;
Apparatus: A liquid chromatographic system equipped with variable wavelength UV-detector and integrator; Column: Kromasil 100-5C18 250x4.6mm, 5μηι or equivalent; Flow rate: 1.0 mL/min; Wavelength: 210 nm; Column temperature: 40°C; Injection volume: 5 μί; Run time: 38 min; Elution: gradient; Buffer: Transfer accurately 1 mL of orthophosphoric acid (85%) in 1000 mL of Milli-Q- water and filter through 0.22μιη Nylon membrane filter paper; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile: Water (90: 10, v/v); Diluent: Acetonitrile: water (80:20, v/v).
The 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} -lH- benzimidazole-7-carboxylic acid compound of formula-2 was analyzed by HPLC under the following conditions;
Apparatus: A liquid chromatographic system equipped with variable wavelength UV-detector and integrator; Column: Kromasil 100-5C18 250x4.6mm, 5μηι or equivalent; Flow rate: 1.0 mL/min; Wavelength: 210 nm; Column temperature: 35°C; Injection volume: 5 μί; Run time: 42 min; Elution: gradient; Buffer: Weigh accurately about 2.0 gm of 1 -octane sulfonic acid sodium salt anhydrous and add 2 mL of ortho phosphoric acid (85%) in 1000 mL of Milli-Q- water. Adjust the pH to 3.0 with dil.NaOH and filter through 0.45 μη Nylon membrane filter paper; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile: Buffer (70:30, v/v); Diluent: Methanol.
(5-methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4- oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate and its potassium salt were analyzed by HPLC under the following conditions;
Apparatus: A liquid chromatographic system equipped with variable wavelength UV-detector and integrator; Column: Cosmicsil column, 150x4.6 mm, 5.0 μιη or equivalent; Flow rate: 1.5 mL/min; Wavelength: 220 nm; Column temperature: 40°C; Injection volume: 10 μί; Run time: 33 min; Diluent: acetonitrile:buffer (80:20, v/v); Elution: gradient; Buffer: Weigh accurately 1.36 gm of potassium dihydrogen orthophosphate into 1000 ml of milli-Q-water. Adjust the pH to 2.8 with diluted ortho phosphoric acid and filtered the solution through 0.22 μηι Nylon membrane filter paper; Mobile phase-A: Buffer; Mobile phase-B: acetonitrile: water (90: 10 v/v); Auto sampler temperature: 5°C.
(5-Methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4- oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium ' salt compound of formula- la produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball mills, roller and hammer mills and jet mills. Milling or micronization may be performed before drying or after the completion of drying of the product.
The present invention is schematically represented as follows. Scheme-1:
Figure imgf000054_0001
Scheme-2:
Figure imgf000055_0001
Azilsartan medoxomil potassium Formula-la
Figure imgf000056_0001
Scheme-4:
Figure imgf000056_0002
Scheme-5:
Figure imgf000057_0001
Formula-7
Formula-9
Scheme-6:
Figure imgf000057_0002
Formula-19a
Figure imgf000057_0003
Azilsartan medoxomil Formula-20a Formula-1
a) cyclization agent b) deprotection
Azilsartan medoxomil Formula-1
Figure imgf000057_0004
Azilsartan medoxomil potassium
Formula-la Scheme-7:
Sc
Figure imgf000058_0001
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples:
Example-1: Preparation of 2-(methoxycarbonyl)-6-nitro benzoic acid (FormuIa-4)
Slowly added thionyl chloride (340 gm) to a pre-cooled solution of 3-nitro phthalic acid compound of formula-3 (400 gm) in methanol (600 ml) at 10-15°C and stirred the reaction mixture for 15 min at the same temperature. Heated the reaction mixture to reflux temperature and stirred for 5 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 0-5°C. Water was slowly added to the reaction mixture at 0-5°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 410.0 gm.
Example-2: Preparation of methyl 2-(chlorocarbonyl)-3-nitrobenzoate (Formula-5)
Thionyl chloride (98 gm) was slowly added to a pre-cooled mixture of dichloromethane (500 ml), 2-(methoxycarbonyl)-6-nitro benzoic acid compound of formula-4 (100 gm) and N,N- dimethyl formamide (10 ml) at 15-20°C and stirred for 30 min at the same temperature. Heated the reaction mixture to reflux temperature and stirred for 4 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 0-5°C and adjusted the pH of the reaction mixture to 9 with 20% sodium carbonate solution at the same temperature. Raised the temperature of the reaction mixture to 15-20°C. Both the organic layer and aqueous layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers, washed with water and dried over sodium sulfate. The resulting organic layer containing methyl 2-(chlorocarbonyl)-3-nitrobenzoate was utilized in the next step without isolating the compound from the reaction mixture.
Example-3: Preparation of methyl 2-(azidocarbonyl)-3-nitrobenzoate (Formula-6)
The organic layer containing methyl 2-(chlorocarbonyl)-3-nitrobenzoate compound of formula-5 obtained in example-2 was added to a pre-cooled mixture of sodium azide (40 gm) and Ν,Ν-dimethyl formamide (160 ml) at 0-5°C and stirred for 60 min at the same temperature. After completion of the reaction, water was added to the reaction mixture at 0-5°C. Both the organic and aqueous layers were separated, the aqueous layer was extracted with dichloromethane. Combined the organic layers, washed with water and dried over sodium sulfate. The resulting organic layer containing methyl 2-(azidocarbonyl)-3-nitrobenzoate was utilized in the next step without isolating the compound from the reaction mixture. Example-4: Preparation of methyl 2-(tert-butoxycarbonylamino)-3-nitrobenzoate (Formula-7)
Tert.butanol (200 ml) was added to the organic layer containing methyl 2-(azidocarbonyl)-3-nitrobenzoate compound of formula-6 obtained in example-3 at 25-30°C and stirred for 15 min at the same temperature. Distilled off the solvent completely under atmospheric pressure at 90-95°C and stirred for 30 min at the same temperature. After the completion of the reaction, water was added at 90-95°C. Cooled the reaction mixture to 25-30°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 110.0 gm.
Example-5: Preparation of methyl 2-(tert-butoxycarbonyl ((2'-cyanobiphenyl-4-yl)methyl) amino)-3-nitrobenzoate (Formula-9)
A mixture of acetonitrile (500 ml), methyl 2-(tert-butoxycarbonylamino)-3-nitrobenzoate compound of formula-7 (100 gm), potassium carbonate (56 gm) and tetra butyl ammonium bromide (10.8 gm) was stirred for 45 min at 25-30°C. 4'-(bromomethyl)biphenyl-2-carbonitrile compound of formula-8 (91.9 gm) was added to the above reaction mixture . Heated the reaction mixture to reflux temperature and stirred for 4 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 40-45 °C. Filtered the unwanted compound and washed with acetonitrile at 40-45°C. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with isopropyl alcohol. 500 ml of isopropyl alcohol was added to the reaction mixture at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 45 min at the same temperature. Cooled the reaction mixture to 40-45 °C and stirred for 40 min at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and dried to get the title compound. Yield: 120.0 gm.
Example-6: Preparation of methyl 2-((2'-cyanobiphenyl-4-yl)methyIamino)-3-nitro benzoate (Formula-10)
Trifluoroacetic acid (292.6 ml) was slowly added to a mixture of dichloromethane (200 ml) and methyl 2-(tert-butoxycarbonyl((2'-cyanobiphenyl-4-yl)methyl)amino)-3- nitrobenzoate compound of formula-9 (100.0 gm) at 25-30°C and stirred for 60 min at the same temperature. After completion of the reaction, distilled off the solvent completely under reduced pressure at below 50°C. Cooled the reaction mixture to 25-30°C, ethyl acetate (400 ml) was added and stirred for 30 min at the same temperature. Filtered the precipitated solid and washed with ethyl acetate. To the wet compound, ethyl acetate (400 ml) was added at 25-30°C and stirred for 30 min at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 75.0 gm.
Example-7: Preparation of methyl 3-amino-2-((2'-cyanobiphenyl-4-yl)methylamino) benzoate (Formula-11)
Raney-Ni (22.62 gm) was added to a mixture of methyl 2-((2'-cyanobiphenyl-4-yl) methylamino)-3-nitrobenzoate compound of formula- 10 (50 gm) and ethyl acetate (450 ml) at 25-30°C. The reaction mixture was hydrogenated for 2 hrs under 2.0-3.0 Kg/cm2 of hydrogen gas pressure at 25-30°C. After completion of the reaction, filtered the reaction mixture and washed with ethyl acetate. Distilled off the solvent completely from the filtrate under reduced pressure and the resulting reaction mixture containing methyl 3-amino-2-((2'-cyanobiphenyl-4- yl)methylamino)benzoate was utilized in the next step without isolating the compound from the reaction mixture.
Example-8: Preparation of methyl l-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-lH- benzimidazoIe-7-carboxylate (Formula-12)
Acetic acid (28.7 gm) followed by tetraethyl orthocarbonate (30.4 gm) were slowly added to the reaction mixture obtained in example-7 at 25-30°C and stirred for 2 hrs at the same temperature. After completion of the reaction, water was added to. the reaction mixture at 25- 30°C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 50.0 gm. Example-9: Purification of methyl l-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-lH- benzimidazole-7-carboxylate (Formula-12)
A mixture of ethyl acetate (350 ml) and methyl l-((2'-cyanobiphenyl-4-yl)methyl)-2- ethoxy-lH-benzimidazole-7-carboxylate (100 gm) was heated to reflux and stirred for 30 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the pure title compound. Yield: 85.0 gm. Example-10: Preparation of methyl 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4- yI)methyl)-lH-benzimidazole-7-carboxylate (FormuIa-13)
A mixture of dimethyl sulfoxide (750 ml) and hydroxylamine hydrochloride (216 gm) was stirred for 15 min at 25-30°C. A solution of triethyl amine (314 gm) in tetrahydrofuran (900 ml) was slowly added to the above reaction mixture at 35-40°C and stirred for 60 min at the same temperature. Filtered the precipitated unwanted solid and washed with tetrahydrofuran. Distilled off the solvent from the filtrate under reduced pressure. To the obtained reaction mixture, methyl 1 -((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy- 1 H-benzimidazole-7-carboxylate compound of formual-12 (100 gm) followed by triethylamine (62 gm) were added at 40-45°C. Heated the reaction mixture to 65-70°C and stirred for 18 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C. The resulting reaction mixture was slowly added to water at 25-30°C and stirred for 1 hr at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound.
Yield: 95.0 gm.
Example-11: Preparation of methyl 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazoI-3-yl) biphenyl-4-yl)methyl)-lH-benzimidazole-7-carboxylate (Fromula-14)
A mixture of tetrahydrofuran (380 ml), methyl 2-ethoxy-l-((2'-(N'-hydroxy carbamimidoyl)biphenyl-4-yl)methyl)-lH-benzimidazole-7-carboxylate compound of formula- 13 (100 gm) and triethyl amine (24 gm) was stirred for 15 min at 25-30°C. Cooled the reaction mixture to 0-5°C. Slowly added ethyl chloroformate (21.5 gm) to the reaction mixture at 0-5°C and stirred for 60 min at the same temperature. After completion of the reaction, filtered the precipitated unwanted solid and washed with tetrahydrofuran. Distilled off the solvent from the filtrate under reduced pressure. Toluene (300 ml) was added to the obtained residue at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 12 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 90 min at the same temperature. Further cooled the reaction mixture to 0-5°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with toluene and dried to get the title compound.
Yield: 65.0gm; Purity by HPLC: 91.60%
Example-12: Purification of methyl 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyI-4-yl)methyl)-lH-benzimidazole-7-carboxylate (Formula-14) A mixture of methanol (900 ml) and methyl 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro- 1 ,2,4- oxadiazol-3-yl)biphenyl-4-yl)methyl)-lH-benzimidazole-7-carboxylate compound of formula-14 (60 gm) was heated to reflux temperature and stirred for 45 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 45 min at the same temperature. Further cooled the obtained reaction mixture to 0-5 °C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the pure title compound.
