WO2011007368A2 - An improved process for preparation of olmesartan - Google Patents
An improved process for preparation of olmesartan Download PDFInfo
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- WO2011007368A2 WO2011007368A2 PCT/IN2010/000467 IN2010000467W WO2011007368A2 WO 2011007368 A2 WO2011007368 A2 WO 2011007368A2 IN 2010000467 W IN2010000467 W IN 2010000467W WO 2011007368 A2 WO2011007368 A2 WO 2011007368A2
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- 0 CCCC(*1Cc(cc2)ccc2-c(cccc2)c2C2=**=**2C2(*(C)=C)*(C)=*2)=*C(C(*)(*)*)=C1C(O)=O Chemical compound CCCC(*1Cc(cc2)ccc2-c(cccc2)c2C2=**=**2C2(*(C)=C)*(C)=*2)=*C(C(*)(*)*)=C1C(O)=O 0.000 description 3
- ZTFVTXDWDFIQEU-UHFFFAOYSA-N BrCc(cc1)ccc1-c(cccc1)c1-c1nnn[n]1C(c1ccccc1)(c1ccccc1)c1ccccc1 Chemical compound BrCc(cc1)ccc1-c(cccc1)c1-c1nnn[n]1C(c1ccccc1)(c1ccccc1)c1ccccc1 ZTFVTXDWDFIQEU-UHFFFAOYSA-N 0.000 description 1
- KZBJJAFGNMRRHN-UHFFFAOYSA-N CCCc1nc(C(C)(C)O)c(C(OCC)=O)[nH]1 Chemical compound CCCc1nc(C(C)(C)O)c(C(OCC)=O)[nH]1 KZBJJAFGNMRRHN-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Definitions
- the invention relates to processes for the preparation of olmesartan medoxomil and intermediates thereof. More particularly, it relates to a process for the preparation of ethy l-4-( 1 -hydroxy- 1 -methy lethyl)-2-propyl- 1 -[[2'-[2-(triphenylmethyl)-2H-tetrazol- 5yl]- biphenyl-4-yl]methyl]imidazole-5-carboxylate, and its use in the preparation of olmesartan medoxomil.
- the invention also relates to crystalline olmesartan medoximil and pharmaceutical compositions that include the crystalline olmesartan medoximil.
- Olmesartan medoxomil is chemically, (5-methyl-2-oxo-2H-l,3-dioxol-4- yl)methyl 4-(2-hydroxypropan-2-yl)-2-propyl-l-( ⁇ 4-[2-(2H-l,2,3,4-tetrazol-5- yl)phenyl]phenyl ⁇ methyl)-lH-imidazole-5-carboxylate having the structural Formula (I):
- Olmesartan medoxomil is an anti-hypertensive pro-drug ester that is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. It is a selective ATi subtype angiotensin II receptor antagonist and blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT 1 receptor in vacular smooth muscle. Olmesartan medoxomil is indicated for the treatment of hypertension and is commercially sold under the trade name Benicar ® . OImesartan medoxomil was first disclosed in U.S. Patent No. 5,616,599.
- the patent also discloses a process for the preparation of olmesartan medoxomil, which involves a coupling reaction between an imidazole derivative and a substituted biphenyl methyl halide, followed by condensation with the dioxolyl compound and subsequent deprotection to get olmesartan medoxomil.
- the coupling reaction involves the use of a strong base such as sodium hydride, which is difficult to handle at an industrial scale.
- the coupling reaction is conducted at a temperature of 6O 0 C.
- the product obtained contains impurities and requires further purification involving column chromatography. The overall process is hazardous, tedious, time consuming and involves many steps.
- EP 1916246 A2 discloses a process for the preparation of ethyl-4-(l -hydroxy- 1- methylethyl)2-propyl-l-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4- yl]methyl] imidazole -5-carboxylate (III) by reacting ethyl-4-(l -hydroxy- 1- methylethyl)-2-propylimidazole-5-carboxylate (V) with N-(triphenyl- methyl)-5-[4'- (bromomethyl)biphenyl-2-yl]tetrazole (IV) in an organic solvent in presence of a base and a phase transfer catalyst.
- the present inventors have now found a way of synthesizing trityl olmesartan medoxomil and olmesartan medoxomil, with an improved process for the preparation of ethyl-4-( 1 -hydroxy- 1 -methylethyl)2-propyl- 1 -[[2'-[2-(triphenylmethyl)-2H-tetrazol- 5yl]biphenyl-4-yl]methyl] imidazole-5-carboxylate of Formula (III).
- the process includes:
- Embodiments of the process may include one or more of the following features.
- reaction of ethyl-4-(l-hydroxy-l-methylethyl)-2-propylimidazole-5- carboxylate of with N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole may be carried out at a temperature from about 40 0 C to about 80 0 C.
- a further or additional solvent may be added after removing the solvent.
- the reaction mixture may be cooled before isolating the compound of Formula (III).
- the process may include further drying of the product obtained.
- a process for the preparation of olmesartan medoxomil includes:
- Y is selected from hydrogen or cation of inorganic base to form salt
- the process may produce crystalline olmesartan medoximil, In particular, it may produce the crystalline olmesartan medoximil having the X-ray diffraction pattern of Figure 1.
