An Improved Process For The Preparation Of Olmesartan
Abstract:
The present invention relates to an improved process for the preparation of Olmesartan medoxomil chemically described as (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl-4-(l- hydroxy-l-methylethyl)-2-propyl-l-[[2"-(lH-tetrazol-5-yl)[1,1"-biphenyl]-4-yl]methyl]- lH-imidazole-5-carboxylic acid of Formula I, which involves the N-alkylation of (5- methyl-2-oxo-l,3-dioxolen-4-yl)methyl-4-(l-hydroxy-l-methylethyl)-2-propylimidazole- 5-carboxylate with 5-(4"-bromomethyl-1,1 "-biphenyl-2-yl)-triarylmethyl-tetrazole synthesized by using cheap and reusable catalyst.
Specification
FIELD OF INVENTION
The present invention relates to an improved process for the preparation of Olmesartan medoxomil chemically described as (5-methyl-2-oxo-l,3-dioxol-4- yl)methyl-4-(l -hydroxy-1 -methylethyl)-2-propyl-1 -[[2'-( 1 H-tetrazol-5-yl)[ 1,1'- biphenyl]-4-yl]methyl]-lH-imidazole-5-carboxylic acid of Formula I, is widely used for the treatment of hypertension which involves the N-alkylation of (5-methyl-2- OXO-l,3-dioxolen-4-yl)methyl-4-(l-hydroxy-1-methylethyl)-2-propylimidazole-5- carboxylate with 5-(4'-bromomethyl-1,1 '-biphenyl-2-yl)-triarylmethyl-tetrazole synthesized by using cheap and reusable catalyst.
BACKGROUND OF THE INVENTION
In EP 0 503 785 B1 processes for the preparation of oimesartan medoxomil isdisclosed involving by reacting (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl-4-(l-hydroxy-1 -methylethyl)-2-propylimidazole-5-carboxylate with 4'-bromomethyl biphenyl-2-carbonitrile and method of converting the nitrile group to a tetrazolyl group is by reacting the nitrile compound with a trialkyl tin halide, in the presence of an alkali metal azide, and then treating the resulting tin compound with an acid or base.
In EP 0 796 852 B1 describes a preparation of 5-substituted tetrazoles without the use of BusSnNs. The process comprises reacting the nitrile with triethylamine hydrochloride and sodium azide.
US 5,744,612 also discloses a process for the preparation of 5-substituted tetrazoles by reacting a benzonitrile with an inorganic azide salt in an aromatic hydrocarbon solvent in the presence of an amine salt.
Though the above two processes does not involve the formation of explosive byproducts, the products cannot be obtained easily from the reaction mass.
In US2008076932A1 describes the preparation of olmesartan by N-alkylation of 2- propyl imidazole-4,5-diester using 4-chlorobenzoyl chloride and further reacting the compound with 2-triphenyl methyl tetrazolyl phenyl-1-boronic acid.
In the prior art EP2036904, US20090I31680 for the synthesis of olmesartan, the N- alkylation was performed using 5-(4'-bromomethyl-l,r-biphenyl-2-yl)-l- triphenylmethyl-lH-tetrazole which was prepared using different methods as described.
In US 5,773,512 tetrazole prepared by reacting 2,5-dibromobenzonitrile with sodium azide and aluminium chloride in DMF which involves the use of drastic conditions.
JACS 1958, 80, 3908 describes synthesis of 5-substituted IH-tetrazoles by reacting sodium azide with DMF and Ammonium chloride which gives explosive byproducts. This process involves a great risk in industrial manufacture of tetrazoles and also results in low yield.
JOC (2001) 66, 7945-50 describes process for the transformation of nitriles to IH- tetrazoles by reacting sodium azide using zinc salt as catalyst.
US 5,502,191 describes a method for preparation of 5-substituted tetrazoles by reacting a compound of the formula R-CN with a Lewis acid and an azide or a preformed metal azide complex, which is further acidified.
Sharpless introduced a synthetic procedure in JOC 2004, 69(8), 2896-2898 describes a process for preparation of tetrazoles using zinc chloride and sodium azide. The main drawback in this process is the high proportion of hydrolyzed byproduct formation.
Synthetic communications, 2006, 36, 1809-1814 and Journal of Molecular catalysis A. 2006, 186-188 discloses a process for the preparation of substituted tetrazoles by reacting sodium azide with nitriles in the presence of a heterogeneous catalyst.
US 5,284,954 discloses a process for the preparation of tetrazoles by reacting an aryl nitrile with trimethyl silyl azide alone or in combination with CU2O are developed which are not suitable for our industrial purpose as the reactants are highly hygroscopic.
Traditionally known methods of preparing 5-substituted 1H-tetrazoles from corresponding nitriles and alkali metal azides is not suitable for large scale preparations, because of the explosive Hydrazoic acid formation. Usually these reactions require higher temperatures.