Yield: 45.0 gm; Purity by HPLC: 98.60%
Example-13: Preparation of 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid (Formula-2)
A solution of lithium hydroxide (16.5 gm) in water (330 ml) was slowly added to a mixture of methanol (1650 ml) and methyl 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol- 3-yl)biphenyl-4-yl)methyl)-lH-benzimidazole-7-carboxylate compound of formula-14 (55 gm) at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 4 hrs at the same temperature. After completion of the reaction, the solvent was distilled off from the reaction mixture under reduced pressure. Carbon (5 gm) was added to the obtained compound at 25-30°C and stirred for 15 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with water. Adjusted the pH of the filtrate to 3.0 with dil.HCl at 25-30°C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. The PX D of the obtained compound is shown in figure- 1.
Yield: 52.0 gm.
Example-14: Preparation of disodium salt of 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)biphenyl-4-yl] methyl}-lH-benzimidazole-7-carboxylic acid (Formula-2a) Ethanol (285 ml) and 28% sodium methoxide solution in methanol (25 gm) were'charged into a clean and dry RBF at 25-30°C. Distilled off the solvent completely under reduced pressure at below 60°C and cooled the reaction mixture to 25-30°C. Ethanol (285 ml) and 2-ethoxy-l- {[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7- carboxylic acid compound of formula-2 (30 gm) were added to the reaction mixture at 25-30°C and stirred for 15 min at 40-45°C. Distilled off the solvent completely under reduced pressure. Cooled the reaction mixture to 25-30°C, ethanol (142 ml) was added and stirred for 15 min at 40-45°C. Distilled off the solvent completely from the reaction mixture under reduced pressure and the resulting reaction mixture containing disodium salt of 2-ethoxy-l-{[2'-(5-oxo-4,5- dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylic acid was utilized in the next step without isolating the compound from the reaction mixture. Example-15: Preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate (Formula-1)
A mixture of 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4- yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2 (50 gm), acetone (1000 ml), sodium bicarbonate (10 gm) and tetra butyl ammonium bromide (2.0 gm) was heated to 40- 45°C and stirred for 60 min at the same temperature. 4-(Chloromethyl)-5-methyl-l,3-dioxol-2- one compound of formula-15a (16.5 gm) was added to the reaction mixture at 40-45pC and stirred for 24 hrs at the same temperature. Sodium bicarbonate (5.0 gm) and 4-(chloromethyl)-5- methyl-l,3-dioxol-2-one compound of formula- 15a (8.0 gm) were added to the reaction mixture at 40-45°C and stirred for 24 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C and filtered. The filtrate was added to a pre-cooled mixture of water and sodium carbonate at 0-5°C. Ethyl acetate and vacuum salt were added to the reaction mixture at 0-5°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated, extracted the aqueous layer with ethyl acetate. Combined the organic layers, washed with brine solution followed by 1 % HC1 solution. The organic layer was dried over sodium sulfate. Carbon (5 gm) was added to the reaction mixture and stirred for 15 min. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. Distilled off the solvent completely under reduced pressure at below 50°C and cooled the residue to 25- 30°C. Ethyl acetate (60 ml) was added to the obtained residue at 25-30°C and stirred for 20 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. The PXRD of the obtained compound is shown in figure-2.
Yield: 18.0 gm; M.R: 167-171°C. Example-16: Preparation of amorphous form of (5-methyl-2-oxo-l,3-dioxoI-4-yl)methyI 2- ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH- benzimidazole-7-carboxylate (Formula-1) 4-(Chloromethyl)-5-methyl-l,3-dioxol-2-one compound of formula- 15a (16 gm) was slowly added to a pre-cooled solution of disodium salt of 2-ethoxy-l- {[2'-(5-oxo-4,5-dihydro- l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2a (32 gm) in N,N-dimethyl formamide (320 ml) at 0-5°C under N2 atmosphere and stirred for 60 hrs at the same temperature. After completion of the reaction, water, ethyl acetate followed by vacuum salt were slowly added to the reaction mixture at 0-10°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with ethyl acetate. Combined the organic layers and washed with brine solution followed by 1 % HC1 solution. Dried the organic layer over sodium sulfate and distilled off the solvent completely under reduced pressure. Acetone (100 ml) was added to the obtained residue at 25-30°C and stirred for 15 min at the same temperature. Carbon (1.0 gm) was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with acetone. Cooled the filtrate to 0-5°C, a solution of potassium 2-ethyl hexanoate (10 gm) in acetone (50 ml) was slowly added to the reaction mixture and stirred for 10 min at the same temperature. Slowly raised the temperature of the reaction mixture to 25-30°C and stirred for 45 min at the same temperature. Heated the reaction mixture to 40-45°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 60 min at the same temperature. Filtered the precipitated solid and washed with acetone. The obtained compound was slowly added to a pre-cooled mixture of water (80 ml) and acetic acid (0.9 gm) at 0-5°C and stirred for 2 hrs at the same temperature. Filtered the solid and washed with water. The obtained wet compound was added to acetone (40 ml) at 25-30°C and cooled the reaction mixture to 0-5°C. Water (40 ml), ethyl acetate (40 ml) followed by vacuum salt (40 gm) were slowly added to the reaction mixture and stirred for 15 min. Both the organic and aqueous layers were separated and extracted the aqueous layer with ethyl acetate. The combined organic layer was dried over sodium sulfate and distilled off the solvent completely under reduced pressure at below 50°C. Cooled the reaction mixture to 25- 30°C, cyclohexane (25 ml) was added and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with cyclohexane and then dried to get the title compound.
The PXRD of the obtained compound is shown in figure-4.
Yield: 5.5 gm; M.R: 68-77°C. Example-17: Preparation of potassium salt of (5-methyl-2-oxo-l,3-dioxoI-4-yI)methyl 2- ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH- benzimidazole-7-carboxylate (Formula-la)
A mixture of 10 gm of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-{[2'-(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1 obtained in example- 15 or example- 16 arid acetone (125 ml) was heated to 40-45°C and stirred for 15 min at the same temperature. Carbon (1.0 gm) was added to the reaction mixture at 40-45°C and stirred for 15 min at the same temperature. Filtered the reaction mixture through hyflow bed and washed with acetone. Cooled the filtrate to 0-5°C and a solution of potassium 2-ethyl hexanoate (3.2 gm) in ethyl acetate (35 ml) was slowly added to the filtrate and stirred for 90 min at the same temperature. Filtered the precipitated solid and washed with ethyl acetate to get the title compound. Yield: 7.5 gm; Purity by HPLC: 97.9%.
Example-18: Preparation of potassium salt of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2- ethoxy-l-{[2,-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyI-4-yl]methyl}-lH- benzimidazole-7-carboxylate (Formula-la)
Acetone (12.5 ml) and (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo- 4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula-1 (1.0 gm) were charged into a clean and dry RBF at 25-30°C. Cooled the reaction mixture to 0-5°C and a pre-cooled solution of potassium tert.butoxide (0.2 gm) in ethyl acetate (3.5 ml) was slowly added to the reaction mixture at the same temperature. Stirred the reaction mixture for 90 min at 0-5°C. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. The PXRD of the obtained compound is shown in figure-5. Yield: 0.6 gm.
Example-19: Preparation of potassium salt of (5-methyl-2-oxo-l,3-dioxoI-4-yl)methyl 2- ethoxy- 1- { [2 '-(5-oxo-4,5-dihy dro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl}- 1 H- benzimidazole-7-carboxylate (Formula-la)
Acetone (18 ml) and (5-methyl-2-oxo-l ,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula-1 (1.0 gm) were charged into a clean and dry RBF at 25-30°C. Cooled the reaction mixture to 0-5°C and a pre-cooled solution of potassium tert.butoxide (0.2 gm) in acetone (4 ml) was slowly added to the reaction mixture at the same temperature. Stirred the reaction mixture for 90 min at 0-5°C. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 0.62 gm. Example-20: Purification of (5-methyl-2-oxo-l,3-dioxoI-4-yl)methyI 2-ethoxy-l-{[2'-(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt (Formula-la)
A mixture of (5-methyl-2-oxo- l,3-dioxol-4-yl)methyl 2-ethoxy- l- {[2'-(5-oxo-4,5- dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} -lH-benzimidazole-7-carboxylate potassium salt compound of formula- la (8.0 gm) and ethyl acetate (40 ml) was heated to 40-45°C and stirred for 20 min at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 45 min at the same temperature. Filtered the compound, washed with ethyl acetate and dried to get the title compound. The PXRD of the obtained compound is shown in figure-5.
Yield: 7.0 gm; M.R: 209-213°C; Purity by HPLC: 99.85%.
Particle size distribution: D(0.1) is 1.21 μπι; D(0.5) is 4.67 μηι; D(0.9) is 262.83 μπι, D(4,3) is 70.37 μτη.
Example-21: Purification of (5-me thy l-2-oxo-l,3-dioxol-4-yl) methyl 2-ethoxy-l-{[2'-(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate potassium salt (Formula-la)
A mixture of (5-methyl-2-oxo- l,3-dioxol-4-yl)methyl 2-ethoxy-l- {[2'-(5-oxo-4,5- dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate potassium salt (8.0 gm) and methyl isobutyl ketone (43 ml) was heated to 40-45°C and stirred for 20 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 45 min at the same temperature. Filtered the compound, washed with methyl isobutyl ketone and dried to get the title compound. The PXRD of the obtained compound is shown in figure-5.
Yield: 6.9 gm; Purity by HPLC: 99.80%.
Example-22: Preparation of 2-(methoxycarbonyl)-6-nitro benzoic acid (Formula-4)
Cone, sulfuric acid (93 gm) was slowly added to a pre-cooled mixture of 3-nitro phthalic acid compound of formula-3 (100 gm) in methanol (200 ml) at 10-15°C. Heated the reaction mixture to 45-50°C and stirred for 20 hrs at the same temperature. After completion of the reaction, distilled off methanol completely from the reaction mixture under reduced pressure and co-distilled with toluene. Water and toluene were added to the reaction mixture at 25-30°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with water followed by toluene to get the title compound.
Yield: 95.0 gm; M.R: 155-160°C.
Example-23: Preparation of methyl 2-(chlorocarbonyI)-3-nitrobenzoate (Formula-5)
Thionyl chloride (97.8 gm) was slowly added to a pre-cooled mixture of 2- (methoxycarbonyl)-6-nitro benzoic acid compound of formula-4 (100 gm), dichloromethane (500 ml) and N,N-dimethylformamide (2.5 ml) at 10-15°C under nitrogen atmosphere. Heated the reaction mixture to 40-45°C and stirred for 7 hrs under nitrogen atmosphere at the same temperature. After completion of the reaction, the reaction mixture was added to ice-cooled water and stirred for 15 min at 10-15°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with 5% sodium carbonate solution. Distilled off the solvent completely from the organic layer and co-distilled with dichloromethane to get the title compound.
Example-24: Preparation of methyl 2-(tert-butoxycarbonylamino)-3-nitrobenzoate (Formula-7)
N,N-Dimethylformamide (100 ml) and tert.butanol (300 ml) were added to methyl 2-(chlorocarbonyl)-3-nitrobenzoate compound of formula-5 obtained in example-23 at 0-5°C and stirred for 20 min at the same temperature. Sodium azide (39.85 gm) was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 60 min at the same temperature. Further heated the reaction mixture to 55-60°C and stirred for 4 hrs at the same temperature. After completion of the reaction, water was added to the reaction mixture at 25-30°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid and washed with water. Cyclohexane (300 ml) was added to the obtained solid and the reaction mixture was heated to reflux temperature and stirred for 45 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 60 min at the same temperature. Filtered the solid and washed with cyclohexane to get the pure title compound. Yield: 100.0 gm; M.R: 106-108°C; Purity by HPLC: 91.58%.