- the crystalline olmesartan medoximil obtained may be formed into a finished dosage form.
- a pharmaceutical composition that includes a therapeutically effective amount of crystalline olmesartan medoximil; and one or more pharmaceutically acceptable carriers, excipients or diluents.
- Figure 1 is an X-ray powder diffraction pattern of crystalline olmesartan medoxomil. DETAILED DESCRIPTION OF THE INVENTION
- the inventors have developed a process for the preparation of ethyl-4-(l- hydroxy- 1 -methylethyl)2-propyl- 1 -[[2'-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl- 4-yl]methyl] imidazole-5-carboxylate of Formula (III),
- reaction of ethyl-4-(l -hydroxy- l-methylethyl)-2- propylimidazole-5-carboxylate of Formula (V) with N-(triphenylmethyl)-5-[4'- (bromomethyl)biphenyl-2-yl]tetrazole of Formula (FV) may be carried out in a mixture of C3-C8 ketones and amides solvents.
- the C 3 -C 8 ketone includes one or more of acetone, methyl isobutyl ketone, methyl ethyl ketone and the like.
- acetone may be used.
- amides include solvents such as N,N-dimethylacetamide, N,N-dimethylformamide, and the like.
- bases include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide, potassium tert-butoxide, and the like.
- the reaction may be carried out at a temperature in the range from about 40 0 C to about 80 0 C, for example at about 50 0 C to about 60 0 C.
- the inventors also have developed a process for preparation and isolation of ethyl-4-( 1 -hydroxy- 1 -methy lethyl)2-propyl- 1 -[[2'-[2-(triphenylmethyl)-2H-tetrazol- 5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate of Formula (III),
- the reaction of ethyl-4-(l -hydroxy- l-methylethyl)-2-propylimidazole-5- carboxylate of Formula (V) with N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2- yljtetrazole of Formula (IV) may be carried out in mixture of a C 3 -Cs ketone and an amide, for example, acetone and N,N-dimethylformamide, in presence of potassium carbonate at a temperature in the range from about 40 0 C to about 80 0 C, for example, at about 50 0 C to about 60 0 C.
- the solvent may be removed.
- the solvent may be removed by a technique, which includes, for example, filtration, evaporation, distillation, distillation under vacuum, decantation and centrifugation.
- additional solvent may be added after removing the solvent.
- the solvent may include one or more OfC 3 -Cg ketones or amides.
- the compound of Formula (III) may be isolated.
- the product may be isolated by a technique, which includes one or more of filtration, filtration under vacuum, decantation and centrifugation.
- the reaction mixture containing compound (III) may be cooled before isolation to obtain better yields. It may be cooled to temperature in the range of about 0 0 C to about 35°C, for example, to about 20 0 C to about 30 0 C.
- the product obtained may be further or additionally dried to achieve the desired moisture values.
- the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
- the compound of Formula (HI) may be converted into olmesartan medoxomil.
- the inventors further developed a process for the preparation of olmesartan medoxomil.
- the process includes:
- Y is selected from hydrogen or cation of inorganic base to form salt
- the hydrolysis of ethyl-4-(l -hydroxy- l-methylethyl)2-propyl-l-[[2'-[2- (triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl] methyl]imidazole-5-carboxylate of Formula (III) may be carried out in a C 3 -Ce ketone solvent.
- ketone solvents include acetone, methyl isobutyl ketone, methyl ethyl ketone, and the like.
- bases include potassium hydroxide, sodium hydroxide, lithium hydroxide, and the like.
- triphenylmethyO ⁇ H-tetrazol-Sy ⁇ biphenyl ⁇ -ylJmethylJimidazole-S-carboxylic acid of Formula (IHa) may be directly converted to trityl olmesartan medoxomil without isolation.
- the trityl olmesartan medoxomil can be isolated by conventional technique like removal of solvent.
- the trityl olmesartan medoxomil can be isolated by extracting the reaction mass with organic solvent like methylene dichloride, ethyl acetate, butyl acetate, isopropyl acetate, toluene, xylene, preferably ethyl acetate and cooling the extracted organic solvent mass to precipitate trityl olmesartan medoxomil.
- the precipitated product can be isolated by filtration and optionally washing with an alcohol like methanol, ethanol, isopropanol, butanol etc., preferably methanol.
- olmesartan medoxomil may be prepared in-situ by esterification of compound of Formula (HIa) in a C 3 -Cs ketone solvent with 4-chloromethyl-5- methyl-2-oxo-l,3-dioxolene in presence of a base and a catalyst.
- the suitable base for the esterification of compound of Formula (Ilia) may include one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide, potassium tert-butoxide, and the like.
- the suitable catalyst may include potassium iodide.
- the esterification may be followed by detritylation of trityl olmesartan medoxomil, for example with aqueous acetic acid.
- the process may produce olmesartan medoxomil in crystalline form.
- the crystalline form of olmesartan medoxomil may be characterized by X-ray diffraction pattern having characteristic peaks at 2-theta values 7.3, 9.2, 12.7 and 16.6 ⁇ 0.2°.