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an improved process for the
preparation of (5-methyl-2-oxo-l,3-dioxol-4-yi) methyl -4-( I-hydroxy-1-methyl
ethyl)-2- propyl -l-[ [2'-(lH- tetrazol -5-yl) [l,r-biphenyl]-4-yl] methyl] -IH-
imidazole-5-carboxylic acid (Olmesartan Medoxomil), which is simple, high purity
and industrially applicable.
The main objective is to generate a process for Olmesartan Medoxomil which is
ecofriendly, commercially viable and easy to commercialize.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of (5-methyl-
2-OXO-1,3-dioxol-4-yl)methyl-4-( I -hydroxy-1 -methylethyl)-2-propyl-1 -[[2'-( IH-
tetrazol-5-yl)[ 1,1 '-biphenyl]-4-yl]methyl]-1 H-imidazole-5-carboxylic acid (Olmesartan Medoxomil) of Formula I,
which comprises:
a) reacting o-tolyl benzonitrile of formula II,
with metal azide in an organic solvent at a temperature ranging from 50-200
°C in the presence of a heterogeneous catalyst to obtain 5-(4'-methyl-l,r-biphenyl-2-yl)-l H-tetrazole of formula HI;
b) triarylmethylation of 5-(4'-methyl-l,r-biphenyl-2-yl)-l H-tetrazole of formula
III using triaryl methyl halide in presence of a base and solvent at a temperature ranging from 50-200 °C to obtain 5-(4'-methylbiphenyl-2-yl)- triarylmethyl-tetrazole compound of formula IV;
c)bromination of 5-(4'-methylbiphenyl-2-yl)-triarylmethyl-tetrazole of formula IV using brominating agent and free radical catalyst in an organic solvent at a temperature ranging from 50-200 °C gives 5-(4'-bromomethyl-l,r-biphenyl- 2-yl)-triarylmethyl-tetrazoie of formula V;
d) reacting 5-(4'-bromomethyl-l,r-biphenyl-2-yl)-triarylmethyl-tetrazole of formula V with 2-(5-methyl-2-oxo-l,3-dioxol-4-yl)ethyl-4-(2-hydroxypropan- 2-yl)-2-propyl-l H-imidazole-5-carboxylate of formula VI,
in presence of a base and in an organic solvent at a temperature ranging from 30-150 °C to get triarylmethyl olmesartan medoxomil of formula VII;
e) deprotection of triarylmethyl olmesartan medoxomil of formula VII in
presence of an acid at a temperature ranging from ˚0 to 100 '˚C gives olmesartan medoxomil of formula I.
DETAILED DESCRIPTION OF THE INVENTION
Apatites are metal basic phosphates for example calcium hydroxy apatites, Ca10(PO4)6(OH)2 (CaHAP). CaHAP attracted wide attention because of its versatile applications in the field of bioceramics, acid base catalysis. Hydroxyapatites (HAPs) possess Ca2+ sites surrounded by PO4 3- tetrahedral parallel to the hexagonal axis, which are of considerable interest in many areas owing to their multiple functionalities. The chemical composition of HAPs can be modified from the stoichiometric form, Ca(PO4)6(OH)2 (Ca/P = 1.67), to the nonstiochiometric Ca- deficient form, Ca10-z(HPO4)z(PO4)6-z(OH)2-z (0 < z < I, 1.5
Documents
Application Documents
| # |
Name |
Date |
| 1 |
3631-che-2010 correspondence others 30-11-2010.pdf |
2010-11-30 |
| 1 |
abstract3631-che-2010.jpg |
2011-09-04 |
| 2 |
3631-che-2010 abstract 30-11-2010.pdf |
2010-11-30 |
| 2 |
3631-che-2010 form-5 30-11-2010.pdf |
2010-11-30 |
| 3 |
3631-che-2010 claims 30-11-2010.pdf |
2010-11-30 |
| 3 |
3631-che-2010 form-2 30-11-2010.pdf |
2010-11-30 |
| 4 |
3631-che-2010 description(complete) 30-11-2010.pdf |
2010-11-30 |
| 4 |
3631-che-2010 form-1 30-11-2010.pdf |
2010-11-30 |
| 5 |
3631-che-2010 description(complete) 30-11-2010.pdf |
2010-11-30 |
| 5 |
3631-che-2010 form-1 30-11-2010.pdf |
2010-11-30 |
| 6 |
3631-che-2010 claims 30-11-2010.pdf |
2010-11-30 |
| 6 |
3631-che-2010 form-2 30-11-2010.pdf |
2010-11-30 |
| 7 |
3631-che-2010 abstract 30-11-2010.pdf |
2010-11-30 |
| 7 |
3631-che-2010 form-5 30-11-2010.pdf |
2010-11-30 |
| 8 |
3631-che-2010 correspondence others 30-11-2010.pdf |
2010-11-30 |
| 8 |
abstract3631-che-2010.jpg |
2011-09-04 |