The compound of formula-7 obtained above can be used as such or it can be purified by convention techniques to get pure compound of formula-7. Example-25: Preparation of methyl 2-(tert-butoxycarbonyl ((2'-cyanobiphenyl-4-yl) methyl)amino)-3-nitrobenzoate (Formula-9)
4'-(bromomethyl)biphenyl-2-carbonitrile compound of formula-8 (92 gm) was added to a mixture of methyl 2-(tert-butoxycarbonylamino)-3-nitrobenzoate compound of formula-7 (100 gm), acetone (600 ml), potassium carbonate (56 gm) and tetra butyl ammonium bromide (10.9 gm) at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 12 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C, filtered the reaction mixture and distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with methanol. 300 ml of methanol was added to the obtained compound at 25-30°C, heated the reaction mixture to reflux temperature and stirred for 30 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound. Yield: 148.0 gm; M.R: 140-150°C. Example-26: Preparation of methyl 2-((2'-cyanobiphenyl-4-yI)methylamino)-3-nitro benzoate (Formula-10)
Methanesulfonic acid (78.9 gm) was slowly added to a mixture of methyl 2-(tert- butoxycarbonyl((2'-cyanobiphenyl-4-yl)methyl)amino)-3-nitrobenzoate compound of formula-9 (100 gm) in dichloromethane (600 ml) at 25-30°C and stirred for 3 hrs at the same temperature. After completion of the reaction, the reaction mixture was added to cool water at 25-30°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with 5% sodium bicarbonate solution followed by water. Combined the organic layers and distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with methanol. 400 ml of methanol was added to the obtained compound at 25-30°C, heated the reaction mixture to 45-50°C and stirred for 30 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound. Yield: 75.0 gm; M.R: 135-145°C. ExampIe-27: Preparation of methyl 3-amino-2-((2'-cyanobiphenyl-4-yl)methyl amino)benzoate (Formula-11) Raney-Ni (50 gm) was added to a mixture of methyl 2-((2'-cyanobiphenyl-4-yl) methylamino)-3-nitrobenzoate compound of formula- 10 (100 gm) and ethyl acetate (1000 ml) at 25-30°C. The reaction mixture was hydrogenated for 2 hrs under 2-3 Kg/cm2 of hydrogen gas pressure at 25-30°C. After completion of the reaction, filtered the reaction mixture through hyflow bed and washed with ethyl acetate. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with methanol. Methanol (300 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 30 min at the same temperature. Cooled the reaction mixture to 10-15°C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound. Yield: 82.0 gm.
Example-28: Preparation of methyl l-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-lH- benzimidazole-7-carboxyIate (Formula-12)
Methyl 3-amino-2-((2'-cyanobiphenyl-4-yl)methylamino)benzoate compound of formula- 1 1 (82 gm) was added to acetic acid (225 ml) at 25-30°C and the reaction mixture was stirred for 10 min at the same temperature. Slowly added tetraethyl orthocarbonate (73 gm) to the reaction mixture at 25-30°C and stirred for 5 hrs at the same temperature. After completion of the reaction, water was added to the reaction mixture at 25-30°C and stirred for 60 min at the same temperature. Filtered the solid and washed with water to get the title compound.
Yield: 83.0 gm.
ExampIe-29: Purification of methyl l-((2'-cyanobiphenyl-4-yI)methyl)-2-ethoxy-lH- benzimidazole-7-carboxylate (Formula-12)
A mixture of methyl l-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-lH-benzimidazole-7- carboxylate compound of formula-12 (83 gm) and toluene (300 ml) was heated to 60-65°C and stirred the reaction mixture for 45 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 60 min at the same temperature. Filtered the precipitated solid and washed with toluene to get pure compound of formula-12.
Yield: 74.0 gm; M.R: 155-165°C; Purity by HPLC: 99.66%.
Example-30: Preparation of 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl) methyi)-lH-benzimidazole-7-carboxylic acid (Formula-16)
Hydroxylamine hydrochloride (127 gm) was added to a mixture of dimethyl sulfoxide (1000 ml), water (1000 ml) and sodium carbonate (193.5 gm) at 25-30°C and stirred for 15 min at the same temperature. Methyl l-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-lH-benzimidazole- 7-carboxylate compound of formula-12 (100 gm) was added to the reaction mixture at 25-30°C. Slowly heated the reaction mixture to 115-120°C and stirred for 7 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 10-15°C. Filtered the reaction mixture and washed the filtrate with ethyl acetate. Water and ethyl acetate were added to the reaction mixture at 25-30°C and cooled the reaction mixture to 10-15°C. Adjusted the pH of the reaction mixture to 7.5 using hydrochloric acid at 10-15°C and stirred for 3 hrs at the same temperature. Filtered the precipitated solid and washed with water to get title compound.
Yield: 95.0 gm; M.R: 200-205°C;
Purity by HPLC: 92.97%; Acid amide impurity: 1.65%.
Example-31: Purification of 2-ethoxy-l-((2'-(N,-hydroxycarbamimidoyl)biphenyl-4-yl) methyl)-lH-benzimidazole-7-carboxylic acid (Formula-16)
A mixture of 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzimidazole-7-carboxylic acid compound of formula-16 (100 gm) and methanol (500 ml) was heated to 45-50°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 45 min at the same temperature. Filtered the precipitated solid and washed with chilled methanol to get pure compound of formula-16.
Yield: 90.0 gm; Purity by HPLC: 98.01%; Acid amide impurity: 0.57%.
Example-32: Preparation of 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazoI-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid (Formula-2)
l,8-diazabicyclo[5.4.0]undec-7-ene (53 gm) and N,N-carbonyldiimidazole (75.5 gm) were added to a mixture of 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- lH-benzimidazole-7-carboxylic acid compound of formula-16 (100 gm) and dichloromethane (500 ml) at 25-30°C and stirred the reaction mixture for 6 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture. Water followed by aq.sodium hydroxide solution were added to the reaction mixture, heated the reaction mixture to 50-55°C and stirred for 3 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C and washed with dichloromethane. Dichloromethane was added to the reaction mixture and cooled to 10-15°C. Acidified the reaction mixture with hydrochloric acid at 10- 15°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid and washed with water to get the title compound.
Yield: 95.0 gm; M.R: 195-205°C; Purity by HPLC: 98.04%. ExampIe-33: Purification of 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid (Formula-2)
A mixture of 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4- yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2 (100 gm) and methanol (500 ml) was heated to reflux temperature and stirred the reaction mixture for 45 min at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get pure compound of formula-2. Yield: 95.0 gm; M.R: 200-205°C; Purity by HPLC: 99.15%.
ExampIe-34: Preparation of (5-methyI-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate (Formula-1)
A mixture of 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylic acid compound of formula-2 (100 gm), acetone (2000 ml), sodium bicarbonate (18.4 gm) and terra butyl ammonium bromide (4 gm) was heated to 40- 45°C and stirred the reaction mixture for 45 min at the same temperature. 4-(chloro methyl)-5- methyl-l,3-dioxol-2-one (32.5 gm) was added to the reaction mixture at 40-45°C and stirred for 24 hrs at the same temperature. Sodium bicarbonate (9.2 gm) and 4-(chloromethyl)-5-methyl- l,3-dioxol-2-one (16.3 gm) were added to the reaction mixture at 40-45°C and stirred for 24 hrs at the same temperature. After completion of the reaction, filtered the reaction mixture and the solvent was completely distilled off from the filtrate under reduced pressure. Ethyl acetate was added to the obtained compound. Cooled the reaction mixture to 5-10°C and water followed by sodium carbonate were added. Sodium chloride was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with 5% aqueous sodium chloride solution, 0.5% hydrochloric acid, water, 0.5% sodium bicarbonate solution followed by again with 5% sodium chloride solution. Distilled off the solvent completely form the organic layer under reduced pressure and co-distilled with acetonitrile. Acetonitrile (150 ml) was added to the obtained compound at 25-30°C and stirred for 30 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 45 min at the same temperature. Filtered the precipitated solid and washed with acetonitrile to get title compound; Yield: 40.0 gm. Example-35: Preparation of (5-rnethyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate using acetone as solvent (Formula-1)
p-Toluenesulfonyl chloride (46 gm), 4-dimethylaminopyridine (6.2 gm), potassium carbonate (45.5 gm) followed by 2-ethoxy-l- {[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl}- lH-benzimidazole-7-carboxylic acid compound of formula-2 (100 gm) were added to a pre-cooled mixture of 4-(hydroxymethyl)-5-methyl-l,3-dioxol-2-one (40 gm) and acetone (1000 ml) at 0-5°C. Raised the temperature of the reaction mixture to 10-15°C and stirred for 6 hrs at the same temperature. After completion of the reaction, water was added to the reaction mixture. Extracted the reaction mixture with ethyl acetate and the organic layer was washed with water, 2% hydrochloric acid, 2% sodium bicarbonate solution followed by again with water. Distilled off the solvent completely from the organic layer and co-distilled with cyclohexane. 300 ml of cyclohexane was added to the obtained compound. Heated the reaction mixture to 50-55°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 45 min at the same temperature. Filtered the solid and washed with cyclohexane to get the title compound.
Yield: 95.0 gm; Purity by HPLC: 98.08%'; Acid impurity: 0.3%; Hydroxy impurity: 0.06%; Amide impurity: 0.40%; Dimer impurity: 0.12%; Unknown impurity: 0.58%.
Example-36: Purification of (5-methyl-2-oxo-l,3-dioxoI-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate (Formula-1)
A mixture of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5- dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula-1 (95 gm) and acetonitrile (500 ml) was heated to reflux temperature and stirred for 30 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with acetonitrile and dried to get pure compound of formula-1. Yield: 85.0 gm; Purity by HPLC: 98.88%; Acid impurity: 0.14%; Hydroxy impurity: 0.03%; Amide impurity: 0.12%; Dimer impurity: 0.1 1%; Unknown impurity: 0.26%.
Example-37: Preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate using methyl isobutyl ketone as solvent (Formula-1)
p-Toluenesulfonyl chloride (46 gm), 4-dimethylaminopyridine (6.0 gm), potassium carbonate (39.5 gm) followed by 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2 (100 gm) were added to a pre-cooled mixture of 4-(hydroxymethyl)-5-methyl-l,3-dioxol-2-one (34.2 gm) and methyl isobutyl ketone (1000 ml) at 0-5°C and stirred the reaction mixture for 15 min at the same temperature. Heated the reaction mixture to 40-45°C and stirred for 18 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 0-5°C, filtered the reaction mixture and washed with methyl isobutyl ketone. Acetone and water were added to the obtained wet compound at 25-30°C and stirred for 15 min at the same temperature. Extracted the reaction mixture with ethyl acetate and the organic layer was washed with 10% sodium chloride solution, aqueous hydrochloric acid solution, water, sodium bicarbonate solution followed by again with 10% sodium chloride solution. Dried the organic layer over sodium sulfate and distilled off the solvent completely from the organic layer under reduced pressure. Ethyl acetate (300 ml) was added to the obtained compound. Heated the reaction mixture to 45-50°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 45 min at the same temperature. Filtered the precipitated solid and washed with ethyl acetate to get title compound. Yield: 75.0 gm; Purity by HPLC: 98.96%. Example-38: Preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyI-4-yl]methyl}-lH-benzimidazole-7-carboxylate using mixture of methyl isobutyl ketone/ethyl acetate as solvent (Formula-1)
p-Toluenesulfonyl chloride (46 gm), 4-dimethylamino pyridine (6.0 gm), potassium carbonate (39.5 gm) followed by 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2 (100 gm) were added to a pre-cooled mixture of 4-(hydroxymethyl)-5-methyl-l,3-dioxol-2-one (34.2 gm), methyl isobutyl ketone (1000 ml) and ethyl acetate (100 ml) at 0-5°C and stirred the reaction mixture for 15 min at the same temperature. Heated the reaction mixture to 40-45°C and stirred for 18 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 0-5°C, filtered the compound and washed with methyl isobutyl ketone. Acetone (750 ml) and water (500 ml) were added to the obtained wet compound at 25-30°C and stirred for 15 min at the same temperature. Extracted the reaction mixture with ethyl acetate and the organic layer was washed with 10% sodium chloride solution, 1% hydrochloric acid solution, water, 1% sodium bicarbonate solution followed by again with 10% sodium chloride solution. Dried the organic layer over sodium sulfate followed by distilled off the solvent completely from the organic layer under reduced pressure. Ethyl acetate (300 ml) was added to the obtained compound, heated the reaction mixture to 40-45°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound.