- the crystalline olmesartan medoxomil can also be characterized by X-ray diffraction pattern having characteristic peaks at 2-theta values 10.7, 11.7, 14.6, 14.9, 19.7, 20.6, 21.9, 23.4, 24.8, 25.3 and 27.6 ⁇ 0.2°.
- the crystalline olmesartan medoximil may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc.
- the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.
- acetone was distilled under vacuum at 45°C to 5O 0 C. The residue was further treated with 200 ml of acetone at 50 0 C to 55°C and stirred for 30 minutes. The reaction mixture was cooled to 25°C to 35°C and gradually to O 0 C to 5°C with stirring. The product was filtered and washed with acetone. The wet-cake approx. 120 g was treated with 800 ml of chilled water at 10 0 C to 15°C and stirred for 1 hour. The product was filtered and washed with water.
- reaction Mass-A 100 g of ethyl-4-(l -hydroxy- l-methylethyl)2-propyl-l-[[2'-[2-(triphenylmethyl) -2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate of Formula (III), 15.65 g of potassium hydroxide and 1 L of acetone were taken in a round bottom flask at 25°C to 30 0 C. The reaction mass was stirred for 4 hours till completion of the reaction by TLC. After the completion of reaction, the reaction mass was filtered through a hyflow bed and washed with acetone (Reaction Mass-A).
- reaction Mass-B 4-chloromethyl-5-methyl-2-oxo-l,3-dioxolene was added to the reaction mixture above at 25°C to 30 0 C (Reaction Mass-B).
- the reaction mass B was heated at 35°C to 4O 0 C and reaction mass -A was added drop wise during 2-3 hours.
- the reaction mixture was maintained for 6 hours.
- the reaction mass was cooled to 25°C and filtered through a hyflow and washed with acetone.
- the reaction mixture was distilled under vacuum at 30 0 C to 40 0 C till thick mass was obtained.
- aqueous acetic acid obtained by mixing 412.5 ml acetic acid in 137.5 ml of water and 100 g of trityl olmesartan medoxomil were taken in a round bottom flask.
- the reaction mass was heated to 35°C to 40 0 C for 3 hours. After completion of the reaction, the reaction mass was cooled to 35°C and treated with 150 ml of water. The reaction mass was further cooled to 0 0 C to 5°C and stirred for 1 hour.
- the reaction mass was filtered and washed with 50 ml of aqueous acetic acid. The filtrate was extracted with 1 L of methylene dichloride.
- the separated aqueous layer was further washed with 500 ml of methylene dichloride.
- the combined organic layer was treated with 400 ml of water at 25 0 C to 30 0 C.
- the separated organic layer was treated with 250 ml of sodium bicarbonate solution and allowed to settle.
- the separated organic layer was again washed with 400 ml of water.
- the methylene dichloride layer was filtered and distilled under vacuum at 40 0 C to 50 0 C to get a residue.
- the residue was treated with 300 ml of ethyl acetate at 30 0 C to 35°C and cooled to 0 0 C to 5°C.
- the isolated product was filtered and washed with 100 ml of chilled ethyl acetate.
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Abstract
The invention relates to processes for the preparation of olmesartan medoxomil and intermediates thereof. More particularly, it relates to a process for the preparation of ethyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-[2-(triphenylmethyl)-2H-tetrazol- 5yl]- biphenyl-4-yl]methyl]imidazole-5-carboxylate, and its use in the preparation of olmesartan medoxomil. The invention also relates to crystalline olmesartan medoximil and pharmaceutical compositions that include the crystalline olmesartan medoximil.
Description
AN IMPROVED PROCESS FOR PREPARATION OF OLMESARTAN
FIELD OF THE INVENTION
The invention relates to processes for the preparation of olmesartan medoxomil and intermediates thereof. More particularly, it relates to a process for the preparation of ethy l-4-( 1 -hydroxy- 1 -methy lethyl)-2-propyl- 1 -[[2'-[2-(triphenylmethyl)-2H-tetrazol- 5yl]- biphenyl-4-yl]methyl]imidazole-5-carboxylate, and its use in the preparation of olmesartan medoxomil. The invention also relates to crystalline olmesartan medoximil and pharmaceutical compositions that include the crystalline olmesartan medoximil. BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
Olmesartan medoxomil is chemically, (5-methyl-2-oxo-2H-l,3-dioxol-4- yl)methyl 4-(2-hydroxypropan-2-yl)-2-propyl-l-({4-[2-(2H-l,2,3,4-tetrazol-5- yl)phenyl]phenyl}methyl)-lH-imidazole-5-carboxylate having the structural Formula (I):
Olmesartan medoxomil is an anti-hypertensive pro-drug ester that is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. It is a selective ATi subtype angiotensin II receptor antagonist and blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in vacular smooth muscle. Olmesartan medoxomil is indicated for the treatment of hypertension and is commercially sold under the trade name Benicar®.
OImesartan medoxomil was first disclosed in U.S. Patent No. 5,616,599. The synthetic method employed is depicted in the following reaction Scheme-1, where an imidazole derivative is condensed with a dioxolyl compound, then reacted with a substituted biphenyl methyl halide to obtain trityl olmesartan medoxomil, which is then deprotected to obtain olmesartan.
Scheme 1
The patent also discloses a process for the preparation of olmesartan medoxomil, which involves a coupling reaction between an imidazole derivative and a substituted biphenyl methyl halide, followed by condensation with the dioxolyl compound and subsequent deprotection to get olmesartan medoxomil.
The coupling reaction involves the use of a strong base such as sodium hydride, which is difficult to handle at an industrial scale. The coupling reaction is conducted at a temperature of 6O0C. The product obtained contains impurities and requires further
purification involving column chromatography. The overall process is hazardous, tedious, time consuming and involves many steps.
EP 1916246 A2 discloses a process for the preparation of ethyl-4-(l -hydroxy- 1- methylethyl)2-propyl-l-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4- yl]methyl] imidazole -5-carboxylate (III) by reacting ethyl-4-(l -hydroxy- 1- methylethyl)-2-propylimidazole-5-carboxylate (V) with N-(triphenyl- methyl)-5-[4'- (bromomethyl)biphenyl-2-yl]tetrazole (IV) in an organic solvent in presence of a base and a phase transfer catalyst.
Scheme-2
International (PCT) Publication No. WO 2007/047838 A2 discloses a mixture of acetone and N,N-dimethylacetamide solvents for condensation of dimethyl-2- propylimidazole-4,5-dicarboxylate (VI) compound with 4-[2-trityltetrazole-5- yl)phenyl} methyl benzyl bromide of formula (IV) in presence of potassium carbonate to obtain dimethyl 2-propyl-l-[4-(2-trityltetrazol-5-yl)phenyl]phenymethylimidazole- 4, 5 -dicarboxy late .
(VIII) Scheme-3
International (PCT) Publication No. WO 2007/017135 A2 discloses a process for the preparation of ethyl-4-(l -hydroxy- l-methylethyl)2-propyl-l-[[2'-[2- (triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl] imidazole-5-carboxylate of formula (III) by reacting ethyl-4-(l -hydroxy- l-methylethyl)-2-propylimidazole-5-
carboxylate of formula (V) with N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2- yljtetrazole (IV) in presence OfK2CO3 in acetonitrile. ,
International (PCT) Publication No. WO 2007/048361 A2 discloses a process for the preparation of ethyl-4-(l -hydroxy- l-methylethyl)2-propyl-l-[[2'-[2- (triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methy 1] imidazole-5-carboxylate of formula (III) by reacting ethyl-4-(l -hydroxy- l-methylethyl)-2-propylimidazole-5- carboxylate of formula (V) with N-(triphenylrnethyl)-5-[4'-(brornomethyl) biphenyl-2- yl]tetrazole of formula (IV) in the presence of potash in acetone in presence of PEG- 400 as a phase transfer catalyst.
International (PCT) Publication No. WO 2007/148344 Al discloses an in-situ process for the preparation of ethyl-4-(l -hydroxy- l-methylethyl)-2-propyl-l-[[2'-[2- (triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl] methyl] imidazole-5-carboxylate of formula (III) by condensing ethyl-4-(l -hydroxy- l-methylethyl)-2-propylimidazole-5- carboxylate of formula (V) with N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2- yljtetrazole of formula (IV) in the presence of potassium carbonate base in acetone solvent in presence of tetrabutylammonium bromide as a phase transfer catalyst.
International (PCT) Publication No. WO 2008/043996 A2 discloses a process for the condensation of ethyl-4-(l-hydroxy-l-methylethyl)-2-propylimidazole-5- carboxylate of formula (V) with N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2- yljtetrazole of Formula (IV) in the presence of a metal hydroxide/carbonate base in a polar aprotic solvent like N,N-dimethylacetamide in absence of phase transfer catalyst to provide ethyl-4-( 1 -hydroxy- 1 -methylethyl)2-propy 1- 1 -[[2'-[2-(triphenylmethyl)-2H- tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate of Formula (III).
International (PCT) Publication No. WO 2009/019304 Al also provides a process for the preparation of ethyl-4-(l -hydroxy- l-methylethyl)2-propyl-l-[[2'-[2- (triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate of Formula (III) by condensation of ethyl-4-(l -hydroxy- 1-methylethy l)-2- propylimidazole-5-carboxylate of Formula (V) with N-(triphenylmethyl)-5-[4'- (bromomethyl)biphenyl-2-yl]tetrazole of Formula (IV) in the presence of LiORH2O in N,N-dimethylacetamide solvent in absence of a phase transfer catalyst.
Further, in a reference article, Synthesis of a novel angiotensin II receptor antagonist olmesartan medoxomil. Huadong Ligong Daxue Xuebao, Ziran Kexueban (2005), 31(2), 189-192, a process for new angiotensin I receptor antagonist, olmesartan medoxomil is disclosed, which involves synthesis using tartaric acid as a starting
material via nitration, cyclization, esterification, Grignard reaction, N-alkyfation, hydrolysis, O-alkylation and N-deprotection in 32.7% overall yield.