Yield: 70.0 gm; Purity by HPLC: 99.22%. Example-39: Preparation of potassium salt of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2- ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yI)biphenyl-4-yl]methyl}-lH- benzimidazole-7-carboxyIate (Formula-la)
A mixture of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5- dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1 (100 gm) and acetone (1500 ml) was heated to 45-50°C and stirred the reaction mixture for 30 min at the same temperature. Carbon (5 gm) was added to the reaction mixture at 45-50°C and stirred for 15 min at the same temperature. Filtered the reaction mixture through hyflow bed and cooled the filtrate to 0-5°C. A solution of potassium 2-ethyl hexanoate (32 gm) in ethyl acetate (500 ml) was added to the filtrate at 0-5°C and stirred for 90 min at the same temperature. Filtered the precipitated solid and washed with ethyl acetate to get the title compound. Yield: 80.0 gm; Purity by HPLC: 97.9%.
Example-40: Purification of potassium salt of (5-methyl-2-oxo-l,3-dioxoI-4-yI)methyI 2- ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yI)biphenyl-4-yl]methyl}-lH- benzimidazole-7-carboxylate (Formula-la)
A mixture of potassium salt of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'- (5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7- carboxylate compound of formula- la (80 gm) and ethyl acetate (400 ml) was heated to 45-50°C and stirred the reaction mixture for 20 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 45 min at the same temperature. Filtered the solid and washed with ethyl acetate to get pure compound of formula- 1 a.
Yield: 70.0 gm; M.R: 209-213°C; Purity by HPLC: 99.85%.
Example-41: Preparation of (5-methyl-2-oxo-l,3-dioxol-4-yI)methyl 2-ethoxy-l-((2'-(N'- hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate
(FormuIa-17)
4-(Chloromethyl)-5-methyl-l,3-dioxol-2-one compound of formula-15a (55.5 gm) was added to a mixture of 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of formula-16 (100 gm), tetra butyl ammonium bromide (15 gm), tetrahydrofuran (750 ml) and sodium carbonate (32 gm) at 25-30°C and stirred the reaction mixture for 4 hrs at the same temperature. Water followed by ethyl acetate was added to the reaction mixture. Both the aqueous and organic layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with 5% sodium bicarbonate solution followed by 5% sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure. Ethyl acetate (300 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 25-30°C, cyclohexane (200 ml) was added and stirred the reaction mixture for 45 min at the same temperature. Filtered the precipitated solid and dried to get the title compound as a crystalline solid. The PXRD pattern of the obtained compound is shown in figure-6.
Yield: 90.0 gm; MR: 170-175°C.
Example-42: Preparation of (5-methyl-2-oxo-l,3-dioxoI-4-yI)methyl 2-ethoxy-l-{[2'-(5-oxo-
4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxyIate
(Formula-1)
750 ml of tetrahydrofuran was added to (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2- ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7- carboxylate compound of formula- 17 (100 gm) and cooled the reaction mixture to 5-10°C. N,N- carbonyldiimidazole (90 gm) and 4-dimethylaminopyridine (6.0 gm) were added to the reaction mixture at 5-10°C and stirred the reaction mixture for 6 hrs at the same temperature. Water (1250 ml) was added to the reaction mixture at 5-10°C and stirred for 45 min at the same temperature. Filtered the precipitated (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'- (N'-hydroxy-N-( 1 H-iniidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d] imidazole-7-carboxylate compound of formula- 18 and washed with water. Dissolved the above wet compound in dichloromethane (750 ml) and the obtained organic layer was washed with water. Distilled off the solvent completely from the organic layer and tetrahydrofuran (500 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 70-75°C and stirred for 14 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and 5% aqueous sodium chloride solution followed by ethyl acetate were added. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure. Ethyl acetate (200 ml) was added to the obtained compound at 25-30°C, heated the reaction mixture to 50-55°C and stirred the reaction mixture for 45 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 45 min at the same temperature. Filtered the precipitated solid and dried to get the title compound. The PXRD pattern of the obtained compound is shown in figure-8.
Yield: 90.0 gm.
Example-43: Preparation of (5-methyI-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'-(N'- hydroxy-N-(lH-imidazole-l-carbohyl)carbamimidoyI)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylate (Formula-18)
750 ml of tetrahydrofuran was added to (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2- ethoxy- 1 -((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole-7- carboxylate compound of formula- 17 (100 gm) and cooled the reaction mixture to 5-10°C. N,N- carbonyldiimidazole (90 gm) and 4-dimethylaminopyridine (6.0 gm) were added to the reaction mixture at 5-10°C and stirred the reaction mixture for 6 hrs at the same temperature. Water (1250 ml) was added to the reaction mixture at 5-10°C and stirred for 45 min at the same temperature. Filtered the precipitated solid and dried to get the title compound.
The PXRD pattern of the obtained compound is shown in figure-7.
Yield: 110.0 gm; M.R: 125-130°C. Example-44: Purification of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-etho -l-((2'·'(N,- hydroxy-N-(lH-imidazole-l-carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylate (Formula-18)
Dissolved the (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'-(N'-hydroxy-N- (lH-imidazole-l-carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7- carboxylate compound of formula-18 (100 gm) in dichloromethane (750 ml) at 25-30°C. Water (250 ml) was added to the reaction mixture at 25-30°C and stirred the reaction mixture for 10 min at the same temperature. Separated the both aqueous and organic layers. Distilled off the solvent completely from the organic layer to get the pure title compound.
Yield: 94.0 gm.
Example-45: Preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-
4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate
(Formula-1)
Tetrahydrofuran (500 ml) was added to (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2- ethoxy- 1 -((2'-(N'-hydroxy-N-( 1 H-imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)- lH-benzo[d]imidazole-7-carboxylate compound of formula-18 (50 gm) at 25-30°C. Heated the reaction mixture to 70-75°C and stirred for 14 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and 5% aqueous sodium chloride solution followed by ethyl acetate were added. Both the organic and aqueous layers were separated, the organic layer was washed with 5% aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure. Ethyl acetate (200 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 45 min at the same temperature. Filtered the precipitated solid and dried to get pure title compound.
Yield: 41.0 gm.
Example-46: Preparation of potassium salt of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2- ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH- benzimidazole-7-carboxylate (Formula-la)
A mixture of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5- dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula- 1 (100 gm) and acetone (1500 ml) was heated to 45-50°C and stirred the reaction mixture for 30 min at the same temperature. Carbon (5 gm) was added to the reaction mixture at 45-50°C and stirred for 15 min at the same temperature. Filtered the reaction mixture through hyflow bed and cooled the filtrate to 0-5°C. A solution of potassium 2-ethyl hexanoate (32 gm) in ethyl acetate (500 ml) was added to the filtrate at 0-5°C and stirred for 90 min at the same temperature. Filtered the precipitated solid and washed with ethyl acetate to get the title compound. Yield: 80.0 gm; Purity by HPLC: 99.7%.
ExampIe-47: Preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'-(N'- hydroxycarbamimidoyI)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxyIate (Formula-17)
p-Toluenesulfonyl chloride (48.2 gm), 4-dimethylaminopyridine (6.2 gm), potassium carbonate (41.5 gm) followed by 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4- yl)methyl)-lH-benzo[d]imidazole-7-carboxylic acid compound of formula- 16 (100 gm) were added to a pre-cooled mixture of 4-(hydroxymethyl)-5-methyl-l,3-dioxol-2-one compound of formula-15c (35.9 gm) and methyl isobutyl ketone (1000 ml) at 0-5°C and stirred for 15 min at the same temperature. Heated the reaction mixture 40-45°C and stirred for 18 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 0-5°C, filtered the reaction mixture and washed the filtrate with methyl isobutyl ketone. Acetone (750 ml) and water (500 ml) were added to the obtained wet compound at 25-30°C and stirred for 15 min at the same temperature. Extracted the reaction mixture with ethyl acetate and the organic layer was washed with 10% sodium chloride solution, aqueous hydrochloric acid solution, water, sodium bicarbonate solution followed by again with 10% sodium chloride solution. Dried the organic layer over sodium sulfate and distilled off the solvent completely from the organic layer under reduced pressure. Ethyl acetate (300 ml) was added to the obtained compound. Heated the reaction mixture to 45-50°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 45 min at the same temperature. Filtered the precipitated solid and washed with ethyl acetate to get title compound. Yield: 75.0 gm. ExampIe-48: Preparation of l-((2'-(N-(tert-butoxycarbonyI)-N'-hydroxy carbamimidoyl) biphenyl-4-yl)methyI)-2-ethoxy-lH-benzo[d]imidazole-7-carboxylic acid (Formula-19a) Di-tert-butyl dicarbonate (76.05 gm) was added to a mixture of 2-ethoxy-l-((2'-(N'- hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- lH-benzimidazole-7-carboxylic acid compound of formul-16 (100 gm), dichloromethane (1000 ml) and triethylamine (46.92 gm) at 25-30°C and stirred the reaction mixture for 9 hrs at the same temperature. After completion of the reaction, water was added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with 1% acetic acid solution followed by with water. Distilled off the organic layer completely under reduced pressure and co-distilled with cyclohexane. Cyclohexane (300 ml) was added to the obtained compound and stirred the reaction mixture for 45 min at 50-55°C. Cooled the reaction mixture to 25-30°C and stirred for 45 min at same temperature. Filter the solid, washed with cyclohexane and dried to get the title compound.
Yield: 120.0 gm; M.R: 115-120°C.
Example-49: Preparation of (5-methyl-2-oxo-l,3-dioxoI-4-yI)methyl l-((2'-(N-(tert- butoxycarbonyl)-N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyI)-2-ethoxy-lH- benzo[d]imidazoIe-7-carboxylate (Formula-20a)
4-(chloromethyl)-5-methyl-l,3-dioxol-2-one compound of formula-15a (28 gm) was added to a mixture of l-((2'-(N-(tert-butoxycarbonyl)-N'-hydroxycarbamimidoyl)biphenyl-4-yl) methyl)-2-ethoxy-lH-benzo[d]imidazole-7-carboxylic acid compound of formula- 19a (100 gm), methyl isobutyl ketone (1000 ml) and sodium bicarbonate (15.83 gm) at 25-30°C. Heated the reaction mixture to 45-50°C and stirred for 6 hrs at same temperature. Cooled the reaction mixture to 25-30°C and stirred for 45 min at the same temperature. Filtered the reaction mixture and washed the filtrate with toluene followed by water. Distilled off the solvent completely from the organic layer under reduced pressure. Toluene (300 ml) was added to the reaction mixture at 25-30°C, heated the reaction mixture to 50-55°C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 25-30°C, cyclohexane (450 ml) was added and stirred the reaction mixture for 45 min at the same temperature. Filtered the precipitated solid, washed with cyclohexane and dried to get the titled compound; Yield: 80.0 gm. Example-50: Preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'-(N'- hydroxycarbamimidoyl)biphenyl-4-yl)methyI)-lH-benzo[d]imidazole-7-carboxylate
(Formula-17) Trifluoroacetic acid (196.84 gm) was added to a mixture of (5-methyl-2-oxo-l,3-dioxol- 4-yl)methyl 1 -((2'-(N-(tert-butoxycarbonyl)-N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-2- ethoxy-lH-benzo[d]imidazole-7-carboxylate compound of formula-20a (100 gm) in dichloromethane (1000 ml) at 25-30°C and stirred the reaction mixture for 45 min at the same temperature. Chilled water (300 ml) was added to the reaction mixture and adjusted the pH of the reaction mixture to 7-8 using 10% sodium bicarbonate solution. Both the organic and aqueous layers were separated, extracted the aqueous layer with dichloromethane. Combined the organic layers and washed with water. Organic layer distilled off completely under reduced pressure and the obtained compound is co-distilled using acetone (100 ml). 300 ml of acetone was added to the obtained compound and stirred the reaction mixture for 45 min at 50-55°C. Cooled the reaction mixture to 0-5°C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with acetone and dried the compound to get the title compound.