The synthesis of ethyl-4-(l -hydroxy- l-methylethyl)-2-propyl-l-[[2'-[2-
(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate of Formula (III) described in the prior art involves use of phase transfer catalyst or specific non-aqueous solvent systems or polar aprotic solvents like dimethylacetamide, each requiring different conditions, temperature, etc. and are not suitable from commercial point of view because of low yields and purity. Hence, there is a constant need to develop more efficient and economical synthetic routes suitable for industrial scale up.
The present inventors have now found a way of synthesizing trityl olmesartan medoxomil and olmesartan medoxomil, with an improved process for the preparation of ethyl-4-( 1 -hydroxy- 1 -methylethyl)2-propyl- 1 -[[2'-[2-(triphenylmethyl)-2H-tetrazol- 5yl]biphenyl-4-yl]methyl] imidazole-5-carboxylate of Formula (III).
SUMMARY OF THE INVENTION
In one general aspect there is provided an improved process for the preparation of ethyl-4-( 1 -hydroxy- 1 -methylethyl)2-propyl- 1 -[[2'-[2-(triphenylmethyl)-2H-tetrazol- 5yl]biphenyl-4-yl] methyl]imidazole-5-carboxylate of Formula (III).
the process includes:
(a) reacting ethyl-4-(l-hydroxy-l-methylethyl)-2-propylimidazole-5-carboxylate of Formula (V) with N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole of Formula (IV),
(b) removing the solvent; and
(c) isolating the compound of Formula (III).
Embodiments of the process may include one or more of the following features.
For example, the reaction of ethyl-4-(l-hydroxy-l-methylethyl)-2-propylimidazole-5- carboxylate of with N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole may be carried out at a temperature from about 400C to about 800C. A further or additional solvent may be added after removing the solvent. The reaction mixture may be cooled before isolating the compound of Formula (III).
The process may include further drying of the product obtained.
In another general aspect there is provided a process for the preparation of olmesartan medoxomil. The process includes:
(a) reacting ethyl-4-(l -hydroxy- l-methylethyl)-2-propylimidazole-5-carboxylate of - Formula (V) with N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole of Formula (IV),
in one or more solvents in the presence of a base and absence of a phase transfer catalyst;
(b) removing the solvent;
(c) isolating the compound of Formula (III); and
(d) converting the compound of Formula (III) to olmesartan medoxomil.
In another aspect there is provided a process for the preparation of olmesartan medoxomil. The process includes:
(a) hydrolyzing ethyl-4-(l -hydroxy- l-methylethyl)2-propyl-l-[[2'-[2-
(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl] methyl]imidazole-5-carboxylate of Formula (III)
in one or more C3-C8 ketone solvents with an inorganic base to get a compound of Formula (IHa);
wherein Y is selected from hydrogen or cation of inorganic base to form salt,
(a) esterifying the compound of Formula (IHa) with 4-chloromethyl-5-methyl-2-oxo-
1,3-dioxolene in one or more C3-C8 ketone solvents in presence of a base and a catalyst to obtain compound of Formula (II);
(b) deprotecting trityl protection group; and
(c) isolating the olmesartan medoxomil.
The process may produce crystalline olmesartan medoximil, In particular, it may produce the crystalline olmesartan medoximil having the X-ray diffraction pattern of Figure 1. The crystalline olmesartan medoximil obtained may be formed into a finished dosage form.
In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of crystalline olmesartan medoximil; and one or more pharmaceutically acceptable carriers, excipients or diluents.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an X-ray powder diffraction pattern of crystalline olmesartan medoxomil. DETAILED DESCRIPTION OF THE INVENTION
The inventors have developed a process for the preparation of ethyl-4-(l- hydroxy- 1 -methylethyl)2-propyl- 1 -[[2'-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl- 4-yl]methyl] imidazole-5-carboxylate of Formula (III),
by reacting ethyl-4-(l -hydroxy- l-methylethyl)-2-propylimidazole-5-carboxylate of Formula (V) with N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole of Formula (IV),
in one or more solvents in the presence of one or more bases and absence of a phase transfer catalyst.
In general, the reaction of ethyl-4-(l -hydroxy- l-methylethyl)-2- propylimidazole-5-carboxylate of Formula (V) with N-(triphenylmethyl)-5-[4'- (bromomethyl)biphenyl-2-yl]tetrazole of Formula (FV) may be carried out in a mixture of C3-C8 ketones and amides solvents.
The C3-C8 ketone includes one or more of acetone, methyl isobutyl ketone, methyl ethyl ketone and the like. In particular, acetone may be used. Examples of amides include solvents such as N,N-dimethylacetamide, N,N-dimethylformamide, and the like. \
Examples of bases include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide, potassium tert-butoxide, and the like.
The reaction may be carried out at a temperature in the range from about 400C to about 800C, for example at about 500C to about 600C.
The inventors also have developed a process for preparation and isolation of ethyl-4-( 1 -hydroxy- 1 -methy lethyl)2-propyl- 1 -[[2'-[2-(triphenylmethyl)-2H-tetrazol- 5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate of Formula (III),
(a) by reacting ethyl-4-(l -hydroxy- l-methylethyl)-2-propylimidazole-5-carboxylate of Formula (V) with N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole of Formula (IV),
in one or more solvents in the presence of a base and absence of a phase transfer catalyst;
(b) removing the solvent; and
(c) isolating the compound of Formula (III).
The reaction of ethyl-4-(l -hydroxy- l-methylethyl)-2-propylimidazole-5- carboxylate of Formula (V) with N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2- yljtetrazole of Formula (IV) may be carried out in mixture of a C3-Cs ketone and an amide, for example, acetone and N,N-dimethylformamide, in presence of potassium carbonate at a temperature in the range from about 400C to about 800C, for example, at about 500C to about 600C.
After the completion of the reaction, the solvent may be removed. The solvent may be removed by a technique, which includes, for example, filtration, evaporation, distillation, distillation under vacuum, decantation and centrifugation.
In another aspect, additional solvent may be added after removing the solvent. The solvent may include one or more OfC3-Cg ketones or amides.
In another aspect, the compound of Formula (III) may be isolated. The product may be isolated by a technique, which includes one or more of filtration, filtration under vacuum, decantation and centrifugation.
In one aspect, the reaction mixture containing compound (III) may be cooled before isolation to obtain better yields. It may be cooled to temperature in the range of about 00C to about 35°C, for example, to about 200C to about 300C.
The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
In yet another aspect, the compound of Formula (HI) may be converted into olmesartan medoxomil.
The inventors further developed a process for the preparation of olmesartan medoxomil. The process includes:
(a) hydrolyzing ethyl-4-( 1 -hydroxy- 1 -methylethyl)2-propyl- 1 -[[2'-[2- (triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl] methyl] imidazole-5-carboxylate of Formula (III),
wherein Y is selected from hydrogen or cation of inorganic base to form salt,
(b) esterifying the compound of Formula (Ilia) with 4-chloromethyl-5-methyl-2-oxo-
1,3-dioxolene in one or more C3-Cs ketone solvents in presence of a base and a catalyst to obtain compound of Formula (II);
(c) deprotecting trityl protection group; and
(d) isolating the olmesartan medoxomil.
The hydrolysis of ethyl-4-(l -hydroxy- l-methylethyl)2-propyl-l-[[2'-[2- (triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl] methyl]imidazole-5-carboxylate of Formula (III) may be carried out in a C3-Ce ketone solvent. Examples of ketone solvents include acetone, methyl isobutyl ketone, methyl ethyl ketone, and the like. Examples of bases include potassium hydroxide, sodium hydroxide, lithium hydroxide, and the like.
The hydrolyzed compound 4-(l -hydroxy- l-methylethyl)2-propyl-l-[[2'-[2-
(triphenylmethyO^H-tetrazol-Syπbiphenyl^-ylJmethylJimidazole-S-carboxylic acid of Formula (IHa) may be directly converted to trityl olmesartan medoxomil without isolation. The trityl olmesartan medoxomil can be isolated by conventional technique like removal of solvent.
The trityl olmesartan medoxomil can be isolated by extracting the reaction mass with organic solvent like methylene dichloride, ethyl acetate, butyl acetate, isopropyl acetate, toluene, xylene, preferably ethyl acetate and cooling the extracted organic solvent mass to precipitate trityl olmesartan medoxomil. The precipitated product can
be isolated by filtration and optionally washing with an alcohol like methanol, ethanol, isopropanol, butanol etc., preferably methanol.
In one aspect, olmesartan medoxomil may be prepared in-situ by esterification of compound of Formula (HIa) in a C3-Cs ketone solvent with 4-chloromethyl-5- methyl-2-oxo-l,3-dioxolene in presence of a base and a catalyst.
The suitable base for the esterification of compound of Formula (Ilia) may include one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide, potassium tert-butoxide, and the like. The suitable catalyst may include potassium iodide. The esterification may be followed by detritylation of trityl olmesartan medoxomil, for example with aqueous acetic acid.
The process may produce olmesartan medoxomil in crystalline form. The crystalline form of olmesartan medoxomil may be characterized by X-ray diffraction pattern having characteristic peaks at 2-theta values 7.3, 9.2, 12.7 and 16.6±0.2°.
The crystalline olmesartan medoxomil can also be characterized by X-ray diffraction pattern having characteristic peaks at 2-theta values 10.7, 11.7, 14.6, 14.9, 19.7, 20.6, 21.9, 23.4, 24.8, 25.3 and 27.6±0.2°.
The crystalline olmesartan medoximil may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. In these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Exam pie- 1: Preparation of ethyl-4-(l-hvdroxy-l-methylethyl)-2-propyl-l-[[2'-r2- (triphenylmethvD-lH-tctrazoI-SyllbiphenvM-vHmethyllimidazole-S-carboxylate of formula (III)
100 g of ethyl-4-(l -hydroxy- l-methylethyl)-2-propylimidazole-5-carboxylate of Formula (V), 172.4 g of potassium carbonate and 700 ml of acetone were taken in a round bottom flask at 25°C to 35°C. 258.4 g of N-(triphenylmethyl)-5-[4'- (bromomethyl)biphenyl-2-yl]tetrazole of Formula (IV) and 100 ml of N,N- dimethylformamide were added to the reaction mixture. The reaction mixture was heated to 55°C to 600C for 20 hours. After completion of the reaction as monitored by TLC, acetone was distilled under vacuum at 45°C to 5O0C. The residue was further treated with 200 ml of acetone at 500C to 55°C and stirred for 30 minutes. The reaction mixture was cooled to 25°C to 35°C and gradually to O0C to 5°C with stirring. The product was filtered and washed with acetone. The wet-cake approx. 120 g was treated with 800 ml of chilled water at 100C to 15°C and stirred for 1 hour. The product was filtered and washed with water. The product was dried in a hot air oven at 500C to 55°C for 15 hours to obtain 214 g (83%) of ethyl-4-(l -hydroxy- 1-methy lethyl)2-propyl-l - [[2'-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5- carboxylate of Formula (III).