Yield: 60.0 gm; M.R: 180-185°C. Example-51: Preparation of (5-methyl-2-oxo-l,3-dioxol-4-yI)methyl 2-ethoxy-l-{[2'-(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxyIate (Formula-1)
A mixture of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'-(N'-hydroxy carbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate compound of fomula-17 (100 gm), 4-dimethylaminopyridine (1 1.25 gm), N,N-carbonyldiimidazole (104.6 gm) and tetrahydrofuran (1000 ml) was heated to the 50-55°C. Stirred the reaction mixture for 12 hrs at 50-55°C. The reaction mixture was poured in 10-15°C pre-cooled mixture of 1% acetic acid (250 ml) and ethyl acetate (250 ml). Stirred the reaction mixture for 15 min and both the organic and aqueous layers were separated. Extracted the aqueous layer with ethyl acetate and combined the organic layers. Washed the total organic layer with 2% sodium bicarbonate solution followed by with water. Distilled off the solvent from organic layer completely under reduced pressure and co-distilled the obtained compound using acetone. 250 ml of acetone was added to the obtained compound, heated the reaction mixture to 45-50°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 45 min at the same temperature. Filtered the precipitated solid and dried to get the title compound.
Yield: 80 gm. Example-52: Preparation of potassium salt of (5-methyl-2-oxo-l,3-dioxoI-4-yl)methyl 2- ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH- benzimidazole-7-carboxylate (Formula- la)
A mixture of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5- dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula-1 (100 gm) and acetone (1500 ml) was heated to 45-50°C and stirred for 30 min at the same temperature. Carbon (5 gm) was added to the reaction mixture at 45-50°C and stirred for 15 min at the same temperature. Filtered the reaction mixture through hyflow bed and cooled the filtrate to 0-5°C. A solution of potassium 2-ethyl hexanoate (32 gm) in ethyl acetate (500 ml) was added to the filtrate at 0-5°C and stirred for 90 min at the same temperature. Filtered the precipitated solid and washed with ethyl acetate to get the title compound.
Yield: 80.0 gm; Purity by HPLC: 97.9%.
Example-53: Preparation of N-((4'-((2-ethoxy-7-(lH-imidazole-l-carbonyl)-lH-benzo[d] imidazol-l-yl)methyl)biphenyl-2-yl)(hydroxyimino)methyl)-lH-imidazole-l-carboxamide (FormuIa-26)
N,N-carbonyldiimidazole (5.65 gm) and 4-dimethylaminopyrdine (0.35 ml) were added to a mixture of 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of formula- 16 (5 gm) and tetrahydrofuran (50 ml) at 25-30°C and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the precipitated solid, washed with purified water and dried to get the title compound.
Yield: 5.0 gm.
Example-54: Preparation of (5-methyl-2-oxo-l,3-dioxoI-4-yl)methyI 2-ethoxy-l-{[2'-(5-oxo- 4,5-dihydro-l,2,4-oxadiazoI-3-yl)biphenyI-4-yI]methyl}-lH-benzimidazoIe-7-carboxylate (Formula-1)
A mixture of 4-(hydroxymethyl)-5-methyl-l,3-dioxolo2-one compound of formula-15c (0.68 gm), tetrahydrofuran (20 ml), tetra butyl ammonium bromide (0.10 gm) and sodium carbonate (0.73 gm) was heated to 55-60°C. The mixture of N-((4'-((2-ethoxy-7-(lH-imidazole- 1 -carbonyl)- 1 H-benzo[d] imidazol- 1 -yl)methyl)biphenyl-2-yl)(hydroxyimino)methyl)- 1 H- imidazole-l-carboxamide compound of formula-26 (2 gm) and tetrahydrofuran (20 ml) was added to the reaction mixture at 55-60°C and stirred at the same temperature. After completion of the reaction, the reaction mixture was cooled to 30-35°C and quenched with water. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with sodium chloride solution and distilled of the solvent completely under reduced pressure. Ethyl acetate (20 ml) was added to the obtained residue at 30-35°C and stirred for 60 min. The obtained solid was filtered, washed with ethyl acetate and dried to get the title compound.
Yield: 1.8 gm.
Example-55: Preparation of (5-methyl-2-oxo-l,3-dioxol-4-yI)methyl 2-ethoxy-l-((2'-(N'- hydroxy-N-(lH-imidazole-l-carbonyl)carbamimidoyl)biphenyI-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylate (Formula-18)
A mixture of toluene (75 ml), sodium bicarbonate (2.62 g), tetra butyl ammonium bromide (1.22 g) and 2-ethoxy-l-((2'-(N'-hydroxy-N-(lH-imidazole-l-carbonyl)carbamimidoyl) biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylic acid compound of formula-25 (10 g) were stirred at 25-30°C for 10 min. 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one compound of formula-15a (4.53 g) was added to the above reaction mixture at 25-30°C and stirred the reaction mixture for 4 hrs at the same temperature. After completion of the reaction, water (50 ml) was added to the reaction mixture. Ethyl acetate was added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Both organic and aqueous layer were separated and aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with sodium chloride solution. Distilled off the solvent completely under reduced pressure at below 65°C. Ethyl acetate was added to the obtained compound at 25-30°C and co-distilled solvent completely under reduced pressure at below 65°C. Further, ethyl acetate was added to the compound. Heated the reaction mixture to 40-45°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 25-30°C. Cyclohexane was added to the reaction mixture at 25-30°C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound.
Yield: 0.7 gm.
Example-56: Preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'-(N'- hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate (Formula-17)
4-(Chloromethyl)-5-methyl-l,3-dioxol-2-one compound of formula- 15a (55.5 gm) was added to a mixture of 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of fonnula-16 (100 gm), tetra butyl ammonium bromide (15 gm), tetrahydrofuran (750 ml) and sodium carbonate (32 gm) at 25-30°C and stirred the reaction mixture for 4 hrs at the same temperature. Filtered the reaction mixture and distilled off the solvent completely from the filtrate under reduced pressure. Acetonitrile (100 ml) and methyl tertiary butyl ether (500 ml) was added to the obtained compound at 25-30°C, heated the reaction mixture to 45-50°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred the reaction mixture for 45 min at the same temperature. Filtered the precipitated solid and dried to get the title compound as a crystalline solid.
The PXR.D pattern of the obtained compound is shown in figure-10.
Yield: 92.0 gm.
ExampIe-57: Preparation of 2-ethoxy-l-((2'-(N'-(ethoxycarbonyIoxy)carbamimidoyI) biphenyl-4-yl)methyl)-lH-benzo[d]imidazoIe-7-carboxylic acid (Formula-27)
Tetrahydrofuran (20 ml) and sodium carbonate (1.5 gm) were added to 2-ethoxy-l-((2'- (N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole-7-carboxylic acid compound of formula-16 (2.0 gm) at 25-30°C. Cooled the reaction mixture to 0-5°C, ethyl chloroformate (0.5 gm) was added and stirred the reaction mixture for 1 hr at the same temperature. Water (10 ml) was added to the reaction mixture and acidified the reaction mixture using acetic acid. Dichloromethane was added to the reaction mixture and both the organic and aqueous layers were separated. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound as a solid. Yield: 1.5 gm.
Example-58: Preparation of (5-methyl-2-oxo-l,3-dioxol-4-yI)methyI 2-ethoxy-l-((2'-(N'- (ethoxycarbonyl oxy)carbamimidoyl)biphenyI-4-yl)methyI)-lH-benzo[d]imidazole-7- carboxylate (Formula-28)
Sodium carbonate (0.25 gm), tetrabutylammonium bromide (0.07 gm) and 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one compound of formula- 15a (0.45 gm) were added to a mixture of 2-ethoxy-l-((2'-(N'-(ethoxycarbonyloxy)carbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of formula-27 (1.0 gm) and tetrahydrofuran (15 ml) at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 2 hrs at the same temperature. Water (15 ml) followed by ethyl acetate (15 ml) were added to the reaction mixture. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 0.8 gm. ExampIe-59: Preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound (Formula-1)
Xylene (5 ml) was added to (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'-(N'- (ethoxycarbonyloxy)carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole-7-carboxylate compound of formula-28 (1.0 gm) at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 2 hrs at the same temperature. Ethyl acetate (5 ml) was added to the reaction mixture and washed with water. Distilled off the solvent completely from the organic layer and the obtained compound was purified by column chromatography to get the title compound.
Yield: 0.2 gm.
Example-60: Preparation of (5-methyl-2-oxo-l,3-dioxol-4-yi)mefhyI 2-ethoxy-l-{[2'-(5-oxo- 4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyI}-lH-benzimidazole-7-carboxylate compound (Formula-1)
Toluene (5 ml) was added to (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'-
(N'-(ethoxycarbonyloxy)carbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7- carboxylate compound of formula-28 (1.0 gm) at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 2 hrs at the same temperature. Washed the reaction mixture with water and distilled off the solvent completely from the organic layer. The obtained compound was purified by column chromatography to get the title compound. Yield: 0.19 gm.
Example-61: Preparation of 2-ethoxy-l-((2'-(N'-hydroxy-N-(lH-imidazoIe-l-carbonyl) carbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylic acid
(FormuIa-25)
0.5N sodium hydroxide solution was added to N-((4'-((2-ethoxy-7-(lH-imidazole-l- carbonyl)- 1 H-benzo[d]imidazol- 1 -yl)methyl)biphenyl-2-yl)(hydroxyimino)methyl)- 1 H- imidazole-l-carboxamide compound of formula-26 (5 gm) at 25-30°C and stirred the reaction mixture for 1 hr at the same temperature. Acidified the reaction mixture using hydrochloric acid. Dichloromethane (50 ml) was added to the reaction mixture and stirred for 10 min. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer to get the title compound as a solid.
Yield: 3.6 gm.

Claims

We Claim:
1. A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- 1- {[2'-(5- oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7- carboxylate compound of formula- 1 and its potassium salt compound of formula- la, comprising of;
a) Reacting the 2-ethoxy- l-((2'-(N'-hydro ycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of formula- 16
Figure imgf000086_0001
Formula- 16
with compound of general formula- 15
Figure imgf000086_0002
Formula- 15
wherein, X= CI, Br, OH;
in presence of a suitable base in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol- 4-yl)methyl 2-ethoxy- 1 -((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H- benzo[d]imidazole-7-carboxylate compound of formula- 17,
Figure imgf000086_0003
Formula- 17
b) reacting the compound of formula- 17 with Ν,Ν-carbonyldiimidazole optionally in presence of a suitable base in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4- yl)methyl 2-ethoxy- 1 -((2'-(N'-hydroxy-N-( 1 H- imidazole- 1 -carbonyl)carbamimidoyl) biphenyl-4-yl) methyl)- lH-benzo d]imidazole-7-carbox late compound of formula- 18,
Figure imgf000087_0001
Formula- 18
c) isolating the compound of formula- 18 as a solid and purifying from a suitable solvent, d) heating the compound of formula- 18 in presence of a suitable solvent to provide (5- iethyl-2-oxo- dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydi oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula- 1 ,
e) treating the compound of formula- 1 with a suitable potassium source in a suitable solvent to provide its potassium salt compound of formula- la.
A process according to claim 1 , wherein step-a) is carried out optionally in presence of a suitable phase transfer catalyst, suitable catalyst or a suitable condensing agent.