Example-2: Preparation of Trityl Olmesartan Medoxomil of Formula (H)
100 g of ethyl-4-(l -hydroxy- l-methylethyl)2-propyl-l-[[2'-[2-(triphenylmethyl) -2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate of Formula (III), 15.65 g of potassium hydroxide and 1 L of acetone were taken in a round bottom flask at 25°C to 300C. The reaction mass was stirred for 4 hours till completion of the reaction by TLC. After the completion of reaction, the reaction mass was filtered through a hyflow bed and washed with acetone (Reaction Mass-A). In another round bottom flask, 500 ml acetone, 19.7 g of potassium carbonate and 5.78 g of potassium iodide were taken. 26.0 g of 4-chloromethyl-5-methyl-2-oxo-l,3-dioxolene was added to the reaction mixture above at 25°C to 300C (Reaction Mass-B). The reaction mass B was heated at 35°C to 4O0C and reaction mass -A was added drop wise during 2-3 hours. The reaction mixture was maintained for 6 hours. After the completion of the reaction, the reaction mass was cooled to 25°C and filtered through a hyflow and washed with
acetone. The reaction mixture was distilled under vacuum at 300C to 400C till thick mass was obtained. The residue was treated with 200 ml ethyl acetate and stirred for 45 minutes at 400C to 450C. The reaction mixture was cooled gradually to 00C to 5°C and stirred. The reaction mass was filtered and wet-cake was washed with chilled ethyl acetate. The wet-cake was further purified in ethyl acetate followed by washing with chilled methanol to obtain 80 g (80%) of trityl olmesartan medoxomil (II).
Example-3: Preparation of olmesartan medoxomil (D
400 ml of aqueous acetic acid obtained by mixing 412.5 ml acetic acid in 137.5 ml of water and 100 g of trityl olmesartan medoxomil were taken in a round bottom flask. The reaction mass was heated to 35°C to 400C for 3 hours. After completion of the reaction, the reaction mass was cooled to 35°C and treated with 150 ml of water. The reaction mass was further cooled to 00C to 5°C and stirred for 1 hour. The reaction mass was filtered and washed with 50 ml of aqueous acetic acid. The filtrate was extracted with 1 L of methylene dichloride. The separated aqueous layer was further washed with 500 ml of methylene dichloride. The combined organic layer was treated with 400 ml of water at 250C to 300C. The separated organic layer was treated with 250 ml of sodium bicarbonate solution and allowed to settle. The separated organic layer was again washed with 400 ml of water. The methylene dichloride layer was filtered and distilled under vacuum at 400C to 500C to get a residue. The residue was treated with 300 ml of ethyl acetate at 300C to 35°C and cooled to 00C to 5°C. The isolated product was filtered and washed with 100 ml of chilled ethyl acetate. The product was dried in hot air oven at 35°C to 400C for 8 hours and at 500C to 55°C for another 8 hours to obtain 56g (81%) of crystalline olmesartan medoxomil having the X-ray powder diffraction pattern as shown in Figure.- 1.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Claims
1. A process for the preparation of ethyl -4-(l -hydroxy- l-methylethyl)2-propyl-l-[[2'- [2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate of Formula (III),
the process comprising:
reacting ethyl-4-( 1 -hydroxy- 1 -methylethyl)-2-propylimidazole-5-carboxylate of Formula (V) with N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole of Formula (IV),
in one or more solvents in the presence of one or more bases and absence of a phase transfer catalyst.
2. The process according to claim 1, wherein the solvent comprises one or more of C3- Cg ketones, amides, or mixtures thereof.
3. The process according to claim 2, wherein the C3-C8 ketone comprises one or more of acetone, methyl isobutyl ketone, and methyl ethyl ketone.
4. The process according to claim 2, wherein the amide comprises one or both of N5N- dimethylacetamide, and N,N-dimethylformamide.
5. The process according to claim 2, wherein the solvent comprises a mixture of acetone and N,N-dimethylformamide.
6. The process according to claim 1, wherein the base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide, and potassium tert- butoxide.
7. The process according to claim 1, further comprising heating reaction mixture from about 400C to about 800C.
8. A process for the preparation of ethyl-4-(l -hydroxy- 1-methylethy l)2-propy 1-1 -[[21- [2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate of Formula (III),
the process comprising:
(a) reacting ethyl-4-(l -hydroxy- l-methylethyl)-2-propylimidazole-5-carboxylate of
Formula (V) with N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2- yljtetrazole of Formula (IV),
in one or more solvents in the presence of a base and absence of a phase transfer catalyst;
(b) removing the solvent; and
(c) isolating the compound of Formula (III).