A process according to claim 1 and claim 2, wherein,
In step-a) the suitable phase transfer catalyst is selected from tetraalkylammonium halides, preferably tetra butyl ammonium bromide (TBAB);
the suitable catalyst is selected from p-toluene sulfonyl chloride, benzene sulfonyl chloride, methanesulfonyl chloride, ethane sulfonyl chloride, thionyl chloride, oxalyl chloride, acylating agents represented by the formula R-CO-X, wherein "R" represents C\-C straight chain or branched chain alkyl group, such as methyl, ethyl, propyl, tert-butyl and the like, a Ci-C6 alkoxy group such as methoxy, ethoxy, propoxy, isobutyloxy and the like; substituted or unsubstituted phenyl group; "X" represents halogens such as CI, Br & I;
the suitable condensing agent is selected from Ν,Ν-carbonyldiimidazole (CDI), alkyl and aryl carbodiimides such as Ν,Ν-diisopropylcarbodiimide (DIC), N,N-dicyclohexyl carbodiimide (DCC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), ditolylcarbodiimide, carbonyl-di-l ,2,4-triazole, alkyl and aryl halo formates such as methyl chloroformate, ethyl chloroformate, phenyl chloroformate, benzyl chloroformate, dialkyl, diaryl and alkyl aryl carbonates of the formula Ri-0-CO-0-R2, wherein "Rj" and "R2" are independently selected from branched or unbranched C1-C4 alkyl or substituted or unsubstituted phenyl group;
In step-a) and step-b) the suitable base is selected from organic bases, inorganic bases or mixtures thereof;
In step-e) the suitable potassium source is selected from potassium 2-ethyl hexanoate, potassium tert.butoxide, potassium hydroxide, potassium bis(trimethylsilyl)amide (KHMDS) and the like;
In step-a) to step-e) the suitable solvent is selected from ether solvents, ketone solvents, ester solvents, polar-aprotic solvents, chloro solvents, hydrocarbon solvents, nitrile solvents, alcoholic solvents, polar solvents or their mixtures;
A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5- oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7- carboxylate compound of formula- 1 and its potassium salt compound of formula- la, comprising of;
a) Reacting the 2-ethoxy-l-((2'-( '-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of formula- 16 with 4-(chloromethyl)-5- methyl-l,3-dioxol-2-one compound of formula- 15a in presence of tetra butyl ammonium bromide and sodium carbonate in tetrahydrofuran to provide (5-methyl-2-oxo-l,3-dioxol- 4-yl)methyl 2-ethoxy- 1 -((2 '-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H- benzo[d]imidazole-7-carboxylate compound of formula-17,
b) reacting the compound of formula-17 with Ν,Ν-carbonyldiimidazole in presence of 4-dimethylaminopyridine in tetrahydrofuran to provide (5-methyl-2-oxo-l,3-dioxol-4-yl) methyl 2-ethoxy- 1 -((2'-(N'-hydroxy-N-( 1 H-imidazole- 1 -carbonyl)carbamimidoyl) biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate compound of formula- 18, c) isolating the compound of formula- 18 as a solid from a mixture of tetrahydrofuran and water,
d) purifying the compound of formula- 18 from dichloromethane, e) heating the compound of formula- 18 in presence of tetrahydrofuran to provide (5-methyl- 2-oxo- 1 ,3 -dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl} - lH-benzimidazole-7-carboxylate compound of formula- 1 , f) treating the compound of formula- 1 with potassium 2-ethyl hexanoate in a mixture of acetone and ethyl acetate to provide its potassium salt compound of formula- la.
A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-((2'-(N'- hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate compound of formula- 17, comprising of reacting the 2-ethoxy- l-((2'-(N'-hydroxy carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole-7-carboxylic acid compound of formula- 16 with compound of general formula- 15 to provide (5-methyl-2-oxo-l,3-dioxol- 4-yl)methyl 2-ethoxy- 1 -((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H- benzo[d]imidazole-7-carboxylate compound of formula- 17.
A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-((2'-(N'- hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate compound of formula- 17, comprising of reacting the 2-ethoxy- l-((2'-(N'-hydroxy carbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylic acid compound of formula-16 with 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one compound of formula-15a in presence of tetra butyl ammonium bromide and sodium carbonate in tetrahydrofuran to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-((2'-(N'-hydroxycarbamimidoyl) biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate compound of formula-17.
A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- 1 -((2'-(Ν'- hydroxy-N-(lH-imidazole-l-carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylate compound of formula- 18, comprising of reacting the (5- methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 -((2'-(N'-hydroxycarbamimidoyl)biphenyl- 4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate compound of formula-17 with N,N- carbonyldiimidazole in a suitable solvent optionally in presence of a suitable base to provide (5-methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 -((2'-(N'-hydroxy-N-( lH-imidazole- 1 - carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate compound of formula- 18.
8. A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-((2'-(N'- hydroxy-N-( 1 H- imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d] imidazole-7-carboxylate compound of fonriula-18, comprising of reacting the (5-methyl-2- oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl) methyl)- lH-benzo[d]imidazole-7-carboxylate compound of formula- 17 with N,N-carbonyl diimidazole in presence of 4-dimethylaminopyridine in tetrahydrofuran to provide compound of formula- 18.
9. A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- 1- {[2'-(5- oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7- carboxylate compound of formula- 1, comprising of heating the (5-methyl-2-oxo-l,3-dioxol- 4-yl)methyl 2-ethoxy- 1 -((2'-(N'-hydroxy-N-( 1 H- imidazole- 1 -carbonyl)carbamimidoyl) biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate compound of formula- 18 in presence of a suitable solvent at a suitable temperature to provide compound of formula- 1.
10. A process according to claim 9, wherein the suitable solvent is selected from chloro solvents, ether solvents, ester solvents, alcoholic solvents, polar solvents, ketone solvents, nitrile solvents, polar-aprotic solvents, hydrocarbon solvents or their mixtures; and the suitable temperature is ranging between 25°C to reflux temperature of the solvent used.
11. Crystalline form-M of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- 1 -((2 '-(N'-hydroxy carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole-7-carboxylate compound of formula- 17, characterized by;
i) Its X-Ray powder diffraction pattern having peaks at 10.0, 15.0, 15.3, 17.6, 20.0, 23.8 and 28.4 ± 0.2 degrees of 2Θ, and
ii) its X-Ray powder diffraction pattern substantially in accordance with figure-6.
12. Compound represented by the following structural formula;
Figure imgf000090_0001
13. Solid state form of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'-(N'-hydroxy-N- ( 1 H-imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole-7- carboxylate. 14. Crystalline form-S of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'-(N'-hydroxy- N-( 1 H-imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole- 7-carboxylate compound of formula- 18, characterized by;
i) Its X-Ray powder diffraction pattern having peaks at 4.1, 7.0, 7.9, 9.1, 10.6, 13.5, 15.7, 16.3, 17.4, 17.8, 19.0, 22.8, 23.5, 24.4, 28.8 ± 0.2 degrees of 2Θ, and
ii) its X-Ray powder diffraction pattern substantially in accordance with figure-7.
15. Crystalline form-L of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5- dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate, characterized by;
a) Its X-Ray powder diffraction pattern having peaks at 8.9, 10.6, 1 1.5, 15.4, 19.7, 20.3,
21.5, 24.6, 25.7, 31.4 and 33.1 ± 0.2 degrees of 2Θ,
b) its X-Ray powder diffraction pattern further comprising peaks at 4.4, 9.3, 17.9, 18.1,
18.6, 19.2, 19.9, 22.4, 22.8, 23.8 ± 0.2 degrees of 2Θ,
c) its X-Ray powder diffraction pattern substantially in accordance with figure-8, d) its differential scanning calorimetric (DSC) thermogram as shown in figure-9.
16. A process for the preparation of crystalline (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2- ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H- benzimidazole-7-carboxylate compound of formula- 1, comprising of;
a) Reacting the (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'-(N'-hydroxy carbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate compound of formula- 17 with Ν,Ν-carbonyldiimidazole in presence of 4-dimethylaminopyridine in tetrahydrofuran to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'-(N'- hydroxy-N-( 1 H-imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)- 1 H- benzo[d]imidazole-7-carboxylate compound of formula- 18,
b) adding water to the reaction mixture and filtering the compound,
c) dissolving the compound obtained in step-b) in dichloromethane, d) distilling off the solvent completely from the organic layer,
e) adding tetrahydrofuran to the reaction mixture,
f) heating the reaction mixture to elevated temperature,
g) cooling the reaction mixture,
h) adding aqueous sodium chloride solution to the reaction mixture,
i) extracting the reaction mixture with ethyl acetate and distilling off the solvent completely from the organic layer,
j) adding ethyl acetate to the compound obtained in step-i),
k) heating the reaction mixture and cooling the reaction mixture,
1) filtering the solid to provide crystalline (5-methyl-2-oxo-l,3-dioxol-4-yl) methyl 2- ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl } - 1 H- benzimidazole-7-carboxylate compound of formula- 1.
17. A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)rnethyl 2-ethoxy-l- {[2'-(5- oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - lH-benzimidazole-7- carboxylate compound of formula- 1 and its potassium salt compound of formula- la, comprising of;
a) Treating the 2-ethoxy-l-((2'-( '-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of formula- 16 with a suitable amine protecting agent optionally in presence of a suitable base in a suitable solvent to provide compound of general formula- 19,
Figure imgf000092_0001
Formula- 19
wherein 'P' represents amine protecting group;
b) reacting the compound of general formula- 19 with compound of general formula- 15 in presence of a suitable base in a suitable solvent optionally in presence of a suitable phase transfer catalyst, suitable catalyst or a suitable condensing agent to provide compound of general formula-20,
Figure imgf000093_0001
Formula-20
c) treating the compound of general formula-20 with a suitable deprotecting agent in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-((2'-(N'- hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate compound of formula- 17,
d) reacting the compound of formula- 17 with Ν,Ν-carbonyldiimidazole optionally in presence of a suitable base in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4- yl)methyl 2-ethoxy- 1 -((2'-(N'-hydroxy-N-( lH-imidazole- l-carbonyl)carbamimidoyl) biphenyl-4-yl) methyl)- lH-benzo[d]imidazole-7-carboxylate compound of formula- 18, e) isolating the compound of formula- 18 as a solid,
f) heating the compound of formula- 18 in presence of a suitable solvent to provide (5- methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4- oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1,
g) treating the compound of formula- 1 with a suitable potassium source in a suitable solvent to provide its potassium salt compound of formula- la. The process according to claim- 17, wherein,
The suitable amine protecting agent is selected from but not limited to di-tert.butyl dicarbonate (DIBOC), benzyl chloroformate, fluorenylmethyloxy carbonyl chloride (FMOC chloride), acetyl chloride, acetic anhydride, benzoyl halides, benzyl halides, tosyl halides, tosyl anhydrides, alkyl trifluoroacetates such as methyl trifluoroacetate, ethyl trifluoro acetate, isopropyl trifluoroacetate, vinyl trifluoroacetate, trifluoroacetic acid, trifluoroacetyl chloride; the amine protecting group 'P' is selected from but not limited to tert-butyloxy carbonyl (BOC), benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxy carbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate group, p-methoxyphenyl (PMP), p-methoxy benzyl (PMB), 3,4-dimethoxybenzyl (DMPM), tosyl (Ts), trifluoroacetyl (TFA); in step-a), step-b) and step-d) the suitable base is selected from inorganic bases like alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates and organic bases;
In step-c) the suitable deprotecting agent is selected based on the protecting group employed. The suitable deprotecting agent is selected from but not limited to acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aq.phosphoric acid, trifluoroacetic acid, methane sulfonic acid; acetyl chloride in combination with alcohols; bases such as alkali metal hydroxides, alkali metal carbonates, cesium carbonate/imidazole, alkali metal bicarbonates, ammonia, ammonium cerium(IV) nitrate (CAN); and organic bases such as methylamine, ethylamine, diethylamine, triethylamine, piperidine; hydrogenating agents such as Pd/C, Pd(OH)2/C (Pearlman's catalyst), palladium acetate, platinum oxide, platinum black, sodium borohydride, Na-liquid ammonia, Raney-Ni, tri(Ci-C6)alkylsilanes, tri(Ci-C6)alkylsilyl halides;
In step-a) to step-g) the suitable solvent is selected form ether solvents, ester solvents, chloro solvents, hydrocarbon solvents, polar solvents, polar-aprotic solvents, ketone solvents, alcoholic solvents or mixtures thereof.