9. The process according to claim 8, wherein the solvent comprises one or more of C3- C8 ketones, amides, or mixtures thereof.
10. The process according to claim 9, wherein the C3-Cs ketone comprises one or more of acetone, methyl isobutyl ketone, and methyl ethyl ketone.
11. The process according to claim 9, wherein the amide comprises one or both of N,N- dimethylacetamide, and N,N-dimethylformamide.
12. The process according to claim 8, wherein the base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium methoxide, and potassium tert- butoxide.
13. The process according to claim 8, wherein removing the solvent comprises one or more of filtration, evaporation, distillation, distillation under vacuum, decantation and centrifugation.
14. The process according to claim 8, wherein the isolating comprises one or more of filtration, filtration under vacuum, decantation and centrifugation.
15. The process according to claim 8, further comprising heating reaction mixture from about 4O0C to about 800C.
16. The process according to claim 8, further comprising adding additional solvent after removing the solvent.
17. The process according to claim 8, further comprising cooling before isolating the compound of Formula (III).
18. The process according to claim 8, further comprising additional drying of the product obtained.
19. The process according to claim 8, further comprising converting the compound of Formula (III) to olmesartan medoximil.
20. A process for the preparation of olmesartan medoxomil, the process comprising:
(a) reacting ethyl-4-(l -hydroxy- l-methylethyl)-2-propylimidazole-5-carboxylate of Formula (V) with N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2- yljtetrazole of Formula (IV),
in one or more solvents in the presence of a base and absence of a phase transfer catalyst;
(b) removing the solvent;
(c) isolating the compound of Formula (III); and
(d) converting the compound of Formula (III) to olmesartan medoxomil.
21. A process for the preparation of olmesartan medoxomil, the process comprising:
(a) hydrolyzing ethyl-4-( 1 -hydroxy- 1 -methylethyl)2-propyl- 1 -[[2'-[2-
(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5- carboxylate of Formula (111) prepared according to claim 1,
in one or more C3-Cg ketone solvents with an inorganic base to get a compound of Formula (Ilia);
where Y is selected from hydrogen or cation from inorganic base to form salt (b) esterifying the compound of Formula (IHa) with 4-chloromethyl-5-methyl-2- oxo-l,3-dioxolene in one or more C3-C8 ketone solvents in presence of a base and a catalyst to obtain compound of Formula (H);
(c) deprotecting trityl protection group; and
(d) isolating the olmesartan medoxomil.
22. The process according to claim 21, wherein the C3-Cs ketone solvent comprises one or more of acetone, methyl isobutyl ketone, methyl ethyl ketone, or mixtures thereof.
23. The process according to claim 21, wherein the inorganic base comprises one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide, or mixtures thereof.
24. The process according to claim 21, wherein the catalyst is potassium iodide.
25. The process according to claim 21, wherein the deprotection of the trityi protective group is carried out with aqueous acetic acid.
26. The process according to claim 21, wherein the olmesartan medoxomil obtained is crystalline.
27. The process according to claim 21, wherein the olmesartan medoximil has the X- ray diffraction pattern of Figure 1.
28. The process according to claim 21, further comprising forming the product obtained into a finished dosage form.
29. Crystalline olmesartan medoxomil characterized by X-ray diffraction pattern having characteristic peaks at 2-theta values 7.3, 9.2, 12.7 and 16.6±0.2°.
30. Crystalline olmesartan medoxomil of claim 29, further characterized by X-ray diffraction pattern having characteristic peaks at 2-theta values 10.7, 11.7, 14.6, 14.9, 19.7, 20.6, 21.9, 23.4, 24.8, 25.3 and 27.6±0.2°.
31. A pharmaceutical composition comprising a therapeutically effective amount of crystalline olmesartan medoximil characterized by X-ray diffraction pattern having characteristic peaks at 2-theta values 7.3, 9.2, 12.7 and 16.6±0.2°, and one or more pharmaceutically acceptable carriers, excipients or diluents.
32. Crystalline olmesartan medoxomil of Formula (I) substantially as herein described with reference to any of the embodiments of the invention illustrated in the accompanying drawings and/or examples.
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CN102850333A (en) * | 2011-06-30 | 2013-01-02 | 北京万生药业有限责任公司 | Olmesartan medoxomil crystal and preparation method thereof |
JP2014234354A (en) * | 2013-05-31 | 2014-12-15 | 株式会社トクヤマ | Method for producing olmesartan medoxomil |
CN104262332A (en) * | 2014-09-16 | 2015-01-07 | 上海信谊百路达药业有限公司 | Preparation method of olmesartan medoxomil |
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CN102850333A (en) * | 2011-06-30 | 2013-01-02 | 北京万生药业有限责任公司 | Olmesartan medoxomil crystal and preparation method thereof |
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CN109761966A (en) * | 2019-01-30 | 2019-05-17 | 浙江省食品药品检验研究院 | A kind of Olmesartan medoxomil crystal and preparation method thereof |
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