19. A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l- {[2'-(5- oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7- carboxylate compound of formula- 1, comprising of;
a) Treating the 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of formula-16. with di-tert-butyl dicarbonate in presence of a suitable base in a suitable solvent to provide l-((2'-(N-(tert- butoxycarbonyl)-N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-2-ethoxy-lH- benzo[d]imidazole-7-carboxylic acid compound of formula- 19a,
Figure imgf000094_0001
Formula- 19a b) reacting the compound of formula- 19a with compound of general formula- 15 in presence of a suitable base in a suitable solvent optionally in presence of a suitable catalyst, suitable phase transfer catalyst or a suitable condensing agent to provide (5-methyl-2- oxo- 1 ,3-dioxol-4-yl)methyl 1 -((2'-(N -(tert-butoxycarbonyl)-N'-hydroxycarbamimidoyl) biphenyl-4-yl)methyl)-2-ethoxy-lH-benzo[d]imidazole-7-carboxylate compound of formula-20a,
c) treating the compound of formula-20a with a suitable deprotecting agent in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'-(N'-hydroxy carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole-7-carboxylate compound of formula- 17,
d) treating the compound of formula- 17 with Ν,Ν-carbonyldiimidazole optionally in presence of a suitable base in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4- yl)methyl 2-ethoxy- 1 -((2'-(N'-hydroxy-N-( 1 H-imidazole- 1 -carbonyl)carbamimidoyl) biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate compound of formula- 18, e) isolating the compound of formula- 18 as a solid from a suitable solvent,
f) heating the compound of formula- 18 in presence of a suitable solvent to provide (5- methyl-2-oxo- 1 ,3 -dioxol-4-yl)methyl 2-ethoxy- 1 - { [2'-(5-oxo-4,5-dihydro- 1,2,4- oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1.
20. A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- 1-{[2'-(5- oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7- carboxylate compound of formula- 1, comprising of;
a) Treating the 2-ethoxy- l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of formula- 16 with di-tert-butyl dicarbonate in presence of triethylamine in dichloromethane to provide l-((2'-(N-(tert- butoxycarbonyl)-N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-2-ethoxy- 1 H- benzo[d]imidazole-7-carboxylic acid compound of formula- 19a,
b) reacting the compound of formula- 19a with 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one compound of formula- 15a in presence of sodium bicarbonate in methyl isobutyl ketone to provide (5-methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 1 -((2'-(N-(tert-butoxycarbonyl)-N'- hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-2-ethoxy-lH-benzo[d]imidazole-7- carboxylate compound of formula-20a,
c) treating the compound of formula-20a with trifluoroacetic acid in dichloromethane to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'-(N'-hydroxy carbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate compound of formula- 17,
d) treating the compound of formula- 17 with Ν,Ν-carbonyldiimidazole in presence of 4-dimethylaminopyridine in tetrahydrofuran to provide (5-methyl-2-oxo-l,3-dioxol-4-yl) methyl 2-ethoxy- 1 -((2 '-(N'-hydroxy-N-( 1 H- imidazole- 1 -carbonyl)carbamimidoyl) biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate compound of formula- 18, e) isolating the compound of formula- 18 as a solid,
f) heating the compound of formula- 18 in presence of tetrahydrofuran to provide (5-methyl- 2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1.
21. A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5- oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7- carboxylate compound of formula-1, comprising of cyclizing the (5-methyl-2-oxo-l,3- dioxol-4-yl)methyl l-((2'-(N-(tert-butoxycarbonyl)-N'-hydroxycarbamimidoyl)biphenyl-4- yl)methyl)-2-ethoxy-lH-benzo[d]imidazole-7-carboxylate compound of formula-20a
Figure imgf000096_0001
Formula-20a
in presence or absence of a suitable catalyst in a suitable solvent to provide (5-methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4- yl]methyl} - lH-benzimidazole-7-carboxylate compound of formula- 1.
22. A process according to claim-21, wherein,
the suitable catalyst is selected from organic and inorganic bases; organic acids such as acetic acid, citric acid, formic acid, trifluoroacetic acid, methane sulfonic acid, ethane sulfonic acid, toluene sulfonic acid, benzene sulfonic acid, trifluoromethane sulfonic acid, oxalic acid; or inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, carbonic acid, formic acid;
The suitable solvent is selected from alcoholic solvents (or) alcoholic solvents in combination with chloro solvents, ether solvents, ester solvents, alcoholic solvents, polar solvents, ketone solvents, nitrile solvents, polar-aprotic solvents, hydrocarbon solvents or mixtures thereof.
23. A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l- {[2'-(5- oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7- carboxylate compound of formula- 1 , comprising of;
a) Reacting the 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of formula- 16 with N,N-carbonyl diimidazole (CDI) in presence or absence of a suitable base in a suitable solvent followed by optionally treating with a suitable aqueous base to provide 2-ethoxy-l -((2'-(Ν'- hydroxy-N-( 1 H-imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)- 1 H- benzo[d]imidazole-7-carboxylic acid compound of formula-25,
Figure imgf000097_0001
Formula-25
b) reacting the compound of formula-25 with compound of general formula- 15 in presence of a suitable base in a suitable solvent optionally in presence of a suitable phase transfer catalyst, suitable catalyst or a suitable condensing agent to provide (5-methyl-2-oxo-l,3- dioxol-4-yl)methyl 2-ethoxy-l - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4- yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula-1.
24. A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l- {[2'-(5- oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7- carboxylate compound of formula-1, comprising of; a) Reacting the 2-ethoxy- l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of formula- 16 with a N,N-carbonyl diimidazole (CDI) in presence or absence of a suitable base in a suitable solvent to provide N-((4'-((2-ethoxy-7-( 1 H-imidazole- 1 -carbonyl)- 1 H-benzo[d]imidazol- 1 -yl) methyl)biphenyl-2-yl) (hydroxyimino)methyl)-l H-imidazole- 1-carboxamide compound of formula-26,
Figure imgf000098_0001
Formula-26
b) reacting the compound of formula-26 with 4-(hydroxymethyl)-5-methyl-l,3-dioxol-2-one compound of formula- 15c
Figure imgf000098_0002
Formula- 15c
in presence of a suitable base in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4- yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate compound of formula- 1.
25. 2-ethoxy- 1 -((2'-(N'-hydroxy-N-( 1 H-imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl) methyl)- lH-benzo[d]imidazole-7-carboxylic acid. 26. N-((4'-((2-ethoxy-7-( 1 H-imidazole- 1 -carbonyl)- 1 H-benzo[d]imidazol- 1 -yl)methyl)biphenyl- 2-yl) (hydroxyimino)methyl)-l H-imidazole- 1-carboxamide.
27. Solid state form of 2-ethoxy- l-((2'-(N'-hydroxy-N-(l H-imidazole- 1 -carbonyl) carbamimidoyl)biphenyl-4-yl)methyl)- lH-benzo[d]imidazole-7-carboxylic acid.
28. Solid state form of N-((4'-((2-ethoxy-7-(lH-imidazole-l-carbonyl)-lH-benzo[d]imidazol-l- yl)methyl)biphenyl-2-yl) (hydroxyimino)methyl)- 1 H-imidazole- 1 -carboxamide.
29. A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l- {[2'-(5- oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7- carboxylate compound of formula- 1, comprising of reacting the 2-ethoxy- l-((2'-(N'-hydroxy- N-( 1 H-imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole- 7-carboxylic acid compound of formula-25 with compound of general formula- 15 in presence of a suitable base in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4-yl) methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H- benzimidazole-7-carboxylate compound of formula- 1. 30. A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l- {[2'-(5- oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7- carboxylate compound of formula- 1, comprising of reacting the N-((4'-((2-ethoxy-7-(lH- imidazole- 1 -carbonyl)- 1 H-benzo[d]imidazol- 1 -yl)methyl)biphenyl-2-yl) (hydroxyimino) methyl)- 1 H-imidazole- 1-carboxamide compound of formula-26 with 4-(hydroxymethyl)-5- methyl-l,3-dioxol-2-one compound of formula-15c in presence of a suitable base in a suitable solvent to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-{[2'-(5-oxo- 4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl) - lH-benzimidazole-7-carboxylate compound of formula- 1. 31. A process for the preparation of N-((4'-((2-ethoxy-7-(l H-imidazole- 1 -carbonyl)- 1H- benzo[d]imidazol- 1 -yl)methyl)biphenyl-2-yl) (hydroxyimino)methyl)- 1 H-imidazole- 1 - carboxamide compound of formula-26, comprising of reacting the 2-ethoxy- l-((2'-(N'- hydroxycarbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole-7-carboxylic acid compound of formula- 16 with a Ν,Ν-carbonyldiimidazole (CDI) in presence or absence of a suitable base in a suitable solvent to provide compound of formula-26.
32. A process for the preparation of N-((4'-((2-ethoxy-7-(l H-imidazole- 1 -carbonyl)- 1H- benzo[d]imidazol- 1 -yl)methyl)biphenyl-2-yl) (hydroxyimino)methyl)- 1 H-imidazole- 1 - carboxamide compound of formula-26, comprising of reacting the 2-ethoxy- l-((2'-(N'- hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylic acid compound of formula- 16 with a Ν,Ν-carbonyldiimidazole (CDI) in presence of 4-dimethyl aminopyrdine in tetrahydrofuran to provide compound of formula-26.
33. Crystalline form-S of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-{[2'-(5-oxo-4,5- dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1, characterized by;
a) its X-Ray powder diffraction pattern having peaks at 8.6, 9.8, 13.0, 16.1, 16.8, 17.2, 17.4, 18.5, 19.3, 19.9, 20.6, 21.9, 22.4, 22.9, 23.5, 25.8, 26.3 ± 0.2 degrees of 2-theta, and b) its DSC pattern having one endotherm at 130°C and another endotherm at 171°C.
34. A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- 1- {[2'-(5- oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - lH-benzimidazole-7- carboxylate potassium salt compound of formula- la, comprising of treating the (5-methyl-2- oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - { [2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate compound of formula- 1 with potassium tert.butoxide in a suitable solvent or mixture of solvents. 35. A process according to claim 34, wherein potassium tert.butoxide is used in an amount ranging from 0.8-1.7 moles, preferably 0.9 to 1.5 moles per one mole of compound of formula-1 at a temperature of -10°C to 60°C, preferably -5°C to 35°C and the suitable solvent is selected from ketone solvents, ester solvents, polar-aprotic solvents, hydrocarbon solvents and/or their mixtures thereof; preferably mixture of acetone and ethyl acetate.
36. A process for the preparation of amorphous form of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H- benzimidazole-7-carboxylate compound of formula-1, comprising of;
a) Condensing the 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4- yl]methyl}-lH-benzimidazole-7-carboxylic acid disodium salt compound of formula-2a with 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one compound of formula- 15a in presence of Ν,Ν-dimethyl formamide to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2- ethoxy- 1 - {[2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H- benzimidazole-7-carboxylate compound of formula-1,
b) treating the compound of formula-1 in-situ with potassium 2-ethyl hexanoate in acetone to provide its potassium salt of formula- la,
c) neutralizing the potassium salt obtained in step-b) by treating in-situ with acetic acid in water to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5- dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate of formula- 1,
d) isolating the compound of formula- 1 from cyclohexane to provide amorphous form of compound of formula- 1.
37. A process for the preparation of methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3- nitrobenzoate compound of formula- 10
Figure imgf000101_0001
Formula- 10
comprising of deprotecting the methyl 2-(tert-butoxycarbonyl((2'-cyanobiphenyl-4-yl) methyl)amino)-3-nitrobenzoate compound of formula-9
Figure imgf000101_0002
Formula-9
by treating it with a suitable boc-deprotecting agent selected from trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, acetyl chloride and tri(Ci-C6 alkyl)silyl halides in a suitable solvent selected from ketone solvents, chloro solvents, alcoholic solvents, ester solvents, polar solvents, ether solvents, hydrocarbon solvents or mixtures thereof to provide methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate compound of formula-10.
38. A process according to claim 37, wherein the boc-deprotecting agent is preferably selected from trifluoroacetic acid, methanesulfonic acid.
39. A process according to claim 38, wherein the boc-deprotecting agent is used in an amount of 2.0-4.0 mole ratio per one mole equivalent of compound of formula-9.
40. A process for the preparation of methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3- nitrobenzoate compound of formula- 10, comprising of deprotecting the methyl 2-(tert- butoxycarbonyl((2'-cyanobiphenyl-4-yl)methyl)amino)-3-nitrobenzoate compound of formula-9 with methanesulfonic acid or trifluoroacetic acid in dichloromethane to provide methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate compound of formula- 10.
41. A process for the preparation of methyl 3-amino-2-((2'-cyanobiphenyl-4-yl)methylamino) benzoate compound of formula- 11,
Figure imgf000102_0001
Formula- 1 1
comprising of reducing the methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate compound of formula- 10 with Raney Ni in a suitable solvent selected from ester solvents, alcoholic solvents, ether solvents, chloro solvents, hydrocarbon solvents or their mixtures to provide methyl 3-amino-2-((2'-cyanobiphenyl-4-yl)methylamino)benzoate compound of formula-11.
42. A process for the purification of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5- oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7- carboxylate potassium salt compound of formula- la, comprising of;
a) Adding a suitable ester solvent, preferably ethyl acetate to (5-methyl-2-oxo-l,3-dioxol-4- yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl] methyl} -lH-benzimidazole-7-carboxylate potassium salt compound of formula- la, b) heating the reaction mixture,
c) cooling the reaction mixture,
d) filtering the solid to provide pure (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l- {[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiaz0l-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole- 7-carboxylate potassium salt compound of formula- 1 a.
43. A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l- {[2'-(5- oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7- carboxylate compound of formula-1, comprising of reacting the 2-ethoxy-l-{[2'-(5-oxo-4,5- dihydro-1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - lH-benzimidazole-7-carboxylic acid compound of formula-2 with 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one compound of formula- 15a in presence of a suitable alkali metal bicarbonate optionally in presence of a suitable phase transfer catalyst such as tetra butyl ammonium bromide in a suitable solvent selected from ketone solvents, polar-aprotic solvents, ester solvents , ether solvents or their mixtures to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5- dihydro-1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} -lH-benzimidazole-7-carboxylate compound of formula- 1.
44. A process for the preparation of 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2, comprising of reacting the 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl) methyl)- lH-benzimidazole-7-carboxylic acid compound of formula- 16 with a suitable cyclization agent in presence of a suitable organic or inorganic base in a suitable solvent to provide compound of formula-2,
wherein the suitable cyclization agent is selected from N,N-carbonyldiimidazole (CDI), carbonyl-di-l,2,4-triazole, alkyl and aryl haloformates such as ethyl chloro formate, phenyl chloro formate, benzyl chloroformate, dialkyl, diaryl and alkyl aryl carbonates of the formula Ri-O-CO-O-R^, wherein "Ri" and "R2" are independently selected from branched or unbranched C 1-C4 alkyl or substituted or unsubstituted phenyl group; and the suitable solvent is selected from chloro solvents, ether solvents, alcoholic solvents, polar solvents or mixtures thereof.
45. A process according to claim 44, wherein the cyclization agent is used in an amount of 1.0- 2.5 mole ratio and the base is used in an amount of 1.0-2.5 mole ratio per one mole equivalent of compound of formula- 16.
46. A process for the preparation of 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2, comprising of reacting the 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl) methyl)- 1 H-benzimidazole-7-carboxylic acid compound of formula- 16 with N,N-carbonyl diimidazole (CDI) in presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in dichloromethane to provide 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2.
47. A process for the preparation of 2-ethoxy-l- {[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2, comprising of;
a) Treating the methyl l-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-lH-benzimidazole-7- carboxylate compound of formula- 12 with hydroxylamine hydrochloride in presence of alkali metal carbonate in a suitable solvent selected from polar solvents, polar-aprotic solvents, alcoholic solvents or mixtures thereof to provide 2-ethoxy-l-((2'-(N'-hydroxy carbamimidoyl)biphenyl-4-yl)methyl)-lH-benzimidazole-7-carboxylic acid compound of formula- 16,
b) reacting the compound of formula- 16 with a suitable cyclization agent in presence of a suitable base in a suitable solvent to provide 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid of formula-2.
48. A process for the preparation of 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl) methyl)- lH-benzimidazole-7-carboxylic acid compound of formula- 16 having less than 5% of acid amide impurity, comprising of treating the methyl l-((2'-cyanobiphenyl-4-yl)methyl)- 2-ethoxy-lH-benzimidazole-7-carboxylate compound of formula- 12 with hydroxylamine hydrochloride in presence of sodium carbonate in a solvent system comprising of mixture of dimethylsulfoxide and water in the ratio of 1 :0.5-1 (v/v) respectively.
49. A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5- oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7- carboxylate compound of formula- 1 and its potassium salt compound of formula- la, comprising of;
a) Deprotecting the methyl 2-(tert-butoxycarbonyl((2'-cyanobiphenyl-4-yl)methyl)amino)- 3-nitrobenzoate compound of formula-9 by treating it with methane sulfonic acid or trifluoroacetic acid in dichloromethane to provide methyl 2-((2'-cyanobiphenyl-4-yl) * methylamino)-3-nitrobenzoate compound of formula- 10,
b) reducing the compound of formula- 10 with Raney Ni in ethyl acetate to provide methyl 3-amino-2-((2'-cyanobiphenyl-4-yl)methylamino)benzoate compound of formula- 1 1, c) reacting the compound of formula- 11 with tetraethyl orthocarbonate in acetic acid to provide methyl l-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-lH-benzimidazole-7- carboxylate compound of formula- 12,
d) treating the compound of formula- 12 with hydroxylamine hydrochloride in presence of sodium carbonate in a mixture of dimethyl sulfoxide and water to provide 2-ethoxy-l- ((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH-benzimidazole-7-carboxylic acid compound of formula- 16,
e) reacting the compound of formula- 16 with Ν,Ν-carbonyl diimidazole (CDI) in presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in dichloromethane to provide 2-ethoxy- l- {[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole- 7-carboxylic acid compound of formula-2,
f) condensing the compound of formula-2 with 4-(chloromethyl)-5-methyl- 1 ,3-dioxol-2-one compound of formula- 15a in presence of sodium bicarbonate and tetrabutyl ammonium bromide in acetone to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'- (5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7- carboxylate compound of formula- 1,
g) treating the compound of formula- 1 with potassium 2-ethyl hexanoate in a mixture of acetone and ethyl acetate to provide its potassium salt compound of formula- la.
50. A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5- oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - lH-benzimidazole-7- carboxylate potassium salt compound of formula- la, comprising of;
a) Reacting the 2-ethoxy-l-((2'-( '-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzimidazole-7-carboxylic acid compound of formula- 16 with N,N-carbonyl diimidazole (CDI) in presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in dichloromethane to provide 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid compound of formula-2, b) condensing the compound of formula-2 with 4-(hydroxymethyl)-5-methyl-l,3-dioxol-2- one compound of formula 15c in presence of p-toluenesulfonyl chloride, potassium carbonate, 4-dimethylamino pyridine in methyl isobutyl ketone optionally in mixture with ethyl acetate to provide compound of formula- 1,
c) treating the compound of formula- 1 with potassium 2-ethyl hexanoate in a mixture of acetone and ethyl acetate to provide its potassium salt compound of formula- la.
51. Crystalline form-Mi of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-((2'-(N'-hydroxy carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole-7-carboxylate compound of formula- 17, characterized by;
i) Its X-Ray powder diffraction pattern having peaks at 5.7, 8.7, 1 1.8, 14.7, 19.5, 22.8 and 23.5 ± 0.2 degrees of 2Θ, and
ii) its X-Ray powder diffraction pattern substantially in accordance with figure- 10.
52. A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- 1-{[2'-(5- oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - lH-benzimidazole-7- carboxylate compound of formula- 1, comprising of;
a) Reacting the 2-ethoxy-l-((2'-(N'-hydroxy-N-(lH-imidazole-l-carbonyl)carbamimidoyl) biphenyl-4-yl)methyl)-lH~benzo[d]imidazole-7-carboxylic acid compound of formula-25 with compound of general formula- 15 in presence of a suitable base in a suitable solvent optionally in presence of a suitable phase transfer catalyst, suitable catalyst or a suitable condensing agent to provide (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- l-((2'-(N'- hydroxy-N-( 1 H-imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)- 1 H- benzo[d] imidazole-7-carboxylate compound of formula- 18,
b) isolating the compound of formula- 18 as a solid,
c) optionally purifying the compound of formula- 18 from a suitable solvent,
d) heating the compound of formula- 18 in presence of a suitable solvent at a suitable temperature ranging from 25°C to reflux temperature of the solvent used to provide (5-methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 - { [2'-(5-oxo-4,5-dihydro- 1 ,2,4- oxadiazol-3 -yl)biphenyl-4-yl]methyl} - 1 H-benzimidazole-7-carboxylate of formula- 1.
53. A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- 1 -((2 '-(Ν'- hydroxy-N-( 1 H-imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d] imidazole-7-carboxylate compound of formula- 18, comprising of reacting the 2-ethoxy- 1- ((2'-(N'-hydiOxy-N-( lH-imidazole- 1 -carbonyl)carbamimidoyl)biphenyl-4-yl)methyl)- 1 H- benzo[d]imidazole-7-carboxylic acid compound of formula-25 with compound of general formula- 15 to provide compound of formula- 18.
54. A process for the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy- 1- {[2'-(5- oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl} - lH-benzimidazole-7- carboxylate compound of formula- 1 , comprising of;
a) Reacting the 2-ethoxy-l-((2'-(N'-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-lH- benzo[d]imidazole-7-carboxylic acid compound of formula- 16 with ethyl chloroformate optionally in presence of a suitable organic or inorganic base in a suitable solvent selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents, polar solvents, polar-aprotic solvents, nitrile solvents, ketone solvents, alcoholic solvents to provide 2-ethoxy- 1 -((2'-(N'-(ethoxycarbonyloxy)carbamimidoyl)biphenyl-4-yl)methyl)- lH-benzo[d]imidazole-7-carboxylic acid compound of formula-27,
b) reacting the compound of formula-27 with compound of general formula- 15 in presence of a suitable organic or inorganic base in a suitable solvent optionally in presence of a suitable phase transfer catalyst, suitable catalyst or a suitable condensing agent to provide (5-methyl-2-oxo- 1 ,3-dioxol-4-yl)methyl 2-ethoxy- 1 -((2'-(N'-(ethoxycarbonyloxy) carbamimidoyl)biphenyl-4-yl)methyl)- 1 H-benzo[d]imidazole-7-carboxylate compound of formula-28,
c) heating the compound of formula-28 in a suitable solvent selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents, polar solvents, polar-aprotic solvents, nitrile solvents, ketone solvents, alcoholic solvents at a suitable temperature optionally in presence of suitable base to provide compound of formula- 1.
55. (5-methyl-2-oxo-l ,3-dioxol-4-yl)methyl 2-ethoxy- l-((2'-(N'-(ethoxycarbonyloxy) carbamimidoyl)biphenyl-4-yl)methyl)-lH-benzo[d]imidazole-7-carboxylate.
56. Compound having the following structural formula
Figure imgf000107_0001
57. Compounds represented by the structural formulae;
Figure imgf000108_0001
58. Use of crystalline intermediate compounds claimed in claims-11, 14, 51 in the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l- {[2'-(5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate and its potassium salt.
59. Use of novel intermediate compounds claimed in claims- 12, 25, 26, 57 in the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol -3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate and its potassium salt. 60. Use of solid state forms of intermediates claimed in claim- 13, 27, 28 in the preparation of (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-{[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol -3-yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylate and its potassium salt.
Dated this day <Ρ¾^ of June 2013
Figure imgf000108_0002
ut or ze gnatory
(Srinivasan Thirumalai Raj an) MSN Laboratories Limited
PCT/IN2013/000367 2012-06-11 2013-06-06 Process for the preparation of (5-methyl-2-oxo-l,3-dioxoi-4-vl)methvl 2- ethoxv-l-{[2'-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-vl)biphenyi-4-vl]methyl}- lh-benzimidazole-7-carboxyiate and its salts WO2013186792A2 (en)

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CN115028589A (en) * 2022-07-21 2022-09-09 浙江普洛家园药业有限公司 Preparation method of azilsartan process impurity

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CN107840827A (en) * 2017-11-06 2018-03-27 江苏中邦制药有限公司 A kind of synthetic method of Azilsartan intermediate
WO2020140193A1 (en) 2019-01-02 2020-07-09 临海市华南化工有限公司 Synthesis method for candesartan cilexetil intermediate
CN115028589A (en) * 2022-07-21 2022-09-09 浙江普洛家园药业有限公司 Preparation method of azilsartan process impurity

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